Clinical trial NCT01467427
Conditions: Congenital Bleeding Disorder Haemophilia B
Sponsor: Novo Nordisk A/S
Start date: 2012-05-16; Completion date: 2023-11-17
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial is conducted in Asia, Europe and North America. The aim of the trial is to evaluate safety, efficacy and pharmacokinetics (the exposure of the trial drug in the body) of NNC-0156-0000-0009 (nonacog beta pegol, N9-GP) in previously treated children with Haemophilia B.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: nonacog beta pegol
Intervention descriptions: intervention 1: A single dose of 40 U/kg will be administered intravenously, i.v. (into the vein) once weekly.

Protocol documents:
Prot_SAP_000.pdf: 
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Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT01467427 
Sponsor trial ID: 
NN7999-3774 
Official title of study: 
An open-label, single-arm, multinational, non-controlled, 
confirmatory trial investigating safety, efficacy and 
pharmacokinetics of NNC-0156-0000-0009 (N9-GP) in 
prophylaxis and treatment of breakthrough bleeding episodes 
in previously treated children with haemophilia B (12 years of 
age and younger at inclusion), with extension phase 
Document date: 
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
1 of 135
Trial ID: NN7999-3774
Safety, Efficacy and Pharmacokinetics of NNC-0156-
0000-0009 in Previously Treated Children with 
Haemophilia B 
An open-label, single-arm, multinational, non-controlled, confirmatory trial 
investigating safety, efficacy and pharmacokinetics of NNC-0156-0000-0009 (N9-GP)
in prophylaxis and treatment of breakthrough bleeding episodes in previously treated 
children with haemophilia B (12 years of age and younger at inclusion), with   
extension phase
Trial Phase: 3
Includes:
Protocol version 2 (10-Oct-2011), global substantial amendment no 1 (30-Mar-2012), Protocol 
version 3 (30-Mar-2012), global substantial amendment no 4 (03-Jul-2013)
Protocol version 4 (03-Jul-2013) was not submitted, global substantial amendment no 4 (04-
Jul-2013), Protocol version 5 (05-Jul 2013), global substantial amendment no 5 (15-Jul-2014), 
global amendment no 6 (12-Jan-2015). Global Amendment no 8 (05-Dec-2016), global 
amendment no 9 version 2 (01-Dec-2017). Global amendment no 10 (27-Jun-2018)
Author:
Name:
, 
Novo Nordisk A/S
Department:  Biopharm Trial Operations 3.
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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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:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
2 of 135
Table of contents 
Page
Table of contents.........................................................................................................................................2
Table of figures ...........................................................................................................................................7
Table of tables.............................................................................................................................................8
List of abbreviations and definition of terms .............................................................................................9
1
Summary............................................................................................................................................12
2
Flow charts.........................................................................................................................................15
3
Introduction .......................................................................................................................................28
3.1
Basic information....................................................................................................................28
3.1.1
Background ...........................................................................................................28
3.1.2
N9-GP ...................................................................................................................29
3.1.3
Risks and benefits ..................................................................................................29
3.2
Rationale for the trial...............................................................................................................30
4
Objectives and endpoints...................................................................................................................32
4.1
Objectives...............................................................................................................................32
4.1.1
Primary objective...................................................................................................32
4.1.2
Secondary objectives .............................................................................................32
4.2
Endpoints................................................................................................................................32
4.2.1
Primary endpoint ...................................................................................................32
4.2.2
Secondary endpoints ..............................................................................................32
4.2.2.1
Safety endpoints...............................................................................32
4.2.2.2
Efficacy endpoints............................................................................32
4.2.2.3
Pharmacokinetic endpoints...............................................................32
4.2.2.4
Patient reported outcomes and health economic endpoints ................33
5
Trial design ........................................................................................................................................34
5.1
Type of trial ............................................................................................................................34
5.2
Rationale for trial design .........................................................................................................34
5.3
Treatment of patients...............................................................................................................35
5.3.1
Prophylaxis............................................................................................................35
5.3.2
Treatment of bleeding episodes ..............................................................................36
5.3.3
Surgery..................................................................................................................36
5.3.4
Patients continuing into the extension phase...........................................................37
5.4
Rationale for treatment............................................................................................................37
6
Trial population .................................................................................................................................39
6.1
Number of patients to be studied .............................................................................................39
6.2
Inclusion criteria .....................................................................................................................39
6.3
Exclusion criteria ....................................................................................................................39
6.4
Withdrawal criteria .................................................................................................................40
6.5
Patient replacement .................................................................................................................41
6.6
Rationale for trial population...................................................................................................41
6.6.1
Rationale for inclusion criteria ...............................................................................41
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
3 of 135
6.6.2
Rationale for exclusion criteria...............................................................................42
6.6.3
Rationale for withdrawal criteria ............................................................................42
7
Trial schedule.....................................................................................................................................43
8
Methods and assessments ..................................................................................................................44
8.1
Visit procedures ......................................................................................................................44
8.1.1
Visit 1 - screening visit ..........................................................................................47
8.1.2
Visit 2....................................................................................................................49
8.1.3
Visit 3....................................................................................................................51
8.1.4
Visit 4 to Visit 10...................................................................................................52
8.1.5
Visit 11 - end of main phase...................................................................................54
8.1.6
Follow-up visit.......................................................................................................55
8.1.7
Visit 12 to Visit 32+...............................................................................................56
8.1.8
End of trial visit .....................................................................................................58
8.1.9
Inhibitor follow-up visit 1-3...................................................................................59
8.1.10
Unscheduled visits .................................................................................................60
8.2
Home treatment.......................................................................................................................61
8.2.1
Prophylactic home treatment..................................................................................61
8.2.2
Home treatment of bleeding episodes.....................................................................62
8.3
Patient related information ......................................................................................................62
8.3.1
Patient reported outcomes and health economic assessments ..................................62
8.3.2
Demographic data..................................................................................................64
8.3.3
Medical history/concomitant illness .......................................................................64
8.3.3.1
Haemophilia treatment history..........................................................65
8.3.4
Bleeding episodes ..................................................................................................66
8.3.4.1
Assessments of bleeding episodes and treatment response ................66
8.3.5
Prophylaxis............................................................................................................68
8.3.6
Surgery..................................................................................................................68
8.3.6.1
Minor surgery ..................................................................................68
8.3.6.2
Major surgery...................................................................................69
8.3.7
Entry of patient eDiary data and eDiary compliance review....................................70
8.4
Adverse event assessments......................................................................................................71
8.5
Clinical assessments................................................................................................................71
8.5.1
Body measurements...............................................................................................71
8.5.2
Physical examinations............................................................................................72
8.5.2.1
Neurological Examination................................................................72
8.5.3
Neurocognitive assessments...................................................................................73
8.5.4
Vital signs..............................................................................................................77
8.6
Blood sampling volume...........................................................................................................77
8.7
Local laboratory assessments...................................................................................................77
8.7.1
Haematology .........................................................................................................78
8.7.2
FIX activity ...........................................................................................................78
8.8
Central laboratory assessments................................................................................................78
8.8.1
Biochemistry .........................................................................................................79
8.8.2
Coagulation-related parameters ..............................................................................79
8.8.3
Recovery for previous FIX product ........................................................................80
8.8.4
FIX activity ...........................................................................................................80
8.8.4.1
One-stage clot activity assay.............................................................81
8.8.4.2
Chromogenic activity assay..............................................................81
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
4 of 135
8.8.5
Antibody assessments ............................................................................................81
8.8.5.1
N9-GP/FIX antibody assay...............................................................81
8.8.5.2
FIX inhibitors...................................................................................82
8.8.6
Host cell protein antibodies....................................................................................83
8.8.7
Allergic reaction testing (conditional) ....................................................................83
8.8.8
Viral assessments (HIV and HCV) and CD4+ lymphocyte count............................84
8.8.9
F9 genotype testing................................................................................................85
8.8.10
Lupus anticoagulant...............................................................................................85
8.8.11
Urinalysis ..............................................................................................................85
8.8.12
Plasma PEG levels.................................................................................................85
8.8.13
Biospecimens for storage .......................................................................................86
8.9
N9-GP administration .............................................................................................................86
8.10
Training and reminders ...........................................................................................................87
8.10.1
Trial card dispensing..............................................................................................87
8.10.2
Home treatment training.........................................................................................87
8.10.3
eDiary and paper diary dispensing and collection ...................................................88
8.10.4
Contact between the investigator/medically qualified person and the patient...........88
8.10.5
Interactive voice/web response system ...................................................................88
8.11
Patient compliance..................................................................................................................89
9
Trial supplies......................................................................................................................................90
9.1
Trial product(s) .......................................................................................................................90
9.2
Non-investigational medicinal product(s) ................................................................................91
9.3
Packaging and labelling of trial product(s)...............................................................................91
9.4
Storage, handling, accountability and destruction of trial product(s) ........................................91
9.5
Auxiliary supply......................................................................................................................93
9.6
Shipment of trial product to patient’s home .............................................................................93
10
Interactive voice/web response system ..............................................................................................94
11
Concomitant illnesses and concomitant medication..........................................................................95
12
Adverse events and technical complaints ..........................................................................................96
12.1
Definitions ..............................................................................................................................96
12.1.1
Technical complaints .............................................................................................98
12.1.2
Reporting of MESI and other reports for expedited reporting..................................98
12.1.2.1
MESI ...............................................................................................98
12.1.2.2
Other reports for expedited reporting..............................................101
12.1.3
Disease-related bleeding ......................................................................................101
12.2
Collection, recording and reporting of adverse events ............................................................101
12.2.1
Follow-up of adverse events.................................................................................103
12.3
Technical complaints and technical complaint samples ..........................................................104
12.3.1
Reporting of technical complaints ........................................................................104
12.3.2
Collection, storage and shipment of technical complaint samples .........................104
12.4
Pregnancies in partners of trial patients..................................................................................105
12.5
Precautions and/or overdose..................................................................................................105
12.6
Safety committee ..................................................................................................................105
12.6.1
Internal Novo Nordisk safety committee ..............................................................105
12.6.2
Stopping rules......................................................................................................105
13
Case report forms ............................................................................................................................107
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
5 of 135
13.1
Rules for completing eCRFs..................................................................................................107
13.2
Corrections to eCRFs ............................................................................................................107
13.3
eCRF flow ............................................................................................................................107
13.4
Paper CRFs for major surgery ...............................................................................................107
13.4.1
Corrections to paper case report forms .................................................................108
13.4.2
Paper case report form flow .................................................................................108
13.5
eDiaries.................................................................................................................................108
13.6
Tablets for neurocognitive assessments .................................................................................109
13.7
Paper diaries for major surgery..............................................................................................110
14
Monitoring procedures ....................................................................................................................111
15
Data management ............................................................................................................................112
16
Computerised systems .....................................................................................................................113
17
Evaluability of patients for analysis ................................................................................................114
18
Statistical considerations .................................................................................................................115
18.1
Sample size calculation .........................................................................................................115
18.2
Statistical methods ................................................................................................................115
18.2.1
General considerations.........................................................................................115
18.2.2
Primary endpoint .................................................................................................115
18.2.3
Confirmatory secondary endpoints .......................................................................116
18.2.4
Supportive secondary endpoints ...........................................................................116
18.2.4.1
Safety endpoints.............................................................................116
18.2.4.2
Efficacy endpoints..........................................................................116
18.2.4.3
Pharmacokinetic endpoints.............................................................117
18.3
Neurocognitive assessments ..................................................................................................119
18.4
Interim analysis.....................................................................................................................119
18.5
Sequential safety analysis/safety monitoring..........................................................................120
18.6
Reporting of F9 genotype......................................................................................................120
18.7
Pharmacokinetic and/or pharmacodynamic modelling ...........................................................120
18.8
Health economics and/or patient reported outcome................................................................120
19
Ethics................................................................................................................................................121
19.1
Informed consent form for trial patients.................................................................................121
19.2
Data handling........................................................................................................................122
19.3
Institutional review board/independent ethics committee .......................................................122
19.4
Regulatory authorities ...........................................................................................................123
19.5
Information to patient during trial..........................................................................................123
20
Premature termination of the trial/trial site....................................................................................124
21
Protocol compliance.........................................................................................................................125
21.1
Audits and inspections...........................................................................................................125
22
Critical documents...........................................................................................................................126
23
Responsibilities.................................................................................................................................128
24
Reports and publications .................................................................................................................129
24.1
Communication and publication............................................................................................129
24.1.1
Authorship...........................................................................................................129
24.1.2
Publications .........................................................................................................129
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
6 of 135
24.1.3
Site-specific publication(s) by investigator(s).......................................................130
24.2
Investigator access to data and review of results ....................................................................130
25
Retention of clinical trial documentation and human biospecimens..............................................131
25.1
Retention of human biospecimens .........................................................................................131
26
Indemnity statement ........................................................................................................................133
27
References ........................................................................................................................................134
Appendix A
Approval of final protocol
Appendix B
Agreement on final protocol
Appendix C
Blood sampling volume rules 
Appendix D
Body mass index chart
Attachment I - Global
List of key staff, relevant departments and CRO(s)
Attachment II - Country
List of key staff and relevant departments
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
7 of 135
Table of figures 
Page
Figure 8-1
Overview of visits ...................................................................................................................44
Figure 8-2
Process flow for inhibitor testing.............................................................................................83
Figure 13-1 eDiary data flow....................................................................................................................109
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
8 of 135
Table of tables 
Page
Table 2-1
Flow chart for the main phase of the trial.................................................................................15
Table 2-2
Detailed flow chart for PK sampling visit (Visit 2) ..................................................................21
Table 2-3
Detailed flow chart for the extension phase of the trial.............................................................24
Table 3-1
The clinical development programme of N9-GP......................................................................30
Table 8-1
Neurocognitive assessments by age and country......................................................................75
Table 18-1
Definition and calculation of PK parameters..........................................................................118
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
9 of 135
List of abbreviations and definition of terms
ABAS-3
Adaptive Behavior Assessment System- Third Edition
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
antithrombin
AUC
area under the curve
BASC3
Behavior Assessment System for Children – Third Edition
BMI
body mass index
BP
blood pressure
BRIEF-2
Behavior Rating Inventory of Executive Function – Second Edition
BRIEF-A
Behavior Rating Inventory of Executive Function – Adult Edition
BU
Bethesda units
BW
body weight
C30min
plasma FIX activity 30 minutes after end of injection
Caregiver
a close person who helps the patient in his daily life. It is not the investigator or the site staff
CHMP
Committee for Medicinal Products for Human Use
CHO
Chinese hamster ovary
CL
total clearance
CNS
central nervous system
CRF 
case report form
CRO
contract research organisation
CRP
C-reactive protein
CV
curriculum vitae
DCF
data clarification form
DISP
dispensing 
DUN
dispensing unit number
eCOA
electronic Clinial Outcome Assessment
eCRF
electronic case report form
ED
exposure day. One exposure day is defined as each day when a patient is administered 
coagulation factor IX for prophylaxis, prevention or on-demand treatment
EDC
electronic data capture
eDiary
electronic diary
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ePRO
electronic patient reported outcomes
EOT
end of trial
FAS
full analysis set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FVII
coagulation factor VII
FVIII
coagulation factor VIII
FIX
coagulation factor IX
FIXa
activated coagulation factor IX
FX
coagulation factor X
FU
follow-up
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
10 of 135
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
HAEMO-QOL haemophilia-quality of life
HCP
host cell protein
HCV
hepatitis C virus
HEMO-SAT
hemophilia satisfaction
HIV
human immunodeficiency virus
HRQOL 
health related quality of life
IB
investigator’s brochure
ICH
International Conference on Harmonisation 
ICMJE
The International Committee of Medical Journal Editors
IEC
independent ethics committee
IFU
inhibitor follow-up
IgE
immunoglobulin E
IMP
investigational medicinal product
INR
international normalised ratio
Investigator
the individual overall responsible for the conduct of the clinical trial at a trial site
IR30
incremental recovery at 30 min calculated by dividing the baseline adjusted FIX activity 
(U/mL) measured in plasma 30 min after dosing by the dose injected at time 0 expressed as 
U/kg body weight
IRB
institutional review board
IU
international unit
i.v.
intravenous
IV/WRS
interactive voice web response system
λz
terminal elimination rate constant
LAR
legally authorised representative
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LPLV
last patient last visit
m
months
MCH
mean corpuscular haemoglobin
MCV
mean corpuscular volume
MESI
medical event of special interest
MIDF
monitor-initiated discrepancy form
MRT
mean residence time
N9-GP
glycopegylated recombinant coagulation factor IX (NNC-0156-0000-0009)
NIMP
non-investigational medicinal product
PCV
packed cell volume
PDCO
Paediatric Committee (EMA)
pd-aPCC
plasma-derived activated prothrombin complex concentrates 
pdFIX
plasma derived FIX
pd-PCC
plasma-derived prothrombin complex concentrates 
PEF
peak expiratory flow
PEG 
polyethylene glycol
PK
pharmacokinetics
PIP
paediatric investigation plan
PRO
patient reported outcomes
PT
prothrombin time
PTP
previously treated patients
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
11 of 135
Recovery
maximum FIX activity after dosing (% or IU/mL)
rFVIIa
activated recombinant factor VII
rFIX
recombinant coagulation factor IX
SAE
serious adverse event
SAS
safety analysis set
SUSAR
suspected unexpected serious adverse reactions
t1/2
terminal half-life
TAPQOL
TNO-AZL preschool quality of life
TEAE
treatment emergent adverse event
TESAE
treatment emergent serious adverse event
TMM
trial materials manual
TNO-AZL
The Dutch institute of Prevention and Health and the Leiden University Hospital
TVP
trial validation plan
UTN
Universal Trial Number
Vss
volume of distribution at steady state
w
weeks
WASI-II
Wechsler Abbreviated Scale of Intelligence, Second Edition
WPPSI-IV
Wechsler Preschool and Primary Scale of Intelligence Fourth Edition
WFH
World Federation of Hemophilia
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
12 of 135
1
Summary
Primary objective:
!
To evaluate immunogenicity of glycopegylated recombinant coagulation factor IX (NNC-0156-
0000-0009; hereafter referred to as N9-GP)
Primary endpoint:
!
Incidence of inhibitory antibodies against coagulation factor IX (FIX) defined as titre ≥0.6 BU
Key secondary objectives:
!
To evaluate safety other than immunogenicity of N9-GP 
!
To evaluate the efficacy of N9-GP in long-term prophylaxis and in the treatment of 
breakthrough bleeding episodes
!
To evaluate the efficacy of N9-GP through the surrogate marker for efficacy, FIX activity
!
To evaluate the pharmacokinetic (PK) properties of N9-GP 
Key secondary endpoints:
!
Number of bleeding episodes during prophylaxis
!
Haemostatic effect of N9-GP in treatment of bleeding episodes by 4-point categorical scale for 
haemostatic response (excellent, good, moderate and poor)
!
Incremental recovery at 30 minutes (IR30min)
!
Trough level (single-dose and steady state)
!
Terminal half-life (t1/2)
Timeframes for evaluation of the endpoints:
All key PK endpoints, except trough steady state, will be evaluated at week 0. Trough steady state 
will be evaluated from week 4 to 44. 
The main evaluation of all key endpoints will be done after 52 weeks of treatment. The evaluation 
of the extension phase will be done after the last patient has completed the trial.
Trial design:
This is an open label, single-arm, multinational, non-controlled, confirmatory trial investigating
safety, efficacy and PK of N9-GP in prophylaxis and treatment of breakthrough bleeding episodes 
in previously treated paediatric male patients with haemophilia B. 
The trial consists of a main phase and an extension phase. The duration of the main phase for each 
patient will be minimum 52 weeks and the extension phase will continue until LPLV. 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
13 of 135
The patients will be stratified into two age groups; 0-6 years and 7-12 years, both inclusive. A 
minimum of 10 patients in each age group must complete the main phase of the trial. The trial has 
one treatment arm where all patients receive N9-GP once weekly for prophylaxis. In the extension 
phase, a single dose of 40 IU/kg once weekly will be administered intravenously. Treatment with 
N9-GP will in addition be administered in case of breakthrough bleeding episodes. 
Trial population:
Around 40 patients will be screened in order to start approximately 24 patients on trial product out 
of which 10 patients in each of the two age groups are expected to complete the main phase of the 
trial. 
The trial population is characterised by the following key inclusion and exclusion criteria:
Key inclusion criteria:
!
Male patients with moderately severe or severe congenital haemophilia B with a FIX activity 
level ≤2% according to medical records
!
Age ∀12 years (until patient turns 13 years, at time of inclusion)
!
Body weight ≥10 kg
!
History of at least 50 exposure days (EDs) to other FIX products
!
The patient and/or parent(s)/caregiver are capable of assessing a bleeding episode, keeping an 
electronic diary (eDiary), capable of conducting home treatment and otherwise able to follow 
trial procedures
Key exclusion criteria:
!
Known history of FIX inhibitors 
!
Current FIX inhibitors #0.6 Bethesda Units (BU)
!
Congenital or acquired coagulation disorder other than haemophilia B
!
Platelet count <50,000/μL at screening 
!
Alanine aminotransferase (ALT) >3 times the upper limit of normal reference ranges at 
screening 
!
Creatinine level #1.5 times above the upper normal limit of normal reference ranges at 
screening 
!
Human immunodeficiency virus (HIV) positive, defined by medical records, and with a CD4+ 
lymphocyte count ∀200/∃L
!
Immune modulating or chemotherapeutic medication (except single pulse treatment, inhaled and 
topical steroids)
!
Previous arterial thrombotic events (myocardial infarction and intracranial thrombosis, as 
defined by medical records)
3URWRFROY_
11
RI
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
14 of 135
Safety assessments:
Adverse events (AEs) and inhibitory antibodies against FIX will be assessed at each visit 
throughout the trial. 
Efficacy assessments:
The number of bleeding episodes and FIX consumption, for prophylaxis and in treatment of 
bleeding episodes, will be monitored throughout the trial. Furthermore, the haemostatic effect of 
N9-GP in treatment of bleeding episodes will be assessed. FIX activity, a surrogate marker for 
efficacy, will be measured pre- and post-dose at visits in the main phase of the trial.
Pharmacokinetic assessments:
Patient’s previous FIX product: If no recovery data are available in medical records, a recovery 
sample will be collected 30 minutes after dosing with the patient’s current product at Visit 1.
N9-GP: All patients must undergo a PK evaluation at Visit 2. The patients will have one PK sample 
taken prior to dosing with N9-GP and one sample taken 30 minutes post-dose. Four additional PK 
samples will be collected at 4 different days during the following 7 days. 
Trial products:
The following trial products will be used in the trial:
! N9-GP Drug Product
! Histidine solvent
N9-GP Drug Product is supplied as freeze-dried powder in single-use vials to be reconstituted with
Histidine solvent. The trial product will be administered as an intravenous (i.v.) bolus injection with 
a maximum injection rate of 4 mL/min.
A single dose of 40 IU/kg N9-GP will be administered intravenously once weekly during the main 
phase of the trial. In the extension phase, the same dosing regimen is administered. Patients who 
experience a bleeding episode should treat the bleeding episode with a single dose of 40 IU/kg N9-
GP, unless the bleeding episode is severe, in this case they should be treated with 80 IU/kg N9-GP.
3URWRFROY_
11
RI
CONFIDENTIAL


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
15 of 135
2
Flow charts
Table 2-1
Flow chart for the main phase of the trial
Visit number
11
25, 8
311
4-611
7-1011
115, 11
FU5,12
IFU1-37
Visit purpose
Screening
N9-GP first 
dose
N9-GP   
second dose
N9-GP dosing
(visits every 
fourth week)
N9-GP dosing 
(visits every 
eight week)
End of 
main 
phase
Follow-
up
visit
Inhibitor  
follow-up 
visits
Time of visit (weeks)
6 w
prior to 
Visit 2
0
1 w
4-12 w
20-44 w
52 w
3 w
after 
Visit 11
Every 4 wks 
after Visit 11
Visit window (days or weeks)
±2 w
-
+1 d
±1 w
±1 w
+2 w
±1 w
±1 w
PATIENT RELATED INFORMATION
Informed consent
X
Consent to genotyping (if applicable)
X
Inclusion/exclusion criteria
X
X
Withdrawal criteria
X
X
X
X
X
Patient Reported Outcome questionnaires
X
X
Demography
X
Concomitant illness
X
Medical history including haemophilia treatment 
history, details on haemophilia, inhibitors and 
joints 
X
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
16 of 135
Visit number
11
25, 8
311
4-611
7-1011
115, 11
FU5,12
IFU1-37
Visit purpose
Screening
N9-GP first 
dose
N9-GP   
second dose
N9-GP dosing
(visits every 
fourth week)
N9-GP dosing 
(visits every 
eight week)
End of 
main 
phase
Follow-
up
visit
Inhibitor  
follow-up 
visits
Time of visit (weeks)
6 w
prior to 
Visit 2
0
1 w
4-12 w
20-44 w
52 w
3 w
after 
Visit 11
Every 4 wks 
after Visit 11
Visit window (days or weeks)
±2 w
-
+1 d
±1 w
±1 w
+2 w
±1 w
±1 w
Medical record of HIV status
X
Medical record of HCV status
X
F9 genotype documentation (if applicable)
X
Concomitant medication
X
X
X
X
X
X
X
X
Date and time of last coagulation factor 
administration
X
X
X
X
Assessments of bleeding episodes
X
X
X
X
X
X
X
Compliance review of drug administration and 
eDiary completion
X
X
X
ADVERSE EVENTS
Adverse events
X
X
X
X
X
X
X
X
CLINICAL ASSESSMENTS
Body measurements
X
X6
X6
X6
Physical examination
X
X14
X
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
17 of 135
Visit number
11
25, 8
311
4-611
7-1011
115, 11
FU5,12
IFU1-37
Visit purpose
Screening
N9-GP first 
dose
N9-GP   
second dose
N9-GP dosing
(visits every 
fourth week)
N9-GP dosing 
(visits every 
eight week)
End of 
main 
phase
Follow-
up
visit
Inhibitor  
follow-up 
visits
Time of visit (weeks)
6 w
prior to 
Visit 2
0
1 w
4-12 w
20-44 w
52 w
3 w
after 
Visit 11
Every 4 wks 
after Visit 11
Visit window (days or weeks)
±2 w
-
+1 d
±1 w
±1 w
+2 w
±1 w
±1 w
Vital signs
X
X
X16
X
LOCAL LABORATORY ASSESSMENTS
Haematology
X
X4
X
CENTRAL LABORATORY ASSESSMENTS
Biochemistry
X
X
Coagulation-related parameters
X4
X
FIX recovery (for previous FIX product)
X3
FIX activity19
-pre-dose
-post-dose (30 min)
X
X
X2
X
X a)
X
X b)
X
X b
X
X
N9-GP/FIX antibodies 
X4
X
X
X
X
X
FIX inhibitors
X
X4
X
X
X
X
X
HCP antibodies
X
X
X
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
18 of 135
Visit number
11
25, 8
311
4-611
7-1011
115, 11
FU5,12
IFU1-37
Visit purpose
Screening
N9-GP first 
dose
N9-GP   
second dose
N9-GP dosing
(visits every 
fourth week)
N9-GP dosing 
(visits every 
eight week)
End of 
main 
phase
Follow-
up
visit
Inhibitor  
follow-up 
visits
Time of visit (weeks)
6 w
prior to 
Visit 2
0
1 w
4-12 w
20-44 w
52 w
3 w
after 
Visit 11
Every 4 wks 
after Visit 11
Visit window (days or weeks)
±2 w
-
+1 d
±1 w
±1 w
+2 w
±1 w
±1 w
Plasma PEG levels20
X
X
X
X
X
X
Allergic reaction testing13
X
X
X
Viral antibody test (if HIV and/or HCV status is 
unknown)
X
CD4+ lymphocyte count (if HIV positive)
X
HCV RNA (if HCV positive)
X18
F9 genotype testing (if applicable)
X10
Lupus anticoagulant
X
TRIAL PRODUCT ADMINISTRATION
Administration of N9-GP
X17
X17
X
X
X9
N9-GP dispensing for home treatment
X
X
X
X9
Drug accountability
X
X
X
X
X
Administration of previous FIX product (if 
applicable)
X3
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
19 of 135
Visit number
11
25, 8
311
4-611
7-1011
115, 11
FU5,12
IFU1-37
Visit purpose
Screening
N9-GP first 
dose
N9-GP   
second dose
N9-GP dosing
(visits every 
fourth week)
N9-GP dosing 
(visits every 
eight week)
End of 
main 
phase
Follow-
up
visit
Inhibitor  
follow-up 
visits
Time of visit (weeks)
6 w
prior to 
Visit 2
0
1 w
4-12 w
20-44 w
52 w
3 w
after 
Visit 11
Every 4 wks 
after Visit 11
Visit window (days or weeks)
±2 w
-
+1 d
±1 w
±1 w
+2 w
±1 w
±1 w
TRAINING AND REMINDERS
Trial card dispensing
X
Home treatment and eDiary training
X
X
X
X
X9
eDiary dispensing 
X
eDiary collection 
X15
Telephone contact with patient/parent(s)/LAR
(halfway through the home-treatment period)
X
X
X
X9
IV/WRS
X
X
X
X
X
X
End of trial form
X
X
Footer
Description
1
Visit 1 can be performed on separate days. The patients should not use coagulation factors within 4 days prior to the laboratory assessments of Visit 1.
2
Additional PK samples will be collected at 24, 48, 96 and 168 hours post-dose. In total, six PK samples will be collected at 4 different days, see Table 2-2.
3
If recovery results for the patient’s previous FIX product are not available in medical records or are older than 1 year or are collected more than 1 hour after dosing, the patient will be 
dosed with his current product at Visit 1 and a FIX recovery sample will be collected 30 minutes after dosing (±10 minutes). This can be done anytime in the period from informed consent 
and until 4 days prior to the laboratory assessments of Visit 1 or directly after all laboratory assessments of Visit 1 have been completed and until 4 days prior to Visit 2. 
4
Will be collected pre-dose and 168 hours post-dose.
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
20 of 135
5
The patients should not use coagulation factors within 4 days prior to Visit 2 and FU visit, and within 6 days prior to Visit 11.
6
Body weight only.(Height at Visit 11 will be collected retrospective if available in medical records and consent obtained)
7
For patients developing FIX inhibitors #5 BU, please refer to Section 8.1.9. If treated with FIX within 4 days prior to the first inhibitor follow up visit (IFU1), the visit must be postponed. 
The end of trial form should be signed at the last IFU visit.
8
Please refer to Table 2-2 for a detailed flow chart for the PK sampling visit (Visit 2).
9
Only applicable for patients continuing in the extension phase. 
10
F9 genotype testing is optional and will only be performed if there is no existing records on the F9 genotype and if the parent(s)/LAR consents. Can be performed at Visit 1 or at any later 
visit. 
11
Between each visit to the trial site there are home treatment periods with dosing once weekly, see Section 8.2.
12
For patients who do not proceed into the extension phase or are withdrawn.
13
Will only be measured in patient developing severe allergic reactions against N9-GP. If a severe allergic reaction develops, additional blood samples should be collected within 15 minutes 
(if possible), 1-4 hours and ~1 week after onset of the reaction at unscheduled visits. 
14
At Visit 8 only.
15 
The eDiary should be collected at Visit 11 for patients who are withdrawn or not continuing in the extension phase.
16
Vital signs will be assessed pre-dose and 60 minutes post-dose.
17
At Visit 2 and 3, the patient has to be observed in a hospital setting for 60 minutes after N9-GP has been administered.
18
Can be performed at Visit 1 or at any later visit.
19
In case a patient has a positive antibody detected at the N9-GP Antibody assay analysis the patient will be asked to have a PK session performed after the next dosing. Blood sampling for 
FIX activity will be performed at the following time points: pre-dose, 30 min, 24h, 48h, 96h and 168h.
20
PEG will be measured if enough plasma is available from leftover samples and if consent obtained.
a)
Only at visit 5
b)
Only at visit 7, 9 and 11
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
21 of 135
Table 2-2
Detailed flow chart for PK sampling visit (Visit 2)
Day 
0
1
2
4
7
Nominal time
Pre-dose
02
30 min3
60 min3
24h3
48 h3
96 h3
168h3
Visit window
-1h1
-
%10 min
%10 min
+8h
%8 h
%8 h
%24 h
PATIENT RELATED INFORMATION
Inclusion/exclusion criteria
X
Withdrawal criteria
X
Concomitant medication
X
X
X
X
X
X
X
X
Date and time of last coagulation factor 
administration
X
Assessments of bleeding episodes4
X
X
X
X
X
ADVERSE EVENTS
Adverse events
X
X
X
X
X
X
X
X
CLINICAL ASSESSMENTS
Body measurements (body weight)
X
Vital signs
X
X
LOCAL LABORATORY ASSESSMENTS
Haematology
X
X
CENTRAL LABORATORY ASSESSMENTS
Coagulation-related parameters
X
X
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
22 of 135
Day 
0
1
2
4
7
Nominal time
Pre-dose
02
30 min3
60 min3
24h3
48 h3
96 h3
168h3
Visit window
-1h1
-
%10 min
%10 min
+8h
%8 h
%8 h
%24 h
FIX activity
X
X6
X
X
X
X
N9-GP/FIX antibodies 
X
X
FIX inhibitors
X
X
HCP antibodies
X
Plasma PEG levels7
X
Allergic reaction testing5
X
N9-GP ADMINISTRATION
Administration of N9-GP
X
Drug accountability
X
TRAINING AND REMINDERS
Home treatment and eDiary training
X
IV/WRS 
X
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
23 of 135
Footer
Description
1
The 1 hour pre-dose time window is only applicable for laboratory assessments. Any other assessments (eg, body measurements, vital signs etc) have to be performed prior to dosing at 
the day of dosing. 
2
The actual time of completed N9-GP injection corresponds to time point = 0.
3
Refers to time elapsed after completed N9-GP injection. 
4
Any bleeding episodes during Visit 2 must be recorded in the eCRF. If a bleeding episode, requiring treatment, occurs within 96 hours after N9-GP administration, the patient can be 
rescheduled for a new PK evaluation at any later visit during the main phase.
5
Will only be measured in patient developing severe allergic reactions against N9-GP. If a severe allergic reaction develops, additional blood samples should be collected within 15 
minutes (if possible), 1-4 hours and ~1 week after onset of the reaction at unscheduled visits. 
6
The blood sample taken 30 minutes post-dose  must not be taken from the same vein as used for N9-GP administration.
7
PEG will be measured if enough plasma is available from leftover samples from already collected samples and if consent obtained 
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
24 of 135
Table 2-3
Detailed flow chart for the extension phase of the trial
Visit number
125
135, 9
145, 9
155, 9
165, 9
175, 9
X1, 5, 9
EOT5
IFU1-32
Additional visit
Months after Visit 11
3 m3
6 m3
12 
m3
18 m3
24 m3
30 m3
Every 6 m3
Minimum 6 
days after 
last            
N9-GP dose
Every 4 wks 
after EOT 
visit
See footnote10
Visit window
±2 w
±2 w
±2 w
±2 w
±2 w
±2 w
±2 w
-
±1 w
±2 w
PATIENT RELATED INFORMATION
Withdrawal criteria
X
X
X
X
X
X
X
X
X
Patient Reported Outcome 
questionnaires
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
Date and time of last coagulation 
factor administration
X
Assessments of bleeding episodes 
X
X
X
X
X
X
X
X
X
Compliance review of drug 
administration and eDiary completion
X
X
X
X
X
X
X
X
X
ADVERSE EVENTS
Adverse events
X
X
X
X
X
X
X
X
X
X
CLINICAL ASSESSMENTS
Body measurements
X
X
X
X
X
X
X
X
X
Physical examination
X
X
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
25 of 135
Visit number
125
135, 9
145, 9
155, 9
165, 9
175, 9
X1, 5, 9
EOT5
IFU1-32
Additional visit
Months after Visit 11
3 m3
6 m3
12 
m3
18 m3
24 m3
30 m3
Every 6 m3
Minimum 6 
days after 
last            
N9-GP dose
Every 4 wks 
after EOT 
visit
See footnote10
Visit window
±2 w
±2 w
±2 w
±2 w
±2 w
±2 w
±2 w
-
±1 w
±2 w
Neurological examination
X
X
Neurocognitive assessments12
X
X
Vital signs
X
X
LOCAL LABORATORY ASSESSMENTS
Haematology
X
CENTRAL LABORATORY ASSESSMENTS 
Biochemistry
X
X
X
FIX activity
-pre-dose
X
X
X
X
X
X
X
X
X
X
N9-GP/FIX antibody and FIX 
inhibitor test
X
X
X
X
X
X
X
X
X
X
HCP antibodies
X
X
X
X
X
X
X
X
X
X
Allergic reaction testing6
X
X
Biospecimen for storage: Serum and 
Plasma (if applicable)
X
X
X
X7
X
X
Biospecimen for storage: Genotype  
(X)8
(X)8
(X)8
(X)8
(X)8
(X)8
(X)8
(X)8
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
26 of 135
Visit number
125
135, 9
145, 9
155, 9
165, 9
175, 9
X1, 5, 9
EOT5
IFU1-32
Additional visit
Months after Visit 11
3 m3
6 m3
12 
m3
18 m3
24 m3
30 m3
Every 6 m3
Minimum 6 
days after 
last            
N9-GP dose
Every 4 wks 
after EOT 
visit
See footnote10
Visit window
±2 w
±2 w
±2 w
±2 w
±2 w
±2 w
±2 w
-
±1 w
±2 w
(if applicable)8
Plasma PEG levels11
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
N9-GP ADMINISTRATION
Administration of N9-GP
X4
X4
X4
X4
X4
X4
X4
X4
N9-GP dispensing for home treatment9
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
TRAINING AND REMINDERS
Home treatmentand eDiary training
X
X
X
X
X
X
X
X
eDiary collection
X
Contact with patient/parent(s)/LAR
(halfway through the home treatment 
period)
X
X
X
X
X
X
X
X
IV/WRS
X
X
X
X
X
X
X
X
X
End of trial form
X
X
3URWRFROY_
11
RI


Protocol
UTN: U1111-1119-5013
Date:
27 June 2018
Status:
Final
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
EudraCT No.: 2011-000826-31
Version:
12.0
Page:
27 of 135
Footer
Description
1
The visit can be repeated until LPLV. X can therefore be any sequential number from 18 – 32+.
2
For patients developing FIX inhibitors #5 BU, please refer to Section 8.1.9. If treated with FIX within 4 days prior to the first inhibitor follow up visit (IFU1), the visit must be postponed,
3
One month is defined as four weeks.
4
Patients can either be dosed with N9-GP at the trial site or at home after the visit (if no lab samples are required).
5
Between each visit to the trial site there are home treatment periods with dosing once weekly or less frequently, see Section 8.2.
6 
Will only be measured in patient developing severe allergic reactions against N9-GP. If a severe allergic reaction develops, additional blood samples should be collected within 15 minutes 
(if possible), 1-4 hours and ~1 week after onset of the reaction at unscheduled visits. 
7
Every second visit, (17, 19 etc) 
8
Biospecimen for storage: genotype sample to be collected once during extension phase
9
The amount of N9-GP dispensed at each visit corresponds to approximately 3 months of home treatment. Halfway in-between two visits from visit 13 additional N9-GP should be dispensed 
for further 3 months home treatment. The patient is not required to attend the clinic only for N9-GP interim dispensing.
10
Between V15 and V17 a subset of patients will be requested to attend an additional visit. If applicable the visit may be planned by the investigator to coincide with the interim dispensing of 
N9-GP. Investigators to affected patients will be informed by Novo Nordisk
11
PEG will be measured if enough plasma samples is available from leftover samples and if consent obtained, from BioSpecimen for storage plasma samples or from designated PEG plasma
samples.
12
Assessments will be performed at every assessment visit in all countries. For selected countries additional assessments will be performed yearly. 
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3
Introduction
3.1
Basic information
In this document the term investigator refers to the individual overall responsible for the conduct of 
the clinical trial at a trial site.
3.1.1
Background
Haemophilia B is a recessive X-linked congenital bleeding disorder characterised by increased 
bleeding tendency due to either a partial or complete deficiency or dysfunction of the essential 
blood coagulation factor IX. It is caused by mutations in the F9 gene, located in the distal part on 
the long arm of the X-chromosome. The gene-defects are transferred from a heterozygotic mother 
(carrier), or are ascribable to new, spontaneous mutations. The incidence of haemophilia B is 
approximately 1 per 25,000 male births.
With a deficiency or absence of FIX, activation of coagulation factor X (FX) becomes severely 
impaired, and consequently, the thrombin burst becomes delayed and insufficient for normal 
haemostasis. The haemostatic plug formed in these patients is therefore fragile and easily dissolved 
by normal fibrinolytic activity, leading to impaired haemostasis, prolonged bleeding and 
rebleeding1. Haemophilia B is classified according to the plasma activity of FIX as severe (<1%), 
moderate (1-5%) or mild (>5-40%). 
The main treatment for patients with haemophilia B is replacement therapy where concentrates of 
FIX are injected intravenously to replace the deficient and/or dysfunctional FIX. Haemophilia care 
is based on treatment of a bleeding episode with a haemostatic agent (on-demand treatment) or -
during recent years - haemostatic agents are administered for longer periods to prevent bleeding 
(bleeding prophylaxis).
The clinical manifestations of haemophilia B are bleeding episodes due to impaired haemostasis. 
The bleeding episodes in patients with severe haemophilia B typically occur spontaneously or after 
mild trauma in joints, muscles and soft tissues. The bleeding episodes often occur in the muscles 
and joints of the elbows, knees and ankles, causing acute haemarthrosis. In repeated cases this is 
followed by synovitis in the affected joint. Recurrent bleeding episodes in the same location, most 
commonly a weight-bearing joint, may lead to chronic arthropathy, muscular atrophy and 
deformities. Bleeding episodes may occur in all parts of the body including rare, but life-threatening 
events such as: bleeding in the central nervous system (CNS), throat, neck or retroperitoneum.
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Today, the most serious complication of replacement therapy is inhibitor development. FIX 
inhibitors are allogenic antibodies to FIX that reduce or eliminate the activity of FIX. For clinical 
purposes, the magnitude of the inhibitor response can be quantified through the performance of a 
functional inhibitor assay from which a BU inhibitor titre can be reported2. The definitions for 
thresholds are 0.6-<5 BU for a “low titre” and ≥5 BU for a “high titre” inhibitor3. Approximately 
1-3% of patients with haemophilia B develop inhibitors following exposure to FIX4-7. Among 
patients with severe haemophilia B the percentage is however as high as 9%7. 
3.1.2
N9-GP
Novo Nordisk A/S is developing a recombinant FIX (rFIX) molecule - N9-GP - with a prolonged 
half-life for the treatment of patients with haemophilia B. The long half-life is achieved by site-
directed glycopegylation that makes it possible to attach a 40 kilodalton polyethylene glycol (PEG) 
molecule to the FIX activation peptide. Upon activation by FIX’s physiological activators, the 
activation peptide – with the attached PEG – is cleaved off, thereby leaving wild type activated FIX 
(FIXa).
The product is intended for FIX replacement therapy in adults and children with haemophilia B. 
N9-GP is under development for both the control and prevention of bleeding episodes, including 
routine prophylaxis, and for treatment and prevention of bleeding during surgery.
For full information on medical aspects, non-clinical data and quality of N9-GP, please refer to the 
current version of the Investigator’s Brochure (IB)8 and any updates hereof.
3.1.3
Risks and benefits
Children are among those who might benefit significantly from prophylaxis with N9-GP. Current 
products available for the treatment of haemophilia B have short half-life of 18-19 hours demanding 
frequent dosing for prophylaxis of bleeding, with 2-3 injections a week9. The prolonged half-life of 
N9-GP offers an expected advantage of once weekly or potentially even less frequent injections.
N9-GP is manufactured in a serum-free process. The recombinant FIX part of N9-GP, has an amino 
acid sequence identical to human FIX and to the currently marketed rFIX product and is produced 
from the Chinese hamster ovary (CHO) cell-line, a mammalian cell line shown to be free of known 
infectious agents. 
Hypersensitivity reactions may occur with the administration of N9-GP, as with any protein injected 
intravenously. Even if N9-GP is not anticipated to be more immunogenic than any other FIX 
products, patients with known or suspected hypersensitivity to N9-GP or related products will be 
excluded from participation in this trial. 
There is a potential risk for development of antibodies against N9-GP and/or FIX that could 
decrease the effectiveness of future treatments with FIX products. However, this risk is not 
expected to be greater than with other FIX products.
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In repeat dose toxicity studies in animals, PEG was shown to be bio-distributed to blood in 
connective tissue and cytoplasm of epithelial cells of the choroid plexus of the brain (refer to IB). 
The potential clinical implications of these animal findings are unknown. No adverse neurologic 
effects of PEG have been reported in infants, children, and adolescents exposed to N9-GP during 
clinical trials. The potential consequences of long term exposure have not been fully evaluated. 
To minimise switching between FIX products, the trial includes an extension phase in which the 
patients can continue with N9-GP treatment until LPLV.   
3.2
Rationale for the trial
The rationale for performing this trial is to investigate safety, efficacy and PK of N9-GP in the 
treatment of haemophilia B patients ≤12 years. Based on clinical and non-clinical studies 
conducted, N9-GP is a promising drug candidate for prevention/prophylaxis and on-demand 
treatment of bleeding episodes in haemophilia B patients. 
The completed phase 1 PK trial (NN7999-3639) showed a mean half-life of N9-GP of 93 hours 
which is approximately 5 times longer than commercially available FIX products. In addition, the 
recovery of N9-GP was 94% higher when compared to rFIX and 20% higher when compared to 
plasma-derived FIX (pdFIX)10.
In compliance with paediatric regulations and to adequately study the safety and efficacy of N9-GP 
in children, the present trial is being carried out in accordance with the paediatric investigation plan 
(PIP) that was approved by the Paediatric Committee (PDCO) of the European Medicines Agency 
(EMA) on 12-Nov-2010. For Europe, EMA requires separate investigation in the paediatric 
population as part of the development programme, and paediatric trial results are now compulsory 
in any new market authorisation application, or at a minimum accepted for full or partial 
waiver/deferral in the PIP, when accepted by the PDCO. In some countries outside the EU, 
paediatric investigation is necessary to achieve labelled indication for children. For an overview of 
the trials in the clinical development programme of N9-GP, please refer to Table 3-1.
Table 3-1
The clinical development programme of N9-GP
Type of trial
Trial description
Trial ID
Status
Phase 1 PK trial 
A multi-centre, multinational, open-label, dose escalation trial evaluating 
safety and PK of ascending intravenous doses of N9-GP in patients with 
haemophilia B
NN7999-3639
(paradigmTM1)
Completed
Phase 3a pivotal 
safety and efficacy 
trial 
A multi-centre, single-blind trial evaluating safety and efficacy, including 
PK, of N9-GP when used for treatment and prophylaxis of bleeding 
episodes in patients with haemophilia B
NN7999-3747
(paradigmTM2)
Completed
Phase 3a surgery 
An open-label, multi-centre, non-controlled trial evaluating efficacy and 
NN7999-3773
Completed
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Type of trial
Trial description
Trial ID
Status
trial 
safety of N9-GP treatment during surgical procedures in patients with 
haemophilia B
(paradigmTM3)
Phase 3b extension 
trial 
An open-label, multi-centre, multinational trial evaluating safety and 
efficacy of N9-GP in treatment of bleeding episodes and long-term 
prophylaxis in haemophilia B patients
NN7999-3775
(paradigmTM4)
Completed
Phase 3 paediatric, 
safety and efficacy 
trial 
An open-label, single-arm, multinational, non-controlled, confirmatory 
trial investigating safety, efficacy and PK of N9-GP in prophylaxis and 
treatment of bleeding episodes in children with haemophilia B with 
extension phase
NN7999-3774
(paradigmTM5)
Current trial
Phase 3b safety 
trial 
An open-label, multi-centre, non-controlled, safety and efficacy trial in 
previously untreated patients with haemophilia B
NN7999-3895
(paradigmTM6)
Ongoing
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4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
!
To evaluate immunogenicity of N9-GP 
4.1.2
Secondary objectives
!
To evaluate safety other than immunogenicity of N9-GP
!
To evaluate the efficacy of N9-GP in long-term prophylaxis and in the treatment of 
breakthrough bleeding episodes
!
To evaluate the efficacy of N9-GP through the surrogate marker for efficacy, FIX activity
!
To evaluate the PK properties of N9-GP 
!
To evaluate patient reported outcomes (PROs) and assess health economic impact of treatment 
with N9-GP
4.2
Endpoints
4.2.1
Primary endpoint
! Incidence of inhibitory antibodies against FIX defined as titre ≥0.6 BU
4.2.2
Secondary endpoints
4.2.2.1 Safety endpoints
!
Adverse events including serious adverse events (SAEs) and medical events of special interest 
(MESI), and development of host cell protein (HCP) antibodies 
4.2.2.2 Efficacy endpoints
!
Number of bleeding episodes during prophylaxis 
!
Haemostatic effect of N9-GP in treatment of bleeding episodes by 4-point categorical scale for 
haemostatic response (excellent, good, moderate and poor)
!
FIX consumption described as frequency of dose/kg for prophylaxis use and number of doses 
and amount consumed for the treatment of bleeding episodes
4.2.2.3 Pharmacokinetic endpoints
Pharmacokinetic endpoints, except trough steady state and FIX activity at 30 minutes (C30min)
steady state, are assessed after a single dose (Visit 2). Steady state trough and C30min will be 
assessed at Visit 4 - Visit 10 during the main phase of the trial.
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! Incremental recovery at 30 minutes (IR30min) ([IU/mL] / [IU/kg])
! Trough level (IU/mL) (single-dose and steady state)
! Area under the curve (AUC) (Uxh/mL)
! Terminal half-life (t1/2) (h)
! Clearance (CL) (mL/h/kg)
! Mean residence time (MRT) (h)
! Volume of distribution at steady state (Vss) (mL/kg)
! FIX activity at 30 minutes (C30min) (IU/mL) (single-dose and steady state)
4.2.2.4 Patient reported outcomes and health economic endpoints
! Changes in health related quality of life (HRQOL) from Visit 1,Visit 11, Visit 17and to Visit 
22/23/24 (the relevant visit where neurocognitive assessments are performed for the first time for 
each patient) , assessed using age and disease specific patient reported outcomes (PRO)
questionnaires: Haemophilia-quality of life (HAEMO-QOL), Hemophilia treatment satisfaction 
(HEMO-SAT), and TNO-AZL preschool quality of life (TAPQOL)
! Health economic impact of N9-GP treatment through characterisation of hospitalisations, 
emergency room visits, missed work and/or school days, and mobility aid requirements
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5
Trial design
5.1
Type of trial
This is an open label, single-arm, multinational non-controlled trial investigating safety, efficacy 
and PK of N9-GP in prophylaxis and treatment of breakthrough bleeding episodes in paediatric 
male patients with haemophilia B. 
The trial consists of a main phase and an extension phase. The duration of the main phase for each 
patient will be minimum 52 weeks. After completion of the main phase, the patients can continue in 
an extension phase. 
For Japan only: The NN7999-3774 trial will be classified as a post-marketing clinical trial if 
obtaining marketing approval in Japan. Therefore, the term ‘chiken’, which is a term for a clinical 
trial conducted for getting marketing approval, is replaced in the protocol and other related
materials/documents with the term ‘post-marketing clinical trial.
The patients will be stratified into two age groups; 0-6 years and 7-12 years. A minimum of 10 
patients in each age group must complete the main phase of the trial with at least 50 EDs. The trial
has one treatment arm where all patients receive N9-GP once weekly for prophylaxis. In the 
extension phase, the same dosing regimen is administered. In addition, N9-GP will be administered 
in case of breakthrough bleeding episodes during the main phase and extension phase.
5.2
Rationale for trial design
The trial design will provide information on safety, efficacy and PK of N9-GP in paediatric 
previously treated patients (PTP) with haemophilia B, aged ≤12 years and a FIX activity level of 
∀2%.
The purpose of the present trial is to provide sufficient exposure to N9-GP to evaluate 
immunogenicity of N9-GP and to provide efficacy and safety data for N9-GP in long-term 
prophylaxis. Prophylaxis of bleeding episodes is cited as the primary goal of therapy in the 
literature and treatment guidelines and must be the goal of all haemophilia care programmes until a 
cure is available9,11,12. Due to a theoretical safety concern regarding PEG, potential clinical effects 
of longer-term exposure to N9-GP with special emphasis on the choroid plexus and the two major 
excretion organs (liver and kidney) will be investigated in more detail : neurological examinations
and neurocognitive assessments as well as laboratory analyses of plasma PEG levels, liver and 
kidney parameters.
The main phase of the trial will generate safety data from at least 50 EDs on each patient collected 
during minimum 52 weeks continuous treatment with measurable FIX activity levels. This number 
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of EDs is as required both by the Food and Drug Administration (FDA) and in the EMA guideline3
for evaluation of immunogenicity of new FIX products and taking potential seasonal differences in 
bleeding patterns into account. One ED is defined as each day a patient is administered FIX for 
prophylaxis, prevention and/or on-demand treatment. 
The trial is not controlled by a placebo group. It is unethical to administer an ineffective treatment 
to patients with haemophilia and the EMA guideline does not require a comparison to placebo3.
There will be no randomisation due to the single-arm nature of the trial. However, the patients will 
be stratified into two age groups at the time of signed informed consent; 0-6 years and 7-12 years, 
both inclusive. Patients belonging to the youngest age group will not be included in the trial before 
PK data from Visit 2 for 5 patients in the 7-12 year age group are evaluated.
The trial design follows current standards for similar trials, and the recently published guideline3
from Committee for Medicinal Products for Human Use (CHMP) of EMA. The EMA guideline 
describes the mandatory components of paediatric trials in patients with haemophilia B.
The rationale for choosing a multinational design is to ensure a sufficient screening pool of patients 
with this rare disorder, to meet local regulatory requirements and to reflect the future patient 
population. 
5.3
Treatment of patients
Around 40 patients will be screened in order to start approximately 24 patients on trial product out 
of which 10 patients in each of the two age groups must complete the main phase of the trial. The 
duration of treatment in the main phase of each patient, from first N9-GP administration to the last 
N9-GP administration, is minimum 52 weeks and at least 50 EDs. The duration of treatment in the 
extension phase is until LPLV. 
The two initial doses of N9-GP will be administered in a hospital setting enabling the patient to be 
observed for potential hypersensitivity reactions. Therefore, all trial sites must be prepared in 
handling hypersensitivity reactions. After the two initial doses of N9-GP have been administered, 
home treatment can be initiated. All patients have previously received at least 50 doses of FIX and 
are by themselves, or helped by parent(s)/caregivers, familiar with or instructed in home treatment 
of both prophylaxis and treatment of bleeding episodes. 
5.3.1
Prophylaxis
All patients will be administered a fixed dose of 40 IU/kg N9-GP once weekly as i.v. injections 
during at least 52 weeks in the main phase of the trial. The dose level chosen is based on modelling 
of data from the phase 1 PK trial (NN7999-3639) and the recommended FIX activity levels 
according to the World Federation of Hemophilia (WFH)9. The regimen is planned to give 
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measurable FIX activity of #1% during the entire prophylaxis period as the aim is to convert severe 
haemophilia to a milder phenotype of haemophilia. 
Fewer administrations than with currently marketed FIX products will be given due to the longer 
plasma half-life of N9-GP. In the main phase, N9-GP must be administered every 7th day %1 day.
Additional prophylactic treatment is not allowed during the main phase of the trial, eg, before
planned physical activity.
5.3.2
Treatment of bleeding episodes
The dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, is a single 
dose of 40 IU/kg since this dose is expected to give a recovery of at least 60-70% FIX activity and 
the FIX activity level 5 days after dosing is still expected to be above 20%. If there is no apparent
effect of 40 IU/kg, the patient or parent(s)/legally authorised representative (LAR) should contact 
the investigator prior to administration of the second dose of 40 IU/kg. A severe bleed should be 
treated immediately at home or at a local emergency room with 80 IU/kg and the trial site must be 
contacted immediately thereafter for further instructions or transport to the trial site. For definition 
of the severity of a bleeding episode, please refer to Section 8.3.4.1. 
5.3.3
Surgery
Minor surgery
Minor surgeries and placement of central venous access ports can be performed while participating 
in this trial by administering an additional dose of 40 IU/kg N9-GP, or aligned to local practice after 
confirmation from sponsor’s medical expert (see Attachment I). The dose level is based on the 
WFH guideline9.
Definition of minor surgery
Minor surgery is defined as an invasive operative procedure where only the skin, the mucous 
membranes or superficial connective tissue is manipulated. Examples of minor surgery include 
implanting pumps in subcutaneous tissue, skin excisions, drainage of abscess or simple dental 
procedures.
Major surgery
Major surgery may be performed during participation in the current trial.
In a separate completed N9-GP surgery trial (paradigm™3) 13 adults and adolescent patients 
underwent major surgery where the haemostatic effect in all study participants was reported as 
either good or excellent and the drug appeared to have a safe and well tolerated profile. 
Major surgery in the current trial should be planned and conducted in accordance with the 
recommendations in the WFH Guidelines for the management of haemophilia9. Determination of 
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dose and dose intervals to achieve adequate haemostasis should include close monitoring of FIX 
activity through and peak levels, consideration of t½ of N9-GP and ongoing evaluation of the 
haemostatic effect.
Major surgery may be performed using general anaesthesia, spinal anaesthesia, epidural 
anaesthesia, conscious sedation, local anaesthesia or with a combination of these modalities. The 
used sedative products should be listed in the concomitant medication.
Further details and requirements when performing major surgery is provided in section 8.3.6.2
Definition of major surgery
Major surgery is defined as any invasive operative procedure that require several days of 
substitution therapy and/or where any one or more of the following occur:
! A body cavity is entered
! A mesenchymal barrier (eg pleura, peritoneum or dura) is crossed
! A fascial plane is opened
! An organ is removed
! When a normal anatomy is operatively altered
! Major elective orthopaedic surgery
5.3.4
Patients continuing into the extension phase
After completion of the main phase, the patient can continue with prophylaxis in the extension
phase until LPLV.
After 10 patients in each of the two age groups (0-6 and 7-12 years of age) have completed the main 
phase, any remaining patients will be offered continued treatment in the extension phase. Data 
collected up to the point where the patient is transferred to the extension phase will be used in the 
analyses of data from the main phase of the trial.
In the extension phase, a single dose of 40 IU/kg once weekly will be administered intravenously. 
5.4
Rationale for treatment
Lack of compliance with a frequent injection schedule is one of the most commonly cited reasons 
for failure of prophylaxis with coagulation factor treatment13. The longer half-life of N9-GP will 
allow for prophylaxis with fewer injections and will presumably result in better compliance.
All patients will be administered a fixed dose of 40 IU/kg N9-GP once weekly as i.v. injections in 
both the main phase and the extension phase of the trial. The dose level is based on modelling of 
data from the phase 1 PK trial (NN7999-3639), from which the two doses levels 10 IU/kg and 40 
IU/kg were chosen for the pivotal trial (NN7999-3747). Although not shown yet in patients with 
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haemophilia B, there is an anticipated higher CL of coagulation factors in children as compared 
with adults, and therefore the higher of the two dose levels has been chosen. This is based on 
published observations in patients with haemophilia A where body weight adjusted CL of 
coagulation factor VIII (FVIII) has been found to decrease with age and/or body weight during 
growth from infancy to adulthood, with a corresponding increase in terminal half-life14.
The maximum dose of N9-GP, based on non-clinical safety data, to be administered to a patient 
within 24 hours is 200 IU/kg, with a maximum individual dose of 80 IU/kg to be administered no 
more frequently than every hour. These doses are only relevant in case of trauma or severe 
bleeding.
Please refer to the IB and any updates hereof for further non-clinical and clinical data8.
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6
Trial population
6.1
Number of patients to be studied
Countries planned to participate: Canada, Germany, Italy, Japan, Malaysia, Taiwan, United 
Kingdom and United States 
Planned number of patients to be screened (ie, documented informed consent): 40
Planned number of patients to be started on trial product: 24
Planned number of patients to complete the main phase of the trial: 20
! Minimum 10 patients must be 7-12 years old at screening 
! Minimum 10 patients must be 0-6 years old at screening 
Planned number of trial sites: 20-30
6.2
Inclusion criteria
1. Informed consent obtained before any trial-related activities. (Trial-related activities are any 
procedure that would not have been performed during normal management of the patient)
2. Male patients with moderately severe or severe congenital haemophilia B with a FIX activity 
level ≤2% according to medical records
3. Age ∀12 years (until patient turns 13 years, at time of inclusion)
4. Body weight ≥10 kg
5. History of at least 50 EDs to other FIX products
6. The patient and/or parent(s)/caregiver are capable of assessing a bleeding episode, keeping an 
eDiary, capable of conducting home treatment and otherwise able to follow trial procedures
6.3
Exclusion criteria
1. Known or suspected hypersensitivity to FIX, hamster protein or related products
2. Previous participation in this trial defined as withdrawal after administration of N9-GP
3. The receipt of any investigational medicinal product (IMP) within 30 days prior to enrolment 
into this trial
4. Documented diagnosis of obesity defined as body mass index (BMI) equal to or greater than the 
95th percentile for age for children ≥2 years (refer to Appendix D)
5. Known history of FIX inhibitors based on existing medical records, laboratory report reviews 
and patient/caregiver interviews
6. Current FIX inhibitors #0.6 BU (central laboratory)
7. Congenital or acquired coagulation disorder other than haemophilia B
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8. Platelet count <50,000/μL at screening (local laboratory)
9. Alanine aminotransferase (ALT) >3 times the upper limit of normal reference ranges at 
screening (central laboratory)
10. Creatinine level #1.5 times above the upper normal limit of normal reference ranges at 
screening (central laboratory)
11. HIV positive, defined by medical records, and with a CD4+ lymphocyte count ∀200/∃L. If the 
patient’s HIV status is unknown or if negative HIV test results in medical records are older than 
one year, it should be tested at the screening visit. If the patient is HIV positive, the CD4+ 
lymphocyte count must be tested
12. Immune modulating or chemotherapeutic medication (except single pulse treatment, inhaled and 
topical steroids)
13. Previous arterial thrombotic events (myocardial infarction and intracranial thrombosis, as 
defined by medical records)
14. Any disease or condition which, according to the investigator’s judgment, could imply a 
potential hazard to the patient, interfere with trial participation or trial outcome
15. Unwillingness, language or other barriers precluding adequate understanding and/or cooperation 
from patients and parent(s)
Patients who are non-compliant with any of the eligibility criteria, but included in the trial, should 
be excluded immediately. If extraordinary circumstances speak in favour of maintaining the patient
in the trial then this is only acceptable if justified and approved by the independent ethics committee 
(IEC)/institutional review board (IRB), and if the regulatory authorities are notified according to 
local requirements.
6.4
Withdrawal criteria
The patient may withdraw at will at any time. The patient’s parent(s) or LAR may withdraw the 
patient from the trial at any time.
The patient may be withdrawn from the trial at the discretion of the investigator or sponsor due to a 
safety concern or if judged non-compliant with trial procedures.
The patient must be withdrawn if the following applies:
1. Development of FIX inhibitors #5 BU confirmed by two consecutive samples at the central 
laboratory
2. Anaphylactic reaction to the trial product (Section 12.1.2)
3. Significant thromboembolic event
4. Incapacity or unwillingness to follow trial procedures
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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UTN: U1111-1119-5013
Status:
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EudraCT No.: 2011-000826-31
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If a patient experiences treatment failure described as more than two bleeding episodes where 
haemostatic response is rated as poor according to Section 8.3.4.1, the investigator should consider 
if it is in the patient’s best interest to continue in the trial.
All data collected prior to withdrawal may be used in the trial analyses if considered relevant by 
Novo Nordisk.
6.5
Patient replacement
Withdrawn patients may be replaced to ensure that 10 patients in each of the two age groups 
complete the main phase of the trial (52 weeks) with at least 50 EDs. It is assumed that minimum 
24 patients must be started on N9-GP to achieve this. However, this may be adjusted during the trial 
based on the actual drop-out rate. 
Re-screening is allowed and patients re-screened in the trial must be provided with a new patient 
number. Patients should be re-screened if the maximum visit window of 8 weeks between Visit 1 
and 2 is exceeded.
6.6
Rationale for trial population
The current trial will enrol patients with haemophilia B as they are the target population for N9-GP 
treatment. The age range is 0-12 years of age, stratified with minimum 10 patients in the age range 
of 0-6 years and minimum 10 patients in the age range of 7-12 years at the time of signing informed 
consent. The patients will count in the age group which they were initially assigned to, even when 
they become older. Since the N9-GP pivotal trial (NN7999-3747) will be conducted in male 
patients 13-70 years of age, N9-GP will be investigated in all age groups, as required by regulatory 
authorities. 
The trial population selection criteria is in line with the guideline developed by CHMP of EMA3.
Children are amongst those who might benefit significantly from prophylaxis. Less frequent 
injections are likely to improve compliance, avoid interruptions of daily life and thereby increase 
the quality of life of the patients.
6.6.1
Rationale for inclusion criteria
! Criterion no. 1 is included in accordance with International Conference on Harmonisation/Good 
Clinical Practice (ICH-GCP).
! Criteria nos. 2, 3 and 5 are included to select the patient group recommended in the EMA 
guideline3.
! Criterion no. 4 is included to protect the patients and is in line with requirements on blood draw 
limits (see Appendix C).
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Trial ID: Trial ID: NN7999-3774
Version:
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Status:
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! Criterion no. 6 is included to ensure enrolment of patients likely to be compliant with the 
protocol, and to preclude enrolment of particularly vulnerable patients.
6.6.2
Rationale for exclusion criteria
! Criteria nos. 1, 4, 11, and 14 are included to prevent unnecessary exposure of potentially fragile 
patients to a new compound.
! Criterion no. 2 is to ensure that a patient only counts once in the data analyses.
! Criteria nos. 3 and 12 are included to minimise any effect of external compounds on the patient's 
coagulation and immune system.
! Criteria nos. 5, and 6 are to prevent exposure of FIX to patients with FIX inhibitors.
! Criteria nos. 7, 8, 9 and 10 are chosen to exclude patients with endogenous abnormalities of the 
coagulation system, other than haemophilia B, and to exclude patients with severely impaired 
liver or kidney function.
! Criterion no. 13 is chosen to minimise the risks of thrombotic manifestations.
! Criterion no. 15 is included to ensure compliance with protocol requirements and to protect the 
patient’s safety.
6.6.3
Rationale for withdrawal criteria
! Criteria nos. 1-5 are included to protect the patient's safety.
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CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
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7
Trial schedule
Planned duration of recruitment period (first patient first visit – last patient first visit): 11 months
All investigators will be notified immediately when the recruitment period comes to an end, after 
which no patients may be screened unless required due to patient withdrawals.
! Planned first trial site ready: 
01-Mar-2012
! Planned date for first patient first visit: 
01-Apr-2012
! Planned date for last patient last visit of main phase: 
01-Apr-2014
! Planned completion of clinical trial report of main phase: 
01-Oct-2014
! Planned date for last patient last visit of extension phase: 
30-Nov-2023
! Planned completion of clinical trial report of extension phase: 
22-May-2024
The trial will end when the last patient has turned 12 years old and has attended a scheduled or EOT 
visit hereafter. The end of the clinical trial is defined as last patient last visit of the extension phase.
Protocol information for this trial will be subject to public disclosure at external web sites 
(www.clinicaltrials.gov, www.clinicaltrialsregister.eu and www.novonordisk-trials.com) according 
to international regulations eg the International Committee of Medical Journal Editors (ICMJE)15, 
the Food and Drug Administration Amendments Act (FDAAA)16 as reflected in Novo Nordisk 
Code of Conduct for Clinical Trial Disclosure.
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CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
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EudraCT No.: 2011-000826-31
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8
Methods and assessments
8.1
Visit procedures
Figure 8-1
Overview of visits
The trial consists of a main phase (Visit 1 – Visit 11) and an extension phase (Visit 12 – EOT visit). Around 40 patients 
will be screened to start approximately 24 patients on trial product out of which at least 10 patients in each of the two 
age groups must complete the main phase of the trial. A PK profile must be obtained for all patients at Visit 2. After 
Visit 3, there will be home treatment periods with dosing once weekly between the visits to the trial site. Patients 
withdrawn during the main phase, or patients not continuing in the extension phase, will be scheduled for a follow-up 
visit (FU). This will be the end of trial visit for these patients.
disp: Interim dispensing of N9-GP trial drug for home treatment
a:
Between V15 and V17, a subset of patients will be requested to attend an additional visit with 
procedures and assessments identical to visit 16. If applicable the visit may be planned by the investigator to coincide 
with the interim dispensing of N9-GP (see Table 2-3 and section 8.1.7).
The main phase of the trial consists of the following visits:
Visit 1: Screening visit.
Patients in the youngest age group (0-6 years) will not be included before PK data from Visit 2 for 5 
patients in the 7-12 years age group are evaluated.
Visit 2: Dosing and PK visit at the trial site.
The patients will have an initial dose of N9-GP at the trial site and will undergo a PK session. The 
patients will have to return to the trial site 4 times during the following 7 days.
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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UTN: U1111-1119-5013
Status:
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Visit 3: Dosing visit at the trial site.
The second dose of N9-GP will be administered at the trial site after the last PK sample of Visit 2 
has been collected. If a bleeding episode occurs between the first and second dose, the patient 
should come to the clinic for treatment with N9-GP. 
Visit 4-10: Dosing visits at the trial site. 
Visit 11: End of main phase. 
Patients, not continuing in the extension phase, will be scheduled for a follow-up visit. Patients 
continuing in the extension phase will be dosed with N9-GP when assessments of Visit 11 are 
completed.
Follow-up visit (FU): Inhibitor testing for patients who are withdrawn or not continuing in the 
extension phase of the trial. 
Inhibitor follow-up visit 1-3 (IFU1-3): Conditional inhibitor follow-up visits, which must be 
conducted if FIX inhibitors are developed or suspected.
The extension phase of the trial consists of the following visits:
Visit 12-17 + Visit X (X = 18 and onwards): Dosing visits at the trial site.
End of trial (EOT) visit: Inhibitor testing for patients who are withdrawn from, or completing the 
extension phase of the trial.
Inhibitor follow-up visit 1-3 (IFU1-3): Conditional inhibitor follow-up visits, which must be 
conducted if high titre FIX inhibitors (#5 BU) are identified.
For a detailed schematic overview of the trial visits and assessments, please refer to the flow charts 
in Section 2 and the trial diagram (Figure 8-1). Procedures of the trial visits are described in detail 
in Sections 8.1.1 to 8.1.10.
It must be stated in the medical records that the patient is participating in the trial. Patients enrolled 
will be provided with a card stating that they are participating in the trial, with contact addresses 
and telephone numbers. The patient and parent(s)/LAR should be instructed to return the card to the 
investigator or destroy the card after the last trial visit.
Screening and enrolment log
The investigator must keep a subject identification list as well as a subject screening and subject 
enrolment log (these may be combined in one document). 
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CONFIDENTIAL
Date:
27 June 2018
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Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
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Informed consent procedure
The patient’s parent(s) and/or caregiver(s) (ie, LAR for the patient) will be provided with full 
written and verbal information about the trial prior to conduct of any trial-related 
procedures/activities, in accordance with GCP and local requirements. The information will include, 
eg, descriptions of N9-GP, the procedures involved, the practical implications of participating, 
responsibilities and rights while participating in the trial including the possible advantages and 
disadvantages. Patients and parent(s)/LAR will have the opportunity to ask questions and have 
ample time to consider participation. If the patient wishes to participate, the parent(s)/LAR will be 
requested to sign and date the informed consent form. This must be done prior to any trial-related 
activities, ie, procedures that would not have been performed during normal management of the 
patient. The patient should sign a child assent form if capable, and if required by local requirements. 
It must be emphasised that any change in a patient’s normal treatment routine is a trial-related 
activity which is not allowed before informed consent has been given. For example; if a patient is 
taken off prophylaxis to allow for 4 days without FIX treatment before screening and the interval 
between the patient’s normal prophylactic doses is less than 4 days, it is a trial related activity. In 
such case, it is essential that the informed consent procedure is completed prior to the trial-related 
activities.
Screening failures
Screening failures are defined as patients for whom the parent(s)/LAR have signed the Informed 
Consent Form, but fail to comply with the inclusion and exclusion criteria or if the consent is 
withdrawn prior to dosing. Data in respect to the screening visit (Visit 1) will be entered in the 
screening failure form in the electronic case report form (eCRF). A screening failure call must be 
made in the interactive voice/web response system (IV/WRS). Serious and non-serious AEs from 
screening failures will be entered by the investigator in the eCRF, and consequently transferred to 
the clinical database. When the trial related procedures have been finalised for screening failures, no 
more AEs should be entered in the eCRF. Follow-up of AEs should be made according to Section 
12. 
For withdrawn patients
Withdrawn patients are defined as patients who meet the withdrawal criteria after dosing, see 
Section 6.4. In case a patient is being prematurely withdrawn from the trial the investigator must 
aim to undertake the procedures for the last visit as soon as possible, if possible. If the patient is
withdrawn prior to Visit 11, an end of main phase visit (Visit 11) and a follow-up (FU visit) should 
be scheduled, and if the patient is withdrawn after Visit 11, an EOT visit should be scheduled. The 
primary reason (AE, non-compliance with protocol or other) for discontinuation must be specified 
in the eCRF. The end of trial form must be completed, final drug accountability must be performed 
and the case book must be signed, even if the patient is not able to attend. All data collected in the 
period the patient participated in the trial will be entered into the eCRF. A withdrawal session must 
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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Status:
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EudraCT No.: 2011-000826-31
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be performed in IV/WRS. If a patient is withdrawn due to inhibitor development, the patient must 
be followed according to Section 8.1.9.
End of trial (EOT) visit
The end of trial form should be signed at the EOT visit or the last visit of the patient. If a patient 
continues in FU or IFU the end of trial form will be signed at the FU visit or the last IFU visit. If a 
patient is withdrawn prior to completion of the trial, all attempts must be made to schedule an end 
of trial visit for the patient. For patients not proceeding into the extension phase, the FU visit will be 
the end of trial. 
8.1.1
Visit 1 - screening visit
Before enrolment in the trial and prior to conduct of any trial-related procedures/activities, the 
parent(s) and/or LAR of the patient must have signed the informed consent form after having 
received written and verbal information about the trial. The patient should sign a child assent form 
if capable, and if required by local requirements. This can be performed on a separate day.
The laboratory assessments of Visit 1 should be scheduled at least 4 days after the last 
administration of coagulation factor products. If the interval between the patient’s normal 
prophylactic doses is less than 4 days, this is considered as a trial-related activity. The visit must be 
rescheduled, if the patient has been administered coagulation factor products within 4 days prior to 
the planned laboratory assessments of Visit 1.
If the patient is enrolled in the trial, the patient will receive a unique patient number, which will be 
assigned to the patient throughout the trial.
If at all possible, planned vaccinations should be postponed beyond the first three months of N9-GP 
treatment.
Prior to any assessments (laboratory and clinical) at Visit 1, baseline PRO data must be collected.
The patient should be registered for screening by the use of IV/WRS.
At Visit 1 the following assessments will be performed and/or recorded in the eCRF:
! Informed consent form, signed, dated including time, see Section 19.1
! Consent to genotyping (if applicable), see Section 8.8.9 and 19.1
! Inclusion and exclusion criteria, see Section 6.2 and 6.3
! PRO questionnaires, see Section 8.3.1
! Demography, see Section 8.3.2
! Concomitant illness, see Section 8.3.3
! Medical history including haemophilia treatment history and details on haemophilia and 
inhibitors and joints, see Section 8.3.3.1
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CONFIDENTIAL
Date:
27 June 2018
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Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
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EudraCT No.: 2011-000826-31
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! Medical records of HIV and hepatitis C virus (HCV) status. If HIV and/or HCV positive, or if 
negative test results are older than one year, or if status is unknown, see Section 8.8.8
! CD4+ lymphocyte count, if HIV positive, see Section 8.8.8
! F9 genotype documentation (if applicable), see Section 8.8.9 and 19.1
! Concomitant medication, see Section 11
! Date and time of last coagulation factor administration 
! Assessments of bleeding episodes (date, severity and location), if any, within the 4 days without 
FIX treatment, see Section 8.3.4
! Adverse events, see Section 12.1
! Body measurements, see Section 8.5.1
! Physical examination, see Section 8.5.2
! Vital signs, see Section 8.5.4
Blood sampling for local laboratory assessments:
! Haematology, see Section 8.7.1
Blood sampling for central laboratory assessments:
! Biochemistry, see Section 8.8.1
! FIX activity, see Section 8.8.4
! FIX inhibitors, see Section 8.8.5.2
! Viral assessments:
!
HIV, see Section 8.8.8. If the patient’s HIV status is unknown or if negative HIV test 
results in medical records are older than one year, please await the central laboratory HIV 
test. If the patient’s HIV status, in medical records, is positive or the central laboratory HIV
test is positive, await the CD4+ lymphocyte count before determining whether or not the 
patient is eligible for the trial
!
HCV, see Section 8.8.8. If the patient’s HCV status is unknown or if negative HCV test 
results in medical records are older than one year, anti-HCV antibodies should be tested by 
the central laboratory. If the patient’s HCV status, in medical records, is positive or the 
central laboratory anti-HCV antibodies test is positive, HCV RNA should be tested
! F9 genotype, if consent is given and documentation is not available in medical records, as 
allowed per local regulations, see Section 8.8.9
! Lupus anticoagulant, see Section 8.8.10
All results necessary for evaluating the inclusion and exclusion criteria, from local and central 
laboratory analyses must be available before determining whether or not the patient can continue in 
the trial in accordance with inclusion and exclusion criteria.
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Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
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Dosing with the patient’s previous FIX product (only for patients without recovery data in 
medical records):
If no recovery data for the patient’s previous FIX product exist in medical records, or if the data is 
older than one year or the recovery sample is collected more than one hour after completed dosing, 
the patient should be dosed with his product at Visit 1 and a recovery sample should be collected. 
This can be done anytime in the period from informed consent and until 4 days prior to the 
laboratory assessments of Visit 1 or directly after all laboratory assessments of Visit 1 have been 
completed and until 4 days prior to the planned Visit 2. 
Post-dose blood sampling for central laboratory assessments after dosing with patient’s 
current product (only for patients without recovery data in medical records):
! FIX recovery: 30 minutes (%10 minutes), see Section 8.8.3
The blood sample taken 30 minutes (%10 minutes) post-dose must not be taken from the same vein 
as used for administration of the patient’s current product.
Training and reminders:
! Dispense trial card, see Section 8.10.1
! An appointment for Visit 2 should be made within four to eight weeks of Visit 1
! A confirmation call in the IV/WRS as soon as the patient is deemed eligible for the trial but no 
later than two weeks prior to the planned Visit 2, see Section 10
! Patient should withhold treatment with coagulation factor products 4 days prior to Visit 2. 
Otherwise, Visit 2 should be rescheduled
! Patients should be reminded that Visit 2 will consist of 5 visit-days to the site during a period of 
8 days
! If possible, planned vaccinations should be postponed beyond the first three months of N9-GP 
treatment
8.1.2
Visit 2 
Visit 2 should preferably take place four to eight weeks after the screening visit (Visit 1). 
The visit should be rescheduled if any of the following applies:
! Major surgery within one month prior to the first planned injection of N9-GP 
! Use of coagulation factors within 4days prior to the first injection of N9-GP 
! Subjective signs of illness or fever within 48 hours prior to the first injection of N9-GP
The patients will be administered their first dose of N9-GP and a 30 minutes post-dose sample will 
be collected. Four PK samples will be collected at 4 different days during the following 7 days. The 
blood samples and assessments to be performed are outlined in Table 2-2. 
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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Status:
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The following will be performed and/or recorded in the eCRF:
Pre-dose assessments to be made before the first dose of N9-GP at the day of dosing:
! Confirmation of inclusion and exclusion criteria, see Section 6.2 and 6.3
! Withdrawal criteria, see Section 6.4
! Concomitant medication, see Section 11
! Date and time of last coagulation factor administration
! Assessments of bleeding episodes (date, severity and location), see Section 8.3.4
! Adverse events, see Section 12.1
! Body measurements (body weight only), see Section 8.5.1
! Vital signs, see Section 8.5.4
Pre-dose sampling for local laboratory assessments to be taken within 1 hour prior to dosing:
! Haematology, see Section 8.7.1
Pre-dose blood sampling for central laboratory assessments to be taken within 1 hour prior to 
dosing:
! Coagulation-related parameters, see Section 8.8.2
! FIX activity, see Section 8.8.4
! N9-GP/FIX antibodies, see Section 8.8.5.1
! FIX inhibitors, see Section 8.8.5.2
! HCP antibodies, see Section 8.8.6
! Allergic reaction testing, see Section 8.8.7
First N9-GP administration:
! Administration of 40 IU/kg N9-GP
! Stop time of injection must be recorded, this corresponds to time point = 0
! Precautions to take when injecting the initial doses of N9-GP, see Section 8.9
Post-dose assessments after the first dose of N9-GP:
! Concomitant medication, see Section 11
! Assessments of bleeding episodes including date, see Section 8.3.4
! Adverse events, see Section 12.1
! Vital signs: 60 minutes (% 10 minutes), see Section 8.5.4
Post-dose blood sampling for local laboratory assessments after the first dose of N9-GP:
! Haematology: 168 hours ( ±24 hours), see Section 8.7.1
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Date:
27 June 2018
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Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
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EudraCT No.: 2011-000826-31
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Post-dose blood sampling for central laboratory assessments after the first dose of N9-GP:
! Coagulation-related parameters: 168 hours ( ±24 hours), see Section 8.8.2
! FIX activity: 30 minutes (%10 minutes), 24 hours (+8 hours), 48 hours (±8 hours), 96 hours 
(±8 hours) and 168 hours (±24 hours), see Section 8.8.4
! N9-GP/FIX antibodies: 168 hours (±24 hours), see Section 8.8.5.1
! FIX inhibitors: 168 hours (±24 hours), see Section 8.8.5.2
The blood sample taken 30 minutes (%10 minutes) post-dose must not be taken from the same vein 
as used for administration of N9-GP.
Training:
! Home treatment/eDiary training, see Sections 8.3.7, 8.9 and 8.10.2
IV/WRS:
! Drug accountability of trial product at Visit 2 must be recorded in the IV/WRS, see Section 10
! Recording of body weight and dispensing of N9-GP for site dosing via IV/WRS, see Section 10
Reminders:
! An appointment for Visit 3 should be made. The second dose of N9-GP (Visit 3) should be 
administered directly after the last assessments of Visit 2 are completed
! If a bleeding episode occurs during Visit 2 or in the period between Visit 2 and 3, the patient 
should come to the trial site for treatment with N9-GP. If a bleeding episode, requiring treatment, 
occurs within 96 hours after N9-GP administration, the patient can be rescheduled for a new PK 
evaluation at any later visit during the main phase of the trial if deemed appropriate by the 
investigator
! If possible, planned vaccinations should be postponed beyond the first three months of N9-GP 
treatment
8.1.3
Visit 3 
Visit 3 should take place directly after Visit 2, preferably on the same day as the 168 hour post-dose 
assessments of Visit 2 are completed.
The following will be performed and/or recorded in the eCRF:
Pre-dose assessments to be made before the second dose of N9-GP at the day of dosing:
! Withdrawal criteria, see Section 6.4
! Concomitant medication, see Section 11
! Assessments of bleeding episodes (date, severity and location), see Section 8.3.4
! Adverse events, see Section 12.1
! Vital signs, see Section 8.5.4
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Protocol
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Date:
27 June 2018
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Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
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EudraCT No.: 2011-000826-31
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Second N9-GP administration (6-8 days after first N9-GP dose):
! The second dose should be administered after all 168 hours post-dose assessments of Visit 2 are 
completed
! Administration of 40 IU/kg N9-GP
! Stop time of injection must be recorded
! Precautions to take when injecting the initial doses of N9-GP, see Section 8.9
Post-dose assessments after the second dose of N9-GP:
! Adverse events, see Section 12.1
! Vital signs: 60 minutes (% 10 minutes), see Section 8.5.4
Training:
! Home treatment/eDiary training, see Sections 8.3.7, 8.9 and 8.10.2
IV/WRS:
! Drug accountability of trial product at Visit 3 must be recorded in the IV/WRS, see Section 10
! Recording of body weight and dispensing of N9-GP for site dosing/home treatment must be 
performed via IV/WRS, see Section 10
Reminders:
! N9-GP dispensing for home treatment
! eDiary dispensing, see Section 8.10.3
! An appointment for Visit 4 (3 weeks±1week) should be made
! Remember telephone contact with the patient halfway through the home treatment period 
between visits (%1 week), see Section 8.10.4
! If possible, planned vaccinations should be postponed beyond the first three months of N9-GP 
treatment
8.1.4
Visit 4 to Visit 10
The home treatment periods are:
! 3 weeks±1 week between Visit 3 and 4
! 4 weeks±1 week between Visit 4, 5 and 6
! 8 weeks±1 week between Visit 6, 7, 8, 9 and 10
! 8 weeks+2 weeks between Visit 10 and 11
The following will be performed and/or recorded in the eCRF:
Pre-dose assessments at the day of dosing:
! Withdrawal criteria, see Section 6.4.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
53 of 135
! Concomitant medication, see Section 11
! Assessments of bleeding episodes (date, severity and location), see Section 8.3.4. Any new 
bleeding episodes detected or bleeding episodes recorded in the eDiary, considered as severe, 
should be entered in the eCRF
! Compliance review of drug administration and eDiary completion, see Sections 8.3.7
! Adverse events since previous visit, see Section 12.1
! Body measurements (body weight, Visit 7, 8, 9 and 10 only), see Section 8.5.1
! Physical examination (Visit 8 only), see Section 8.5.2
Pre-dose blood sampling for central laboratory assessments to be taken within 1 hour prior to 
dosing:
! FIX activity, see Section 8.8.4
! N9-GP/FIX antibodies, see Section 8.8.5.1
! FIX inhibitors, see Section 8.8.5.2
N9-GP administration:
! Administration of 40 IU/kg N9-GP, see Section 8.9
! Stop time of injection must be recorded, this corresponds to time point = 0
Post-dose assessments:
! Adverse events, see Section 12.1
Post-dose blood sampling for central laboratory assessments to be taken 30 minutes (%10 
minutes) after dosing:
! FIX activity, see Section 8.8.4
The blood sample taken 30 minutes (%10 minutes) post-dose must not be taken from the same vein 
as used for administration of N9-GP.
IV/WRS:
! Drug accountability for all the products dispensed, or any product returned from the previous 
visits, must be recorded in IV/WRS, see Section 10
! Recording of body weight and dispensing of N9-GP for site dosing/home treatment must be 
performed via IV/WRS, see Section 10
Training:
! Home treatment/eDiary training, if the site suspects that the patient is not fully confident with 
self administration and how to deal with safety related signs and symptoms, see Sections 8.3.7, 
8.9 and 8.10.2
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
54 of 135
Reminders for each visit: 
! An appointment for the next visit should be made
! N9-GP dispensing for home treatment
! Remember telephone contact with the patient halfway through each home treatment period 
between visits (%1 week), see Section 8.10.4
8.1.5
Visit 11 - end of main phase
Visit 11 can be scheduled as soon as the patient has been in 52 weeks of prophylactic treatment with 
N9-GP. In case the patient has been treated with N9-GP within 6 days prior to the planned Visit 11, 
the visit should be postponed. 
The following will be performed and/or recorded in the eCRF:
! Withdrawal criteria, see Section 6.4
! PRO questionnaires, see Section 8.3.1
! Concomitant medication, see Section 11
! Assessments of bleeding episodes (date, severity and location), see Section 8.3.4. Any new 
bleeding episodes detected or bleeding episodes recorded in the eDiary, considered as severe, 
should be entered in the eCRF
! Compliance review of drug administration and eDiary completion, see Section 8.3.7
! Adverse events since previous visit, see Section 12.1
! Body measurements (retrospective height at visit 11 will be collected if available in medical 
records ± 3 months from visit and consent obtained), see Section 8.5.1
! Physical examination, see Section 8.5.2
! Vital signs, see Section 8.5.4
Pre-dose blood sampling for local laboratory assessments:
! Haematology, see Section 8.7.1
Pre-dose blood sampling for central laboratory assessments:
! Biochemistry, see Section 8.8.1
! Coagulation-related parameters, see Section 8.8.2
! FIX activity, see Section 8.8.4
! N9-GP/FIX antibodies, see Section 8.8.5.1
! FIX inhibitors, see Section 8.8.5.2
! HCP antibodies, see Section 8.8.6
! Allergic reaction testing, see Section 8.8.7
N9-GP administration (only for patients continuing in the extension phase):
! Administration of 40 IU/kg N9-GP, see Section 8.9
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
55 of 135
Post-dose assessments (only for patients continuing in the extension phase):
! Adverse events, see Section 12.1
IV/WRS (only for patients continuing in the extension phase):
! Drug accountability for all the products dispensed, or any product returned from the previous 
visits, must be recorded in IV/WRS, see Section 10
! Recording of body weight and dispensing of N9-GP for site dosing/home treatment must be 
performed via IV/WRS, see Section 10
IV/WRS (only for patients not continuing in the extension phase):
! Drug accountability for any product returned from the previous visits, must be recorded in 
IV/WRS, see Section 10
! Perform a completion session in IV/WRS, see Section 10
Training (only for patients continuing in the extension phase):
! Home treatment/eDiary training; if the site suspects that the patient is not fully confident with 
self-administration and how to deal with safety related signs and symptoms, see Sections 8.3.7, 
8.9 and 8.10.2
Reminders (only for patients not continuing in the extension phase): 
! eDiary collection, see Section 8.10.3
! An appointment for a follow-up visit should be made within 3 weeks±1 week
! Treatment with N9-GP is ended
! After this visit, the patient can be treated with other coagulation factors than N9-GP according to 
standard practice 
! The patient should not be treated with any coagulation factors within 4 days before the FU visit
Reminders (only for patients continuing in the extension phase): 
! An appointment for Visit 12 (3 months±2 weeks) should be made
! N9-GP dispensing for home treatment. 
! Remember telephone contact with the patient halfway through the home treatment period (%1
week), see Section 8.10.4
8.1.6
Follow-up visit
This follow-up visit is for patients who are withdrawn during the main phase or not continuing in 
the extension phase. The visit should take place 3 weeks%1 week after Visit 11.
If FIX inhibitors are identified at this visit the patient should attend inhibitor follow-up visits, please 
refer to Section 8.1.9.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
56 of 135
If a bleeding episode occurs within 4 days prior to the planned FU visit, and the patient has been 
treated with coagulation factors, the visit should be postponed.
The following will be performed and/or recorded in the eCRF:
! Concomitant medication, see Section 11
! Date and time of last coagulation factor administration
! Assessments of bleeding episodes (date, severity and location), see Section 8.3.4
! Adverse events since previous visit, see Section 12.1
! End of trial form
Blood sampling for central laboratory assessments:
! FIX activity, see Section 8.8.4
! N9-GP/FIX antibodies, see Section 8.8.5.1
! FIX inhibitors, see Section 8.8.5.2
Reminder:
! Follow up on any AEs according to Section 12.2.1
8.1.7
Visit 12 to Visit 32+
Visit 12 to Visit 32+ are scheduled 6 months %2 weeks apart, with the reference to when visit 11 
took place. 
Between V15 and V17, a subset of patients will be requested to attend an additional visit. 
Procedures and assessments will be identical to visit 16. If applicable the visit may be planned by 
the investigator to coincide with the interim dispensing of N9-GP halfway in-between two visits. 
Novo Nordisk will inform relevant investigators who in turn should schedule the visit date with the 
affected patients.
.
The home treatment periods are:
! 3 months±2 weeks between Visit 11, 12 and 13.
! 6 months±2 weeks between Visit 13, 14, 15, 16, 17 and up to 32+. The amount of N9-GP 
dispensed at each visit corresponds to approximately 3 months of home treatment. Halfway in-
between two visits additional N9-GP should be dispensed for further 3 months home treatment. 
The patient is not required to attend the clinic only for N9-GP interim dispensing.
The following will be performed and/or recorded in the eCRF:
Pre-dose assessments:
! Withdrawal criteria, see Section 6.4
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
57 of 135
! PRO questionnaires (visit 17 only), see Section 8.3.1
! Concomitant medication, see Section 11
! Assessments of bleeding episodes (date, severity and location), see Section 8.3.4. Any new 
bleeding episodes detected or bleeding episodes recorded in the eDiary, considered as severe, 
should be entered in the eCRF
! Compliance review of drug administration and eDiary completion, see Section 8.3.7
! Adverse events since previous visit, see Section 12.1
! Body measurements, see Section 8.5.1
! Physical examination, see Section 8.5.1
! Neurological examination, see Section 8.5.2.1
! Neurocognitive assessments, see Section 8.5.3
! Vital signs (Visit 12 and EOT), see Section 8.5.4
Pre-dose blood sampling for central laboratory assessments:
! Biochemistry, see Section 8.8.1
! N9-GP/FIX antibodies, see Section 8.8.5.1
! FIX inhibitors, see Section 8.8.5.2
! FIX activity, see section 8.8.4
! HCP antibodies, see Section 8.8.6
! PEG, see Section 8.8.12
! Biospecimens for storage, if applicable (visit 13, 15, 17, etc), see section 8.8.13 and 25.1
! Urinalyses, see Section 8.8.11
N9-GP administration (either at the trial site or at home after the visit):
! Administration of 40 IU/kg of N9-GP, see Section 8.9
! The date and the actual time of completion of the injection must be recorded in the eCRF or 
patient eDiary
Post-dose assessments (only if the patient is dosed at the trial site):
Adverse events, see Section 12.1
IV/WRS:
! Drug accountability for all the products dispensed or any product returned from the previous 
visit must be recorded in IV/WRS, see Section 10
! Recording of body weight and dispensing of N9-GP for site dosing/home treatment must be 
performed via IV/WRS, see Section 10
Training and reminders:
! An appointment for the next visit should be made
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
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! N9-GP dispensing for home treatment
! Remember contact with the patient halfway through each home treatment period (%1 week), see 
Section 8.10.4
! Home treatment/eDiary training (if applicable), see Section 8.10.2
! The EOT visit should be scheduled minimum 6 days after the last N9-GP administration
8.1.8
End of trial visit
End of Trial visit should take place within the 2 months prior to the End of Trial date listed in 
section 7. The End of Trial visit may replace a scheduled visit if last scheduled visit took place 6 
months ago. 
If a bleeding episode occurs prior to the EOT visit, and the patient is treated with N9-GP, the visit 
should be postponed with at least 6 days.
The following will be performed and/or recorded in the eCRF:
! Withdrawal criteria, see Section 6.4
! Concomitant medication, see Section 11
! Assessments of bleeding episodes (date, severity and location), see Section 8.3.4. Any new 
bleeding episodes detected or bleeding episodes recorded in the eDiary, considered as severe, 
should be entered in the eCRF
! Compliance review of drug administration and eDiary completion, see Section 8.3.7
! Adverse events since previous visit, see Section 12.1
! Body measurements, see Section 8.5.1
! Physical examination, see Section 8.5.2
! Neurological examination, see section 8.5.2.1
! Neurocognitive assessments, see section 8.5.3
! Vital signs, see Section 8.5.4
! End of trial form
Blood sampling for local laboratory assessments:
! Haematology, see Section 8.7.1
Blood sampling for central laboratory assessments:
! Biochemistry, see Section 8.8.1
! FIX activity, see Section 8.8.4
! N9-GP/FIX antibodies, see Section 8.8.5.1
! FIX inhibitors, see Section 8.8.5.2
! HCP antibodies, see Section 8.8.6
! PEG, see Section 8.8.12
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
59 of 135
! Allergic reaction testing, see Section 8.8.7
! Biospecimens for storage, if applicable, see section 8.8.13 and 25.1
! Urinalyses, see Section 8.8.11
IV/WRS:
! Drug accountability for any product returned from the previous visit must be recorded in 
IV/WRS, see Section 10
! Perform a completion session in IV/WRS, see Section 10
Reminder:
! eDiary collection, see Section 8.10.3
8.1.9
Inhibitor follow-up visit 1-3 
The inhibitor follow-up visits should only be conducted if a new high titre FIX inhibitor (#5 BU) is 
identified and confirmed at an assessment visit or unscheduled visit by the central laboratory. As 
soon as possible after this has been confirmed, the N9-GP treatment should be stopped and the 
patient scheduled for an end of trial visit (Visit 11, if during the main phase, or EOT visit, for the 
extension phase). The end of trial visit should preferably be performed prior to initiation of 
treatment with another FIX product. The first IFU visit must be scheduled 4 weeks±1 week after the 
end of trial visit and the patient must, as a minimum, attend three inhibitor follow-up visits (IFU1-3) 
with 4 week±1 week intervals. Additional follow-up visits may be arranged at intervals as long as 
clinically warranted. 
In case the patient has been treated with coagulation factors within 4 days prior to the first inhibitor 
follow up visit (IFU1), the visit must be postponed, please also refer to Section 8.8.5.2 for further 
details.
If low titre inhibitors (<5 BU) are identified and confirmed by the central laboratory during the 
main phase, the patient is allowed to continue with N9-GP treatment. In this case, the patient should 
be scheduled for Visit 11, and thereafter proceed into the extension phase. If low titre inhibitors are 
detected during the extension phase, the patient can continue as planned.
The following will be performed and/or recorded in the eCRF:
! Concomitant medication, see Section 11
! Date and time of last coagulation factor administration
! Adverse events, see Section 12.1
! End of trial form (at the last visit)
Blood sampling for central laboratory assessments:
! Biochemistry, see Section 8.8.1
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
60 of 135
! FIX activity, see Section 8.8.4
! N9-GP/FIX antibodies, see Section 8.8.5.1
! FIX inhibitors, see Section 8.8.5.2
! HCP antibodies, see Section 8.8.6
! PEG, see Section 8.8.12
! Allergic reaction testing, see Section 8.8.7
! Urinalyses, see Section 8.8.11
Reminder:
! Follow up on any AEs according to Section 12.2.1
8.1.10
Unscheduled visits 
It is possible to perform unscheduled visits during the trial. An unscheduled visit can be performed 
any time after the enrolment and until the end of trial visit, either as a telephone visit or a site visit. 
Patients can attend an unscheduled visit due to a bleeding episode, suspicion of inhibitor 
development, any AE, or sampling for laboratory tests etc.
Visits/contacts with the site regarding non-trial related activities do not need to be reported as an 
unscheduled visit.
The following can be performed at an unscheduled visit, if deemed relevant:
! Withdrawal criteria, see Section 6.4
! Concomitant medication, see Section 11
! Date and time of last dose of coagulation factor prior to an unscheduled visit 
! Assessments of bleeding episodes (date, severity and location), see Section 8.3.4
! Health economic resource use: where treatment for a severe bleed occurred, how the patient 
arrived at the treatment facility (eg, ambulance), and general and intensive care ward 
hospitalisation days 
! Compliance review of drug administration and eDiary completion, see Section 8.3.7
! Adverse events since previous visit, see Section 12.1
! Body measurements, see Section 8.5.1
! Physical examination, see Section 8.5.2
! Vital signs, see Section 8.5.4
! Haematology, see Section 8.7.1
! Biochemistry, see Section 8.8.1
! Coagulation-related parameters, see Section 8.8.2
! FIX activity, see Sections 8.7.2 (local laboratory) and 8.8.4 (central laboratory)
! N9-GP/FIX antibodies, see Section 8.8.5.1
! FIX inhibitors, see Section 8.8.5.2
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
61 of 135
! HCP antibodies, see Section 8.8.6
! PEG, see Section 8.8.12
! Allergic reaction testing, see Section 8.8.7
! Viral antibody test (HIV and/or HCV), see Section 8.8.8
! CD4+ lymphocyte count, see Section 8.8.8
! HCV RNA, see Section 8.8.8
! F9 genotype testing, see Section 8.8.9
! Lupus anticoagulant, see Section 8.8.10
! Urinalyses, see Section 8.8.11
! Administration of N9-GP, see Section 8.9
! Dispensing of N9-GP for site dosing/home treatment must be performed via IV/WRS, see 
Section 10
! Home treatment/eDiary training, see Sections 8.9, 8.10.2 and 8.3.7
! Drug accountability of N9-GP, see Section 10
! eDiary dispensing, see Section 8.10.3
! eDiary collection, see Section 8.10.3
! Surgery, see Section 8.3.6.1 and 8.3.6.2
! Biospecimens for storage (if applicable)  see section 8.8.13
8.2
Home treatment 
Home treatment with administration of N9-GP can start after N9-GP administrations have been 
performed in the trial site at Visit 2 and Visit 3, but may be postponed until the patient and/or the 
patient’s parent(s)/caregiver are comfortable with the reconstitution and administration process. A 
caregiver is a close person who helps the patient in his daily life. It is not the investigator or the site 
staff.
8.2.1
Prophylactic home treatment
The dose for prophylaxis during the main phase is 40 IU/kg once weekly (% 1 day). In the extension 
phase of the trial the same dosing regimen is administered.
In case a patient has treated a bleeding episode on a day not planned for prophylaxis dosing, the 
next prophylactic dose should still be taken on the planned day. If a bleeding episode occurs earlier 
on the same day as the planned prophylaxis, the dose should be registered for the bleeding episode 
and not as prophylaxis and the planned prophylaxis dose later same day should be omitted. When a 
prophylaxis dose has been taken and if a bleeding episode occurs later the same day, the bleeding 
episode should be treated and registered independent of the prophylaxis dose. 
Bleeding episodes must be treated as described in Section 8.2.2.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
62 of 135
The following procedures and assessments must be performed:
! N9-GP administrations once weekly (every 7th day ±1 day), during the extension phase
! Adverse events calls by the investigator/medically qualified person halfway through the home 
treatment period (%1 week)
! Completion of the patient eDiary, including details of all bleeding episodes and N9-GP 
administrations (see Section 8.3.7)
If an individual patient has not reached 50 EDs after 52 weeks continuous treatment, the trial 
participation should be prolonged further until at least 50 EDs are reached. This will be done by 
extending the home treatment period between Visit 10 and Visit 11.
8.2.2
Home treatment of bleeding episodes
Bleeding episodes must be treated as soon as identified. The dose for treatment of an uncomplicated 
mild/moderate bleeding episode, for example a joint bleed, is a single dose of 40 IU/kg. At steady 
state, this dose is expected to give a recovery of at least 60-70% FIX activity and the activity level 5
days after dosing is still expected to be above 20%. If there is no observed effect of 40 IU/kg, the 
patient or parents(s)/LAR should contact the investigator prior to administration of the second dose 
of 40 IU/kg.
A severe bleeding episode should be treated immediately at home, at the trial site or at a local 
emergency room with 80 IU/kg. If treated at home, the trial site must be contacted immediately for 
further instructions or transport. 
Patients and parents(s)/caregiver are instructed by the investigator how to treat themselves for a 
bleeding episode at home and how to record this in the eDiary.
The following procedures and clinical assessments must be performed:
! N9-GP administration for treatment of any bleeding episodes
! Completion of the patient eDiary, including details of all bleeding episodes and N9-GP 
administrations (see Section 8.3.7)
8.3
Patient related information
8.3.1
Patient reported outcomes and health economic assessments
Patient reported outcomes will be assessed at Visit 1, Visit 11, Visit 17 and Visit 22/23/24 (the 
relevant visit where neurocognitive assessments are performed for the first time for each patient) . 
The questionnaires should preferably be completed before any other trial-related activities during 
these visits.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
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Several questionnaires will be used to assess disease and age-group specific quality of life and 
treatment satisfaction. 
The following questionnaires should be completed by the patient and/or parent(s)/LAR:
For patients below the age of 4:
! TAPQOL children; Questionnaire for parents (6 months–6 years)
For patients aged 4-7: 
! HAEMO-QOL; Questionnaire for children I (4-7 years, to be read to the child)
! HAEMO-QOL parents; Questionnaire for parents I (4-7 years)
! HEMO-SAT parents; Questionnaire for parents
For patients aged 8-12: 
! HAEMO-QOL; Questionnaire for children II (8-12 years)
! HAEMO-QOL parents; Questionnaire for parents II (8-12 years)
! HEMO-SAT parents; Questionnaire for parents
The PRO questionnaires are disease and age-group specific and are designed to minimise patient 
burden. The patients and parent(s)/LAR will continue at Visit 11 and Visit 17 with the same 
questionnaires as completed at Visit 1 regardless of changes in age. For those patients that grow out 
of their initial age group during the trial, patients and parent(s)/LAR should – in addition to the 
questionnaires applicable to the patient’s initial age group –  at Visit 17 complete the questionnaires 
applicable to the age group, in which the patient has grown into at the time of Visit 17. For patients 
having grown out of the upper age group (8 – 12 years) at Visit 17, patients and parents(s)/LAR 
should continue with only the same questionnaires as completed at Visit 1. At the end of trial visit 
only the questionnaire completed at Visit 17 representing the patient actual age group at the time of 
Visit 17 or the upper age group (8-12 years) should be completed.
The HAEMO-QOL questionnaires were originally developed and validated in UK English. They 
have been translated and linguistically validated into other languages. The HEMO-SAT 
questionnaire was developed in UK English and has been translated and linguistically validated into 
other languages. The TAPQOL questionnaire was developed and validated in Dutch (Netherlands) 
and has been translated into other languages.
The PRO data will be entered in the database and analysed by Novo Nordisk. Analyses will be 
made after all data are collected. 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
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To characterise the impact of prophylactic treatment on health economic resource use, the 
following data should be recorded by the trial staff in the eCRF:
! Bleed related treatment: where treatment occurred, how the patient arrived at the treatment 
facility, and, if relevant, the number of general and intensive care hospitalisation days
The following will be recorded on an ongoing basis in the patient’s eDiary for health economic 
purposes:
! Number of bleed related days the patient was unable to attend preschool or school
! Number of bleed related days the patient used mobility aids (wheelchair and/or crutches)
! Number of bleed related days the patient’s parent(s)/caregiver was unable to work
! Number of bleed related days the patient’s parent(s)/caregiver was unable to attend 
school/studies
8.3.2
Demographic data
Demographic data will be collected as allowed per local law:
!
Date of birth or age
!
Ethnicity 
!
Race
8.3.3
Medical history/concomitant illness
Complete medical history will be obtained during the screening procedure. In the event a diagnosis 
is unknown, the description of symptoms will be recorded. Onset date for all significant illnesses 
within the last 5 years should be recorded. All chronic illnesses should be recorded.
The following organ systems should be assessed:
! Central and peripheral nervous systems
! Eyes-ears-nose-throat
! Cardiovascular
! Respiratory
! Gastrointestinal
! Renal-genitourinary
! Endocrine-metabolic
! Musculoskeletal
! Dermatologic
! Haematopoietical-lymphatic
! Immunological
Conditions related to the following items should be assessed:
! Allergies, including any drug sensitivities
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
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! Abuse of drug or any substance
Details on haemophilia and inhibitors:
! Diagnosis of haemophilia B (date)
! Other coagulation-related diseases
! Classification of haemophilia B and FIX activity level (%) from medical history
! Underlying gene defect (if known)
! Clinical suspicion of inhibitors data from medical history
! Number of inhibitor tests and/or FIX recovery tests within the last 5 years 
! Relatives with haemophilia B and inhibitors
Details on joints:
! Current target joint(s), including number of bleeding episodes for the last 12 months in each 
current target joint. A target joint is defined as a joint with three or more bleeding episodes
within a consecutive period of 6 months. When there has been no bleeding episode in the joint 
for the last 12 months, it is no longer considered a target joint
! List of joints which during the patient’s life have caused special problems, in terms of repeated 
or frequent bleeding episodes. This list can be compiled through discussion between the 
patient/parent(s) and investigator
! List of joints with arthropathy, including a description of the degree of arthropathy
8.3.3.1
Haemophilia treatment history
For patients currently on prophylaxis, the following should be recorded:
!
Number of months on prophylaxis
!
Dose and frequency of dosing
!
rFIX or pdFIX product
!
Recovery results for previous FIX product (% or IU/mL) 
!
Dose and number of doses most commonly used to treat a bleeding episode
!
Number of bleeding episodes within the last 12 months prior to initiation of prophylactic 
therapy (number of treatment requiring bleeding episodes/number of non-treatment requiring 
bleeding episodes)
!
Number of bleeding episodes within the last 12 months (number of treatment requiring bleeding 
episodes/number of non-treatment requiring bleeding episodes). 
!
History of switching FIX products (type of products and age at switching)
For patients currently on on-demand treatment, the following should be recorded:
!
Number of months on on-demand treatment
!
Dose and number of doses most commonly used to treat a bleeding episode
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Date:
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Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
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UTN: U1111-1119-5013
Status:
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EudraCT No.: 2011-000826-31
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!
Number of bleeding episodes within the last 12 months (number of treatment requiring bleeding 
episodes/number of non-treatment requiring bleeding episodes).
!
rFIX or pdFIX product
!
Recovery results for previous FIX product (% or IU/mL)
!
History of switching FIX products (type of products and age at switching)
For all patients, the following should be recorded:
! Surgeries within the last 5 years, if applicable
!
Date of surgery
!
Indication
!
rFIX or pdFIX product
! Number of EDs prior to trial entry, must be >50 days
!
If it is not possible to count the actual number of exposures in the patient’s medical records,
the investigator should make a written statement with an estimate based on, eg, patient age, 
treatment frequency, medical history, discussion with previous doctor/transfer note, and 
other relevant information
! Vaccinations in the last 12 months
! Planned vaccinations in the next 12 months from time of screening visit (should be recorded as 
concomitant medication at the time of vaccination)
8.3.4
Bleeding episodes
8.3.4.1
Assessments of bleeding episodes and treatment response
All bleeding episodes and treatment of bleeding episodes will be recorded in the medical records 
and/or the eCRF by the investigator/trial staff or in the eDiary by the patient or parent(s)/caregiver. 
For details regarding treatment and reporting in connection with a bleeding episode, please refer to 
Section 8.2.2 and 8.3.7.
If a patient experience a bleeding episode at home, treatment with N9-GP should be initiated 
irrespectively of severity of the bleeding episode, please refer to Section 8.2.2 for details. The 
bleeding episode will per default be considered as mild/moderate when it is uncomplicated and can 
be treated at home. If the patient is in contact with the investigator, it is the responsibility of the 
investigator to assess the severity of the bleeding episode.
The severity of bleeding episodes is defined as:
! Mild/Moderate: Bleeding episodes that are uncomplicated joint bleeds, muscular bleeds without 
compartment syndrome, mucosal- or subcutaneous bleeds. If the patient is discharged, these 
bleeding episodes can be treated at home and details of the bleeding episodes entered in the 
eDiary by the patient or parent(s)/LAR.
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Trial ID: Trial ID: NN7999-3774
Version:
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! Severe: All intracranial, retroperitoneal, iliopsoas and neck bleeds must be categorised as severe. 
Muscle bleeds with compartment syndrome and bleeds associated with a significant decrease in 
the haemoglobin level (>3g/dl) should also be reported as severe. These bleeding episodes must 
be treated immediately at home or at the local emergency room, and the trial staff must be 
contacted. The details of severe bleeding episodes must be entered in the eCRF by the
investigator or trial staff. Traumatic bleeding episodes at other locations than described above 
can always be considered severe at the investigators discretion.
For bleeding episodes the following should be recorded in either the eCRF or the eDiary 
(refer to Section 8.2.2 and 8.3.7):
! Date and time of onset of bleeding episode
!
Date and time of stop of bleeding episode
! Cause of the bleeding episode
!
Spontaneous, traumatic or other origin
! Anatomical location of bleeding episodes
!
Location (including left or right side) and description of tissue, eg, CNS, joint, 
gastrointestinal, subcutaneous, muscle, mucosal or other
!
If assessed by the patient any pain, swelling and restriction of motion should be indicated
!
If assessed by a medically qualified person, the result of the physical examination of the 
bleeding episode should be recorded
! Treatment of bleeding episodes
!
Number of doses, amount, vial concentration, and time of each dose of N9-GP
!
Other haemostatic medication (eg, tranexamic acid)
!
Pain relieving medication
!
Other therapy used (ice, compression, etc)
! Haemostatic response
!
The assessment for haemostatic response will be made by the patient or parent(s)/caregiver
and discussed with the investigator during visits to the trial site. If there is no observed 
effect of 40 IU/kg, the investigator should be contacted prior to administration of the 
second dose of 40 IU/kg. If the investigator re-classifies a mild/moderate bleeding episode 
to a severe bleeding episode, treatment with a double dose of 40 IU/kg is considered as a 
single injection of 80 IU/kg.
!
The 4-point scale is defined below and will take into account the improvement in signs of 
bleeding episodes, mainly by pain relief, but also taking swelling and motion into account. 
The evaluation should take place during and at 8 hours. 
!
The 4-point scale is defined as follows: 
!
Excellent – abrupt pain relief and/or clear improvement in objective signs of bleeding 
within 8 hours after a single injection
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
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EudraCT No.: 2011-000826-31
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!
Good – noticeable pain relief and/or improvement in signs of bleeding within 8 hours after 
a single injection
!
Moderate – probable or slight beneficial effect within the first 8 hours after the first 
injection but requiring more than one injection within 8 hours
!
Poor – no improvement, or worsening of symptoms within 8 hours after two injections
Classification of re-bleed will be performed at the time of the statistical analysis, according to the 
following criteria: A re-bleed is defined as a worsening of symptoms in the same location after an 
initial period of improvement, either on treatment or within 72 hours after stopping the treatment. If 
a bleeding episode occurs in the same location later than 72 hours after stopping the treatment it is 
considered as a new bleeding episode.
Consequences of a bleeding episode
The following will be recorded by the trial staff in the eCRF for health economic purposes:
! Bleed related treatment at unscheduled visits where treatment occurred: how the patient arrived 
at the treatment facility, and, if relevant, the number of general and intensive care hospitalisation 
days
The following will be recorded in the patient’s eDiary for health economic purposes:
! Number of bleed related days the patient was unable to attend preschool or school
! Number of bleed related days the patient used mobility aids (wheelchair and/or crutches)
! Number of bleed related days the patient’s parent(s)/caregiver was unable to work
! Number of bleed related days the patient’s parent(s)/caregiver was unable to attend 
school/studies
8.3.5
Prophylaxis
Prophylactic injections will be recorded in the eDiary unless the dose is given at the trial site, in 
which case the details will be recorded in the eCRF. 
For prophylaxis the following should be recorded in either the eCRF or the eDiary:
! Date and time of N9-GP administration
! Dose administered (mL)
! Vial concentration (2000 IU or 500 IU per vial) – only to be recorded in the eCRF and only 
when dose is given at the trial site
! Reason for prophylaxis (planned or in connection with surgery)
8.3.6
Surgery
8.3.6.1
Minor surgery
Preventive N9-GP treatment before minor surgery and placement of central venous access port can 
be performed within this trial at the investigator’s discretion according to local guidelines. A dose 
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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Status:
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of 40 IU/kg N9-GP prior to minor surgery is recommended to prevent perioperative bleeding 
episodes. For the definition of minor surgery, refer to section 5.3.3.
For minor surgery the following should be recorded in either the eCRF or the eDiary:
! Date and time of preventive dose before surgery
! Type of surgery
! Indication for surgery
! Date of surgery
! Start and stop time of surgery
8.3.6.2
Major surgery
Major surgery can be performed while participating in the present trial. For definition of major 
surgery refer to section 5.3.3. Novo Nordisk must be contacted in due time prior to surgery, to 
ensure sufficient supply of N9-GP.
N9-GP dosing prior to, during and after surgery should aim at FIX activity levels as defined and 
recommended in the WFH Guidelines for the management of haemophilia9. The preoperative N9-
GP dose should aim at FIX activity level of approximately 100% which is expected to be achieved 
with dose of 40 or 80 IU/kg of N9-GP. Trough and peak levels, and incremental recovery of the 
particular patient must be taken into consideration by the Investigator when deciding the dose. 
During the postoperative phase, clinical haemostatic response combined with close FIX activity 
monitoring is recommended to determine appropriate intervals for postoperative dosing of 40 IU/kg 
N9-GP. The dose interval should be adjusted in order to reach postoperative FIX activity levels as 
recommended by the WFH Guidelines for the management of haemophilia9. 
The site must have ability to measure FIX activity at a local laboratory.  Please refer to section 8.7.2
for requirements to assay calibration with the N9-GP reference standard.
It is the responsibility of the Investigator to determine when the patient must stop the weekly 
prophylaxis administrations of N9-GP prior to the surgery and when these should be resumed after 
the surgery.  If the patient has not resumed weekly prophylaxis within 6 days from the day of 
surgery the reason must be documented. The first weekly prophylaxis dose after surgery should be 
omitted if it falls on the same day (+/-1day) as the last postoperative dose. The following must be 
documented: 
! Date and time the patient stops the weekly prophylaxis with 40 IU/kg N9-GP prior to the surgery 
Date and time the patient resumes the weekly prophylaxis with 40/kg N9-GP after the post-
surgery period
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CONFIDENTIAL
Date:
27 June 2018
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Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
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EudraCT No.: 2011-000826-31
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During this period, all bleeding episodes and any haemostatic treatment administered must be 
recorded in a paper CRF when the patient is at the site and in a paper diary when the patient is at 
home; the patient is requested to hand in the eDiary to the site to avoid duplicate entries.  
Perioperative procedures, assessments and blood sampling will be performed at the Investigators 
discretion and documented in the patients’ medical records. The following must be performed and 
recorded in a paper CRF:
! Type of surgery (e.g. arthroscopy), indication (e.g. prosthetic knee replacement) and location
! Elective or emergency surgery
! Duration of surgical procedure: The date and time of first incision (knife-to-skin) and skin 
closure (last stitch)
! Concomitant medication, including anaesthetics and haemostatic medication, see section 11
! Clinical narrative incl. description of any complication, estimated blood loss, if any re-operations 
etc.
! Blood product transfusions, if any: Type, volume (mls), Start date and time
! Other i.v. infusions, if any: Type (ex. saline, crystalloids/colloids), concentration and volume 
(mls), Start date and time
! Haemoglobin measurements, if any (results in local units eg. g/dL or mmol/L)
! Clinical evaluation of haemostatic response will be assessed by the Surgeon, Anaesthesiologist 
and/or Investigator based on experience as follows:
!
Excellent: Better than expected/predicted in this type of procedure
!
Good: As expected in this type of procedure
!
Moderate: Less than optimal for the type of procedure but haemostatic response maintained 
without change of treatment regimen
!
Poor: Bleeding due to inadequate therapeutic response with adequate dosing, change of 
regimen required
8.3.7
Entry of patient eDiary data and eDiary compliance review 
During the home treatment period the patient or the patient’s parent(s)/caregiver must ensure that all 
prophylactic home treatment, bleeding episodes, treatment of bleeding episodes and assessments 
thereof are captured in the eDiary. Data should not be recorded in the eDiary until after Visit 3.
As a minimum the following data will be collected in the eDiary:
! Date and time of prophylactic home treatment with N9-GP
! Dose administered (mL)
! Vial concentration (2000 IU or 500 IU per vial)
! Reason for prophylaxis (planned or in connection with minor surgery)
! Date and time of onset of bleeding episode
! Date and time of stop of bleeding episode
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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Status:
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! Cause of bleeding episode (eg, spontaneous)
! Location of the bleeding episode
! Symptoms related to the bleeding episode (swelling, reduced mobility or pain) 
! Treatment of the bleeding episode (N9-GP dose and time of administration)
! Other therapy used (ice, compression etc)
! Pain relieving medication
! Evaluation of the haemostatic response (excellent, good, moderate or poor)
! Number of bleed related days the patient was unable to attend preschool or school
! Number of bleed related days the patient used mobility aids (wheelchair and/or crutches)
! Number of bleed related days the patient’s parent(s)/caregiver was unable to work
! Number of bleed related days the patient’s parent(s)/caregiver was unable to attend 
school/studies
The investigator must carefully instruct the patient and parent(s)/caregiver in how to evaluate a 
bleeding episode, the haemostatic response after treatment and how to complete the eDiary.
The entries made in the patient eDiary will be reviewed by the investigator to ensure consistency 
and compliance. The information in the patient’s eDiary is regarded as source data. If information is 
missing in the eDiary, but is available in the medical records, then this information can be used.
8.4
Adverse event assessments
Monitoring of AEs will be performed from screening until the post-treatment follow-up period, 
according to the procedures described in Section 12.
For recording of bleeding episodes, please refer to Sections 8.3.4 and 12.1.3.
For details regarding the contact between the investigator/medically qualified person and patient,
please refer to Section 8.10.4.
8.5
Clinical assessments 
Clinical assessments should preferably be performed prior to blood sampling and prior to 
administration of N9-GP unless it is clearly stated otherwise. All assessments should be recorded in 
the eCRF if nothing else is stated.
8.5.1
Body measurements
!
Body weight, wearing light clothing only (kg)
!
Height, without shoes (cm) (Visit 1, to be measured at every visits going forward from approval 
of amendment 9. Height at Visit 11 ± 3 month will furthermore be collected retrospectively if 
available in medical records upon patient/parent(s)/LAR consent)
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Date:
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Version:
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Status:
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!
Body mass index calculation (kg/m2) (Visit 1 only)
8.5.2
Physical examinations
The physical examinations will be performed according to local procedure and should include:
! General appearance
! Head, ears, eyes, nose, throat and neck
! Respiratory system
! Cardiovascular system
! Gastrointestinal system, including mouth
! Musculoskeletal system
! Central and peripheral nervous systems (general evaluation)
! Elaborated neurological examination, see Section 8.5.2.1
! Skin
! Lymph node palpation
! Signs and symptoms of vascular thrombosis (eg but not limited to swelling, tenderness and leg 
pain)
8.5.2.1
Neurological Examination 
Following aspects of the neurological examination will be assessed:
! General appearance including language, social and developmental aspects
! Parameters including handedness, head circumference and level of consciousness
! Cranial nerves in relation to
! Sight including reaction to light, visual fields and acuity, and eye movements
! Facial sensation and movement
! Hearing
! Palate sound and tongue movement
! Trapezius muscle function
! Tone of truncal, upper and lower extremity right and left
! Strength of upper and lower extremity right and left
! Reflexes of biceps, triceps, knee and ankle jerk, all right and left as well as Babinski
! Sensory aspect of cold, pin prick, light touch and proprioception (tor up(down)
! Gait with regards to walking, running, on heels and toes, tandem (toe/heel walk), standing or 
hop one leg/foot right and left, and Romberg sign
! Coordination and Fine Motor including finger-to-nose, rapid index finger tab and rapid finger 
movement right and left 
!
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! Each aspect of the neurological examination will be categorised into normal, abnormal (pre-
existing or new) or not examined. Some aspects of the neurological examination may not be 
applicable for children in particular age groups. 
!
! Any preexisting physical or neurological finding that was present at the time of enrolment in 
the study should be reported as medical history, new abnormal findings or any changes in the 
findings which fulfil the criteria of an AE must be recorded as such (see Section 12.1).
!
8.5.3
Neurocognitive assessments 
Neurocognitive assessments should be performed according to Table 2-3 and Table 8-1. The 
following neurocognitive domains will be assessed in all countries:
!
Executive function
!
Attention/processing speed /working memory 
Further, the following neurocognitive domains will be assessed in Canada, United Kingdom, and 
the United States:
!
Neurocognitive function and intelligence
!
Emotional behaviour 
!
Adaptive behaviour
At the discretion of the site and to facilitate scheduling the neurocognitive assessments, these may 
be made up to 1 month before or after the scheduled visits, except for the EOT visit where it may 
only be up to 1 month before visit. In general, the timing of the neurocognitive assessments should 
be planned to allow as much flexibility for the patients as possible. All assessments should be
performed using generally accepted standardised testing parameters to ensure optimal conditions for 
performance. A description of neurocognitive assessments, training, equipment and related 
procedures will be provided in the manual for neurocognitive assessments which should be 
followed accordingly.
An External Expert Review Panel will evaluate the results of the neurocognitive assessments in 
context of the Structured Developmental History and Haemophilia history for each patient. 
Information regarding responsibilities, procedures, meeting frequency and workflow to be used by 
the External Expert Review Panel are specified in the External Expert Review Panel charter. 
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Trial ID: Trial ID: NN7999-3774
Version:
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A CRO will provide the results from the External Expert Review Panel to Investigator as narrative 
reports including normalised domain scores and categorical assessment. It is the responsibility of 
the Investigator to report any findings if considering qualifying for an AE, If any findings are 
present at V0 it should be recorded as medical history.
The following Structured Developmental History and Haemophilia History data will be collected in 
connection with neurocognitive assessments:
!
Demographics
!
Parents/caregivers
!
Brothers/sisters/other children
!
Child´s residence
!
Pregnancy
!
Birth
!
Development
!
Medical history
!
Family health
!
Educational history
!
Haemophilia history
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UTN: U1111-1119-5013
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Table 8-1
Neurocognitive assessments by age and country
Domain:
Executive Function
Attention / 
Processing Speed
Structured 
Developmental History 
and Haemophilia 
History
General Intelligence
Behavioural / 
Emotional
Adaptive behaviour
Countries:
For all countries
Additional testing for Canada, United Kingdom, and the United States
Visit number:
All assessment visits and EOT
Yearly testing at assessment visits and EOT
Patient age
(years : 
months)
6:0 to 6:11
BRIEF-2 ( 5-18y 
Parent form)
COGSTATE (Custom 
Battery - Peds (4-9)
Structured 
Developmental History 
and Haemophilia History
WPPSI-IV
BASC-3 (PRS-C 
Parent 6-11 form)
ABAS-3 (5-21y Parent
form)
7:0 to 7:11
BRIEF-2 ( 5-18y 
Parent form)
COGSTATE (Custom 
Battery - Peds (4-9)
Structured 
Developmental History 
and Haemophilia History
WASI-II
BASC-3 (PRS-C 
Parent 6-11 form)
ABAS-3 (5-21y Parent
form)
8:0 to 9:11
BRIEF-2 (5-18y 
Parent form)
COGSTATE (Custom 
Battery - Peds (4-9)
Structured 
Developmental History 
and Haemophilia History
WASI-II
BASC-3 ( PRS-C 
Parent 6-11 form and
SRP-C 8-11 patient 
form)
ABAS-3 (5-21y Parent
form)
10:0 to 10:11
BRIEF-2 (5-18y 
Parent form)
COGSTATE (Custom 
Battery - Adult (10-21)
Structured 
Developmental History 
and Haemophilia History
WASI-II
BASC-3 ( PRS-C 
Parent 6-11 form and 
SRP-C 8-11 patient 
form)
ABAS-3 (5-21y Parent
form)
11:0 to 11:11
BRIEF-2 (5-18y 
Parent form)
BRIEF-2 (11-18 SR)
COGSTATE (Custom 
Battery - Adult (10-21)
Structured 
Developmental History 
and Haemophilia History
WASI-II
BASC-3 ( PRS-C 
Parent 6-11 form and
SRP-C 8-11 patient 
form)
ABAS-3 (5-21y Parent 
form)
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Domain:
Executive Function
Attention / 
Processing Speed
Structured 
Developmental History 
and Haemophilia 
History
General Intelligence
Behavioural / 
Emotional
Adaptive behaviour
For all countries
Additional testing for  Canada, United Kingdom, and the United States
All assessment visits and  EOT
Yearly testing at assessment visit and EOT
Patient age 
(years : 
months)
12 to 15
BRIEF-2 (5-18y 
Parent form)
BRIEF-2 (11-18 SR)
COGSTATE (Custom 
Battery - Adult (10-21)
Structured 
Developmental History 
and Haemophilia History
WASI-II
BASC-3 (PRS-A 
Parent 12-21 form and
SRP-A 12-21 patient 
form)
ABAS-3 ( 5-21y 
Parent form)
16 to 17
BRIEF-2 (5-18y 
Parent form)
BRIEF-2 (11-18 SR)
COGSTATE (Custom 
Battery - Adult (10-21)
Structured 
Developmental History 
and Haemophilia History
WASI-II
BASC-3 (PRS-A 
Parent 12-21 BASC-3 
SRP-A 12-21)
ABAS-3 (5-21y Parent   
and 16-89 Adult)
18 to 21
BRIEF-A (18-90 Adult)
COGSTATE (Custom 
Battery - Adult (10-21)
Structured 
Developmental History 
and Haemophilia History
WASI-II
BASC-3 (PRS-A 
Parent 12-21 BASC-3 
SRP-College 18-25)
ABAS-3 ( 5-21y 
Parent and 16-89 
Adult)
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8.5.4
Vital signs
Before measurement of vital signs the patient should preferably rest comfortably for at least 
three minutes and all measurements should, if possible, be performed using the same method and 
position (eg sitting or lying down) throughout the trial for each individual patient. 
Vitals signs include assessment of:
! Body temperature (°C or &F)
! Pulse (beats/min)
! Blood pressure (BP) (mm Hg)
! Respiratory rate (breaths/min)
8.6
Blood sampling volume
Blood samples for laboratory analysis of safety, efficacy and PK parameters will be drawn as 
outlined in Table 2-1, Table 2-2 and Table 2-3. The blood sampling volume for the patient should 
not exceed 1% of the total blood volume at one occasion or 3% within in 28 days (see Appendix C). 
This is in accordance with European regulatory guidelines (Directive 2001/20/EC)17 and FDA 
requirements. In total, approximately 90 mL blood will be collected per patient during the main 
phase of the trial and approximately 9-18 mL blood per visit and patient during the extension phase.
It is recommended not to attempt venepuncture more than 3 times for the purpose of obtaining 
sufficient blood sampling. If failing, documentation must be available in medical record.
8.7
Local laboratory assessments 
Local laboratory results are considered as source data and must be signed, dated and categorised by 
the investigator. The laboratory results must be categorised as “normal”, “out of normal range, not 
clinically significant” or “out of normal range, clinically significant”. A clinically significant value 
must be recorded as an AE, or if present at Visit 1 it should be recorded as concomitant illness.
Laboratory equipment in local laboratories may provide standard analyses not requested in the 
protocol but produced automatically in connection with the requested analyses. Such data will not 
be transferred to the eCRF or the trial database, but must be reported to the investigator. The 
investigator must review all laboratory results for concomitant illnesses and AEs and report these 
according to the protocol.
Storage handling, and disposition of samples analysed at local laboratories will be performed 
according to local laboratory procedures. It will be possible for the trial site to report in other 
predefined units than listed below.
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Version:
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8.7.1
Haematology
! Platelet count (thrombocytes) (∋109/L)
! Haemoglobin (mmol/L)
! Red blood cell count (erythrocytes) (∋1012/L)
! Mean corpuscular volume (MCV) (fL)
! Packed cell volume (haematocrit) (PCV) (%)
! Mean corpuscular haemoglobin (MCH) (fmol)
! White blood cell count (leucocytes) (∋109/L)
! Differential white blood cell count (% or ∋109/L)
! Lymphocytes
! Monocytes
! Neutrophils
! Eosinophils
! Basophils
8.7.2
FIX activity
! FIX activity (% or IU/mL)
The trial site must have ability to measure FIX activity at a local laboratory and the investigator can 
at any time during the trial assess FIX activity at his/her discretion. If an APTT based one-stage 
clotting assay is used it should be calibrated with a N9-GP reference standard. The reference 
standard will be provided by Novo Nordisk together with a description of how to handle, store and 
use. The site must ensure that the reference standard has not expired and order new when relevant.
Dependent on the type of APTT reagent used by the local laboratory an exemption from the
requirement of using the N9-GP reference standard can be made, in such cases Novo Nordisk will 
need to approve the suggested assay set-up on an individual basis. For approval of specific APPT
reagents in the one-stage clotting assay the investigator must contact Novo Nordisk.
FIX activity may also be measured with a chromogenic assay if available at the local laboratory. In 
such cases the N9-GP reference standard is not needed.
8.8
Central laboratory assessments 
The central laboratory will analyse and report all laboratory data to Novo Nordisk A/S
electronically in a manner that anonymity of patients will be maintained. The central laboratory 
results will be reported to the investigator by fax or email. Upon review of the results the 
investigator must sign and date the laboratory reports. A clinically significant value must be 
recorded as an AE, or if present at Visit 1 it should be recorded as concomitant illness.
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The quality control of the central laboratory test results will be performed according to the 
regulations and specifications set by the authorities at the location of the central laboratory used for 
this trial.
The central laboratory equipment may provide analyses not requested in the protocol, but produced 
automatically in connection with the requested analyses. Such data will not be transferred to the 
trial database, but may be reported to the investigator according to specifications in the laboratory 
standard operating procedures and requirements. The additional data, if any, is specified in the 
central laboratory manual. The investigator must review all laboratory results for concomitant 
illnesses and AEs and report these according to the protocol. 
A detailed description in the central laboratory manual of procedures for sampling, handling, 
particulars of instrumentation, shipment of laboratory samples and all materials such as test tubes 
and labels will be provided by the central laboratory. The central laboratory manual and the central 
laboratory results will include the reference ranges. It will be possible for the central laboratory to 
report in other predefined units than listed below.
If the patient or parent(s)/LAR agree, residuals from all blood samples will be stored for possible 
future testing, but for no longer than 15 years from end of trial. If the patient or parent(s)/LAR do 
not agree upon this, all samples will be destroyed after finalisation of the trial report, except 
antibody samples which will be stored for possible future testing, at least until evaluation of the 
clinical trial by regulatory authorities.
8.8.1
Biochemistry
! Sodium (mmol/L)
! Potassium (mmol/L)
! Creatinine (∃mol/L)
! Albumin (g/L)
! Total bilirubin (∃mol/L)
! Aspartate aminotransferase (AST) (IU/L)
! Alanine aminotransferase (ALT) (IU/L)
! Gamma glutamyl transferase (GGT) (IU/L)
! Alkaline phosphatase (IU/L)
! C-reactive protein (CRP) (mg/L)
! Urea 
8.8.2
Coagulation-related parameters
! Prothrombin time (PT) (sec, INR) 
! Activated partial thromboplastin time (aPTT) (sec)
! Fibrinogen (g/L)
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! Antithrombin (AT) (%)
8.8.3
Recovery for previous FIX product
Recovery results for the patient’s previous FIX product should be collected from medical records. 
Recovery is defined as maximum FIX activity after dosing. 
If recovery results are not available or are older than 1 year, or collected more than 1 hour after 
dosing, a new recovery sample should be collected. In this case, the patient should be dosed with his 
previous FIX product and a recovery sample should be collected 30 minutes±10 minutes after 
dosing. This can be done anytime in the period from informed consent and until 4 days prior to the 
laboratory assessments of Visit 1 or directly after all laboratory assessments of Visit 1 have been 
completed and until 4 days prior to the planned Visit 2.  
! FIX activity (% or IU/mL)
8.8.4
FIX activity 
The analysis of plasma FIX activity will be performed at a laboratory selected by Novo Nordisk
A/S or at a Novo Nordisk laboratory. The procedures for analyses should follow the 
recommendations provided by Novo Nordisk A/S. A description of the method and assay validation 
will be submitted with the final report of the trial.
The patient is enrolled in the trial based on the FIX activity reported in the medical records. If for 
some reason the baseline FIX activity level is not reported in the medical records, the patient may 
be enrolled in the trial based on the central laboratory results from Visit 1.
Visit 1:
! FIX activity (% or IU/mL)
All other visits:
! FIX activity (% or IU/mL)
Blood samples for analysis of FIX activity will be collected from all patients at Visit 2; pre-dose 
and 30 minutes, 24 hours, 48 hours, 96 hours and 168 hours post-dose. Pre-dose samples and 30 
minutes post-dose samples will be collected at visit 5, 7, 9 and 11 during the main phase and pre-
dose samples will be collected at the dosing visits during the extension phase. The sampling time 
points are relative to completion of N9-GP administration, and actual time must be documented.
The  analysis of PK will be based on a  one-stage clot assay. 
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8.8.4.1
One-stage clot activity assay
The one-stage bioassay (FIX activity clot assay) measures the activity of the compound in a specific 
process (clot formation). The FIX activity assay is a modified one-stage clot assay (modified aPTT 
assay). A primary reference standard of N9-GP is used, which biological activity is determined 
relative to the Ph. Eur. Human Coagulation Factor IX, batch 2. The biological activity in the 
reference material is defined so that one unit of N9-GP equals one FIX IU at establishment.
8.8.4.2
Chromogenic activity assay
The chromogenic bioassay (FIX activity chromogenic assay) measures the activity of the compound 
with a two-stage method. The FIX activity is determined by measuring the FVIIIa/FIXa-mediated 
FX activation with a chromogenic FXa substrate. It is a validated assay calibrated with an internal 
N9-GP reference standard or normal human plasma. This assay will be used for exploratory 
purposes. After the implementation of amendment 10 the chromogenic assay will no longer be used 
in this trial.
8.8.5
Antibody assessments  
The N9-GP/FIX antibody and FIX inhibitor assessments will be performed at a laboratory selected 
by Novo Nordisk A/S or at a Novo Nordisk laboratory. The procedures for analyses should follow 
the recommendations provided by Novo Nordisk A/S. A description of the method and assay 
validation will be submitted with the final report of this trial.
8.8.5.1
N9-GP/FIX antibody assay
Screening for N9-GP antibodies and for FIX antibodies is based on a bridging ELISA and is 
validated according to international recognised guidelines18. Samples measured above the assay cut-
point will be subject to a confirmation test where the signal will be inhibited with excess of 
unlabelled N9-GP. Also an investigation of cross reactivity to rFIX will be performed as a 
confirmation test by inhibition with excess of unlabelled rFIX. A polyclonal rabbit antibody that 
neutralises the FIX clot activity is used for the preparation of the positive control samples. 
Confirmed antibody positive samples will be titrated below two times cut-point and results given as 
a titre.
FIX activity levels measured at the scheduled visits will be reviewed by Novo Nordisk on an 
ongoing basis. If any post dose FIX activity level is below 60% of expected level defined as the
post dose activity at visit 4 and there is no specific reason, an N9-GP antibody analysis (bridging 
ELISA assay) will be performed on the corresponding sample as soon as possible for this patient. 
In case a patient has a positive antibody detected in the N9-GP antibody assay, the patient will be 
asked to attend the site for the next planned N9-GP administration followed by a PK session
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!
FIX activity (% or IU/ml)
Blood sampling during the PK session will be performed at the following time points (identical to 
Visit 2): pre-dose, 30 minutes (% 10 min), 24h (% 8 hours), 48h (% 8 hours), 96h (% 8 hours) and 
168h (% 24 hours).
8.8.5.2
FIX inhibitors
Detection of FIX inhibitors (neutralising antibodies) will be carried out using a Nijmegen modified 
FIX Bethesda assay following heat pre-treatment of samples. The assay is validated according to 
international recognised guidelines19. The assay is based on measurement of the FIX activity 
(inhibitory activity) in plasma samples mixed with a fixed amount of normal plasma pool in buffer. 
Inhibitors will be considered as “low positive” with 0.6-<5 BU and “high positive” with a BU ≥5. 
Inhibitors will be recognised by comparison to a clinical cut-point of ≥0.6 BU. A polyclonal 
antibody, that neutralises the FIX clot activity, is used for the preparation of the positive control 
samples.
If FIX inhibitor development is suspected during the course of the trial due to for instance increased 
number of bleeding episodes, bleeding episodes difficult to treat, recovery and trough levels below 
expected values or a positive local inhibitor test, the patient must attend an unscheduled visit as 
soon as possible and a blood sample must be shipped to the central laboratory for inhibitor analysis.
If the result of the Bethesda assay is positive, a second confirmatory Bethesda assay should be 
performed by the central laboratory. The confirmatory samples should be collected as soon as 
possible, but no sooner than 6 days after the last dose of N9-GP. If high titre inhibitors are identified 
and confirmed (# 5 BU) or significant clinical impact is seen, the patient should be withdrawn. In 
case low titre inhibitors (0.6–<5 BU) are identified and confirmed, the patient can continue with 
N9-GP treatment. If the low titre inhibitors are identified during the main phase, the patient should 
be scheduled for Visit 11, and can thereafter proceed into the extension phase. If this happens 
during the extension phase, the patient can continue as planned (see Figure 8-2).
Blood samples for FIX activity (trough and optional 30 minutes post dose), N9-GP/FIX antibodies 
and lupus anticoagulant must be taken in conjunction with the second confirmatory inhibitor sample 
(unscheduled visit).
At least three inhibitor follow-up visits should be scheduled for patients with high titre inhibitors 
and additional follow-up visits may be arranged at intervals as long as judged clinically warranted 
(see Section 8.1.9). 
If an investigator decides to perform inhibitor testing locally, he/she must also send a duplicate 
sample for inhibitor testing at the central laboratory. The results from the central laboratory will be 
used in the official analysis of trial data. A positive inhibitor test must always be reported as a 
MESI no matter if the test is performed locally or centrally (refer to Section 12.1.2). 
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Figure 8-2
Process flow for inhibitor testing
8.8.6
Host cell protein antibodies
All patients will be examined for the development of antibodies against HCP. The samples will be 
analysed at a laboratory selected by Novo Nordisk A/S or at a Novo Nordisk laboratory.
8.8.7
Allergic reaction testing (conditional)
Allergic reaction testing will only be performed in patients developing severe allergic reactions
related to N9-GP treatment.
New test at Inhibitor follow-up visit
!
Continue with trial product
!
If during main phase, schedule the 
patient for Visit 11 and thereafter 
extension phase visits
!
If during extension phase, the patient 
can continue as planned
!
Report follow-up on MESI
!
PK session  (see 8.8.4)
Negative inhibitor test
Inhibitor testing:
!
Inhibitor test at an Unscheduled or Assessment visit 
2nd positive inhibitor test (<5 BU)
1st positive inhibitor test (#5 BU) –
report MESI
2nd positive inhibitor test (#5 BU)
!
Discontinue trial product
!
Schedule the patient for an end of 
trial visit (Visit 11 or EOT), as 
soon as possible
!
An inhibitor follow-up visit must 
be scheduled four weeks after end 
of trial visit
!
At least two additional inhibitor 
follow-up visits must be scheduled 
four weeks apart
!
Report follow-up on MESI
!
Continue in 
the trial
!
On-going 
FIX activity 
ill
1st positive inhibitor test ( <5 BU) –      
report MESI     
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If a severe allergic reaction related to treatment occurs, blood samples should be taken within 
15 minutes (if possible), 1-4 hours and ~1 week after onset of the reaction at unscheduled visits. In 
this case, mandatory tests and selected optional exploratory tests will be performed, if considered 
relevant by Novo Nordisk Global Safety: The allergic reaction assessments will be performed at a
laboratory selected by Novo Nordisk A/S or at a Novo Nordisk laboratory. 
Allergic reaction testing in relation to positive inhibitor reaction, will only be performed once for 
each IFU visit, hence not 1-4 hours and 1 week after onset of the reaction.
Mandatory tests ( 30 minutes-3 hours and ~1 week):
! Immunoglobulin E (IgE) antibodies against N9-GP
! IgE antibodies against rFIX
! FIX inhibitors 
! N9-GP/FIX binding antibodies
! Tryptase
Optional exploratory tests:
! IgE antibodies against CHO-HCP; all time points
! Anaphylaxins (C3a, C4a, C5a), <15 minutes and ~1 week 
! Histamine, <15 minutes and ~1 week 
! Complement activation test (C3, C4), 30 minutes - 3 hours and ~1 week 
Optional exploratory tests will be performed using scientific sound non -validated tests. If relevant, 
baseline levels for optional exploratory test can be set using samples from other patients enrolled in 
the trial.
Detection of IgE antibodies against N9-GP and rFIX will be determined using the ImmunoCAP 
platform. Visit 2 samples (pre-dosing of N9-GP) and subsequent samples will be measured to 
follow IgE development over time. Caps will be coated with N9-GP or rFIX, and the specific IgE 
will be detected with anti-IgE antibody conjugate. Positive control samples will be based on a 
mouse monoclonal anti-N9-GP antibody humanised with regards to the IgE constant region.
Samples read ≥0.35 kUA/L will be subject to a confirmation test where the signal will be inhibited 
with excess of unlabelled N9-GP or rFIX.
8.8.8
Viral assessments (HIV and HCV) and CD4+ lymphocyte count
! HIV 1 and 2 antibodies
! CD4+ lymphocyte count
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If the patient’s HIV status is unknown or if negative HIV test results in medical records are older 
than one year, HIV status should be tested at Visit 1. If the patient is HIV positive, the CD4+ 
lymphocyte count must be tested.
! Anti-HCV antibodies 
! HCV RNA
If the patient’s HCV status is unknown or if negative HCV test results in medical records are older 
than one year, anti-HCV antibodies should be tested at Visit 1. If the patient is HCV positive in 
medical records or if the anti-HCV antibodies test is positive, HCV RNA should be tested.
8.8.9
F9 genotype testing
At Visit 1 all patients and parent(s)/LAR will be asked about documentation of previous F9
genotype tests. If not available, F9 genotype testing will be offered at Visit 1 or at any later visit 
where blood draw volume limits are not exceeded, and if allowed according to local law. 
Investigator, parent(s) or LAR have the right to refuse to provide patients’ F9 genotype 
documentation or to refuse genotyping. The F9 genotype is analysed at a laboratory selected by 
Novo Nordisk A/S. No further analysis will be carried out for any other parameters and samples 
will be disposed of appropriately after the test. All test results are kept strictly confidential.
8.8.10
Lupus anticoagulant
! Lupus anticoagulant (dilute Russell’s viper venom time)
8.8.11
Urinalysis
The following parameters will be evaluated based on a urine sample:
! Albumin/Creatinine ratio
! Blood
! Leucocytes
! Protein
! Glucose
! pH
Albumin/creatinine ratio will be measured at the central laboratory the rest will be analysed with 
dip-stick at site.
8.8.12
Plasma PEG levels
The plasma concentration of PEG will be analysed for exploratory purposes. Plasma PEG levels 
will be measured in residuals, in Biospecimens for storage or in dedicated samples going forward 
from approval of amendment 9.
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8.8.13 Biospecimens for storage
The patient or parent(s)/legally authorised representative (LAR) will be asked to consent to blood 
sampling for potential future assessments. The samples should only be taken if blood volume 
limitations allows for this. The samples will be stored at a Novo Nordisk appointed central 
laboratory (biorepository) and Novo Nordisk will have access for up to 15 years after the end of 
trial after which all samples will be destroyed according to standard operating procedures at the 
central laboratory. Refer to section 25.1. for information about long term retention of blood samples 
for exploratory purposes. It is voluntary for patients to participate in the collection of samples for 
Biospecimen, and the patient will not be withdrawn if decline to participate.
8.9
N9-GP administration
N9-GP will be administered while the patient is in a comfortable position. 
At the trial site
The two first doses must be administered at the trial site by, or under direct supervision of, the 
investigator or an attending physician.
Precautions to take when injecting the first dose of N9-GP (Visit 2):
! The patient has to be observed for 60 minutes in a hospital setting after N9-GP has been fully 
administered, with the line used left in place, if possible. 
! The first 0.5 mL of N9-GP should be administered slowly (for the duration of 1 minute), while 
the remaining N9-GP volume should be administered over a period of at least 2 minutes. The 
patient is to be observed closely during this administration, and the injection should be stopped 
immediately if any signs of allergic or anaphylactic reactions appear.
Precautions to take when injecting the second dose of N9-GP (Visit 3):
! The patient has to be observed for 60 minutes in a hospital setting, with the line used left in 
place, if possible. 
! The dose of N9-GP should be administered as an i.v. bolus injection (maximum 4 mL/min). The 
patient is to be observed closely during this administration, and the injection should be stopped 
immediately if any signs of allergic or anaphylactic reactions appear.
!
Drug injection kits (butterflies etc) will be provided by Novo Nordisk. Choice of butterfly 
or cannula for N9-GP injections is at the discretion of the investigator. If a central venous 
access port or cannula, sealed with heparin is used, it has to be flushed and sealed with 
saline the evening before administration of N9-GP. 
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The actual time of completion of the injection will be recorded and corresponds to trial time 
point = 0. All following PK sample time points at Visit 2 is relative to t = 0. The sample taken 
30 minutes (%10 minutes) post-dose, must not be taken from the same vein as used for 
administration of N9-GP.
During remaining visits at trial site (Visit 4 to Visit X):
! The injection should be performed as an i.v. bolus injection (maximum 4 mL/min). The date and 
the actual time of completion of the injection must be recorded in the eCRF. The actual time of 
completion of the injection will be recorded and corresponds to trial time point = 0.
At home:
! Home treatment with administration of N9-GP can start after N9-GP administrations have been 
performed in the trial site at Visit 2 and Visit 3, or when the patient or the patient’s 
parent(s)/caregiver are comfortable with the reconstitution and administration process. 
! Home treatment may be given by the patient, parent(s)/caregiver or a home nurse, as applicable.
! The injection should be performed as an i.v. bolus injection (maximum 4 mL/min). The date and 
the actual time of completion of the injection must be recorded in the patient’s eDiary. 
! In case a patient has treated a bleeding episode on a day not planned for prophylaxis dosing, the 
next prophylactic dose should still be taken on the planned day. If a bleeding episode occurs 
earlier on the same day as the planned prophylaxis, the dose should be registered for the bleeding 
episode and not as prophylaxis and the planned prophylaxis dose later same day should be 
omitted. When a prophylaxis dose has been taken and if a bleeding episode occurs later the same 
day, the bleeding episode should be treated and registered independent of the prophylaxis dose. 
In the extension phase, a single dose of 40 IU/kg once weekly (% 1 day) will be administered
intravenously. This must be documented in the medical records and the eCRF. In the extension 
phase, the patient can be administered the planned doses of N9-GP either at the trial site or at home 
after the visit.
8.10
Training and reminders
8.10.1
Trial card dispensing
At Visit 1 the patient will receive a trial card stating that the patient is participating in a clinical 
trial. Telephone numbers and contact persons at the trial site will be listed.
8.10.2
Home treatment training
Home treatment with administration of N9-GP can start after N9-GP administrations have been 
performed in the trial site at Visit 2 and Visit 3 (see Section 8.1.2 and 8.1.3), but may be postponed 
until the patient and/or the patient’s parent(s)/caregiver are comfortable with the reconstitution and 
administration process. All patients and/or parent(s)/caregivers must be carefully instructed in 
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recognising and dealing with signs and symptoms of an anaphylactic reaction. This includes 
knowledge of which medical facility to contact in this situation. 
If the patient does not follow the planned dosing schedule, the investigator must retrain the patient 
and/or the patient’s parent(s)/caregiver. The training must be documented in the medical records.
8.10.3
eDiary and paper diary dispensing and collection
The eDiary will be dispensed to the patients at Visit 3. For details regarding entry of patient diary 
data in the eDiary, please refer to Section 8.3.7. No data should be entered in the eDiary until after 
Visit 3.
For patients withdrawn during the main phase or not continuing in the extension phase, the eDiary 
will be collected at Visit 11. For patients completing the extension phase, the eDiary will be 
collected at the EOT visit.
A paper diary will be dispensed to the patient in the period prior to the surgery where the weekly 
prophylaxis has been stopped and until the post-surgery period has stopped. All haemostatic 
treatment administered at home during this period will be recorded in a paper diary and the patient 
must be requested to hand in the eDiary to the site to avoid duplicate entries.
8.10.4
Contact between the investigator/medically qualified person and the patient
The investigator and/or medically qualified person must establish contact with the patient at least 
once halfway through each home treatment period, either by visits at the trial site or other contacts, 
e.g. telephone calls.
The communication will focus on the well-being of the patient and will include all AEs. The 
investigator/medically qualified person should not suggest specific AEs to patients, but should 
inquire generally about how the patient feels and ask the patient or parent(s)/caregiver questions 
such as: “How do you feel?”/ “How do you believe your child feels?” and “Have you had any 
medical problems since the last contact?”/ “Has your child had any medical problems since the last 
contact?”.
At each contact the investigator will at a minimum capture/evaluate: 
! Assessment of bleeding episodes
! Adverse events
! N9-GP administration compliance
! eDiary compliance
8.10.5
Interactive voice/web response system
Please refer to Section 10 regarding the IV/WRS. 
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For details on how to use the IV/WRS, please refer to the trial specific IV/WRS user documents 
provided to the trial site. 
8.11
Patient compliance
Assessment of patient compliance with protocol procedures for determination of continuation of the 
trial will be done at the investigator’s discretion and by Novo Nordisk. 
Failure to comply with scheduled visits and N9-GP administration may result in withdrawal in 
accordance with the protocol withdrawal criteria. Treatment with FIX concentrates, other than N9-
GP, during the trial is not allowed and violation of this may lead to withdrawal due to non-
compliance (please refer to Section 11). Compliance with N9-GP prophylaxis must be addressed at 
each visit.
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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UTN: U1111-1119-5013
Status:
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9
Trial supplies
9.1
Trial product(s)
The following trial products will be supplied by Novo Nordisk A/S, Denmark:
! N9-GP Drug Product
! Histidine solvent 4.2 mL
N9-GP Drug Product is supplied as freeze-dried powder for injection in single use vials with a 
nominal content of 2000 IU/vial or 500 IU/vial to be reconstituted with 4.2 mL Histidine solvent. 
After reconstitution each vial contains 500 IU/mL or 125 IU/mL N9-GP, respectively. The 
reconstituted solution is a clear and colourless solution free from clearly visible particles. The 
reconstituted solution must not be further diluted.
Detailed instruction regarding reconstitution and dosing will be given in the Trial Materials Manual 
(TMM). After reconstitution the appropriate volume of the vials will be drawn into a syringe. The 
content of several vials N9-GP may be combined in one syringe. N9-GP may not be added to or 
mixed with any other material. 
Administration of the appropriate volume of N9-GP will be given as an i.v. bolus injection. 
Maximum injection rate is 4 mL/min (please refer to Section 8.9). The investigator will explain to 
the patient/caregiver how much this corresponds to in terms of injection time when administering 
N9-GP at home. If a central venous access port or cannula is used for N9-GP injection at dosing 
visits, and is sealed with heparin, it has to be flushed and sealed with saline the evening before the 
visit. This procedure is not necessary prior to home treatment injections.
The maximum dose to be administered to a patient within 24 hours is 200 IU/kg, with a maximum 
individual dose of 80 IU/kg to be administered no more frequently than every hour. These doses are 
only relevant in case of trauma, severe bleeding or surgery.
If the patient lacks recovery data for his previous FIX product, he will be dosed with this product at 
Visit 1. The FIX product is either a Non-Investigational Medicinal Product (NIMP) or IMP 
(Germany).
For Germany only:  In accordance with German GCP-Verordnung, the patient's previous FIX 
product is also defined as an IMP. The patient's previous FIX product could be any of the products 
currently authorised in Germany. The Summary of Product Characteristics for the actual IMP will 
be submitted.
In accordance with GCP-Verordnung §5, for IMPs (8) currently authorised in Germany, and which 
are intended for use in the clinical trial without any additional manufacturing steps, special labelling 
on the containers and outer packaging is not necessary. This is allowed by the concept of the 
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clinical trial. The particulars according to GCP-Verordnung § 5 (1) will be shown in an 
accompanying document.
9.2
Non-investigational medicinal product(s) 
If the patient lacks recovery data for his previous FIX product, he will be dosed with this product at 
Visit 1. In this case, the patient’s FIX product is defined as a NIMP. Traceability of the FIX 
products will be ensured by recording the brand name and batch number in the eCRF. 
Novo Nordisk A/S will not provide the previous FIX products but will reimburse trial sites for the 
cost of the products used at Visit 1. 
9.3
Packaging and labelling of trial product(s)
Novo Nordisk A/S will label and pack the trial product.
N9-GP Drug Product and Histidine solvent will be provided in boxes. The boxes will be provided 
with labels containing the following information: product name, expiry date, storage conditions. 
Each trial product vial will have a unique Dispensing Unit Number (DUN) for identification and 
traceability.
Labelling will be in accordance with Annex 1320, local law and trial requirements. 
The details of the packaging and labelling of the trial product will be provided in the TMM supplied 
by Clinical Supplies Coordination, Novo Nordisk A/S.
9.4
Storage, handling, accountability and destruction of trial product(s)
The trial products (N9-GP Drug Product and 4.2 mL Histidine solvent) at the site must be stored in 
a secure place, for N9-GP Drug Product under refrigeration at 2-8°C, and for the Histidine solvent 
at 2-25&C, both protected against light and are hereby stable until the expiry date given. It is 
recommended to use the reconstituted N9-GP immediately following reconstitution. If not used 
immediately, the reconstituted product can be stored in the vial for up to 4 hours below 30°C. 
Exposure to direct sunlight as well as freezing must be avoided after reconstitution. As for other 
parenteral preparations, the product should be inspected visually for particulate matter and 
discoloration prior to administration and discarded if either is present.
At home, the patient should store the trial products in a refrigerator until use. The site must 
carefully instruct the patient and parent(s)/caregiver in how to store the trial product. No 
temperature monitoring is required after the trial products are taken home by the patient.
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Version:
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The investigator must ensure the availability of proper storage conditions at the site and record and 
evaluate the temperature. The storage facilities must be checked frequently (at least once every 
working day) using a calibrated temperature logging device. A temperature log must be kept at the 
site. The investigator must ensure that the monitor is contacted in case of deviations outside the 
acceptable temperature range.
The temperature recorder should be either: 
!
Electronic with minimum interval of logging of 1 hour or ;
!
Manual with a min-max calibrated thermometer; the actual, minimum and maximum 
temperatures must be logged on working days
Dispensing and drug accountability
The IV/WRS will allocate the trial product in uniquely packed DUNs to the patient at each 
dispensing visit. The DUNs will be dispensed in accordance with the patient’s body weight.
! No trial products should be dispensed to any person not enrolled in the trial
! Unused trial product must be stored separately from used trial product
! Once a patient is dosed, all trial drug product vials (used, partly used or unused, returned and 
lost/damaged) must be recorded in the Drug Accountability Module
The investigator or delegated person, eg, a trial nurse will perform drug accountability in the 
IV/WRS Drug Accountability Module. 
Drug accountability must be performed for all delivered trial drug products. Trial product will be 
dispensed at dispensing or assessments visits, as appropriate. 
All used, partly used or unused trial products returned by the patient must be stored separately from 
non-allocated trial products. 
All trial drug products must be retained for inspection by the monitor. The monitor will, upon 
completion of drug accountability, arrange for the destruction of used, expired unused and broken 
vials of the supplied trial drug products.
The TMM, detailing the handling of the trial materials, will be provided by Novo Nordisk A/S.
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 (a pharmacist in principle). The trial product storage manager should control and take 
accountability of the trial drug products in accordance with procedures specified by Novo Nordisk 
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.
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9.5
Auxiliary supply
All auxiliaries supplies used in this trial will be provided by Novo Nordisk A/S such as syringes, 
butterflies, sterile swabs, vial adapters etc.
9.6
Shipment of trial product to patient’s home
For selected countries and if permitted by local regulations, the investigator may offer to send trial 
product and auxiliaries from the trial site or pharmacy to the patient’s home by courier service.
The process for sending trial product from the trial site or pharmacy to a patient’s home is described 
in the “Trial site/pharmacy instruction for shipment of trial product to patients’ homes” 
document.  This document contains detailed instructions for preparing packaging and setting up the 
pick-up of trial product, handover of trial product from the trial site or pharmacy staff to the courier, 
required temperature monitoring of trial product, delivery to and receipt of trial product by the 
patient. The process for returning trial product to the trial site or pharmacy by courier is also 
described in this document.
Investigators, trial site/pharmacy staff and patients who will be involved in shipment of trial product 
to the patient’s home will be adequately trained in this process.
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Version:
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10
Interactive voice/web response system
A trial specific IV/WRS will be set-up, and can be accessed at any time via internet or via telephone 
using toll-free telephone numbers. Some sessions may be available only as web sessions and can be 
accessed via internet. Accessibility to the IV/WRS must be restricted to and controlled by 
authorised persons. As a minimum, the system will be used for enrolling of patients, dispensing of 
trial product, controlling of expiry date of trial product, ordering of trial product, and screening 
failure data.  
Since the trial product will not be shipped to the site before screening, the investigator should be 
encouraged to make a confirmation call in the IV/WRS as soon as the patient is deemed eligible for 
the trial and no later than two weeks prior to the planned Visit 2. Otherwise the trial product may 
not be available in time for dosing at Visit 2.
IV/WRS user documents, containing detailed descriptions, will be provided to the site.
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Version:
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11
Concomitant illnesses and concomitant medication
Definitions:
Concomitant illness:
any illness that is present at the start of the trial (ie, at the first visit).
Concomitant medication: any medication, other than the N9-GP, that is taken during the trial, 
including the screening periods.
Details of all concomitant illnesses and medication must be recorded at trial entry (ie, at the first 
visit). Any changes in concomitant medication must be recorded at each visit. If a change is due to 
an AE then this must be recorded and reported according to Section 12. If the change influences the 
patient’s eligibility to continue in the trial then the monitor must be informed.
The information collected for each concomitant medication includes (at a minimum) start date, stop 
date or continuation and indication.
11 Concomitant illnesses and concomitant medication: 
Treatment of bleed in low titre inhibitor patients
Low titre inhibitor patients (<5 BU) who do not respond sufficiently to N9-GP treatment may be 
treated with activated recombinant factor VII (rFVIIa) for period of up to 4 weeks.
Prohibited medication
Plasma-derived prothrombin complex concentrates (pd-PCC) and plasma-derived activated 
prothrombin complex concentrates (pd-aPCC) are not allowed during the course of the trial.
! Coagulation Factors, not allowed in the 4 days prior to Visit 2: FVIII, FIX and coagulation factor 
VII (FVII) containing products other than N9-GP and other FIX-containing products like fresh 
frozen plasma or cryoprecipitate
! Anti-coagulants such as Heparin and vitamin-K antagonists except if they are used in relation to 
major surgery. Heparin is allowed for sealing of central venous access ports and cannulae 
according to local practice. An exception is when the ports are used for injection of N9-GP at 
dosing visits. In this case, heparin-sealed ports or cannulae have to be flushed and sealed with 
saline the evening before the visit. This procedure is not necessary prior to home treatment 
injections.
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Status:
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12
Adverse events and technical complaints
12.1
Definitions
Adverse event (AE):
Any untoward medical occurrence in a patient administered a pharmaceutical 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 medicinal product, whether or 
not considered related to the medicinal product.
Note: This includes events from the first trial related activity after the patient has signed the 
informed consent and until post treatment follow-up period as defined in the protocol.
An AE can also be a clinical laboratory abnormality regarded as clinically significant i.e. an 
abnormality that suggests a disease and/or organ toxicity, and is of a severity that requires active 
management (ie, change of dose, discontinuation of trial product, more frequent follow-up or 
diagnostic investigation).
A worsening in concomitant illness must be recorded as an AE. A worsening of an ongoing AE 
should be reported on a new AE form by making a new assessment for seriousness and/or severity.
The following should not be recorded as AEs: 
! Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the patient has signed the informed consent
! Pre-existing conditions found as a result of screening procedures. These should be recorded as 
medical history/concomitant illness.
Serious adverse event (SAE):
A SAE is an experience that at any dose results in any of the following:
! Death
! A life-threatening experience a)
! In-patient hospitalisation or prolongation of existing hospitalisation b)
! A persistent or significant disability/incapacity c)
! A congenital anomaly/birth defect
! Important medical events d) that may not result in death, be life-threatening a) or require 
hospitalisation may be considered a SAE when, based upon appropriate medical judgement, they 
may jeopardise the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
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!
a)  The term “life-threatening” in the definition of SAE refers to an event in which the 
patient was at risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death if it were more severe.
!
b)  The term “hospitalisation” is used when a patient is: 
! Admitted to a hospital/in-patient (irrespective of the duration of physical stay), or;
! Not admitted to a hospital/not in-patient, but stays at the hospital for treatment or observation for 
more than 24 hours.
! 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 neither be reported as AEs or SAEs. Likewise, hospital admissions for surgical 
procedures planned prior to trial inclusion are not considered AEs or SAEs.
!
c)  The term “disability/incapacity” means that following the event the patient has 
significant, persistent or permanent change, impairment, damage or disruption in his body 
function or structure, physical activity and/or quality of life.
!
d)  The term “important medical events” means events which may jeopardise the patient or 
require intervention to prevent a seriousness criterion. It can be AEs which suggest a 
significant hazard or puts the patient at risk, such as drug-interactions, contra-indications or 
precautions, occurrence of malignancies 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 a serious AE.
Severity assessment definitions:
!
Mild – No or transient symptoms, no interference with the patient’s daily activities
!
Moderate – Marked symptoms, moderate interference with the patient’s daily activities
!
Severe – Considerable interference with the patient’s daily activities, unacceptable.
Relationship to trial product (N9-GP) assessment definitions:
!
Probable – Good reasons 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.
Outcome categories and definitions: 
! Recovered – Fully recovered, or by medical or surgical treatment the condition has returned to 
the level observed at the first trial related activity after the patient signed the informed consent
! Recovering – The condition is improving and the patient is expected to recover from the event. 
This term should only be used when the patient has completed the trial
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! Recovered with sequelae – As a result of the AE the patient suffered persistent and significant 
disability/incapacity (eg became blind, deaf, paralysed). If the sequelae meet seriousness criteria, 
the AE must be reported as an SAE
! Not recovered
! Fatal
! Unknown – This term should only be used in cases where the patient is lost to follow-up.
12.1.1
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
! The physical or chemical appearance of trial products (e.g. discoloration, particles or
contamination)
! All packaging material including labelling
12.1.2
Reporting of MESI and other reports for expedited reporting
12.1.2.1
MESI 
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a
special focus.
A MESI should be reported following the same reporting requirements and timelines as for SAEs 
(see Section 12.2) irrespective of the MESI fulfils a SAE criterion.
The following are defined as MESIs in this trial:
1. Medication errors concerning trial products
!
The following should be reported:
!
Administration of wrong drug
!
Wrong route of administration, such as intramuscular instead of i.v.
!
Administration of an accidental overdose: more than 20% from the intended dose
2. Inhibitor formation against FIX is always considered a MESI. Blood samples for measurement 
of FIX inhibitors will be analysed at a central laboratory selected by Novo Nordisk A/S. 
However, if an investigator obtains any indication of inhibitor formation by clinical signs or 
local laboratory results, this should also be reported as a MESI
3. Thromboembolic events (clinical signs or laboratory indications of arterial and venous 
thrombosis including myocardial infarction, pulmonary embolism, cerebral 
infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events 
and peripheral artery occlusion, see definitions below)
4. Anaphylactic reaction as defined by Sampson et al 200621 (see below).
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5. Allergic reaction including, but not limited to, any acute IgE mediated reaction or delayed type 
hypersensitivity (clinical signs may include various types of skin rashes) that does not meet the 
definition of anaphylaxis as described by Sampson et al21
6. CNS-related adverse events, including but not limited to any learning and behavioural deficits”. 
Examples include but are not limited to:
!
Headache
!
Seizures
!
Vision problems
!
Acute changes in mental status
!
Developmental, cognitive or behavioural issues
7. Renal adverse events including new onset of renal disorder or renal impairment or acute and 
chronic renal failure.
Medical events of special interest must always be reported to Novo Nordisk as a SAE. So the AE 
form in the eCRF should be filled in. If for any reason the electronic data capture (EDC) application 
is unavailable, then fax, telephone or email Novo Nordisk.
Also complete the Safety Information Form on paper case report forms (CRFs). Forward a copy 
electronically in PDF format by fax or courier to Novo Nordisk. Reporting timelines for a MESI are 
the same as a SAE (see section 12.2).
Definition of an acute, evolving, or recent myocardial infarction
Either one of the following two criteria satisfies the diagnosis for an acute, evolving or recent 
myocardial infarction:
1. Typical rise and gradual fall in troponin T or more rapid rise and fall in creatine kinase, muscle 
and brain or biochemical markers of myocardial necrosis with at least one of the following:
a.
Ischaemic symptoms
b. Subsequent development of pathologic Q waves on the ECG
c.
ECG changes indicative of ischaemia (ST segment elevation or depression)
d. Coronary artery intervention (eg angioplasty)
2. Pathologic findings of an acute myocardial infarction (i.e., pathologic findings of an acute 
myocardial infarction will be defined when criteria a and b below are fulfilled):
a.
Increase in troponin T above the "diagnostic" limit: i.e. > 0.03 μg/L
b. Patients with:
!
ST-segment elevation: New ST-segment elevation at the J point in two or more contiguous 
leads with the cut-off points >= 0.2mV in leads V1, V2 or V3 and 0,1 mV in other leads 
(contiguity in the frontal plane is defined by the lead sequence aVL, I inverted aVR, II, 
aVF, III)
!
No ST-segment elevation: ST-segment depression and or T-wave inversion in two or more 
contiguous leads >= 0.1 mV
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Definition of pulmonary embolism
Obstruction of a pulmonary artery or one of its branches, most frequently by detached fragments of 
thrombus from a leg or pelvic vein, diagnosed by at least one of the following:
!
Positive findings in ventilation/perfusion scan
!
Positive findings in a spiral(helical) computed tomography or angiography
!
Positive findings in a magnetic resonance imaging
!
Positive findings in a pulmonary angiography
Definition of cerebral thrombosis/infarction
Acute neurological injury that persists for at least 24 hours and occurs as a result of either a 
thrombosis or embolic process, diagnosed by at least one of the following:
!
Computerised tomography
!
Magnetic resonance scan
!
Magnetic resonance angiogram
!
Cerebral angiography
Deep vein thrombosis
Venous thrombosis demonstrated by compression ultrasound, duplex ultrasound, or colour Doppler 
imaging.
Definition of other clinically significant thromboembolic events
Sign or suspicion of clinically significant thromboembolic event, eg visceral arterial 
embolus/thrombus, extremity arterial embolus/thrombus or portal venous thrombosis.
Superficial thrombophlebitis is not considered a clinically significant thromboembolic event unless 
evaluated so by the investigator.
Peripheral artery occlusion
Clinical signs of acute arterial occlusion verified by either ankle-brachial index test, Doppler or 
ultrasound (Duplex) imaging, computed tomographic angiography, magnetic resonance 
angiography, or conventional angiography.
Clinical criteria for diagnosing anaphylaxis (Sampson et al. 200621)
Anaphylaxis is highly likely when two or more of the following occur rapidly after exposure to a 
likely allergen for that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg generalised hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg dyspnea, wheese-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia)
c. Reduced BP or associated symptoms (eg hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg crampy abdominal pain, vomiting)
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12.1.2.2
Other reports for expedited reporting
Other reports for expedited reporting should be reported following the same reporting requirements 
and timelines as for SAEs (see section 12.2) irrespective of the report fulfils a SAE criterion.
The following is defined as other reports for expedited reporting in this trial:
1. Suspected transmission of an infectious agent via a trial product
Other reports for expedited reporting must always be reported to Novo Nordisk on the AE form in 
the eCRF.
12.1.3
Disease-related bleeding
Bleeding episodes and other symptoms (eg pain, swelling, synovitis, arthralgia, injection site 
haematoma) in connection with bleeding episodes that are evaluated by the investigator as part of 
the underlying disease should never be reported as AEs/SAEs unless the event is fatal, life-
threatening or evaluated by the investigator as related to trial product or trial procedure. In case of a 
fatal/life-threatening bleeding episode, it should always be reported as a SAE. All bleeding episodes 
and other symptoms related to the underlying disease will be captured in the eCRF or dairy.
12.2
Collection, recording and reporting of adverse events
All events meeting the definition of an AE must be collected and reported. Bleeding episode and 
other symptoms in connection with bleeding episodes that are evaluated by the investigator as part 
of the underlying disease must be collected from start of any trial related activity and reported 
according to Section 12.1.3. During each contact with the trial site (visit or telephone, excluding 
safety visits, where the patient is not seeing the investigator or his/her staff eg visits to the 
laboratory) the patient must be asked about AEs, eg, “Have you experienced any problems since the 
last contact?”.
All AEs, either observed by the investigator or reported by the patient, must be recorded by the 
investigator and evaluated. 
Novo Nordisk’ assessment of expectedness is done according to the reference documents:
! IB, N9-GP, current version and any updates hereof8.
For Japan only: If obtaining marketing approval in Japan, sponsor’s assessment of expectedness is 
done according to the package insert of the commercial products in Japan. Additionally, the IB is 
also used for the assessment of expectedness for reporting to the Investigator and the head of a site.
The investigator should record the diagnosis, if available. If no diagnosis is available then the 
investigator should record each sign and symptom as individual AEs.
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All AEs (including MESIs) must be recorded by the investigator on the standard AE form. If more 
than one sign or symptom is to be reported, use a separate AE form for each sign and symptom. For 
SAEs complete a safety information form for each event. However, if several symptoms or 
diagnosis occur as part of the same clinical picture, only one set of safety information form pages 
can be used to describe all the SAEs. 
MESIs must always be reported to the department responsible for global product safety on the AE 
form and the safety information form, irrespective of ser iousness within the same timelines as for 
SAEs.
The investigator must report initial information on all SAEs and MESIs to Novo Nordisk within 
24 hours of obtaining knowledge about the event. Contact details (fax, telephone and e-mail) for 
reporting of SAEs and MESIs are provided in Attachment II.
The investigator must complete and forward electronically in pdf format/fax copies to Novo 
Nordisk:
! AE form in the eCRF within 24 hours
! Safety information form on the paper CRFs within 5 calendar days of obtaining knowledge 
about the SAE.
For AEs: Only AE form to be filled in. For SAEs/MESIs: AE form in the eCRF within 24 hours and 
SIF on the paper CRFs within 5 calendar days.
If for some reason the EDC application is unavailable then the AE information should be r eported 
to Novo Nordisk by fax, telephone or e-mail within the same timelines.
Novo Nordisk must inform the IRBs/IECs in accordance with local requirement and GCP, unless 
locally this is an obligation of the investigator, as for example in the US.
Novo Nordisk must always inform the regulatory authorities in accordance with local requirements 
and GCP.
Novo Nordisk will notify the investigator of trial product related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with the local requirements. In addition, the investigator 
will be informed of any trial related procedure SAEs that may warrant a change of any trial 
procedure.
For Japan only: Novo Nordisk must inform the health authorities and the relevant parties of SAE 
information in accordance with the Japanese requirements in force and ICH GCP22.
Investigators will be notified of trial-related SAEs in accordance with the local requirements in 
force and ICH GCP22.
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Trial ID: Trial ID: NN7999-3774
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The monitor must be informed accordingly.
12.2.1
Follow-up of adverse events
During and following a patient’s participation in a clinical trial, the investigator should ensure that 
adequate medical care is provided to the patient for any AE, including clinically significant 
laboratory values related to the trial. The investigator should inform the patient when medical care 
is needed for AE(s) of which the investigator becomes aware.
The follow up information should only include new (updated and/or additional) information that 
reflects the situation at the time of the investigator’s signature.
Follow-up information (corrections, new or additional information) should be reported within 
24 hours of obtaining knowledge of the information for SAEs, and if previously non-serious AEs 
become SAEs/MESIs.
All non-serious AEs must be followed until the outcome of the event is “recovering”, “recovered” 
or “recovered with sequelae” or until the end of the post-treatment follow-up stated in the protocol, 
whichever comes first, and until all queries related to these AEs have been resolved. AEs ongoing at 
time of death (where death is due to another AE) may be closed with an outcome of “recovering” or 
“not recovered”. 
The investigator must ensure that the worst case severity and seriousness is kept consistent.
The investigator must record follow-up information on non-serious AEs by updating the AE form in 
the eCRF. The follow-up information should only include new (updated and/or additional) 
information that reflects the situation at the time of the investigator’s signature.
Queries or follow-up requests from Novo Nordisk should be responded to within 14 calendar days, 
unless otherwise specified. The investigator must forward follow-up information on SAEs and 
MESIs within 5 calendar days of obtaining the information. This must be done by updating the AE 
form in the eCRF and/or completing a new safety information form marked follow -up on paper 
CRF and forwarding these to Novo Nordisk. If for any reason the EDC application is unavailable, 
then fax, telephone or e-mail to Novo Nordisk. 
All SAEs and MESIs must be followed up until the outcome of the event is “recovered”, “recovered 
with sequelae” or “fatal” and until all queries have been resolved. Cases of chronic conditions or 
cancer or AEs ongoing at time of death (where death is due to another AE) may be closed with the 
outcome of “recovered” or “not recovered”. Cases can be closed with an outcome of “recovering” 
when the patient has completed the trial and is expected by the investigator to recover.
After access to update the AE form in eCRF is removed, the investigator must record any SAE and 
MESI follow-up information, if required, on the paper CRFs provided at trial closure.
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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Status:
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12.3
Technical complaints and technical complaint samples
12.3.1
Reporting of technical complaints 
All technical complaints, on any of the following products:
!
N9-GP 2000 IU/vial
!
N9-GP 500 IU/vial
!
Histidine solvent, 4,2 ml
!
Novo Nordisk Trial Injection Kit
which occur from the time of first usage until the time of 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 
MESIs.
Technical complaints must be reported on a separate technical complaint form:
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each batch or lot number must be 
completed
The investigator must complete and forward the technical complaint form by fax, e-mail or courier 
to Novo Nordisk, within the same timelines as for reporting AEs, SAEs and MESIs as follows (see 
Section 12.2):
!
Technical complaint assessed as related to a SAE and/or MESI within 24 hours of the trial 
site obtaining knowledge of the complaint
!
All other technical complaints within 5 calendar days
12.3.2
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 the 
sample is sent as soon as possible. A copy of the technical complaint form must be included in the 
shipment of the sample. If several samples are returned in one shipment, the individual sample and 
the corresponding technical complaint form must be clearly separated.
If the technical complaint sample was not retained or collected, the investigator must specify on the 
technical complaint form why it was not retained.
!
The investigator must ensure that the technical complaint sample is labelled with the batch 
number and, if available, the DUN number. All parts of the DUN should be returned.
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Version:
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Storage and shipment of the technical complaint sample should be done in accordance with the 
conditions described for the product (see Section 9). 
12.4
Pregnancies in partners of trial patients
In the case of an AE (with a causal relationship evaluated as possible or probable by the 
investigator) in the foetus, newborn infant(s) or infant(s)/toddler(s) of a trial patient’s partner, who 
is potentially exposed to the trial product via the trial patient, the pregnancy and the AE should be 
reported on pregnancy form Part A and Part B and an AE form.
12.5
Precautions and/or overdose
As with any protein injected i.v., hypersensitivity reactions may occur. The possible events include 
rash, pruritus, fever, nausea, headache, vomiting and changes in BP. If any of these events are 
suspected, further N9-GP administration should be stopped and the patient should receive treatment 
as appropriate according to the hospital practice and guidelines. 
If an overdose is suspected and in case of a safety concern, further N9-GP administration should be 
stopped and the patient be withdrawn from the trial. The patient should receive treatment as 
appropriate according to the hospital practice and guidelines.
12.6
Safety committee
12.6.1
Internal Novo Nordisk safety committee
Novo Nordisk will constitute an internal safety committee to perform ongoing safety surveillance of 
N9-GP in all phase 3 trials (pivotal (NN7999-3747), surgery (NN7999-3773), extension (NN7999-
3775) and paediatric (NN7999-3774)). The safety committee works according to a written guideline 
and will meet regularly to discuss and evaluate the overall safety of N9-GP for this trial and all 
other N9-GP trials.
12.6.2
Stopping rules
Any event occurring after administration of N9-GP fulfilling the SAE/MESI criteria must be 
reported to Novo Nordisk within 24 hours. If one of the below mentioned stopping criteria is 
fulfilled, enrolment of additional patients will be placed on hold. All investigators will be informed 
in writing. An urgent safety committee meeting will be called for to decide whether or not the trial 
can continue with or without modifications. Dosing of patients on treatment may continue while 
further evaluation of the SAE/MESI is made by the safety committee, unless otherwise decided by 
the safety committee. The evaluation of fulfilment of the below stopping rules by the safety 
committee will take into consideration whether or not the patient was dosed according to protocol.
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! Inhibitor formation (Bethesda Unit of ≥0.6 BU) in two patients. A patient has inhibitor 
formation if the patient has been tested positive for inhibitors at two consecutive tests fro m the 
central laboratory
! Anaphylaxis in two patients after trial product administration21
! Occurrence of two significant thromboembolic events in two different patients (eg myocardial 
infarction, pulmonary embolism, cerebral thrombosis/infarction or oth er significant 
thromboembolic event)
! Death related to trial product assessed by Novo Nordisk or by the investigator
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Trial ID: Trial ID: NN7999-3774
Version:
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Status:
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13
Case report forms
Novo Nordisk will provide a system for EDC. This system and support services to the system will 
be supplied by a vendor. The activities of this vendor will be under the direction and supervision of 
Novo Nordisk. Paper CRFs will be used for collection of data from major surgeries.
13.1
Rules for completing eCRFs
Ensure that all relevant questions are answered, and that no empty data blocks exist.
If a test/assessment has not been done and will not be available, or if the question is irrelevant (eg is 
not applicable) indicate this according to the data entry instructions.
The investigator must ensure that all information derived from source documentation is consistent 
with the source information. By signing the case book electronically, the investigator confirms that 
the information is complete and correct.
13.2
Corrections to eCRFs
Corrections to the CRF data will be made by the investigator or the investigator’s authorised staff. 
An audit trail will be maintained in the EDC application containing as a minimum: 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 of the investigator’s 
signature on the case book then the case book must be signed again by the investigator.
13.3
eCRF flow
The investigator must ensure that data is recorded in the eCRFs as soon as possible after the visit 
(preferably within three days). When data is entered it will be available to Novo Nordisk for data 
verification activities.
Site specific CRF data (in an electronic readable format) will be provided to the investigator after 
the trial database is released, and access to update the trial data in EDC has been removed. This data 
will be retained by the trial site.
When the final clinical trial report is available the data will be archived by Novo Nordisk.
13.4
Paper CRFs for major surgery
Data recorded for major surgery batch will be captured in paper CRF. Original paper CRF will be 
collected by monitor, and a copy must be retained at site.
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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Status:
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Please ensure using legible print and use of ballpoint when completing the paper CRF. Ensure that 
all questions are answered, and that no empty data blocks exist. Ensure that no information is 
recorded outside the data blocks. If an assessment or test 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 indicate this by writing “NA” (not applicable) in the appropriate answer field.
Investigator must ensure that all information is consistent with the source documentation by signing 
the affirmation statement and confirming that information in the CRF and related forms is complete 
and correct.
13.4.1
Corrections to paper case report forms
Corrections to the data in CRFs may only be made by drawing a straight line through the incorrect 
data and then writing the correct entry next to the data that was crossed out. Each correction must 
be initialled, dated and explained (if necessary). If corrections are made by the investigator’s 
authorised staff after the date of the investigator’s signature on the affirmation statement, the 
affirmation statement must be signed and dated again by the investigator. Corrections necessary 
after the CRFs have been removed from the trial site must be documented on a data clarification 
form (DCF) or a monitor-initiated discrepancy form (MIDF). If the affirmation statement for the 
subject has not yet been signed, any corrections must be approved by the investigator or her/his 
authorised staff. If the affirmation statement for the subject has already been signed, the investigator 
must approve any correction.
13.4.2
Paper case report form flow
The investigator must ensure that data is recorded in the CRF as soon as possible after the visit
13.5
eDiaries
Novo Nordisk will provide patients and/or parent(s)/LAR with an eDiary for electronic recording of 
details of their bleeding episodes, see Section 8.10.3. The eDiary and related support services will 
be supplied by a vendor that will be working under the direction and supervision of Novo Nordisk. 
At Visit 3, the patients will be provided with the eDiary and trained in the use thereof. The eDiary 
will be returned by the patient at either Visit 11 (for patients not continuing in the extension phase) 
or at the EOT visit.
Data will be entered by the patient or parent(s)/LAR in the eDiary device. All data entered will be 
automatically transferred from the device to the electronic patient reported outcomes (ePRO) 
database, where it is kept as a certified copy of the source data. Data entered in the device will upon 
confirmation of a successful back-up be deleted from the device.
The eDiary will contain built in edit checks, to ensure that all relevant questions are answered. 
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Version:
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The eDiary device is not intended to support the subsequent review and modification of completed 
entries. In case of corrections to transferred data are needed, a query flow must be initiated by the 
investigator. Upon review by Novo Nordisk, data will be corrected accordingly by the vendor. An 
audit trail will be maintained.
Data in the ePRO database will be viewable to relevant sites and Novo Nordisk personnel on a 
secure, password protected web portal. Data will be transferred to the Novo Nordisk trial database 
at defined intervals. For details on eDiary data flow, see Figure 13-1.
Figure 13-1
eDiary data flow
13.6
Tablets for neurocognitive assessments
The CRO will provide the sites with tablets for neurocognitive assessments including Structured 
Developmental History and Haemophilia History. In some occurrences these assessments will be 
collected on paper forms.
Data will be entered on the tablets at site by the patient, patient’s parent(s)/LAR(s) and in some 
cases by trained staff.
All data entered will be transferred from the tablets to a database. The results of the assessments 
will be viewable when transmitted from the tablet. The web based portal is password protected.
ePRO Vendor
Investigator site
Subject
Novo Nordisk
ePRO database
Device
Web Portal
W b P
t l
Trial  
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Trial ID: Trial ID: NN7999-3774
Version:
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Status:
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13.7
Paper diaries for major surgery
The patient will be provided with a paper diary by Novo Nordisk A/S that is to be completed during 
the period where regular N9-GP prophylaxis is paused due to major surgery. During this period the 
eDiary must be stored at site and not returned to the patient until regular prophylaxis is resumed.
Original paper diaries will be collected by monitor, and a copy must be retained at site.
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Date:
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Version:
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Status:
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EudraCT No.: 2011-000826-31
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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 accountability. The visit intervals will depend on the outcome of the remote monitoring of the 
eCRFs, the trial site's recruitment rate and the compliance of the trial site to the protocol and GCP. 
The monitor should visit a site soon after a patient has been screened. The intervals between 
monitoring visits must not exceed 28 weeks whilst patients are in the trial.
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 records 
and reports that are important to the evaluation of the trial. In addition, the investigator should be 
available for discussions with the monitor eg by telephone.
For screening failures: Data for the screening visit must be entered in the eCRF within preferably 
5 days after data are available and the Screening Failure Form must be completed. Source data 
verification is not required. All data entered in the eCRF will be transferred into the trial database.
For withdrawn patients: All data collected in the period the patient participated in the trial will be 
entered in the eCRF.
Information on prophylactic home treatment and treatment of bleeding episodes will be collected in 
the eDiaries (refer to Section 8.3.7). The completed eDiaries are considered source data. The patient 
will only be identified by patient number and the monitor will verify and ensure that the eCRFs and 
eDiaries are completed.
For all data recorded, the source document must be defined in a source document agreement at each 
site.
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Version:
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15
Data management
Data management is the responsibility of Novo Nordisk A/S. Data management may be delegated 
under an agreement of transfer of responsibilities to another data management unit within Novo 
Nordisk or external contract research organisation (CRO). 
Appropriate measures such as encryption of data files will be used to assure confidentiality of 
patient data when it is transmitted over open networks.
Laboratory data will be transferred electronically from the central laboratory performing clinical 
analyses. In cases where laboratory data are transferred via non-secure electronic networks, data 
will be encrypted during transfer. The electronic laboratory data will be considered source data.
The central and local laboratories will provide laboratory reports to the investigator. The laboratory 
reports must be signed and dated by the investigator and stored at the trial site as source data.
Data will be entered and delivered in an
file and loading into
The patient and biological material obtained from the patient will be identified by patient number, 
trial site and trial identification number. Appropriate measures such as encryption or deletion will 
be enforced to protect the identity of human patients in all presentations and publications as 
required by local/regional/national requirements.
The system for neurocognitive testing and support services for the system will be supplied by a 
CRO. The CRO will collect, query and process data from Structured Developmental History and 
Haemophilia History as well as Neurocognitive Assessments. The CRO will transfer assessment 
results and outcomes from the External Review Panel to NovoNordisk.
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Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems which are 
described in NN 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. 
Novo Nordisk will collect information on the practical use of these systems within the conduct of 
this clinical trial. 
Novo Nordisk will use the Global Haemophilia Network Investigator Portal to distribute and share 
trial-related documents and information with the participating sites.
The eDiary , and the electronic devices for neurocognitive assessments software and hardware 
implementation are compliant with the requirements of FDA 21 CFR Part 11 and ICH E6 (EU 
directive for personal data protection). After trial completion, each trial site will be supplied with 
CDs. These will contain site-specific patient records including the patient’s eDiaries and audit trail 
including any data additions and corrections made on each form. The eDiary vendor will 
furthermore retain and securely store copies of all archived documents and data for 15 years or as 
required by local data retention laws for trial data. 
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Evaluability of patients for analysis
All main descriptions and analysis of efficacy and PK data will be based on the Full Analysis Set 
(FAS), as defined in ICH E9 guidelines23. The FAS includes all patients with efficacy data after 
exposure to N9-GP. The safety analysis and descriptions will be based on the Safety Analysis Set 
(SAS). The SAS will consist of all patients exposed to N9-GP.
Pharmacokinetics analyses will be done on the FAS although it may be decided prior to database 
lock in exceptional cases to exclude patients or observations from these analyses based on protocol 
deviations and relevant overviews and listings (based on the trial database) prepared by the trial 
statistician. The decisions will be documented and the documentation will be stored together with 
the remaining trial documentation.
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18
Statistical considerations
Novo Nordisk A/S will be responsible for the statistical analysis.
The main statistical reporting of the trial will be performed when 10 patients in each age group have
completed the initial main phase (52 weeks) with at least 50 EDs. Data from patients that have 
entered the extension phase at this point will be included up to this cut-off date. This reporting will 
form the basis for the submission for approval.
The entire extension phase will be reported separately when it is completed.
18.1
Sample size calculation
No formal sample size calculations have been performed. The sample size is based on the 
requirements in the EMA guideline3.
18.2
Statistical methods
18.2.1
General considerations
Except for the confidence interval for inhibitor rate , for annualised bleeding rate the evaluation of 
data will be based on descriptive statistics, ie summary tables, listings and figures.Multiple bleeding 
locations occurring from the same event (eg, due to a bicycle accident) or at the same time point
will be counted as one bleeding episode.
Neurocognitive assessments will be evaluated primarily based upon reference ranges gained from 
children and young adults of a parallel observational haemophilia normative study (HAEM -4436, 
eTHINK) and secondarily upon normative reference ranges from the general population to the 
extent possible. Individual case review by an External Expert Review Panel, considering also 
analysis of factors influencing outcome in haemophilia and reported in the structured developmental 
history, will be reflected in narrative and categorical assessments (see Section 8.5.3 ). 
In general all summaries and analyses will also be made by age subgroup (0-6 and 7-12 years of 
age).
18.2.2
Primary endpoint
Incidence of inhibitory antibodies against FIX defined as ≥0.6 BU
The primary objective and endpoint will be evaluated when the main phase of the trial is completed 
and will include all data from patients already having entered the extension phase up to that cut-off 
date.
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The rate of neutralising inhibitors will be reported and a 1-sided 97.5% upper confidence limit will 
be provided based on an exact calculation for a binomial distribution. For the calculation of the rate 
the numerator will include the patients with inhibitors, while the denominator will include all 
patients with a minimum of 10 EDs plus any patient with less than 10 EDs but with inhibitors. 
Adequate safety with regard to inhibitors will be concluded if the observed rate is lower than or 
equal to 5%, corresponding to at most 1 inhibitor observed.
When the extension phase is completed, inhibitors in the extension phase will be listed.
18.2.3
Confirmatory secondary endpoints
The trial has no confirmatory secondary endpoints.
18.2.4
Supportive secondary endpoints
18.2.4.1
Safety endpoints
Adverse events including SAEs, MESI and development of HCP antibodies
Treatment emergent AEs (TEAEs, defined as AEs occurring after dosing with trial product) and 
treatment emergent SAEs (TESAEs) will be summarised by frequency of events and frequency of 
patients with any event. Similar summaries cross-classified by severity and by causal relation to 
trial product will also be made. 
AE’s occurring in the time period between the patients stops weekly prophylaxis treatment to go to 
major surgery and to the date and time when patient resumes weekly prophylaxis treatment will be 
presented in a listing.
MESIs will be summarised similarly to AEs.
Furthermore, listings will be provided displaying all TEAEs and TESAEs including pertinent 
clinical information.
HCP antibodies will be listed.
All additional safety parameters such as laboratory parameters, including calculation of eGFR 
(estimated glomerular filtration rate), and physical examinations, including neurological 
assessments, will be summarised and listed.
18.2.4.2
Efficacy endpoints
Number of bleeding episodes during prophylaxis 
Number of bleeding episodes during prophylaxis will also be presented by type (spontaneous, 
traumatic or other origin). 
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Annualised bleeding rate will be summarised and a 95% two sided confidence interval will be 
provided based on a Poisson regression model adjusting for exposure time and allowing for over-
dispersion.
Bleeding episodes occurring in the time period between the patients stops weekly prophylaxis to go 
to major surgery and to the date and time when patient resumes weekly prophylaxis treatment will 
be presented in a listing and will not be included in the estimation of the annualised bleeding rate 
during prophylaxis treatment. 
As sensitivity analysis data from patients withdrawing prematurely (but after more than 1 mont h on 
prophylaxis) will be imputed using a last observation carried forward (LOCF) approach. If patients 
drop out due to ineffective prophylaxis this may give a more correct estimate of the treatment 
effect.
Annualised bleeding rate will also be summarised by type of bleeding episode and by age group.
Haemostatic effect of N9-GP in treatment of bleeding episodes
Summaries of this endpoint will include bleeding episodes from both the main phase and the 
extension phase up to the cut-off date since they will be treated in the same manner. Summaries will 
however also be provided for the main phase and the extension phase separately.
Description of the haemostatic effect of N9-GP when used for treatment of bleeding episodes will 
be measured and listed according to the four point scale for haemostatic response (excellent, good, 
moderate and poor). 
A success rate will be calculated based on counting good or excellent as successes and poor and 
moderate as failures.
Acute efficacy, efficacy when treating bleeding episodes, will also be summarised by type of 
bleeding and by age group as well as for the main phase and the extension phase separately as 
mentioned above.
FIX consumption
Amount of N9-GP used for prophylaxis and number of doses and amount consumed per bleeding 
episode (IU/kg BW/bleeding episode) will be summarised and listed.
18.2.4.3
Pharmacokinetic endpoints
Pharmacokinetic endpoints, except trough steady state and C30min steady state, are assessed after a 
single dose (Visit 2). Steady state trough and C30min will be assessed at Visit 4 - Visit 10 during the 
main phase of the trial.
! IR30min ( [IU/mL] / [IU/kg] )
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Trial ID: Trial ID: NN7999-3774
Version:
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! Trough level (IU/mL) (single dose and steady state)
! AUC (Uxh/mL)
! Terminal half-life (t1/2), (h)
! CL (mL/h/kg)
! MRT (h)
! Vss (mL/kg)
! C30min (IU/mL) (single-dose and steady state)
Table 18-1
Definition and calculation of PK parameters
Parameter
Description
Calculation
IR30min
Peak activity recorded 30 minutes after 
end of injection and reported as 
[IU/mL]/[IU/kg]
The incremental recovery is calculated by dividing 
the pre-dose subtracted FIX activity (IU/mL) 
measured in plasma 30 minutes after dosing by the 
dose injected at time 0 expressed as IU/kg body
weight
Trough level 
(single dose)
Lowest activity recorded at Visit 2, 168 
hours post-dose (immediately before next 
dose is given) and reported as (IU/mL) 
Trough level 
(steady state)
Lowest activity recorded immediately 
before next dose is given (after Visit 3) 
and reported as (IU/mL)
t1/2
Terminal half-life (h)
t1/2 = ln(2)/λz, where λz is the terminal elimination 
rate. The terminal elimination rate will be estimated 
using linear regression on the terminal part of the 
log(activity) versus time profile
CL
Total plasma clearance of drug after 
intravenous administration (mL/h/kg)
CL= Dose/AUC
AUC
Area under the activity versus time 
profile from time zero to infinity. 
Measure of total plasma exposure 
(Uxh/mL)
AUC = AUC(0-t) + C(t)/λz ,
where C(t)  is the last measurable activity.
MRT 
Mean residence time (h)
MRT = AUMC/AUC, where AUMC is the area 
under the first moment curve, ie, the area under the 
curve txC(t), calculated with the same method as 
AUC (linear trapezoidal method + extrapolated area) 
Vss 
Apparent volume of distribution at 
steady-state (mL)
Vss = CLxMRT
C30min
(single-dose)
The FIX activity recorded 30 minutes 
after end of injection (IU/mL) at Visit 2
C30min
(steady state)
The FIX activity recorded 30 minutes 
after end of injection (IU/mL) at Visit 
4 -Visit 10
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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UTN: U1111-1119-5013
Status:
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EudraCT No.: 2011-000826-31
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PK endpoints will be summarised and listed. PK will also be summarised by age group. All PK 
endpoints will be calculated based on baseline corrected plasma concentration.
Trough level (steady state)
Mean FIX trough activity levels during prophylaxis will be calculated as a mean of patient means. 
FIX trough activity levels of the main phase will be summarised. Plasma concentrations below 
lower limit of quantification (LLOQ) will be set to half the value of the LLOQ.
Only measurements taken at least 5 days and no more than 10 days after last dose as well as 
measurements taken at least 14 days after last bleeding episode will be included in the calculation of 
steady state trough.
C30min (steady state)
Mean C30min during prophylaxis will be calculated as a mean of patient means. C30min levels of the 
main phase will be summarised.
18.3
Neurocognitive assessments 
Age-adjusted domain and composite scores for each neurocognitive instrument will be calculated 
using available methods. 
The individual patient overall/domain/sub-scores for each neurocognitive assessment instrument 
will be expressed as an individual’s Z-score (i.e. an indication of how many standard deviations a 
domain score is from the mean) and compared to reference ranges from normative data for children 
and young adults with haemophilia (adjusted for appropriate identified covariates) (HAEM-4436, 
eTHINK study).
All the scores will be provided by a CRO. The individual score versus time of exposure (years) will 
be presented graphically by patient. In addition, all data and scores will be summarised and listed.
18.4
Interim analysis
The main phase of the trial will be analysed and reported before the extension phase is completed. 
All main conclusions from the trial will be based on this reporting. The interim analysis will cover 
all endpoints. Furthermore interim analyses may be performed in association with marketing 
authorisation applications or in connection with Health Authorities e.g. FDA, EMA and PMDA 
requirement for/during the regulatory review or to obtain safety data.
Some inspections of the data will be performed in the course of the trial in order to comply with 
various health authorities requests. Safety and PK data for the first five patients in the age group 
7-12 years will be summarised and evaluated before dosing can commence in the age group 0-6
years. PK data from the first five patients in the age group 0-6 years will be summarised and 
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Version:
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Status:
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evaluated for the purpose of adjusting the dose level if the PK profile is found to have a clinically 
relevant difference from adults.
18.5
Sequential safety analysis/safety monitoring
Novo Nordisk A/S will constitute an internal safety committee to perform ongoing safety 
surveillance. The trial will be subject to stopping rules evaluated by this safety committee (Section 
12.6.2). 
18.6
Reporting of F9 genotype 
Information about underlying gene defects of F9 will be listed in the clinical trial report. No 
statistical analysis will be performed.
18.7
Pharmacokinetic and/or pharmacodynamic modelling
Population PK is not a part of the planned statistical analysis.
18.8
Health economics and/or patient reported outcome
Health economic data and changes in PRO data (from the screening visit) will be summarised and 
listed using descriptive statistics. In case a new age fitted PRO questionnaire was introduced at V17 
this will be used to calculate change from V17 to Visit 22/23/24. The PRO used at visit 17 will also 
be used at Visit 22/23/24 (the relevant visit where neurocognitive assessment s are performed for 
the first time for each patient) 
Health economic calculations will be performed separately by the Novo Nordisk Health Economic 
Department.
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Date:
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Trial ID: Trial ID: NN7999-3774
Version:
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UTN: U1111-1119-5013
Status:
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19
Ethics
The trial will be conducted in compliance with ICH GCP22, applicable regulatory requirements, and 
in accordance with the Declaration of Helsinki24.
After completion of the main phase, patients will continue with prophylaxis in the extension phase. 
If the patient does not wish to continue in the extension phase, he will consult with the investigator 
to decide on the best available treatment.
19.1
Informed consent form for trial patients
In seeking and documenting informed consent, the investigator must comply with the applicable 
regulatory requirements, and adhere to the ICH GCP22 and the requirements in the Declaration of 
Helsinki24.
Prior to any trial-related activity, the investigator must give the patient and/or the patient’s 
parent(s)/LAR oral and written information about the trial in a form that the patient or the patient’s 
parent(s)/LAR can read and understand. This includes the use of impartial witness, where required. 
In this trial the notion of LAR include both parents and legal representatives, as defined in Member 
States’ national laws, who consents on behalf of the child.
Consent: As a child is unable to provide legally binding consent, informed consent must be sought 
from the parent(s)/LAR on the child’s behalf. The specific and written informed consent of the 
parent(s)/LAR must be sought prior to enrolling a child in the trial. Information about the trial 
should be given by an experienced investigator.
Assent: When a patient deemed legally incompetent, such as a child, is able to give assent to 
decisions about participation in trial, the investigator must offer the possibility for the child to give 
assent in addition to the consent of the parent(s)/LAR. An "assent form" will be provided and can 
be used when appropriate and when the child is capable of forming an opinion and assessing.
The requirement for obtaining informed consent from a patient’s parent(s)/LAR is that the patient is 
unable to provide informed consent, and the process has been approved by the relevant IRB/IEC.
A voluntary, signed and personally dated, including time, informed consent form will be obtained 
from the patient and/or the patient’s LAR prior to any trial-related activity. 
The responsibility for seeking informed consent must remain with the investigator or an adequately 
medically qualified person delegated by the investigator. The written informed consent must be 
signed and personally dated, including time, by the parent(s)/LAR, and by the person who seeks the 
informed consent.
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Version:
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If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the investigator must inform the patient and/or the patient’s parent(s)/LAR 
in a timely manner, and a revised written informed consent must be obtained.
F9 genotype testing/collection of previous genotype documentation
Genotype testing is offered to the patients participating in this trial. If documentation of the 
patients’ genotype already exists, the patient and/or the patient’s parent(s)/LAR must give their 
consent before the data can be collected for trial purpose. Prior to any trial-related activity, the 
investigator must provide the patient with the possibility to abstain from the genetic 
testing/collection of previous documentation, but still be able to participate in the trial.
Only the F9 genotype will be analysed by the central laboratory selected by Novo Nordisk A/S and 
no other genomic analyses will be carried out. Samples will be appropriately disposed of, after the 
test. All test results are kept strictly confidential in sufficient consideration of individual 
information.
19.2
Data handling
If the patient or the patient’s parent(s)/LAR withdraws the previously given informed consent, if the 
patient dies and no consent is available from a patient’s parent(s)/LAR, or if the patient is lost to 
follow up, the patient’s data will be handled as follows:
! Data collected will be retained by Novo Nordisk A/S and entered into the database
! Safety events will be reported to the department responsible for global product safety, Novo 
Nordisk/regulatory authorities according to local/national requirements.
If data is used, it will always be in accordance with local law and IRB/IEC procedures.
19.3
Institutional review board/independent ethics committee
Prior to commencement of the trial, the protocol, any protocol amendments, patient 
information/informed consent form, any other written information to be provided to the patient, 
patient recruitment procedures (incl. advertisement), if any, IB, available safety information, 
information about payments and compensation available to patients if not mentioned in the patient 
information, the investigator’s current curriculum vitae (CV) and/or other documentation 
evidencing qualifications, and other documents as required by the local IRB/IEC should be 
submitted. The submission letter should clearly identify the trial identification number, version, 
EudraCT no., title and/or the date of the documents that have been submitted to the IRB/IEC. 
Written approval/favourable opinion must be obtained from IRB/IEC prior to commencement of the 
trial.
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During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to IB, unexpected SAEs 
where a causal relationship cannot be ruled out, substantial protocol amendments to the protocol, 
non-substantial protocol amendments according to local requirements, deviations to the protocol 
implemented to eliminate immediate hazards to the patients, new information that may affect 
adversely the safety of the patients 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 patients), annually written summaries of 
the trial status, and other documents as required by the local IRB/IEC.
Substantial protocol amendments must not be implemented before approval/favourable opinion, 
unless necessary to eliminate immediate hazards to the patients.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records should be filed in the investigator’s trial file and copies must be sent to Novo 
Nordisk.
19.4
Regulatory authorities
Regulatory authorities will receive the clinical trial application, substantial/non-substantial protocol 
amendments, reports on SAEs, and the clinical trial report according to national requirements.
For Japan only: Regulatory authorities will receive the clinical trial notification, notifications of 
protocol amendments, reports on SAEs, and the clinical trial report according to the national 
requirements.
19.5
Information to patient during trial
The trial site will be offered a communication package to the patient and/or the patient’s 
parent(s)/LAR(s) during the conduct of the trial. The package content is issued by Novo Nordisk. 
The communication package will contain the letters intended for distribution to the patients. The 
letters will be translated and adjusted to local requirements and distributed to the patient and/or the 
patient’s parent(s)/LAR(s) by the investigator. The patient and/or the patient’s parent(s)/LAR(s) 
may receive letters during the trial and a “thank you for your participation letter ” after completion 
of the trial. 
All written information to patient will be submitted to IRB/IEC for approval/favourable opinion and 
to regulatory authorities for approval or notification according to local regulations.
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20
Premature termination of the trial/trial site
Novo Nordisk, investigator or a pertinent regulatory authority may decide to stop the trial/trial site 
or part of the trial at any time, but agreement on procedures to be followed must be obtained.
If a trial is prematurely terminated or suspended, the investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the investigator and/or Novo 
Nordisk should promptly inform the IEC/IRB and provide a detailed written explanation. The 
pertinent regulatory authorities should be informed according to national regulations.
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation should 
be provided to the IEC/IRB in case it will have an impact on the planned follow-up of the patients 
who have participated in the trial. If so, the actions needed to protect the patients should be 
described.
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21
Protocol compliance 
Deviations from the protocol should be avoided.
If deviations occur then the investigator must inform the monitor, and the implications of the 
deviation must be reviewed and discussed.
Protocol deviations must be documented stating the reason, date, the actions taken, and the impact 
for the patients and/or the trial except for protocol deviations where no corrections are required as 
described in the trial specific validation checks in the approved trial validation plan (TVP). The 
investigator must approve these as outlined in the TVP. 
The documentation for the protocol deviations must be kept in the investigator’s trial file and Novo 
Nordisk’s trial master file.
21.1
Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk internal Quality 
Audit System or an inspection from domestic or foreign regulatory authorities. The investigator and 
the site staff as well as Novo Nordisk clinical staff have an obligation to cooperate and assist in 
such audits and inspections. This includes giving auditors and inspectors direct access to all source 
documents and other documents relevant to the conduct of the clinical trial at the site.
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22
Critical documents
Before the investigator starts the trial (i.e. the site has green light for screening patients), the 
following documents must be available to Novo Nordisk:
! regulatory approval and/or notification as required 
! curricula vitae of investigator and sub-investigator(s) (current, dated and signed and/or supported 
by an official regulatory document)
! signed receipt of IB
! signed and dated agreement on the final protocol
! signed and dated agreement on any substantial protocol amendment(s), if applicable
! approval/favourable opinion from IEC/IRB clearly identifying the documents reviewed: the 
protocol, any substantial protocol amendments, patient information/informed consent form and 
any other written information to be provided to the patient, patient recruitment procedures
! copy of IEC/IRB approved patient information/informed consent form/any other written 
information/advertisement
! list of IEC/IRB members/constitution
! financial agreement(s)(for US: verification under disclosures per CFR of Financial Conflict of
Interest25).
! FDA financial disclosure form or local equivalent, as applicable
! laboratory reference ranges
! laboratory certification/QA scheme/other documentation
! laboratory methods
! for US sites: FDA form 1572 must be completed by each investigator and individual clinical 
trial staff, if directly involved in the treatment or evaluation of research making a direct and 
significant contribution to the data 
FDA form 1572:
For US sites:
! Intended for US sites
! Conducted under the IND
! All US investigators and clinical trial staff, 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
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As documented in writing by protocol signature, all investigators will fully comply ICH GCP 22, 
applicable regulatory requirements, and in accordance with the Declaration of Helsinki24.
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23
Responsibilities
All staff (Novo Nordisk, site, laboratory, CRO etc) must conduct the trial in compliance with ICH 
GCP22, applicable regulatory requirements, and in accordance with the Declaration of Helsinki24. 
The investigator is accountable for the conduct of the trial. If any tasks are delegated, the 
investigator should maintain a list of appropriately qualified persons to whom he/she has delegated 
specified significant trial-related duties.
A qualified physician, who is an investigator or a sub-investigator for the trial, should be 
responsible for all trial-related medical decisions.
The investigator will follow the instructions from Novo Nordisk when processing 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.
In case the investigator is not able to fulfil the role as investigator (eg retirement), a new 
investigator must be appointed in collaboration with Novo Nordisk. 
Upon request from Novo Nordisk, the investigator will provide Novo Nordisk with the necessary 
information to enable Novo Nordisk to ensure that such technical and organisational safety 
measures have been taken.
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24
Reports and publications
The information obtained during the conduct of this trial is considered confidential, and can 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.
The investigator to be designated with the responsibility to review and sign the clinical trial report 
(signatory investigator) will be a member of the Advisory Board and investigator in this trial. 
24.1
Communication and publication
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 
by other means.
Novo Nordisk reserves the right to not release data until specified milestones, eg when the clinical 
trial report is available. This includes the right to not release interim results of clinical trials, 
because the release of such information can invalidate the results of the entire trial.
At the end of the trial, one or more manuscripts for publication will be prepared collaboratively 
between investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication 
and/or communication for less than 60 days to protect intellectual property.
24.1.1
Authorship
Authorship of publications should be in accordance with guidelines from The ICMJE Uniform 
Requirements (sometimes referred to as the Vancouver Criteria26).
24.1.2
Publications
The results of this trial will be subject to public disclosure at external web sites according to 
international regulations, which is reflected in Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure.
In all cases, the trial results shall be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations of the trial. All authors will be given the 
relevant statistical tables, figures, and reports needed to support the planned publication. In the 
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event of any disagreement about the content of any publication, both the investigators’ and Novo 
Nordisk’s opinions shall be fairly and sufficiently represented in the publication.
In a multi-centre trial based on the collaboration of all trial sites, any publication of results must 
acknowledge all trial sites.
Novo Nordisk maintains the right to be informed of any investigator plans for publication 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 
the Novo Nordisk trial manager prior to submission for comments. Comments will be given within 
four weeks from receipt of the planned communication.
24.1.3
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 
patients; and therefore may not be supported by Novo Nordisk. It is Novo Nordisk’s 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 and to ask for deferment of 
publication of individual site results until after the primary manuscript is accepted for publication.
24.2
Investigator access to data and review of results
As owners of the trial database, Novo Nordisk has discretion to determine who will have access to 
the database. Generally, trial databases are only made available to regulatory authorities.
Individual investigator(s) will have their own research participants' data after the investigator results 
meeting.
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25 Retention of clinical trial documentation and human biospecimens
Patient notes 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 after trial 
completion, Novo Nordisk can refer the investigator to an independent archiving provider who has 
a system in place that allows only the investigator to access the files.
The investigator must be able to get hold of his/her trial documents without involving Novo 
Nordisk in any way. 
Clinical trial documentation must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the IMP. 
For Japan: The clinical trial site should retain clinical trial documentation until approval, or 3 
years after the date of premature termination or completion of the clinical trial. The sponsor should 
retain clinical trial documentation for 5 years after the approval (in case of drug subject to re-
examination, until re-examination is completed), or 3 years after the date of premature termination 
or completion of the clinical trial.
Novo Nordisk will maintain Novo Nordisk’s documentation pertaining to the trial as long as the 
product is on the market plus 20 years. The files from the investigator site/institution will be 
retained 15 years after the completion of the trial, or longer if required by national regulations.     
25.1
Retention of human biospecimens
Antibody samples (samples for binding antibodies and inhibitors) and all remaining blood samples 
will be stored until the trial has been evaluated by appropriate authorities or until the project 
terminates, but no longer than 15 years from end of trial. As new biomarkers related to the disease 
and/or safety, efficacy, or mechanism of action of N9-GP may evolve during the conduct of the 
trial, the analyses of the stored biospecimens may also include biomarkers that are unknown at 
present or have not been included in the scientific hypothesis at initiation of the trial. As new 
biomarkers related to the disease and/or safety, efficacy, or mechanism of action of N9-GP may 
evolve during the conduct of the trial, the analyses of the stored biospecimens may also include 
biomarkers that are unknown at present or have not been included in the scientific hypothesis at 
initiation of the trial.
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
132 of 135
The samples will be stored at Novo Nordisk designated central laboratory (biorepository) with 
access to the samples. Samples might be transferred to other countries, if not prohibited by local 
regulations. The patient’s identity will remain confidential and samples will only b e marked and 
identified by a unique sample ID. No direct identification of the patient will be stored together with 
the samples. The analyses will not have any medical consequences for the patients or their relatives. 
Only Novo Nordisk staff and central laboratory personnel (if applicable) will have access to the 
stored bio specimens.
In the event that the collected biospecimens (plasma, serum and genotype 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 and analytically valid and quantifiable. 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. Potentially, observations of 
neoplastic diseases, serious genetically hereditary diseases, other untreatable diseases, or any other 
abnormal findings could be part of the observations. Patients or parent(s)/LAR may at any time 
contact the investigator if they wish to be informed about results derived from stored biospecimens 
obtained from their own body.
Storage and disposition of samples analyses at local laboratories will be performed according to 
local laboratory procedures.
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
133 of 135
26
Indemnity statement
Novo Nordisk carries product liability for its products and liability 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 by the clinics or 
doctors conducting experiments, or by persons for whom the said clinic or doctors are responsible.
Novo Nordisk accepts liability in accordance with applicable local laws and guidelines.
For France only: The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 
2004 art. 88 I, IX Journal Officiel of 11 August 2004). "The sponsor is responsible for identification 
of the harmful consequences of the biomedical research for the person lending himself thereto and 
for indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice 
is not attributable to his fault or the fault of any intervening party, without the sponsor's being 
entitled to call on acts by a third party or the voluntary withdrawal of the person who had initially 
consented to cooperating in the research".
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
134 of 135
27
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Protocol
CONFIDENTIAL
Date:
27 June 2018
Novo Nordisk
Trial ID: Trial ID: NN7999-3774
Version:
12.0
UTN: U1111-1119-5013
Status:
Final
EudraCT No.: 2011-000826-31
Page:
135 of 135
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