Clinical trial NCT02141074
Conditions: Congenital Bleeding Disorder Haemophilia B
Sponsor: Novo Nordisk A/S
Start date: 2014-07-02; Completion date: 2022-10-27
Enrollment: 54 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial is conducted globally. The aim of the trial is to investigate the safety and efficacy of nonacog beta pegol (N9-GP) in previously untreated patients with Haemophilia B.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: nonacog beta pegol
Intervention descriptions: intervention 1: For intravenous (i.v.) injection. A single dose of 40 U/kg, unless the bleeding episode is severe in which case it should be treated with 80 U/kg.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02141074 
Sponsor trial ID: 
NN7999-3895 
Official title of study: 
An Open-label Single-arm Multicentre Non-controlled Phase 3 
a Trial Investigating Safety and Efficacy of Nonacog Beta 
Pegol (N9-GP) in Prophylaxis and Treatment of Bleeding 
Episodes in Previously Untreated Patients With Haemophilia 
B (FIX Activity Below or Equal to 2 Percent) 
Document date: 
05 November 2019 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header of Page 2 is the date of compilation of the documents and not of an update to content.


Link
Link
List of contents
Protocol ...............................................................................................................................................
Protocol attachment ...........................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
nonacog beta pegol
Trial ID: NN7999-3895 Final
Clinical Trial Report
Appendix 16.1.1
24 February 2023
1.0
Final
16.1.1 Protocol and protocol amendments
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
Page:
1 of 119
  
Protocol
Trial ID:NN7999-3895
Safety and Efficacy of nonacog beta pegol (N9-GP) in 
Previously Untreated Patients with Haemophilia B
An open-label single-arm multicentre non-controlled phase 3a trial investigating safety and efficacy 
of nonacog beta pegol (N9-GP) in prophylaxis and treatment of bleeding episodes in previously 
untreated patients with haemophilia B (FIX activity ≤2%)
Includes:
Protocol Amendment no 1 (25-Mar-2015), Protocol Amendment no 2 (15-Jan-2016), Protocol 
Amendment no 4 (13-Dec-2016), Protocol Amendment no 5 (11-Dec-2017), Protocol Amendment 
no 6 (29-Jun-2018), Local Protocol Amendment no 7 (31-Jul-2019) (Only applicable for Spain) and 
Protocol Amendment no 8 (05-Nov-2019).
Trial phase: 3a
Protocol originator: 
, International Trial Manager
Biopharm, Trial Operations 2
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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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
Page:
2 of 119
  
Table of contents
Page
Table of contents.........................................................................................................................................2
Table of figures ...........................................................................................................................................7
Table of tables.............................................................................................................................................7
List of abbreviations ...................................................................................................................................8
1
Summary............................................................................................................................................11
2
Flow chart ..........................................................................................................................................14
3
Background information and rationale for the trial.........................................................................19
3.1
Background information..........................................................................................................19
3.2
Rationale for the trial...............................................................................................................20
3.3
N9-GP (nonacog beta pegol) ...................................................................................................20
3.4
Risk and benefits.....................................................................................................................21
4
Objective(s) and endpoint(s)..............................................................................................................23
4.1
Objective(s) ............................................................................................................................23
4.2
Endpoint(s) .............................................................................................................................23
4.2.1
Primary Endpoint...................................................................................................23
4.2.2
Secondary Endpoint...............................................................................................23
5
Trial design ........................................................................................................................................24
5.1
Type of trial ............................................................................................................................24
5.2
Rationale for trial design .........................................................................................................24
5.3
Treatment of patients...............................................................................................................25
5.3.1
Previous exposure to FIX products.........................................................................25
5.3.2
Pre-prophylaxis treatment ......................................................................................26
5.3.3
Prophylaxis treatment ............................................................................................26
5.3.4
Treatment of bleeding episodes ..............................................................................26
5.3.5
Requirements for the first 20 injections ..................................................................27
5.3.6
Treatment of bleeding episodes in low titre inhibitor (<5 BU) patients....................27
5.3.7
Treatment of suspected severe bleeding episodes ...................................................27
5.3.8
Surgery..................................................................................................................27
5.3.9
Vaccinations ..........................................................................................................29
5.4
Treatment after end of trial......................................................................................................29
5.5
Rationale for treatment............................................................................................................30
6
Trial population .................................................................................................................................31
6.1
Number of patients..................................................................................................................31
6.2
Inclusion criteria .....................................................................................................................31
6.3
Exclusion criteria ....................................................................................................................31
6.4
Withdrawal criteria .................................................................................................................32
6.4.1
Only applicable for Spain: Temporary discontinuation of trial treatment.................32
6.5
Patient replacement .................................................................................................................32
6.6
Rationale for trial population...................................................................................................33
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Protocol
CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
Page:
3 of 119
  
6.6.1
Rationale for inclusion criteria ...............................................................................33
6.6.2
Rationale for exclusion criteria...............................................................................33
6.6.3
Rationale for withdrawal criteria ............................................................................33
7
Milestones...........................................................................................................................................34
8
Methods and assessments ..................................................................................................................35
8.1
Visit procedures ......................................................................................................................35
8.1.1
Visit 0 – screening visit..........................................................................................37
8.1.1.1
Pre-prophylaxis treatment.................................................................38
8.1.1.2
Prophylaxis treatment.......................................................................39
8.1.2
Visit 1 – first dosing with N9-GP ...........................................................................39
8.1.3
Visit 2-20 – main phase..........................................................................................40
8.1.3.1
Treatment outside trial site ...............................................................40
8.1.4
Visit 21-22 – main phase........................................................................................41
8.1.5
Visit 23 – end of main phase..................................................................................42
8.1.6
Visit 24-27 – extension phase.................................................................................42
8.1.7
Visit 28 - end of extension phase............................................................................43
8.1.8
Visit 29-X until end of trial ....................................................................................43
8.1.9
End-of-trial visit ....................................................................................................44
8.1.10
Unscheduled visit...................................................................................................44
8.1.11
Inhibitor Follow-Up visit .......................................................................................44
8.1.12
Home treatment .....................................................................................................45
8.1.12.1
Prophylactic home treatment ............................................................45
8.1.12.2
Home treatment of bleeding episodes ...............................................46
8.2
Patient related information ......................................................................................................46
8.2.1
Concomitant illness and medical history.................................................................46
8.2.1.1
Details on haemophilia and haemophilia treatment history................46
8.2.1.2
Allergies ..........................................................................................46
8.2.2
Concomitant medication ........................................................................................47
8.2.3
Treatment of bleeding episodes in low titre inhibitor patients < 5 BU.....................47
8.2.4
Prohibited medication ............................................................................................47
8.2.5
Demography ..........................................................................................................47
8.3
Clinical assessments................................................................................................................47
8.3.1
Body measurements...............................................................................................48
8.3.2
Physical examinations............................................................................................48
8.3.2.1
Neurological Examination................................................................48
8.3.3
Neurocognitive assessments...................................................................................49
8.3.4
Vital signs..............................................................................................................54
8.4
Laboratory assessments...........................................................................................................54
8.4.1
Local laboratory assessments .................................................................................55
8.4.1.1
FIX activity......................................................................................55
8.4.2
Central laboratory assessments...............................................................................55
8.4.2.1
FIX activity......................................................................................56
8.4.2.2
Antibody assessments.......................................................................56
8.4.2.3
HIV testing and CD4+ lymphocyte count .........................................58
8.4.2.4
Haematology....................................................................................59
8.4.2.5
Biochemistry....................................................................................59
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CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
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8.4.2.6
F9 and HLA genotype testing ...........................................................60
8.4.2.7
Investigation of allergic reactions .....................................................60
8.4.2.8
Urinalysis.........................................................................................61
8.4.2.9
Exploratory analysis of PEG in plasma.............................................61
8.4.3
Blood sampling in infants and children...................................................................62
8.4.4
Storage of samples.................................................................................................62
8.5
N9-GP administration .............................................................................................................62
8.6
Bleeding episodes ...................................................................................................................64
8.6.1
Assessments of bleeding episodes and treatment response......................................64
8.7
Surgery ...................................................................................................................................66
8.7.1
Minor surgery ........................................................................................................67
8.7.2
Major surgery ........................................................................................................67
8.8
Training and reminders ...........................................................................................................68
8.8.1
Trial card dispensing..............................................................................................68
8.8.2
Home treatment training.........................................................................................68
8.8.3
Electronic diary (eDiary)........................................................................................69
8.8.3.1
eDiary dispensing and collection ......................................................69
8.8.4
Contact between the investigator/medically qualified person and the patient...........69
8.8.5
Interactive web response system.............................................................................70
8.9
Patient compliance..................................................................................................................70
9
Trial supplies......................................................................................................................................72
9.1
Trial product ...........................................................................................................................72
9.2
Packing, labelling and dispensing............................................................................................73
9.3
Storage....................................................................................................................................74
9.4
Drug accountability and destruction ........................................................................................75
9.5
Auxiliary supply......................................................................................................................75
9.6
Shipment of trial product to patient’s home .............................................................................75
10
Interactive /web response system (IWRS).........................................................................................77
11
Adverse events and technical complaints ..........................................................................................78
11.1
Definitions ..............................................................................................................................78
11.2
Reporting of adverse events.....................................................................................................83
11.3
Follow-up of adverse events....................................................................................................85
11.4
Technical complaints and technical complaint samples............................................................86
11.4.1
Reporting of technical complaints ..........................................................................86
11.4.2
Collection, storage and shipment of technical complaint samples ...........................87
11.5
Precautions and/or overdose....................................................................................................87
11.6
Committees related to safety ...................................................................................................87
11.6.1
Novo Nordisk safety committee .............................................................................87
12
Case report forms ..............................................................................................................................89
12.1
Corrections to case report forms ..............................................................................................89
12.2
Case report form flow .............................................................................................................90
12.3
Electronic diary.......................................................................................................................90
12.4
Tablets for neurocognitive assessments ...................................................................................91
13
Monitoring procedures ......................................................................................................................92
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CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
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14
Data management ..............................................................................................................................94
15
Computerised systems .......................................................................................................................95
16
Statistical considerations ...................................................................................................................96
16.1
Sample size calculation ...........................................................................................................97
16.2
Definition of analysis sets........................................................................................................97
16.3
Primary endpoint.....................................................................................................................97
16.4
Secondary endpoints ...............................................................................................................98
16.4.1
Confirmatory secondary endpoints.........................................................................98
16.4.2
Supportive secondary endpoints .............................................................................98
16.4.2.1
Number of bleeding episodes during prophylaxis..............................98
16.4.2.2
Haemostatic effect............................................................................98
16.4.2.3
FIX activity......................................................................................99
16.4.2.4
FIX consumption..............................................................................99
16.4.2.5
Safety endpoints...............................................................................99
16.5
Neurocognitive assessments ..................................................................................................100
16.6
Interim reporting ...................................................................................................................100
16.7
Sequential safety analysis and safety monitoring ...................................................................101
16.8
Reporting of F9 and HLA genotype.......................................................................................101
17
Ethics................................................................................................................................................102
17.1
Informed consent ..................................................................................................................102
17.2
Data handling........................................................................................................................103
17.3
Information to patient, parent(s)/LAR(s) during the trial........................................................103
17.4
Premature termination of the trial and/or trial site..................................................................104
18
Protocol compliance.........................................................................................................................105
19
Audits and inspections .....................................................................................................................106
20
Critical documents...........................................................................................................................107
21
Responsibilities.................................................................................................................................109
22
Reports and publications .................................................................................................................110
22.1
Communication of results......................................................................................................110
22.1.1
Authorship...........................................................................................................111
22.1.2
Trial site-specific publication(s) by investigator(s) ...............................................111
22.2
Investigator access to data and review of results ....................................................................112
23
Retention of clinical trial documentation and human biospecimens..............................................113
23.1
Retention of clinical trial documentation ...............................................................................113
23.2
Retention of human biospecimens .........................................................................................113
24
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........115
25
Indemnity statement ........................................................................................................................116
26
References ........................................................................................................................................118
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Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
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Approval of Final Protocol
Agreement on Final Protocol
Attachment I – Global List of key staff and relevant departments and vendors
Attachment II – Country List of key staff and relevant departments
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CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
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Table of figures
Page
Figure 5–1 Patient flow chart ....................................................................................................................25
Figure 8–1 Visit flow diagram ..................................................................................................................35
Figure 16–1 Individual patient flow and time period for main trial report ....................................................96
Table of tables
Page
Table 2–1
Flow chart visits and assessments............................................................................................14
Table 2–2
Flow chart explanatory descriptions ........................................................................................17
Table 3-1
The clinical development programme of N9-GP......................................................................21
Table 5-1
Intravenous N9-GP treatment ..................................................................................................29
Table 8-1 
Neurocognitive assessments by age for all countries................................................................51
Table 8-2
Additional neurocognitive assessments by age for English speaking countries (e.g. 
Australia, Canada, United Kingdom, and the United States).....................................................52
Table 8-3
4-point scale............................................................................................................................66
Table 9-1
Trial Product ...........................................................................................................................72
Table 9-2
Storage....................................................................................................................................74
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CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
Page:
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List of abbreviations
ABAS-3
Adaptive Behavior Assessment System – Third Edition
AE
adverse event
BASC-3
Behavior Assessment System for Children – Third Edition
BRIEF2
Behavior Rating Inventory of Executive Function – Second 
Edition
BRIEF-P
Behavior Rating Inventory of Executive Function – Preschool 
Edition.
BP
blood pressure
BU
Bethesda units
BW
body weight
CFR
code of federal regulations
CHMP
committee for medical products for human use
CHO
Chinese hamster ovary
CNS
central nervous system
CLAE
clinical laboratory adverse event
CRF
case report form 
CRO
contract research organisation
CTA
clinical trial application
CTR
clinical trial report
DCF
data clarification form
DUN
dispensing unit number
eCOA
electronic clinical outcome assessment
eCRF
electronic case report form
ED
exposure day (Definition: One exposure day is defined as each 
day when a patient is administered coagulation factor IX/blood 
components for any reason regardless number of doses)
eDiary
electronic diary
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOT
end of trial
FAS
full analysis set
FDA
food and drug administration
FPFV
first patient first visit
FVIIa
activated coagulation factor VII
FIX
coagulation factor IX
FIXa
activated coagulation factor IX
FX
coagulation factor X
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Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
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GCP
good clinical practice
HCP
host cell protein
HLA
human leucocyte antigen
IB
investigator’s brochure
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IgE
immunoglobulin E
IFU
inhibitor follow up
IND
investigational new drug
IRB
institutional review board
IR30min
incremental recovery 30 min
IU
international unit (1 IU of N9-GP and 1 U of N9-GP are 
equivalent and can be used interchangeably. In this protocol IU is 
used, however U may appear in some trial related documents, e.g. 
IMP labels)
I.V.
intravenous
IWRS
interactive web response system 
LAR
legally acceptable representative
LOCF
last observation carried forward
LPFV
last patient first visit
LPLV
last patient last visit
M
months
MESI
medical event of special interest
N9-GP
nonacog beta pegol, glycopegylated recombinant coagulation 
factor IX
NIMP
non-investigational medicinal product
OD
on-demand
PDCO
paediatric committee (EMA)
Pd-aPCC
plasma-derived activated prothrombin complex concentrates 
PEG
polyethylene glycol
PI
principal investigator
PIP
paediatric investigation plan
PK
pharmacokinetics
PPX
prophylaxis
PUP
previously untreated patient
rFIX
recombinant coagulation factor IX
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Date:
05 November 2019
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Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
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SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SI
the international system of units
SIF
safety information form
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment emergent adverse event
TESAE
treatment emergent serious adverse event
TMM
trial materials manual
UTN
universal trial number
V
visit
W
weeks
WASI-II
Wechsler Abbreviated Scale of Intelligence, Second Edition 
WPPSI-IV
Wechsler Preschool and Primary Scale of Intelligence, Fourth 
Edition 
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Date:
05 November 2019
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Trial ID: NN7999-3895
Version:
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UTN: U1111-1135-9557
Status:
Final
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1
Summary
Primary Objective

To evaluate immunogenicity of N9-GP (nonacog beta pegol)
Primary Endpoint

Incidence of inhibitory antibodies against FIX 
Secondary Objectives

To evaluate safety of N9-GP (nonacog beta pegol)

To evaluate efficacy of N9-GP (nonacog beta pegol)
o
in long-term prophylaxis treatment 
o
in the treatment of bleeding episodes 
o
through the surrogate marker: FIX activity
o
through monitoring of number of doses and consumption of N9-GP
Key Secondary Endpoint

Number and frequency of adverse events, serious adverse events, and Medical Events of Special 
Interest

Number of breakthrough bleeding episodes during prophylaxis (annualised bleeding rate)

Haemostatic effect by 4-point haemostatic response scale (“excellent”, “good”, “moderate” and 
“poor”)
Time Frame of the Objectives/Endpoint
All objectives/endpoints will be evaluated when minimum 20 PUPs have reached at least 50 
exposure days (EDs), when minimum 40 PUPs have reached at least 100 EDs, and at end of trial. 
End of trial will be 30 Oct 2022.
Trial design
The trial is an open label, single-arm, multinational, non-controlled confirmatory trial investigating 
safety and efficacy of N9-GP in prophylaxis and treatment of breakthrough bleeding episodes in 
haemophilia B previously untreated patients with FIX activity ≤ 2%.The trial has one treatment arm 
in which at least 40 patients should achieve at least 100 exposure days with N9-GP.
The European medicines agency requires submission of safety and efficacy data from a minimum of 
50 exposure days in at least 20 patients for approval of the indication in previously untreated 
patients, with a post-approval extension phase according to guideline to follow-up in at least 40 
patients, for a minimum of 100 exposure days. When minimum 20 patients have reached at least 50 
exposure days, the analysis and evaluation for the main trial report will be performed. All patients 
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Date:
05 November 2019
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Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
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continue in the extension phase for the purpose of acquiring data for a minimum of 100 exposure 
days in at least 40 patients. 
Trial population
60 patients are planned to be screened and at least 40 patients are expected to complete the trial.
The trial population is characterised by the following inclusion and exclusion criteria:
Inclusion Criteria

Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial

Male,  < 6 years of age at the time of signing informed consent

Patients with the diagnosis of haemophilia B (FIX activity level ≤ 2%) based on medical records 
or central laboratory results

Previously untreated or exposed to FIX containing products less than or equal to 3 exposure 
days (5 previous exposure days to blood components are acceptable)
Exclusion Criteria

Any history of FIX inhibitors (defined by medical records)

Known or suspected hypersensitivity to trial product or related products 

Previous participation in this trial. Participation is defined as first dose administered of trial 
product

Receipt of any investigational medicinal product within 30 days before screening

Congenital or acquired coagulation disorder other than haemophilia B

Any chronic disorder or severe disease which, in the opinion of the Investigator, might 
jeopardise patient’s safety or compliance with the protocol

Patient’s parent(s)/LAR(s) mental incapacity, unwillingness to cooperate, or a language barrier 
precluding adequate understanding and cooperation
Assessments
Safety assessments
The following key assessments for safety will be used in the trial:

Antibody assessment: inhibitory and binding antibodies

Other adverse events, incl. allergic reactions, anaphylactic reactions and thromboembolic events
Efficacy assessments
The following key assessments for efficacy will be used in the trial:

Bleeding episodes
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Protocol
CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
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
Haemostatic effect in treatment of bleeding episodes

Number of doses to treat a bleed
Pharmacokinetics, pharmacodynamics and other assessments
The following key assessments for pharmacokinetics, pharmacodynamics and other assessments 
will be used in the trial:

FIX activity measured as trough and peak
Trial product
The following trial product will be used in the trial:

nonacog beta pegol hereafter referred to as N9-GP 
N9-GP is supplied as a sterile freeze-dried powder for solution 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. 
Patients are treated with 40 IU/kg N9-GP for:

bleeding episodes

pre-prophylaxis or 

prophylaxis
A bleeding episode should be treated with a single dose of 40 IU/kg, unless the bleeding episode is 
severe in which case it should be treated with 80 IU/kg.
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2
Flow chart
Table 2–1
Flow chart visits and assessments
Visit number
015
1-2013, 15
21-22
23
24-27
28
29-X17
IFU
EOT
Visit purpose
Screening
Dosing
Dosing
End of 
Main
Dosing
End of 
extension
Dosing
(until 
EOT)
ONLY for 
inhibitor 
patients
End of 
Trial
Time of visit (ED(s))19
0
1-20
30,40
50
60, 70, 80, 
90
100
124, 148, 
172, …
Visit interval 19
±1
Day
10 ± 2 
weeks
10+2
Weeks
10 ± 2
weeks
10+2
weeks
24 ± 417
weeks
PATIENT RELATED 
INFORMATION
Informed consent 10
X
Assent form, if applicable1
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Inclusion / Exclusion criteria
X
Eligibility evaluation
X
Withdrawal criteria
X
X
X
X
X
X
Demography
X
Concomitant illness &  
medical history
X
Details on haemophilia and 
haemophilia treatment history
X
Concomitant medication
X
X
X
X
X
X
X
X
X
ADVERSE EVENTS
Adverse events2
X
X
X
X
X
X
X
X
X
CLINICAL 
ASSESSMENTS
Body measurements3
X21
X21
X21
X21
X21
X21
X21
X21
Physical examination
X
X
X
X
Neurological examination24
Visit 1 and 
20
X
Visit 26
X
X
X
Neurocognitive assessments25
Visit 1 and 
X
Visit 26
X
X
X
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Visit number
015
1-2013, 15
21-22
23
24-27
28
29-X17
IFU
EOT
Visit purpose
Screening
Dosing
Dosing
End of 
Main
Dosing
End of 
extension
Dosing
(until 
EOT)
ONLY for 
inhibitor 
patients
End of 
Trial
Time of visit (ED(s))19
0
1-20
30,40
50
60, 70, 80, 
90
100
124, 148, 
172, …
Visit interval 19
±1
Day
10 ± 2 
weeks
10+2
Weeks
10 ± 2
weeks
10+2
weeks
24 ± 417
weeks
20
Vital signs4
X
Visit 14
X
X
X
CENTRAL 
LABORATORY 
ASSESSMENTS
FIX activity – trough7
(X)5
Visit 1, 
5,10,15, 20
X
X
X
X
X
X
X
FIX activity – recovery
30 min post-dose6
Visit 1,10, 
20
X
X
N9-GP binding antibodies7
Visit 1, 
5,10,15,20
X
X
X
X
X
X
X
FIX inhibitor test7, 16
Visit 1,5,10,-
15,20
X
X
X
X
X
X
X
HCP antibodies7
X
X
X
X
HIV  antibodies 
(X)8
CD4+ lymphocyte count and 
HIV viral load
(X)8
Haematology
X
(Visit 1)9
X
X
X
Biochemistry
X
(Visit 1)9
Visit 21
X
Visit 26
X
X
X
F9 + HLA genotype testing
(X)10
(X)10
Allergic reaction testing20
(X)
(X)
Plasma PEG levels
X22
Visit 21
X
Visit 26
X
X
X
Urinalysis23
Visit 1 and 
20
X
Visit 26
X
X
X
TRIAL PRODUCT 
ADMINISTRATION
N9-GP administration
X
X
X
X
X
X
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Visit number
015
1-2013, 15
21-22
23
24-27
28
29-X17
IFU
EOT
Visit purpose
Screening
Dosing
Dosing
End of 
Main
Dosing
End of 
extension
Dosing
(until 
EOT)
ONLY for 
inhibitor 
patients
End of 
Trial
Time of visit (ED(s))19
0
1-20
30,40
50
60, 70, 80, 
90
100
124, 148, 
172, …
Visit interval 19
±1
Day
10 ± 2 
weeks
10+2
Weeks
10 ± 2
weeks
10+2
weeks
24 ± 417
weeks
N9-GP dispensing for home 
treatment
(X)13
X
X
X
X
X18
N9-GP accountability
X
X
X
X
X
X
X
TRAINING AND 
REMINDERS
Trial card dispensing
X
Home treatment training
X
X
X
X
X
X
eDiary training
X11
X11
X11
X11
X11
X11
Compliance check of eDiary 
data, protocol requirements, 
used drug and bleeding 
episode evaluation 
X
X
X
X
X
X
X
Contact with 
patients/parent/LAR12
(X)12
(X)12
IWRS14
X
X
X
X
X
X
X
X
End of trial form
X
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Table 2–2
Flow chart explanatory descriptions
Footer
Description
1
Any patient above the age of 3 years should sign a child assent form, if capable, and if required by local requirements. This can be performed on a separate day. As this is a 
long term trial the investigator should check the progressing maturation of the child and its ability to assent throughout the trial
2
When Informed consent has been obtained all adverse events must be reported in the eCRF
3
For practical purposes, when dispensing trial drug, the body weight from an earlier measurement (or visit) can be used if the measurement was performed within the previous 
12 weeks (in children < 3 years of age, within 6 weeks). After visit 29, a body weight measured within the previous 12 weeks for all age groups can be used. Please refer to 
Section 8.3.1.
4
Vital signs should be measured prior to dosing at screening, V1, V23, V28 and EOT. In addition vital signs should also be measured 30±10 minutes after the first injection 
with N9-GP at V1
5
FIX activity should only be measured at V0 if diagnosis of haemophilia B (FIX≤2%) has not been documented in the patients’ medical record. FIX activity at V0 can either be 
measured at local or central laboratory depending on the urgency of receiving the result i.e. in case V0 and V1 are combined
6
FIX recovery activity is measured 30 min ±10 min after dosing at the following EDs: 1, 10, 20, 50 and 100. For details please refer to Section 8.4.2.1
7
Blood samples must be collected within 1 hour prior to dosing at dosing visits
8
HIV antibodies are only to be assessed, if status is unknown (i.e. previous test older than 6 months). Tests for CD4+ lymphocyte count and HIV viral load are only required 
for HIV positive patients. Sampling can be postponed to the earliest convenient visit to ensure that the allowed blood volume is not exceeded
9
In case V1 is more than a month after V0, haematology and biochemistry need to be retaken at V1 prior to dosing. Biochemistry also needs to be retaken at visit 1 if 
biochemistry at V0 was a local assessment. Please refer to Section 8.4.2.4 and 8.4.2.5
10
F9 and HLA genotype sample should be taken prior to administrating the first dose of N9-GP or at a visit as soon as possible thereafter taking the limitation of the allowed 
blood sampling volume into account.  
11
eDiary training prior to initiating home treatment to ensure that the patient’s parent(s)/LAR(s) are comfortable entering data in the eDiary. Retrain in the use of the eDiary as 
applicable at V21-VX to ensure entry of correct eDiary data
12
When site visits are more than 3 months apart the Investigator must contact the patient’s parents/LAR at least every 12 weeks ± 1week to ensure the patients well-being. For 
details please refer to Section 8.8.4. Primarily expected to be applicable for patients treated according to pre-prophylaxis (V1-V20) and who visit the trial site less frequent 
than every 3 months. In addition all visits from V29 –VX will be scheduled every 24 weeks.
13
It will be possible to administer ED 11-20 outside the trial site (except ED 15 and 20 since blood sampling is needed). This is only allowed if the trial site can ensure presence 
of a relevant health care professional qualified of handling anaphylactic reactions
14
IWRS to be used for screening, visit registration, trial drug dispensing, drug accountability and completion. Refer to Section 10 for more information.
15
V0 and V1 can be combined to one visit, if the patient fulfils the in- and exclusions criteria
16
Blood sampling for FIX .inhibitor testing must be performed prior to administrating the first dose of N9-GP to the patient at visit 1. An inhibitor test must be performed before 
surgery if the previous inhibitor test was performed more than 30 days prior to surgery.
17
V29 to VX will be performed every 24 weeks ± 4 weeks until End of Trial 
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18
At every dosing visit from V29-VX, drug will be dispensed to cover up to 3 months of treatment
19
When the patient has commenced prophylaxis, visits can for practical purposes be planned according to the predicted number of EDs based on the patient’s prophylaxis 
regimen. A visit does not need to be re-scheduled even if the actual EDs between visits turn out higher due to treatment of bleeding episodes during the home treatment period
20
Allergic reaction testing can be taken at visit 0 or visit 1 pre-dose, taking the limitation of the allowed blood sampling volume into account.
21
Height will be collected at visit 0, visit 21, visit 23, visit 26, and at all visits from visit 28 to EOT visit. In case visit 1 is more than a month after visit 0, height needs to be 
redone at visit 1. For patients who have already attended visit 23 and 28 height at these two visits ± 1 month will be collected retrospective if available in medical records
upon parent(s)/LAR(s) consent.
22
Blood samples for PEG analysis should be taken at visit 0 taking the limitation of the allowed blood sampling volume into account. If not taken at visit 0, the blood sample 
should be taken at visit 1 pre-dose, if the blood volume allows.
23
Urine sample should be obtained if possible. It can be collected at home same day and brought to site if transported cold according to Section8.4.2.8. 
24
The neurological examination can for all visits be made within ±1 month of the visits, except for the visit 1 and EOT visit where it can be made at visit date or up to 1 month 
ahead of the visit. 
25
The neurocognitive assessments can for all visits be made within ±1 month of the visits, except for visit 1 and EOT visit where it can be made at visit date or up to 1 month 
ahead of the visit. For details see Table 8-1 and Table 8-2.
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki.2
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
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 (FIX). It is caused by mutations in the F9 gene, located in the distal part 
on the long arm of the X-chromosome. The incidence of haemophilia B is approximately 1 per 
25,000 male births. Haemophilia care is based on prevention (prophylaxis) and/or “on-demand 
treatment” of bleeding episodes with a haemostatic agent.
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 
rebleeding3. Haemophilia B is classified according to the plasma activity of FIX as severe (<1%), 
moderate (1-5%) or mild (>5-40%). 
The predominant treatment for patients with haemophilia B is factor 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 or - during 
recent decades - haemostatic agents are administered for longer periods to prevent bleeding 
(bleeding prophylaxis).
The most commonly used products for the treatment of haemophilia B are plasma derived FIX and 
recombinant FIX (rFIX). Both have half-lives of 18-19 hours requiring 2-3 weekly injections for 
prophylaxis of bleeding episodes.4
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 muscles and 
weight bearing joints (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
disabling deformities. Bleeding may occur in all parts of the body including rare, but life-
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threatening events such as: e.g. bleeding in the central nervous system (CNS), throat, neck or 
retroperitoneum.
3.2
Rationale for the trial
The rationale for performing this trial is to investigate safety and efficacy of N9-GP in the treatment 
of previously untreated patients (PUP) with haemophilia B, hereby supporting anticipated 
marketing authorisation of N9-GP and line extension in the PUP population. 
EMA requires separate investigation of PUPs as part of the development programme initiated 
before market authorisation (MA) gets obtained. A final guideline on the clinical investigation of 
recombinant and human plasma-derived factor IX products5 from the Committee for Medical 
Product for Human Use (CHMP), describes the mandatory components for trials in PUP. In some 
countries outside the EU, PUP Paediatric investigation is necessary to achieve labelled indication 
for all children.
3.3
N9-GP (nonacog beta pegol)
Novo Nordisk A/S is developing a recombinant coagulation factor IX, N9-GP (nonacog beta pegol), 
with a prolonged half-life for treatment of haemophilia B patients. The steady state half-life based 
on PK from the phase 3 trial of previously treated adults and adolescents haemophilia B was
determined to 111 hours. 
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.6 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)7 and any updates hereof.
For an overview of the trials in the clinical development programme of N9-GP, please refer to
Table 3-1
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Table 3-1
The clinical development programme of N9-GP
Trial ID
Trial description
Status
NN7999-3639
(paradigmTM1)
A multi-centre, multi-national, open-label, dose escalation trial 
evaluating safety and pharmacokinetics of ascending intravenous 
doses of N9-GP in non-bleeding patients with haemophilia B
Phase 1 
(PK trial)
Completed
NN7999-3747
(paradigmTM2)
A multi-centre, single-blind trial evaluating safety and efficacy, 
including pharmacokinetics, of N9-GP when used for treatment 
and prophylaxis of bleeding episodes in patients with haemophilia 
B
Phase 3a 
(safety and 
efficacy 
trial)
Completed
NN7999-3773
(paradigmTM3)
An open-label, multi-centre, un-controlled trial to assess efficacy 
and safety of N9-GP during surgical procedures in patients with 
haemophilia B
Phase 3a 
(surgery 
trial)
Completed
NN7999-3775
(paradigmTM4)
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
Phase 3b 
(extension 
trial)
Completed
NN7999-3774
(paradigmTM5)
An open-label, single-arm, multinational, non-controlled, 
confirmatory trial investigating safety, efficacy and 
pharmacokinetics of N9-GP in prophylaxis and treatment of 
bleeding episodes in children with haemophilia B with extension 
phase
Phase 3 
(paediatric, 
safety and 
efficacy 
trial)
On-going
(main 
phase 
completed)
NN7999-3895
(paradigmTM6)
An open-label, single-arm, multicentre non-controlled trial 
investigating safety and efficacy of N9-GP in prophylaxis and 
treatment of bleeding episodes in previously untreated patients 
with haemophilia B
Phase 3a
(safety 
trial)
Current 
trial
3.4
Risk and benefits
Children are among those who might benefit significantly from prophylaxis with N9-GP. The most 
commonly used products  for the treatment of haemophilia B have short half-life of 18-19 hours 
demanding frequent dosing for prophylaxis of bleeding episodes, with 2-3 injections a week8. The 
prolonged half-life of N9-GP offers an expected advantage of once weekly or potentially even less 
frequent injections, which reduces the burden of treatment while maintaining effective haemostasis. 
Likewise it may promote adherence to therapy due to less frequent injections.6 The pivotal phase 3 
trial (NN7999-3747) demonstrated a prophylactic protection of 40 IU/kg N9-GP once weekly and 
showed that 99% of bleeding episodes in the 40 IU/kg arm were stopped with a single dose of N9-
GP.
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 is produced from the Chinese hamster ovary (CHO) cell-
line, a mammalian cell line shown to be free of known infectious agents. 
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The primary concern in PUPs is the risk of development of neutralising antibodies to FIX 
(inhibitors). Development of binding antibodies and inhibitors will be monitored closely throughout 
the trial.
Hypersensitivity reactions may occur with the administration of N9-GP, as with any protein injected 
intravenously. Patients will be closely monitored for development of hypersensitivity reactions, in 
relation to the first 20 exposures with N9-GP. 
Correlation between allergic reactions and the development of inhibitors have been observed with 
FIX treatment. If patients develop inhibitors, they will be carefully instructed how to react if an 
allergic reaction occurs following N9-GP administration. 
Pegylation of proteins is a well-established technology which is used in the treatment of a variety of 
clinical disorders.9 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, for 
further information refer to the current version of the Investigator’s Brochure (IB)7. The potential 
clinical implications of these animal findings are unknown. No adverse neurological 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. Due to this
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 examination, age-appropriate 
neurocognitive assessments and laboratory analyses of plasma PEG levels, liver and kidney 
parameters).
No safety issues have been identified in the completed and ongoing clinical trials with N9-GP and 
the risk/benefit ratio for N9-GP is therefore expected to be favorable. For further information refer 
to the current version of the IB7.
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4
Objective(s) and endpoint(s)
4.1
Objective(s)
Primary Objective

To evaluate immunogenicity of N9-GP (nonacog beta pegol)
Secondary Objectives

To evaluate safety of N9-GP (nonacog beta pegol)

To evaluate efficacy of N9-GP (nonacog beta pegol)
o
in long-term prophylaxis treatment 
o
in the treatment of bleeding episodes 
o
through the surrogate marker: FIX activity
o
through monitoring of number of doses and consumption of N9-GP
4.2
Endpoint(s)
4.2.1
Primary Endpoint

Incidence of inhibitory antibodies against FIX
4.2.2
Secondary Endpoint

Number and frequency of adverse events (AEs), serious AEs (SAEs) and Medical Events of 
Special Interest (MESI)* 

Number of breakthrough bleeding episodes during prophylaxis (annualised bleeding rate)*

Haemostatic effect by 4-point haemostatic response scale (“excellent”, “good”, “moderate” and 
“poor”)*

Incremental recovery at 30 minutes (IR30min), FIX activity at 30 minutes (C30min) and trough 
level

Amount of drug administered and number of doses needed to treat a bleeding episode
*Key supportive secondary endpoint prospectively selected for posting on (e.g. clinicaltrials.gov 
and EudraCT).
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5
Trial design
5.1
Type of trial
This is an open label, single-arm, multinational, non-controlled confirmatory trial investigating 
safety and efficacy of N9-GP in prophylaxis and treatment of breakthrough bleeding episodes in 
haemophilia B PUPs with FIX activity ≤ 2%.
The trial has one treatment arm in which at least 40 patients should achieve 100 exposure days of 40 
IU/kg N9-GP.
The trial consists of four parts: screening, main (i.e. core) phase, extension phase and a prophylaxis 
period until EOT, see Table 5-1.
EMA requires submission of safety and efficacy data from a minimum of 50 EDs in at least 20 
patients for approval of indication in PUPs, with a post-approval extension phase according to 
guideline to follow in at least 40 patients, for a minimum of 100 EDs. Sixty (60) patients are 
planned to enter screening.5 When minimum 20 patients have reached a minimum of 50 EDs the 
analysis and evaluation for the main report will be performed. All patients will continue in the 
extension phase for the purpose of acquiring data for a minimum of 100 EDs in at least 40 patients. 
Results from all patients, in all parts of the trial, will be reported in a final report when the last 
patient has completed the trial.
The trial design is based on the guideline on clinical investigation of recombinant and human 
plasma-derived factor IX products developed by CHMP in EU.5
For Japan only: The NN7999-3895 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.’
5.2
Rationale for trial design
The trial is designed to investigate immunogenicity of N9-GP in PUPs who are known to have the 
highest risk of inhibitor formation.10 A minimum of 100 EDs will provide the required exposure to 
N9-GP in order to investigate the immunogenicity, safety other than immunogenicity and efficacy 
of N9-GP.
A multinational design has been chosen to ensure a sufficient screening pool of patients with this 
rare disorder, to meet local regulatory requirements and to reflect the anticipated patient population. 
There will be no randomisation or stratification.
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5.3
Treatment of patients
The duration of a patient’s treatment with N9-GP in the main phase of the trial is until Visit 23 (50 
EDs) has been reached. 
The duration of N9-GP treatment in the extension phase is at least 50 EDs or until global LPLV 
(30-Oct-2022). Thereafter treatment with N9-GP will continue until LPLV. Trial overview will be 
as shown in Figure 5–1.
60 patients are planned to be screened and at least 40 patients are expected to complete the trial.
Figure 5–1
Patient flow chart 
The trial is designed to reflect common practice in haemophilia treatment centres. Most children 
will initially receive on-demand (episodic) treatment for minor skin/mucosa bleeding episodes, and 
after the first joint and/or muscle bleed, switch to prophylaxis in order to prevent bleeding episodes 
and musculoskeletal damage. This is usually done when the child is between 1 and 2 years of age. 
Prior to starting treatment at Visit 1, the family and investigator will choose between prophylaxis 
and pre-prophylaxis treatment. One exposure day is defined as each day when a patient is 
administered N9-GP for any reason regardless of number of doses.
5.3.1
Previous exposure to FIX products
Due to the rarity of the condition, recruitment for clinical trials of PUPs with severe or moderate 
Haemophilia B is highly challenging. According to EMA guidelines only PUPs are eligible for 
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participation. However, patients that are ‘minimally exposed’ (up to 3 EDs of commercial FIX) can 
enter this trial in agreement with PDCO at EMA. 
In addition to the above, maximum 5 previous blood product (e.g. plasma, cryoprecipitate, 
erythrocyte concentrate or platelets) EDs are allowed. 
5.3.2
Pre-prophylaxis treatment
If it is decided by the investigator and family not to initiate regular once weekly prophylaxis 
immediately after Visit 0, the patient can instead, until he is 24 months of age or until 20 ED, be 
treated on-demand for bleeding episodes and/or have a slow start-up of prophylaxis (i.e. pre-
prophylaxis) with a dose of 40 IU/kg at intervals longer than a week. 
The decision regarding pre-prophylaxis treatment will be made at visit 0. Pre-prophylaxis treatment 
will be administered as a dose of 40 IU/kg N9-GP (or 80 IU/kg for a severe bleed), see Section 
5.3.4.
Pre-prophylaxis treated patients will have regular contact with trial site at least every 12 weeks, if 
dosing with N9-GP is not planned and/or required, until initiation of prophylaxis.
5.3.3
Prophylaxis treatment
Regular prophylaxis must be initiated no later than 24 months of age or upon reaching 20 EDs 
whichever comes first, with a dose of 40 IU/kg N9-GP administered every 7th day (± 1 day).  
If considered relevant, the investigator is permitted to prescribe administration of extra N9-GP 
bleeding preventive doses before demanding physical activities (e.g. sports). The next regular 
prophylaxis dose should not be postponed but be administered on the usual dosing day.
5.3.4
Treatment of bleeding episodes
The patient’s parent(s)/LAR(s) will be instructed by the trial site on how to treat a bleeding episode 
at home and record this in the eDiary, see Sections 8.1.12.1 , 8.6 and 8.6.1. 
In case of a treatment requiring bleeding episode, immediate treatment with N9-GP as intravenous 
injection of 40 IU/kg in case of mild or moderate bleeding or 80 IU/kg in case of a severe bleeding 
episode can be administered. The investigator must always be contacted in case of a severe bleeding 
episode. These doses can be repeated, but not exceeding 200 IU/kg per 24 hours Table 5-1.
An additional dose of 40 IU/kg for a mild/moderate bleeding episode is only allowed after 
consultation with the investigator. If a mild/moderate bleeding episode has not improved within 24 
hours, the patient’s parent(s)/LAR(s) should contact the investigator. 
For treatment of bleeding episodes prior to reaching the first 20 EDs please refer to Section 5.3.5.
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5.3.5
Requirements for the first 20 injections
The risk of anaphylaxis and allergic reactions is evaluated as being highest during the first 20 EDs.8, 
10 For this reason it is a requirement in this protocol to administer the first 10 N9-GP injections at 
the trial site and it is recommended to administer at least the first 20 injections at the site. If the 
Investigator in accordance with local practice or guidelines decides to allow treatment outside the 
trial site prior to reaching 20 EDs this must be with a health care professional present that will be 
able to manage an anaphylactic reaction and could for example be at the emergency room, local 
paediatrician or at home, see Section 8.1.3.1.
5.3.6
Treatment of bleeding episodes in low titre inhibitor (<5 BU) patients 
Low titre inhibitor patients who do not respond sufficiently to N9-GP treatment may be treated with 
bypassing agents according to local label for a period of up to 2 years. It is recommended to avoid 
FIX containing bypassing agents. Bypassing agents are not considered trial medication. Patients
will stay in the trial and continue the N9-GP treatment 40 IU/kg once weekly.
5.3.7
Treatment of suspected severe bleeding episodes
In case of an abdominal or head trauma where there is a risk of a severe traumatic bleeding episode 
it is allowed to initiate treatment before clinical symptoms arise. This is defined as preventive 
treatment of suspected severe traumatic bleeding episode. The recommended dose is 80 IU/kg. The 
site must be contacted and the event documented either in the eDiary or in the eCRF as treatment of 
bleeding episode.
5.3.8
Surgery
Minor surgery
Minor surgeries (procedures where only one dose of N9-GP is considered sufficient prior to the 
surgery) can be performed while participating in this trial by administering a dose of 40 IU/kg N9-
GP, see Table 5-1. 
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. For this trial, examples of minor surgery 
include:

Implanting and removing ports in subcutaneous tissue (see * in Table 5-1)

Skin excisions 

Drainage of abscess

Simple dental procedures 
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
Circumcision 
Major surgery 
Major surgery may be performed after 20 EDs in the current trial. 
In a separate completed N9-GP surgery trial (NN7999-3773/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 N9-GP 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 haemophilia.8 Determination of
dose and dose intervals to achieve adequate haemostasis should include close monitoring of FIX 
activity trough and peak levels, taken into consideration the half-life of N9-GP and ongoing clinical 
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 are provided in Section 8.7.
Definition of major surgery
Major surgery is defined as any invasive operative procedure that require several days of FIX 
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 mater) is crossed

A fascial plane is opened

An organ is removed

When normal anatomy is operatively altered

Major elective orthopaedic surgery
Treatment with N9-GP during surgery will be included in the overall count of N9-GP EDs. Upon 
completion of the surgical/invasive procedure the patient will continue prophylactic treatment with 
N9-GP as before the surgery.
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Table 5-1
Intravenous N9-GP treatment
Indication
Dosage*
Frequency
Pre-prophylaxis during main phase  
(prior to 20EDs)
(pt. less than 24 months of age)
40 IU/kg 
On-demand or intervals longer than 
once weekly 
Prophylaxis during main phase 
40 IU/kg
Once weekly (±1 day)
Prophylaxis during 
extension phase 
40 IU/kg 
Once weekly (±1 day)
Mild/moderate bleeding episode
40 IU/kg
Single dose for bleeding episodes. 
Additional doses only after 
consultation with the investigator
Severe bleeding episode
(The investigator must be contacted)
80 IU/kg, not exceeding 200 IU/kg 
per 24 hours
Single dose for bleeding episodes. 
Severe bleeding episodes can be 
treated with further dose if instructed 
by the investigator
Minor surgery
40 IU/kg 
(*Port implantation: 80 IU/kg)
Single dose prior to surgery
Major surgery, only allowed after 20 
EDs
In accordance with the WFH 
Guidelines8 and local standard of 
practise 
In accordance with the WFH 
Guidelines8 and local standard of 
practise 
Low titre inhibitor
40 IU/kg
Once weekly (±1 day)
*The dose to administer will be calculated by IWRS and defined in whole mL for doses above 3mL.
5.3.9
Vaccinations
Vaccinations are allowed before entering the trial but should preferably not take place until 3 
months after the first N9-GP exposure, as vaccination activates the immune system, thereby
potentially increasing the risk of inhibitor development.
5.4
Treatment after end of trial
After trial end the investigator will agree with the patient’s parent(s)/LAR(s) upon the best available 
treatment for the patient. Novo Nordisk will not provide any trial product to a patient after the end 
of the trial unless required in accordance with local law or regulation.
When discontinuing the trial product the patient should be switched to a suitable marketed product 
at the discretion of the investigator.
It is expected that N9-GP will be granted marketing authorisation and is commercially available 
when the patients complete this trial. However, this cannot be guaranteed.
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5.5
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 treatment6. The increased half-life of N9-GP will 
allow for prophylaxis with fewer injections than currently available products and will most likely 
result in improving compliance.
The dose levels for this trial are based on PK data from the phase 1 PK trial (NN7999-3639), PK 
data from 10 IU/kg and 40 IU/kg in the pivotal trial (NN7999-3747) and PK data from children 
participating in the paediatric trial (NN7999-3774).
Please refer to the IB7 and any updates hereof for further non-clinical and clinical data.
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 60
Number of patients planned to be started on trial product: 60
Number of patients expected to complete the trial: 40
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered "yes".
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial. (Note: By consenting to this trial, the parent(s)/LAR(s) accepts that genotype of
the patient’s haemophilia B mutation is analysed/recorded and used for trial purposes).
2. Male, < 6 years of age at the time of signing informed consent.
3. Patients with the diagnosis of haemophilia B (FIX activity level ≤ 2%) based on medical 
records or central laboratory results.
4. Previously untreated or exposed to FIX containing products less than or equal to 3 EDs (5 
previous exposure days to blood components are acceptable).
6.3
Exclusion criteria
For an eligible patient, all exclusion criteria must be answered “no”.
1. Known or suspected hypersensitivity to trial product or related products.
2. Previous participation in this trial. Participation is defined as first dose administered of trial 
product.
3. Receipt of any investigational medicinal product within 30 days before screening.
4. Congenital or acquired coagulation disorder other than haemophilia B.
5. Any chronic disorder or severe disease which, in the opinion of the investigator, might 
jeopardise patient’s safety or compliance with the protocol.
6. Patient’s parent(s)/LAR(s) mental incapacity, unwillingness to cooperate, or a language barrier 
precluding adequate understanding and cooperation.
7. Any history of FIX inhibitors (defined by medical records)
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6.4
Withdrawal criteria
The patient may withdraw at will at any time either by the patient or by the patient’s parent(s) or the 
patient’s LAR. The patient’s request to discontinue must always be respected.
The patient may be withdrawn from the trial at the discretion of the investigator due to a safety 
concern or if judged non-compliant with trial procedures.
The patient must be withdrawn if the following applies:
1. Dosed in the trial, but not fulfilling the inclusion and/or exclusion criteria
2. Development of FIX inhibitors ≥ 5 BU confirmed by two consecutive tests (central laboratory) 
and associated with N9-GP binding antibodies (the patient must be withdrawn from N9-GP 
treatment upon confirmation of FIX inhibitor ≥ 5 BU and attend three inhibitor follow-up visits) 
3. Anaphylactic reaction to the trial product, for definition see section 11.1
4. Major surgery prior to 20 EDs. see section 5.3.8
5. Significant thromboembolic event, see Section 11.1
6. Incapacity or unwillingness to follow trial procedures
7. Participation in another clinical trial while participating in this trial
If a patient experiences treatment failure where haemostatic response is rated as poor according to 
Section 8.6, the investigator should consider if it is in the patient’s best interest to continue in the 
trial.
All data collected prior to withdrawal will be used in the trial analyses.
Temporary or permanent discontinuation of treatment with trial product will not lead to withdrawal
from the trial.
6.4.1
Only applicable for Spain: Temporary discontinuation of trial treatment
Temporary treatment discontinuation is allowed at the discretion of the investigator and the reason
for discontinuation must be recorded in the eCRF. Treatment with trial product may be resumed if 
the circumstances later allow. Date and last trial product dose should be recorded in the eCRF. 
Resupply status in the IWRS should be put on hold when a patient is on treatment pause. The 
eDiary will not be used during temporary discontinuation of trial product.
6.5
Patient replacement
Withdrawn patients may be replaced to ensure that at least 40 patients complete the trial with a 
minimum of 100 ED.
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6.6
Rationale for trial population
The selection of the trial population is based on the specific requirements found in the final 
guideline on the clinical investigation of recombinant and human plasma-derived factor IX 
products5 from the CHMP and in the Paediatric Investigation Plan (PIP) in agreement with the 
Paediatric Committee (PDCO).
Children are among those who might benefit significantly from prophylaxis. Less frequent 
injections with N9-GP as compared to other treatment options 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).
Criterion no. 2 is included due to Novo Nordisk A/S has decided to use an age cut-off 
of 6 years.
Criterion no. 3 is included to select the patient group based on the CHMP guideline5.
Criterion no. 4 is included to select the patient group based on the CHMP guideline 
and in accordance with recent PIP modification allowing inclusion of minimally 
treated patients.
6.6.2
Rationale for exclusion criteria
Criteria nos. 1 and 5 are included to prevent unnecessary exposure of potentially 
fragile patients to a new compound.
Criterion no. 2 is included to ensure that a patient only counts once in the data 
analyses.
Criterion no. 3 is included to minimise any effect of external compounds on the 
patient's coagulation and immune system. 
Criterion no. 4 is chosen to exclude patients with endogenous abnormalities of the 
coagulation system, other than haemophilia B.
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.
Criterion no. 7 is included to exclude patients with FIX inhibitors since inhibitor 
development is the primary safety endpoint of the trial.
6.6.3
Rationale for withdrawal criteria
Criteria nos. 1-7 are included to protect the patient's safety and reliability of the data.
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7
Milestones
Planned duration of recruitment period: First patient first visit (FPFV) to last patient first visit 
(LPFV): 75 months 
First Patient First Visit:  02-Jul-2014
Planned Last Patient First Visit: 30-Sep-2020
End of trial is defined as Last Patient Last Visit: 30-Oct-2022
The duration of N9-GP treatment in the trial is a minimum of 100 EDs for at least 40 patients and 
will continue until Last Patient Last Visit for the trial, which will be 30 October 2022. 
Planned completion of clinical trial report (CTR): Q2 2023
Recruitment
The screening rate will be followed closely via the interactive web response system (IWRS) in 
order to estimate when to stop screening. All investigators will be notified immediately when the 
recruitment period ends, after which no further consent will be sought from additional families and 
the IWRS will be closed for further screening, unless additional screening is needed due to patient 
replacement.
All subjects included in the screening period and eligible for the trial will enter the trial. 
Trial registration
Information of the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and 
clinicaltrials.jp. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure, it 
will also be disclosed according to other requirements such as those of the International Committee 
of Medical Journal Editors (ICMJE)11, the Food and Drug Administration Amendment Act 
(FDAAA)12, European Commission Requirements13 and other relevant recommendations or 
regulations. If a patient requests to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the patient. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations.
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8
Methods and assessments
8.1
Visit procedures
Specific procedures, assessments and methods for the scheduled visits are described in the section 
below, and the list of assessments for each visit is presented in the flow chart, see Table 2–1 and 
visit flow diagram Table 8-1.
Figure 8–1
Visit flow diagram 
Screening and enrolment log
The investigator must keep a patient screening log, a patient identification code list and a patient 
enrolment log. The patient screening log and patient enrolment log may be combined in one list.
At screening, patients will be provided with a trial card stating that they are participating in a trial 
and given contact address(es) and telephone number(s) of relevant trial site staff. Patient’s
parent(s)/LAR(s) should be instructed to return the trial card to the investigator at the last trial visit 
or to destroy the trial card after the last visit.
It must be stated in the medical records that the patient is participating in the trial, including the 
patient number.
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Informed consent procedure
The patient’s parent(s) / LAR(s) 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, see Section 17.1. 
A child assent form will be provided to patients above 3 years of age according to local 
requirements. This can be performed on a separate day. As this is a long term trial the investigator
should check the progressing maturation of the child and its ability to assent throughout the trial.
Informed consent including haemophilia B mutation genotyping at screening must be obtained. 
Screening failures
Screening failures are defined as patients for whom the parent(s)/LAR(s) have signed the Informed 
Consent Form but fail to comply with the inclusion and/or exclusion criteria or if the consent is 
withdrawn prior to dosing. 
For screening failures, the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial.
Serious and non-serious adverse events (AE) from screening failures must be transcribed by the 
investigator into the case report form (eCRF). Follow-up of SAEs must be carried out according to 
Section 11.3. A screening failure session must be made in the IWRS. The case book must be signed.
Re-screening is not allowed after the first dose of trial product – see excl. criteria no. 2 in Section 
6.3.
For withdrawn patients
Withdrawn patients are defined as patients who meet the withdrawal criteria after dosing, see 
Section 6.4
If a patient is withdrawn from the trial, the investigator must aim to perform the end of trial visit, as 
soon as possible except for patients with a high titre inhibitor.
The end of trial form must be completed, and final drug accountability must be performed even if 
the patient is not able to come to the trial site. A withdrawal session must be made in the IWRS and 
the case book must be signed. 
All data collected in the period the patient participated in the trial must be documented.
Although a patient or patient’s parent(s)/LAR(s) is not obliged to give his/her reason(s) for 
withdrawing from a trial, the investigator must make a reasonable effort to ascertain the reason(s), 
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while fully respecting the patient’s rights. Where the reasons are obtained, the primary reason(s) for 
discontinuation must be specified on the end-of-trial form in the eCRF e.g.:

Adverse events (AEs)

Protocol violation

Lack of efficacy

Lost to follow up

Withdrawal by patient or parent(s)/LAR(s) 

Technical problems

Other
End of trial 
The end of trial (EOT) form should be filled in at the End-of-Trial visit or the last visit of the 
patient. If a patient is withdrawn prior to completion of the trial, all attempts must be made to 
schedule the end of trial visit for the patient. 
For a patient with high titre inhibitor the EOT visit should be performed in connection with the third 
follow-up visit. 
In general
Review of eDiary reports, laboratory reports etc. must be documented either on the front page of the 
documents and/or in the patient’s medical record. 
In accordance with local law a caregiver may take over the responsibilities from the 
parent(s)/LAR(s) of handling and administrating the trial drug, filling in the eDiary and attending 
visits at site. The caregiver must be trained to the same extent as the parent(s)/LAR(s) in the 
relevant responsibilities. 
Prior to a visit the investigator must request the patient’s parent(s)/LAR(s) to return any trial 
medication , solvent or injection kits if this would expire during the following home treatment 
period. The patient’s parent(s)/LAR(s) must also be instructed in never using any expired trial 
materials.
Any corrections made by the investigator to the eDiary entries must be discussed with the patient’s 
parent(s)/LAR(s) and the conclusion documented in the medical record. Care must be taken not to 
bias the patient’s parent(s)/LAR(s).
8.1.1
Visit 0 – screening visit
The patient’s parent(s)/LAR(s) must give signed and dated informed consent prior to any trial 
related activities. Signing of the informed consent can take place before visit 0, if allowed by local 
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Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
Page:
38 of 119
law. All patients will be provided with a copy on the patient information and a copy of the signed 
and dated Informed Consent Form.
For all patients with a signed Informed Consent/Assent form, the patient will be assigned a unique 6 
digits patient number, which will follow the patient throughout the trial.
A screening period (interval between visit 0 (V0) and V1) is allowed until the first dose of N9-GP is 
required. 
The screening visit (V0) can be combined with the first treatment of N9-GP (V1), hereby allowing 
patients to be enrolled in the trial and treated for their first bleeding episode immediately after 
having confirmed inclusion and exclusion criteria.
All results necessary for evaluating the inclusion and exclusion criteria must be available before 
determining whether or not the patient can continue in the trial and whether it will be possible to 
receive the first dose of N9-GP at the same day.
If the screening results do not become available during the screening visit, and if the next visit is not 
planned, the patient’s parent(s)/LAR(s) must be informed when eligibility has been evaluated by the 
investigator.
Assessments for V0 are listed in Table 2–1.
Reminders:

Dispense trial card, see Section 8.8.1

Screening call in the IWRS, see Section 10

Discuss treatment regimen: prophylaxis versus pre-prophylaxis

In case V1 is not planned or performed within 3 month from visit 0 the investigator must 
contact the patient’s parent(s)/LAR(s) at least every 12 weeks ± 1 week, See Sections 8.8.4 and 
8.1.10.

During the screening period the patient cannot be treated with commercially available FIX 
product
8.1.1.1
Pre-prophylaxis treatment
Pre-prophylaxis is optional and is the period before start of regular prophylaxis. The pre-
prophylaxis period stops when the patient has reached 20 EDs or has turned 24 months of age, 
whatever comes first.
During pre-prophylaxis the following dosing regimens applies: 

dosing with 40 IU/kg N9-GP
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Date:
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Trial ID: NN7999-3895
Version:
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UTN: U1111-1135-9557
Status:
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
individualised prophylaxis dosing intervals but less frequent than once weekly

on-demand treatment of bleeding episodes

minor surgery
See further Section 5.3.2 and 5.3.8.
Dosing visits during the pre-prophylaxis period can be performed at any time until ED 20. Visits 
during the pre-prophylaxis period without dosing should be performed as unscheduled visits, see 
Section 8.1.10. 
The site must make sure that the patient’s parent(s)/LAR(s) are contacted at least every 12 weeks ± 
1 week if no further visit is planned, Section 8.8.4. 
Visit 1-20 occurs when the patient needs treatment of a bleed and /or is planned individually per 
patient at the investigator and patient’s parent(s)/LAR(s) discretion.
8.1.1.2
Prophylaxis treatment
Prophylaxis treatment can begin at visit 1 or at any time during the pre-prophylaxis period and must 
be initiated latest when the patient has reached 20 EDs on pre-prophylaxis or has turned 24 months 
of age, whatever comes first.
The dosing frequency is once weekly ±1 day (preferable the same day of the week).
For patients that enter the prophylaxis treatment after a period of pre-prophylaxis the next visit in 
the sequence will be determined by the numbers of EDs. 
8.1.2
Visit 1 – first dosing with N9-GP
Visit 1 will take place after the screening visit (V0) whenever the first treatment of N9-GP is 
administered, if not already combined with V0.
Before administrating the first dose of N9-GP the FIX inhibitor test for central laboratory must be 
taken and sent to central laboratory for analysis. In case of subjective signs of illness and/or fever 
within 48 hours prior to the first injection of N9-GP the dose should be postponed, if possible.
The patient will continue treatment on either:

Pre-prophylaxis treatment. See Sections 5.3.2 and 8.1.1.1.

Prophylaxis treatment. See Sections 5.3.3 and 8.1.1.2.
Assessments for V1 are listed in Table 2–1. In case V0 and V1 have been combined into one visit, 
assessments should only be performed once, but recorded at both visits in the eCRF.
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Date:
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Trial ID: NN7999-3895
Version:
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UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
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Reminders
Next visit should be scheduled if applicable, see Sections 8.1.1.1 and 8.1.1.2
In case V2 is not planned or performed within 3 months from visit 1 the Investigator must 
contact the patient’s parent(s)/LAR(s) at least every 12 weeks ± 1week. See Sections 8.8.4 and 
8.1.10.
Drug accountability of trial product at V1 must be recorded in the IWRS, see Section 10
Recording of body weight, see Section 8.3.1, and dispensing of N9-GP for trial site dosing via 
IWRS, see Section 10.
8.1.3
Visit 2-20 – main phase
The 10 first N9-GP exposure days (EDs) (V1-V10) must take place at the trial site. 
ED11-20 should preferable take place at trial site however administration can take place outside the 
trial site, if a health care professional qualified of handling anaphylactic reactions is present, see 
Section 5.3.5. Visit 15 (ED 15 ± 1) and visit 20 (ED 20 ± 1) are mandatory at site due to blood 
sampling.
All doses should be registered in the eCRF. In case the patient is treated outside the trial site the 
trial site should be informed and the details hereof should be entered in the eCRF.
Assessments for V2-V20 are listed in Table 2–1.
Reminders
In case next visit is not planned or performed within 3 months from the previous visit the 
investigator must contact the patient’s parent(s)/LAR(s) at least every 12 weeks ± 1week. See 
Sections 8.8.4 and 8.1.10.
Recording of body weight, see Section 8.3.1, and dispensing of N9-GP for trial site dosing must 
be performed via IWRS, see Section 10
Drug accountability of trial product must be recorded in the IWRS, see Section 10
eDiary dispensing, see Section 8.8.3.1
eDiary training, see Section 8.8.3 and 12.3
8.1.3.1
Treatment outside trial site
It is the responsibility of the investigator to ensure the safety of the patient and adherence to the 
protocol, ICH, GCP and local regulations also when the patient is treated outside trial site.
Prior to allowing treatment outside trial site at ED 11 to ED 14 and ED 16 to ED 19 the Investigator 
must have a plan describing how this can be done in a safe and responsible manner. 
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Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
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The plan should be prepared for each individual patient and should describe the circumstances 
under which the treatment outside trial site is performed, e.g. how it can be ensured that a health 
care professional qualified to handle anaphylactic reactions can be present, how training is 
performed, and how appropriate documentation is obtained. The plan must also address that the 
patient may need trial drug at home/not at home. 
The plan should include an instruction for the patient’s parent(s)/LAR(s) with the directions for use 
and describe the importance of having a health care professional present to handle anaphylactic 
reactions during administration and how to act in case of emergency bleeding episodes.
The process should be discussed with Novo Nordisk, if applicable approved by IRB/IEC, and must 
always comply with local regulations. 
8.1.4
Visit 21-22 – main phase
From V21 all patients (including patients previously on pre-prophylaxis) will be on prophylaxis 
treatment with N9-GP. Between the visits the patient will receive N9-GP treatment at home if 
comfortable with home administrations or at the site, see Section 8.1.12
Visits at EDs: 30 ± 2 EDs, and 40 ± 2 EDs.
The visits should be scheduled taking into account the patient’s regular dosing day in the week.
Assessments for V21 and V22 are listed in Table 2–1.
Reminders
An appointment for the next visit should be made
Recording of body weight, see Section 8.3.1, and dispensing of N9-GP for site dosing/home 
treatment must be performed via IWRS, see Section 10
Drug accountability of trial product must be recorded in the IWRS, see Section 10
The Investigator must prior to the visit instruct the patient’s parent(s)/LAR(s) in returning any 
trial medication, solvent or injection kits that would expire during the following home treatment 
period
Home treatment training, if the trial site suspects that the patient’s parent(s)/LAR(s) is not fully 
confident with administration and how to deal with safety related signs and symptoms , see 
Sections 8.5 and Sections 8.6
eDiary training, see Section 8.8.3 and 12.3
eDiary compliance review, see Section 12.3.
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Date:
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Trial ID: NN7999-3895
Version:
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UTN: U1111-1135-9557
Status:
Final
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8.1.5
Visit 23 – end of main phase
Visit 23 should take place at either ED 50, ED 51 or ED 52. 
Assessments for V23 are listed in Table 2–1.
Reminders
An appointment for the next visit should be made
Recording of body weight, see Section 8.3.1, and dispensing of N9-GP for trial site dosing/home 
treatment must be performed via IWRS, see Section 10
Drug accountability of trial product must be recorded in the IWRS, see Section 10
The Investigator must prior to the visit instruct the patient’s parent(s)/LAR(s) in returning any 
trial medication, solvent or injection kits that would expire during the following home treatment 
period
Home treatment training, if the trial site suspects that the patient’s parent(s)/LAR(s) is not fully 
confident with administration and how to deal with safety related signs and symptoms, see 
Sections 8.5 and 8.6
eDiary training, see Section 8.8.3 and 12.3
eDiary compliance review, see Section 12.3.
8.1.6
Visit 24-27 – extension phase
The patient will continue prophylaxis throughout the extension phase, with 40 IU/kg N9-GP once 
weekly. See Table 2–1.
Visits at EDs: 60 ± 2 EDs, 70 ± 2 EDs, 80 ± 2 EDs, and 90 ± 2 EDs.
The visits should be scheduled taking into account the patient’s dosing day.
The duration of the extension phase is approximately 1 year for a patient to achieve a total of 100 
EDs.
Assessments for V24-V27 are listed in Table 2–1.
Reminders
An appointment for the next visit should be made
Recording of body weight, see Section 8.3.1, and dispensing of N9-GP for trial site dosing/home 
treatment must be performed via IWRS, see Section 10
Drug accountability of trial product must be recorded in the IWRS, see Section 10
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Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
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The Investigator must prior to the visit instruct the patient’s parent(s)/LAR(s) in returning any 
trial medication, solvent or injection kits that would expire during the following home treatment 
period
Home treatment training,see Section 8.1.12 and 8.8.2.
eDiary training, see Section 8.8.3 and 12.3
eDiary compliance review, see Section 12.3
8.1.7
Visit 28 - end of extension phase
V28 should take place at either ED 100, ED 101 or ED 102.
Assessments for V28 are listed in Table 2–1.
Reminders
An appointment for the next visit should be made
Recording of body weight, see Section 8.3.1, and dispensing of N9-GP for trial site dosing/home 
treatment must be performed via IWRS, see Section 10
Drug accountability of trial product must be recorded in the IWRS, see Section 10
The Investigator must prior to the visit instruct the patient’s parent(s)/LAR(s) in returning any 
trial medication, solvent or injection kits that would expire during the following home treatment 
period
eDiary compliance review, see Section 12.3
8.1.8
Visit 29-X until end of trial
After visit 29 visits are scheduled 24 weeks ± 4 weeks apart. This schedule will last until End of 
Trial. 
At every dosing visit from V29-VX, drug will be dispensed to cover up to 3 months of treatment. If 
the visit is a N9-GP dispensing visit only, the patient is not required to attend the clinic only for this 
purpose. Assessments for V29-X are listed in Table 2–1.
Reminders
An appointment for the next visit should be made
Recording of body weight, see Section 8.3.1, and dispensing of N9-GP for trial site dosing/home 
treatment must be performed via IWRS, see Section 10
Drug accountability of trial product must be recorded in the IWRS, see Section 10
The Investigator must prior to the visit instruct the patient’s parent(s)/LAR(s) in returning any 
trial medication, solvent or injection kits that would expire during the following home treatment 
period
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Trial ID: NN7999-3895
Version:
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UTN: U1111-1135-9557
Status:
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eDiary compliance review, see Section 12.3
8.1.9
End-of-trial visit
The EOT visit is the last visit in the trial. 
The EOT will take place after completion of at least 100 EDs or if the patient is withdrawn from the 
trial. For a patient with high titre inhibitor the EOT visit should be performed in connection with the 
third inhibitor follow-up visit, for scheduled visits other than inhibitor follow-up visits, the EOT 
visit may replace a scheduled visit if this scheduled visit is scheduled within two weeks of the 
planned EOT visit. 
Assessments for the EOT are listed in Table 2–1.
Reminders 
Drug accountability of trial product must be recorded in the IWRS, see Section 10
eDiary compliance review, see Section 12.3
eDiary LogPad collection, see Section 8.8.3.1
Complete EOT form
8.1.10
Unscheduled visit 
Unscheduled visits of trial related character can be performed at any time during the trial and the 
purpose must be documented.
The following forms can be found in the unscheduled visit in the eCRF:

Central lab

Dosing of N9-GP

Surgery (Record on ‘unscheduled visit’ form in eCRF even if performed on a regular visit)

PK session (Record on ‘unscheduled visit’ form in eCRF even if performed on a regular visit)
8.1.11
Inhibitor Follow-Up visit 
The inhibitor follow-up visit (IFU) should be performed when a patient has a confirmed high titre 
inhibitor (≥5BU) according to section 8.4.2.2. The patient must be withdrawn from N9-GP 
treatment upon confirmation of the second test of high titre inhibitor. Three inhibitor follow-up 
visits must be scheduled with 4 weeks ±7 days interval after confirmation of the inhibitor.
The end of trial visit and EOT assessments should take place in connection with the third IFU visit.
The IWRS withdrawal session should not be performed before EOT visit.
In case the patient has been treated with FIX coagulation factors including plasma-derived activated 
prothrombin complex concentrates (pd-aPCC) within 4 days or FVIIa within 1 day prior to the first 
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Date:
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Trial ID: NN7999-3895
Version:
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UTN: U1111-1135-9557
Status:
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inhibitor follow up visit, the visit must be postponed, please refer to Section 8.4.2.2 for further 
details.
In the rare case where a patient develops N9-GP binding antibodies and where it at the same time is 
evaluated by the Investigator that the patient should not continue in the trial based on e.g. decreased 
drug efficacy, the patient should attend inhibitor follow up visits similar to those described for 
patients with inhibitors.
Assessments to be performed

Adverse Events

Concomitant medication

Sampling for inhibitor test

Sampling for FIX activity test

Sampling for N9-GP binding antibodies

Sampling for Lupus anticoagulant
Reminder
Follow up on any AEs according to Section 11.2
8.1.12
Home treatment
Home treatment with N9-GP can commence any time after the first 20 EDs and the patient’s 
parent(s)/LAR(s) are comfortable with the reconstitution and administration process. See Section
5.3.5
8.1.12.1
Prophylactic home treatment
During main and extension phase, the dose for prophylaxis is 40 IU/kg once weekly ±1 day, See 
Table 5-1 and Section 8.5
Bleeding episodes must be treated as described in Section 8.6.
The following procedures must be performed during home treatment between visits:
N9-GP administrations once weekly ±1 day (preferable same week day)
Prior to each N9-GP administration the patient’s parent(s)/LAR(s) must check that neither N9-
GP, solvent nor injection kit have expired
Contact to the investigator/medically qualified person in case of severe bleeding episodes or if 
bleeding episodes has not responded sufficiently to treatment within 24 hours
Completion of the patient eDiary, including details of all bleeding episodes and N9-GP 
administrations 
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Trial ID: NN7999-3895
Version:
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UTN: U1111-1135-9557
Status:
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8.1.12.2
Home treatment of bleeding episodes
Bleeding episodes must be treated as soon as identified according to Table 5-1 and Section 8.6. 
Patient’s parents(s)/LAR(s) will be instructed by the investigator on how to treat their child for a 
bleeding episode at home and how to record this in the eDiary.
The following procedures must be performed
N9-GP administration for treatment of any bleeding episodes, see Section 8.6
Completion of the patient eDiary, including details of all bleeding episodes and N9-GP 
administrations.
8.2
Patient related information
8.2.1
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial at the first visit, (V0) or 
found as a result of a screening procedure. All concomitant illnesses should be reported including
the disease under investigation.
Medical history is a medical event that the patient has experienced in the past, which should be 
obtained during the screening procedure including haemophilia treatment history. In the event that a 
diagnosis is unknown, the description of symptoms will be recorded. All significant symptoms 
and/or illnesses since births should be recorded.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE.
8.2.1.1
Details on haemophilia and haemophilia treatment history
All available information on haemophilia, prior to screening should be recorded including 
diagnostic FIX activity level, if known. If possible, information about relatives with haemophilia B 
and inhibitors should be obtained.
Any previous exposures to FIX concentrates and/or blood product components prior to visit 0 must 
be recorded incl. type or brand, dose/kg bodyweight and date of administration
8.2.1.2
Allergies
Any allergies, including any drug sensitivities should be recorded. 
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8.2.2
Concomitant medication
A concomitant medication is any medication including vaccination, other than the investigational 
medicinal product (N9-GP), which is taken during the trial until EOT.
Details of any concomitant medication must be recorded at the first visit, (V0). Changes in 
concomitant medication must be recorded at each visit as they occur.
The information collected for each concomitant medication includes (at a minimum) trade name or 
generic name, indication, start date and stop date or continuation.
If a change in medication is due to an AE, then this must be recorded and reported according to 
Section 11.2. If the change influences the patient’s eligibility to continue in the trial, the monitor 
must be informed.
8.2.3
Treatment of bleeding episodes in low titre inhibitor patients < 5 BU
Bleeding episodes in low titre inhibitor patients that do not respond sufficiently to N9-GP treatment 
may in addition be treated with bypassing agents according to local label for a period of up to 2 
years. It is recommended to avoid FIX containing bypassing agents. Patients will stay in the trial 
and continue the 40 IU/kg N9-GP treatment. The time of administration of other haemostatic 
medication (including bypassing agents) should be entered in the eCRF/eDiary. 
8.2.4
Prohibited medication
Treatments with other FIX concentrates are not allowed, during the course of the trial. 
If possible, use of Tranexamic acid should be avoided.
Heparin sealing of central venous access ports and cannula is allowed.
8.2.5
Demography
Demographic data will be collected as allowed per local law:
Date of birth, year or age (year:months)
Ethnicity 
Race
8.3
Clinical assessments 
Clinical assessments should preferably be performed prior to blood sampling and prior to 
administration of N9-GP unless it is stated otherwise. 
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8.3.1
Body measurements

Height will be collected at visits according to Table 2–1. For patients who have already attended 
visit 23 and/or visit 28 height at these visits ± 1 month will be collected retrospectively if 
available in medical records upon parent(s)/LAR(s) consent

Body weight, wearing light clothing only
Body weight should be measured in connection with regularly visits where trial drug is dispensed. 
For practical purposes when dispensing trial drug the body weight from an earlier measurement (or 
visit) can be used if the measurement was performed within the previous 12 weeks (in children < 3 
years of age, within 6 weeks). After visit 29, a body weight measured within the previous 12 weeks 
for all age groups can be used. If new body weight is not needed to be measured at a visit, the body 
weight from last weighing should be used.
8.3.2
Physical examinations
The physical examinations will be performed according to local procedure and should include:
General appearance
Head, ears, eyes, nose, throat and neck
Lymph node palpation
Abdomen
Skin
Respiratory system
Musculoskeletal system
Central and peripheral nervous systems (general evaluation)
Elaborated neurological examination, see Section 8.3.2.1
Cardiovascular system
8.3.2.1
Neurological Examination 
Following aspects of the neurological examination will be assessed:
General appearance including language, social and developmental aspects, handedness, head 
circumference, fontanelle assessment (<18 months), 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, and 
trapezius muscle function
Tone of truncal, upper and lower extremity right and left, and general tone (<18 months)
Strength of upper and lower extremity right and left
Reflexes of biceps, triceps, knee and ankle jerk, all right and left, Babinski as well as infantile 
reflexes (<6 months)
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Sensory aspect of cold, pin prick, light touch and proprioception (toe up/down)
Gait with regards to walking, running, on heels and toes, tandem (toe/heel walk), stand/hop on 
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 
The timing of the neurological assessments should be planned to allow as much flexibility for the 
patients as possible and can be made within ±1 month of the visits, except for the visit 1 and EOT 
visit where the neurological assessments can be made at the visit date or up to 1 month ahead of the 
visit. In addition to this after trying to obtain the various assessments within acceptable limits 
without success the individual assessments can be omitted. Moreover, some aspects of the 
neurological examination may not be applicable for children in particular age groups as evaluated 
by the Investigator. Each aspect of the neurological examination will be categorised into normal, 
abnormal (pre-existing or new) or not examined.
8.3.3
Neurocognitive assessments
Neurocognitive assessments should be performed according to Table 2–1, Table 2–2, Table 8-1 and 
Table 8-2
The following domains will be assessed in all countries:

Executive function 

Attention/processing speed/working memory 
Further, the following domains will be assessed in English speaking countries (e.g. Australia, 
Canada, United Kingdom, and the United States):

Neurodevelopment or cognitive function and intelligence 

Emotional behaviour 

Adaptive behaviour
The timing of the neurocognitive assessments should be planned to allow as much flexibility for the 
patients as possible and can be made within ±1 month of the assessment visits, except for the visit 1 
and EOT visit where the neurocognitive assessments can be made at the visit date or up to 1 month 
ahead of the visit. The first assessment should be planned for the visit immediately after the patient 
turns either 1 or 2 years of age depending on country. Hereafter the visit schedule as found in Table 
8-1 and Table 8-2 should be followed except if the next planned assessment visit is within three 
months of the initial assessment. All assessments should be performed using generally accepted 
standardised testing parameters to ensure optimal conditions for performance. A description of
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neurocognitive assessments, training, equipment and related procedures will be provided in the
Manual for neurocognitive assessments.
An independent 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.
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 considered 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 the 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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Table 8-1
Neurocognitive assessments by age for all countries 
Domain
Structured Developmental History 
and Haemophilia History
Executive Function
Attention / Processing Speed
Assessment visits
The first assessment should be planned for the visit immediately after the patient turns 2 years of age. Hereafter the following 
visit schedule should be followed except if the visit is within 3 months from the initial assessment: Visit 1, visit 20, visit 23, visit 
26, visit 28, visit 29, and all subsequent visits until and including EOT
Patient age (year:months)
1:0 to 1:11
2:0 to 3:6
Structured Developmental History 
and Haemophilia History
BRIEF-P (BRIEF-P 2:0-5:11y Parent)
3:7 to 3:11
Structured Developmental History 
and Haemophilia History
BRIEF-P (BRIEF-P 2:0-5:11y Parent)
4:0 to 5:11
Structured Developmental History 
and Haemophilia History
BRIEF-P (BRIEF-P 2:0-5:11y Parent)
 (Custom Battery - Peds (4-9)
6:0 to 6:11
Structured Developmental History 
and Haemophilia History
BRIEF-2 (BRIEF2 5-18y Parent)
 (Custom Battery - Peds (4-9)
7:0 to 7:11
Structured Developmental History 
and Haemophilia History
BRIEF-2 (BRIEF2 5-18y Parent)
 (Custom Battery - Peds (4-9)
8:0 to 9:11
Structured Developmental History 
and Haemophilia History
BRIEF-2 (BRIEF2 5-18y Parent)
 (Custom Battery - Peds (4-9)
10:0 to 10:11
Structured Developmental History 
and Haemophilia History
BRIEF-2 (BRIEF2 5-18y Parent)
 (Custom Battery - Adult (10-21)
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UTN: U1111-1135-9557
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Table 8-2
Additional neurocognitive assessments by age for English speaking countries (e.g. Australia, Canada, United Kingdom, 
and the United States)
Domain
Developmental History and 
Haemophilia History
Neurodevelopment / General 
Intelligence
Behavioural / Emotional
Adaptive behaviour
Assessment visits
The first assessment should be planned for the visit immediately after the patient turns 1 year of age. Hereafter the following visit 
schedule should be followed except if the visit is within 3 months from the initial assessment: Visit 1, visit 23, visit 28, visit 30, 
visit 32, visit 34, …, until and including EOT
Patient age (year:months)
1:0 to 1:11
Structured Developmental History 
and Haemophilia History
Bayley-III
ABAS-3 (0-5y Parent)
2:0 to 3:6
Structured Developmental History 
and Haemophilia History
Bayley-III
BASC3 (PRS-P Parent 2-5)
ABAS-3 ( 0-5y Parent)
3:7 to 3:11
Structured Developmental History 
and Haemophilia History
BASC3 (PRS-P Parent 2-5)
ABAS-3 (0-5y Parent)
4:0 to 5:11
Structured Developmental History 
and Haemophilia History
WPPSI-IV
BASC3 (PRS-P Parent 2-5)
ABAS-3 (0-5y Parent)
6:0 to 6:11
Structured Developmental History 
and Haemophilia History
WPPSI-IV
BASC3 (PRS-C Parent 6-11)
ABAS-3 (5-21y Parent)
7:0 to 7:11
Structured Developmental History 
and Haemophilia History
WASI-II
BASC3 (PRS-C Parent 6-11 
form)
ABAS-3 (5-21y Parent form)
8:0 to 9:11
Structured Developmental History 
and Haemophilia History
WASI-II
BASC3 (PRS-C Parent 6-
11form and SRP-C 8-11 patient 
form)
ABAS-3 (5-21y Parent form)
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10:0 to 10:11
Structured Developmental History 
and Haemophilia History
WASI-II
BASC3 (PRS-C Parent 6-11 
form and SRP-C 8-11 patient 
form)
ABAS-3 (5-21y Parent form)
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CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
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8.3.4
Vital signs
When dosing the first time (V1), vital signs should be recorded pre-dose and post-dosing of N9-GP. 
Hereafter vital signs will only be measured pre-dose and according to Table 2–1.
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 (e.g. sitting) throughout the trial for each individual patient. 
Vitals signs include assessment of:
Body temperature (C/F)
Blood pressure (BP) (mm Hg)
Pulse (beats/min)
If not possible to perform some or all of the above measurements, it is allowed to evaluate the child 
for normal appearance checking for signs and symptoms of acute or chronic disease.
If a change in clinical assessments after V0 is due to an AE, then this must be recorded and reported 
according to Section 11.2.
8.4
Laboratory assessments
Blood samples for laboratory analysis of safety, and efficacy parameters will be drawn as outlined 
in Table 2–1. Approximate total volumes of blood to be taken from each patient see Section 8.4.3.
The sample taken 30 minutes (±10 minutes) post-dose can be taken from the same vein as used for 
administration of N9-GP if more than 30 minutes have passed after the injection. The same device 
used for trial drug injection cannot be used for blood draw post-dose.
Laboratory results being out of normal range must be categorised as “out of normal range, not 
clinically significant” or “out of normal range, clinically significant”. A laboratory result evaluated 
as “out of normal range, clinically significant” must be recorded as an AE, or if present at V0 it 
should be recorded as concomitant illness.
The central laboratories provide results to the trial site in the units preferred by the trial sites while 
the results that are transferred to the trial database will always be in SI units.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the eCRF or the trial database, 
but abnormal values must be reported to the investigator. 
The investigator must review all laboratory results for concomitant illnesses and AEs and report 
these according to this protocol.
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8.4.1
Local laboratory assessments 
The trial site must be able to analyse for FIX activity and inhibitors locally if needed to decide on 
the appropriate medical care. Results of any analyses performed locally will not be recorded in the 
eCRF except for results at Visit 0.
Local laboratory results are considered as source data and must be signed, dated and categorised by 
the investigator. 
Storage handling, and disposition of samples analysed at local laboratories will be performed 
according to local laboratory procedures.
8.4.1.1
FIX activity

FIX activity (% or IU/mL)
If V0 and V1 are combined, as one combined screening visit, and if FIX activity ≤ 2% has not been 
documented in the patient medical records, it should be analysed locally and documented in the 
patient medical records.
FIX activity can be measured using a one-stage clotting or a chromogenic assay. 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 this 
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 aPTT 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.
8.4.2
Central laboratory assessments 
Central laboratory will throughout the protocol cover both the central laboratory as well as 
specialised laboratory analysing samples for all sites. 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. 
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.
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A detailed description of procedures for sampling, handling, shipment of laboratory samples and all 
materials such as test tubes and labels will be provided in the laboratory manual by the central 
laboratory. The central laboratory manual and the central laboratory results will include the 
reference ranges.
8.4.2.1
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 will follow the recommendations 
provided by Novo Nordisk A/S. A description of the method will be included in the final report of 
this trial.
FIX activity samples should be taken according to Table 2–1.
FIX activity will be measured by the use of the FIX one-stage clotting assay.
Until the implementation of Amendment 6 to the protocol any surplus samples were analysed for 
FIX activity using the chromogenic assay if deemed relevant.
One-stage clotting assay
The FIX one-stage clotting assay is a modified activated partial thromboplastin time (aPTT) assay.
The one-stage assay measures the activity of the compound in a specific process (clot formation).
8.4.2.2
Antibody assessments
The analysis will be performed at a laboratory selected by Novo Nordisk A/S or at a Novo Nordisk 
laboratory. The procedures for analyses will follow the recommendations provided by Novo 
Nordisk A/S. A description of the method will be included in the final report of this trial.
Plasma samples will be collected for assessment of:

N9-GP binding antibodies 

FIX inhibitors

HCP antibodies
Antibody samples should be taken according to Table 2–1.
N9-GP binding antibodies 
Screening for antibodies is based on assays that are validated according to international recognised 
guidelines.14-16 Samples measured above the assay cut-point will be subject to a confirmation test. 
Samples positive in the confirmatory test will be characterised for specificity to N9-GP, rFIX, and 
PEG. Isotyping of the anti-drug antibodies will possibly also be performed. 
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Samples will be analysed regularly for N9-GP binding antibodies and will be reported to the 
investigators at the end of the trial, or when considered relevant. A positive binding antibody 
sample will not by itself call for any action, but will be part of the continuous evaluation by sponsor 
of patient safety and treatment efficacy. In case of clinical suspicion of reduced treatment efficacy, 
an unscheduled visit must be scheduled by the investigator for measurement of FIX inhibitors, N9-
GP binding antibodies and peak/trough FIX activity respectively.
FIX inhibitors 
A FIX inhibitor test is defined as positive if the titre is ≥0.6 BU. 
A patient has inhibitory antibodies (inhibitor) if tested positive for inhibitors (≥0.6 BU) at two 
consecutive tests performed at the central laboratory and also tested positive for N9-GP binding 
antibodies.
If the result of an inhibitor test is positive, a second confirmatory inhibitor test should be performed 
by the central laboratory (except for the visit 1 sample that will not need to be confirmed). The 
confirmatory samples should be collected between 1 and 4 weeks after the first positive inhibitor 
test, but no sooner than 7 days after the last dose of N9-GP. Sampling for assessments of FIX 
activity (trough and recovery), N9-GP binding antibodies and lupus anticoagulant must also be 
performed at the same time. 
If the result from the lupus anticoagulant test is positive and N9-GP binding antibody test is 
negative the patient is considered inhibitor negative and can continue in the trial. If the result from 
the lupus anticoagulant test is positive and N9-GP binding antibody test is positive the patient is 
considered inhibitor positive.
The confirmatory test will define the level of inhibitors. Inhibitors will be considered as low titre 
between 0.6 BU and <5 BU and high titre ≥ 5 BU.
If a patient has a confirmed high titre inhibitor N9-GP treatment must be stopped and inhibitor 
follow-up visits must be planned, see Section 8.1.11.
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 plasma sample must be shipped to a central laboratory for inhibitor analysis.
If an investigator decides to perform inhibitor testing locally, he/she must send a duplicate sample 
for inhibitor testing at a central laboratory. The results from the central laboratory will be used in 
the analysis of trial data. A positive inhibitor test must always be reported as a MESI irrespective of 
the test being performed locally or at the central laboratory (refer to Section 11.2, 11.1).
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Version:
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Status:
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Assessment for FIX inhibitors will be carried out using a heat modified Nijmegen FIX Bethesda 
assay analysed at a central laboratory. The assay is validated according to international recognised 
guidelines.14, 17 The assay is based on measurement of the ability of a plasma sample to inhibit FIX 
in normal plasma.
PK session (conditional) 
In the event of a concern about reduced treatment efficacy it is strongly recommended to perform an 
unscheduled visit where pre-dose and 30 min post-dose FIX activity (through and peak) and binding 
antibodies will be assessed. In case of development of binding antibodies a PK session is 
recommended to be performed with a dose of 40 IU/kg. The PK session will help to address the 
impact on the efficacy of the N9-GP treatment. 
Novo Nordisk can decide based on bleedings, N9-GP usage and the PK profile to call for a safety 
committee meeting regarding recommendation on the trial continuation of the patient and how the 
patient should be followed if recommended to continue in the trial. The investigator will be 
informed of the recommendation from the safety committee.
The suggested time-points for blood sampling for a PK profile session are: pre-dose (within 1 hour 
prior to dosing), 30 min (± 10 min), 24 h (± 8 h), 48 h (± 8 h). Optional time-points are 72 h (± 8 h) 
and 96 h (± 8 h).
HCP antibodies 
All patients will be assessed for the development of antibodies against Chinese hamster ovary host 
cell proteins (HCP). Screening for Chinese hamster ovary HCP antibodies is based on assays that 
are validated according to international recognised guidelines.14-16 Samples measured above the 
assay cut-point will be subject to a confirmation test, where the signal will be sought inhibited with 
excess HCP antigen. The samples will be analysed at a laboratory selected by Novo Nordisk A/S or 
at a Novo Nordisk laboratory.
HCP antibodies will be taken according to Table 2–1. Samples will be analysed at the end of the 
trial, or when confirmed relevant by Novo Nordisk.
8.4.2.3
HIV testing and CD4+ lymphocyte count 
All patients will be assessed for HIV at visit 0, if status is unknown, or if HIV negative results in 
medical record are older than 6 months. Sampling can be postponed to the earliest convenient visit 
to ensure that the allowed blood volume is not exceeded.
Tests for CD4+ lymphocyte count and HIV viral load are only required for HIV positive patients. 
HIV positive patients should have CD4+ lymphocytes >200/µL and the HIV viral load <400,000 
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copies/mL. If the patient is not immunocompetent according to the above mentioned criteria 
relevant anti-HIV treatment should be initiated.
Results can be transferred from the medical records if obtained within the last 6 months. 

HIV antibodies (positive/negative)

CD4+ lymphocyte count 

HIV viral load
HIV and CD4+ samples should be taken according to Table 2–1.
8.4.2.4
Haematology
Haemoglobin (g/L)
Haematocrit (%)
Leucocytes (x109/L)
Thrombocytes (x109/L)
Haematology samples should be taken according to Table 2–1 however

If test results for the above mentioned haematology parameters are available from within one 
month prior to V0 they can be used for the V0 haematology assessment

If test results are  more than one month old at visit 0  a new sample must be drawn and shipped 
for analysis at the central laboratory

If V1 is more than a month after V0 a new haematology sample for central laboratory must be 
drawn at visit 1 prior to administration the first dose of N9-GP. 

Results from haematology samples taken within ±1 month of visits 23 and 28, or within 1 
month before EOT, can be used for the respective visits if analysed at the central laboratory.
8.4.2.5
Biochemistry
The following analyses will be performed by the central lab 

Creatinine 

Alanine aminotransferase (ALT) 

C-reactive protein (CRP) 

Urea / BUN 

Total bilirubin 
And to the extent the blood volume collected allows:

Sodium

Potassium

Albumin 

Aspartate aminotransferase (AST) 
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
Gamma glutamyl transferase (GGT)

Alkaline phosphatase
Biochemistry samples should be taken according to Table 2–1; however

If test results for creatinine, alanine aminotransferase, and C-reactive protein are available 
from within one month prior to V0 they can be used for the V0 biochemistry assessment

If V1 is more than a month after V0 a new biochemistry sample for central laboratory must 
be drawn at visit 1 prior to administrating the first dose of N9-GP

If biochemistry assessments at V0 were local assessments a new biochemistry sample for 
central laboratory must be drawn at V1 prior to administrating the first dose of N9-GP if the 
blood volume allows

Results from biochemistry samples taken within ± 1 month of visits 23, visit 26, and at all 
visits from visit 28 to EOT visit can be used for the respective visits if analysed at the 
central laboratory.
8.4.2.6
F9 and HLA genotype testing
At Visit 0, all patient’s parent(s)/LAR(s) will be asked about documentation of previous F9 and 
Human Leucocyte Antigen (HLA) genotype tests and results should be recorded in the eCRF, if 
available. If not available or if it needs to be re-tested, based on the investigators discretion, F9 and 
HLA genotype sample should be taken prior to administrating the first dose of N9-GP or as soon as 
possible taking the limitation of the allowed blood sampling volume into account. The F9 and HLA
genotype analysis will be performed at a laboratory selected by Novo Nordisk A/S. No analysis will 
be performed concerning other genes than F9 and HLA. Samples will be disposed appropriately 
after the test and all test results are kept confidential.
Only applicable for Israel: The parent(s)/LAR(s)/caregiver of withdrawn trial patients enrolled 
under protocol version 1, dated 4 November 2013, will be approached for consent to obtaining the 
F9 genotype, if already available. 
8.4.2.7
Investigation of allergic reactions
Allergic reaction testing will only be performed in patients developing a severe allergic reaction 
which by the investigator is assessed to be related to the N9-GP treatment. The baseline sample 
taken at Visit 0 or Visit 1 pre-dose will only be analysed in this case and further blood samples 
should be taken at an unscheduled visit as soon as convenient, but no later than 2 months after the 
event. The allergic reaction assessments will be performed at a laboratory selected by Novo Nordisk 
A/S or at a Novo Nordisk laboratory. 
Tests to be performed: 

N9-GP IgE antibodies

FIX IgE antibodies
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
FIX inhibitors

Tryptase

N9-GP/rFIX binding antibodies
Other supportive allergic tests related to an allergic reaction may be performed by Novo Nordisk:

HCP IgE antibodies

HCP IgG antibodies

Histamine (Only relevant if sample is drawn within 15 min of the allergic reaction)

Complement activation test (C3, C4) (Only relevant if sample is drawn within 15 min of the 
allergic reaction)
If relevant, baseline levels for optional tests can be set using samples from other patients enrolled in 
the trial.
Patients developing a severe allergic reaction should be carefully investigated and followed up for 
inhibitor development.
8.4.2.8
Urinalysis
Urine samples should be taken according to Table 2–1. Urine samples should be obtained if 
possible, but to increase flexibility for patient, it can be made at home same day of visit and brought 
to site if transported in a cooling bag. 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.
8.4.2.9
Exploratory analysis of PEG in plasma
The plasma concentration of PEG will be analysed for exploratory purposes according to Table 2–1. 
Blood samples for PEG analysis should be taken at visit 0 taking the limitation of the allowed blood 
sampling volume into account. If not taken at visit 0 the blood sample should be taken at visit 1 pre-
dose, if the blood volume allows.
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8.4.3
Blood sampling in infants and children
The blood sampling volume for the patient must not exceed 1% of the total blood volume at one 
occasion or 3% within in 28 days. This is in accordance with European regulatory guidelines 
(Directive 2001/20/EC).18
If all samples are taken the total volume of blood to be collected for each patient per visit will not 
exceed 18 mL.
Detailed instructions will be provided to the trial sites regarding blood sampling volumes and 
prioritisation of samples. If trial sites as part of routine assessments perform additional blood draws, 
they must ensure that the blood sampling volume will not exceed the above requirements.
It is recommended not to attempt venepuncture more than 3 times for the purpose of obtaining 
sufficient blood sampling. Documentation must be available in medical records. The vein used for 
trial drug injection cannot be used for blood sampling until more than 30 minutes have passed after 
the injection. The same device used for trial drug injection cannot be used for blood draw post-dose.
Port-a-caths and other central venous access devices should preferably not be used for blood 
sampling due to a risk of dilution or contamination with drugs (e.g. heparin). Should it be necessary 
to use such a device, it should preferably have been locked with saline prior to use. 
Only applicable for Portugal: For venous punctures, pain control measures are allowed according 
to local practice.
8.4.4
Storage of samples
Storage and disposition of samples analysed at local laboratories will be performed according to 
local laboratory procedures. 
All remaining blood samples stored at the central laboratory will be destroyed after finalisation of 
the CTR, except for samples for antibody assessment and other biospecimens (see Section 23.2).
Antibody samples (samples for binding antibodies and inhibitors) will be stored until drug approval 
by Food and Drug Administration (FDA) and/or European Medicines Agency (EMA). The retained 
antibody samples may be used for further characterisation for antibody responses towards trial drug 
if required by health authorities or for safety reasons, see Section 23.2.
8.5
N9-GP administration
N9-GP will be administered while the patient is in a comfortable position and according to Table 
5-1. 
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The first 20 EDs with N9-GP should be administered at the trial site. It is however possible to 
administer EDs 11-20 outside trial site if this is according with local procedures and must be under 
supervision of a health care professional qualified of handling anaphylactic reactions. 
Precautions to take when injecting the first dose of N9-GP (V1)

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

The date and the actual time of completion of the injection must be recorded in the eCRF
Precautions to take when injecting the second dose of N9-GP (V2)
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 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 

The date and the actual time of completion of the injection must be recorded in the eCRF
Precautions to take when injecting ED 3-20 of N9-GP (V3-V20) at trial site

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
Precautions to take when injecting ED 11-20 of N9-GP (V11-V20) outside the trial site

Presence of a relevant health care professional qualified of handling anaphylactic reactions

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
Trial 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. 
The actual time of completion of the injection will be recorded and corresponds to trial time 
point = 0. 
Home treatment from ED 21 and until EOT
Home treatment with administration of N9-GP can start after 20 EDs if the patient or the patient’s 
parent(s)/LAR(s) are comfortable with the reconstitution and administration process. 
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Home treatment may be given by the patient’s parent(s)/LAR(s) 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
All treatment requiring bleeding episodes should be treated and registered independently of the 
on-going prophylaxis treatment regime
If a bleeding episode occurs earlier at 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 a bleeding episode occurs later the same day, the 
bleeding episode should be treated and registered independent of the prophylaxis dose.
8.6
Bleeding episodes
All bleeding episodes and treatments with N9-GP must be recorded in the eCRF by the investigator
or in the eDiary by the patient’s parent(s)/LAR(s). Bleeding episodes and other symptoms (eg 
synovitis, arthralgia, injection site haematoma) in connection with bleeding episodes should not 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 life-threatening bleeding episode, it should 
always be reported as a SAE.  
8.6.1
Assessments of bleeding episodes and treatment response
The severity of bleeding episodes is defined as

Mild/moderate: Bleeding episodes that are uncomplicated joint bleeding episodes, muscular 
bleeding episodes without compartment syndrome, mucosal- or subcutaneous bleeding 
episodes. These bleeding episodes can be treated at home after visit 20 and details of the 
bleeding episodes should be entered in the eDiary by the patient’s parent(s)/LAR(s).

Severe: All intracranial, retroperitoneal, iliopsoas and neck bleeding episodes must be 
categorised as severe. Muscle bleeding episodes with compartment syndrome and/or bleeding 
episodes associated with a significant decrease in the haemoglobin level (>3g/dl) should also be 
reported as severe (it is the investigators decision if haemoglobin measurements should be 
performed). The investigator must be contacted if a severe bleeding episode occurs.
In case of treatment requiring bleeding episode occurs outside the trial site’s opening hours and 
prior to home treatment or treatment outside trial site (Section 5.3.5) has been initiated, the patient 
must be treated according to local procedure.
Bleeding Episode - information to be collected
Information about bleeding episodes prior to the 20 ED (V20) should always be recorded in eCRF. 
In case the patient is treated outside the trial site the trial site should be informed in case of a 
bleeding episode and the details hereof. After 20 EDs bleeding episodes must be recorded either in 
the eDiary (if treated at home) or in the eCRF (if treated at the trial site), see Section 12.3. 
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Classification and recording of severe bleeding episodes is the responsibility of the investigator and 
should always be registered in the eCRF.
Date and time the bleeding episode started
Date and time the bleeding episode stopped
Cause of the bleeding episode
i.e. spontaneous, traumatic or due to surgery
Anatomical location of bleeding episodes
Treatment of bleeding episodes
amount, date and time of each dose of N9-GP

Severity of treatment requiring bleeding

mild/moderate, severe

Haemostatic response assessed by the 4-point scale defined in the below Table 8-3
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Table 8-3
4-point scale
Classification
N9-GP dosing
Description
Excellent

One dose within 8 hours 
Abrupt pain relief and/or clear 
improvement in objective signs of 
bleeding 
Good

One dose within 8 hours 
Noticeable pain relief and/or 
improvement in signs of bleeding 
Moderate

More than one dose within 8 
hours
Probable or slight beneficial effect 
after the first injection
Poor

More than one dose within 8 
hours 
No improvement or worsening of 
symptoms 
Re-bleed
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 new bleeding episode within 72 hours after stopping of a previous 
bleeding episode at the same or a subset of the same anatomical locations
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
8.7
Surgery
Before any surgery is performed blood samples for assessment of FIX inhibitors must be taken and 
send to central lab unless samples has already been sent to central lab within the last 30 days. The 
results do not have to be available before the surgery.
Emergency surgeries are allowed in this trial if adequate supply of N9-GP is available at site to 
ensure haemostasis and wound healing.
Patients undergoing surgery will continue the regular visit schedule, but additional visits may be 
performed in the peri-operative period as decided by the investigator. Surgery will be documented 
as unscheduled visits. It is up to the investigator to decide how long the post-surgery period should 
be and when the patient should resume regular prophylaxis or pre-prophylaxis treatment. All N9-GP 
doses administered in relation to a surgery must be registered on the surgery form in the eCRF or 
eDiary.
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8.7.1
Minor surgery
Preventive N9-GP treatment before minor surgery including placement or removal of central 
venous access port can be performed within this trial at the investigator’s discretion according to 
local guidelines. A dose of 40 IU/kg N9-GP prior to minor surgery is recommended to prevent 
perioperative bleeding episodes, see Table 5-1. Definition of minor surgery, see Section 5.3.8. For 
minor surgery the following should be recorded in the eCRF:

Date, time and volume of preventive dose before surgery

Type of surgery

Indication for surgery 

Location of surgery 

Date of surgery

Start and stop date and time of surgery
8.7.2
Major surgery
Major surgery can be performed while participating in the present trial. For definition of major 
surgery, see Section 5.3.8. 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 haemophilia.8 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 post-operative 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 haemophilia.8
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 IU/kg N9-GP after the post-
surgery period
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During this period, all bleeding episodes and any haemostatic treatment administered must be 
recorded in the eCRF when the patient is at the site and in the eDiary when the patient is at home, 
refer to Section 12.3.
Perioperative procedures, assessments and blood sampling will be performed at the Investigators 
discretion and documented in the patients’ medical records. 

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

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 

Clinical evaluation of haemostatic response to be evaluated upon completion of the surgical 
procedure 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
8.8
Training and reminders
8.8.1
Trial card dispensing
At V0 the patient’s parent(s)/LAR(s) 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.
8.8.2
Home treatment training
Home treatment training with administration of N9-GP can start after administrations of the first 3 
EDs at trial site until V20 (see Section 8.1.12 ), but may be postponed until the patient’s 
parent(s)/LAR(s) are comfortable with the reconstitution and administration process.
A home treatment guide for the reconstitution will be available as handouts for the patient’s 
parent(s)/LAR(s).
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Training in reconstitution and administration must be performed until parent(s)/LAR(s) feel 
comfortable in handling the treatment. The training must be documented in the medical records.
All patient’s parent(s)/LAR(s) must be carefully instructed in recognising and dealing with signs 
and symptoms of an anaphylactic reaction. If the patient does not follow the planned dosing 
schedule, the investigator must retrain the patient’s parent(s)/LAR(s).
8.8.3
Electronic diary (eDiary)
Pre-prophylaxis treatment, prophylaxis treatment and bleeding episodes should be recorded in 
eCRF for the first 20 EDs. When the first 20 EDs have been administered, the data will be captured
either in eCRF and/or eDiary according to Section 12.3.
Parent(s)/LAR(s) should be trained in using the eDiary before or when they receive the eDiary. If 
needed the training must be repeated until the parent(s)/LAR(s) use the eDiary as intended.
It will be the responsibility of the investigator to assess the eDiary data throughout the conduct of 
the trial and to ensure entry compliance.
During the home treatment period the patient’s parent(s)/LAR(s) should ensure that all prophylactic 
home treatment, bleeding episodes, treatment of bleeding episodes as well as haemostatic 
evaluation of the treatment of bleeding episodes are captured in the eDiary.
8.8.3.1
eDiary dispensing and collection
The eDiary will be dispensed to the patient’s parent(s)/LAR(s) latest at the visit when home 
treatment is started.
For details regarding patient’s diary, please refer to Section 12.3.
For patients completing the trial or in case of withdrawal, the eDiary will be collected at the EOT 
visit.
8.8.4
Contact between the investigator/medically qualified person and the patient
The investigator and/or medically qualified person must establish contact with the patient’s 
parent(s)/LAR(s) at least every 12 weeks ± 1 week, if site visits are more than 3 months apart, either 
by visits at the trial site or other contact e.g. telephone calls. All trial related contacts must be 
captured in eCRF.
The patient and patient’s parent(s)/LAR(s) should be notified that they will be contacted according 
to the protocol. 
The communication will focus on the well-being of the patient, including enquiry of all AEs, and 
any medical treatment (including treatment of bleeding episodes) since the last contact. The 
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investigator/medically qualified person should not suggest specific AEs to patient’s 
parent(s)/LAR(s), but should inquire e.g. “how is your child doing?”, “has your child had any 
problems since the last contact?” and “have you remembered to enter all treatments in the eDiary?”
The expiration date of the drug and solvent that the patient has received should be checked by the 
site staff before the patient’s next visit to determine if an extra visit is relevant and to inform the 
patient of which unused vials to return to the site. Expiry of injection kits should be discussed.
All attempts to contact the patient’s parent(s)/LAR(s) must be documented in a source document. If 
a successful contact cannot be made after 3 documented attempts no further attempts are required. If 
the patient’s parent(s)/LAR(s) have withdrawn consent, this must be documented.
At each contact the investigator will at a minimum capture/evaluate
Assessment of bleeding episodes
Adverse events 
Concomitant Medication 
eDiary compliance
N9-GP administration compliance
8.8.5
Interactive web response system
Please refer to Section 10 regarding the IWRS. 
For details on how to use the IWRS, please refer to the trial specific IWRS user documents 
provided to the trial site. 
8.9
Patient compliance
Throughout the trial the investigator will remind the patient’s parent(s)/LAR(s) to follow the trial 
procedures and requirements to ensure patient compliance. If a patient is found to be non-compliant, 
the investigator will remind the patient’s parent(s)/LAR(s) of the importance of following the 
instructions given including taking the trial product as described. 
Assessment of patient compliance with protocol procedures for determination of continuation of the 
trial will be done by the investigator. 
Failure to comply with scheduled visits and N9-GP administration may result in withdrawal in 
accordance with the protocol withdrawal criteria, see Section 6.4.
Treatment with FIX concentrate, 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 8.2.4). Regarding by-
passing agent, see Section 8.2.3.
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Compliance with N9-GP treatment must be addressed at each visit. Compliance check includes a 
cross check between number of injections recorded in eDiary, expected number of injections and 
the used/returned vials.
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9
Trial supplies
Trial supplies comprise trial product and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Material Manual (TMM) and Handling instruction.
Trial product must not be dispensed to any person not included in the trial (excluding patient’s 
parent(s)/LAR(s)).
Auxiliary supplies comprise supplies other than trial products, e.g. needles and syringes.
9.1
Trial product
The following trial product will be provided by Novo Nordisk A/S, Denmark.
Table 9-1
Trial Product
Trial Product
Strength
Dosage form
Route of 
administration
N9-GP (nonacog 
beta pegol)

500 IU/vial

2000 IU/vial
Freeze-dried Powder 
for solution for 
injection
i.v. injection
N9-GP is supplied as a sterile freeze-dried powder for solution 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 diluted further. The trial product must not be used if it does not 
appear clear and colourless free from clearly visible particles.
After reconstitution the appropriate volume of the vials will be drawn into a syringe. Maximum 4 
mL should be withdrawn from each vial of reconstituted N9-GP. The content of several vials may 
be combined in one syringe. N9-GP may not be added to or mixed with any other material than 
Histidine.
Administration of the appropriate volume of N9-GP will be given as i.v. bolus injection. Maximum 
injection rate is 4 mL/min (please refer to Section 8.5).
The investigator must explain to the patient’s parent(s)/LAR(s) how much this corresponds to in 
terms of injection time when administering N9-GP at home. 
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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 than every hour. These doses are only 
relevant in case of trauma, severe bleedings or surgery.
Histidine for reconstitution of the N9-GP trial product will be supplied by Novo Nordisk. Novo 
Nordisk will not supply any further Non Investigational Medical Products (NIMPs).
9.2
Packing, labelling and dispensing
Labelling of the trial product will be in accordance with Annex 1319, local regulations and trial 
requirements. Novo Nordisk A/S will label and pack the trial product.
N9-GP and Histidine will be provided in boxes. The boxes will be provided with labels containing 
the following information: product name, expiry date and storage conditions. Each trial product box
will have a unique Dispensing Unit Number (DUN) for identification and traceability. 
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.
The IWRS will allocate the trial product in uniquely numbered DUs to the patient at each 
dispensing visit. The DUs will be dispensed in accordance with the patient’s body weight. Trial 
product will be dispensed at dispensing or assessments visits, as appropriate.
The investigator must document that direction for use is given to the patient’s parent(s)/LAR(s) 
orally and/or in writing at each dispensing visit according to the Handling instruction.
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9.3
Storage
Storage must be done according to the table below.
Table 9-2
Storage
Products
Storage conditions
(not-in-use)
In-use conditions
N9-GP (nonacog beta pegol) 

2-8°C 

Protect from light

4 hours below 30°C 

Do not freeze

Avoid direct sunlight
Histidine

2-25°C

Protect from light 
N/A
The trial product N9-GP powder and Histidine solvent must be stored in a secure place at trial site. 
For N9-GP under refrigeration at 2-8°C, and for Histidine solvent at 2-25°C, both protected from
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. ‘In use time’ starts from completion of the reconstitution, see the Handling 
instruction for further details. The trial site must carefully instruct the patients’ parent(s)/LAR(s) in 
how to store the trial product. No temperature monitoring is required after the trial product is taken 
home by the patient.
The investigator must ensure the availability of proper storage conditions, record and evaluate the 
temperature. The investigator must inform Novo Nordisk immediately if any trial product has been 
stored outside specified conditions (e.g. outside temperature range).
Unused trial product must be stored separately from used trial product.
Trial product that has been stored improperly must not be dispensed to any patient before it has 
been re-evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
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9.4
Drug accountability and destruction
Drug accountability is the responsibility of the investigator. The investigator or delegated person, 
e.g., a trial nurse will perform drug accountability in the IWRS Drug Accountability Module. 
Once a patient is dosed, all trial drug product vials (dispensed, used, partly used or unused, returned 
and lost/damaged) must be recorded in the IWRS Drug Accountability Module. 
Drug accountability is not required for Histidine solvent used for reconstitutions, but it is the 
responsibility of the investigator or delegate to follow Histidine expiry and prevent patient use after 
expiry.
Returned trial product (used/partly used or unused including empty packaging material) can be 
stored at room temperature and must be stored separately from non-allocated trial product.
All trial drug products must be retained for drug accountability checked 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.
Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented.
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 trial 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.
9.5
Auxiliary supply
Auxiliary supplies are equipment such as needles, syringes, butterflies, sterile swabs, vial adaptor 
etc. These will be provided by Novo Nordisk A/S, if applicable.
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, 
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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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10 Interactive /web response system (IWRS)
A trial specific IWRS will be set-up, which can be accessed at any time via internet or via 
telephone. Access to the IWRS must be restricted to and controlled by authorised persons.
IWRS is used for:

Screening

Screening failure

Medication arrival

Dispensing

Withdrawal*

Completion

Drug accountability

Data change
* For inhibitor patients attending inhibitor follow-up the IWRS withdrawal session should not be 
performed prior to EOT on the third inhibitor follow-up visit.
IWRS call can be done the day before the actual visit.
IWRS user manuals will be provided to each trial site.
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11 Adverse events and technical complaints 
11.1
Definitions
Adverse event:
An adverse event (AE) is any untoward medical occurrence in a patient administered a product, 
and which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:

A clinically significant worsening of a concomitant illness.

A clinical laboratory adverse event (CLAE): A clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due to 
the abnormality.
The following should not be reported as AEs:

Bleeding episodes and other symptoms (eg synovitis, arthralgia, injection site haematoma) in 
connection with bleeding episodes should not 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 life-threatening bleeding episode, it should always be reported as a SAE. All bleeding 
episodes and other findings related to underlying disease will be captured in Section 8. 

Pre-existing conditions, including those found as a result of screening procedures (pre-existing 
conditions should be reported as medical history or concomitant illness).

Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent.
The following three definitions are used when assessing an AE:

Severity assessment

Mild - no or transient symptoms, no interference with the 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.

Causality assessment
The following terms are used when assessing the relationship between an AE and the relevant 
trial product:

Probable - Good reason and sufficient documentation to assume a causal relationship.

Possible - A causal relationship is conceivable and cannot be dismissed.
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
Unlikely - The event is most likely related to aetiology other than the trial product.

Final outcome of an AE

Recovered/resolved - The patient has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
patient’s parents/LAR(s) signed the informed consent.

Recovering/resolving - The condition is improving and the patient is expected to recover 
from the event. This term is only applicable if the patient has completed the trial or has 
died from another AE.

Recovered/resolved with sequelae – The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.

Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known.

Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he/she died should be 
assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved with 
sequelae" or "not recovered/not resolved". An AE with fatal outcome must be reported as 
an SAE.

Unknown - This term is only applicable if the patient is lost to follow-up.
Serious adverse event:
A serious adverse event (SAE) is an experience that at any dose results in any of the following:

Death.

A life-threateninga experience.

In-patient hospitalisationb or prolongation of existing hospitalisation.

A persistent or significant disability or incapacityc.

A congenital anomaly or birth defect.

Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical 
judgement - they may jeopardise the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of SAEd. 

Suspicion of transmission of infectious agents via the trial product and formation of 
inhibitor antibodies must always be considered an SAE.

FIX inhibitory antibodies (confirmed by two consecutive tests, see Section 8.4.2.2 must 
always be considered a SAE
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 was more severe.
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b. The term "hospitalisation" is used when a patient: 

Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 

Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a patient's ability to conduct normal life functions (eg following the 
event or clinical investigation the patient has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasiasis or convulsions that do not result in hospitalisation or development of drug 
dependency or drug abuse.
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or more of the below 
defined MESI criteria.
1. Medication errors concerning trial product:

Administration of wrong drug 

Wrong route of administration

Accidental administration of a lower or higher dose than intended. The administered dose 
must deviate from the intended dose to an extent where clinical consequences for the trial 
patient were likely to happen as judged by the investigator, although not necessarily did 
happen.
2. Inhibitor formation against FIX. Blood samples for measurement of FIX inhibitors will be 
analysed at a central laboratory selected by Novo Nordisk A/S. If an investigator obtains 
information of a positive central laboratory result or any indication of inhibitor formation by 
clinical signs or local laboratory results, this should be reported as a MESI prior to confirmation 
by two central laboratory results.
3. Thromboembolic events (clinical signs or laboratory indications of arterial and venous 
thrombosis including myocardial infarction, pulmonary embolism, cerebral 
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infarction/thrombosis, deep vein thrombosis, other clinically significant thormboembolic events 
and peripheral artery occlusion, see definitions below).
4. Anaphylactic reaction as defined by Sampson et al 200620 (see below).
5. Allergic reaction including, but not limited to, any acute immunoglobulin E (IgE) mediated 
reaction of delayed type hypersensitivity (clinical signs may include various types of skin 
rashes) that does not meet the definition of anaphylaxis as described by Sampson en al20.
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
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:

Ischaemic symptoms

Subsequent development of pathologic Q waves on the ECG

ECG changes indicative of ischaemia (ST segment elevation or depression)

Coronary artery intervention (e.g. 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
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:
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
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, e.g.:

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.
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Clinical criteria for diagnosing anaphylaxis (infants and children only) (Sampson et al. 
200620): 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, 
or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT LEAST 
ONE OF THE FOLLOWING
a) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b) Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], 
syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient 
(minutes to several hours):
a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-
tongue-uvula)
b) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)
d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic 
BP from that person’s baseline*
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, 
less than (70 mm Hg + [2x age]) from 1 to 10 years.
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:

The physical or chemical appearance of trial product (e.g. discoloration, particles or 
contamination)

The packaging material (e.g. leakage, cracks, rubber membrane issues or errors in labelling text)
11.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the patient’s parent(s)/LAR(s) has signed the informed 
consent until the end of the trial. The events must be recorded in the applicable CRF forms in a 
timely manner. See timelines below.
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AEs experienced after signing of informed consent and before first dosing should only be reported 
if associated with trial related activities.
During each contact with the trial site staff (trial site visits and telephone contacts) the patient 
and/or patient’s parent(s)/LAR(s) must be asked about AEs and technical complaints, e.g. “Have 
your child experience any problems since the last contact?”
All AEs, either observed by the investigator or reported by the patient, must be reported by the 
investigator and evaluated. Novo Nordisk assessment of expectedness is performed according to the 
following reference documents: Investigator’s Brochure7, N9-GP, current version and any updates 
thereto.
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. 
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as an individual AE using separate AE forms.
For each SAE and MESI an electronic Safety Information Form (eSIF) should be completed in
addition to the AE form in the eCRF. If several symptoms or diagnoses occur as part of the same 
clinical picture, one SIF may be used to describe all the SAEs. All concerned AE numbers must be 
included in the AE number field on the SIF.
MESIs, regardless of seriousness, must be reported using both the AE form and the safety 
information form. For MESIs of allergic aetiology, the hypersensitivity questionnaire must be 
completed.
The AE form for a non-serious AE should be signed when the event is resolved or at the end of the 
trial.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF/CRF within the specified 
timelines:

SAEs and MESIs: The AE form within 24 hours and the safety information form within 5 calendar days 
of the investigator's first knowledge of the event.
Both forms must be signed within 7 calendar days from the date the information was entered in the 
eCRF. 

MESIs of allergic aetiology: The hypersensitivity questionnaire must be completed within 14 days
If the eCRF is unavailable, the concerned AE and SIF (if applicable) information must be reported 
on paper forms and sent to Novo Nordisk by fax, e-mail or courier within the same timelines as 
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stated above. When the eCRF becomes available again, the investigator must re-enter the 
information on the appropriate forms in the eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigators trial file.
Reporting of trial product-related SUSARs by the sponsor:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change to any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and GCP1, unless 
locally this is an obligation of the investigator.
11.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF.
Follow up information must be reported to Novo Nordisk according to the following:

SAEs: All SAEs must be followed until the outcome of the event is "recovered/resolved", 
"recovered/resolved with sequelae" or "fatal", and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome "recovering/resolving" or "not recovered/not resolved". Cases 
can be closed with the outcome of "recovering/resolving" when the patient has completed the 
follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator's first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 

Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
"recovering/resolving", "recovered/resolved" or "recovered/resolved with sequelae" or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
"recovering/resolving" or "not recovered/not resolved". Cases can be closed with the outcome of 
"recovering/resolving" when the patient has completed the follow-up period and is expected by 
the investigator to recover.

Non-serious AE fulfilling the MESI criteria: Follow-up information on MESIs should only 
include new (e.g. corrections or additional) information and must be reported within 14 
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calendar days of the investigator's first knowledge of the information. This is also the case for 
previously reported non-serious AEs which subsequently fulfil the MESI criteria. 
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow up with re-
assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
11.4
Technical complaints and technical complaint samples
11.4.1
Reporting of technical complaints 
All technical complaints on any of the following products:

N9-GP 500 IU/vial

N9-GP 2000 IU/vial

Histidine vial

Novo Nordisk trial injection kit 
which occur from the time of first usage of product until the time of the last usage of the product,
must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AE(s), SAE(s) and/or 
MESI(s). 
Technical complaints must be reported on a separate technical complaint form for each product 
listed. If the technical complaint involves more than one batch, lot number or more than one DUN, 
a technical complaint form for each batch, lot number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:

Technical complaint assessed as related to an SAE within 24 hours

All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not patient related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above.
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11.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form must be 
sent with the sample.
The investigator must ensure that the technical complaint sample contains the batch, lot number 
and, if available, the dispensing unit number (DUN).
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable.
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage, see Section 9.
11.5
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 blood pressure. 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 prior to further treatment 
with N9-GP. 
If an overdose is suspected further N9-GP administration should be stopped and the patient should 
receive treatment as appropriate according to hospital practice and guidelines prior to further 
treatment with N9-GP.
11.6
Committees related to safety
11.6.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal N9-GP safety committee to perform ongoing safety 
surveillance.
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. 
Any event occurring after administration of N9-GP fulfilling the SAE/MESI criteria must be 
reported to Novo Nordisk. If one of the below mentioned criteria is fulfilled, all investigators will 
be informed in writing, and an extraordinary safety committee meeting will be called for to decide 
whether or not the trial can continue with or without modifications. 
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
Anaphylaxis in two patients after trial product administration

Occurrence of two significant thromboembolic events in two different patients (e.g. myocardial 
infarction, pulmonary embolism, cerebral thrombosis/infarction or other significant 
thromboembolic events)

Death related to trial product assessed by Novo Nordisk or by the Investigator
Dosing of patients on treatment may continue while further evaluation of the SAE/MESI is made, 
but recruitment of additional patients will be put on hold unless otherwise decided by the safety 
committee. The evaluation of fulfilment of the above criteria by the safety committee will take into 
consideration whether or not the patient was dosed according to protocol.
Furthermore, the safety committee will meet following every inhibitor (neutralising antibody, 
Bethesda unit of ≥ 0.6) confirmed by two consecutive tests at the central laboratory. Recruitment of 
new patients may continue during safety committee assessment of inhibitor formation.
Finally, the safety committee might meet in case of development of binding antibodies and 
suspicion of decreased drug efficacy.
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12 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be supplied by a vendor. The activities of this vendor will be 
under the direction and supervision of Novo Nordisk.
The investigator or delegated person should ensure that all relevant questions are answered, and that 
no empty data field exists.
If a test or an assessment has not been done and will not be available, or if the question is irrelevant 
(e.g. is not applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRF:
1. Hypersensitivity questionnaire 
In addition paper AE forms, safety information forms and Technical Complaint forms will be 
provided. These must be used when access to the eCRF is revoked or the eCRF is unavailable.
On the paper CRF form print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks.
If a test or an assessment has not been done and will not be available, indicate this by writing “ND” 
(not done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not 
applicable) indicate this by writing “NA” (not applicable) in the appropriate answer field. Further 
guidance can be obtained from the instructions in the CRF.
The investigator must ensure that all information derived from source documentation is consistent 
with the source information. By electronically signing the case book in the eCRF, the investigator 
confirms that the information in the eCRF including related forms is reviewed, complete and 
correct.
12.1
Corrections to case report forms
Corrections to the eCRF data may be made by the investigator or the investigator's authorised staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's authorised staff after the date the investigator has 
signed the case book, the case book must be signed and dated again by the investigator.
Corrections to the data in paper 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 were crossed out. Each 
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correction must be initialled, dated and explained (if necessary) by the investigator or the 
investigator’s authorised staff. 
Corrections necessary after the paper CRFs have been removed from the investigator’s trial site 
must be documented on a Data Clarification Form (DCF) or a Monitor-Initiated Discrepancy Form 
(MIDF).
12.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 3 days after the visit. Once data have been entered, it will be available to Novo Nordisk for 
data verification and validation purposes. 
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
When the final Clinical Trial Report (CTR) is available, the data will be archived by Novo Nordisk.
12.3
Electronic diary
Novo Nordisk will provide the patient’s parent(s)/LAR(s) with an eDiary for electronic recording of 
details of their child’s prophylaxis administration, bleeding episodes and treatment hereof, see 
Sections 8.1.1 and 8.6. The eDiary and related support services will be supplied by a vendor 
working under the direction and supervision of Novo Nordisk. 
When initiating home treatment, the patient’s parent(s)/LAR(s) will receive the eDiary and they will 
be trained in the use thereof by the investigator or delegated person. Data will be entered by the 
patient’s parent(s)/LAR(s) in the eDiary device during home treatment. 
During trial site visits, data will be recorded in the eCRF by the trial staff and should not be entered 
by the patient’s parent(s)/LAR(s) in the eDiary. The eDiary will be returned by the patient’s 
parent(s)/LAR(s) at the EOT visit. 
All data entered will be transferred from the device to an electronic 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 have built in edit checks and reminders, to ensure that all relevant questions are 
answered. 
eDiary data transferred to the electronic database will be viewable to relevant trial site staff and 
Novo Nordisk personnel on a secure, password protected web portal.
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It is the responsibility of the investigator or delegated staff to review and thereby ensure the eDiary 
data quality. Following must be checked as minimum: that the eDiary data is complete, consistent 
and according to the requirements defined in this protocol. Upon review the investigator or 
delegated staff must document that the review has taken place and any actions required e.g. 
retraining of patients.
It must be confirmed by the patient’s parent(s)/LAR(s) if missing eDiary data need to be entered 
and/or if the transferred eDiary data needs to be corrected. This is done by filling in and forwarding 
a Data Clarification Form (DCF) to the eDiary vendor. An audit trail will be maintained.
12.4
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 the collection of these 
assessments will be done on paper forms. 
Data will be entered on the tablet 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 tablet to a database. 
The results of the assessments will be viewable on a web based portal when transmitted from the 
tablet. The web based portal is password protected.
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13 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. 
After site initiation visit, site should be contacted every quarter, and visited at least every 6 months. 
The contacts (calls or visits) can be part of a monitoring visit in another trial. These contacts should 
be documented. 
A monitoring visit must be performed as soon as possible after FPFV and no longer than 4 weeks 
after. The monitoring 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 
intervals between monitoring visits must not exceed 12 weeks whilst patients are in the trial
between visit 0 and visit 28. In the period after visit 28, intervals between monitoring visits must 
not exceed 24 weeks ± 4 weeks (whilst patients are on the trial), provided site contact at least every 
12 weeks. The monitor must be given direct access to source documents (original documents, data 
and records). Direct access includes permission to examine, analyse, verify and reproduce any 
record(s) and report(s) that are important to the evaluation of the trial. If the electronic medical 
record does not have a visible audit trail, the investigator must provide the monitor with signed and 
dated printouts. In addition, the relevant trial site staff should be available for discussions at 
monitoring visits and between monitoring visits (e.g. by telephone).
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
All data must be verifiable in source documentation other than the eCRF, except for the following 
data that may be recorded directly in the eCRF and will then be considered source data:

Ethnicity

Race
The patient will only be identified by patient number and the monitor will verify and ensure that the 
eCRFs and eDiary are completed. Also it must be checked that the eDiary data review has been 
documented by investigator and that the needed action has been taken, if any.
Monitors must review the patient’s medical records and other source data (e.g. the diaries) to ensure 
consistency and/or identify omissions compared to the CRF. If discrepancies are found, the 
investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit addressing any action to be taken.
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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 except for informed consent, reason for screening failure and for data 
relating to any AEs if applicable. 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 into eCRF.
All information captured during visits to the trial site will be collected either in the eCRF, via tablet
or on paper questionnaires. When home treatment is initiated all bleeding episodes and injections 
with N9-GP occurring outside the trial site should be entered in the eDiary by the patient’s 
parents/LAR (see Section 8.8.3). The completed eDiary is considered source data. 
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14 Data management
Data management is always the responsibility of Novo Nordisk. 
Data management may be delegated under an agreement of transfer of responsibilities to another 
data management unit within Novo Nordisk or an external Clinical Research Organisation (CRO).
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of patient data, when they are transmitted over open networks. 
Laboratory data from central laboratories will be transferred electronically from the laboratory 
performing the analyses. In cases where laboratory data are transferred via non-secure electronic 
networks, data will be encrypted during transfer.
The central and local laboratories will provide laboratory reports to the investigator for storage at 
the trial site. The laboratory report must be signed and dated by the investigator or delegated person 
and stored at the trial site as source data.
The patient and any biological material obtained from the patient will be identified by patient 
number and trial identification number. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of patients in all presentations and 
publications as required by local, regional and national requirements.
The system and paper based questionnaires for neurocognitive assessments and support services for 
the systems will be supplied by a CRO. The CRO will collect, query, and process data from 
Structured Developmental and Haemophilia History, as well as Neurocognitive assessments. The 
CRO will transfer assessment results and outcomes from the External Expert Review Panel to Novo 
Nordisk. 
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15 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures (SOPs) 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 CONNECT as investigator portal to distribute and share trial-related 
documents and information with the participating sites.
The eDiary and tablets 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).1, 21 After trial completion, each trial site will be supplied with long-life CDs. These 
CDs 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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16 Statistical considerations
Novo Nordisk A/S will be responsible for the statistical analysis.
The main statistical reporting of the trial will be performed when at least 20 patients have 
completed main phase (minimum 50 weeks) with at least 50 EDs and completed visit 23. Data from 
patients not yet having completed main phase and data from patients that have entered extension 
phase at this point will be included up to latest visit prior to this cut-off date. The data will be 
presented for the main phase and extension phase separately as well as combined. Except for the 
confidence interval for inhibitor rate and for annualised bleeding rate, the evaluation of data will be 
based on descriptive statistics, i.e. summary tables, listings and figures. 
An updated statistical reporting of the trial with supportive data will be performed when at least 40 
patients have had at least 100 EDs. Data from all patients will be included up to latest visit prior this 
cut-off date. The data will be presented for the main + extension phase and the extended 
prophylaxis period (beyond 100 EDs) separately as well as combined. 
All data will be reported separately in a final report when the trial is completed.
Figure 16–1
Individual patient flow and time period for main trial report
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Multiple bleeding locations occurring from the same event (e.g. due to a fall) or at the same time 
point will be counted as one bleeding episode.
All bleeding endpoints will be evaluated based on bleeding episodes treated with N9-GP unless the 
bleeding was considered clinically insignificant (non-treatment requiring bleeding episode) and the 
associated treatment given was part of prophylaxis.
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 8.3.3).
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. If created, the SAP will be 
finalised before the first database lock. 
16.1
Sample size calculation
No formal sample size calculations have been performed. The sample size of 40 completers is based 
on EMA guideline5.
16.2
Definition of analysis sets
Descriptions and analysis of efficacy will be based on the Full Analysis Set (FAS), as defined in 
ICH E9 guidelines.22 The FAS includes all patients exposed 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.
The patients or observations to be excluded, and the reasons for their exclusion must be documented 
and signed by those responsible before database lock. The patients and observations excluded from 
analysis sets, and the reason for this, will be described in the clinical trial report.
16.3
Primary endpoint
The primary endpoint is a safety endpoint defined as incidence of inhibitory antibodies against FIX.
The rate of inhibitory antibodies 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 
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patients with a minimum of 10 exposure days plus any patient with less than 10 exposure days but 
with inhibitors. 
16.4
Secondary endpoints
16.4.1
Confirmatory secondary endpoints
There are no confirmatory secondary endpoints.
16.4.2
Supportive secondary endpoints
16.4.2.1
Number of bleeding episodes during prophylaxis
Annualised bleeding rate will be summarised and a 95% two sided confidence interval will be 
provided based on a negative binomial regression model with number of bleeding episodes 
requiring treatment with N9-GP (also referred to as breakthrough bleeding episodes) as the outcome 
variable, and adjusting for exposure time. For comparison with previous trials, a sensitivity analysis 
based on a Poisson regression model allowing for over-dispersion will also be performed.
Since it must be expected that some patients will withdraw, it becomes essential to account for how 
such withdrawals may affect the analyses of the prophylaxis effect. The analyses above already 
account for possible different treatment durations by using treatment duration as an offset. This is a 
proper adjustment if withdrawal is not related to the observed bleeding frequency. However, since it 
is possible that patients will withdraw exactly because of the observed bleeding rate it is important 
to perform sensitivity analyses that may account for withdrawn patients possibly being qualitatively 
different from completing patients.
Specifically, this will be done by performing sensitivity analyses for all prophylaxis analyses using 
a last observation carried forward (LOCF) approach for all patients with at least 1 month 
prophylaxis treatment duration by calculating the yearly bleeding episode rate for withdrawn 
patients and use that as an endpoint. As an example; a patient with 6 bleeding episodes in 4 months 
will have an endpoint value of 18 corresponding to a maintained bleeding rate of 18 bleeding 
episodes per year. For patients withdrawing within 1 month this method is considered to give too 
uncertain LOCF values, hence imputation will not be attempted for such patients.
Annualised bleeding rate will also be summarised by type of bleeding episode.
16.4.2.2
Haemostatic effect
Description of the haemostatic effect of N9-GP when used for treatment of bleeding episodes will 
be summarised and listed according to the four point scale for haemostatic response (poor, 
moderate, good and excellent). 
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A success rate will be calculated based on counting good or excellent as successes and poor and 
moderate as failures and based only on reported outcomes.
For the calculation of the success rate the numerator will include all treated bleeding episodes with 
a reported haemostatic response of good or excellent, while the denominator will include all treated 
bleeding episodes with a reported haemostatic response. A sensitivity analysis will also be 
conducted where the denominator also includes treated bleeding episodes with missing response 
(i.e. missing response is counted as a failure).
Haemostatic effect will be determined based on haemostatic response for bleeding episodes 
occurring both during pre-prophylaxis and prophylaxis period.
Haemostatic response will also be summarised by type of bleeding.
16.4.2.3
FIX activity
Incremental recovery 30 minutes post dosing (IR30min), FIX activity 30 minutes post dosing (C30min),
and trough FIX activity level will be assessed at visits according to Table 2–1.
FIX trough level is defined as the activity recorded immediately before N9-GP injection is given 
and reported as IU/mL. IR30min is defined as the rise in FIX activity per IU/kg administered and is
recorded 30 minutes after the end of N9-GP injection, and reported as [IU/mL]/[IU/kg]. It is 
calculated as the pre-dose subtracted FIX activity recorded 30 minutes after ended N9-GP injection 
and dividing the administered dose (IU/kg body weight (bw)).
16.4.2.4
FIX consumption 
Amount of N9-GP used for prophylaxis (IU/Kg/month/year) and amount consumed per bleeding 
episode (number of doses and IU/kg bw/bleeding episode) will be summarised and listed.
16.4.2.5
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.
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.
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All additional safety parameters such as laboratory parameters, including calculation of estimated 
glomerular filtration rate (eGFR), and physical examinations, including neurological assessments,
will be summarised and listed.
16.5
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 per patient.
In addition, all data and scores will be summarised and listed.
16.6
Interim reporting
All data from main phase of the trial will be analysed and reported when minimum 20 patients have 
completed main phase with at least 50 EDs and completed visit 23. This report will cover all 
endpoints and will form the basis for the paediatric indication. Data from patients that have entered 
extension phase at this point will be included up to latest visit prior this cut-off date. The data will 
be presented separately for the main phase and extension as well as combined. The main conclusion 
from the trial will be drawn based on the main phase data.
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.
An updated report with supportive data will be made when minimum 40 patients have had at least 
100 EDs. A final report with supportive data will be made when all patients have completed both 
parts of the trial.
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16.7
Sequential safety analysis and safety monitoring
Novo Nordisk A/S will constitute an internal safety committee to perform on-going safety 
surveillance. The trial will be subject to thresholds evaluated by the safety committee (see Section 
11.6.1).
16.8
Reporting of F9 and HLA genotype
Information about underlying gene defects of F9 and HLA will be listed in the clinical trial report. 
No statistical analysis will be performed. 
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17 Ethics
Participation in this trial could be a possible benefit for the patient in terms of closer monitoring of 
the patient by the investigator, compared to standard care and possible avoidance of bleeding 
episodes. As with all investigational drugs, there is an anticipated risk of potential side effect (ref. 
IB).7
The trial will be conducted in compliance with ICH GCP1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki2. 
17.1
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the patient and/or the patient’s 
parent(s)/LAR(s)) verbal and written information about the trial and the procedures involved in a 
form that the patient or the patient’s parent(s)/LAR(s) can read and understand. This includes the 
use of an impartial witness where required. In this trial the notion of LAR is the legal 
representatives, as defined in Member States’ national laws, who consent on behalf of the child.
The patient or the patient’s parent(s)/LAR(s) must be fully informed of their rights and 
responsibilities while participating in the trial as well as possible disadvantages of being treated 
with the trial product.
The investigator must ensure the patient and/or patient’s parent(s)/LAR(s) ample time to come to a 
decision whether or not to participate in the trial.
The requirement for obtaining informed consent from a patient’s parent(s)/LAR(s) 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 informed consent form must be obtained from the 
patient’s parent(s)/LAR(s) before any trial-related activity. In this trial where informed consent and 
exposure to the N9-GP may occur on the same day, informed consent form must include a time 
field next to the date field.
Consent: As a child is unable to provide legally binding consent, informed consent must be sought 
from the patient’s 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. 
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For children, from birth to the age of 3 years old, it is not possible to obtain assent and 
understanding of research is not expected.18
Patients above the age of 3 years old should sign a child assent form, if capable, and if required by 
local requirements. This can be performed on a separate day; especially for long-term trials here the 
investigator should check the progressing maturation of the child and its ability for assent.
The responsibility for seeking informed consent must remain with the investigator, but the task may 
be delegated by the investigator to a medically qualified person, in accordance with local
requirements. The written informed consent including time must be signed and personally dated by 
the person who seeks the informed consent before trial-related activity.
The informed consent form contains a section explaining that Novo Nordisk is asking permission to 
store left over blood from blood samples and use it to analyse for further analyses characterising 
biomarkers within the trial. The accept is voluntary and independent on participation in the trial. 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 provided and a new informed 
consent must be obtained.
F9 and HLA genotype testing/collection of previous genotype documentation:
If documentation of the patients’ genotype already exists, the data can be used for trial purpose. 
Only the F9 and HLA 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.
17.2
Data handling
If the patient is withdrawn from the trial or lost to follow up, then the patient’s data will be handled 
as follows:

Data already collected and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report

Safety events will be reported to the Novo Nordisk and regulatory authorities according to 
local/national requirements
If data are used, it will always be in accordance with local law and IRBs/IECs.
17.3
Information to patient, parent(s)/LAR(s) during the 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/booklets intended for distribution to the 
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patients. The letters/booklets will be translated and adjusted to local requirements and distributed to 
the patient and/or the patient’s parent(s)/LAR(s) by discretion of the investigator. The patient and/or 
the patient’s parent(s)/LAR(s) may receive a "welcome to the trial letter" and a "thank for your 
participation letter" at the end of the trial. Further the patient and/or the patient’s parent(s)/LAR(s) 
may receive trial letters and/or small toy during the trial period. 
All information inclusive material and toys to the patients will be submitted to the health authorities 
and IECs/IRBs for approval according to local regulations.
17.4
Premature termination of the trial and/or trial site
Novo Nordisk, the investigator, the IRBs/IECs or a regulatory authority may decide to stop the trial, 
part of the trial or a trial site at any time, but subject to the following procedure.
If a trial is suspended or prematurely terminated, the investigator must inform the patients promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk should also 
promptly inform the IRBs/IECs and provide a detailed written explanation. The relevant regulatory 
authorities must be informed.
If, after the termination of the trial, the risk/benefit analysis changes, the new evaluation should be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of patients who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the patients
should be described.
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18 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on all protocol deviations must be kept in the investigator’s trial file and Novo 
Nordisk trial master file.
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19 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during and after the trial. The investigator and the trial site staff as well as Novo Nordisk 
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 at the trial site 
relevant to the clinical trial. This includes permission to examine, analyse, verify and reproduce any 
record(s) and report(s) that are relevant to the evaluation of the trial.
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20 Critical documents
An Investigator Portal (CONNECT) will be used as primary media for exchange and handling of 
investigator trial file documents between Novo Nordisk and the trial site.
Before a trial site is allowed to start screening patients, the following documents must be available 
to Novo Nordisk:

Regulatory approval and/or acknowledgement of notification as required 

Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, patient information/informed consent form, any 
other written information to be provided to the patient and patient recruitment materials

List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)

Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)

Signed receipt of Investigator's Brochure 

Signed and dated agreement on the final protocol

Signed and dated agreement on protocol amendment, if applicable

Financial agreement(s)

Source document agreement

Central laboratory certification and normal ranges

Insurance statement, if applicable

Signed and dated Investigator Agreement

Financial disclosure form from investigator and sub-investigator(s)
Only applicable for US trial sites: 

For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest

For US trial sites: FDA form 1572 must be completed and signed by each investigator
FDA form 1572:
For US sites:

Intended for US trial sites

Conducted under the IND

All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:

Intended for participating trial site 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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Novo Nordisk will analyse and report data from all trial sites together.
For local lab parameters the following will be collected:

Laboratory normal ranges

Laboratory certification/QA scheme/other documentation

Laboratory methods (only non-standard assays) and/or analytic methods
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki 2. 
By signing the protocol, each investigator also agrees to allow Novo Nordisk making investigator's 
name and information about trial site name and address publically available if this is required by 
national or international regulations.
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21 Responsibilities
All staff (Novo Nordisk, trial site, laboratory, CRO etc) will conduct the trial in compliance with 
ICH GCP1, applicable regulatory requirements and the Declaration of Helsinki.2
The investigator is accountable for the conduct of the trial at his/her trial site. If any tasks are 
delegated, the investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated specified significant trial-related duties. The investigator must ensure that there is 
adequate training for all staff participating in the conduct of the trial. It is the investigator’s 
responsibility to supervise the conduct of the trial and to protect the rights, safety, and well-being of 
the patients. At least investigator must be trained in the protocol at a Novo Nordisk meeting or by 
web training in the protocol. It is recommended that all site staff takes the web protocol training. A 
qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible for 
all trial-related medical decisions. The investigator must ensure adequate supervision of the conduct 
of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator’s trial file. The documents should be kept in a secure locked facility, 
so no unauthorised persons can get access to the data. The patient identification code list should be 
kept securely and separate from the personal data.
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator should delegate responsibility for medical care 
of patients to a specific qualified physician who will be readily available to patients during that 
time.
If the investigator is no longer able to fulfil the role of investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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22 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by Novo Nordisk for regulatory purposes and for the general development of the trial product. 
All information supplied by Novo Nordisk in connection with this trial shall remain the sole 
property of Novo Nordisk and is to be considered confidential information. No confidential 
information shall be disclosed to others without prior written consent from Novo Nordisk. Such 
information shall not be used except in the performance of this trial. The information obtained 
during this trial may be made available to other physicians who are conducting other clinical trials 
with the trial product, if deemed necessary by Novo Nordisk. Provided that certain conditions are 
fulfilled, Novo Nordisk may grant access to information obtained during this trial to researchers 
who require access for research projects studying the same disease and/or trial product studies in 
this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report.
A principal investigator will be designated as the signatory investigator with the responsibility to 
review and sign the main report based on data from when at least 20 PUP have reached at least 50 
EDs.
22.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure23.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
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disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the principal investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
the Novo Nordisk trial manager before submission for comments. Comments will be given within 
four weeks from receipt of the planned communication.
22.1.1
Authorship
Authorship of publications should be determined in accordance with the Uniform Requirements of 
the International Committee of Medical Journal Editors (sometimes referred to as the Vancouver 
Criteria24).
Authorship credit should be based on:

Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data; 

Drafting the article or revising it critically for important intellectual content; and 

Final approval of the version to be published.
22.1.2
Trial 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 a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual trial site results until the primary manuscript is accepted for publication. As Novo 
Nordisk wants to live up to the industry publication policy, submission for publication of such 
primary policy will take place no later than 18 months after trial completion.
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22.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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23 Retention of clinical trial documentation and human biospecimens
23.1
Retention of clinical trial documentation
Patient’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Trial site-specific CRFs and other patient data (in an electronic readable format or as 
paper copies or prints) will be provided to the investigator before access is revoked to the systems 
and/or electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If 
the Novo Nordisk provided data (e.g. the CD-ROM) is not readable during the entire storage period, 
the investigator can request a new copy, as a copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the investigator trial site/institution must be retained for 15 years after the 
completion of the trial, or longer if required by national regulations. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
23.2
Retention of human biospecimens
Storage and disposition of samples analysed at local laboratories will be performed according to 
local laboratory procedures. 
Blood samples apart from antibody and biospecimen samples will be destroyed after the finalisation 
of the CTR. Antibody samples (samples for binding antibodies and inhibitors) will be stored until 
drug approval by Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) 
or until the project terminates, but no longer than 15 years from end of trial. Biospecimens will be 
destroyed at the latest 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 hypotheses at initiation of the trial. The samples will be 
stored at Novo Nordisk A/S or a Novo Nordisk designated referral bio-repository with access to the 
samples. Samples might be transferred to other countries, if not prohibited by local regulations. The 
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patient’s identity will remain confidential and samples will only be marked and identified by a 
unique sample ID (patient number and visit number). 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 bio-repository personnel (if applicable) will 
have access to the stored bio specimens. 
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24 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or sponsor, as applicable, must promptly report the following to the 
IRB/IEC, in accordance with local requirements: updates to IB, unexpected SAEs where a causal 
relationship cannot be ruled out, protocol amendments according to local requirements, deviations 
to the protocol implemented to eliminate immediate hazards to the 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.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC (not 
applicable for Japan).
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, 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.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application (CTA), protocol amendments, 
reports on SAEs, and the CTR according to national requirements.
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25 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
Only applicable for Argentina: Novo Nordisk Pharma Argentina S.A. has contracted insurance 
(policy reference number 87828 and its respective updates) with the company 
 
. Domiciled in 
. Telephone 
number: 
.
Only applicable for Australia: Medicines Australia Guidelines for Compensation for Injury 
Resulting From Participation in a Company-sponsored Clinical Trial. Version 160104B dated 16 
January 2004.
Only applicable for Austria: Arzneimittelgesetz (BGBI. Nr. 185/1983) last amended with BGBl. I 
Nr. 48/2013.
Only applicable for France: 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 of 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".
Only applicable for Netherlands: Wetgeving betreffende geneesmiddelen; geneesmiddelenwet 1 
juli 2007 (Medicines Law, 1 July 2007). De Wet Medisch-wetenschappelijk Onderzoek met mensen 
(WMO), 1 maart 2006 (Medical Research Involving Human Subjects Act, 1 March 2006). Besluit 
verplichte verzekering bij medisch-wetenschappelijk onderzoek met mensen 2015, 24 november 
2014 (Decree compulsory insurance in medical research involving human subjects 2015, 24 
November 2014). 
Only applicable for Poland: Novo Nordisk carries liability for the Study exclusively in the scope 
defined by the applicable laws and in particular by the Civil Code and the Pharmaceutical Law 
dated 6 September 2001 (uniform version Journal of Laws of 2008 No. 45 item 271 with 
amendments). In order to support potential claims for liability attributable to the Study, Novo 
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Protocol
CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
Page:
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Nordisk and Investigator are covered by the Insurance Policy issued according to applicable Polish 
law’.
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Protocol
CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
Page:
118 of 119
  
26 References
1.
International Conference of Harmonisation. ICH Harmonised Tripartite Guideline E6(R1): 
Guideline for Good Clinical Practice. 10 Jun 1996.
2.
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013.
3.
Vander AJ, Sherman JH, Luciano DS. Hemostasis:The Prevention of Blood Loss. In: 
Vander AJ, Sherman JH, Luciano DS, editors. Human Physiology. 6th ed: McGraw-Hill, 
Inc.; 1994. p. 741-50.
4.
BeneFIX - Summary of Product 
Characteristics. http://www.emea.europa.eu/humandocs/PDFs/EPAR/Benefix/emea-
combined-h139en.pdf  . 2009.
5.
EMA. Committee for medicinal products for human use (CHMP), Guideline on the Clinical 
Investigation of Recombinant and Human Plasma-derived Factor IX Products, 
EMEA/CHMP/BPWP/144552/2009. 7/21/2011 2011.
6.
Negrier C, Knobe K, Tiede A, Giangrande P, Moss J. Enhanced pharmacokinetic properties 
of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with 
hemophilia B. Blood. 2011;118(10):2695-701.
7.
Novo Nordisk A/S. Investigator's Brochure, Nonacog beta pegol - Treatment and 
Prophylaxis of bleeding in adults and children with Haemophilia B, 8th Edition. 13-Oct-
2017.
8.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. 
Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1-47.
9.
Ivens IA, Baumann A, McDonald TA, Humphries TJ, Michaels LA, Mathew P. PEGylated 
therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers. 
Haemophilia. 2013;19(1):11-20.
10.
Chitlur M, Warrier I, Rajpurkar M, Lusher JM. Inhibitors in factor IX deficiency a report of 
the ISTH-SSC international FIX inhibitor registry (1997-2006). Haemophilia. 
2009;15(5):1027-31.
11.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
12.
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007. 27 September 2007.
13.
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, article 11. Official Journal of the European Communities. 01 May 
2001.
14.
Guidance for industry. Assay development for immunogenicity testing therapeutic proteins. 
Food and Drug Administration. 2009 2009.
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Protocol
CONFIDENTIAL
Date:
05 November 2019
Novo Nordisk
Trial ID: NN7999-3895
Version:
8.0
UTN: U1111-1135-9557
Status:
Final
EudraCT No.: 2012-004867-38
Page:
119 of 119
  
15.
Mire-Sluis AR, Barrett YC, Devanarayan V, Koren E, Liu H, Maia M, et al. 
Recommendations for the design and optimization of immunoassays used in the detection of 
host antibodies against biotechnology products. Journal of Immunological Methods. 
2004;289(1-2):1-16.
16.
Shankar G, Devanarayan V, Amaravadi L, Barrett YC, Bowsher R, Finco-Kent D, et al. 
Recommendations for the validation of immunoassays used for detection of host antibodies 
against biotechnology products. Journal of Pharmaceutical and Biomedical Analysis. 
2008;48(5):1267-81.
17.
Gupta S, Indelicato SR, Jethwa V, Kawabata T, Kelley M, Mire-Sluis AR, et al. 
Recommendations for the design, optimization, and qualification of cell-based assays used 
for the detection of neutralizing antibody responses elicited to biological therapeutics. 
Journal of Immunological Methods. 2007;321(1-2):1-18.
18.
European Medicines Agency. Ethical considerations for clinical trials on medicinal products 
with the paediatric population. Recommendations of the Ad hoc group for the development 
of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the 
conduct of clinical trials on medicinal products for human use. 2008.
19.
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products (ENTR/F/2/AM/an D[2010] 
3374). 03 Feb 2010.
20.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et 
al. Second symposium on the definition and management of anaphylaxis: summary report--
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7.
21.
U.S. Food and Drug Administration. Code of Federal Regulations, 21 CFR Part 11, 
Electronic Records, Electronic Signatures. 2009 2009.
22.
ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. International 
Conference on Harmonisation E9 Expert Working Group. Stat Med. 1999;18(15):1905-42.
23.
Novo Nordisk A/S. http://www.novonordisk-trials.com/website/content/how-we-disclose-
trial-information.aspx.
24.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
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16.1.01 
Protocol Attachment 
 
Protocol Attachment I is located in the Trial Master File. 
If applicable, Protocol Attachment II is also located in the Trial Master File. 
Content: Global key staff and Country key staff. 
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
nonacog beta pegol
Trial ID: NN7999-3895 Final
Clinical Trial Report
Appendix 16.1.1
24 February 2023
1.0
Final
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02141074 
Sponsor trial ID: 
NN7999-3895 
Official title of study: 
An Open-label Single-arm Multicentre Non-controlled Phase 3 
a Trial Investigating Safety and Efficacy of Nonacog Beta 
Pegol (N9-GP) in Prophylaxis and Treatment of Bleeding 
Episodes in Previously Untreated Patients With Haemophilia 
B (FIX Activity Below or Equal to 2 Percent) 
Document date* 
15 July 2019 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header of Page 2 is the date of compilation of the documents and not of an update to content.


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
nonacog beta pegol
Trial ID: NN7999-3895 Final
Clinical Trial Report
Appendix 16.1.9
24 February 2023
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
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STAT001-TMP-001, V4
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Statistical Analysis Plan
Safety and Efficacy of nonacog beta pegol (N9-GP) in Previously Untreated Patients with Haemophilia B
Protocol Number: NN7999-3895
Sponsor:
Novo Nordisk
Address:
SAP Version:  2.0
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1.
Note
has prepared a Statistical Analysis Plan (SAP) for the Sponsor to review and sign-off for study NN7999-3895. 
Analyses will be conducted after this document has been finalized and officially signed. Anything in italics is taken 
directly from the protocol. For more details, please refer to the study protocol.
2.
Version History
Version Number
Date
Reason for Revision
1.0
22 April 2019
Initial Version
2.0
15 July 2019
Revised based on sponsor requests
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3.
Signature Page for SAP Approval
The following signatures indicate the approval of the statistical analysis plan for the study NN7999-3895.
Name (print):
Position:
Novo Nordisk
Name (print):
Position:
Date (DD-MMM-YYYY):
16-Jul-2019
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4.
Table of Contents
1.
Note................................................................................................................................................................... 2
2.
Version History................................................................................................................................................... 2
3.
Signature Page for SAP Approval....................................................................................................................... 3
4.
Table of Contents............................................................................................................................................... 4
5.
Abbreviations..................................................................................................................................................... 5
6.
Introduction........................................................................................................................................................ 6
7.
Study Objectives Related to Neurocognitive Assessments ................................................................................. 6
8.
Study Design ..................................................................................................................................................... 6
8.1.
General Description.................................................................................................................................. 6
8.2.
Scheduled Visits....................................................................................................................................... 6
9.
Analysis Set and Population............................................................................................................................... 7
9.1.
Unblinding Procedure............................................................................................................................... 7
9.2.
Analysis Set ............................................................................................................................................. 7
9.2.1.
Full Analysis Set (FAS)............................................................................................................... 7
9.3.
Sample Size and Analysis Population....................................................................................................... 7
9.4.
Handling of missing data .......................................................................................................................... 7
10.
Analysis Endpoints, Initial Assessment Definition, and Outcome Measures ........................................................ 7
10.1. Analysis Endpoints................................................................................................................................... 7
10.2. Initial Assessment Definition..................................................................................................................... 7
10.3. Definition of Findings – Initial and Follow-Up............................................................................................. 8
10.4. Outcome Measures Related to Neurocognitive Assessment Analysis ....................................................... 8
10.5. Other Outcome Measures ...................................................................................................................... 14
10.6. Derived Variables................................................................................................................................... 15
10.6.1.
Standardized Scores: Comparison of Individual Scores to Age-Matched Normative Data for 
 Computerized Cognitive Tests (Age-Adjusted Z-Scores)............................................ 15
10.6.1.1.Age-Matched Normative Data for 
 Computerized Cognitive Tests ................. 15
10.6.2.
Conversion of Scale Outcome Measures into Age-Adjusted Z-Scores....................................... 17
10.6.3.
Standardized Scores: Comparison of Individual Scores to eTHINK Hemophilia Normative Data 
(Hemophilia-Adjusted Z-Scores)............................................................................................... 17
11.
Data Quality Assurance.................................................................................................................................... 18
11.1.
 Computerized Test Completion Criteria ................................................................................... 18
12.
Statistical Methodology .................................................................................................................................... 19
12.1. Analysis Overview.................................................................................................................................. 19
12.2. Analyses ................................................................................................................................................ 19
References................................................................................................................................................................ 20
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5.
Abbreviations
Abbreviation Description
ABAS-3
Adaptive Behavior Assessment System – Third Edition
BASC-3
Behavior Assessment System for Children – Third Edition
BRIEF2
Behavior Rating Inventory of Executive Function – Second Edition
BRIEF-A
Behavior Rating Inventory of Executive Function – Adult Edition
BRIEF-P
Behavior Rating Inventory of Executive Function – Preschool Edition
CI
Confidence Interval
DET
Detection Test
ED
Exposure Day (Definition: One exposure day is defined as each day when a patient is 
administered coagulation factor IX/blood components for any reason regardless number 
of doses)
FAS
Full Analysis Set
HNAS
Hemophilia Normative Analysis Set
IDN
Identification Test
IQR
Interquartile range (25th, 75th percentiles)
N9-GP
nonacog beta pegol, glycopegylated recombinant coagulation factor IX
ONB
One Back Test
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SD
Standard Deviation
SDH
Structured Development History
TLF
Tables, Listings, and Figures
WASI-II
Wechsler Abbreviated Scale of Intelligence – Second Edition 
WPPSI-IV
Wechsler Preschool and Primary Scale of Intelligence – Fourth Edition
WSD
Within-Subject Deviation
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6.
Introduction
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the principal features of the 
analysis described in the NN7999-3895 Study Protocol related to neurocognitive assessments and includes detailed 
procedures for executing the statistical analysis of the neurocognitive assessment data.
The SAP is finalized and signed prior to database lock. For operational efficiency, an earlier time is usually targeted. If 
needed, revisions to the approved SAP may be made prior to database lock. Revisions will be version controlled.
Any changes from the analyses planned in the SAP will be justified in the statistical report.
Prior to database lock, a dry run analysis will occur.
7.
Study Objectives Related to Neurocognitive Assessments
To evaluate neurodevelopmental, neurocognitive and neurobehavioral outcomes on N9-GP exposed patients.
8.
Study Design
8.1.
General Description
Please see Sections 5, 8.1, and 8.2 of the study protocol for a general description of the study design.
8.2.
Scheduled Visits 
Table 1: Visit Schedule for Neurocognitive Assessments
Visit Number
Scheduled Interval
Analysis 
Visit
1, 20, 23, 26, 28-50

BRIEF: Every 6 months (all countries)

 Battery: Every 6 months (all countries)

SDH: Every 6 months (all countries)

HH: Every 6 months (all countries)

Bayley-III / WPPSI-IV / WASI-II: Every 1 year (English-
speaking countries only)

ABAS-3: Every 1 year (English-speaking countries only)

BASC: Every 1 year (English-speaking countries only)
Yes
End of Trial
Yes
Unscheduled Visit
No
Study visits will be renamed such that the first visit is “Initial Assessment”, the next is “Assessment 2”, the following is 
“Assessment 3”, and so on, to account for the fact that not all subjects will be starting their neurocognitive assessments 
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at the same visit. If patients start on pre-prophylaxis and switch to prophylaxis at Visit 20, the assessments will be 
displayed under “Prophylaxis” in the tables.
The patient’s age when the Structured Developmental History (SDH) is completed will be used as the Visit Age for 
each visit.
9.
Analysis Set and Population
9.1.
Unblinding Procedure
The unblinding procedure was not described in protocol for study NN7999-3895 because an open-label design was 
used. Once all data discrepancies within the database are resolved with the clinical research units, the database is 
locked.
9.2.
Analysis Set
9.2.1.
Full Analysis Set (FAS)
All main descriptions and analysis of efficacy will be based on the Full Analysis Set (FAS), as defined in ICH E9 
guidelines. The FAS includes all patients exposed to N9-GP.
9.3.
Sample Size and Analysis Population
60 patients are planned to be screened and 40 patients are expected to complete the trial.
For details, please see protocol Section 16.1.
9.4.
Handling of missing data
No imputations will be performed in the event of missing data due to dropouts or omitted visits. All incomplete subject 
profiles will be retained in the analysis. In view of issues of reliability, all analyses will be conducted with completion 
failures removed.
10.
Analysis Endpoints, Initial Assessment Definition, and 
Outcome Measures
10.1.
Analysis Endpoints
The analysis endpoints are z-scores and change in z-scores for each neurocognitive assessment (see Table 2 for 
more details) against eTHINK population and US normative population (international normative population for 
 
computerized tests), as well as responses on the Structural Development History and Hemophilia History. 
10.2.
Initial Assessment Definition
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Initial Assessment data is the first assessment that has cognitive data for each subject. This first set of cognitive data 
may occur at different visits depending on the subject.
10.3.
Definition of Findings – Initial and Follow-Up
Based on the results from the eTHINK trial (all age groups pooled) the mean and standard deviation (SD) will be 
calculated for composite scores of all tests (see Table 2 for primary outcome measures). Each patient’s individual 
results from each test (initial and follow-up assessments) from this trial will be compared to the mean and SD from the 
respective test from the eTHINK trial. If the patient’s results are greater than 1 SD above the eTHINK mean (or less 
than -1 SD below the eTHINK mean), this will be treated as potential increase (or decrease) of the respective 
neurocognitive function and will be discussed with experts at the external expert review panel (EERP). If the absolute 
value of change from the eTHINK mean is ≤1 SD, the change will be categorized as “normal variation” rather than 
signal. If less than three different test results from the same visit are outside the defined threshold of 1 SD, the result 
will also be categorized as “normal variation”, but still discussed with experts during the EERP.
10.4.
Outcome Measures Related to Neurocognitive Assessment Analysis
The cognitive tests administered include computerized tests from the 
 Battery and traditional neurocognitive 
instruments. 
Bayley Scales of Infant and Toddler Development – Third Edition (Bayley-III; Neurodevelopment)
Bayley Scales of Infant and Toddler Development – Third Edition (Bayley-III) is a revision of the Second Edition (BSID-
II), but while the prior provided mental, motor and behavioral scales, the psychologist-administered Bayley-III provides 
cognitive, language, motor, social-emotional, and adaptive behavioral scales. To avoid duplication in domains, the 
adaptive behavioral scale of Bayley-III will not be performed as it is identical to the Adaptive Behavioral Assessment 
System, 2nd edition (ABAS-2), and ABAS-3 is already being used in this study. 

Bayley III (ages 1:0 to 3:6 years), excluding ABAS-2 domain test 
Primary scales of intelligence have continued to be an integral part of assessment of neurocognitive function. 
Assessment of intelligence across multiple domains is different in the pre-school setting from that of older children and 
adults.
Wechsler Preschool and Primary Scale of Intelligence – Fourth Edition (WPPSI-IV; General Intelligence)
The Wechsler Preschool and Primary Scale of Intelligence – Fourth Edition (WPPSI-IV) is the latest edition of the 
individually administered early childhood intelligence test with origins dating back to the original 1967 Wechsler 
Preschool and Primary Scale of Intelligence. The WPPSI-IV is divided into two distinct age bands (2 years 6 months to 
3 years 11 months and 4 years 0 months to developmental changes during the age range covered. Only the latter will 
be used in this study due 7 years 7 months) corresponding to different subtest batteries due to significant cognitive 
ability and to overlap with Bayley-III in infants. Six of the WPPSI-IV subtests will be completed in this study: 3 subtests 
to align to WASI-II (Block Design, Matrix Reasoning, Similarities) and 5 partially overlapping subtests required to 
generate a composite or full scale IQ (Matrix Reasoning, Information, Similarities, Picture Memory, Bug Search); Matrix 
Reasoning also provides a proxy for non-verbal IQ. 

WPPSI-IV 4:0-7:7 (ages 4:0-6:11 years)
o
Block Design
o
Matrix Reasoning
o
Similarities
o
Information
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o
Picture Memory
o
Bug Search
Wechsler Abbreviated Scale of Intelligence – Second Edition (WASI-II; General Intelligence)
The Wechsler Abbreviated Scale of Intelligence – Second Edition (WASI-II) is an abbreviated measure of intelligence 
designed for individuals 6 to 90 years of age. Primarily used in clinical, psychoeducational, and research settings, the 
WASI-II was developed to quickly and accurately estimate intelligence when administration of a full battery is not 
feasible or necessary. The WASI-II is classified as a Level C measure, and can be administered and interpreted by 
individuals with a doctorate degree in psychology or a related discipline. Administration time is approximately 30 min 
for the four-subtest form. 

WASI-II (ages 7-21) 
Behavior Assessment System for Children (BASC; Behavior/Emotion)
Behavioral assessment is multidimensional, including adaptive and problem behavior to identify emotional and 
behavioral problems. It typically includes a combination of assessment in various or school setting, and through self-
report of older children and adolescents to identify their thoughts settings, through parents to assess the home or 
community, through teachers to assess the preschool and feelings. The Behavioral Assessment System for Children 
(BASC) was developed in 1992 as a multidimensional assessment including Structured Developmental History (SDH), 
Parent Rating Scale (PRS), Teacher Rating Scale (TRS), Self-Report of Personality (SRP) and Student Observation 
System (SOS), which can be used separately or in combination. The current third edition, BASC-3, provides a 
comprehensive set of rating scales that measure areas important for IDEA and DSM-5 classifications. In this cross-
sectional study, the parent rating scale (PRS) and self-report of personality (SRP) will be utilized.  

BASC3 Parent response scale Preschool (PRS-P 2-5y) (ages 24 months-5 years) 

BASC3 Parent response scale Child (PRS-C 6-11y) (ages 6-11 years) 

BASC3 Parent response scale Adolescent (PRS-A 12-21y) (ages 12-21) 

BASC3 Self-Reported Personality Child (SRP-C 8-11y) (ages 8-11) 

BASC3 Self-Reported Personality Adolescent (SRP-A 12-21y) (ages 12-17) 

BASC3 Self-Reported Personality College (SRP-College 18-25y) (age 18-21)
Adaptive Behavior System – Third Edition (ABAS-3; Adaptive Behavior)
Adaptive behavior refers to “the level of everyday performance of tasks that is required for a person to fulfill typical 
roles in society, including maintaining independence and meeting cultural expectations regarding personal and social 
responsibility”. Measurements of adaptive behavior have been utilized by school psychologists and other mental health 
professionals as part of assessment/diagnosis, evaluation of behavioral conditions, and one of five domains that are a 
basis for eligibility for special education, is recommended in guidelines by the American Association on Intellectual and 
Developmental Disabilities6 and by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Measures of 
adaptive behavior are impaired in autism spectrum disorders8 and attention deficit hyperactivity disorder. Adaptive 
behavior scales typically use semi-structured interview forms and are typically completed by parents, teachers, and 
other caregivers familiar with the child or adolescent and their behavior.
Evidence based reviews suggest that adaptive behavioral assessments should be part of a comprehensive 
assessment of children and adolescents. In this study, the Adaptive Behavior Assessment System – Third Edition 
(ABAS-3) scale focused on home and community setting will be used. 

ABAS-3 Parent 0-5y (ages 12 months to 5 years)

ABAS-3 Parent 5-21y (ages 6-21)
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
ABAS-3 Adult 16-89y (ages 16-21)
Behavior Rating Inventory of Executive Function (BRIEF; Executive Function)
Self-regulation skills have pervasive and long-lasting implications for the development of children’s academic abilities 
and psychopathology, and is most associated with the construct of executive function. Executive Function is 
characterized by three intercorrelated factors: inhibitory control, working memory, and shifting. Inhibitory control (IC) is 
defined as the ability to inhibit a prepotent response in favor of a subordinate response. Working memory (WM) is 
defined as the ability to maintain, update, and manipulate information within memory. Shifting (SH) is defined as the 
ability to switch attention between mental sets or tasks, or the ability to engage and disengage with specific aspects 
within tasks. Rating scales involving either self-report or parent and teacher reports of EF skills in everyday situations 
have been developed. The Behavior Rating Inventory of Executive Function (BRIEF) is a parent- or teacher-rating 
scale of everyday EF behaviors in school-age children. The second edition BRIEF2 was designed and modified to be 
used in conjunction with performance-based measures to allow for a comprehensive understanding of children’s EF 
skills. Modified from BRIEF to address preschool issues, Behavior Rating Inventory of Executive Function – Preschool 
version (BRIEF-P), is intended to be completed by teachers or parents of 2- to 6-year old children, with ratings based 
on the child’s observed behaviors within the relevant home or school environments. Behavior Rating Inventory of 
Executive Function – Adult version (BRIEF-A) is modified from BRIEF to address issues in adults aged 18-90 years 
old. In this study, parent ratings will be captured for ages 2-18 (BRIEF-P and BRIEF2) and self-report of adolescents 
and adults (ages 11-21, BRIEF2 and BRIEF-A).

BRIEF-P (Preschool) Parent 2:0-5:11y (ages 24 months to 5 years)

BRIEF2 Parent 5-18y (ages 6-18 years)

BRIEF2 Self Report 11-18y (ages 11-18 years)

BRIEF-A Self Report 18-90y (ages 18-21)
 Custom Battery (DET, IDN, ONB; Attention/Processing Speed)
Clinical assessment of attention usually depends on three sources of information: (1) psychometric tests designed to 
measure other cognitive functions, (2) specific neuropsychological tests of attention; and direct behavioral observation 
and measurement. Assessment often requires the clinician to obtain information about performance under different 
conditions. Measures of attention include attention span, divided attention, switching, response intention and planning, 
sustained performance and vigilance, and information-processing speed. 
Information processing speed along with working memory have been identified as measures of cognitive impairment. 
While traditionally clinicians assessed with the Paced Auditory Serial Addition Test (PASAT), over the past decade the 
advent of computerized tests of information processing have been relied on to assess processing speed. 
The 
 computerized cognitive test battery proposed for this study includes an assessment of processing speed, 
attention/vigilance, and working memory.

 Custom Battery (Peds platform, ages 4-9; Adult platform, ages 10-21)
o
Detection test (processing speed, psychomotor function)
o
Identification test (attention/vigilance)
o
One Back Test (working memory)
Note: Ages 4-5 years old will be administered with pediatric Detection and Identification. Ages 6-9 years old will be 
administered with pediatric Detection, Identification, and One Back. Ages 10-21 will be administered with adult 
Detection, Identification, and One Back.
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Although each of the
 computerized cognitive tests yields multiple outcome measures, research by 
 
has identified a set of measures that are optimal for the detection of cognitive change in clinical trials at both the group 
and individual level (Falleti et al., 2006; Maruff et al., 2009; Bland & Altman, 1996a; Bland & Altman, 1996b).   
For each 
 computerized cognitive test, a single primary outcome measure was selected prior to data analysis 
from each test in the battery to minimize experiment-wise error rates. Each primary outcome measure was selected 
because it has been shown to be optimal for the detection of change because: 
a)
It is drawn from a data distribution that contains only a small probability of floor or ceiling effects and no 
restriction in the range of possible performance values (Falleti et al., 2006; Bland & Altman, 1996a; Bland & 
Altman, 1996b).
b)
It is drawn from a normal distribution or a distribution which can be corrected to normal through the use of 
appropriate mathematical transformation (e.g., logarithmic base 10, or arcsine) (Falleti et al., 2006; Bland & 
Altman, 1996a; Bland & Altman, 1996b).
Table 2 below summarizes the outcome measures for the neurocognitive assessments with the instruments from which 
they were derived.
Table 2: Neurocognitive Instruments Administered in Study NN7999-3895 and their Primary, Secondary, and 
Exploratory Outcome Measures
Primary Outcome Measure
Secondary Outcome Measure
Exploratory Outcomes
BAYLEY-III1
Cognition Composite
Communication Composite
Motor Composite
Social-Emotional Composite
Receptive communication
Expressive communication
Fine Motor
Gross Motor
WPPSI-IV1
Full-Scale IQ
Verbal Comprehension Index 
Block Design subtest 
Matrix Reasoning subtest 
Similarities subtest 
Information subtest 
Picture Memory subtest 
Bug Search subtest 
WASI-II1
Full-Scale IQ
Verbal Comprehension Index 
Perceptual Reasoning Index 
Vocabulary subtest 
Similarities subtest
Matrix Reasoning subtest
Block Design subtest
BRIEF-P2
Global Executive Composite Index
Inhibitory Self-Control Index
Flexibility Index
Emergent Metacognition Index
Inhibit Scale
Emotional Control Scale
Shift Scale
Working Memory Scale
Plan/Organize Scale
BRIEF-2 Parent Report2
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Global Executive Composite Index
Behavioral Regulation Index 
Emotion Regulation Index
Cognitive Regulation Index 
Inhibit Scale
Self-Monitor Scale
Emotional Control Scale
Shift Scale
Initiate Scale
Working Memory Scale
Plan/Organization Scale
Organization of Materials Scale
Task Monitor Scale
BRIEF-2 Self Report2
Global Executive Composite Index
Behavioral Regulation Index 
Emotion Regulation Index
Cognitive Regulation Index 
Inhibit Scale
Self-Monitor Scale
Emotional Control Scale
Shift Scale
Working Memory Scale
Plan/Organization Scale
Task Completion Scale
BRIEF-A2
Global Executive Composite Index
Behavioral Regulation Index 
Metacognitive Index
Inhibit Scale
Self-Monitor Scale
Emotional Control Scale
Shift Scale
Initiate Scale
Working Memory Scale
Plan/Organization Scale
Organization of Materials Scale
Task Monitor Scale
BASC3 Parent Rating Scale Preschool (PRS-P)
Externalizing Problems Composite2
Internalizing Problems Composite2
Behavioral Symptoms Index2
Hyperactivity Domain2
Aggression Domain2
Anxiety Domain2
Depression Domain2
Somatization Domain2
Attention Problems Domain2
Atypicality Domain2
Withdrawal Domain2
Adaptive Skills Composite1
Adaptability Domain1
Social Skills Domain1
Activities of Daily Living Domain 1
Functional Communication Domain1
BASC3 Parent Rating Scale Child (PRS-C)
Externalizing Problems Composite2
Internalizing Problems Composite2
Behavioral Symptoms Index2
Hyperactivity Domain2
Aggression Domain2
Conduct Problems Domain2
Anxiety Domain2
Depression Domain2
Somatization Domain2
Attention Problems Domain2
Atypicality Domain2
Withdrawal Domain2
Adaptive Skills Composite1
Adaptability Domain1
Social Skills Domain1
Activities of Daily Living Domain1
Functional Communication Domain1
Leadership Domain1
BASC3 Parent Rating Scale Adolescent (PRS-A)
Externalizing Problems Composite2
Internalizing Problems Composite2
Behavioral Symptoms Index2
Hyperactivity Domain2
Aggression Domain2
Conduct Problems Domain2
Anxiety Domain2
Depression Domain2
Somatization Domain2
Attention Problems Domain2
Atypicality Domain2
Withdrawal Domain2
Adaptive Skills Composite1
Adaptability Domain1
Social Skills Domain1
Activities of Daily Living Domain1
Functional Communication Domain1
Leadership Domain1
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BASC3 Self Rating Scale Child (SRP-C)
School Problems Composite2
Internalizing Problems Composite2
Inattention/Hyperactivity Composite2
Emotional Symptoms Index2
Attitude to School Domain2
Attitude to Teachers Domain2
Locus of Control Domain2
Social Stress Domain2
Anxiety Domain2
Depression Domain2
Sense of Inadequacy Domain2
Atypicality Domain2
Personal Adjustment Composite1
Relations with Parents Domain1
Interpersonal Relationships Domain1
Self-Esteem Domain1
Self-Reliance Domain1
BASC3 Self Rating Scale Adolescent (SRP-A)
School Problems Composite2
Internalizing Problems Composite2
Inattention/Hyperactivity Composite2
Emotional Symptoms Index2
Attitude to School Domain2
Attitude to Teachers Domain2
Sensation Seeking Domain2
Locus of Control Domain2
Social Stress Domain2
Anxiety Domain2
Depression Domain2
Somatization Domain2
Sense of Inadequacy Domain2
Hyperactivity Domain2
Attention Problems Domain2
Atypicality Domain2
Personal Adjustment Composite1
Relations with Parents Domain1
Interpersonal Relationships Domain1
Self-Esteem Domain1
Self-Reliance Domain1
BASC3 Self Rating Scale College (SRP-COL)
Internalizing Problems Composite2
Inattention/Hyperactivity Composite2
Emotional Symptoms Index2
Locus of Control Domain2
Social Stress Domain2
Anxiety Domain2
Depression Domain2
Sense of Inadequacy Domain2
Somatization Domain2
Attention Problems Domain2
Hyperactivity Domain2
Sensation Seeking Domain2
Alcohol Abuse Domain2
School Maladjustment Domain2
Atypicality Domain2
Personal Adjustment Composite1
Relations with Parents Domain1
Interpersonal Relationships Domain1
Self-Esteem Domain1
Self-Reliance Domain1
ABAS Parent 0-5 year old1
Conceptual Reasoning Domain
Social Interactions Domain
Practical Functioning Domain
Adaptive Behavior Domain Score
Communication Skill Area
Functional Pre-Academics Skill 
Area
Self-Direction Skill Area
Leisure Skill Area
Social Skill Area
Community Use Skill Area
Home Living Skill Area
Health and Safety Skill Area
Self-Care Skill Area
Motor Skill Area
ABAS Parent 5-21 year old1
Conceptual Reasoning Domain
Social Interactions Domain
Practical Functioning Domain
Adaptive Behavior Domain Score
Communication Skill Area
Functional Academics Skill Area
Self-Direction Skill Area
Leisure Skill Area
Social Skill Area
Community Use Skill Area
Home Living Skill Area
Health and Safety Skill Area
Self-Care Skill Area
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ABAS Adult 16-89 year old1
Conceptual Reasoning Domain
Social Interactions Domain
Practical Functioning Domain
Adaptive Behavior Domain Score
Communication Skill Area
Functional Academics Skill Area
Self-Direction Skill Area
Leisure Skill Area
Social Skill Area
Community Use Skill Area
Home Living Skill Area
Health and Safety Skill Area
Self-Care Skill Area
 Pediatrics 4-5 year old
Detection2
Identification2
Attention Domain Composite1
Pediatric 6-9 year old
Detection2
Identification2
One Back (speed)2
One Back (accuracy)1
Attention Domain Composite1
 Adult 10-21 year old
Detection2
Identification2
One Back (speed)2
One Back (accuracy)1
Attention Domain Composite1
[1] Higher scores indicate better performance (multiplicand = +1).
[2] Lower scores indicate better performance (multiplicand = -1).
10.5.
Other Outcome Measures
The following composite scores will be computed and analyzed:
-
Attention Domain Composite
o
Peds Age 4-5: DET, IDN speed scores must exist
o
Peds Age 6-9: DET, IDN, ONB speed scores; at least two of three scores must exist
o
Ages 10-21: DET, IDN, ONB speed scores; at least two of three scores must exist
The composite scores will be calculated by:
1)
Standardizing each of the test scores included in the cognitive domains against age-matched US normative 
population (international normative population for 
 computerized tests) data for that test (Section 
10.6.1 specifies the procedure for the standardization of the tests for the purposes of creating the Attention 
Domain Composite score).
2)
Computing the average of the available standardized test scores if the required number of scores available is 
met (as described above).
The Attention Domain Composite score is normalized based on age and therefore serves as the age-adjusted z-score 
in summary tables without any further calculations.
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10.6.
Derived Variables
10.6.1.
Standardized Scores: Comparison of Individual Scores to Age-Matched Normative Data for 
 
Computerized Cognitive Tests (Age-Adjusted Z-Scores)
A comparison of individual scores to age-matched normative data will also be conducted. The process will be as 
follows:

Performance on each neurocognitive outcome measure will be standardized relative to age-matched normative 
data (i.e., the score will be converted to a z-score by subtracting the age matched mean from the normative 
sample and dividing by the age-matched standard deviation (SD) from the same normative sample)

The multiplicand equals 1 for outcome measures for which a higher score is indicative of better cognitive 
performance and -1 for outcome measures where a lower score is indicative of better cognitive performance. 
Please see Table 2 for details regarding the multiplicand for each outcome measure.

The z-score will be calculated as follows:
 −	
 () =
 −̅

∗
Where:
t = is the outcome measure indicator
i = indexes subject i
j = indexes the jth assessment for subject i
x = cognitive score
̅ = mean performance score of the age-matched normative sample for outcome measure 
t                   
 = Standard Deviation of the age-matched normative sample for outcome measure t
10.6.1.1. Age-Matched Normative Data for 
 Computerized Cognitive Tests
Note: These tables are stored in XLS format in nD ID: 004758297.
Table 3. Detection 
Age (Years)
Mean
SD
4
2.82934
0.12057
5
2.77951
0.11345
6
2.74635
0.09264
7
2.66173
0.09901
8
2.63129
0.13746
9
2.58581
0.13506
10
2.56241
0.08007
11
2.53830
0.07896
12
2.52938
0.07682
13
2.51597
0.07535
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14
2.51298
0.08101
15
2.50910
0.07674
16
2.50538
0.07644
17
2.50197
0.07528
18-34
2.45444
0.07337
Table 4. Identification
Age (Years)
Mean
SD
4
3.01615
0.07030
5
2.94433
0.11321
6
2.94156
0.06801
7
2.87557
0.07695
8
2.84589
0.11548
9
2.80141
0.09222
10
2.76101
0.07096
11
2.73223
0.07068
12
2.71368
0.06719
13
2.69591
0.06782
14
2.68636
0.06954
15
2.67744
0.06687
16
2.67182
0.06561
17
2.66634
0.06456
18-34
2.64200
0.06351
Table 5. One Back – Speed
Age (Years)
Mean
SD
6
3.17567
0.06515
7
3.07410
0.11496
8
3.03745
0.11140
9
3.00543
0.11960
10
2.96038
0.09147
11
2.92315
0.08742
12
2.90079
0.08970
13
2.88112
0.08832
14
2.86992
0.08875
15
2.85673
0.08837
16
2.84739
0.08920
17
2.83990
0.09017
18-34
2.78579
0.09418
Table 6. One Back – Accuracy
Age (Years)
Mean
SD
6
1.14048
0.23689
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7
1.13669
0.20779
8
1.16183
0.23773
9
1.30178
0.18364
10
1.30448
0.14716
11
1.31396
0.14210
12
1.32934
0.14177
13
1.32993
0.13466
14
1.33324
0.13896
15
1.34055
0.13843
16
1.34830
0.13575
17
1.35444
0.13472
18-34
1.39617
0.12998
10.6.2.
Conversion of Scale Outcome Measures into Age-Adjusted Z-Scores
All primary, secondary, and exploratory outcome measures for scales will need to be converted to z-scores. Outcome 
measures will be available in one of three forms: standard score, T-score, or scaled score. The Table 7 below defined 
the general properties of each score form, along with the conversion formula for changing these into z-scores.
Table 7: Scale Outcome Measure Conversion to Z-Scores
Score Name
Mean
SD
Z-Score Conversion Formula
Standard Score
100
15
(Standard Score – 100) / 15 * multiplicand
T-Score
50
10
(T-Score – 50) / 10 * multiplicand
Scaled Score
10
3
(Scaled Score – 10) / 3 * multiplicand
10.6.3.
Standardized Scores: Comparison of Individual Scores to eTHINK Hemophilia Normative Data
(Hemophilia-Adjusted Z-Scores)
A comparison of individual scores to eTHINK hemophilia normative data will also be conducted. The process will be as 
follows:

Performance on each neurocognitive outcome measure will be standardized relative to eTHINK hemophilia
normative data (i.e., the age-adjusted z-score will be converted to a hemophilia-adjusted z-score by subtracting 
the mean from the eTHINK hemophilia normative sample and dividing by the eTHINK hemophilia normative 
standard deviation (SD) from the same normative sample)

The z-score will be calculated as follows:
 =
 −̅

Where:
̅ = cognitive hemophilia-adjusted z-score                   
t = is the outcome measure indicator
i = indexes subject i
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j = indexes the jth assessment for subject i
x = cognitive age-adjusted z-score
̅ = mean performance score of the eTHINK hemophilia normative sample for outcome measure 
t                   
 = Standard Deviation of the eTHINK hemophilia normative sample for outcome measure t
Tables similar to the above Tables 3-6 will be generated based on the eTHINK study and re-used here.
11.
Data Quality Assurance
 Computerized Tests
Data from the 
 computerized test battery will be collected on iPads at site(s) and uploaded to the 
 
database for processing. 
 data management staff will query any data discrepancies. Queries will be confirmed 
and resolved with the sponsor.
Traditional Neurocognitive Instruments
Before raters could administer the neurocognitive instruments to subjects, they were required to become certified by 
completing online training requirements (i.e., didactic training videos and for some scales (Bayley-III, WPPSI-IV, and 
WASI-II) demonstrations showing proper administration and scoring of the scales). A neuropsychologist at 
 
then evaluated the completed source document and audio recording from the practice administration. The 
neuropsychologist issued corrective feedback, if necessary. During the study, 
 monitored the first Bayley-III, 
WPPSI-IV, and WSI-II administrations for each rater to ensure quality. For these administrations, raters submitted the 
source document of their administration. A neuropsychologist at 
 then evaluated the completed source 
document and issued corrective feedback, if necessary.
11.1.
 Computerized Test Completion Criteria
For each of the 
computerized tests, subjects must provide sufficient responses to allow computation of 
reliable performance measures. For the majority of 
computerized tests, the term “sufficient” has been defined 
as a Test Completion criterion. The number of trials required for Test Completion is unique to each test. They do not 
vary for different patient groups or study samples.
The completion criteria set forth a priori for each test were as follows:

DET: The number of responses provided by the subject is ≥ 100% of the desired number of trials (responses ≥ 
35)

IDN: The number of responses provided by the subject is ≥ 100% of the desired number of trials (responses ≥ 
30)

ONB: The number of responses provided by the subject is ≥ 100% of the desired number of trials (responses ≥ 
31)
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12.
Statistical Methodology
12.1.
Analysis Overview 
All statistical analyses and summary information will be generated according to this Statistical Analysis Plan (SAP). 
Data collected in this study will be presented using standardized scores, comparing cognitive outcome measures 
against age-matched norms, hemophilia norms, the most recent prior assessment, and the Initial Assessment.
12.2.
Analyses
Cognitive outcome measures from the neurocognitive instruments will have a series of z-scores calculated. This 
includes age-adjusted US normative (international normative for 
computerized tests) z-scores (see Section 
10.6.1), age-adjusted hemophilia z-scores (see Section 10.6.3), z-score change from prior (for both age- and 
hemophilia-adjusted z-scores), and z-score change from Initial Assessment (for both hemophilia- and age-adjusted z-
scores). The above z-scores will be tabulated descriptively (n, mean, standard deviation, median, interquartile range 
(first quartile, third quartile), min, max).
Individual domains/scores by visit will be plotted per patient for each instrument.
A subject listing including scores, z-scores (age- and hemophilia-adjusted), change from prior z-scores (age- and 
hemophilia-adjusted) and change from initial assessment z-scores (age- and hemophilia-adjusted) on each
neurocognitive instrument and outcome measure will be generated. All z-scores will be adjusted so that positive scores 
reflect improvement.
All analyses will be done in SAS (v9.4).
See Appendix 1 for an example of the tables, listing, and figures (TLF).
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References
Bland, J. M., & Altman, D. G. (1996a). Statistics notes: Measurement error. British Medical Journal, 312(7047), 1654.
Bland, J. M., & Altman, D. G. (1996b). Statistics notes: Measurement error and correlation coefficients. British Medical 
Journal, 313(7048), 41-42.
Falleti, M. G., Maruff, P., Collie, A., & Darby, D. G. (2006). Practice effects associated with the repeated assessment of 
cognitive function using the CogState battery at 10-minute, one week and one month test-retest intervals. Journal of 
Clinical and Experimental Neuropsychology, 28(7), 1095-1112.
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