Clinical trial NCT02137850
Conditions: Congenital Bleeding Disorder Haemophilia A
Sponsor: Novo Nordisk A/S
Start date: 2014-06-26; Completion date: 2023-06-07
Enrollment: 124 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 turoctocog alfa pegol (N8-GP) in previously untreated patients (PUPs) with haemophilia A.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: turoctocog alfa pegol
Intervention descriptions: intervention 1: For intravenous (i.v.) injection. Frequency and dosage (20-75 U/kg) dependent on whether given as treatment for bleeding episode or as prophylaxis

Protocol documents:
Prot_SAP_000.pdf: 
Cover Page for Protocol and SAP 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02137850
Sponsor trial ID: 
NN7088-3908
Official title of study: 
Safety and Efficacy of turoctocog alfa pegol (N8-GP) in
Previously Untreated Patients with Haemophilia A
Document date:* 
15 June 2020
a
* Document date refers to the date on which the document was most recently updted.
Note: The date in the header of Page 2 is the date of compilation of the documents, and not of an update to content.


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List of contents
Protocol ...............................................................................................................................................
Attachment I and II............................................................................................................................
Amendment  log..................................................................................................................................
Amendment  1 - PT ............................................................................................................................
Amendment 2 - Global.......................................................................................................................
Amendment 3 - Global.......................................................................................................................
Amendment  4 - IL .............................................................................................................................
Amendment 5 - Global.......................................................................................................................
Amendment  6 - IL .............................................................................................................................
Amendment  7 - JP.............................................................................................................................
Amendment 8 - Global.......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
turoctocog alfa pegol
Trial ID: NN7088-3908
Clinical Trial Report
Appendix 16.1.1
24 February 2022
1.0
Final
16.1.1 Protocol and protocol amendments
Redacted protocol 
Includes redaction of personal identifiable information only. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
1 of 114
Protocol
Trial ID:NN7088-3908
Safety and Efficacy of turoctocog alfa pegol (N8-GP) in 
Previously Untreated Patients with Haemophilia A
An open-label single-arm multicentre non-controlled phase 3a trial investigating safety and efficacy 
of N8-GP in prophylaxis and treatment of bleeding episodes in previously untreated paediatric 
patients with severe haemophilia A 
Trial phase: 3a
Protocol originator: 
, International Trial Manager
Haemophilia, Clinical 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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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
2 of 114
Table of contents   
Page
Table of contents...............................................................................................................................................2
Table of figures.................................................................................................................................................6
Table of tables...................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................11
2
Flow chart ................................................................................................................................................14
3
Background information and rationale for the trial............................................................................18
3.1
Background information..............................................................................................................18
3.1.1
Haemophilia A...........................................................................................................18
3.1.2
N8-GP........................................................................................................................18
3.1.3
N8-GP clinical data....................................................................................................19
3.2
Rationale for the trial...................................................................................................................20
3.3
Risk and benefits..........................................................................................................................21
4
Objective(s) and endpoint(s) ..................................................................................................................24
4.1
Objective(s)..................................................................................................................................24
4.2
Endpoint(s)...................................................................................................................................24
4.2.1
Primary Endpoint.......................................................................................................24
4.2.2
Secondary Endpoint...................................................................................................24
5
Trial design ..............................................................................................................................................25
5.1
Type of trial .................................................................................................................................25
5.2
Rationale for trial design..............................................................................................................26
5.3
Treatment of patients ...................................................................................................................27
5.3.1
Pre-prophylaxis treatment..........................................................................................28
5.3.2
Prophylaxis treatment ................................................................................................28
5.3.3
Treatment of bleeding episodes .................................................................................29
5.3.4
Treatment of suspected bleeding episodes.................................................................30
5.3.5
Surgery.......................................................................................................................31
5.3.6
Treatment of patients with FVIII inhibitors...............................................................32
5.3.7
Vaccinations...............................................................................................................34
5.4
Treatment after end of trial ..........................................................................................................34
5.5
Rationale for treatment ................................................................................................................35
6
Trial population.......................................................................................................................................36
6.1
Number of patients.......................................................................................................................36
6.2
Inclusion criteria ..........................................................................................................................36
6.3
Exclusion criteria.........................................................................................................................36
6.4
Withdrawal criteria ......................................................................................................................36
6.5
Patient replacement......................................................................................................................37
6.6
Rationale for trial population.......................................................................................................37
6.6.1
Rationale for inclusion criteria...................................................................................38
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
3 of 114
  
6.6.2
Rationale for exclusion criteria..................................................................................38
6.6.3
Rationale for withdrawal criteria ...............................................................................38
7
Milestones.................................................................................................................................................39
8
Methods and assessments .......................................................................................................................41
8.1
Visit procedures...........................................................................................................................41
8.1.1
Visit 0 – screening visit .............................................................................................43
8.1.1.1
Pre-prophylaxis treatment ...................................................................44
8.1.1.2
Prophylaxis treatment..........................................................................44
8.1.2
Visit 1 – first dosing with N8-GP ..............................................................................45
8.1.3
Visit 2, 3, 4-6 – main phase .......................................................................................45
8.1.4
Visit 7-8 – main phase ...............................................................................................46
8.1.5
Visit 9 – end of main phase........................................................................................47
8.1.6
Visit 10-13 – extension phase....................................................................................47
8.1.7
Visit 14 - end of extension phase...............................................................................48
8.1.8
Visit 15-X until end of trial........................................................................................48
8.1.9
End of trial visit .........................................................................................................49
8.1.10
Unscheduled visit.......................................................................................................49
8.1.11
ITI Visit......................................................................................................................49
8.1.12
Home treatment..........................................................................................................50
8.1.12.1
Prophylactic home treatment...............................................................50
8.1.12.2
Home treatment of bleeding episodes .................................................50
8.2
Patient related information...........................................................................................................51
8.2.1
Concomitant illness and medical history...................................................................51
8.2.1.1
Details on haemophilia........................................................................51
8.2.1.2
Allergies ..............................................................................................51
8.2.2
Concomitant medication............................................................................................51
8.2.3
Treatment of bleeding episodes in inhibitor patients.................................................52
8.2.4
Prohibited medication................................................................................................52
8.2.5
Demography...............................................................................................................52
8.3
Clinical assessments ....................................................................................................................52
8.3.1
Body measurements...................................................................................................52
8.3.2
Physical examination.................................................................................................52
8.3.3
Vital signs ..................................................................................................................53
8.4
Laboratory assessments ...............................................................................................................53
8.4.1
Local laboratory assessments.....................................................................................54
8.4.1.1
FVIII activity.......................................................................................54
8.4.2
Central laboratory assessments..................................................................................54
8.4.2.1
FVIII activity.......................................................................................55
8.4.2.2
Antibody assessments .........................................................................55
8.4.2.3
HIV testing and CD4+ lymphocyte count...........................................58
8.4.2.4
Haematology .......................................................................................58
8.4.2.5
Biochemistry .......................................................................................58
8.4.2.6
F8 and HLA genotype testing..............................................................59
8.4.2.7
Allergic reaction testing ......................................................................59
8.4.3
Blood sampling in infants and children .....................................................................60
8.4.4
Storage of samples.....................................................................................................60
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
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8.5
N8-GP administration..................................................................................................................61
8.6
Bleeding episodes ........................................................................................................................61
8.6.1
Assessments of bleeding episodes and treatment response .......................................62
8.7
Surgery.........................................................................................................................................63
8.7.1
Minor surgery ............................................................................................................63
8.7.2
Major surgery.............................................................................................................63
8.8
Training and reminders................................................................................................................64
8.8.1
Trial card dispensing..................................................................................................64
8.8.2
Home treatment training ............................................................................................64
8.8.3
Electronic diary (eDiary) ...........................................................................................65
8.8.3.1
eDiary dispensing and collection ........................................................65
8.8.4
Contact between the investigator/medically qualified person and the patient...........65
8.8.5
Interactive voice/web response system......................................................................66
8.9
Patient compliance.......................................................................................................................66
9
Trial supplies ...........................................................................................................................................68
9.1
Trial product ................................................................................................................................68
9.2
Packing, labelling and dispensing................................................................................................69
9.3
Storage .........................................................................................................................................69
9.4
Drug accountability and destruction............................................................................................70
9.5
Auxiliary supply ..........................................................................................................................71
10 Interactive voice/web response system (IV/WRS)................................................................................72
11 Adverse events and technical complaints..............................................................................................73
11.1
Definitions ...................................................................................................................................73
11.2
Reporting of adverse events.........................................................................................................78
11.3
Follow-up of adverse events........................................................................................................81
11.4
Technical complaints and technical complaint samples ..............................................................82
11.4.1
Reporting of technical complaints .............................................................................82
11.4.2
Collection, storage and shipment of technical complaint samples ............................82
11.5
Precautions and/or overdose ........................................................................................................83
11.6
Committees related to safety........................................................................................................83
11.6.1
Novo Nordisk safety committee ................................................................................83
11.6.2
Rules for putting the enrolment on hold ....................................................................83
12 Case report forms....................................................................................................................................85
12.1
Corrections to case report forms..................................................................................................85
12.2
Case report form flow..................................................................................................................86
12.3
Electronic diary............................................................................................................................86
13 Monitoring procedures ...........................................................................................................................88
14 Data management....................................................................................................................................90
15 Computerised systems.............................................................................................................................91
16 Statistical considerations ........................................................................................................................92
16.1
Sample size calculation................................................................................................................93
16.2
Definition of analysis sets............................................................................................................93
16.3
Primary endpoint..........................................................................................................................93
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
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16.4
Secondary endpoints....................................................................................................................93
16.4.1
Confirmatory secondary endpoints............................................................................93
16.4.2
Supportive secondary endpoints ................................................................................94
16.4.2.1
Number of bleeding episodes during prophylaxis...............................94
16.4.2.2
Haemostatic effect...............................................................................94
16.4.2.3
Incidence of high titre inhibitors .........................................................95
16.4.2.4
FVIII consumption..............................................................................95
16.4.2.5
Safety endpoints..................................................................................95
16.4.2.6
Other assessments ...............................................................................95
16.5
Interim reporting..........................................................................................................................96
16.6
Sequential safety analysis and safety monitoring........................................................................96
16.7
Reporting of F8 and HLA genotype.............................................................................................96
17 Ethics........................................................................................................................................................97
17.1
Informed consent .........................................................................................................................97
17.2
Data handling...............................................................................................................................98
17.3
Information to patient, parent(s)/LAR(s) during the trial ............................................................99
17.4
Premature termination of the trial and/or trial site.......................................................................99
18 Protocol compliance..............................................................................................................................100
19 Audits and inspections ..........................................................................................................................101
20 Critical documents ................................................................................................................................102
21 Responsibilities......................................................................................................................................104
22 Reports and publications......................................................................................................................105
22.1
Communication of results..........................................................................................................105
22.1.1
Authorship ...............................................................................................................106
22.1.2
Trial site-specific publication(s) by investigator(s) .................................................106
22.2
Investigator access to data and review of results.......................................................................106
23 Retention of clinical trial documentation and human biospecimens................................................107
23.1
Retention of clinical trial documentation...................................................................................107
23.2
Retention of human biospecimens.............................................................................................107
24 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............109
25 Indemnity statement .............................................................................................................................110
26 .References.............................................................................................................................................112
Approval of Final Protocol
Agreement on Final Protocol
Attachment I – Global List of key staff and relevant departments and CRO(s)
Attachment II – Country List of key staff and relevant departments
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CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
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Table of figures  
Page
Figure 5–1
Patient flow chart....................................................................................................................27
Figure 8–1
Visit flow diagram..................................................................................................................41
Figure 11–1
Initial reporting of AEs...........................................................................................................80
Figure 16–1
Individual patient flow and time periods for trial reporting ...................................................92
Table of tables   
Page
Table 2–1
Flow chart visits and assessments...........................................................................................14
Table 2–2
Flow chart explanatory descriptions.......................................................................................17
Table 5–1
Intravenous N8-GP treatment.................................................................................................34
Table 8–1
4-point scale............................................................................................................................62
Table 9–1
Trial Product...........................................................................................................................68
Table 9–2
Storage....................................................................................................................................69
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CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
7 of 114
  
List of abbreviations
AE
adverse event
APCC
activated prothrombin complex concentrate 
BP
blood pressure
BU
Bethesda Units
BW
body weight
CRF 
case report form
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
CRO
contract research organisation
CTA
clinical trial application
CTR
clinical trial report
CV
curriculum vitae
DU
dispensing unit 
DUN
dispensing unit number
eCRF
electronic case report form
ED
exposure day (Definition: An exposure day (ED) is any day on 
which the patient has been exposed to trial product)
eDiary
electronic diary
EMA
European Medicines Agency
EOT
end of trial
eSIF
electronic safety information form
F8
factor VIII gene
FAS
full analysis set
FDA
Food and Drug Administration
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CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
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FPFV
first patient first visit
FVII
coagulation factor VII
FVIII
coagulation factor VIII
FVIIIa
activated coagulation factor VIII
FX
coagulation factor X
FU
follow-up
GCP
Good Clinical Practice
HCP
host cell protein
HIV
human immunodeficiency virus
HLA
human leucocyte antigen
HTC
haemophilia treatment centre
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IgE
immunoglobulin E
IMP
investigational medicinal product
IND
investigational new drug
IRB
institutional review board
IR30min
incremental recovery 30 min
ITI
immune tolerance induction
IU
international unit
I.V.
intravenous
IV/WRS
interactive voice/web response system 
LAR
legally acceptable representative
LOCF
last observed carried forward
M
months
MedDRA
medical dictionary for regulatory activities
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CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
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MESI
medical event of special interest
N8-GP
turoctocog alfa pegol, glycopegylated recombinant coagulation 
factor FVIII
NIMP
non-investigational medicinal product
PDCO
Paediatric Committee (EMA)
Pd-aPCC
plasma-derived activated prothrombin complex concentrates 
PdFVIII
plasma derived FVIII
Pd-PCC
plasma-derived prothrombin complex concentrates
PEG
polyethylene glycol
PI
principal investigator
PIP
paediatric investigation plan
PK
pharmacokinetics
PPX
prophylaxis
PT
prothrombin time
PTP
previously treated patients
PUP
previously untreated patients
rFVIIa
activated recombinant factor VII
rFVIII
recombinant coagulation factor VIII
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SIF
safety information form
SDV
source data verification
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment emergent adverse event
TESAE
treatment emergent serious adverse event
TMM
trial materials manual
UNS
unscheduled visit
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04 November 2013
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Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
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UTN
universal trial number
V
visit
W
weeks
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Date:
04 November 2013
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Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
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1
Summary
Objective(s) and endpoint(s):
Primary Objective

To evaluate immunogenicity of N8-GP (turoctocog alfa pegol) in previously untreated patients 
(PUPs) with severe haemophilia A
Primary Endpoint

Incidence of FVIII inhibitors 
Secondary Objectives

To evaluate safety other than immunogenicity of N8-GP (turoctocog alfa pegol) in PUPs with 
severe haemophilia A

To evaluate efficacy of N8-GP (turoctocog alfa pegol) in PUPs with severe haemophilia A
o
in long-term prophylaxis treatment (bleeding preventive effect)
o
in the treatment of bleeding episodes 
Key Secondary Endpoint

Frequency of adverse events including serious adverse events and medical events of special 
interest.

Incidence of confirmed high titre inhibitors (defined as inhibitor titre > 5BU).

Number of breakthrough bleeding episodes during prophylaxis with N8-GP (annualised 
bleeding rate).

Haemostatic effect of N8-GP in treatment of bleeding episodes, assessed by a predefined 4-
point haemostatic response scale (“excellent”, “good”, “moderate” and “none”).
Time frames for evaluation of Objectives/Endpoints
All objectives/endpoints will be evaluated when the first 50 PUP have reached at least 50 exposure 
dates, when the first 100 PUP have reached 100 exposure dates, and at end of trial. End of trial will 
be up to 4 years after the patient has reached 100 exposure dates.
Trial design:
This is a multi-national, non-randomised, open label phase 3 trial investigating the safety (including 
immunogenicity) and efficacy of N8-GP in prophylaxis and treatment of bleeds in a paediatric 
population of PUPs (age below 6 years) with severe haemophilia A (factor VIII baseline level < 
1%). There will only be one treatment arm and no comparator.
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CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
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The European medical agency requires submission of safety and efficacy data from minimum 50 
exposure days in at least 50 patients for approval of the indication in PUPs, with a post-approval 
commitment to follow- at least 100 patients for a minimum of 100 exposure days. When the first 50 
patients have reached a minimum of 50 exposure days, the analysis and evaluation for the main trial 
report will be performed. All patients continue in the extension phase for the purpose of collecting 
data for a minimum of 100 exposure days in at least 100 patients. 
Trial population:
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, age < 6 years at the time of signing informed consent

Diagnosis of severe haemophilia A (factor VIII activity level < 1%) based on medical records
or central laboratory results

No prior use of purified clotting factor products (5 previous exposure to blood components is 
acceptable) 
Exclusion criteria

Any history of FVIII inhibitor (defined by medical records)

Known or suspected hypersensitivity to trial product or related products 

Previous participation in this trial. Participation is defined as administration of trial product

Receipt of any investigational medicinal product within 30 days before screening

Congenital or acquired coagulation disorder other than haemophilia A. 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)/legally acceptable representative(s) mental incapacity, unwillingness to 
cooperate, or a language barrier precluding adequate understanding and cooperation 
Assessments:
Key Safety assessments

Antibody assessment: binding antibodies towards trial product (N8-GP) and inhibitory
antibodies (factor VIII inhibitors)

Other adverse events
Key Efficacy assessments

Breakthrough bleeding episodes (annualised bleeding rate)
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Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
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
Haemostatic effect in treatment of bleeds

Number of doses to treat a bleed
Trial product
The following trial product will be used in the trial:

N8-GP (500 U/vial and 2000 U/vial)
N8-GP is supplied as a sterile, freeze-dried powder in a single use vial with a nominal content of 
500 U/vial or 2000 U/vial to be reconstituted with 4.3 mL 0.9% Sodium Chloride solution for 
intravenous injection
N8-GP is used for prevention and treatment of bleeding episodes.
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UTN: U1111-1148-1897
Date:
04 November 2013
Status:
Final
Novo Nordisk
Trial ID: NN7088-3908
EudraCT No.: 2013-004025-88 
Version:
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2
Flow chart
Table 2–1
Flow chart visits and assessments
Visit number
01
11
2
3
4-6
7-8
9
10-13
1418
15-X19
EOT
Visit purpose
Screening
Dosing
Dosing
Dosing
Dosing
Dosing
End of 
main
Dosing
End of 
extension
Dosing
(until EOT)
End of
Trial
Time of visit (ED(s))2
0
1
2
5
10, 15, 203
30,40
50
60, 70, 80, 
90
100
NA
Visit interval (ED(s))2
0
0
3±1
5±2
10±2
10+2
10±2
10+2
24w±4w

PATIENT RELATED 
INFORMATION
Informed consent
X
Assent form, if applicable4
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Informed Consent for 
Genotyping
(X)12
(X)12
(X)12
(X)12
(X)12
(X)12
Inclusion / Exclusion 
criteria
X
Eligibility evaluation
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
Demography
X
Concomitant illness & 
Medical history
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
ADVERSE EVENTS
Adverse events5
X
X
X
X
X
X
X
X
X
X
X
CLINICAL 
ASSESSMENTS
Body measurements6
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
Vital signs7
X
X7
X
X
X
CENTRAL 
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Visit number
01
11
2
3
4-6
7-8
9
10-13
1418
15-X19
EOT
Visit purpose
Screening
Dosing
Dosing
Dosing
Dosing
Dosing
End of 
main
Dosing
End of 
extension
Dosing
(until EOT)
End of
Trial
Time of visit (ED(s))2
0
1
2
5
10, 15, 203
30,40
50
60, 70, 80, 
90
100
NA
Visit interval (ED(s))2
0
0
3±1
5±2
10±2
10+2
10±2
10+2
24w±4w

LABORATORY 
ASSESSMENTS
FVIII activity – trough9
X8
X
X
X
X
X
X
X
X
X
FVIII activity – recovery 
(30 post-dose)
X
X
X
X
X
X
X
X
N8-GP/FVIII binding 
antibodies9
X
X
X
X
X
X
X
X
X
PEG antibodies9
X
X
X
X
FVIII inhibitor test9
X
X
X
X
X
X
X
X
X
HIV 1 and 2 antibodies
(X)10
CD4+ lymphocyte count 
and HIV viral load
(X)10
Haematology
X
X11
X
X
X
Biochemistry
X
X11
X
X
X
F8 + HLA genotype testing
(X)12
(X)12
(X)12
(X)12
(X)12
(X)12
Allergic reaction testing
X
TRIAL PRODUCT 
ADMINISTRATION
N8-GP administration
X
X
X
X
X
X
X
X
X
Change of regimen
X
X
X
X
X
X
X
X
N8-GP dispensing for 
home treatment
X13
X
X
X
X
X
X
X17
N8-GP accountability
X
X
X
X
X
X
X
X
X
X
TRAINING AND 
REMINDERS
Trial card dispensing
X
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Visit number
01
11
2
3
4-6
7-8
9
10-13
1418
15-X19
EOT
Visit purpose
Screening
Dosing
Dosing
Dosing
Dosing
Dosing
End of 
main
Dosing
End of 
extension
Dosing
(until EOT)
End of
Trial
Time of visit (ED(s))2
0
1
2
5
10, 15, 203
30,40
50
60, 70, 80, 
90
100
NA
Visit interval (ED(s))2
0
0
3±1
5±2
10±2
10+2
10±2
10+2
24w±4w

Home treatment training
X
X
X
X
X
X
X
X
X
eDiary training
X14
X14
X14
X14
X14
X14
X14
X14
X14
Compliance check of
eDiary data, protocol 
requirements and used 
drug
X
X
X
X
X
X
X
X
X
Contact with patient’s 
parent/LAR
(X)16
(X)16
IV/WRS15
X
X
X
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
V0 and V1 can be combined to one visit, if the patient fulfils the in- and exclusion criteria
2
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 or lower due to treatment of bleeding episodes during the home treatment period.
3
If not already on prophylaxis, all patients must initiate prophylaxis treatment no later than at V6. Pre-prophylaxis is only allowed for children below the age of 24 months or up to 
V6, whatever comes first.
Visits at 10EDs±2EDs, 15EDs±2EDs, 20EDs±2EDs must be performed even the window allows 2 visits to be 2 EDs aside (eg ED12 and ED13)
4
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 his ability to assent throughout the trial.
5
After Informed consent has been obtained all Adverse Events must reported in the eCRF
6
The frequency of body weight measurements should follow local practice, but should at least be measured every 10 weeks in children ≥3 years of age and within a timeframe of 6 
weeks in children <3 years of age. Please refer to Section 8.3.1
7
Vital signs should be measured prior to dosing at all screening, V1, V9, V14 and EOT. In addition vital signs should also be measured 30±10minutes after the first injection with 
N8-GP at V1.
8
FVIII activity should only be measured at V0 if diagnosis of haemophilia A (FVIII<1%) has not been documented in the patients’ medical record. FVIII 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 
9
Blood samples must be collected prior to dosing at dosing visits. Please check that the required washout period has been met for inhibitor testing, see section 8.1.1.3
10
HIV 1 and 2 antibodies are only to be assed, 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
11
In case V1 is more than a month after V0, Haematology and Biochemistry need to be retaken at V1 prior to dosing, see Section 8.4.2.4 and 8.4.2.5
12
F8 and HLA genotype sample is only allowed upon patient’s parent(s)/LAR(s) signing the consent for genotyping and should only be done if not already documented in patient’s 
medical record. The sample can be collected at any visit between V0 and V9, taking the limitation of the allowed blood sampling volume into account
13
Home treatment can be postponed until the patient’s parent(s)/LAR(s) are comfortable with reconstitution procedure and administration of N8-GP
14
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 V2-VX to ensure entry of correct eDiary data
15
IV/WRS to be used for screening, visit registration, trial drug dispensing, drug accountability and completion. Refer to Section 10 for more information
16
When site visits are more than 3 months apart the Investigator must contact the patient’s parent(s)/LAR(s) at least every 12 weeks ± 1week to ensure 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-V6) and whom visit the trial site less frequent than 
every 3 months. In addition all visits from V15-VX will be scheduled every 24 weeks ±4 weeks
17
At every dosing visit from V15-VX, drug will be dispensed to cover up to 3 months of treatment. Depending on patient’s treatment regimen, an additional dispensing visit might 
be needed to cover treatment in the entire period between visits.
18
In case V14 will be the EOT visit, the procedures for the EOT visit should be followed
19
V15 to VX will be performed every 24 EDs ± 4EDs until the End of Trial
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Status:
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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
3.1.1
Haemophilia A
Haemophilia A is a recessive X-linked congenital bleeding disorder, resulting from deficiency of 
the essential blood coagulation factor VIII (FVIII) and characterised by increased bleeding 
tendency. Haemophilia is classified as “severe (<1%)”, “moderate (1-5%)” or “mild (>5%)” 
according to the plasma activity of the affected clotting factor. 
The primary goals of haemophilia care are the prevention of bleeding episodes (prophylaxis), rapid 
and definitive treatment of bleeding episodes that do occur, and provision of adequate haemostasis 
during surgery and other major challenges to haemostasis. Currently, these goals are essentially met 
for patients with haemophilia A by intravenous (i.v.) injections of the commercially available FVIII 
products approximately 3 times a week. However, with currently marketed FVIII products, the 
clinical practice for prophylaxis is associated with substantial unmet medical needs, primarily 
linked to cumbersome, frequent and painful i.v. administration of the haemostatic agent. 
Consequently adherence to prophylaxis is in general suboptimal, and non-compliance with a 
frequent injection schedule is one of the most commonly cited reasons for failure of prophylaxis 
with FVIII products. 
The most serious complication of haemophilia treatment with current FVIII products is FVIII 
inhibitor development. These inhibitors are antibodies formed as an immune response to allogeneic 
FVIII, which reduce or eliminate the activity of FVIII proteins. This condition develops in about 
30% of previously untreated patients (PUPs) with severe haemophilia A following exposure to 
FVIII products.3,4 Availability of a recombinant human FVIII (rFVIII) product with reduced 
immunogenicity has been the priority request by the haemophilia community for many years. The 
immunogenicity of N8-GP will be monitored in the clinical setting and further investigated in 
nonclinical models to explore preliminary findings of reduced binding and uptake of N8-GP in 
human antigen presenting cells.
3.1.2
N8-GP
N8-GP is a glycopegylated recombinant coagulation FVIII hereafter referred to as N8-GP and
represents a new rFVIII with a longer terminal half-life (t½) than currently available rFVIII 
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products. Clinical areas of interest include prevention (prophylaxis) and treatment of bleeding 
episodes in patients with haemophilia A without inhibitors, as well as the prevention of bleeding in 
surgery undertaken in these patients.
The N8-GP product is based on turoctocog alfa, which is a state of the art serum-free truncated 
rFVIII containing 21 amino acids of the wild type B-domain. N8-GP is a rFVIII molecule where a 
single 40-kDa polyethylene glycol (PEG) is specifically attached to a unique O-glycan in the 
truncated B-domain of turoctocog alfa, manufactured using three enzymes all produced by 
recombinant technology. When activated by thrombin, the B-domain containing the pegylation is 
cleaved off, thus generating active FVIII (FVIIIa) which is similar in structure to native activated 
FVIII - a key feature of the compound. N8-GP is a recombinant product, not based on human blood 
components, and hence the risk of transmission of viral and other blood-borne diseases has been 
eliminated. No animal-derived components besides the cell line (Chinese Hamster Ovary (CHO) 
cells) are used during the manufacturing process. 
For full information on medicinal aspects and qualities of the N8-GP product please refer to the 
investigator brochure (IB).5
3.1.3
N8-GP clinical data
In accordance with the European Medicines Agency (EMA) guidelines and other regulatory advice 
the clinical programme for N8-GP was initiated with a first-human-dose trial to document the 
essential PK characteristics of the product and to obtain initial safety information. 
In the first human dose trial (NN7088-3776), a single dose of N8-GP (25, 50 or 75 U/Kg) was 
administered to 26 adult previously treated patients (PTPs) with severe haemophilia A being in a 
non-bleeding state. N8-GP was well-tolerated and the safety profile of N8-GP appeared similar to 
that of marketed FVIII products. The mean half-life of N8-GP was shown to be 18.4 hours, 
corresponding to a 1.6-fold prolongation compared to the half-life of commercially available FVIII 
products (patient’s previous product including rFVIII and plasma derived FVIII (pdFVIII)).6
Three clinical trials investigating the safety and efficacy of N8-GP are on-going. The pivotal trial
(pathfinder™2) in adolescents and adults aims to document the safety and efficacy of a prophylactic 
regimen with 50 U/Kg body weight (bw) of N8-GP given every four days. The surgery trial
(pathfinder™3) aims to document the safety and efficacy of N8-GP during major surgery. The 
pathfinder™5 trial evaluates PK, safety and efficacy of N8-GP in previously treated children 
(below 12 years of age).
An internal review of safety and efficacy data for 52 bleeding episodes reported by 10 patients in 
the pivotal pathfinder™2 trial (including adolescent and adult PTPs) was performed in order to 
initiate N8-GP prophylaxis treatment in patients from the US participating in pathfinder™2, and to 
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allow the pathfinder™3 surgery trial to open globally. The cut-off-date was 12-Feb-2013. Among 
the patients included in the review N8-GP was well tolerated and no safety issues have been 
identified. In particular no FVIII inhibitors were detected and no treatment related serious adverse 
events (SAEs) were reported. The efficacy data showed that N8-GP effectively arrests bleeding 
episodes (96% of bleeds treated successfully) and thereby has the intended haemostatic potential. 
These results were confirmed in a subsequent review of safety and efficacy data from 20 adults and 
adolescents having at least 50 N8-GP exposure days (EDs)1 in the pathfinder™2 trial, performed 
according to the EMA guideline7, in order to allow the pathfinder™5 trial in paediatric PTPs below 
12 years to be initiated (first patient first visit (FPFV) 20-Feb-2013). In conclusion, currently 
available clinical data indicate that N8−GP effectively arrests bleeds and has shown the intended 
haemostatic potential. In addition, no safety issues have been reported. Recently one case of low-
titre FVIII inhibitor formation after multiple exposure to N8-GP has been reported in the ongoing 
phase 3 trial NN7088-3859 in adolescent and adult PTPs (as per 28-Jul-2013 this trial included 182 
patients being treated with N8-GP). The FVIII inhibitor formation was reported for an 18-years-old 
patient receiving N8-GP every 4th day for prophylaxis. After 94 exposures to N8-GP a FVIII 
inhibitor test was positive for the first time, with an observed titre of 1.3 BU. The result was 
confirmed in the follow-up test 14 days later (1.9 BU). Hence, the protocol definition for the 
presence of a FVIII inhibitor was met.
In accordance with the EMA guideline7, N8-GP exposure of PUPs may be initiated when treatment 
data from 20 paediatric PTPs with at least 50 N8-GP EDs are available from the pathfinder™5 trial, 
including data from a minimum of 10 patients below 6 years, and pharmacokinetic investigations in 
children (below 12 years) are completed.
For further information on medicinal aspects, non-clinical data and quality of N8-GP please refer to 
the IB.5
3.2
Rationale for the trial
N8-GP represents a new recombinant FVIII product with a prolonged half-life developed to 
decrease the burden of treatment and thereby increase treatment compliance for patients with 
haemophilia A, potentially leading to better clinical outcomes.
The N8-GP clinical programme is designed to generate data on the pharmacokinetic (PK), safety 
and efficacy profile of N8-GP in all age groups. 
Given the prolonged half-life of N8-GP it is expected that bleeding prophylaxis, treatment of acute 
bleeding episodes, and control and prevention of bleeding in the surgical setting may be achieved 
                                                
1 An exposure day (ED) is any day on which the patient has been exposed to trial product. This will be used for 
reporting purposes.
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with a reduced frequency and number of injections as compared to current treatment options. This 
may increase treatment compliance, and thereby potentially leading to better clinical outcomes for 
patients with haemophilia A.
The rationale for performing the pathfinder™6 trial is to evaluate the safety (including 
immunogenicity) and efficacy of N8-GP in the treatment of PUPs with severe haemophilia A in 
accordance with EMA requirements.7 For Europe, EMA requires a separate investigation in the 
PUP population as part of the development programme to be initiated before market authorisation.7
The approval of the indication in PUPs will be based on a clinical trial in a minimum of 50 PUPs 
evaluated for efficacy and safety during at least 50 EDs connected with a post-approval 
commitment to follow up at least 100 PUPs for a minimum of 100 EDs. The 50 patients will 
continue to reach at least 100 EDs, and additional 50 patients will be included also to reach at least 
100 EDs.
Given the prolonged half-life of N8-GP it is expected that bleeding prophylaxis, treatment of acute 
bleeds, and control and prevention of bleeding in the surgical setting may be achieved with a 
reduced frequency and number of injections as compared to current treatment options. This may 
increase treatment compliance, and thereby potentially leading to better clinical outcomes for 
patients with haemophilia A.
Finally, as the HIV and hepatitis C epidemics in patients with haemophilia have subsided, the most 
serious complication of haemophilia treatment with current FVIII products is FVIII inhibitor 
development. These inhibitors are antibodies formed as an immune response to allogeneic FVIII, 
which reduce or eliminate the activity of FVIII proteins. This condition develops in about 30% of 
PUPs with severe haemophilia A following exposure to FVIII products.3,4
3.3
Risk and benefits
Children are among those who might benefit from prophylaxis with N8-GP. Current products 
available for the treatment of haemophilia A have short half-life of approximately12 hours 
demanding frequent dosing for prophylaxis of bleeding episodes, with 3 - 4 weekly injections. The 
prolonged half-life of N8-GP offers an expected advantage of twice 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.
The recombinant FVIII part of N8-GP has an amino acid sequence almost identical to human FVIII
and to the currently marketed rFVIII products and is produced by the CHO cell-line AAMP5, a 
mammalian cell line shown to be free of known infectious agents. 
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There is a risk for development of antibodies against N8-GP and/or FVIII that could decrease the 
effectiveness of future treatment with FVIII products. However, this risk is not expected to be 
higher than with other FVIII products.
The benefits of N8-GP in PUPs include reduced frequency of injections compared with existing 
FVIII treatments due to the long half-life of N8-GP. Lack of compliance with a frequent injection 
schedule is one of the most commonly cited reasons for failure of prophylaxis with factor 
treatments.8 Less frequent dosing is anticipated to result in a higher compliance. Furthermore, less 
frequent dosing regimens are believed to cause less interruption of daily life, which might improve 
the quality of life of the patients and their families.
N8-GP is manufactured in a serum-free process and the risk of transmission of viruses, prions and 
other known blood-borne diseases have been eliminated. Monoclonal antibodies used for 
purification of the product further reduce the risk of allergic reactions.
The primary concern in PUPs is the risk of development of inhibitory antibodies to FVIII 
(inhibitors). Potential development of inhibitors will be monitored by a Nijmegen modified 
Bethesda assay (which has a high sensitivity for low concentrations of inhibitors), and testing for 
presence of N8-GP binding antibodies will be performed shortly after each visit. A patient is 
diagnosed with inhibitor formation if the patient has been tested positive for inhibitors at two 
consecutive tests from the central laboratory. If antibodies are identified, these will be further 
characterised on an exploratory basis and there will be close follow-up and case-by-case 
evaluations.
As with other proteins, allergic type hypersensitivity reactions, including anaphylaxis/anaphylactoid 
reactions, may occur. As the N8-GP product contains trace amount of hamster cell proteins
antibodies to these may occur. Parent(s)/legally acceptable representatives (LAR)(s) to patients 
enrolled in the present trial will be informed of the signs of immediate type hypersensitivity 
reactions including hives, pruritus, generalised urticaria, angioedema, hypotension (e.g. dizziness or 
syncope), shock and acute respiratory distress (e.g. tightness of the chest, wheezing). 
PEGylation of proteins is a well-established technology which is used in the treatment of a variety 
of clinical disorders9 and the nonclinical safety profiling of N8-GP has not identified any safety 
concerns in relation to humans in the dose range proposed for the present trial.
N8-GP is currently being investigated in previously treated patients. The first human dose trial 
(NN7088-3776) demonstrated that a single dose of N8-GP is generally well-tolerated, and that N8-
GP has a prolonged half-life compared to commercially available FVIII products. No safety 
concerns have been raised based on review of data (cut-off date was 12-Feb-2013) from patients 
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enrolled in the pivotal safety and efficacy trial (NN7088-3859) and the risk/benefit ratio for N8-GP 
is therefore expected to be favourable. 
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4
Objective(s) and endpoint(s)
4.1
Objective(s)
Primary Objective

To evaluate immunogenicity of N8-GP in previously untreated patients (PUPs) with severe 
haemophilia A
Secondary Objectives

To evaluate safety other than immunogenicity of N8-GP in PUPs with severe haemophilia A

To evaluate efficacy of N8-GP in PUPs with severe haemophilia A
o
in long-term prophylaxis treatment (bleeding preventive effect)
o
in the treatment of bleeding episodes 
4.2
Endpoint(s)
4.2.1
Primary Endpoint

Incidence of FVIII inhibitors 
4.2.2
Secondary Endpoint

Frequency of Adverse events (AEs) including serious AEs and Medical Events of Special 
Interest (MESI).* 

Incidence of confirmed high titre inhibitors (defined as inhibitor titre > 5BU)*

Number of breakthrough bleeding episodes during prophylaxis with N8-GP (annualised 
bleeding rate).*

Haemostatic effect of N8-GP in treatment of bleeding episodes, assessed by a predefined 4-
point haemostatic response scale (“excellent”, “good”, “moderate” and “none”).*

Consumption of N8-GP for prophylaxis (number of injections and U/Kg per month and per 
year)

Consumption of N8-GP for treatment of bleeding episodes (number of injections and U/Kg 
required per bleeding episode)

Total consumption of N8-GP per patient (prevention and treatment of bleeding episodes) per 
month and annualised value
*Key supportive secondary endpoint prospectively selected for posting on clinicaltrials.gov
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5
Trial design
5.1
Type of trial
This is a multi-national, non-randomised, open label phase 3 trial investigating the safety (including 
immunogenicity) and efficacy of N8-GP in prophylaxis and treatment of bleeds in a paediatric 
population of PUPs (age below 6 years) with severe haemophilia A (FVIII baseline level < 1%). 
There will only be one treatment arm and no comparator. 
The trial design is based on the guideline on clinical investigation of recombinant and human 
plasma-derived factor VIII products developed by Committee for Medicinal Products for human use 
(CHMP) in EU.7
The number of patients to be investigated in this trial follows the minimum EU guideline 
requirements for approval of the indication in PUPs, which will be based on a pre-authorisation 
clinical trial in a minimum of 50 PUPs evaluated for efficacy and safety during at least 50 EDs, 
connected with a post-approval commitment to follow-up at least 100 PUPs for a minimum of 100 
EDs.7
According to the EMA Guideline treatment with N8-GP in the pathfinder™6 PUP trial may start 
when 20 patients participating in the paediatric PTP trial (pathfinder™5) are available (including 
data from a minimum of 10 paediatric patients below 6 years of age), and pharmacokinetic 
investigations in paediatric PTPs are completed.7
For the individual patient the trial consists of four parts; screening, main phase and extension phase
and a prophylaxis period until end of trial Figure 5–1. 
In the main phase of the trial patients will receive treatment with N8-GP until they reach a 
minimum of 50 N8-GP EDs each, or until they develop high-titre inhibitors. An ED is defined as 
any day during which the patient has been exposed to N8-GP, including doses given for treatment 
of bleeding episodes, prophylaxis, surgery and for the purpose of PK assessment. If N8-GP is 
administered more than once during the same day, this will still count as one ED. When at least 50 
patients have reached a minimum of 50 EDs each in the main phase, the analysis and evaluation for 
the main trial report will be performed. EDs during immune tolerance induction therapy (ITI) will 
not count in the determination of when a patient has reached 50 EDs.
Patients will be followed in the extension phase until at least 100 patients have reached at least 100 
EDs each. Results from all patients in all parts of the trial will be reported as supportive results 
when the last patient has completed or left the trial.
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Status:
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Patients who develop inhibitors during the trial may continue treatment with N8-GP and will 
follow an alternative treatment regimen and visit schedule, see Section 5.3.6. These patients will be 
considered as a separate cohort and will be evaluated accordingly.
If needed, the patients can undergo minor or major surgical procedures during the trial. Upon 
completion of the surgery the patient can continue prophylaxis treatment with N8-GP as before the 
surgery.
5.2
Rationale for trial design
The trial design follows current standards for similar trials, and the EMA “Guideline on the clinical 
investigation of recombinant and human plasma-derived factor VIII products”7.
The trial design will provide information on safety and efficacy of N8-GP in paediatric PUPs below 
6 years of age with severe haemophilia A (FVIII activity level of <1%).
The purpose of the present trial is to evaluate immunogenicity of N8-GP and to document the safety 
and efficacy of N8-GP in long-term prophylaxis and treatment of bleeding episodes in paediatric 
PUPs. 
The main phase of the trial will generate safety and efficacy, aiming for a minimum of 50 EDs per 
patient. This number of EDs is required by the EMA guideline7 for evaluation of new FVIII 
products. The trial does not include a placebo control group, as it is considered unethical to 
administer an ineffective treatment to patients with haemophilia. An active control has not been 
included as extensive comparative data from recently registered rFVIII products are available in 
comparable global populations including patients from EU and US.14, 15 Furthermore, the EMA 
guideline does not require a comparison to neither placebo nor an active comparator.
There will be no randomisation due to the single-arm nature of the trial.
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.
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Figure 5–1
Patient flow ch
5.3
Treatment of patient
Trial visit schedule will be as 
According to common practise
(episodic) treatment for minor
muscle or severe bleed, switch
damage. This is usually done w
The main phase of the trial is d
on the decision made by the in
directly with N8-GP prophylax
treatment (pre-prophylaxis trea
investigator and patient’s pare
For each patient at least the tw
setting enabling observation fo
least 1 hour after dosing. After
parent/caregiver/support perso
administration of the initial do
parent/caregiver/support perso
both prophylaxis and treatmen
for their N8-GP injections unti
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hart
ts
shown in Figure 5–1.
e in haemophilia care, most children will initi
r skin/mucosa bleedings episodes and after the
h to prophylaxis in order to prevent bleeds and
when the child is between 1 and 2 years of ag
designed to reflect common practice in haemo
nvestigator and the child’s parent(s)/LAR(s) p
xis (prior to any experienced bleeds) or with N
atment), and subsequently switch to prophyla
ent(s)/LAR(s) whether to start on prophylaxis 
wo initial doses of N8-GP will be administered
or potential adverse reactions. The patient mu
rwards, home treatment with i.v. self-injectio
on can be initiated if no safety concerns were 
oses of N8-GP. The investigator should ensure
on is sufficiently trained and confident with ho
nt of bleeding episodes. The patients can com
il they are comfortable with home treatment.
04 November 2013
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ially receive on-demand 
e first joint and/or 
d musculoskeletal 
ge. 
ophilia treatment. Based 
patients can either begin 
N8-GP on-demand
axis. It is decided by the 
or pre-prophylaxis.
d in a hospital/clinic 
ust be observed for at 
on by the 
raised after 
e that 
ome treatment, including 
me to the clinic/trial site 
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Version:
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The duration of a single patient’s treatment in the main phase of the trial is until 50 N8-GP EDs is 
reached, or until development of high-titre inhibitors, but will be maximum 26 weeks if the 
recommended twice weekly dosing is used for prophylaxis. 
The duration of N8-GP treatment in the extension phase is at least 50 EDs or up to a minimum total 
100EDs (for both the main and extension phases) for each patient. Once a patient has achieved 
100EDs, he may be offered the option to continue in the extension phase until either N8-GP is 
commercially available in the relevant country or until the marketing authorisation application for 
N8-GP is rejected in the relevant country unless the N8-GP trial, part of the trial or a trial site is 
terminated by Novo Nordisk or a relevant authority for any reason. In any event, the Last Patient 
Last Visit for the trial will be no later than 13 May 2019 whether or not the product is commercially 
available in the relevant country. Novo Nordisk will not provide any patient with trial medication 
after the end of the trial.
Treatment with FVIII products other than the investigational product, N8-GP, is not allowed.
Previous exposure to FVIII products is not allowed in this trial. Previous exposure to maximum 5 
plasma infusions, Pd-aPCC, and/or cryoprecipitate is allowed.
5.3.1
Pre-prophylaxis treatment
At the beginning of the main phase of the trial, slow start prophylaxis and on-demand treatment of 
bleeds with trial product (N8-GP) will be allowed at the discretion of the investigator and patient’s 
parent(s)/LAR(s). The decision regarding pre-prophylaxis treatment will be made at visit 0 or 1. 
The N8-GP dose for pre-prophylaxis treatment (except for bleeding episodes) is approximately 60 
U/Kg body weight (bw) (within the dosing range of 50-75 U/Kg) to be administered as a single 
bolus dose intravenously (i.v.) less than once every 7 days (at the discretion of the investigator). 
Whole mL dosing is allowed from above 3 mL, explained in the trial material manual. For treatment 
of bleeding episodes see Table 5–1.
Switching from pre-prophylaxis treatment to prophylaxis should follow guideline in Section 5.3.3.
For regular safety monitoring (including blood sampling for inhibitor analysis) pre-prophylaxis 
treated patients must attend regular site visits (see Table 2–1). 
5.3.2
Prophylaxis treatment
Prophylaxis with regular N8-GP administration must be initiated no later than at the patient’s age of 
24 months, or after 20 EDs in pre-prophylaxis, whatever comes first.
The N8-GP dose for prophylaxis treatment is approximately 60 U/Kg bw to be administered as a 
single bolus dose i.v. at each administration day, preferably in the morning. However, it is allowed 
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to dose within the dose range 50-75 U/Kg bw, enabling whole mL dosing. Whole mL dosing is 
allowed from above 3 mL.
During the main phase of the trial patients should receive prophylaxis with i.v. injections of N8-GP 
preferably twice weekly, with doses to be separated by at least 3 calendar days and no more than 4 
calendar days. An increase in N8-GP dose frequency from twice weekly to every third day is 
permitted at the investigators discretion (should be based on patient’s individual bleeding pattern). 
Furthermore it is allowed to start prophylaxis in the main phase with a once-weekly dosing regimen, 
if considered sufficient for bleeding prevention by the investigator. 
In the extension phase, all patients should continue the prophylaxis dosing regimen as prescribed at 
the end of the main phase. However, preferably after being 12 months on the same prophylaxis 
regimen (main phase and extension phase combined), the investigator is permitted to increase or 
decrease the N8-GP dosing interval within the range of every 3rd day to every 7th day (every 3rd day, 
twice weekly, every 4th day, every 5th day, every 6th day or every 7th day (once weekly)) based on 
the patient’s bleeding pattern. 
The dose can be administered +1 day of the planned dosing date.
Furthermore, if considered relevant, the investigator is permitted to prescribe administration of extra 
N8-GP bleeding preventive doses before demanding physical activities (e.g. sports).The next 
regular prophylaxis dose should not be postponed due to an extra prophylaxis dose, but still be 
administered on the usual dosing day. 
In the event of a concern about reduced treatment efficacy an unscheduled visit can be scheduled 
where a PK session may be performed to investigate the elimination (recovery, clearance and half-
life) of N8-GP. Antibody tests should be taken if not done recently. The PK data may potentially be 
used to adjust the dose or dosing regimen. 
5.3.3
Treatment of bleeding episodes
Patient’s parent(s)/LAR(s) will be instructed by the trial site on how to treat a bleeding episode at 
home and record in the electronic diary (eDiary). Treatment requiring bleeding episodes should 
immediately (i.e., when the patient experiences the first clinical symptoms of a bleeding episode) be 
treated with N8-GP at doses of 20-75 U/Kg bw, depending on severity and location of the bleeding 
episode, see Table 5–1. For treatment of severe/life-threatening bleeding episodes administration of 
higher doses of N8-GP is permitted at the investigators discretion. For recommended dose levels 
see Table 5–1.
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Status:
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At least the first 2 treatment-requiring bleeding episodes should be treated in the presence of a 
qualified health care professional. If the patient cannot be brought quickly to the trial site, the trial 
site must be contacted for treatment instructions or transport. A severe bleeding episode should 
immediately be treated at home or at the local emergency room, and the trial site must be contacted 
for further instructions or transport. For severe bleeding episodes before the 2nd EDs the treatment 
must take place at the site.
In case of treatment requiring bleeding episodes prior to home treatment, these should immediately 
be treated at trial site. In case the bleeding episode occurs outside trial site opening hours, the 
bleeding episode should be treated according to local practice.
The need for a second dose of N8-GP should be evaluated within 8 hours of the initial dose. If two 
doses are not sufficient to treat the bleeding episode, and immediately in the case of a severe 
bleeding episode, the trial site must be contacted as soon as possible for further instructions and/or 
transport to the trial site for an unscheduled visit. 
Total number of N8-GP doses and frequency of dosing for treatment of a bleeding episode is 
decided by the investigator based on the individual bleeding episode characteristics and haemostatic 
response to treatment, and/or based on local guideline or standard of practice. Dosing guidance may 
be provided at a scheduled or unscheduled visit at the clinic or by telephone contact to the trial site. 
If a haemostatic response to treatment cannot be achieved (i.e. the bleed does not stop) within 48 
hours after initiating treatment with N8-GP, another FVIII product may be selected at the discretion 
of the investigator, and the patient must be withdrawn from the trial. 
If a bleeding episode occurs on a planned prophylaxis dosing day before administration of the 
prophylaxis dose, or if a bleeding episode extends into such a day, the bleeding episode must be 
treated with the full prophylaxis dose (this dose should be recorded as treatment of a bleeding 
episode) (does not apply for surgeries). The patient should at all times follow the original 
prophylaxis dosing scheme unless a dose has already been given to treat a bleeding episode during 
the same day.
Treatment of bleeding episodes with N8-GP will be included in the overall count of ED.
5.3.4
Treatment of suspected 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 equivalent to 
treatment of a severe bleeding episode
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5.3.5
Surgery
Minor surgeries, dental extractions and placement of central venous access ports can be performed 
while participating in this trial by administering extra doses of N8-GP equivalent to the dose for a 
severe bleeding episode (see Table 5–1), or aligned to local standard of practice, or guidelines for 
treatment of patients with haemophilia A with FVIII in the perioperative period. 
Major surgery will only be allowed after the individual patient has reached 50 N8-GP EDs, and 
upon completions of the pathfinder™3 surgery trial (NN7088-3860). The treatment regimen for 
major surgery will be based on results from the pathfinder™3 surgery trial (NN7088-3860) and PK 
data obtained in the pathfinder™5 trial (NN7088-3885) in paediatric PTPs. Novo Nordisk will 
communicate when major surgeries are allowed in this trial.    
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
Skin excisions
Drainage of abscess
Simple dental procedures
Circumcision
Definition of major surgery
Major surgery is defined as any invasive operative procedure that require several days of FVIII 
substitution therapy and/or where any one or more of the following occur: 
A body cavity is entered
A mesenchymal barrier (e.g., pleura, peritoneum or dura) is crossed
A fascial plane is opened
An organ is removed
When normal anatomy is operatively altered
Major elective orthopaedic surgery
Treatment with N8-GP during surgery will be included in the overall count of N8-GP EDs. Upon 
completion of the surgical/invasive procedure the patient can continue prophylaxis treatment with 
N8-GP as before the surgery.
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5.3.6
Treatment of patients with FVIII inhibitors
Approximately 20–30% of PUPs with severe haemophilia A develop inhibitors to infused FVIII 
rendering use of such replacement therapy ineffective. Patients who develop inhibitory antibodies 
remain at higher risk for morbidity and mortality associated with recurrent or uncontrolled bleeding 
events.
The majority of haemophilia patients with inhibitors develop high-titre (> 5 BU) inhibitors, and 
demonstrate an anamnestic rise in their inhibitor titre when re-exposed to FVIII. In these patients 
even frequent, high-dose FVIII substitution therapy becomes ineffective in controlling bleeding 
episodes as the infused coagulation factor products are neutralised by the inhibitor. Administration 
of FVIII bypassing agents (rFVII or activated prothrombin complex concentrates) becomes 
necessary for treatment of bleeding episodes. 
Treatment of bleeding episodes with by-passing agents, i.e. rFVIIa or APCC according to local 
standard care, is allowed for patients who develop FVIII inhibitors within this trial. By-passing 
agents are not considered trial medication.
The ultimate goal of treatment in patients with high-titre inhibitors is to permanently eradicate the 
inhibitor by immune tolerance induction therapy (ITI), thereby making it possible for the patient to 
be treated routinely with FVIII replacement therapy. The therapeutic concept is based on long-term 
uninterrupted high exposure to FVIII in an effort to sufficiently tolerize the immune system. In that 
state, the clinical responsiveness to FVIII replacement therapy is restored. 
Based on the available evidence, all patients with high-titre inhibitors (> 5 BU) should undergo ITI 
using the same type of product that the patient was using at the time of inhibitor development.10
This approach is supported by an international expert panel11 which concurred with treatment 
guidelines which recommend that ITI should be conducted with the same concentrate as the one 
against which antibodies were developed.12,13 This should ensure successful tolerance induction and 
reduce the risk of further inhibitor development to new molecules. It may therefore be expected that 
N8-GP will be favourable over the use of commercially available FVIII products for ITI in patients 
who developed FVIII inhibitors within this trial. 
Novo Nordisk plans that patients who develop inhibitors, within this trial, will be offered continued 
treatment with N8-GP, including ITI for a maximum of 24 months. ITI with N8-GP will not be 
initiated until Novo Nordisk has reviewed the clinical data available after completion of the N8-GP 
pivotal and surgery trial (pathfinder™2 and pathfinder™3), and of the paediatric PTP trial 
(pathfinder™5) data needed for opening the paediatric PUP trial according to EMA requirements.
It is expected to use a N8-GP dosing regimen for ITI similar to local standard care/guidelines 
applied for ITI with marketed FVIII products. For each individual patient, ITI regimens with N8-GP 
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would have to be reviewed by the investigator every month, and more formally reviewed every 3 
months by Novo Nordisk.
Based on experience with marketed FVIII products, a successful ITI can be expected in about 60–
80% of cases receiving ITI with N8-GP, leading to several important benefits for the patient, 
including:

allowing regular FVIII replacement therapy in case of bleeding and surgery

enabling prophylactic treatment with FVIII to prevent haemophilic arthropathy and life-
threatening bleedings

improving the patient`s quality of life (less morbidity etc.)
With current knowledge, the benefit/risk ratio for using N8-GP for ITI is expected to be favourable, 
and similar as being described in Section 3.3. Non-clinical and clinical data on N8-GP do not 
suggest any alteration to the established safety profile of current rFVIII products. It is evaluated as 
unlikely that clinical significant adverse events will occur in humans specifically as a result of N8-
GP being used for ITI. However, close monitoring is strongly recommended when N8-GP will be 
used for ITI in this trial.
It may also be decided by the Investigator and/or parent/legal representative to withdraw the patient 
who developed FVIII inhibitors.
Patients will be evaluated after 12 months of ITI treatment, based on the level of inhibitors. If 
inhibitors are still positive after 12 months, but the decline from peak titre level is ≥ 20%, ITI may 
continue for a maximum period of 24 month in total.
If needed and decided by the Investigator, the initiation of the ITI can be delayed but it has to start 
within 6 months from the time of diagnosis of inhibitor. Inhibitor patients that commence ITI with 
N8-GP will follow an alternative treatment regimen and visit schedule (see Section 8.1.11). If the 
inhibitor disappears during the ITI (see Section 8.4.2.2, the patient should resume prophylaxis 
treatment as recommended in Section 5.3.2. For patients still with positive inhibitors after 12 
months ITI, continued trial participation will be evaluated by the investigator and sponsor based on 
the level of inhibitors, within the predefined specifications of withdrawal criteria 8, see Section 6.4. 
However, if the inhibitor persists after 24 months of ITI, the patient will be withdrawn from the 
trial. 
For patients who develop low titre and/or clinically insignificant inhibitors (< 5 BU), the dose level 
and dosing frequency of N8-GP will be decided by the Investigator based on clinical evaluation.  
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Table 5–1
Intravenous N8-GP treatment
Indication
Dosage
Frequency
Pre-prophylaxis
(pt. less than 24 months of age)
Approximately 60 U/Kg (50-75U/Kg) On-demand or slow start prophylaxis 
(less than weekly dosing)
Prophylaxis – main phase
Approximately 60 U/Kg (50-75U/Kg) Every 3rd day, twice weekly or every 
7th day(±1 day)
Prophylaxis – extension phase 
Approximately 60 U/Kg (50-75U/Kg) Every 3rd day, twice weekly, every 4th
day, every 5th day, every 6th day or 
every 7th day(±1 day)
Mild/moderate bleeding episode
20-60 U/Kg
On-demand (breakthrough bleeding 
episodes)
Severe bleeding episode
40-75 U/Kg
For treatment of severe/life-
threatening bleeding episodes 
administration of higher doses of N8-
GP is permitted at the investigator’s 
discretion
On-demand 
Minor surgery
40-75 U/Kg 
In accordance with local standard of 
practice of the participating trial site
Major surgery, only allowed after 50 
EDs
Recommended doses regimens will 
be provided when the N8-GP surgery 
trials completed 
On-demand
Low titre inhibitor
Recommendation 60 U/Kg (50-75 
U/Kg) for prevention and treatment 
of bleeding episodes
Dosing interval as needed
Maximum dose/day
200 U/Kg
Total maximum dose over 24 hours
5.3.7
Vaccinations
Vaccination are allowed before entering the trial but should preferably not take place until 3 months 
after the first N8-GP exposure, as vaccination activates the immune system of the patient, 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. 
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When discontinuing trial product the patient should be switched to a suitable marketed product at 
the discretion of the investigator.
It is expected that N8-GP will be granted marketing authorisation and is commercially available 
when the patients complete this trial. However, this cannot be guaranteed.
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 treatment8. The increased half-life of N8-GP will 
allow for prophylaxis with fewer injections than currently available products and will most likely 
result in improving compliance.
The dose level is based on PK data from the phase 1 PK trial (NN7088-3776) which showed that 
the t½ of N8-GP was prolonged by approximately 1.6-fold compared to the patient’s previous FVIII 
product. In the pivotal trial, pathfinder™2 (NN7088-3859), a fixed dose of 50 U/Kg bw is 
administered i.v. every fourth day. Due to an anticipated higher clearance of FVIII in children, 
compared with adults 14 a slightly higher and more frequent dose schedule has been chosen for this 
trial. With the longer plasma half-life of N8 GP it is expected that 2 administrations of N8-GP per 
week will provide the same prophylactic effect as 3 or 4 weekly injections with currently marketed 
FVIII products. 
Please refer to the IB and any updates here of for further pre-clinical and clinical data.5
The rationale for introducing the dose level of 60U/Kg is, primarily to explore and utilise the full 
potential of the molecule, by reducing the burden of treatment due to less frequent dosing. Please 
refer to the IB and any updates hereof for further non-clinical and clinical data.
The rationale behind the once weekly dosing is to enable slow start prophylaxis as often done in 
clinical practice. This every 7 day dosing may continue if considered sufficient.  
The reason for providing the possibility of ITI of patients who develops high-titre inhibitors is to 
permanently eradicate the inhibitor, thereby making it possible for the patient to be treated routinely 
with FVIII replacement therapy. Based on the available evidence patients should undergo ITI using 
the same type of product that the patient was using at the time of inhibitor development. This 
approach is supported by an international expert panel which concurred with treatment guidelines 
which recommend that ITI therapy should be conducted with the same concentrate as the one 
against which antibodies were developed. This should ensure successful tolerance induction and 
reduce the risk of further inhibitor development to new molecules. 
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 150
Number of patients planned to be started on trial product: 125
Number of patients expected to complete the trial: 100
6.2
Inclusion criteria
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial
2. Male, age < 6 years of age at the time of signing informed consent
3. Diagnosis of severe haemophilia A (FVIII activity level < 1%) based on medical records or 
central laboratory results
4. No prior use of purified clotting factor products (5 previous exposures to blood components is 
acceptable)
For an eligible patient, all inclusion criteria must be answered “yes”.
6.3
Exclusion criteria
1. Any history of FVIII inhibitor (defined by medical records)
2. Known or suspected hypersensitivity to trial product or related products
3. Previous participation in this trial. Participation is defined as first dose administered of trial 
product
4. Receipt of any investigational medicinal product within 30 days before screening
5. Congenital or acquired coagulation disorder other than haemophilia A
6. Any chronic disorder or severe disease which, in the opinion of the Investigator, might 
jeopardise patient’s safety or compliance with the protocol.
7. Patient’s parent(s)/LAR(s) mental incapacity, unwillingness to cooperate, or a language barrier 
precluding adequate understanding and cooperation  
For an eligible patient, all exclusion criteria must be answered “no”.
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.
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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. Anaphylactic reaction to the trial product, for definition see Section 11.1
3. Major surgery before 50 EDs, see Section 5.3.4
4. Significant thromboembolic event, see Section 11.1
5. Incapacity or unwillingness to follow trial procedures
6. Use of coagulations factors other than N8-GP or anti-coagulants unless in relation to ITI
7. ITI treatment has not been started within 6 months from the date of confirmation of positive 
FVIII inhibitor (BU ≥ 0.6/mL)
8. FVIII inhibitor titre decline from peak level is less than 20% after 12 months of ITI treatment
9. FVIII inhibitor is positive (BU ≥ 0.6/mL) after 24 months of ITI treatment.
10. After completed ITI treatment (maximum 24 months), prophylaxis treatment as described in the 
protocol is not resumed/started.
If a patient experiences treatment failure where haemostatic response is rated as none 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 may be used in the trial analyses if considered relevant by 
Novo Nordisk.
6.5
Patient replacement
Withdrawn patients may be replaced to ensure that 100 patients complete the trial with at least 100 
EDs. Assuming a drop-out rate of 20%, it is estimated that 125 patients must be started on N8-GP to 
obtain the 100 completed patients. This may, however, be adjusted during the trial based on the 
actual drop-out rate.
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 VIII 
products7 from the CHMP and in the paediatric investigational plan (PIP) in agreement with the 
Paediatric Committee (PDCO).
Children are among those who benefit significantly from prophylaxis. Less frequent injections with 
N8-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.
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Version:
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Status:
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6.6.1
Rationale for inclusion criteria
Criterion no. 1 is included in accordance with International Conference on 
Harmonisation/Good Clinical Practice (ICH-GCP).1,2
Criterion no. 2 is included due to Novo Nordisk has decided to use an age cut-off of 6 
years.
Criteria no. 3, 4 are included to select the patient group based on the CHMP guideline7.
6.6.2
Rationale for exclusion criteria
Criterion no.1 is included to exclude patients with FVIII inhibitors since inhibitor 
development is the primary safety endpoint of the trial.
Criteria 2 and 6 are to prevent unnecessary exposure of potentially fragile patient to a 
new compound.
Criterion no. 3 is included to ensure that a patient only counts once in the data analyses 
and to ensure the patient is a PUP.
Criterion no. 4 is included to minimise any effect of external compounds on the 
patient's coagulation and immune system.
Criterion no. 5 is chosen to exclude patients with endogenous abnormalities of the 
coagulation system, other than haemophilia A.
Criterion no 7 is included to ensure enrolment of patients likely to be compliant with 
the protocol, and to preclude enrolment of particularly vulnerable patients.
6.6.3
Rationale for withdrawal criteria
Criteria nos. 1-6 are included to protect the patient's safety and reliability of the data.
Criteria nos. 7-10 are included to ensure appropriate treatment of inhibitor patients.
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Date:
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Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
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7
Milestones
Planned duration of recruitment period (FPFV – LPFV): approximately 42 months 
Planned FPFV: 01-May-2014
Planned LPFV: 02 -Apr-2018
End of trial is defined as LPLV: 13-May-2019
The duration of the trial for each individual country will vary. However, the end of trial will be no 
later than 13 May 2019.
The end of the clinical trial is defined as last visit of the last patient.
Planned completion of clinical trial report (CTR): November 2019.
The duration of N8-GP treatment in the trial is a minimum total 100EDs for a particular patient. 
Once a patient has achieved 100EDs, they may be offered the option to continue in the trial until 
either N8-GP is commercially available in the relevant country or until the marketing authorisation 
application for N8-GP is rejected in the relevant country unless the N8-GP trial, part of the trial or a 
trial site is terminated by Novo Nordisk or a relevant authority for any reason. In any event, the 
LPLV for the trial will be no later than 30 June 2018 whether or not the product is commercially 
available in the relevant country. 
The following exceptions will be made:

Patients with inhibitor will be allowed to receive ITI treatment for up to 24 months.
Recruitment
The screening rate will be followed closely via the interactive voice/web response system 
(IV/WRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further consent will be sought from 
additional families and the IV/WRS, will be closed for further screening, unless additional 
screening is needed due to patient replacement. 
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)15, the Food and Drug Administration Amendment Act 
(FDAAA)16, European Commission Regulation for EudraCT17 and other relevant recommendations 
or regulations. If a patient requests to be included in the trial via the Novo Nordisk e-mail contact at 
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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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Version:
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Status:
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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
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 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 giving 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.
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. 
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Version:
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Status:
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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 for obtaining genotyping must be collected, if applicable.
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 eCRF. Follow-up of 
SAEs must be carried out according to Section 11.3. A screening failure session must be made in 
the IV/WRS. The case book must be signed.
Re-screening is not allowed after the first dose of trial product – see exclusion criterion no. 3 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. 
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 IV/IWRS
and case book must be signed in the eCRF. 
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 should make a reasonable effort to ascertain the reason(s), 
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

Protocol violation

Lack of efficacy

Lost to follow up
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
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. 
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.
If clarification of entries or discrepancies in the eDiary is needed, the patient’s parent(s)/LAR(s)
must be questioned and a conclusion made 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. 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 N8-GP 
is required. 
The screening visit (V0) can be combined with the first treatment of N8-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 N8-GP at the same day. 
If the screenings results do not become available during the screening visit, and if the next visit is 
not planned, the patient and parent(s)/LAR(s) must be informed when eligibility has been evaluated 
by investigator.
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Version:
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Status:
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Assessments for V0 are listed in Table 2–1.
Reminders

Dispense trial card, see Section 8.8.1

A Screening call in the IV/WRS, 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 ± 1week, see Sections 8.8.4 and
8.1.9.

During the screening period the patient cannot be treated with commercially available FVIII
products
8.1.1.1
Pre-prophylaxis treatment
Pre-prophylaxis is optional and is the period before start of regular prophylaxis.
During pre-prophylaxis the following dosing regimen applies: 

approximately 60 U/Kg N8-GP within the range of 50-75 U/Kg bw, see Section 5.3

individualised prophylactic dosing intervals but less frequent than every 7th day(once weekly)

on-demand treatment of bleeding episodes
See further Section 5.3.1.
Dosing visits during the pre-prophylaxis period can be performed at any time until ED 20 being 
either part of visits in Table 2–1 or being registered as an unscheduled visit if the dose is not part of 
Table 2-1. Visits during the pre-prophylaxis period without dosing should be performed as 
unscheduled visits, see Section 8.1.9. 
The site must make sure that the patient’s parent(s)/LAR(s) are contacted at least at least every 12 
weeks ± 1week if no planned visits, Section 8.8.4. 
Visits 1-6 are when the patient needs treatment of a bleeding episode and/or planned individually 
per patient at the investigator and patient’s parent(s)/LAR(s) discretion.
8.1.1.2
Prophylaxis treatment
A patient may change from pre-prophylaxis to prophylaxis at any time during the pre-prophylaxis 
period or must be initiated when the patient has reached 20 EDs, or has turned 24 months of age, 
whatever comes first. 
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Version:
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Status:
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The dosing frequency during main phase is individualised within the following interval: twice 
weekly, every 3rd day or every 7th day. Changes to the regimen should be recorded in the IV/WRS. 
If changes occur between visits, it should be recorded in an unscheduled visit, see Section 8.1.9.
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. 
8.1.1.3
Wash-out prior to visits
A washout period is required prior to visits including inhibitor testing. The required wash-out 
period is at least 72 hours.
In case the wash-out period has not been fulfilled the scheduled visit should be re-scheduled unless 
the visit is due to a bleeding episode treated at site during the pre-prophylaxis period or prior to 
initiating home treatment.
8.1.2
Visit 1 – first dosing with N8-GP
V1 will take place after the screening visit (V0) whenever the first treatment of N8-GP is 
administered, if not already combined with V0.
In case of subjective signs of illness and/or fever within 48 hours prior to the first injection of N8-
GP the dose should be postponed, if possible.
The patient will continue treatment on either:

Pre-prophylaxis treatment. See Sections 5.3.1 and 8.1.1.1.

Prophylaxis treatment. See Sections 5.3.1 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.
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 month 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 8.1.9
Drug accountability of trial product at V1 must be recorded in the IV/WRS, see Section 10
Recording of body weight, see Section 8.3.1, and dispensing of N8-GP for trial site dosing via 
IV/WRS, see Section 10.
8.1.3
Visit 2, 3, 4-6 – main phase
The 2 first N8-GP injections must take place at trial site (V1+V2). Hereafter the injections can be 
administered at the trial site or outside the trial site.
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If the treatment is given at site the doses should be registered in the eCRF. If not given at site, the 
dose should be registered in the eDiary. 
Visits at ED: 2, 5 ± 1 ED, 10 ± 2 EDs, 15 ± 2 EDs, 20 ± 2 EDs. 
The visits should be scheduled taking into account the patient’s regular dosing day(s) in the week.
Assessments for V2-V6 are listed in Table 2–1.
Reminders
In case next visit is not planned or performed within 3 month 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 8.1.9
All visits must be planned to allow for the required wash-out of 72 hours, see Section 8.8.3.1
Recording of body weight, see Section 8.3.1, and dispensing of N8-GP for trial site dosing and 
home treatment from visit 2 must be performed via IV/WRS, see Section 10
Drug accountability of trial product must be recorded in the IV/WRS, see Section 10
Investigator must ensure that patient’s parent(s)/LAR(s) return any trial medication that would 
expire during the next home treatment period
eDiary dispensing at V2 or when treatment outside trial site is initiated, see Section 8.8.3.1
eDiary training, see Section 8.8.3
8.1.4
Visit 7-8 – main phase
From V6 all patients (including patients previously on pre-prophylaxis) will be on prophylaxis 
treatment with N8-GP on twice weekly, every 3rd day or every 7th day. Between the visits the 
patient will receive N8-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 visit should be scheduled taking into account the patient’s dosing day.
Assessments for V7-V8 are listed in Table 2–1.
Reminders 
An appointment for the next visit should be made
All visits must be planned to allow for the required wash-out of 72 hours, see Section 8.8.3.1
Recording of body weight, see Section 8.3.1, and dispensing of N8-GP for trial site dosing/home 
treatment must be performed via IV/WRS, see Section 10
Drug accountability of trial product must be recorded in the IV/WRS, see Section 10
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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
eDiary compliance review, see Section 12.3.
8.1.5
Visit 9 – end of main phase
Visit 9 should take place at either ED 50, ED 51 or ED 52.
Assessments for V9 are listed in Table 2–1.
Reminders 
An appointment for the next visit should be made
Next visits must be planned to allow for the required wash-out of 72 hours, see Section 8.8.3.1
Recording of body weight, see Section 8.3.1, and dispensing of N8-GP for trial site dosing/home
treatment must be performed via IV/WRS, see Section 10
Drug accountability of trial product must be recorded in the IV/WRS, see Section 10
Home treatment, 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 10-13 – extension phase
The patient will continue prophylaxis throughout the extension phase, with 60 U/Kg in the regimen 
of every 3rd day, twice weekly, every 4th day, every 5th day, every 6th day or every 7th day. See Table 
5–1. Changes to the regimen should be recorded in the eCRF. If changes occur between visits, it 
should be recorded in an unscheduled visit, see Section 8.1.9.
Visit 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 between 6 months and 1 year depending on the dosing 
frequency, for a patient to achieve a total of 100 EDs.
Assessments for V10-V13 are listed in Table 2–1.
Reminders
An appointment for the next visit should be made
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Next visits must be planned to allow for the required wash-out of 72 hours, see Section 8.8.3.1
Recording of body weight, see Section 8.3.1, and dispensing of N8-GP for trial site dosing/home 
treatment must be performed via IV/WRS, see Section 10
Drug accountability of trial product must be recorded in the IV/WRS, see Section 10
Home treatment, see Sections 8.1.12 and 8.8.2.
eDiary training, see Section 8.8.3
eDiary compliance review, see Section 12.3
8.1.7
Visit 14 - end of extension phase
Visit 14 should take place at either ED 100, ED 101 or at ED 102.
Assessments for V14 are listed in Table 2–1.
Reminders 
An appointment for the next visit should be made
Next visit must be planned to allow for the required wash-out of 72 hours, see Section 8.8.3.1
Recording of body weight, see Section 8.3.1, and dispensing of N8-GP for trial site dosing/home 
treatment must be performed via IV/WRS, see Section 10
Drug accountability of trial product must be recorded in the IV/WRS, see Section 10
eDiary compliance review, see Section 12.3
8.1.8
Visit 15-X until end of trial
If N8-GP is not commercially available in a patient’s country at the time of visit 14, the trial period 
may be extended with visits that are scheduled 24 weeks ± 4 weeks. These additional visits are 
referred to as visit 15 to visit X, where X can be any visit from 16 and onwards. This option for the 
patient to continue in the extension phase of the trial may be offered until either N8-GP becomes 
commercially available in the relevant country, or until the marketing authorisation application is 
rejected in the relevant country unless the N8-GP trial, part of the trial or a trial site is terminated by 
Novo Nordisk or a relevant authority for any reason, the End of Trial visit must be scheduled within 
1 month provided always that the Last Patient Last Visit for the prophylaxis period until end of trial
will be no later than 13 May 2019 whether or not the product is commercially available in the 
relevant country at this time. 
At every dosing visit from V15-VX, drug will be dispensed to cover up to 3 months of treatment. 
Depending on patient’s treatment regimen, additional dispensing visits might need to be scheduled 
to cover treatment in the period between visits.
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Assessments for V15-VX are listed in Table 2–1.
8.1.9 
End of trial visit
The EOT visit can take place at any time after completion of 100EDs or if the patient is withdrawn 
from the trial.
Assessments for the EOT are listed in Table 2–1
Reminders 
Drug accountability of trial product must be recorded in the IV/WRS, 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
Bleeding episodes
Dosing of N8-GP
Surgery
PK session
Change of regimen
8.1.11 
ITI Visit
N8-GP treatment may continue in case of low titre FVIII inhibitor (≤5BU) confirmed by central 
laboratory, that does not result in clinically ineffective treatment with N8-GP. Patients may follow 
the visit flow either as described in Table 2–1, or visits at the discretion of the investigator.
In case of high titre FVIII inhibitor (>5BU) confirmed by central laboratory the investigator must 
decide how to proceed with treatment. Novo Nordisk will communicate when ITI is allowed in this 
trial, see Section 5.3.6.
If ITI is initiated, the patient will follow a visit schedule prescribed by the investigator and 
according to local standard of practice. Monthly visits are recommended, and the below listed 
assessments are recommended to be performed:
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Adverse Events
Concomitant medication
Sampling for inhibitor test
Sampling for FVIII activity test
Bleeding episode evaluation
Review of eDiary
Body measurements, see Section 8.3.1
Treatment of bleeding episodes with bypassing agents is allowed at the discretion of the investigator 
according to local practice, see Section 11.2. 
Reminder
Follow up on any AEs according to Section 11.2
For patients returning to regular prophylaxis N8-GP treatment, the visit schedule is taken up from 
V9 end of main phase Table 2–1, even when the corresponding total ED does not match.
8.1.12
Home treatment
Home treatment with N8-GP can commence any time after the first 2 EDs and the patient’s 
parent(s)/LAR(s) are comfortable with the reconstitution and administration process, see Section 
5.3.
8.1.12.1
Prophylactic home treatment
After 2 doses home treatment can be initiated with prophylaxis doses of approximately 60 U/Kg 
(50-75U/Kg). The regimen should follow Table 5–1, and adjusted as needed during the trial.
Bleeding episodes must be treated as described in Section 8.6.
The following procedures must be performed during home treatment between visits:
N8-GP administrations according to regimen prescribed by investigator.
Contact to the investigator/medically qualified person in case of severe bleeding episodes
Completion of the patient eDiary, including details of all bleeding episodes and N8-GP
administrations (see Section 8.6)
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.
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The following procedures must be performed
N8-GP administration for treatment of treatment requiring bleeding episodes, see Section 8.6
Completion of the patient eDiary, including details of all bleeding episodes and N8-GP 
administrations (see Section 8.6).
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). All 
concomitant illnesses should be reported including 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 birth 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
All available information on haemophilia, prior to screening should be recorded including 
diagnostic FVIII activity level, if known. If possible, information about relatives with haemophilia 
A and inhibitors should be obtained. 
8.2.1.2
Allergies
Any allergies, including any drug sensitivities should be recorded. 
8.2.2
Concomitant medication
A concomitant medication is any medication including vaccination, other than the investigational 
medicinal product (N8-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.
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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 inhibitor patients
Bleeding episodes in inhibitor patients that do not respond sufficiently to N8-GP treatment may be 
treated with by-passing agents according to local practice.
8.2.4
Prohibited medication
Treatment with other FVIII 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 cannulae is allowed.
8.2.5
Demography
Demographic data will be collected as allowed per local law:
Date of birth, year or age
Ethnicity 
Race
8.3
Clinical assessments 
Clinical assessments should preferably be performed prior to blood sampling and prior to 
administration of N8-GP unless it is stated otherwise.
8.3.1
Body measurements

Height at screening

Body weight, wearing light clothing only (Kg)
Body weight should be measured in connection with regularly visit where trial drug is dispensed.
For practical purposes when dispensing trial drug the weight from an earlier measurement (or visit) 
can be used if the measurement was performed within the previous 10 weeks (in children <3 years 
of age, within 6 weeks). 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 examination
The physical examinations will be performed according to local procedure and should include:
General appearance
Head, ears, eyes, nose, throat and neck
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Lymph node palpation
Abdomen
Skin
Respiratory system
Musculoskeletal system
Central and peripheral nervous systems
8.3.3
Vital signs
When dosing at the trial site (V1), vital signs should be recorded pre-dose and post-dosing of N8-
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 must not be taken from the same vein as used 
for administration of N8-GP.
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. 
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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.
8.4.1
Local laboratory assessments 
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
FVIII activity
FVIII activity will be analysed at the predefined time point as at a central laboratory selected by 
Novo Nordisk but the investigator can at any time during the trial assess FVIII activity at his/her 
discretion. 
If V0 and V1 are combined, as one combined screening visit, and if FVIII activity <1% has not 
been documented in the patient medical records, it should be analysed locally and documented in 
the patient medical records. In this case the local laboratory should use their standard FVIII activity 
assay with the assay calibrator routinely used for FVIII activity analysis.
A N8-GP reference standard must be used as assay calibrator in the FVIII activity assay after the 
patient has been dosed with N8-GP. The reference standard will be provided by Novo Nordisk 
together with a description of how to the reference standard should be handled, stored and used.
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 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
FVIII activity 
The analysis of plasma FVIII activity will be performed at a laboratory selected by Novo Nordisk or 
at a Novo Nordisk laboratory. The procedures for analyses will follow the recommendations 
provided by Novo Nordisk. A description of the method will be included in the final report of this 
trial.
FVIII activity should be measured according to Table 2–1.
FVIII activity will be measured by the use of two different assays developed and validated for N8-
GP: 

FVIII chromogenic assay

FVIII one-stage clotting assay
In each assay both an N8-GP reference standard and a human plasma standard calibrated against the 
WHO international FVIII standard are used as assay calibrators. 
FVIII chromogenic assay
The FVIII chromogenic assay measures the activity of the compound with a two-stage method. The 
FVIII activity is determined by measuring the FVIIIa/FIXa-mediated activation of coagulation 
factor X (FX) activation (first stage) and the subsequent cleavage of a chromogenic activated 
coagulation factor X (FXa) substrate (second stage).
The FVIII one-stage clotting assay
The FVIII one stage 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 or at a Novo Nordisk 
laboratory. The procedures for analyses will follow the recommendations provided by Novo 
Nordisk. A description of the method will be included in the final report of this trial.
Plasma samples will be collected for assessment of:

N8-GP/FVIII binding antibodies 
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
PEG antibodies

FVIII inhibitor 
Antibody assessment should be measured according to Table 2–1.
N8-GP/FVIII binding antibodies
Screening for antibodies is based on assays that are validated according to international recognised 
guidelines.18-20 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 N8-GP, rFVIII and 
PEG. Isotyping of the anti-drug antibodies will possibly also be performed. 
If a patient develops N8-GP binding antibodies and the recovery value at that visit is less than 60% 
of recovery values after the first N8-GP administrations and FVIII level at time of inhibitor 
sampling (pre-dose) is more than 0.020 U/mL, Novo Nordisk will ask the Investigator to call the 
patient for an unscheduled visit for collection of a new sample for assessment of inhibitors and 
binding antibodies which should will be taken after a 7 days wash out period. 
A patient that tests negative for inhibitors following a 7 days wash out will confirm a negative 
inhibitor test and the patient will continue in the trial. 
This algorithm will not apply for those who enter the trial with positive test for N8-GP binding 
antibodies and will not be triggered more than twice for an individual patient, unless increases in 
antibody levels are observed. Furthermore, a 7 days wash out period will only be applied if the 72 
hours wash out is not sufficient to avoid drug interference in the inhibitor assay.
Samples will be analysed regularly for N8-GP binding antibodies, results will be reported to 
investigators at the end of trial and will be included in the CTR.
PEG antibodies
Screening for PEG antibodies is based on assays that are validated according to international 
recognised guidelines.18-20 Samples measured above the assay cut-point will be subject to a 
confirmation test.
Samples will be analysed for PEG binding antibodies at the end of trial.  
FVIII inhibitors
Assessment for FVIII inhibitors will be carried out using a heat modified Nijmegen FVIII Bethesda 
assay analysed at the central laboratory. The assay is validated according to international recognised 
guidelines.18, 21 The assay is based on measurement of the FVIII activity (inhibitory activity) in 
plasma samples mixed with a fixed amount of normal plasma pool in buffer. Inhibitors will be 
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considered: 0.6 BU ≤ low titre inhibitor ≤ 5 BU, high titre inhibitors are defined as > 5 BU.
Inhibitors will be recognised by comparison to a clinical cut-point of ≥0.6 BU. 
If FVIII 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 the central laboratory 
for inhibitor analysis.
Any sampling for the inhibitor test must be performed at least 4 days after last administration of 
N8-GP to allow for wash-out of the drug.
If the result of the inhibitor test is positive, a second confirmatory inhibitor test should be performed 
by the central laboratory. The confirmatory samples should be collected as soon as possible, but no 
sooner than 4 days after the last dose of N8-GP. Assessments of FVIII activity (recovery) and 
binding antibodies must be performed. If considered relevant a lupus anticoagulant test can be 
performed. 
A positive confirmed inhibitor is considered to have disappeared if the inhibitor titre is < 0.6 BU on 
2 consecutive inhibitor tests (performed with 1 month intervals) and the FVIII recovery is ≥66% of 
expected values. A patient with repeated positive test result will count only once in the 
determination of the inhibitor incidence rate.
If an investigator decides to perform inhibitor testing locally, he/she must send a duplicate sample 
for inhibitor testing at the 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). 
PK assessment (optional)
In the event of a concern about reduced treatment efficacy in a patient with or without confirmed 
positive test for binding antibodies towards N8-GP/ or inhibitors an unscheduled visit can be 
scheduled where a PK session may be performed with a dose of 60 U/Kg to investigate the 
elimination (recovery, clearance and half-life) of N8-GP. The PK data may potentially be used to 
adjust the dose or dosing regimen. 
The following time-points for blood sampling for the PK profile are suggested: pre-dose, 30 
minutes (± 10 min), 1h (± 10 min), 24h (± 8 hours), 48h (± 8 hours), and 96h (± 8 hours).
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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 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 viral load <400,000 
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 1 and 2 antibodies

CD4+ lymphocyte count

HIV viral load
HIV and CD4+ assessments should be measured according to Table 2–1.
8.4.2.4
Haematology
Haemoglobin (mmol/L)
Haematocrit (%)
Leucocytes (x109/L)
Thrombocytes (x109/L)
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 older, a new sample must be 
drawn and assessed at the central laboratory.
Haematology should be measured according to Table 2–1.
8.4.2.5
Biochemistry

Creatinine (µmol/L)

Alanine aminotransferase (ALT) (IU/L)

C-reactive protein (CRP) (mg/L)
If test results for the above mentioned biochemistry parameters are available from within one month 
prior to V0, they can be used for the V0 biochemistry assessment, if older, a new sample must be 
drawn and assessed at the central laboratory.
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Biochemistry should be measured according to Table 2–1.
8.4.2.6
F8 and HLA genotype testing 
At Visit 0, all patient’s parent(s)/LAR(s) will be asked about documentation of previous Factor VIII 
gene (F8) and Human Leucocyte Antigen (HLA) genotype tests. If not available or if it needs to be 
re-tested, based on the investigators discretion, F8 and HLA genotype testing will be offered if 
allowed according to local law. The F8 and HLA genotype analysis will be performed at a 
laboratory selected by Novo Nordisk, using DNA isolated from leucocytes from the patient’s blood. 
No analysis will be performed concerning other genes than F8 and HLA. Samples will be disposed 
appropriately after the test and all test results are kept confidential.
Investigator and/or patient’s parent(s)/LAR(s) have the right to refuse to provide patient’s F8 and 
HLA genotype documentation or to refuse genotyping. This will not prevent the patient from
participating in the trial.
F8 and HLA genotype can be measured any time from visit 0 to visit 8. 
F8 and HLA genotype can be measured according to Table 2–1.
Applicable for Japan only: If documentation of the patient´s genotype already exists, the patient is 
offered to provide his data for the trial. If no previous data exists and genotyping consent is 
obtained, FVIII and HLA genotype analysis is performed at the laboratory in Bonn, Germany, using 
DNA isolated from leucocytes from the patient’s blood. No analysis will be performed concerning 
other genes than F8 and HLA. Samples will be disposed appropriately after the test and all test 
results are kept confidential.
Applicable for Israel only: No genotype testing or genotype information will be collected.
8.4.2.7
Allergic reaction testing 
Allergic reaction testing will only be performed in patients developing severe allergic reactions 
related to N8-GP treatment as judged by the Investigator. The baseline sample will be analysed for 
assessment of the allergic reaction.
If a severe allergic reaction related to treatment occurs, blood samples should be taken at an 
unscheduled visit as soon as convenient, and not later than 2 months after the event. The allergic 
reaction assessments will be performed at a laboratory selected by Novo Nordisk or at a Novo 
Nordisk laboratory.
Test to be performed:
N8-GP IgE antibodies
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FVIII IgE antibodies
FVIII inhibitors
N8-GP/rFVIII binding antibodies
Optional tests at the discretion of the investigator:
HCP IgE antibodies
Murine IgG antibodies
If relevant, baseline levels for optional test can be set using samples from other patients enrolled in 
the trial.
Patients developing severe allergic reaction should be carefully investigated and followed up for 
inhibitor development. 
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)22. 
The total volume of blood to be collected for each patient per visit will not exceed 10 mL. 
Detailed instructions will be provided to the trial sites regarding blood sampling volumes and 
prioritisation of the 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 record.
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. 
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 biospecimens, see Section 23.2.
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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).
8.5
N8-GP administration
N8-GP will be administered while the patient is in a comfortable position according to Table 5–1. 
During ED 1-2 with treatment at the trial site (V1 -V2):
The first 2 N8-GP doses should be administered at trial site by, or under direct supervision of an 
attending physician.
Trial injection kits (butterflies etc) will be provided by Novo Nordisk. Choice of butterfly or 
cannula for N8-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. 
During ED 3-100 with treatment at trial site and at home (after V2):
Home treatment with administration of N8-GP can start after 2 EDs if the patient or the patient’s 
parent(s)/LAR(s) are comfortable with the reconstitution and administration process. If not the drug 
administration can take place at site.
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 (approximately 2 min for an 
injection). 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 regimen.
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 the same day should be omitted. The dose for the treatment of bleeding episode on a 
prophylaxis day should be approximately 60 U/Kg, and then the prophylaxis dose should not be 
taken.
When a prophylaxis dose has been taken and a bleeding episode occurs later the same day, the 
bleeding episode should be treated and registered independently of the prophylaxis dose. 
8.6
Bleeding episodes
All bleeding episodes and treatments with N8-GP must be recorded in the eCRF by the investigator 
or in the eDiary by the patient’s parent(s)/LAR(s). 
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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 V2 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 in case of a severe bleeding episode.
In case of treatment requiring bleeding episode outside the trial site opening hours prior to 2 EDs 
the patient must be treated according to local procedures.
Bleeding Episode – information to be collected
Information about bleeding episodes prior to the 2 ED (V2) 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 2 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.
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, and time of each dose of N8-GP
Haemostatic response assessed by the 4-point scale defined in Table 8–1
Table 8–1
4-point scale
Classification
Description
Excellent
Abrupt pain relief and/or clear improvement in objective signs of bleeding 
within approximately 8 hours after a single injection
Good
Definite pain relief and/or improvement in signs of bleeding within 
approximately 8 hours after a single injection, but possibly requiring more than 
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Classification
Description
one injection for complete resolution
Moderate
Probable or slight beneficial effect within approximately 8 hours after the first 
injection, but usually requiring more than one injection
None
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 bleed within 72 hours after stopping of a previous bleed 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
Preventive N8-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 40-75 U/Kg N8-GP prior to minor surgery is recommended to prevent 
perioperative bleeding episodes, see Table 5–1. Major surgeries are only allowed after 50 EDs and 
when the result from the pathfinder™3 (NN7088-3860) is available, see Section 5.3.4. 
Preventive N8-GP treatment prior to surgery should be captured in eCRF or in the eDiary.
8.7.1
Minor surgery
Definition of minor surgery, see Section 5.3.4.
For minor surgery the following should be recorded:

Date, time and volume of preventive dose before surgery

Type of surgery

Indication for surgery

Date of surgery

Start time of surgery
8.7.2
Major surgery
Definition of major surgery, see Section 5.3.4.
FVIII inhibitor sample should be taken prior to surgery and analysed at the central laboratory.
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For major surgery the following should be recorded in the eCRF:

Date, time and volume of preventive dose before surgery

Type of surgery

Indication for surgery

Date of surgery

Start and stop time of surgery

Clinical evaluation of haemostatic response, see Table 8–1

Clinical narrative of the procedure
Injections with N8-GP administered after surgery has been completed should be reported either in 
the eCRF (injections administered at site) or in the eDiary (injections administered at home), see
Section 12.3
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 N8-GP can start after administrations of the first 
dose at the trial site (see Section 8.1.12 ), and should continue until the patient’s parent(s)/LAR(s)
are comfortable with the reconstitution and administration process.
A home treatment guide for the reconstitution and administration process will be available as hands-
out for the patient’s parent(s)/LAR(s). 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. This includes knowledge of which medical facility to 
contact in this situation. 
If the patient does not follow the planned dosing schedule, the investigator must retrain the patient’s 
parent(s)/LAR(s). 
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8.8.3
Electronic diary (eDiary)
Pre-prophylaxis treatment, prophylaxis treatment and bleeding episodes should be recorded in the 
eCRF for the first 2 EDs. When the first 2 EDs have been administered, the data will be captured
either in eCRF 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) must ensure that all pre-
prophylaxis and 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) at V2.
For details regarding patient’s eDiary, 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 contact 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 to all AEs, and 
any medical treatment (including treatment of bleeding episodes) since the last contact. The 
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?” and “has your child had any 
medical problems since the last contact?”, and “have you remembered to enter all treatment in the 
eDiary?”.
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The expiry date of the drug that the patient has received should be checked by the site staff before 
the patient’s next visit to determine if an extra dispensing is relevant and to inform the patient of 
which unused vials to return to the site.
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
N8-GP administration compliance
8.8.5
Interactive voice/web response system
Please refer to Section 10 regarding the IV/WRS. 
For details on how to use the IV/WRS, please refer to the trial specific IV/WRS user documents 
provided to the trial site. 
8.9
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 products as described. 
Assessment of patient compliance with protocol procedures for determination of continuation of the 
trial will be done by the investigator’s discretion. 
Failure to comply with scheduled visits and N8-GP administration may result in withdrawal in 
accordance with the protocol withdrawal criteria, see Section 6.4.
Treatment with FVIII concentrates, other than N8-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 agents, see Section 8.2.3.
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Compliance with N8-GP treatment must be addressed at each visit. Compliance check includes a 
cross check between number of injections recorded in eDiary, expected number of doses 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 product, e.g. needles and syringes.
9.1
Trial product
The following trial product will be provided by Novo Nordisk, Denmark:
Table 9–1
Trial Product
Trial product
Strength
Dosage form
Route of 
administration
N8-GP (turoctocog 
alfa pegol)

500 U/vial,
53µg/vial

2000 U/vial,
211µg/vial
Freeze-dried Powder 
for solution for 
injection
i.v. injection
N8-GP is supplied as a sterile freeze-dried powder for solution for injection in single use vials with 
a nominal content of 2000 U/vial or 500 U/vial to be reconstituted with 4.3 mL 0.9% Sodium 
Chloride Solution. After reconstitution each vial contains 500 U/mL or 125 U/mL N8-GP, 
respectively. The reconstituted solution is colourless and clear to almost-clear with a pH of 6.9. The 
reconstituted solution must not be diluted further. Trial product must not be used if it does not 
appear colourless and clear to almost-clear.
After reconstitution the appropriate volume of the vials will be drawn into a syringe. The content of 
several vials may be combined in one syringe. N8-GP may not be added to or mixed with any other 
material.
Administration of the appropriate volume of N8-GP will be given as i.v. bolus injection over 
approximately 2 minutes (from start to completion of injection).
The investigator must explain to the patient’s parent(s)/LAR(s) the injection process of N8-GP at 
home. 
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Status:
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The maximum dose to be administered to a patient within 24 hours is 200 U/Kg, with a maximum 
individual dose of 75 U/Kg. These doses are only relevant in case of trauma, severe bleedings or 
surgery.
Novo Nordisk will not supply any Non Investigational Medical Products (NIMPs).
9.2
Packing, labelling and dispensing
Labelling of the trial product will be in accordance with Annex 1323, local regulations and trial 
requirements. Novo Nordisk A/S will be responsible for labelling and packaging of the trial 
product. Third party vendors may be employed.
N8-GP and Sodium Chloride will be provided in boxes. The boxes will be provided with labels 
containing the following information: product name, expiry date, storage conditions. Each trial 
product 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.
The IV/WRS 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.
9.3
Storage
Table 9–2
Storage
Storage must be done 
according to the table below
Storage conditions(not-in-
use)
In-use conditions
N8-GP (turoctocog alfa pegol)

2-8˚C 

Protect from light

4 hours below 30˚C 

Do not freeze

Avoid direct sunlight
0.9 % Sodium Chloride 
Solution

2-30°C

Protect from light 
N/A
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The trial product N8-GP powder and Sodium Chloride Solution must be stored in a secure place at
trial site. For N8-GP under refrigeration at 2-8°C, and for Sodium Chloride Solvent at 2-30°C, both 
protected against light and are hereby stable until the expiry date given. It is recommended to use 
the reconstituted N8-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.
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, and record and evaluate 
the temperature. The investigator must inform Novo Nordisk immediately if any trial product has 
been stored outside specified conditions (e.g. outside temperature range).
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.
9.4
Drug accountability and destruction
Drug accountability is the responsibility of the investigator. The investigator or delegated person, 
eg, a trial nurse will perform drug accountability in the IV/WRS 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 IV/WRS Drug Accountability Module. 
Drug accountability is not required for Sodium Chloride Solution used for reconstitutions.
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(s).
All trial drug product 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 product.
Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of product must be documented.
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For Japan only: Responsibility for storage and drug accountability of the trial drug product 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 product 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 product in accordance with procedures specified by Novo Nordisk. 
The head of the trial site or the trial product storage manager must ensure the availability of proper 
storage conditions, and record and evaluate the temperature.
9.5
Auxiliary supply
Auxiliary supplies are equipment such as needles, syringes, butterflies, sterile swabs, vial adaptor 
etc. These will be provided by Novo Nordisk.
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10 Interactive voice/web response system (IV/WRS)
A trial specific IV/WRS will be set-up, and can be accessed at any time via internet or via 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons.
IV/WRS is used for:

Screening

Screening failure

Medication arrival

Dispensing

Withdrawal

Completion

Drug accountability

Data change
IV/WRS call can be done the day before the actual visit.
IV/WRS user guides 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, ie 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 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(s):
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
Probable - Good reason and sufficient documentation to assume a causal relationship.

Possible - A causal relationship is conceivable and cannot be dismissed.

Unlikely - The event is most likely related to aetiology other than the trial product.

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 parent(s)/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 
inhibitory antibodies must always be considered an SAE.

FVIII inhibitory antibodies (confirmed by two consecutive tests see Section 8.4.2.2) must 
always be considered a SAE
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a. The term "life threatening" in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
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 

Administration of an overdose with the intention to cause harm (eg suicide attempt)

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
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2.
Inhibitor formation against FVIII. Blood samples for measurement of FVIII inhibitors will be 
analysed at a central laboratory selected by Novo Nordisk. 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 
infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events 
and peripheral artery occlusion, see definitions below)
4.
Anaphylactic reaction as defined by Sampson et al 200624 (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 et al 200624
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:
o
Ischaemic symptoms
o
Subsequent development of pathologic Q waves on the ECG
o
ECG changes indicative of ischaemia (ST segment elevation or depression)
o
Coronary artery intervention (eg angioplasty)
2. Pathologic findings of an acute myocardial infarction (i.e., pathologic findings of an acute 
myocardial infarction will be defined when criteria a and b below are fulfilled):
o
Increase in troponin T above the "diagnostic" limit: i.e. > 0.03 µg/L
o
Patients with:

ST-segment elevation: New ST-segment elevation at the J point in two or more 
contiguous leads with the cut-off points >= 0.2mV in leads V1, V2 or V3 and 0,1 
mV in other leads (contiguity in the frontal plane is defined by the lead sequence 
aVL, I inverted aVR, II, aVF, III)

No ST-segment elevation: ST-segment depression and or T-wave inversion in two or 
more contiguous leads >= 0.1 mV
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Definition of pulmonary embolism:
Obstruction of a pulmonary artery or one of its branches, most frequently by detached fragments of 
thrombus from a leg or pelvic vein, diagnosed by at least one of the following:

Positive findings in ventilation/perfusion scan

Positive findings in a spiral(helical) computed tomography or angiography

Positive findings in a magnetic resonance imaging

Positive findings in a pulmonary angiography
Definition of cerebral thrombosis/infarction:
Acute neurological injury that persists for at least 24 hours and occurs as a result of either a 
thrombosis or embolic process, diagnosed by at least one of the following:

Computerised tomography

Magnetic resonance scan

Magnetic resonance angiogram

Cerebral angiography
Deep vein thrombosis: 
Venous thrombosis demonstrated by compression ultrasound, duplex ultrasound, or colour Doppler 
imaging.
Definition of other clinically significant thromboembolic events:
Sign or suspicion of clinically significant thromboembolic event, eg:

visceral arterial embolus/thrombus, 

extremity arterial embolus/thrombus or 

portal venous thrombosis.
Superficial thrombophlebitis is not considered a clinically significant thromboembolic event unless 
evaluated so by the investigator.
Peripheral artery occlusion: 
Clinical signs of acute arterial occlusion verified by either ankle-brachial index test, Doppler or 
ultrasound (Duplex) imaging, computed tomographic angiography, magnetic resonance 
angiography, or conventional angiography.
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Clinical criteria for diagnosing anaphylaxis (Sampson et al. 200624): 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 (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT LEAST 
ONE OF THE FOLLOWING 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b.
Reduced BP or associated symptoms of end-organ dysfunction (eg, 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 (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (eg, 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* 
b. Adults: systolic BP of less than 90 mm Hg or greater than 
*30% decrease from that person’s baseline
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 (eg discoloration, particles or 
contamination)

The packaging material (eg 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 
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consent until the end of trial visit. The events must be recorded in the applicable CRF forms in a 
timely manner. See timelines below and Figure 11–1.
AEs between consent and 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
you experienced 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 brochure,5 N8-GP, current version and any updates 
thereto.
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, see Figure 11–1. If several symptoms or diagnoses occur as 
part of the same clinical picture, one eSIF may be used to describe all the SAEs. All concerned AE 
numbers must be included in the AE number field on the eSIF.
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 within the specified timelines:

SAEs: The AE form within 24 hours and the safety information form within 5 calendar days 
of the investigator's first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in the 
eCRF. 
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
Non-serious AE fulfilling the MESI criteria: The AE form and the safety information form 
within 14 calendar days of the investigator’s first knowledge of the event.
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must re-enter the information on the appropriate 
forms in the eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigators trial file.
Figure 11–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by the sponsor:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP1. In addition, the 
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 
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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 (eg 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 (eg corrections or additional) information and must be reported within 14 calendar
days of the investigator's first knowledge of the information. This is also the case for previously
reported non-serious AEs which subsequently fulfil the MESI criteria.
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow up with re-
assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo 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.
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11.4
Technical complaints and technical complaint samples
11.4.1
Reporting of technical complaints 
All technical complaints on any of the following products:

N8-GP 500 U/vial

N8-GP 2000 U/vial

Sodium Chloride 0.9 % vial

Novo Nordisk trial injection kit 
which occur from the time of first usage of trial 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 DU, a 
technical complaint form for each batch, lot number or for each DU 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.
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).
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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 N8-GP administration should be stopped and the patient should receive 
treatment as appropriate according to the hospital practice and guidelines. 
If an overdose of N8-GP is suspected further N8-GP administration should be stopped prior to any 
further N8-GP administration and the patient should receive treatment as appropriate according to 
hospital practice and guidelines.
11.6
Committees related to safety
11.6.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal safety committee to perform ongoing safety surveillance of 
N8-GP. The safety committee works according to a written guideline and will meet regularly to 
discuss and evaluate the overall safety for N8-GP for this trial and all other N8-GP trials. The Novo 
Nordisk safety committee can take action with regard to the patient safety for the trial based upon
observations of the overall information for N8-GP. Pre-defined rules for setting the enrolment on 
hold is described in Section 11.6.2.
The safety committee might meet to evaluate data at any time point during the conduct of the trial if 
deemed necessary.
11.6.2
Rules for putting the enrolment on hold
A safety analysis will be performed to evaluate the development of inhibitor at the following 
predefined time point:
• after the first 25 patients have been to visit 6 (20-25 exposure days )
The expected rate of inhibitors is about 30% in PUPs with severe haemophilia A.4 In case of 
confirmed FVIII inhibitor formation in 12 or more of all exposed patients, all cases of inhibitor 
formation will be evaluated by the N8-GP safety committee. During these evaluations, ongoing 
treatment in the trial will continue, however new patients will not be enrolled in the trial. The 
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evaluation will provide the basis for a decision on any actions required for the trial to allow for 
continuation of enrolment or decision to terminate the trial, and will be documented in the safety 
committee meeting minutes.
During the evaluation the safety committee will also evaluate risk factors for inhibitor formation 
such as ethnicity, family history of inhibitors, FVIII gene mutation type, age at first FVIII 
treatment, reason for first treatment, treatment duration after first treatment, the details of any 
surgery (including type of surgery, amount of product used, and outcome), any recent infection and 
any recent vaccination. Furthermore the time of occurrence of inhibitor formation (after how many 
exposures) and whether the inhibitor is a high or low titre will be evaluated. 
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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 
(eg is not applicable), indicate this according to the date 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.
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks.
If a test 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 (eg 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.
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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 
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 5 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 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, surgery and treatment hereof, 
see Sections 8.1.12.1 and 8.6. The eDiary and related support services will be supplied by a vendor 
working under the direction and supervision of Novo Nordisk. 
At visit 2, the patient’s parent(s)/LAR(s) will receive the eDiary and they will be trained in the use 
hereof by the investigator or delegated person. After visit 2 (after 2 EDs) and onwards, 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. 
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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.
It is the responsibility of the Investigator 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 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 Correction Request to the eDiary vendor. An audit trail will be maintained.
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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. 
The first monitoring visit will 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. 
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 (eg 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 (eg the diaries) to ensure 
consistency and/or identify omissions compared to the eCRF. If discrepancies are found, the 
investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit addressing any action to be taken.
For screening failures: Data for the screening visit must be entered in the eCRF within preferably 
3 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 
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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 in the eCRF. When home 
treatment is initiated all bleeding episodes and injections with N8-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.
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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 the Global Haemophilia Network Investigator Portal to distribute and share 
trial-related documents and information with the participating sites.
The eDiary software and hardware implementation are compliant with the requirements of FDA 21 
CFR Part 11 and ICH E6 (EU directive for personal data protection).1,25 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 conside
Novo Nordisk will be responsi
The main statistical reporting o
phase (minimum 25 weeks) w
will not count in the determina
having completed the main ph
point will be included up to lat
and will form the basis for the
and for the extension phase sep
Except for the confidence inte
of data will be based on descri
An updated reporting of the tri
at least 100 EDs. Data from al
data will be presented for the m
100 EDs) separately as well as
All data,, will be reported sepa
Figure 16–1
Individual pati
Multiple bleeding locations oc
point will be counted as one bl
CONFIDENTIAL
Date:
Version:
Status:
Page:
erations
ible for the statistical analysis.
of the trial will be performed when 50 patient
with at least 50 EDs and completed visit 9. ED
ation of when a patient has reached 50 EDs. D
hase and data from patients that have entered e
test visit prior to this cut-off date. This report
 paediatric indication. The data will be presen
parately as well as combined. 
rval for inhibitor rate and for annualised blee
iptive statistics, i.e. summary tables, listings a
ial with supportive data will be performed wh
ll patients will be included up to latest visit pr
main + extension phase and the extended prop
s combined. 
arately in a final report when the trial is comp
ient flow and time periods for trial reporti
ccurring from the same event (e.g., due to a fa
leeding episode.
04 November 2013
Novo Nordisk
1.0
Final
92 of 114
ts have completed main 
Ds during ITI treatment 
Data from patients not yet 
extension phase at this 
t will cover all endpoints, 
nted for the main phase 
eding rate, the evaluation 
and figures. 
hen 100 patients have had 
rior this cut-off date. The 
phylaxis period (beyond 
pleted.
ng
all) or at the same time 
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All bleeding endpoints will be evaluated based on bleeding episodes treated with N8-GP unless the 
bleeding was considered clinically insignificant (non-treatment requiring bleeding episode) and the 
associated treatment given was part of prophylaxis.
Patients initiating ITI treatment will for the statistical analyses be considered like withdrawals and 
data collected during ITI treatment period will be summarised and reported separately. Evaluation 
of these data will be considered exploratory only.
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 100 completers is 
based on EMA guideline7.
16.2
Definition of analysis sets
Descriptions and analysis of efficacy data will be based on the Full Analysis Set (FAS), as defined 
in ICH E9 guidelines.26 The FAS includes all patients exposed to N8-GP. The safety analysis and 
descriptions will be based on the Safety Analysis Set (SAS). The SAS will consist of all patients 
exposed to N8-GP.
16.3
Primary endpoint
The primary endpoint is a safety endpoint defined as incidence of inhibitory antibodies against 
FVIII.
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 
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 in this trial
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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 N8-GP as the outcome variable, and adjusting for exposure time. For 
comparison with previous trial, 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 N8-GP when used for treatment of bleeding episodes will 
be summarised and listed according to the four point scale for haemostatic response (none, 
moderate, good and excellent). 
A success rate will be calculated based on counting good or excellent as successes and none 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).
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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
Incidence of high titre inhibitors
The rate of high titre inhibitors (defined as inhibitor titre > 5BU) will be reported similar to the 
primary endpoint
16.4.2.4
FVIII consumption
Total amount of N8-GP used, amount of N8-GP used for prophylaxis (U/Kg/month/year) and 
amount consumed per bleeding episode (number of injections and U/Kg bw/bleeding episode) will 
be summarised and listed. 
16.4.2.5
Safety endpoints
Adverse events including SAEs and MESI
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 produce 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.
All additional safety parameters such as laboratory parameters and physical examinations will be 
summarised and listed.
16.4.2.6
Other assessments
Incremental recovery (IR30min), FVIII activity at 30 minutes (C30min) and trough level will be 
assessed at visit according to Table 2–1.
FVIII trough level is defined as the activity recorded immediately before N8-GP injection, and 
reported as (U/mL). IR30min is defined as the peak activity recorded 30 minutes after the end of N8-
GP injection, and reported as [U/mL]/[U/Kg]. It is calculated by subtracting the FVIII trough level 
from the FVIII activity recorded 30 minutes after ended N8-GP injection, and dividing the 
difference by the dose injected at time 0 expressed as U/Kg bw.
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16.5
Interim reporting
All data from main phase of the trial will be analysed and reported when the first 50 patients have 
completed main phase with at least 50 EDs and completed visit 9. 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 for separately for the main phase and extension as well as combined. 
An updated report will be made when the first 100 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.
16.6
Sequential safety analysis and safety monitoring
Novo Nordisk 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).
In addition a safety analysis will be performed to evaluate the development of inhibitor at the 
following predefined time point:
after the first 25 patients have been to visit 6 (20-25 exposure days)
The expected rate of inhibitors is about 30% in PUPs with severe haemophilia A4. In case of 
confirmed FVIII inhibitor formation in 12 or more of all exposed patients, all cases of inhibitor 
formation will be evaluated by the N8-GP safety committee. During these evaluations, ongoing 
treatment in the trial will continue, however new patients will not be enrolled in the trial. The 
evaluation will provide the basis for a decision on any actions required for the trial to allow for 
continuation of enrolment or decision to terminate the trial, and will be documented in the safety 
committee meeting minutes (see Section 11.6.2). 
16.7
Reporting of F8 and HLA genotype
Information about underlying gene defects of F8 and HLA will be listed in the clinical trial report, 
except for Israel. 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 effect1. 
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 N8-GP may occur on the same day, informed consent form must include a time 
field next to the data 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 expected22.
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.
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.
F8 and HLA genotype testing/collection of previous genotype documentation (not applicable 
for Israel):
Genotype testing is offered to the patients participating in this trial. If documentation of the 
patients’ genotype already exists, the patient and/or the patient’s parent(s)/LAR(s) must give their 
consent before the data can be collected for trial purpose. Prior to any trial-related activity, the 
investigator must provide the patient’s parent(s)/LAR(s) with the possibility to abstain from the 
genetic testing/collection of previous documentation, but still be able to participate in the trial.
Only the F8 and HLA genotype will be analysed by the central laboratory selected by Novo Nordisk 
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.
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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 
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 toys during the trial period. 
All information inclusive all 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 will be used as media for exchange and handling of investigator trial file 
documents between Novo Nordisk and the trial site and for electronic storage of these documents 
during trial conduct.
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, subject 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

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 trial sites:

Intended for US trial sites

Conducted under the IND

All US investigators, as described above, will sign FDA Form 1572
For trial sites outside the US:

Intended for participating trial site outside of the US

Not conducted under the IND
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
All investigators outside of the US will not sign FDA form 1572
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
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
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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CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
104 of 114
  
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 Helsinki2.
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.
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 (ie those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator’s trial file. The documents should be kept in a secure locked facility, 
so no unauthorized persons can get access to the data. The 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 (eg 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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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
105 of 114
  
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.
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 the first 50 PUPs 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 Disclosure.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
106 of 114
  
Where required by the journal, the principal investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
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 
Criteria27).
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.
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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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
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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 (eg 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.
For Japan: The trial site should retain clinical trial documentation until approval, or 3 years after 
the date of premature termination or completion of the clinical trial. The sponsor should retain 
clinical trial documentation for 5 years after the approval (in case of drug patient to re-examination, 
until re-examination is completed), or 3 years after the date of premature termination or completion 
of the clinical trial.
23.2
Retention of human biospecimens
Storage and disposition of samples analysed at local laboratories will be performed according to 
local laboratory procedures. 
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). 
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
108 of 114
  
All remaining blood samples will be stored until the trial has been evaluated by appropriate 
authorities or until the project terminates, but no longer than 15 years from end of trial. As new 
biomarkers related to the disease and/or safety, efficacy, or mechanism of action of N8-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 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 patient’s identity will remain confidential and samples 
will only be marked and identified by a unique sample ID. No direct identification of the patient 
will be stored together with the samples. The analyses will not have any medical consequences for 
the patients or their relatives. Only Novo Nordisk staff and bio-repository personnel (if applicable) 
will have access to the stored bio specimens. 
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
109 of 114
  
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.
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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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
110 of 114
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 Sancor Cooperativa 
de Seguros LTDA. Domiciled in Independencia 333, Sunchales, Santa Fé, Argentina. Telephone 
number: 0800-444-28500.
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 applicaple 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 
van 23 juni 2003, houdende regels inzake de verplichte verzekering bij medischwetenschappelijk 
onderzoek met mensen (Decree of 23 June 2003, containing rules for compulsory insurance in 
medical research involving human subjects (Medical Research (Human Subjects) Compulsory 
Insurance Decree).
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
111 of 114
  
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 
Nordisk and Investigator are covered by the Insurance Policy issued according to applicable Polish 
law’
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
112 of 114
  
26 .References
1 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Good 
Clinical Practice, 01-May-1996, Geneva, Switzerland. 1996.
2 WMA. Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects. 2010. 
3 Gouw SC, van der Bom JG, Marijke van den BH. Treatment-related risk factors of inhibitor 
development in previously untreated patients with hemophilia A: the CANAL cohort study. 
Blood 2007; 109(11):4648-4654.
4 Gouw SC, van der Bom JG, Ljung R, Escuriola C, Cid AR, Claeyssens-Donadel S et al. 
Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 
368(3):231-239.
5 Investigator's Brochure, N8-GP, 4th Edition. Novo Nordisk A/S. 2013.
6 Tiede A, Brand B, Fischer R, Kavakli K, Lentz SR, Matsushita T et al. Enhancing the 
pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated 
recombinant factor VIII in patients with hemophilia A. J Thromb Haemost 2013; 11(4):670-
678.
7 EMA. Committee for medicinal products for human use (CHMP), Guideline on the clinical 
investigation of recombinant and human plasma-derived factor VIII products, 
EMA/CHMP/BPWP/144533/2009. 2011.
8 Geraghty S, Dunkley T, Harrington C, Lindvall K, Maahs J, Sek J. Practice patterns in 
haemophilia A therapy -- global progress towards optimal care. Haemophilia 2006; 12(1):75-
81.
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 Astermark J. Immune tolerance induction in patients with hemophilia A. Thromb Res 2011; 
127 Suppl 1:S6-S9.
11 Benson G, Auerswald G, Elezovic I, Lambert T, Ljung R, Morfini M et al. Immune tolerance 
induction in patients with severe hemophilia with inhibitors: expert panel views and 
recommendations for clinical practice. Eur J Haematol 2012; 88(5):371-379.
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
113 of 114
  
12 Astermark J, Morado M, Rocino A, van den Berg HM, von DM, Gringeri A et al. Current 
European practice in immune tolerance induction therapy in patients with haemophilia and 
inhibitors. Haemophilia 2006; 12(4):363-371.
13 DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E. International workshop on 
immune tolerance induction: consensus recommendations. Haemophilia 2007; 13 Suppl 1:1-
22.
14 Collins PW, Fischer K, Morfini M, Blanchette VS, Bjorkman S. Implications of coagulation 
factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. 
Haemophilia 2011; 17(1):2-10.
15 De AC, 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):1250-1251.
16 Food and Drug Administration Amendments Act of 2007. 2007.
17 European Commission Regulation for EudraCT. 2011. 
18 FDA. Guidance for Industry Assay Development for Immunogenicity Testing of Therapeutic 
Proteins. Draft Guidance. 2009. 31-1-2013. 
19 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. J Immunol Methods 2004; 289(1-2):1-16.
20 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. J Pharm Biomed Anal 2008; 48(5):1267-1281.
21 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. J Immunol 
Methods 2007; 321(1-2):1-18.
22 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. Ethical Considerations for Clinical Trials on Medicinal Products Conducted with 
the Paediatric Population. EC Directive 2008.
23 The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines to 
Good Manufacturing Practice, Medicinal Products for Human and Veterianry Use, Annex 13 
Investigational Medicinal Products. 2010. 
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Protocol
CONFIDENTIAL
Date:
04 November 2013
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88 
Page:
114 of 114
  
24 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. Ann Emerg Med 2006; 47(4):373-380.
25 Food and Drug Administration. Food and Drug Administration: Code of Federal Regulations, 
21 CFR Part 11, Electronic Records, Electronic Signatures. 2009.
26 ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. International 
Conference on Harmonisation E9 Expert Working Group. Stat Med 1999; 18(15):1905-1942.
27 International Committee of Medical Journal Editors (ICMJE): Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals: writing and editing for biomedical 
publication. Haematologica 2004; 89(3):264.
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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:
turoctocog alfa pegol
Trial ID: NN7088-3908
Clinical Trial Report
Appendix 16.1.1
24 February 2022
1.0
Final
CONFIDENTIAL


Log of Protocol Amendments 
UTN: U1111-1148-1897 
Date: 
08 February 2022 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7088-3908 
EudraCT No.: 2013-004025-88 
Version: 
2.0 
Page: 
1 of 2 
 
 
Log of Protocol Amendments 
Trial ID:  
Protocol 
amendment no 
Date  
Final,  
Version 
Country(ies) and/or trial 
site(s) affected 
Brief content 
1 
NA 
NA 
Portugal 
Protocol amendment no 1 was dedicated to 
Portugal but never finalised. Due to SOP 
requirements the countries now have their own 
logs and this log will only cover global 
amendments 
2 
20-Mar-2015 
2.0 
All 
(Final Version 1.0 never shared)  
Detailed information on Major surgery and ITI, 
extended trial timelines 
3 
01-Nov-2016 
1.0 
All 
Amendment 3 includes a new secondary 
endpoint to assess the ITI treatment outcome and 
monitoring of antibody development  against  
Host Cell Protein (HCP).   
4 
14-Jun-2018 
1.0 
Israel 
Protocol Amendment 4 is for Israel seeking 
permission to obtain the F8 genotype. 
5 
13-Jun-2019 
1.0 
All  
Interim analysis when approximately 45 patients 
have reached 50 exposure days, and 
administrative changes 
6 
21-jun-2019 
1.0 
Israel 
Protocol amendment 6 for Israel for obtaining 
informed consent from withdrawn patients to 
provide genotype results 
VV-TMF-1130009|2.0|NN7088 -3908
  Protocol Amendment  final log|1 of 2


Log of Protocol Amendments 
UTN: U1111-1148-1897 
Date: 
08 February 2022 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7088-3908 
EudraCT No.: 2013-004025-88 
Version: 
2.0 
Page: 
2 of 2 
 
 
7 
02-jul-2019 
1.0 
Japan 
Protocol amendment 7 for Japan is due to the 
regulatory category of this clinical trial should be 
updated in accordance with Japanese regulations. 
This is mandatory before NNPL obtains 
marketing approval of N8-GP. 
8 
15-Jun-2020 
1.0 
All 
- Close recruitment of trial NN7088-3908 with 
between 50 to 100 patients completing, 
(rather than the protocol agreed 100 patients 
completing), but maintain the protocol 
defined trial end date 13 November 2021. 
Anti-PEG IgG + additional IgM antibody 
analyses have been implemented. 
 
VV-TMF-1130009|2.0|NN7088 -3908
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EudraCT No.: 2013-004025-88 
Date: 
CONFIDENTIAL 
Version: 
Status: 
Page: 
Protocol Amendment 
no 1.0 
to Protocol, final version 1.0 
dated 04 November 2013 
Trial ID: NN7088-3908 
30 July 2014 
Novo Nordisk 
0.1 
Final 
1 of 5 
An open-label single-arm multicentre non-controlled phase 3a trial 
investigating safety and efficacy of NS-GP in prophylaxis and 
treatment of bleeding episodes in previously untreated paediatric 
patients with severe haemophilia A 
Trial phase: 3a 
Applicable to: Portugal 
Amendment originator: 
Name: 
 
Department or business area: Medical Department 
CONFIDENTIAL


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Trial ID: NN7088-3908 
UTN: Ul 111-1148-1897 
EudraCT No.: 2013-004025-88 
CONFIDENTIAL 
Date: 
Version: 
Status: 
Page: 
30 July 2014 
Novo Nordisk 
0.1 
Final 
2 of 5 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


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Trial ID: NN7088-3908 
UTN: Ul 111-1148-1897 
EudraCT No.: 2013-004025-88 
Table of contents 
CONFIDENTIAL 
Date: 
Version: 
Status: 
Page: 
30 July 2014 
Novo Nordisk 
0.1 
Final 
3 of5 
Page 
1 
Introduction including rationale for the protocol amendment ............................................................. 4 
2 
Changes ...................................................................................................................................................... 5 
CONFIDENTIAL


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Protocol Amendment 
Trial ID: NN7088-3908 
UTN: Ul 111-1148-1897 
EudraCT No.: 2013-004025-88 
CONFIDENTIAL 
Date: 
Version: 
Status: 
Page: 
30 July 2014 
Novo Nordisk 
0.1 
Final 
4 of5 
1 
Introduction including rationale for the protocol amendment 
The purpose of this amendment is to include information that is missing in the Protocol Version 1.0, 
according to the Central Ethics Committee in Portugal, referring to the use of the pain control 
measures for venous punctures. 
The amendment will be submitted to the Central Ethics Committee for Approval in Portugal. 
According to local legislation, this amendment does not need to be submitted to Regulatory 
Authorities but only to the Ethics Committee in Portugal. 
In this protocol amendment: 
• 
Any new text is written in italics. 
• 
Any text deleted from the protocol is written using strike through. 
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2 
Changes 
CONFIDENTIAL 
Date: 
Version: 
Status: 
Page: 
30 July 2014 
Novo Nordisk 
0.1 
Final 
5 of 5 
The following sentence will be added at the end of section 5.3 Treatment of Patients, on final 
protocol. 
Only applicable for Portugal: 
For venous punctures, pain control measures are allowed according to local practice. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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Protocol Amendment
no 2
to Protocol, final version 1.0
dated 04 November 2013
Trial ID: NN7088-3908
Safety and Efficacy of turoctocog alfa pegol (N8-GP) in 
Previous Untreated Patients with Haemophilia A
An open-label single arm multicentre non-controlled phase 3a trial investigating safety and efficacy 
of N8-GP in prophylaxis and treatment of bleeding episodes in previous untreated paediatric 
patients with severe haemophilia A
Trial phase: 3a
Applicable to all countries
Amendment originator:
, International Trial Manager
Department:Haemophilia, Clinical 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.


Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................2
Table of Tables..................................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................6
Table of Figures   
Page
No table of figures entries found.
Table of Tables   
Page
No table of figures entries found.
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CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
3 of 41
1
Introduction including rationale for the protocol amendment
Rationale for amendment
Below list is the items that have been changed and the rationales for the amendment. The reason for the 
creating the amendment now is the availability of results from the pathfinder™2 (NN7088-3859), 
pathfinder™3 (NN7088-3860) and pathfinder™5 (NN7088-3885). 
1.
Major surgeries has been allowed after having completed the pathfinder™3 surgery trial. (section 5.3.5, 
8.7)
a.
Recommendations for doses has been added (section 5.3.5, 8.7)
b.
Details on definition of data sampling has been updated and data collection from minor and 
major surgery aligned (section 5.3.5, 8.1.10, 8.7)
c.
Haemostatic response for surgery 4-point scale added (section 8.6.1, 8.7.1)
2.
ITI recommendations and requirements have been updates after new data available from pathfinder™2 
pivotal trial, pathfinder™3 surgery trial and pathfinder™5 paediatric trial to support the ITI 
recommendations. (section 5.3.6)
a.
Dose recommendations added (section 5.3.6, 8.1.11)
b.
Detailing of recommendations for low titre inhibitor patients added (section 5.3.6, 5.5, 6.4, 6.6.3)
c.
How to evaluate the ITI treatment before returning to prophylaxis added (section 5.3.6, 6.4, 
6.6.3, 8.1.11, 8.4.2.2, 16) 
d.
ITI doses will count as overall number of doses (section 5.1)
3.
Prolonged recruitment period and prolonged trial. Prolongation is due to postponed submission of the 
application for market approval of N8-GP (section 5.3, 7, 8.1)
4.
Updated text on when trial could start as needed data is available at this point (section 3.1.3, 5.1, 5.3, 
8.7)
5.
Addition of mandatory inhibitor test before treatment including addition of a withdrawal criterion if 
positive at visit 1 before first dosing. This has been added because of the risk of developing inhibitors 
after receipt of maximum 5 doses of blood components. (section 2, 6.2, 6.4, 8.1 )
6.
Precised when safety committee should meet instead of having an interval for the meeting (section 
11.6.2, 16.6)
7.
PK time points have been changed based on the need experienced from the first patients enrolled in the 
trial. (section 8.4.2.2)
8.
Allergic reaction sampling updated with 2 new tests, as found relevant based on the experience form the 
first patients enrolled in the trial. (section 8.4.2.7)
9.
All wash out periods before pre-dose blood sampling has been aligned to be 72 hours instead of either 
72hour or 4 days. This changed in implemented because of new information from the pathfinder™5 
paediatric trial. (section 8.4.2.2)
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CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
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EudraCT No.: 2013-004025-88
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10. Analyses of binding antibodies and PEG antibodies have been changed to not only being analysed at the 
end of the trial to also being analysed when considered relevant, based on experience from first patients 
in the trial. (section 8.4.2.2 )
11. Added a window for sampling of blood at visits to allow more flexibility for the patients and sites 
(section 8.1, 8.4 )
12. Clarified inclusion criterion 4 to be covering only FVIII purified product and not all faction products 
(section 1, 5.3, 6.2)
13. Added cardio vascular to physical examination (section 8.3.2)
14. Elaborated on drug reconstitution and solvent supplies (section 9)
15. Added informed consent can be signed before first visit (section 8.1)
16. Clarified dosing regimen text and visit windows (5.3, 8.1, 
17. Reminder of monitoring of expiry of solvent, injection kits, and reference standard based on experience 
from pathfinder™ and guardian™ programmes. (section 8.1, 8.8.4, 9.4)
18. Added information that the vein used for drug infusion can be used for blood sampling half an hour after 
the infusion to ease the problematic blood draw from infants (section 8.4 )
19. Changed the form of writing visit windows in table 2-1 after feedback of being difficult to understand 
(section 2)
20. Elaborated figure 8-1 to be more precise for visits during the pre-prophylaxis period. (Section 8.1)
21. Added that if according to local law a caregiver can take over some of a parent(s)/LAR(s) task to allow 
more flexibility for patients (section 8.1)
22. Added reminders to the visit 15-X to help site following the trial requirements (section 8.1.3)
23. Requirement for site to be able to analyse FVIII activity and inhibitor samples locally to ensure 
immediate action if needed for the patient’s safety. This has been added based from experience from the 
initiation of the trial (section 8.4.1.1 )
24. Added extra samples to be taken together with the confirmatory inhibitor test to ensure a positive test is 
not a false positive and to ensure sufficient knowledge of the inhibitor (section 8.4.2.2)
25. Added that monitoring visit intervals can be prolonged when site only have patients attending visits 
every 24 weeks, but monitor needs to ensure contact to site at least every 12 weeks (section 13)
26. Added that the e-learning of the protocol is mandatory for Investigator if investigator has not attended 
the investigators meetings (section 21)
27. Deleted specific text for Japan upon request from Japan (section 23.1)
28. Added required text for Portugal upon amendment 1 (section 25)
29. Clarified table 2-1 elements (section 2)
30. Updated total blood sampling volume after having finalised lab set-up (section 8.4.3)
31. Clarified where to enter data in eCRF and eDiary (section 8.1, 8.2, 8.8)
32. Clarified location to align with rest of protocol (section 5.3)
33. Deleted repetitive text (section 3.2)
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Date:
20 March 2015
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Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
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EudraCT No.: 2013-004025-88
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34. Added required elements from new protocol template. It was decided not to change to the new protocol 
template as this would change the protocol too much for sites convenience, but all relevant elements 
from the new protocol template has been added to the protocol. (section 3, 4, 5, 6, 8, 16, 17, 20, 21, 22, 
23, 24)
Corrected abbreviation order, spelling, grammar and clarifications, text formatting, and incorrect section 
references.
In this protocol amendment:

Any new text is written in italics.

Any text deleted from the protocol is written using strike through.
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Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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2
Changes
General over whole protocol

IV/WRS to IWRS

Bleed to Bleeding episode

Spelling corrections and grammatical corrections and corrected section references have not been listed below
List of Abbreviations
CRP
C-reactive protein
APTT
activated partial thromboplastin time 
1 Summary
Trial population:
Inclusion criteria
…..

No prior use of purified factor VIII containing clotting factor products (5 previous exposure days to blood 
components is acceptable)
2 Flow Chart
Table 2-1
Visit number
01
11
2
3
4-6
7-8
9
10-13
1418
15-X19
EOT
Time of visit 
(ED(s))2
0
1
2
5
10, 15, 
203
30,40
50
60, 70, 
80, 90
100
NA
Visit interval 
(ED(s))2
0
0
3±1
5±2
10±2
10+2
10±2
10+2
24w±4w
Adverse events5
X
X
X
X
X
X
X
X
X
X
X
Vital signs7
X
X7
X
X
X
FVIII activity –
recovery (30 min
post-dose)
X
X
X
X
X
X
X
X
FVIII inhibitor test9
X18
X
X
X
X
X
X
X
X
HIV 1 and 2
antibodies
(X)
10
F8 + HLA
genotype testing
(X)12
(X)12
(X)12
(X)12
(X)12
(X)12
eDiary training
X14
X14
X14
X14
X14
X14
X14
X14
X14
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CONFIDENTIAL
Date:
20 March 2015
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Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
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EudraCT No.: 2013-004025-88
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Compliance check 
of eDiary data, 
protocol 
requirements, and
used drug and 
bleeding episode 
evaluation
X
X
X
X
X
X
X
X
X
X
Table 2-2
3
If not already on prophylaxis, all patients must initiate prophylaxis treatment no later than at V6 or shortly after at ED 20. 
Pre-prophylaxis is only allowed for children below the age of 24 months or up to V6, whatever comes first.
Visits at 10EDs±2EDs, 15EDs±2EDs, 20EDs±2EDs must be performed even the window allows 2 visits to be 2 EDs aside 
(e,g, ED12 and ED13)
5
After Informed consent has been obtained all Adverse Events if associated with trial related activities must be reported in the 
eCRF
7
Vital signs should be measured prior to dosing at all screening V1, V9, and at V14 and at EOT. In addition vital signs should 
also be measured 30±10minutes after the first injection with N8-GP at V1.
9
Blood samples must be collected prior to dosing at dosing visits. Please check that the required washout period has been met 
for inhibitor testing, see section 8.1.1.3 Before any surgeries are performed an inhibitor test must be taken if this test is more 
than 30 days
12
F8 and HLA genotype sample is only allowed upon patient’s parent(s)/LAR(s) signing the consent for genotyping and should 
only be done if not already documented in patient’s medical record. The sample can be collected at any visit between V0 and 
V89, taking the limitation of the allowed blood sampling volume into account. Genotype is not applicable for Israel.
18
In case V14 will be the EOT visit, the procedures for the EOT visit should be followed Inhibitor sample at visit 1 before 
dosing is mandatory
19
V15 to VX will be performed every 24 weeks EDs ± 4 weeks EDs until the End of Trial
3 Background information and rationale for the trial
3.1.1 Haemophilia A
…..
The most serious complication of haemophilia treatment with current FVIII products is FVIII 
inhibitor development. These inhibitors are antibodies formed as an immune response to allogeneic 
FVIII, which reduce or eliminate the activity of FVIII proteins. This condition develops in about 
30% of previously untreated patients (PUPs) with severe haemophilia A following exposure to 
FVIII products.3,4 Availability of a recombinant human FVIII (rFVIII) product with reduced 
immunogenicity has been the priority request by the haemophilia community for many years. The 
immunogenicity of N8-GP will be monitored in the clinical setting and further investigated in 
nonclinical models to explore preliminary findings of reduced binding and uptake of N8-GP in 
human antigen presenting cells.
Immune tolerance induction (ITI) therapy is the first-choice approach in patients with high-
responding FVIII inhibitors, and the only proven strategy for eradicating FVIII inhibitors. Based on 
clinical evidence and international consensus recommendations, most patients are attempted 
tolerised with the same product that was being used at the time of inhibitor development.
…
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CONFIDENTIAL
Date:
20 March 2015
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Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
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EudraCT No.: 2013-004025-88
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3.1.3 N8-GP clinical data
…
In accordance with the EMA guideline7, N8-GP exposure of PUPs may be was initiated when 
treatment data from 20 paediatric PTPs with at least 50 N8-GP EDs are was available from the 
pathfinder™5 trial, including data from a minimum of 10 patients below 6 years, and 
pharmacokinetic investigations in children (below 12 years) are were completed.
….
3.2 Rationale for the trial
The rationale for performing the pathfinder™6 trial is to evaluate the safety (including 
immunogenicity) and efficacy of N8-GP in the treatment of PUPs with severe haemophilia A in 
accordance with EMA requirements.7 For Europe, EMA requires a separate investigation in the 
PUP population as part of the development programme to be initiated before market authorisation.7
The approval of the indication in PUPs will be based on a clinical trial in a minimum of 50 PUPs 
evaluated for efficacy and safety during at least 50 EDs connected with a post-approval 
commitment to follow up at least 100 PUPs for a minimum of 100 EDs. The 50 patients will 
continue to reach at least 100 EDs, and additional 50 patients will be included also to reach at least 
100 EDs.
Given the prolonged half-life of N8-GP it is expected that bleeding prophylaxis, treatment of acute 
bleeding episodes, and control and prevention of bleeding in the surgical setting may be achieved 
with a reduced frequency and number of injections as compared to current treatment options. This 
may increase treatment compliance, and thereby potentially leading to better clinical outcomes for 
patients with haemophilia A.
3.3 Risk and benefits
……
N8-GP is currently being investigated in previously treated patients. The first human dose trial 
(NN7088-3776) demonstrated that a single dose of N8-GP is generally well-tolerated, and that N8-
GP has a prolonged half-life compared to commercially available FVIII products. No safety 
concerns have been raised based on review of data (cut-off date was 12-Feb-2013 28-Jul-2014) 
from patients enrolled in the pivotal safety and efficacy trial (NN7088-3859) and the risk/benefit 
ratio for N8-GP is therefore expected to be favourable.
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CONFIDENTIAL
Date:
20 March 2015
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Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
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EudraCT No.: 2013-004025-88
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4 Objective(s) and endpoint(s)
…
4.2.2 Secondary Endpoint
….
*Key supportive secondary endpoint prospectively selected for posting (e.g. on clinicaltrials.gov 
and EudraCT). 
5 Trial design
5.1 Type of trial
…
According to the EMA Guideline treatment with N8-GP in the pathfinder™6 PUP trial was able to
may start when 20 patients participating in the paediatric PTP trial (pathfinder™5) were are
available (including data from a minimum of 10 paediatric patients below 6 years of age), and 
pharmacokinetic investigations in paediatric PTPs were are completed.
….
In the main phase of the trial patients will receive treatment with N8-GP until they reach a 
minimum of 50 N8-GP EDs each or until they develop high titre inhibitor. An ED is defined as any 
day during which the patient has been exposed to N8-GP, including doses given for treatment of 
bleeding episodes, prophylaxis, surgery, and for the purpose of PK assessment. If N8-GP is 
administered more than once during the same day, this will still count as one ED. When at least 50 
patients have reached a minimum of 50 EDs each in the main phase, the analysis and evaluation for 
the main trial report will be performed. EDs during immune tolerance induction therapy (ITI) will 
not count in the determination of when a patient has reached 50 EDs.
Patients will be followed in the extension phase until at least 100 patients have reached at least 100 
EDs each. EDs during immune tolerance induction therapy (ITI) will count in the determination of 
when a patient has reached 100 EDs.  
….
5.3 Treatment of patients
Trial overview visit schedule will be as shown in Figure 5-1.
…. 
For each patient at least the two initial doses of N8-GP given on the first 2 EDs will be administered 
in a site hospital/clinic setting enabling observation for potential adverse reactions. The patient must 
be observed for at least 1 hour after dosing. If no safety concerns were raised after administration of 
these initial doses of N8-GP, Afterwards home treatment with i.v. self-injection by the 
parent/caregiver/support person can be initiated. If no safety concerns were raised after 
administration of the initial doses of N8-GP The investigator should ensure that 
parent/caregiver/support person is sufficiently trained and confident with home treatment, including 
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CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
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EudraCT No.: 2013-004025-88
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both prophylaxis and treatment of bleeding episodes. The patients can come to the clinic/trial site 
for their N8-GP injections until they are comfortable with home treatment.
…
The duration of N8-GP treatment in the extension phase is at least 50 EDs or up to a minimum at 
least a total of 100 EDs (for both the main and extension phases) for each patient. Once a patient 
has achieved 100 EDs, he may be offered the option to continue in the extension phase until either 
N8-GP is commercially available in the relevant country or until the marketing authorisation 
application for N8-GP is rejected in the relevant country unless the N8-GP trial, part of the trial or a 
trial site is terminated by Novo Nordisk or a relevant authority for any reason. In any event, the Last 
Patient Last Visit for the trial will be no later than 13 November 2021 May 2019 whether or not the 
product is commercially available in the relevant country. Novo Nordisk will not provide any 
patient with trial medication after the end of the trial. 
Treatment with FVIII products other than the investigational product, N8-GP, is not allowed. 
Previous exposure to FVIII products is not allowed in this trial. Previous exposure to maximum 5 
plasma infusions, Pd-aPCC, and/or cryoprecipitate is allowed. Maximum 5 previous blood product 
(e.g. plasma, cryoprecipitate, erythrocyte concentrate or platelets) infusions are allowed.
5.3.1 Pre-prophylaxis treatment 
….
The N8-GP dose for pre-prophylaxis treatment (except for bleeding episodes) is approximately 60 
U/Kg body weight (bw) (within the dosing range of 50-75 U/Kg) to be administered as a single 
bolus dose intravenously (i.v.) with more than one week between doses less than once every 7 days
(at the discretion of the investigator). Whole mL dosing is allowed from above 3 mL. This is
explained in further detail in the trial materials manual. For treatment of bleeding episodes see 
Table 5-1.
…
5.3.2 Prophylaxis treatment
…
During the main phase of the trial patients should receive prophylaxis with i.v. injections of N8-GP 
preferably twice weekly, with doses to be separated by at least 3 calendar days and no more than 4 
calendar days. Based on the patient’s individual bleeding pattern, an increase in N8-GP dose 
frequency from twice weekly to every third day is permitted at the investigators discretion (should 
be based on the patient’s individual bleeding pattern). 
… 
In the extension phase, all patients should continue the prophylaxis dosing regimen as prescribed at 
the end of the main phase. However, preferably after having been being 12 months on the same 
prophylaxis regimen for 12 months (main phase and extension phase combined), the investigator is 
permitted to increase or decrease the N8-GP dosing frequency interval within the range of every 3rd
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Date:
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Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
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day to every 7th day (every 3rd day, twice weekly, every 4th day, every 5th day, every 6th day or every 
7th day (once weekly)) based on the patient’s bleeding pattern. 
The dose can be administered ±+1 day of the planned dosing date (this window is related to the 
dosing regimen and not to the visit window).
… 
In the event of a concern about reduced treatment efficacy an unscheduled visit can be scheduled 
where a PK session may be performed to investigate the elimination ( recovery, clearance and half-
life) of N8-GP. Antibody tests should be taken if not done recently. The PK data may potentially be 
used to adjust the dose of dosing regimen. 
5.3.3 Treatment of bleeding episodes
Patient’s parent(s)/LAR(s) will be instructed by the trial site on how to treat a bleeding episode at 
home and how to record the bleeding episodes, the treatment and the response to treatment in the 
electronic diary (eDiary). Treatment requiring bleeding episodes should be treated immediately 
(i.e., when the patient experiences the first clinical symptoms of a bleeding episode, or when 
observed by parent(s)/LAR(s)) be treated with N8-GP at doses of 20-75 U/Kg bw, depending on 
severity and location of the bleeding episode, see Table 5-1. 
For treatment of severe/life-threatening bleeding episodes administration of higher doses of N8-GP 
is permitted at the investigators discretion. For recommended dose levels see Table 5-1. In cases of 
a severe bleeding episode the site must be contacted. 
At least the first 2 treatment-requiring bleeding episodes should be treated in the presence of a 
qualified health care professional. If the patient cannot be brought quickly to the trial site, the trial 
site must be contacted for treatment instructions or transport. A severe bleeding episode should 
immediately be treated at home or at the local emergency room, and the trial site must be contacted 
for further instructions or transport. For severe bleeding episodes before the 2nd EDs the treatment 
must take place at the site.
In case of Treatment requiring bleeding episodes prior to the start of the home treatment these
should immediately be treated at the trial site. In case the bleeding episode occurs outside trial site 
opening hours, the bleeding episode should be treated according to local practice. 
5.3.4 Treatment of suspected bleeding episodes
In case of a 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 and will be recorded in EDC 
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Status:
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as other severe bleeding episodes. The recommended dose is equivalent to treatment of a severe 
bleeding episode
5.3.5 Surgery
Patients undergoing surgical procedures while participating in this trial can receive bleeding 
preventive treatments with N8-GP. Minor surgeries, dental extractions and placement of central 
venous access ports can be performed while participating in the trial by administering extra doses of 
N8-GP equivalent to the dose for a severe bleeding episode (see Table 5-1), or aligned to local 
standard of practice, or guidelines for treatment of patients with haemophilia A with FVIII in the 
perioperative period. 
Major surgery will only be allowed after the individual patient has reached 50 N8-GP EDs. The 
major surgery should be planned and conducted in accordance with recommendation in the WFH 
guidelines for management of haemophilia (ref 29) and local guidelines. Determination of dose and 
dose interval should include close monitoring of FVIII activity trough and peak levels considering 
the T½ of N8-GP and clinical evaluation of the haemostatic effect. 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. and upon completions of the pathfinder™3 surgery trial 
(NN7088-3860). The treatment regimen for major surgery will be based on results from the 
pathfinder™3 surgery trial (NN7088-3860) and PK data obtained in the pathfinder™5 trial 
(NN7088-3885) in paediatric PTPs. Novo Nordisk will communicate when major surgeries are 
allowed in this trial.
….
Definition of major surgery
Major surgery is defined as any invasive operative procedure that requires several days more than 3 
days of FVIII substitution therapy and/or where any one or more of the following occur: 
A body cavity is entered
A mesenchymal barrier (e.g., pleura, peritoneum or dura) is crossed 
A fascial plane is opened
An organ is removed
When normal anatomy is operatively altered 
Major elective orthopaedic surgery
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CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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Doses of N8-GP should be aimed at securing haemostasis and in accordance with recommendation 
in the WFH guidelines for management of haemophilia (ref 29) and/or local guidelines. In the 
recovery period the patient should be dosed with N8-GP according to local standard of practice 
and/or general guidelines for treatment of patients with haemophilia A. Determination of dose and 
dose interval should include close monitoring of FVIII activity trough and peak levels considering 
the T½ of N8-GP.
…
5.3.6 Treatment of patients with FVIII inhibitors
… 
Patients who develop FVIII inhibitors during this trial may receive N8-GP and/or Treatment of 
bleeding episodes with by-passing agents, e.g. i.e. rFVIIa or APCC for treatment of bleeding 
episodes according to local standard care is allowed for patients who develop FVIII inhibitors 
within this trial. However, N8-GP dose levels used should not exceed 75 U/kg as a single dose and 
not exceed 200 U/kg as a maximum 24 hour dose. Treatment with FVIII concentrates other than 
N8-GP is not allowed. By-passing agents are not considered trial medication. 
The ultimate goal of treatment in patients with high-titre inhibitors is to permanently eradicate the 
inhibitor by immune tolerance induction therapy (ITI), thereby making it possible for the patient to 
be treated routinely with FVIII replacement therapy again. The therapeutic concept is based on 
long-term uninterrupted high exposure to FVIII in an effort to sufficiently tolerise the immune 
system. In that state, the clinical responsiveness to FVIII replacement therapy is restored. 
…. 
Novo Nordisk plans that Patients who develop inhibitors, within this trial, will be offered continued
treatment with N8-GP, including ITI for a maximum of 24 months. ITI with N8-GP will not be 
initiated until Novo Nordisk has reviewed the clinical data available after completion of the N8-GP 
pivotal and surgery trial (pathfinder™2 and pathfinder™3), and of the paediatric PTP trial 
(pathfinder™5) data needed for opening the paediatric PUP trial according to EMA requirements.
It is expected to use a N8-GP dosing regimen for ITI similar to local standard care/guidelines 
applied for ITI with marketed FVIII products. For each individual patient, ITI regimens with N8-GP 
would have to be reviewed by the investigator every month, and more formally reviewed every 3 
months by Novo Nordisk.
If patients with (usually low titre) inhibitors respond well to treatment with N8-GP then the patient 
can continue the prophylaxis. These patients can still start ITI treatment within 6 months after the 
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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confirmatory inhibitor test. If the inhibitor is still present (BU>/=0.6) at 6 months after the 
confirmatory test the patient must start ITI or withdraw from the trial.
Based on experience with marketed FVIII products, a successful ITI can be expected in about 60–
80% of cases receiving ITI with N8-GP, leading to several important benefits for the patient, 
including:
……
5.3.6.1 ITI therapy with N8-GP
Patients who develop inhibitors, within the pathfinder™6 trial, will be offered continued ITI 
treatment with N8-GP for a maximum of 24 months. ITI therapy with FVIII concentrates other than 
N8-GP is not allowed within the trial. It may also be decided by the Investigator and/or parent/legal 
representative to withdraw the patients who developed developing FVIII inhibitors.
Patients will be evaluated after 12 months of ITI treatment, based on the level of inhibitors. If 
inhibitors are still positive after 12 months, but the decline from peak titre level is ≥ 20%, ITI may 
be continued for a the total maximum period of 24 month in total.
If needed and decided by the Investigator, the initiation of the ITI can be delayed but it has to start 
within 6 months from the time of diagnosis of inhibitor. Inhibitor patients that commence ITI with 
N8-GP will follow an alternative treatment regimen and visit schedule (see Section 8.1.11). ). For 
each individual patient, ITI regimen with N8-GP will need to be reviewed by the investigator every 
month, and formally reviewed every 3 months by Novo Nordisk.
The used N8-GP dosing regimen is at the discretion of the investigator, but a N8-GP dosing 
regimen similar to the local standard of care applied for ITI with marketed FVIII products is 
recommended. However, daily N8-GP dose levels used for ITI should not exceed 75 U/kg as a 
single dose and not exceed 200 U/kg as a maximum 24 hour dose.
The FVIII inhibitor level will be evaluated continuously in all patients that receive N8-GP for ITI. If 
the inhibitor disappears during the ITI (see Section 8.4.2.2), the patient should resume prophylaxis 
treatment as recommended in Section 5.3.2. Patients will be evaluated after 12 months and 24 
months of ITI treatment, based on the level of inhibitors, within the predefined specifications of 
withdrawal, see Section 6.4. If inhibitors are still positive after 12 months, but the decline from 
peak titre level is ≥ 20%, ITI may continue for a maximum period of 24 month in total.For patients 
still with positive inhibitors after 12 months ITI, continued trial participation will be evaluated by 
the investigator and sponsor based on the level of inhibitors, within the predefined specifications of 
withdrawal criteria 8, see Section 6.4. However, if the inhibitor persists after 24 months of ITI, the 
patient will be withdrawn from the trial. 
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
15 of 41
Criteria for successful ITI therapy with N8-GP: In line with international consensus, and based on 
the mean N8-GP half-life observed in adults (18.5h) and children < 6 years of age (15h), successful 
N8-GP ITI outcome is based on the achievement of three stringent efficacy criteria

Undetectable inhibitor titre < 0.6 BU 

Normalized FVIII in vivo recovery, defined as ≥ 66% of expected incremental recovery 

N8-GP half-life ≥ 9 hours after a 72 h treatment-free washout period
Once the inhibitor is confirmed to be negative, FVIII recovery should be measured after an 
injection of 60 U/kg of N8-GP without washout period. When FVIII recovery is shown to be ≥66% 
of the expected incremental recovery, based on PK data obtained in paediatric PTPs, a FVIII half-
life study needs to be conducted after administration of 60 U/kg of N8-GP after a 72 hours 
treatment-free washout period. This half-life study should be repeated, if necessary based on 
investigators discretion, until the half-life is confirmed to be ≥ 9 hours. Blood samples for FVIII 
half-life evaluation should be taken pre-dose and 1h, 6h, 24 h, 48 h, and optional 72 h post-dose 
(see Section 8.4.2). If half-life is 9 hours the ITI should continue.
For patients who develop low titre and/or clinically insignificant inhibitors (≤<5 BU), the dose 
level and dosing frequency of N8-GP will be decided by the Investigator based on clinical 
evaluation.  
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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Table 5-1
Intravenous N8-GP treatment
Indication
Dosage
Frequency
Pre-prophylaxis 
(pt. less than 24 months of age)
Approximately 60 U/Kg (50-75U/Kg) On-demand or slow start prophylaxis 
(less than weekly dosing more than 
one week between doses)
Prophylaxis – main phase 
Approximately 60 U/Kg (50-75U/Kg) Every 3rd day, twice weekly or every 
7th day(±1 day)
Prophylaxis – extension phase 
Approximately 60 U/Kg (50-75U/Kg) Every 3rd day, twice weekly, every 4th
day, every 5th day, every 6th day or 
every 7th day(±1 day)
Mild/moderate bleeding episode
20-60 U/Kg
On-demand (breakthrough bleeding 
episodes) (site must be contacted if 
more than 2 doses needed)
Severe bleeding episode
40-75 U/Kg
For treatment of severe/life-
threatening bleeding episodes 
administration of higher doses of N8-
GP is permitted at the investigator’s 
discretion guided by repetitive 
measurements of trough and 
recovery
On-demand (site must be contacted)
Minor surgery
40-75 U/Kg 
In accordance with local standard of 
practice of the participating trial site
Major surgery, only allowed after 50 
EDs
Recommended doses regimens will 
be provided when the N8-GP surgery 
trials completed In accordance with 
WHF guideline and local standard of 
practice of the participating trial site
On demand In accordance with WHF 
guideline and local standard of 
practice of the participating trial site
Low titre inhibitor
Recommendation 60 U/Kg (50-75 
U/Kg) for prevention and treatment 
of bleeding episodes
Dosing interval as needed
High titre inhibitors
ITI treatment according to local 
standard. Maximum of 75 U/Kg as 
single dose, maximum of 200 U/Kg 
over 24 hours
Maximum dose/day
200 U/Kg
Total maximum dose over 24 hours
…..
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
17 of 41
5.5 Rationale for treatment
…..
The reason for providing the possibility of ITI of patients who develops high titre inhibitors is to 
permanently eradicate the inhibitor, thereby making it possible for the patient to be treated routinely 
with FVIII replacement therapy….. 
6
Trial population
….
6.2 Trial population
…
4 No prior use of purified factor VIII containing clotting factor products (5 previous exposure 
days to blood components are is acceptable) 
….
6.4 Withdrawal criteria
…

The patient must be withdrawn if the following applies:
1. Dosed in the trial, but not fulfilling the inclusion and/or exclusion criteria
2. Anaphylactic reaction to the trial product, for definition see Section 11.1
Major surgery before 50 EDs, see Section 5.3.4
Significant thromboembolic event, see Section 11.1
Incapacity or unwillingness to follow trial procedures
Use of coagulations factors other than N8-GP or anti-coagulants unless in relation to ITI
ITI treatment has not been started within 6 months from the date of confirmation of positive FVIII 
inhibitor (BU ≥ 0.6/ml) unless the FVIII inhibitor has disappeared (BU<0.6) under continuous 
prophylactic treatment within the 6 months.
FVIII inhibitor titre decline from peak level is less than 20% after 12 months of ITI treatment
FVIII inhibitor is positive (BU ≥ 0.6/ml) after 24 months of ITI treatment.
After completed ITI treatment (maximum 24 months), prophylaxis treatment as described in the 
protocol is not resumed/started
Positive inhibitor test result from visit 1 before first dosing (a positive sample does not have to be 
confirmed in a confirmatory test)
Participation in another clinical trial throughout the trial.
….
6.6.3 Rationale for withdrawal criteria
Criteria nos. 1-6 are included to protect the patient's safety and reliability of the data.
Criteria nos. 7-1012 are included to ensure appropriate treatment of inhibitor patients.
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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7 Milestones
Planned duration of recruitment period (FPFV – LPFV): approximately 42 months 
Planned FPFV: 26-Jun-2014 01 May 2014
Planned LPFV: 02 October 2020 02 Apr 2018
End of trial is defined as LPLV:  13 November 2021 13 May 2019
The duration of the trial for each individual country will vary. However, the end of trial will be no 
later than 13 May 2019 13 November 2021
The end of the clinical trial is defined as last visit of the last patient.
Planned completion of clinical trial report (CTR): November 2019 14 May 2022.
The duration of N8-GP treatment in the trial is a minimum total 100EDs for a particular patient. 
Once a patient has achieved 100EDs, they may be offered the option to continue in the trial until 
either N8-GP is commercially available in the relevant country or until the marketing authorisation 
application for N8-GP is rejected in the relevant country unless the N8-GP trial, part of the trial or a 
trial site is terminated by Novo Nordisk or a relevant authority for any reason. In any event, the 
LPLV for the trial will be no later than 13 November 2021 30 June 2018 whether or not the product 
is commercially available in the relevant country. 
8 Mathods and assessments
…
Fig 8-1: added to pre-prophylaxis box – Visits at: ED 5,10,15,20
…
Screening and enrolment log
….
At screening, patients will be provided with a trial card stating that they are participating in a trial 
and giving 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. 
Each patient will be assigned a unique 6-digit number. It must be stated in the medical records that 
the patient is participating in the trial, including the patient number.
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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Informed consent procedure
….
Informed consent for obtaining genotyping must be collected, if applicable. Genotype consent is not 
applicable for Israel.
….
For withdrawn patients
… 
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 
case book must be signed in the eCRF.
…
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. 
If considered relevant a caregiver can 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 equally as the parent(s)/LAR(s) in the relevant responsibilities. Site must 
follow the local law and local guidelines for decision of which task a caregiver can take 
responsibility for.
Site must document correspondence with patient’s parent(s)/LAR(s) concerning returning or 
destruction of trial drug, solvent and injection kits that are to expire or has expired.
….
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 
law. All patients will be provided with a copy on the patient information and a copy of the signed 
and dated Informed Consent Form.
….
Pre-prophylaxis treatment
Pre-prophylaxis is optional and is the period before start of regular prophylaxis. The pre-
prophylaxis period ends when the patient has reached 20 EDs or has turned 24 months of age, 
whatever comes first, and the patient must begin prophylaxis regimen.
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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During pre-prophylaxis the following dosing regimen applies: 

approximately 60 U/Kg N8-GP within the range of 50-75 U/Kg bw, see Section 5.3

individualised prophylactic dosing intervals but less frequent than every 7th day(once weekly)

on-demand treatment of bleeding episodes or minor surgeries
See further Section 5.3.2.
…
8.1.1.2 Prophylaxis treatment
Prophylaxis treatment can begin A patient may change from pre-prophylaxis to prophylaxis at visit 
1 or at any time during the pre-prophylaxis period or but must be initiated when the patient has 
reached 20 EDs on pre-prophylaxis or has turned 24 months of age, whatever comes first. 
The dosing frequency during main phase is individualised within the following interval: twice 
weekly, every 3rd day or every 7th day. Changes to the regimen should be recorded in the IWRS. If 
changes occur between visits, it should be recorded in an unscheduled visit, see Section 8.1.9.
For patient that enter the prophylaxis treatement after a period of pre-prophylaxis the next visit in 
the sequence will be determinated by the numbers of EDs.
…
8.1.2 Visit 1 – first dosing with N8-GP
V1 will take place after the screening visit (V0) whenever the first treatment of N8-GP is 
administered, if not already combined with V0. 
Before the first dose of N8-GP is given as a minimum the inhibitor test must be taken and send to 
central laboratory for analysis. 
…
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 visit in the eCRF.
8.1.3 Visit 2, 3, 4-6 – main phase
The 2 first N8-GP EDs injections must take place at trial site (V1+V2). Hereafter the injections can 
be administered at the trial site or outside the trial site.
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
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… 
Visits at ED: 2 (V2), 5 ± 1 ED (V3), 10 ± 2 EDs (V4), 15 ± 2 EDs (V5), 20 ± 2 EDs (V6). 
….
Reminders
….
Investigator must ensure that patient’s parent(s)/LAR(s) return any trial medication that would 
expire and avoid use of any expired solvent or injection kit during the next home treatment 
period 
…..
Visit 7-8 – main phase
From V6 or shortly after at ED 20 all patients (including patients previously on pre-prophylaxis) 
will be on prophylaxis treatment with N8-GP on twice weekly, every 3rd day or every 7th day. 
Between the visits the patient will receive N8-GP treatment at home if comfortable with home 
administrations or at the site, see Section 8.1.12.
Visits at EDs: 30 ± 2 EDs (V7), and 40 ± 2 EDs (V8).
…
Reminders 
….
Drug accountability of trial product must be recorded in the IWRS, see Section 10
Investigator must ensure that patient’s parent(s)/LAR(s) return any trial medication that would 
expire and avoid use of any expired solvent or injection kit during the next home treatment 
period 
…..
Visit 9 – end of main phase
Visit 9 should take place at either ED 50, ED 51 or ED 52.
Assessments for V9 are listed in Table 2-1.In the extension phase the patient will continue 
prophylaxis with 60 U/Kg in the regimen of every 3rd day, twice weekly, every 4th day, every 5th day, 
every 6th day or every 7th day. See Table 5-1. Changes to the regimen should be recorded in the 
eCRF. 
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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Reminders 
….
Drug accountability of trial product must be recorded in the IWRS, see Section 10
Investigator must ensure that patient’s parent(s)/LAR(s) return any trial medication that would 
expire and avoid use of any expired solvent or injection kit during the next 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
….
Visit 10-13 – extension phase
…
Visit at EDs: 60 ± 2 EDs (V10), 70 ± 2 EDs (V11), 80 ± 2 EDs (V12), and 90 ± 2 EDs (V13). 
…
Reminders
…
Drug accountability of trial product must be recorded in the IWRS, see Section 10
Investigator must ensure that patient’s parent(s)/LAR(s) return any trial medication that would 
expire and avoid use of any expired solvent or injection kit during the next home treatment 
period 
Home treatment training, see Sections 8.1.12 and 8.8.2.
…
Visit 14 - end of extension phase
….
Reminders 
…
Drug accountability of trial product must be recorded in the IWRS, see Section 10
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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Investigator must ensure that patient’s parent(s)/LAR(s) return any trial medication that would 
expire and avoid use of any expired solvent or injection kit during the next home treatment 
period 
….
Visit 15-X until end of trial
If N8-GP is not commercially available in a patient’s country at the time of visit 14, the trial period 
may be extended with visits that are scheduled 24 weeks ± 4 weeks. These additional visits are 
referred to as visit 15 to visit X, where X can be any visit from 16 and onwards. This option for the 
patient to continue in the extension phase of the trial may be offered until either N8-GP becomes 
commercially available in the relevant country, or until the marketing authorisation application is 
rejected in the relevant country unless the N8-GP trial, part of the trial or a trial site is terminated by 
Novo Nordisk or a relevant authority for any reason. The End of Trial visit must be scheduled 
within 1 month provided always that after it has been communicated to site to close the trial the last 
patietn last visit for the prophylaxis period until end of trial but no later than 13 May 2019
November 2021 whether or not the product is commercially available in the relevant country at this 
time. 
At every dosing visit from V14V15-VX, drug will be dispensed to cover up to 3 months of 
treatment. Depending on patient’s treatment regimen, additional dispensing visits might need to be 
scheduled to cover treatment in the period between visits.
Assessments for V15-VX are listed in Table 2-1.
Reminders 
An appointment for the next visit should be made
Next visit must be planned to allow for the required wash-out of 72 hours, see Section 8.8.3.1
Recording of body weight, see Section 8.3.1, and dispensing of N8-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
Investigator must ensure that patient’s parent(s)/LAR(s) return any trial medication that would 
expire and avoid use of any expired solvent or injection kit during the next home treatment 
period 
eDiary compliance review, see Section 12.3
……
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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8.1.10 Unscheduled visit 
…
The following forms can be found in the unscheduled visit in the eCRF:
Central lab
Bleeding episodes
Dosing of N8-GP
Surgery*
PK session*
Change of regimen
* Surgery and PK session can also be performed during a regular visit but are to be registered 
under unscheduled visits.
8.1.11 ITI Visit 
…
In case of high titre FVIII inhibitor (>5BU) confirmed by central laboratory the investigator must 
decide how to proceed with treatment. Novo Nordisk will communicate when ITI is allowed in this 
trial, see Section 5.3.6. ITI with N8-GP must be initiated within 6 months of the confirmatory 
inhibitor test. The used N8-GP dose and dosing regimen is at the discretion of the investigator but 
should not exceed 75 U/Kg for a single dose, and not exceed a total daily dose of 200 U/Kg. By-
passing agents can be used to treat bleeding episodes.
If ITI is initiated, the patient will follow a visit schedule prescribed by the investigator and 
according to local standard of practice. Monthly visits are recommended, and the below listed 
assessments are recommended to be performed:  
….
Bleeding episode evaluation (only if treatment with N8-GP)
…
Reminder
Follow up on any AEs according to Section 11.2
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
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After ITI treatment, when the inhibitor is confirmed to be negative, a FVIII recovery test should be 
performed to confirm the recovery. A dose of 60 U/Kg should be used. Before returning to regular 
prophylaxis treatment a PK session must be performed after a 72 hours treatment-free wash-out 
period, see Section 8.4.2.2 for PK session details.
For patients returning to regular prophylaxis N8-GP treatment, the visit schedule is taken up from 
where the patient left the visits according to Table 2-1. The patient must not attend the same visit 
number twice. V9 end of main phase Table 2-1 even when the corresponding total ED does not 
match.
8.1.12.1 Prophylactic home treatment
…..
The following procedures must be performed during home treatment between visits:
N8-GP administrations according to regimen prescribed by investigator
Check trial drug, solvent and injection kit for expiry date before use
Contact to the investigator/medically qualified person in case of severe bleeding episodes
Completion of the patient eDiary, including details of all bleeding episodes and N8-GP 
administrations (see Section 8.6)
…..
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 
disease under investigation.
….
8.2.2 Concomitant medication
A concomitant medication is any medication including vaccination, other than the investigational 
medicinal product (N8-GP), which is taken during the trial until EOT. By-passing agents should 
also be listed as concomitant medication.
….
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Date:
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Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
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8.3.1 Body measurements

Height at screening

Body weight, wearing light clothing only (Kg)
…
8.3.2 Physical examination
The physical examinations will be performed according to local procedure and should include:
…..
Central and peripheral nervous systems 
Cardiovascular system
….
8.4 Laboratory assessments
….
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.
….
8.4.1.1 FVIII activity 
FVIII activity will be analysed at the predefined time point as at a central laboratory selected by 
Novo Nordisk but the investigator can at any time during the trial assess FVIII activity at his/her 
discretion. 
Site must be able to analyse for FVIII activity and inhibitors locally to ensure immediate results if 
needed to evaluate the patient’s safety.
If V0 and V1 are combined, as one combined screening visit, and if FVIII activity <1% has not 
been documented in the patient medical records, it should be analysed locally and documented in 
the patient medical records. In this case the local laboratory should use their standard FVIII activity 
assay with the assay calibrator routinely used for FVIII activity analysis.
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Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
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A N8-GP reference standard must be used as assay calibrator in the FVIII activity assay after the 
patient has been dosed with N8-GP. The reference standard will be provided by Novo Nordisk 
together with a description of how to the reference standard should be handled handle, stored and 
used.
After the patient has been dosed with N8-GP, FVIII activity should be measured with an activated 
partial thromboplastin time (APTT) based one-stage clotting assay calibrated by a N8-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 request a new one when relevant.
Dependent on the type of APTT reagent used by the local lab an exemption from this requirement 
can be made, in such cases Novo Nordisk will need to approve the suggested assay on an individual 
basis. For approval of APTT based assays please contact Novo Nordisk. 
If available, FVIII activity may be measured with a chromogenic assay. In such cases a N8-GP 
reference standard is not needed.
….
8.4.2.1 FVIII activity 
…
FVIII activity should be measured according to Table 2-1.Historical value of FVIII activity can be 
used for inclusion of the patient from any time since the child was born. In relation to visit if an 
activity samples has been taken within ±1 week (for EOT only – 1 week) from the visit and send to 
central lab, this can be used for the visit assessment if the requirements for 72 hours wash out is 
respected.
…
FVIII activity will be measured by the use of two different assays developed and validated for N8-
GP (except for V0 that will only be analysed in one assay):
FVIII chromogen assay
FVIII one-stage clotting assay
….
8.4.2.2 Antibody assessments  
…
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Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
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Antibody assessment should be measured according to Table 2-1. Antibody samples taken within ±1 
week from the visit (for EOT only – 1 week) and send to central lab can be used for the visit 
assessment if the requirements for 72 hours wash out.
N8-GP/FVIII binding antibodies  
……
Samples will be analysed regularly for N8-GP binding antibodies, results will be reported to 
investigators at the end of trial, or whenever considered relevant, and will be included in the CTR.
PEG antibodies
…
Samples will be analysed for PEG binding antibodies at the end of trial or whenever considered 
relevant.  
FVIII inhibitors 
…
Any sampling for the inhibitor test must be performed at least 4 days 72 hours after last 
administration of N8-GP to allow for wash-out of the drug, unless that patient is known to have 
increased clearance of N8-GP due to the presence of FVIII inhibitors.unless that patient is 
undergoing ITI treatment.
If the result of the inhibitor test is positive, a second confirmatory inhibitor test should be performed 
by the central laboratory (except for visit 1 sample that will not need to be confirmed). The 
confirmatory samples should be collected as soon as possible, but no sooner than 72 hours 4 days
after the last dose of N8-GP. Sampling for assessments of FVIII activity (trough and recovery), and
binding antibodies, lupus anticoagulant and PEG antibodies must be performed at the same time. If 
considered relevant a lupus anticoagulant test can be performed.If the result from the lupus 
anticoagulant, the binding antibodies and/or the PEG antibodies analyses are positive we 
recommend the analyses to be repeated regularly.
….
PK assessment (optional)
In the event of a concern about reduced treatment efficacy in a patient with or without confirmed 
positive test for binding antibodies towards N8-GP/ or inhibitors an unscheduled visit is 
recommended to can be scheduled where a PK session may be performed with a dose of 60 U/Kg to 
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Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
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investigate the elimination (recovery, clearance and half-life) of N8-GP. The PK data may 
potentially be used to adjust the dose or dosing regimen. 
After having completed ITI treatment a PK session must be performed ensuring the N8-GP half-life 
to be ≥ 9 hours. A dose of 60 U/Kg should be given after a 72 hours treatment-free wash-out period.
The following time-points for blood sampling for the PK profile are suggested: pre-dose, 30 min (± 
10 min), 1h (± 1030 min), 6h (± 2 hours), 24h (± 8 hours), 48h (± 8 hours), and optional 72h 96h (± 
8 hours). 
8.4.2.3 HIV testing and CD4+ lymphocyte count 
….
Results can be transferred from the medical records if obtained within the last 6 months. 

HIV 1 and 2 antibodies (positive/negative)
….
8.4.2.4 Haematology
Haemoglobin (mmolg/L)
….
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 older, a new sample must be 
drawn and assessed at the central laboratory. If V1 is more than a month apart from V0, 
Haematology should be retaken.
Haematology should be measured according to Table 2-1.For visit 9, 14 and EOT Haematology 
sample taken within ±1 month (V9 and V14) and -1 month (EOT) and send to central lab can be 
used for the visit assessment. 
8.4.2.5 Biochemistry
….
If test results for the above mentioned biochemistry parameters are available from within one month 
prior to V0, they can be used for the V0 biochemistry assessment, if older, a new sample must be 
drawn and assessed at the central laboratory. If V1 is more than a month apart from V0, 
Biochemistry should be retaken.
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Date:
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Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
Final
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Biochemistry should be measured according to Table 2-1.For visit 9, 14 and EOT Biochemistry 
sample taken within ±1 month (V9 and V14) and -1 month (EOT) and send to central lab can be 
used for the visit assessment. 
8.4.2.6 F8 and HLA genotype testing (not applicable for Israel) 
…..
F8 and HLA genotype can be measured any time from visit 0 to visit 8. 
F8 and HLA genotype can be measured according to Table 2-1.
….
8.4.2.7 Allergic reaction testing 
Allergic reaction testing will only be performed in patients developing severe allergic reactions 
related to N8-GP treatment as judged by the Investigator. The Baseline sample will only be 
analysed for assessment in case of the allergic reactions.
If a severe allergic reaction related to treatment occurs, blood samples should be taken at an 
unscheduled visit as soon as convenient, but and not later than 2 months after the event. The allergic 
reaction assessments will be performed at a laboratory selected by Novo Nordisk or at a Novo 
Nordisk laboratory. 
Test to be performed: 
N8-GP IgE antibodies
FVIII IgE antibodies
FVIII inhibitors 
N8-GP/FVIII binding antibodies
Optional tests at the discretion of the investigator:
HCP IgE antibodies
HCP IgG antibodies
PEG antibodies
Murine IgG antibodies
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Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
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…
8.4.3 Blood sampling in infants and children
….. 
The total volume of blood to be collected for each patient per visit will not exceed 12.5 10 mL. 
…
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 record. The vein used for 
drug injection should not be used for blood sampling until more than 30 minutes have passed after 
the injection. The same device use for drug injection may not be used for blood draw post-dose.
…. 
8.4.4 Storage of samples
…. 
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 drug if 
required by health authorities or for safety reasons, see Section 23.2.
8.5 N8-GP administration
N8-GP will be administered while the patient is in a comfortable position according to Table 5-1. 
During ED 1-2 with treatment at the trial site (V1 -V2):
The first 2 N8-GP doses should be administered at trial site.
Trial injection kits (butterflies etc) will be provided by Novo Nordisk. Choice of between butterfly 
or cannula for N8-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. 
During ED 3-100 and/or until EOT with treatment at trial site and at home (after V2):
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Date:
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Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
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…
8.6.1 Assessment of bleeding episodes and treatment response
Table 8-1 Haemostatic response for bleeding episode - 4-point scale
8.7 Surgery
Before any surgery is performed blood samples for assessment of inhibitors must be taken and send 
to central lab unless a test has been taken and send to central lab within 30 days (but the results 
does not have to be available before the surgery).
Preventive N8-GP treatment before minor surgery including placement or removal of central 
venous access port can be performed during within this trial at the investigator’s discretion 
according to local guidelines. A dose of 40-75 U/Kg N8-GP prior to minor surgery is recommended 
to prevent perioperative bleeding episodes, see Table 5-1. Major surgeries are only allowed after 50 
EDs and when the results from the pathfinder™6 (NN7088-3860) is available. Prior to major 
surgery a dose of maximum 75 U/kg is recommended , see Section 5.3.5.
Preventive N8-GP treatment prior to surgery should be captured in eCRF or in the eDiary.
Emergency surgeries are allowed in this trial if adequate supply of N8-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 N8-
GP doses administered in relation to a surgery must be registered on the surgery from in the eCRF.
8.7.1 Minor surgery
Definition of minor surgery, see Section 5.3.4
For minor surgery the following should be recorded

Date, time and volume of preventive dose before surgery

Type of surgery

Indication for surgery

Date of surgery

Start time of surgery*

Withdrawal criteria (if other than the trial drug is used)
8.7.1 Data collection during Major surgery
Definition of minor and major surgery, see Section 5.3.5
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Date:
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Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
Final
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FVIII inhibitor sample should be taken prior to surgery and analysed at the central laboratory.
For major surgery surgeries the following should be recorded in the eCRF:

Date, time and volume of preventive dose before surgery

Type of surgery

Indication for surgery

Date of surgery

Start and stop time of surgery*

Dosing of N8-GP in relation to the surgery

Clinical evaluation of haemostatic response, see Table 8-1 8-2

Concomitant medication incl. blood products

Adverse events

Clinical narrative of the procedure

Withdrawal criteria (e.g. if other than the trial drug is used)
*Start and stop of surgery is defined as knife-to-skin and last stitch, or similar that seems 
appropriate.
Injections with N8-GP administered after surgery has been completed should be reported either in 
the eCRF (injections administered at site) or in the eDiary (injections administered at home), see 
Section 12.3
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:
Table 8–2 Haemostatic response for Surgery - 4-point scale
Classification
Description
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
None
Bleeding due to inadequate therapeutic response with adequate 
dosing, change of regimen required
. 
…
8.8.2 Home treatment training
….
A home treatment guide for the reconstitution and administration process will be available as hands-
out for the patient’s parent(s)/LAR(s). 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.
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Novo Nordisk
Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
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….
8.8.3 Electronic diary (eDiary)
…
During the home treatment period the patient’s parent(s)/LAR(s) must ensure that all pre-
prophylaxis and 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. 
The details of bleeding episodes should be entered by the parent(s)/LAR(s) in the eDiary. In case a 
parent(s)/LAR(s) is unable to enter a bleeding episode in the eDiary, or in case the patient is 
hospitalised, the Investigator will report the bleeding episode in the eCRF.
…
8.8.4 Contact between the investigator/medically qualified person and the patient
….
The expiry 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 dispensing is relevant and to inform the 
patient of which unused vials to return to the site. Expiry of injection kits should be discussed.
….
9 Trial supplies
9.1 Trial product
….
After reconstitution the appropriate volume of the vials will be drawn into a syringe. Maximum 4 
mL can be withdrawn from each vial of reconstituted N8-GP and the content of several vials may be 
combined into one syringe. The content of several vials may be combined in one syringe. N8-GP 
may not be added to or mixed with any other material than Sodium Chloride Solution. 
…
Novo Nordisk will not supply any Non Investigational Medical Products (NIMPs). 0.9% Sodium 
Chloride Solution for reconstitution of the N8-GP trial product will be supplied by Novo Nordisk.
…
9.3 Storage
….
The trial product N8-GP powder and Sodium Chloride Solution must be stored in a secure place at 
trial site. For N8-GP under refrigeration at 2-8°C, and for Sodium Chloride Solvent at 2-30°C, both 
protected against light and are hereby stable until the expiry date given. It is recommended to use 
the reconstituted N8-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 
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Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
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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.
….
9.4 Drug accountability and destruction
…
Drug accountability is not required for Sodium Chloride Solution used for reconstitutions, but it is 
the responsibility of the investigator or delegate to follow Sodium Chloride Solution expiry and 
prevent patient use after expiry.
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, if applicable.
11 Adverse events and technical complaints 
11.1 Definitions
……
Definition of an acute, evolving, or recent myocardial infarction:
1. 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)
……
Clinical criteria for diagnosing anaphylaxis (infants and children only) (Sampson et al. 
200624): 
…
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 patient’s baseline* 
b. Adults: systolic BP of less than 90 mm Hg or greater than 
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Date:
20 March 2015
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Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
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* 30% decrease 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.
….
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 N8-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 N8-GP.
….
11.6.2 Rules for putting the enrolment on hold
A safety analysis will be performed to evaluate the development of inhibitor at the following 
predefined time point:
• after the first 25 patients have reached been to visit 6 (20 - 25 exposure days )
….
12 Case report forms 
….
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 if the eCRF is unavailable.
….
12.2 Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 3 5 days after the visit. Once data have been entered, it will be available to Novo Nordisk for 
data verification and validation purposes. 
….
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, surgery and treatment hereof, 
see Sections 8.1.12.1and 8.6. The eDiary and related support services will be supplied by a vendor 
working under the direction and supervision of Novo Nordisk. 
…..
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Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
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It is the responsibility of the Investigator or delegate 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.
…
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. 
The first 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 at 
site between V0 and V14. If all patients at site are in the period after V14, intervals between 
monitoring visits must not exceed 26 weeks, provided on site contact at least every 12 weeks. .  
….
16 Statistical considerations
Novo Nordisk will be responsible for the statistical analysis.
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
The main statistical reporting of the trial will be performed when 50 patients have completed main 
phase (minimum 25 weeks) with at least 50 EDs and completed visit 9. EDs during ITI treatment 
will not count in the determination of when a patient has reached 50 EDs.
….
16.2 Definition of analysis sets
Descriptions and analysis of efficacy data will be based on the Full Analysis Set (FAS), as defined 
in ICH E9 guidelines.26 The FAS includes all patients exposed to N8-GP. The safety analysis and 
descriptions will be based on the Safety Analysis Set (SAS). The SAS will consist of all patients 
exposed to N8-GP.
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Trial ID: NN7088-3908
Version:
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UTN: U1111-1148-1897
Status:
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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.
….
16.4.2.6 Other assessments
…
FVIII trough level is defined as the activity recorded immediately before N8-GP injection, and 
reported as (IU/mL). IR30min is defined as the peak activity recorded 30 minutes after the end of N8-
GP injection, and reported as [IU/mL]/[IU/Kg]. It is calculated by subtracting the FVIII trough level 
from the FVIII activity recorded 30 minutes after ended N8-GP injection, and dividing the 
difference by the dose injected at time 0 expressed as U/Kg bw.
…
16.6 Sequential safety analysis and safety monitoring
…
after the first 25 patients have reached been to visit 6 (20 - 25 exposure days)
….
17 Ethics
…
17.1 Informed Consent
…
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.
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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The informed consent contains a section explaining that Novo Nordisk is asking to store left over 
blood from blood samples and use it to analyse for further analyses within the trial characterising 
biomarkers within the trial.The accept is voluntary and independent on participation in the trial. 
…
20 Critical documents
…

List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
….
For local lab parameters the following will be collected:
….

Laboratory methods (only non-standard assays) and/or analytic methods
…..
21 Responsibilities
…..
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 provided by Firecrest. It is recommended that all site staff takes the 
Firecrest protocol training.
….
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 
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
40 of 41
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.
…
23 Retention of clinical trial documentation and human biospecimens
23.1 Retention of clinical trial documentation
…
For Japan: The trial site should retain clinical trial documentation until approval, or 3 years after 
the date of premature termination or completion of the clinical trial. The sponsor should retain 
clinical trial documentation for 5 years after the approval (in case of drug patient to re-examination, 
until re-examination is completed), or 3 years after the date of premature termination or completion 
of the clinical trial.
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 and other biospecimen 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). All remaining blood samples will be stored until the trai lhas 
been evaluated by appropiate authorities or until the project terminates, but no longer than 15 years 
from end of trial. As new biomarkers related to the disease and/or safety, efficacy, or mechanism of 
action of N8-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 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 patient’s identity will remain confidential and 
samples will only be marked and identified by a unique sample ID. No direct identification of the 
patient will be stored together with the samples. The analyses will not have any medical 
consequences for the patients or their relatives. Only Novo Nordisk staff and bio-repository 
personnel (if applicable) will have access to the stored bio specimens. 
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Protocol Amendment
CONFIDENTIAL
Date:
20 March 2015
Novo Nordisk
Trial ID: NN7088-3908
Version:
2.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
41 of 41
…..
24 Institutional Review Boards/Independent Ethics Committees and regulatory 
authorities
…..
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).
….
25 Indemnity statement
…..
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 
Nordisk and Investigator are covered by the Insurance Policy issued according to applicable Polish 
law’
Only applicable for Portugal: For venous punctures, pain control measures are allowed according 
to local practice.
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Protocol Amendment
CONFIDENTIAL
Date:
01 November 2016
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
1 of 8
Protocol Amendment
no 3
to Protocol, final version 3.0
dated 17 April 2015
Trial ID: NN7088-3908
Safety and Efficacy of turoctocog alfa pegol (N8-GP) in 
Previous Untreated Patients with Haemophilia A
Trial phase: 3a
Applicable to all countries
Amendment originator:
, International Trial Manager
Department: 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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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
01 November 2016
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
2 of 8
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................2
Table of Tables..................................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
4.2.2
Secondary Endpoint.......................................................................................................................4
5.3.6.1 ITI therapy with N8-GP.................................................................................................................4
8.4
Laboratory assessments .................................................................................................................5
8.4.2.2. Antibody assessments....................................................................................................................5
8.6.1. Assessments of bleeding episodes and treatment responses .............................................................7
13Monitoring procedures............................................................................................................................7
16 Statistical considerations........................................................................................................................8
16.4.2.7 Outcome of ITI..............................................................................................................................8
Table of Figures   
Page
No table of figures entries found.
Table of Tables   
Page
No table of figures entries found.
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Protocol Amendment
CONFIDENTIAL
Date:
01 November 2016
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
3 of 8
1
Introduction including rationale for the protocol amendment
This protocol amendment has been prepared to include the following changes to the protocol:

Addition of ITI treatment secondary endpoint in order to assess the outcome of ITI. ITI 
treatment outcome assessment updated and description of the ITI treatment secondary 
endpoint added to the statistical section of the protocol in relation to this. No new blood 
samples will be required as the samples collected for checking criteria for successful ITI 
treatment will be used.

Added clarification that the dose of 60 U/kg of N8-GP to be used before taking the samples 
to assess the outcome of ITI is recommended. This provides more flexibility to investigator
if he/she wants to keep the patient on a constant dose.

Half life of FVIII changed from 9 h to 6 h after assessment of available data on FVIII 
activity from paediatric trial NN 7088-3885 using the time points for half life activity 
calculation provided in the pathfinderTM6 protocol. 

72 h time post-dose sample is equally important to other samples in half-life evaluation, 
therefore, the word optional has been deleted.

Added clarification about categorisation of clinical significance for lab parameters which are 
out of range due to underlying condition.

Monitoring of antibody development against Host Cell Protein (HCP) has been added. No 
new blood samples will be required as the samples collected for the N8-GP binding antibody 
analysis will be used. The rationale for implementing the HCP antibody analysis is based on 
a recommendation from the U.S. Food and Drug Administration (FDA).

Assessment of severity of the bleeding episode added into the list of information to be 
collected on the bleeding episode in order to align with all the trials in NN7088 program. 

Blood sampling for N8-GP binding antibodies at ITI-visits has been added in order to have 
an overview of inhibitor dynamics in relation to the whole N8-GP binding antibody 
dynamics for ITI patients.

Allowed collection of additional PEG antibodies samples at a scheduled or unscheduled visit 
per investigator’s discretion. The rational is to provide flexibility to investigator if he/she 
suspects the development of PEG antibodies at any given stage of the trial.

Addition of several data points to be source data verified for screening failures in order to 
comply with the CDISC format.
In this protocol amendment:

Any new text is written in italics.

Any text deleted from the protocol is written using strike through.
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Protocol Amendment
CONFIDENTIAL
Date:
01 November 2016
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
4 of 8
2
Changes
Table 2–2
Flow chart explanatory descriptions 
9
Blood samples must be collected prior to dosing at dosing visits. Please check that the required washout period has been met 
for inhibitor testing, see section 8.1.1.3 Before any surgeries are performed an inhibitor test must be taken if this test is more 
than 30 days. HCP antibodies will be analysed using samples taken for the N8-GP binding antibodies at the time points 
described in section8.4.2.2.
4.2.2
Secondary Endpoint
Frequency of Adverse events (AEs) including serious AEs and Medical Events of Special Interest 
(MESI).* 
Incidence of confirmed high titre inhibitors (defined as inhibitor titre > 5BU)*
Number of breakthrough bleeding episodes during prophylaxis with N8-GP (annualised bleeding 
rate).*
Haemostatic effect of N8-GP in treatment of bleeding episodes, assessed by a predefined 4-point 
haemostatic response scale (“excellent”, “good”, “moderate” and “none”).*
Consumption of N8-GP for prophylaxis (number of injections and U/Kg per month and per year)
Consumption of N8-GP for treatment of bleeding episodes (number of injections and U/Kg required 
per bleeding episode)
Total consumption of N8-GP per patient (prevention and treatment of bleeding episodes) per month 
and annualised value
Outcome of ITI,  assessed by a predefined 4-point ITI outcome scale (“success”, “partial success”, 
“failure”, “other”)
5.3.6.1 ITI therapy with N8-GP
…
Criteria for successful assessing the outcome of ITI therapy with N8-GP: 
Success: in line with international consensus13, and based on the mean N8-GP half-life observed in 
adults (18.5h) and children < 6 years of age (15h), successful N8-GP ITI outcome is based on the 
achievement of three stringent efficacy criteria

Undetectable inhibitor titre < 0.6 BU 

Normalized FVIII in vivo recovery, defined as ≥ 66% of expected incremental recovery 

N8-GP half-life ≥ 9 6 hours after a 72 h treatment-free washout period
Partial success: 

Reduction in inhibitor titre to ≤ 5 BU 

Clinical effect of N8-GP therapy as judged by the investigator
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Protocol Amendment
CONFIDENTIAL
Date:
01 November 2016
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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Failure: 

Failure to attain defined success or partial success within 24 months of uninterrupted ITI 
with N8-GP

Inhibitor decrease <20% after one year of ITI treatment
Other:

Not fulfilling above criteria, e.g. early withdrawal from ITI treatment etc.
Once the inhibitor is confirmed to be negative, FVIII recovery should be measured after an injection 
of recommended 60 U/kg of N8-GP without washout period. When FVIII recovery is shown to be 
≥66% of the expected incremental recovery, based on PK data obtained in paediatric PTPs, a FVIII 
half-life study needs to be conducted after administration of recommended 60 U/kg of N8-GP after 
a 72 hours treatment-free washout period. This half-life study should be repeated, if necessary based 
on investigators discretion, until the half-life is confirmed to be ≥ 6 hours. Blood samples for FVIII 
half-life evaluation should be taken pre-dose and 1h, 6h, 24 h, 48 h, and optional 72 h post-dose 
(see Section 8.4.2.2). If half-life is < 9 6 hours the ITI therapy should continue.
…
8.4
Laboratory assessments
…
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. Categorisation of clinical significance for out of range 
results may not be required for the following laboratory parameters (parts of the underlying 
disorder) and the investigator is therefore not required to perform a categorisation even though 
these parameters are listed in the laboratory report: e.g. FVIII activity, FVIII inhibitors, binding 
FVIII antibodies, PEG antibodies, HCP antibodies and genotype testing including HLA. 
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.
…
8.4.2.2. Antibody assessments  
The analysis will be performed at a laboratory selected by Novo Nordisk or at a Novo Nordisk 
laboratory. The procedures for analyses will follow the recommendations provided by Novo 
Nordisk. A description of the method will be included in the final report of this trial.
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Protocol Amendment
CONFIDENTIAL
Date:
01 November 2016
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
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Plasma samples will be collected for assessment of:
N8-GP/FVIII binding antibodies
Host Cell Protein (HCP) antibodies 
PEG antibodies
FVIII inhibitor 
Antibody assessment should be measured according to Table 2–1 5-1. Antibody samples taken 
within ±1 week from the visit (for EOT only – 1 week) and send to central lab can be used for the 
visit assessment if the requirements for 72 hours wash out.
…
HCP antibodies
A selection of the samples collected for the N8-GP/FVIII binding antibody analysis will be analysed 
for HCP antibodies. HCP are small pieces of protein remaining from the synthesis of recombinant 
FVIII in CHO cells. These proteins are removed during the purification, however very small 
amounts may be present in the drug product and could potentially cause an immune response. This 
analysis will be performed depending on the amount of sample available. 
The analysis of HCP antibodies is planned to include samples taken at the following time points: 
pre-dose prior to first N8-GP exposure and hereafter approximately every 6 months until the visit 9, 
hereafter every 12 months. 
If deemed necessary more samples may be analysed to fully characterise the individual patient’s 
HCP antibody profile.
PEG antibodies
Screening for PEG antibodies is based on assays that are validated according to international 
recognised guidelines.19-21 Samples measured above the assay cut-point will be subject to a 
confirmation test.
PEG antibodies should be measured according to Table 2–1 and if required, investigator may take 
additional PEG-antibodies samples at other visits. Samples will be analysed for PEG binding 
antibodies at the end of trial or whenever considered relevant.  
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Protocol Amendment
CONFIDENTIAL
Date:
01 November 2016
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
7 of 8
8.6.1. Assessments of bleeding episodes and treatment responses
…
Bleeding Episode – information to be collected
Information about bleeding episodes prior to the 2 ED (V2) 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 2 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.
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
Severity of the bleeding episode, assessed by the investigator as defined in 8.6.1
Amount, and time of each dose of N8-GP
Haemostatic response assessed by the 4-point scale defined in Table 8–1
…
13
Monitoring procedures 
…
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 at site 
between V0 and V14. If all patients at site are in the period after V14, intervals between monitoring 
visits must not exceed 26 weeks, provided on site contact at least every 12 weeks.
…
For screening failures: Data for the screening visit must be entered in the eCRF within preferably 3 
days after data are available and the Screening Failure Form must be completed. Source data 
verification is not required except for informed consent, date of visit, demographics (sex, date of 
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Protocol Amendment
CONFIDENTIAL
Date:
01 November 2016
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
8 of 8
birth and race), violated inclusion/exclusion criteria, screening failure form 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.
…
16 Statistical considerations
……
Patients initiating ITI treatment will for the statistical analyses be considered like withdrawals and 
data collected during ITI treatment period will be summarised and reported separately. Evaluation 
of these data will be considered exploratory only. 
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 
16.4.2.7 Outcome of ITI
Outcome of ITI,  assessed by a predefined 4-point ITI outcome scale (“success”, “partial success”, 
“failure”, “other”), for patient(s) who undergo ITI treatment during the trial, will be summarised.
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Protocol Amendment no 4 
CONFIDENTIAL 
Date: 
14
 
June 2018
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1.0
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT No.: 2013-004025-88 
Page: 
1 of 5 
Protocol Amendment 
no 4 
to Protocol, version 4 
dated 01-November-2016 
Trial ID: NN7088-3908 
Safety and Efficacy of turoctocog alfa pegol (N8-GP) in 
Previously Untreated Patients with Haemophilia A 
Trial phase: 3a 
Applicable to Israel 
Amendment originator: 
, Clinical Trials Manager  
Department: Haemophilia, Clinical Operations NN IL 
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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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 4 
CONFIDENTIAL 
Date: 
14
 
June 2018 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1.0 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT No.: 2013-004025-88 
Page: 
2 of 5 
 
 
 
 
Table of Contents    
 
 
 
Table of  Contents............................................................................................................................................2 
1 
Introduction including rationale for the protocol amendment ............................................................. 3 
2 
Changes ...................................................................................................................................................... 3 
Table of contents ............................................................................................................................................... 3 
Table 2–2  
Flow chart explanatory descriptions ........................................................................ 3 
 
 
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Protocol Amendment no 4 
CONFIDENTIAL 
Date: 
14
 
June 2018 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1.0 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT No.: 2013-004025-88 
Page: 
3 of 5 
 
 
1 
Introduction including rationale for the protocol amendment 
Patients with congenital haemophilia A have a mutation in coagulation Factor 8 (F8) gene. The 
different types of mutations in the F8 gene are associated with different probabilities for 
development of inhibitors. Inhibitors are antibodies that neutralises the factor VIII activity thereby 
rendering treatment with replacement factor products, such as N8-GP, difficult.    
 
Israel was excluded from F8 and HLA genotype testing however, since the incidence of FVIII 
inhibitors is the primary endpoint of the trial and certain mutations are related to very high inhibitor 
rates, the mutation composition of the trial population is pivotal for the understanding of the 
immunogenicity.  
 
With the current protocol amendment Novo Nordisk is seeking permission to obtain the F8 
genotype from the patients in Israel, if already available. If not available or if it needs to be re-
tested, based on the investigators discretion, F8 and HLA genotype testing will be offered. 
 
The results will be part of the clinical data analysis and reporting and used for trial specific 
purposes only. All information will be kept confidential. 
 
 
In this protocol amendment: 
 Any new text is written in italics. 
 Any text deleted from the protocol is written using strike through. 
 
2 
Changes 
Table of contents 
8.4.2.6  
F8 and HLA genotype testing (not applicable for Israel) ....................64 
 
Table 2–2  Flow chart explanatory descriptions 
Footer 12.  F8 and HLA genotype sample is only allowed upon patient’s parent(s)/LAR(s) signing 
the consent for genotyping and should only be done if not already documented in patient’s medical 
record. The sample can be collected at any visit between V0 and V8, taking the limitation of the 
allowed blood sampling volume into account. Genotype is not applicable for Israel 
 
 
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Protocol Amendment no 4 
CONFIDENTIAL 
Date: 
14
 
June 2018 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1.0 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT No.: 2013-004025-88 
Page: 
4 of 5 
 
 
 
8.1 
Visit procedures 
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 for obtaining genotyping must be collected, if applicable. Genotype consent is not 
applicable for Israel. 
 
8.4.2.6  
F8 and HLA genotype testing (not applicable for Israel) 
At Visit 0, aAll patient’s parent(s)/LAR(s) will be asked about documentation of previous Factor 
VIII gene (F8) and Human Leucocyte Antigen (HLA) genotype tests. If not available or if it needs 
to be re-tested, based on the investigators discretion, F8 and HLA genotype testing will be offered if 
allowed according to local law. The F8 and HLA genotype analysis will be performed at a  
laboratory selected by Novo Nordisk, using DNA isolated from leucocytes from the patient’s blood. 
No analysis will be performed concerning other genes than F8 and HLA. Samples will be disposed 
appropriately after the test and all test results are kept confidential. 
Investigator and/or patient’s parent(s)/LAR(s) have the right to refuse to provide patient’s F8 and 
HLA genotype documentation or to refuse genotyping. This will not prevent the patient from 
participating in the trial. 
F8 and HLA genotype can be measured any time from visit 0 to visit 8 during the trial. 
Applicable for Japan only: If documentation of the patient´s genotype already exists, the patient is 
offered to provide his data for the trial. If no previous data exists and genotyping consent is 
obtained, FVIII and HLA genotype analysis is performed at the laboratory in Bonn, Germany, using 
DNA isolated from leucocytes from the patient’s blood. No analysis will be performed concerning 
other genes than F8 and HLA. Samples will be disposed appropriately after the test and all test 
results are kept confidential. 
Applicable for Israel only: No genotype testing or genotype information will be collected. 
 
16.7  
Reporting of F8 and HLA genotype 
Information about underlying gene defects of F8 and HLA will be listed in the clinical trial report, 
except for Israel. No statistical analysis will be performed. 
 
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Protocol Amendment no 4 
CONFIDENTIAL 
Date: 
14
 
June 2018 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1.0 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT No.: 2013-004025-88 
Page: 
5 of 5 
 
 
17.1  
Informed consent 
F8 and HLA genotype testing/collection of previous genotype documentation (not applicable 
for Israel): 
 
Genotype testing is offered to the patients participating in this trial. If documentation of the 
patients’ genotype already exists, the patient and/or the patient’s parent(s)/LAR(s) must give their 
consent before the data can be collected for trial purpose. Prior to any trial-related activity, the 
investigator must provide the patient’s parent(s)/LAR(s) with the possibility to abstain from the 
genetic testing/collection of previous documentation, but still be able to participate in the trial. 
Only the F8 and HLA genotype will be analysed by the central laboratory selected by Novo Nordisk 
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. 
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Protocol Amendment no 5
CONFIDENTIAL
Date:
13 June 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
Status:
Final
Page:
1 of 5
Protocol Amendment
no 5
to Protocol, version 4
dated 01 November 2016
Trial ID:NN7088-3908
Safety and Efficacy of turoctocog alfa pegol (N8-GP) in Previously Untreated Patients with 
Haemophilia A
Trial phase: 3a
Applicable to all countries
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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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 5
CONFIDENTIAL
Date:
13 June 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
Status:
Final
Page:
2 of 5
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................4
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Protocol Amendment no 5
CONFIDENTIAL
Date:
13 June 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
Status:
Final
Page:
3 of 5
1
Introduction including rationale for the protocol amendment
The trial has been on-going since 2013, and a per protocol interim analysis is planned to evaluate 
safety and efficacy when 50 patients have reached 50 exposure days according to the previous 
version of the EMA Guideline on the clinical investigation of recombinant and human plasma-
derived factor VIII products (2011). The target of 50 patients with 50 exposure days with the 
present recruitment rate is estimated to be 2021.
Recruitment is extremely difficult in Previously Untreated Patients (PUPs) and the risk of 
developing neutralising antibodies is high. The concurrent development of many therapeutic 
products for hemophilia treatment decreases the availability of previously untreated patients for 
clinical trials, suggesting that informative studies performed in a meaningful number of PUPs will 
not be feasible in a timely manner. Therefore, formal PUP studies are not required according to the 
updated EMA guideline (2018). 
However, this trial was established prior to the new stance from EMA, which now does not stipulate 
the need for PUP trials. Given that the original target will delay retrieval of data, it has been decided 
to incorporate an interim data analysis to provide valuable information within this sub-population in 
a more timely manner as every PUP should be closely monitored with regards to treatment 
performance and inhibitor development.
The following minor clarifications to protocol text have been made:

The weighing intervals and the visit windows of the protocol have been aligned. A weight, 
which is measured up to 12 weeks before a visit can be used for trial product dispending in 
children more than 3 years of age as well as for all children after visit 15 (table 2.2 and 
section 8.3.1).

During the clinical development programme it was demonstrated that the specific 
chromogenic assay set-up employed with NHP as calibrator over-estimated plasma FVIII 
activity and the one-stage clotting assay in the applied setup under-estimated the activity of 
N8-GP when using NHP as calibrator due to PEG interference with the aPTT reagent. 

Categorisation of clinical significance for out of range lab parameters due to underlying 
condition removed in order to make categorisation equal for all laboratory results.

Administrative changes, including incorporation of previously approved local amendments.
In this protocol amendment:

Any new text is written in italics.

Any text deleted from the protocol is written using strike through.
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Protocol Amendment no 5
CONFIDENTIAL
Date:
13 June 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
Status:
Final
Page:
4 of 5
2
Changes
Sections 1, 5.1, and 16: 
Due to the extended time frame of the trial related to slow recruitment rate from the available PUP 
population, an interim analysis will be performed to retrieve safety data.
Table 2-2:
The frequency of body weight measurements should follow local practice, but should at least be 
measured every 10 weeks in children ≥3 years of age and within a timeframe of 6 weeks in children 
<3 years of age. For practical purposes, when dispensing trial drug after V15, the body weight from 
an earlier measurement (or visit) can be used for all age groups if the measurement was performed 
within the previous 12 weeks. Please refer to Section 8.3.1
Section 8.3.1:
Body weight should be measured in connection with regularly visit where trial drug is dispensed. 
For practical purposes when dispensing trial drug the weight from an earlier measurement (or visit) 
can be used if the measurement was performed within the previous 10 weeks (in children <3 years 
of age, within 6 weeks). If new body weight is not needed to be measured at a visit, the body weight 
from last weighing should be used. After visit 15, a body weight measured within the previous 12 
weeks for all age groups can be used.
8.4. Laboratory assessments
…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. Categorisation of clinical significance for out of range 
results may not be required for the following laboratory parameters (parts of the underlying 
disorder) and the investigator is therefore not required to perform a categorisation even though these 
parameters are listed in the laboratory report: e.g. FVIII activity, FVIII inhibitors, binding FVIII 
antibodies, PEG antibodies, HCP antibodies and genotype testing including HLA. …
8.4.1.1 FVIII activity
After the patient has been dosed with N8-GP, FVIII activity should be measured with a qualified an
APTT based one-stage clotting assay or chromogenic assay, which means that some assays may use
calibrated by an N8-GP reference standard for calibration. The N8-GP 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 request a new one when relevant.
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Protocol Amendment no 5
CONFIDENTIAL
Date:
13 June 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
Status:
Final
Page:
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Dependent on the type of aPTT reagent used in the one-stage clotting assay, by the local lab an 
exemption from this requirement can be made. In such cases Novo Nordisk will need to approve the 
suggested assay on an individual basis. For approval of aPPT based assays please contact Novo 
Nordisk. 
8.4.2.1 FVIII activity
In each assay both an N8-GP reference standard and a human plasma standard calibrated against the 
WHO international FVIII standard are used as assay calibrators. 
16.5 Interim reporting
An interim efficacy and safety evaluation is planned when approximately 50 patients have reached 
25 exposure days. The data will be presented for separately for the main phase and extension as 
well as combined.
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Protocol Amendment no 6
CONFIDENTIAL
Date:
21 June 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
Status:
Final
Page:
1 of 4
Protocol Amendment
no 6
to Protocol, version 5
dated 13 June 2019
Trial ID: NN7088-3908
Safety and Efficacy of turoctocog alfa pegol (N8-GP) in Previously Untreated Patients with 
Haemophilia A
Trial phase: 3a
Applicable to Israel
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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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 6
CONFIDENTIAL
Date:
21 June 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
Status:
Final
Page:
2 of 4
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
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Protocol Amendment no 6
CONFIDENTIAL
Date:
21 June 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
Status:
Final
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
Patients with congenital haemophilia A have a mutation in coagulation Factor VIII (F8) gene. The 
different types of mutations in the F8 gene are associated with different probabilities for 
development of inhibitors. Inhibitors are antibodies that reduce or eliminate the activity of Factor 
VIII proteins thereby rendering treatment with replacement factor products, such as N8-GP, 
difficult.
Patients from Israel were excluded from the F8 and Human Leucocyte Antigen (HLA) genotype 
testing in the previous versions of protocol. However, since the incidence of Factor VIII inhibitors 
is the primary endpoint of the trial and certain mutations are related to very high inhibitor rates, the 
mutation composition of the trial population is pivotal for the understanding of the immunogenicity.
Protocol Amendment no 4 version 1.0 dated 14 June 2018 (applicable only for Israel), which has 
recently been approved by the Health Authorities in Israel introduced F8 and HLA genotype testing 
for all patients going forward. Protocol Amendment no 4 version 1.0 dated 14 June 2018 was 
incorporated in protocol version 5 dated 13 June 2019.
With the current protocol amendment Novo Nordisk is seeking permission to obtain the F8 and 
HLA genotype testing results from withdrawn patients if already available in documentation.
The results will be part of the clinical data analysis and reporting and used for trial specific 
purposes only. All information will be kept confidential.
In this protocol amendment:

Any new text is written in italics.

Any text deleted from the protocol is written using strike through.
2
Changes
17.1 Informed consent
F8 and HLA genotype testing/collection of previous genotype documentation:
Genotype testing is offered to the patients participating in this trial. If documentation of the
patients’ genotype already exists, the patient and/or the patient’s parent(s)/LAR(s) must give their
consent before the data can be collected for trial purpose. Prior to any trial-related activity, the
investigator must provide the patient’s parent(s)/LAR(s) with the possibility to abstain from the
genetic testing/collection of previous documentation, but still be able to participate in the trial.
Only the F8 and HLA genotype will be analysed by the central laboratory selected by Novo Nordisk
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Protocol Amendment no 6
CONFIDENTIAL
Date:
21 June 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
Status:
Final
Page:
4 of 4
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.
Only applicable for Israel: The parent(s)/LAR(s) of withdrawn trial patients will be approached for 
consent to obtaining the F8 and HLA genotype testing results if already available in documentation.
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Protocol Amendment no 7
CONFIDENTIAL
Date:
02 July 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
1 of 3
Protocol Amendment
no 7
to Protocol, version 4.0
dated 01 Nov 2016
Trial ID: NN7088-3908
Safety and Efficacy of turoctocog alfa pegol (N8-GP) in
Previously Untreated Patients with Haemophilia A
Trial phase: 3a
Applicable to Japan
Amendment originator:
, Trial Manager, Clinical Operations, CMR, Japan
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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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 7
CONFIDENTIAL
Date:
02 July 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
2 of 3
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
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Protocol Amendment no 7
CONFIDENTIAL
Date:
02 July 2019
Novo Nordisk
Trial ID: NN7088-3908
Version:
1.0
UTN: U1111-1148-1897
Status:
Final
EudraCT No.: 2013-004025-88
Page:
3 of 3
1
Introduction including rationale for the protocol amendment
In accordance with Japanese regulations, the regulatory category of this clinical trial has been 
updated and the assessment of expectedness clarified.
In this protocol amendment:

Any new text is written in italics.

Any text deleted from the protocol is written using strike through.
2
Changes
5.1   Type of trial
…
The trial design is based on the guideline on clinical investigation of recombinant and human 
plasma-derived factor VIII products developed by CHMP in EU.9
For Japan only: The NN7088-3908 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.’
…
11.2   Reporting of adverse events
…
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 brochure,7 N8-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.
…
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Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
1 of 10 
Protocol Amendment 
no 8 
to Protocol, version 1.0 
dated 04 November 2013 
Final Protocol version 1.0 (04-Nov-2013) including: 
Amendment no. 1, version 0.1, Portugal (30-Jul-2014) 
Amendment no. 2, version 2.0 (20-Mar-2015) 
Amendment no. 3, version 1.0 (01-Nov-2016) 
Amendment no. 4, version 1.0, Israel (14-Jun-2018) 
Amendment no. 5, version 1.0 (13-Jun-2019) 
Amendment no. 6, version 1.0, Israel (21-Jun-2019) 
Amendment no. 7, version 1.0, Japan (02-Jul-2019) 
Trial ID: NN7088-3908 
Safety and Efficacy of turoctocog alfa pegol (N8-GP) in Previously Untreated Patients with 
Haemophilia A 
Trial phase: 3a  
Applicable to all countries 
 
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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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
2 of 10 
Table of Contents   
1 
Introduction including rationale for the protocol amendment ............................................................. 3 
2 
Changes ...................................................................................................................................................... 4 
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Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
3 of 10 
 
 
1 
Introduction including rationale for the protocol amendment 
The foremost purpose of this eighth protocol amendment is to finalise the NN7088-3908 trial prior 
to the milestone of 100 patients achieving 100 exposure days (EDs). Novo Nordisk A/S (NN) would 
like to maintain the current protocol defined trial end date of 13 November 2021 (LPLV). However, 
NN has predicted that the trial will not reach the originally targeted 100 patients by the protocol 
defined end of recruitment date of 02 October 2020. Based on the number of currently recruited 
patients and the recruitment rate in the trial, it has been predicted that the trial would need to 
continue at least until Q4 2025 to reach the milestone of 100 patients with 100 EDs. Still, NN 
expects to have completed the main phase with 50 patients with 50 EDs and V9 by Q3 2020. It has 
therefore been decided to maintain the planned date of LPLV, but to terminate recruitment of 
patients into NN7088-3908 with a predicted lower patient number than originally planned. This 
decision ensures that the paediatric investigation plan (PIP) commitment to EMA is achieved. In 
addition, PUP trials are no longer an EMA requirement in Haemophilia 
(https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-
recombinant-human-plasma-derived-factor-viii-products-revision-2_en.pdf), consequently all 
regulatory commitments will be met.  
On 29 May 2019, the Safety Committee for N8-GP validated a safety signal in the NN7088-3908 
trial. The safety signal was related to a transient low incremental recovery (IR) following the initial 
administrations of turoctocog alfa pegol in the absence of detectable inhibitors in a proportion of 
previously untreated patients (PUPs) within the first 5 exposure days. The observed low IR was 
generally transient, and the majority of patients returned to baseline levels over time. To ensure 
additional insights into the efficacy and safety of N8-GP during low IR periods, an intensified PEG 
antibody analysis has been implemented. The analysis will be done from blood samples collected 
for N8-GP binding antibodies. Therefore, no additional blood samples will need to be collected. 
Other clarifications to the protocol:  
To align the protocol with the most recent monitoring process, which has been simplified to allow 
for more risk-based monitoring, the protocol has been updated so that monitoring on-site visits can 
be substituted with remote monitoring when considered feasible.  
 
In this protocol amendment: 
• Any new text is written in italics. 
• Any text deleted from the protocol is written using strike through. 
 
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Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
4 of 10 
 
 
2 
Changes 
Following sections in the protocol are affected by this eighth protocol amendment: 
 
1     Summary  
[…] 
Time frames for evaluation of Objectives/Endpoints 
All objectives/endpoints will be evaluated when the first 50 PUPs have reached at least 50 exposure 
days with V9 dates, when the first 100 PUP have reached 100 exposure dates, and at end of trial. 
End of trial will be up to 4 years after the first patient has reached 100 exposure dates days. 
[…] 
Trial design: 
[…] 
The European medical agency requires required submission of safety and efficacy data from 
minimum 50 exposure days in at least 50 patients for approval of the indication in PUPs, with a 
post-approval commitment to follow- at least 100 patients for a minimum of 100 exposure days. 
When the first 50 patients have reached a minimum of 50 exposure days and V9, the analysis and 
evaluation for the main trial report will be performed. All patients Patients may continue in the 
extension phase for the purpose of collecting data for a minimum of 100 exposure days in at least 
100 patients.  
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Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
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2    Flow chart  
Table 2-1 Flow chart visits and assessments 
 
[…] 
Table 2-2 Flow chart explanatory descriptions 
9. Blood samples must be collected prior to dosing at dosing visits. Please check that the required 
washout period has been met for inhibitor testing, see section 8.1.1.3 Before any surgeries are 
performed an inhibitor test must be taken if this test is more than 30 days. HCP antibodies and PEG 
antibodies will be analysed using samples taken for the N8-GP binding antibodies at the time points 
described in section 8.4.2.2. 
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Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
6 of 10 
 
 
3    Background information and rationale for the trial 
[…] 
3.2    Rationale for the trial  
[…] 
The rationale for performing the pathfinder™6 trial is to evaluate the safety (including 
immunogenicity) and efficacy of N8-GP in the treatment of PUPs with severe haemophilia A in 
accordance with EMA requirements. For Europe, EMA requires required a separate investigation in 
the PUP population as part of the development programme to be initiated before market 
authorisation. The approval of the indication in PUPs paediatric investigation plan (PIP) will be 
based on a clinical trial in a minimum of 50 PUPs evaluated for efficacy and safety during at least 
50 EDs connected with a post-approval commitment to follow up at least 100 PUPs for a minimum 
of 100 EDs. The 50 patients will continue in an extension phase to collect long term safety data. to 
reach at least 100 EDs, and additional 50 patients will be included also to reach at least 100 EDs. 
[…] 
5    Trial design  
5.1    Type of trial 
[…] 
The number of patients to be investigated in this trial follows a PIP by EMA which Novo Nordisk 
has committed to. the minimum EU guideline requirements for approval of the indication in PUPs, 
which will be based on a pre-authorisation clinical trial in a minimum of 50 PUPs evaluated for 
efficacy and safety during at least 50 EDs, connected with a post-approval commitment to follow-
up at least 100 PUPs for a minimum of 100 EDs. 
According to the previous EMA Guideline treatment with N8-GP in the pathfinder™6 PUP trial 
was able to start when 20 patients participating in the paediatric PTP trial (pathfinder™5) were 
available (including data from a minimum of 10 paediatric patients below 6 years of age), and 
pharmacokinetic investigations in paediatric PTPs were completed. 
[…] 
Patients will be followed in the extension phase until at least 100 patients have reached at least 100 
EDs each LPLV. EDs during immune tolerance induction therapy (ITI) will count in the 
determination of when a patient has reached 100 EDs a patient’s total number of EDs reached at 
his EOT visit.  
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CONFIDENTIAL


Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
7 of 10 
 
 
5.2    Rationale for trial design 
[…] 
The main phase of the trial will generate safety and efficacy, aiming for a minimum of 50 EDs per 
patient. This number of EDs is was previously required by the EMA guideline9 for evaluation of 
new FVIII products. The trial does not include a placebo control group, as it is considered unethical 
to administer an ineffective treatment to patients with haemophilia. An active control has not been 
included as extensive comparative data from recently registered rFVIII products are available in 
comparable global populations including patients from EU and US.14, 15 Furthermore, the EMA 
guideline does not require a comparison to neither placebo nor an active comparator. 
[…] 
5.3.6.1    ITI therapy with N8-GP 
[…] 
Patients who develop inhibitors, within the pathfinder™6 trial, will be offered continued ITI 
treatment with N8-GP for a maximum of 24 months, also in case this extends past LPLV of the 
trial. ITI therapy with FVIII concentrates other than N8-GP is not allowed within the trial. It may 
also be decided by the Investigator and/or parent/legal representative to withdraw the patients 
developing FVIII inhibitors. 
[…] 
6    Trial population 
6.1    Number of patients  
Number of patients planned to be screened: 150 
Number of patients planned to be started on trial product: 125 
Number of patients expected to complete the trial: 100 
Due to slow recruitment rate from the available PUP population, these patient numbers may not be 
met in time for LPLV.   
6.5    Patient replacement  
Withdrawn patients may be replaced to ensure that 100 patients complete the trial with at least 100 
EDs. Assuming a drop-out rate of 20%, it is estimated that 125 patients must be started on N8-GP to 
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CONFIDENTIAL


Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
8 of 10 
 
 
obtain the 100 completed patients. This may, however, be adjusted during the trial based on the 
actual drop-out rate. 
[…] 
7    Milestones 
[…] 
Patients with inhibitors will be allowed to receive continued ITI treatment for up to 24 months, also 
in case this extends after LPLV. 
[…] 
8    Methods and assessments 
[…] 
8.1.9 End of trial visit 
The EOT visit can take place at any time after completion of 100 EDs and V14 or if the patient is 
withdrawn from the trial. 
[…] 
8.4.2.2    Antibody assessments 
[…] 
PEG antibodies 
PEG IgM/IgG antibodies should be measured according to Table 2–1 and if required, investigator 
may take additional PEG-antibodies samples at other visits. Samples will be analysed regularly for 
PEG binding antibodies at the end of trial or whenever considered relevant and results will be 
reported to investigators at the end of trial, or whenever considered relevant, and will be included 
in the CTR.  
[…] 
13    Monitoring procedures 
[…] 
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, 
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CONFIDENTIAL


Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
9 of 10 
 
 
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. at site 
between V0 and V14. If all patients at site are in the period after V14, intervals between monitoring 
visits must not exceed 26 weeks, provided site contact at least every 12 weeks.   
[…] 
16    Statistical considerations 
[…] 
An updated reporting of the trial with supportive data will be performed when 100 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.  
A final report of the trial will be made after the LPLV cut-off on 13 November 2021. In case some 
ITI patients haven’t finished their treatment at the time of LPLV, an addendum to the final report 
will be made once the last ITI patient has completed the trial. 
All data will be reported separately in a final report when the trial is completed. 
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CONFIDENTIAL


Protocol Amendment no 8 
CONFIDENTIAL 
Date: 
15 June 2020 
Novo Nordisk 
Trial ID: NN7088-3908 
Version: 
1 
UTN: U1111-1148-1897 
Status: 
Final 
EudraCT no.: 2013-004025-88 
Page: 
10 of 10 
 
 
 
Figure 16-1    Individual patient flow and time periods for trial reporting 
[…] 
16.1    Sample size calculation 
No formal sample size calculations have been performed. The sample size of 100 completers is was 
based on previous EMA guideline9. 
[…] 
16.5    Interim reporting  
[…] 
An updated report will be made when the first 100 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 
[…] 
A final report of the trial will be made after the LPLV cut-off on 13 November 2021. In case some 
ITI patients have not finished their treatment at the time of LPLV, an addendum to the final report 
will be made once the last ITI patient has completed the trial.  
 
 
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