Clinical trial NCT01480180
Conditions: Congenital Bleeding Disorder Haemophilia A
Sponsor: Novo Nordisk A/S
Start date: 2012-01-30; Completion date: 2018-12-10
Enrollment: 186 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of the trial is to evaluate the safety and efficacy, including pharmacokinetics (the exposure of the trial drug in the body) of NNC 0129-0000-1003 (N8-GP) in subjects with Haemophilia A.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: turoctocog alfa pegol
Intervention descriptions: intervention 1: Administered i.v.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT01480180 
Sponsor trial ID: 
NN7088-3859 
Official title of study: 
A multi-national trial evaluating safety and efficacy, including 
pharmacokinetics, of NNC 0129-0000-1003 when 
administered for treatment and prophylaxis of bleeding in 
patients with haemophilia A.  
Document date: 
01-May-2019 
 


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List of contents
Protocol ...............................................................................................................................................
Attachment I and II............................................................................................................................
Substantial amendment 1 - NL..........................................................................................................
Substantial amendment 2 - Global....................................................................................................
Substantial amendment 3 - TR..........................................................................................................
Substantial amendment 4 - ES ..........................................................................................................
Substantial amendment 5 - FR..........................................................................................................
Substantial amendment 6 - Global....................................................................................................
Substantial amendment 7 - BR..........................................................................................................
Substantial amendment 8 - RU .........................................................................................................
Substantial amendment 9 - FR..........................................................................................................
Substantial amendment 10 - Global..................................................................................................
Substantial amendment 11 - IL.........................................................................................................
Substantial amendment 12 - Global..................................................................................................
Substantial amendment 13 - Global..................................................................................................
Substantial amendment 14 - Global..................................................................................................
Substantial amendment 15 - Global..................................................................................................
Substantial amendment 16 - US........................................................................................................
Substantial amendment 17 - FR........................................................................................................
Substantial amendment 18 - Global..................................................................................................
Substantial amendment 19 - Global..................................................................................................
Substantial amendment 20 - DK, IT, NL, CH .................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
7XURFWRFRJDOIDSHJRO
NN7088-3859 Ext 2 )inal
Clinical Trial Report
Appendix 16.1.1
0D\2019

)LQDO
16.1.1 Protocol and protocol amendments
Substantial amendment 2 -*OREDO................................................................................. Link
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
1 of 112
Protocol
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003
when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A
Trial phase: 3
Author:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
2 of 112
Table of contents 
Page
Table of contents...............................................................................................................................................2
Table of figures.................................................................................................................................................6
Table of tables...................................................................................................................................................7
List of Abbreviations........................................................................................................................................8
1
Summary..................................................................................................................................................10
2
Flow Chart...............................................................................................................................................14
3
Introduction.............................................................................................................................................18
3.1
Basic Information ........................................................................................................................18
3.1.1
Haemophilia A ............................................................................................................18
3.1.2
N8-GP..........................................................................................................................19
3.1.3
N8-GP Clinical Data ...................................................................................................19
3.1.4
Risk and Benefits.........................................................................................................20
3.2
Rationale for the Trial..................................................................................................................20
4
Objective(s) and Endpoint(s)..................................................................................................................22
4.1
Objectives ....................................................................................................................................22
4.1.1
Co-Primary Objectives................................................................................................22
4.1.2
Secondary Objectives..................................................................................................22
4.2
Endpoint(s)...................................................................................................................................22
4.2.1
Co-Primary Endpoints.................................................................................................22
4.2.2
Secondary Endpoints...................................................................................................22
4.2.2.1
Confirmatory Secondary Efficacy Endpoint............................................22
4.2.2.2
Additional Supportive Efficacy Endpoints ..............................................22
4.2.2.3
Safety Endpoints......................................................................................23
4.2.2.4
Pharmacokinetic Endpoints .....................................................................23
4.2.3
Exploratory Endpoints.................................................................................................23
5
Trial Design..............................................................................................................................................24
5.1
Type of Trial................................................................................................................................24
5.2
Rationale for Trial Design ...........................................................................................................25
5.3
Treatment of Patients...................................................................................................................26
5.3.1
Prophylaxis..................................................................................................................26
5.3.2
Treatment of Bleeding episodes..................................................................................27
5.3.3
Patients Participating in PK procedures ......................................................................28
5.3.4
Surgery ........................................................................................................................28
5.3.5
Patients Continuing Into Other N8-GP Trials .............................................................28
5.4
Rationale for Treatment...............................................................................................................29
6
Trial Population ......................................................................................................................................30
6.1
Number of Patients to be Studied ................................................................................................30
6.2
Inclusion Criteria .........................................................................................................................30
6.3
Exclusion Criteria ........................................................................................................................30
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
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6.4
Criteria for rescheduling planned visits .......................................................................................31
6.5
Withdrawal Criteria .....................................................................................................................32
6.6
Patient Replacement ....................................................................................................................32
6.7
Rationale for Trial Population .....................................................................................................32
7
Trial Schedule..........................................................................................................................................34
8
Methods and Assessments ......................................................................................................................35
8.1
Visit Procedures...........................................................................................................................35
8.1.1
Visit 1 – Screening Visit for All Patients....................................................................37
8.1.2
Visit Schedule for Patients on Prophylaxis not Undergoing PK Evaluation and 
for Patients on On-Demand treatment.........................................................................39
8.1.2.1
Visit 3-13 for Patients on Prophylaxis not Undergoing PK 
Evaluation and Patients on On-Demand Treatment.................................40
8.1.3
Visit Schedule for Patients on Prophylaxis Undergoing PK Evaluation.....................42
8.1.3.1
Visit 2a for Patients on Prophylaxis Undergoing PK Evaluation............42
8.1.3.2
Visit 2b for Patients on Prophylaxis Undergoing PK Evaluation............43
8.1.3.3
Visit 7 for Patients on Prophylaxis Undergoing PK Evaluation..............44
8.1.4
Follow-up visit (only for patients withdrawn due to development of FVIII 
inhibitors) ....................................................................................................................46
8.1.5
Unscheduled Visits......................................................................................................47
8.1.6
Transfer of Patients due to Major Surgeries................................................................48
8.2
Efficacy Assessments ..................................................................................................................48
8.2.1
Bleeding Episodes.......................................................................................................48
8.2.1.1
Definition of Severity of Bleeding episodes............................................49
8.2.1.2
Definition of Haemostatic Response: ......................................................49
8.3
Safety Assessments......................................................................................................................50
8.3.1
Adverse Events............................................................................................................50
8.3.2
Antibody Assessments ................................................................................................50
8.3.2.1
N8-GP antibody assay..............................................................................50
8.3.2.2
FVIII inhibitors........................................................................................51
8.3.2.3
Antibody Assessments in case of Allergic/Anaphylactic Reaction.........52
8.3.3
Physical Examination..................................................................................................52
8.3.4
Vital Signs...................................................................................................................52
8.3.5
ECG.............................................................................................................................53
8.3.6
Local Laboratory Tests................................................................................................53
8.3.6.1
Haematology............................................................................................54
8.3.6.2
Urinalysis.................................................................................................54
8.3.6.3
FVIII activity (local laboratory)...............................................................55
8.3.7
Central Laboratory Assessments.................................................................................55
8.3.7.1
Biochemistry............................................................................................56
8.3.7.2
Coagulation related Parameters ...............................................................56
8.3.7.3
FVIII Activity (central laboratory) ..........................................................56
8.3.7.4
Viral assessments (HIV, Hepatitis B and C)............................................57
8.3.7.5
FVIII genotype testing (Not applicable to Brazil) ...................................57
8.4
Other Assessments.......................................................................................................................58
8.4.1
Demographic data........................................................................................................58
8.4.2
Body Measurements....................................................................................................58
8.4.3
eDiaries........................................................................................................................58
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
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Version:
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Status:
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8.4.4
Medical History/Concomitant Illness..........................................................................59
8.4.4.1
Documentation of Inhibitor Status...........................................................60
8.4.4.2
Bleeding Treatment History including History of Bleeding Episodes.....60
8.4.5
PRO Questionnaires and Health Economics ...............................................................61
8.5
Patient Compliance......................................................................................................................62
8.5.1
Definition of Treatment Compliance...........................................................................63
9
Trial Supplies...........................................................................................................................................64
9.1
Trial Product(s)............................................................................................................................64
9.2
Trial Product Administration.......................................................................................................64
9.3
Packaging and Labelling of Trial Product(s)...............................................................................64
9.4
Storage, Handling, Accountability and Destruction of Trial Product(s)......................................65
9.5
Auxiliary Supply..........................................................................................................................66
10 Interactive Voice/Web Response System (IV/WRS)............................................................................67
11 Concomitant Illnesses and Concomitant Medication...........................................................................68
12 Adverse Events and Pregnancies ...........................................................................................................69
12.1
Definitions ...................................................................................................................................69
12.1.1
Technical Complaint ...................................................................................................71
12.1.2
Medical Event of Special Interest................................................................................71
12.1.3
Disease-related Bleeding.............................................................................................74
12.2
Collection, Recording and Reporting of Adverse Events............................................................74
12.2.1
Follow-up of Adverse Events......................................................................................75
12.3
Technical Complaints and Technical Complaint Samples ..........................................................77
12.3.1
Collection and Reporting of Technical Complaints ....................................................77
12.3.2
Collection, Storage and Shipment of Technical Complaint Samples..........................78
12.3.3
Pregnancies in Partners of Trial Patients.....................................................................79
12.4
Precautions...................................................................................................................................79
12.5
Safety Committee(s) ....................................................................................................................79
12.5.1
Internal Novo Nordisk Safety Committee...................................................................79
12.5.2
Data Monitoring Committee........................................................................................79
12.5.3
Stopping Rules ............................................................................................................79
13 Case Report Forms .................................................................................................................................81
13.1
Rules for Completing eCRFs.......................................................................................................81
13.2
Corrections to eCRFs...................................................................................................................81
13.3
eCRF Flow...................................................................................................................................81
13.4
eDiary...........................................................................................................................................82
14 Monitoring procedures ...........................................................................................................................83
15 Data Management...................................................................................................................................84
16 Computerised Systems............................................................................................................................85
17 Evaluability of Patients for Analysis .....................................................................................................86
17.1
Safety Analysis Set......................................................................................................................86
17.2
Full Analysis Set..........................................................................................................................86
17.3
Documentation of Analysis Sets..................................................................................................86
18 Statistical Considerations .......................................................................................................................87
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
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18.1
Sample Size Calculation ..............................................................................................................87
18.2
Statistical Methods.......................................................................................................................88
18.2.1
General Considerations ...............................................................................................88
18.2.2
Primary Endpoint(s) ....................................................................................................88
Historical Control for Hypothesis Test for Prophylaxis............................................................................89
18.2.3
Confirmatory Secondary Endpoints ............................................................................92
18.2.4
Supportive Secondary Endpoints ................................................................................93
18.2.4.1
The Number of Injections of N8-GP required per Bleed.........................93
18.2.4.2
Amount of N8-GP required per Bleed.....................................................93
18.2.4.3
PK Endpoints...........................................................................................93
18.3
Safety Endpoints..........................................................................................................................94
18.4
Interim Analysis...........................................................................................................................95
18.5
Sequential Safety Analysis/Safety Monitoring............................................................................95
18.6
Explorative Statistical Analysis for Pharmacogenetics and Biomarkers.....................................95
18.7
PK and/or PD Modelling .............................................................................................................96
18.8
Health Economics and/or Patient Reported Outcome..................................................................97
19 Ethics........................................................................................................................................................98
19.1
Informed Consent Form for Trial Patients...................................................................................98
19.2
Data Handling..............................................................................................................................99
19.3
Institutional Review Boards/Independent Ethics Committee......................................................99
19.4
Regulatory Authorities...............................................................................................................100
20 Premature Termination of the Trial/Trial Site ..................................................................................101
21 Protocol Compliance.............................................................................................................................102
21.1
Audits and Inspections...............................................................................................................102
22 Critical Documents................................................................................................................................103
23 Responsibilities......................................................................................................................................104
24 Reports and Publications......................................................................................................................105
24.1
Communication and Publication................................................................................................105
24.1.1
Authorship.................................................................................................................105
24.1.2
Publications ...............................................................................................................105
24.1.3
Site-Specific Publication(s) by Investigator(s)..........................................................107
24.2
Investigator Access to Data and Review of Results ..................................................................107
25 Retention of Clinical Trial Documentation.........................................................................................108
26 Indemnity Statement.............................................................................................................................109
References .....................................................................................................................................................110
Attachment I - Global
List of Key Staff, Relevant Departments
Attachment II - Country
List of Key Staff and Relevant Departments
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Table of figures 
Page
Figure 3-1 Overview of the pathfinder™clinical trial programme................................................................21
Figure 8-1 Overview of visits and home treatment periods .............................................................................35
Figure 13-1 eDiary Data Flow..........................................................................................................................82
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
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Table of tables 
Page
Table 2-1
Flow Chart for Patients on Prophylaxis and On-Demand Treatment ..........................................14
Table 2-2  PK Flow Chart for Selected Patients having PK Sampling Performed at Visit 2a and Visit 7.......17
Table 12-1 Handling of Not Recovered Non-Serious AEs from pathfinder™3................................................77
Table 18-1 Historical mean total annual bleeding rate in Haemophilia A patients with an endogenous 
FVIII:C activity <2%...................................................................................................................90
Table 18-2 Definition and Calculation of PK Parameters..............................................................................94
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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List of Abbreviations
AE
adverse event
ALAT
alanine aminotransferase 
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the curve
BMI
body mass index
BP
blood pressure
BU
Bethesda unit
BW
Body weight
CHO
chinese hamster ovary
CL
total clearance
CNS
central nervous system
CRF
case report form
CRO
contract research organisation
CRP
c-reactive protein
CTA
clinical trial application
CTN
clinical trial notification
DUN
dispensing unit number
ECG
electrocardiogram
eCRF
electronic case report form
ED
exposure days
EDC
electronic data capture
EMA
European Medicines Agency
EOT
end of trial
EQ-5D
Euroqol 5 dimension self-report questionnaire
FAS
full analysis set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FPFV
first patient first visit
FVII
coagulation factor seven
FVIII
coagulation factor eight
FVIII:C
factor eight clotting activity
FIX
coagulation factor nine
FU
follow up
GCP
good clinical practice
GGT
gamma-glutamyl transferase
HAEMO-QOL
haemophilia-quality of life
HAEM-A-QOL
haemophilia-adult-quality of life
HEMO-SAT     
haemophilia-satisfaction
HE
health economics
HIV
human immunodeficiency virus
HCV
hepatitis C
HCP
host cell proteins
IB
Investigators Brochure
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
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ICH
International Conference on Harmonisation 
ICMJE
The International Committee of Medical Journal Editors
IEC 
Independent Ethics Committee
IgG
immunoglobulin g
IgE
immunoglobulin e
IMP
investigational medicinal product
IRB 
Institutional Review Board
i.v.
intravenous
IV/WRS
interactive voice/web response system
LAR
legally acceptable representative 
LOCF
last observation carried forward
LPLV 
last patient last visit
MedDRA
Medical Dictionary for Regulatory Activities
MESI
medical event of special interest
MRT
mean residence time
NIMP
non investigational medicinal product
NOAEL
no observed adverse effect level
PCV
packed cell volume
pd-aPCC
plasma derived activated plasma coagulation factor concentrates
pd-PCC
plasma derived plasma poagulation factor concentrates
PK
pharmacokinetic
PRO
patient reported outcome
N8-GP
glycopegylated recombinant coagulation factor VIII (NCC 0129-0000-1003)
PEF
peak expiratory flow
PEG
polyethylene glycol
PTP
previously treated patient
PUP
previously untreated patient
rFVIII
recombinant factor eight
SAE
serious adverse event
SUSAR 
suspected unexpected serious adverse reactions
t½
terminal half life
TGA
thrombin generating assay
TMM
trial materials manual
turoctocog alfa
recombinant coagulation factor VIII  
TVP
trial validation plan
Vss
volume of distribution at steady state
WFH
World Federation of Hemophilia 
VWF
Von Willebrand Factor
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
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1
Summary
Co-Primary Objectives
!
To evaluate the immunogenicity of NNC 0129-0000-1003 (hereafter referred to as N8-GP) in 
previously treated patients with Haemophilia A
!
To evaluate the clinical efficacy of N8-GP in bleeding prophylaxis (number of bleeds during 
prophylaxis)
Secondary Objectives
!
To evaluate the clinical efficacy of N8-GP when treating bleeds in patients with haemophilia A
!
To evaluate the safety of N8-GP when used for prevention of bleeds and treatment of bleeds in 
patients with haemophilia A
!
To evaluate PK properties of N8-GP 
!
To evaluate Patient Reported Outcomes 
!
To evaluate the health economic impact of N8-GP treatment
!
Generation of a population based PK-model for N8-GP
Co-Primary Endpoints
!
The Incidence rate of FVIII-inhibitors ∀0.6 BU
!
Annualised bleeding rate in the prophylaxis arm 
Key Secondary Endpoint
!
Haemostatic effect of N8-GP when used for treatment of bleeds, assessed on a four-point scale 
for haemostatic response (excellent, good, moderate and none) by counting excellent and good 
as success and moderate and none as failure
The endpoints will be analysed based on all available information until the end of trial (EOT) visit 
and up to approximately 19 months.
Trial design:
This phase 3 trial is a multi-centre, multi-national, open-label, non-randomised trial evaluating 
safety, pharmacokinetics and clinical efficacy of N8-GP when used for treatment of bleeding 
episodes and for long-term prophylaxis. 
A minimum of 115 patients must complete the trial in 2 treatment arms including at least 10 
patients in on-demand treatment and 105 patients in prophylaxis treatment with N8-GP every 4 
days. Whether a patient will receive prophylaxis treatment or on-demand treatment is the choice of 
the patient and Investigator and will be decided at the screening visit.
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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Version:
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A minimum of 15 of the patients in the prophylaxis arm must undergo two PK sessions to obtain 13 
patients with two PK profiles. In order to ensure recruitment of patients for PK it is planned that the 
first patients (approximately 10) entering the prophylaxis arm must undergo PK sessions.
Treatment duration is approximately 7-19 months. In the prophylaxis arm, all patients will continue
in the trial until the last patient has received at least 50 exposure days (EDs) of N8-GP, thus all
patients in the prophylaxis arm will receive at least 50 EDs of N8-GP and the average exposure to 
N8-GP will be above 1 year. The purpose of the on-demand arm is to ensure that sufficient bleed 
treatment data are collected in the trial. The on-demand patients can switch to prophylaxis treatment 
after approximately 6 months on-demand treatment if, the prophylaxis arm is still open for 
enrollment, or continue on-demand treatment until end of trial (EOT).
When this trial is completed, all patients will be offered to continue treatment in the extension trial 
NN7088-3861 (pathfinder™4) provided approval in the respective countries. 
If the patients need to undergo surgery during the present trial they can switch into the surgery trial 
NN7088-3860 (pathfinder™3). Upon completion of the surgery the patients can return to the 
NN7088-38591 (pathfinder™2) trial.
Please refer to Figure 3-1 for a description of the transfer of patients between trials.
Trial Population:
Approximately 150 previously treated patients (PTPs) with severe (FVIII <1%) haemophilia A in a 
non-bleeding state will be screened to allow for a minimum of 115 patients to complete the trial. 
The trial population is characterised by the following key inclusion and exclusion criteria:
Key Inclusion Criteria
!
Male patients with severe congenital haemophilia A (FVIII activity <1%, according to medical 
records) 
!
Documented history of at least 150 EDs to other FVIII products 
!
Age >12 years (except for Croatia where the lower age limit will be 18 years)
Key Exclusion Criteria
!
Previous participation in this trial defined as withdrawal after administration N8-GP
!
Any history of FVIII inhibitors, see section 8.4.4.1
!
FVIII inhibitors > 0.6 BU/mL at screening
                                                
1 patients that enter the surgery trial as on-demand patients will continue in the pathfinder™2 trial in the on-demand arm
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
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Version:
1.0
Status:
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!
HIV positive, defined by medical records with CD4+ count #200/∃L or a viral load of >400000 
copies/mL If the data is not available in medical records within last 6 months, CD4+ will be 
measured at the screening visit
!
Congenital or acquired coagulation disorders other than haemophilia A
!
Previous significant thromboembolic events (e.g. myocardial infarction, cerebrovascular disease 
or deep venous thrombosis) as defined by available medical records
!
Platelet count < 50,000 platelets/∃L (laboratory value at the screening visit)
!
ALAT > 3 times the upper limit of normal reference ranges at central laboratory
!
Creatinine level ∀1.5 times above upper normal limit (according to central laboratory reference 
ranges)
!
Ongoing immune modulating or chemotherapeutic medication 
Safety Assessments
AEs, antibody assessment, haematology, biochemistry and FVIII activity will be measured 
throughout the trial. Furthermore, Vital signs, physical examination, electrocardiogram (ECG), 
Urinalysis, viral assessments and lupus anticoagulant will be measured.
Efficacy Assessments
Haemostatic effect of N8-GP when used for treatment of bleeding episodes (excellent, good, 
moderate, none), number of bleeding episodes per patient, consumption of N8-GP required per 
bleed and total number of N8-GP injections administered to the patient per bleed during the trial.
Furthermore, patient reported outcomes will be assessed.
PK Assessments
The PK sessions with N8-GP will be performed at visit 2a and 7 and the parameters assessed 
include Incremental recovery, trough level, AUC, Terminal half-life (t½) , Clearance, Mean 
Residence time (MRT) and Vss (Volume of distribution at steady state). The first sample will be 
taken within one hour prior to the administration of N8-GP and the last sample will be taken 96
hours after.
Trial Product(s):
The following trial products will be used in the trial:
!
N8-GP drug product
N8-GP 2000 U/vial 211μg/vial drug product is a lyophilised powder in single use vials with a 
nominal content of 2000 U/vial produced by Novo Nordisk A/S, Denmark. Each vial is to be 
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
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reconstituted with 4.3 mL of 0.9% NaCl. After reconstitution each vial contains 500 U/ml N8-GP at 
pH 6.9. Sodium Chloride 0.9% solution will be provided by Novo Nordisk.
In the prophylaxis arm, each patient will receive prophylaxis treatment with a N8-GP dose of 50
U/kg body weight (BW) every 4 days. In most cases this will be home treatment with intravenous 
(i.v.) self-injection by the patient. Patients participating in the on-demand arm and patients in the 
prophylaxis arm will be treated with 20-75 U/kg BW in case of bleeding episodes.
Patients participating in the PK sessions (visit 2a and 7) will be administered one dose of N8-GP of 
50 U/kg BW.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
Date:
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2
Flow Chart
Table 2-1 Flow Chart for Patients on Prophylaxis and On-Demand Treatment
Visit number
1
2a1
2b
3
4
5
6
71, 2
8 
9 
10 
11 
12 
13 
14
Un-
sched
uled 
visit 
Time of visit
Weeks
2w
prior to 
visit 2a
0
4 days 
after Visit 
2
4w
8w
12w
20w
28w 
36w
44w
52w
60w
68w
76w 
EOT
Follow
-up
Visit window
Weeks
+1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
X
In/exclusion criteria
X
X3
Pharmacogenomic (FVIII genotype) 
consent4
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding treatment history
X
Concomitant illness
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demography
X
Genotype (FVIII genotype)4
X
Haemophilia details
X
History of bleeding episodes
X
History of surgery
X
Medical history
X
Date and time of last coagulation factor 
administration 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EFFICACY
Bleeding episodes (rating severity) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAFETY
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X5
X5
X5
X5
X5
X5
X
Physical examination
X
X
X
X5
X5
X
X5
X5
X5
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X  
X
X
Antibodies
FVIII inhibitors 6, 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
Date:
30 September 2011
Status:
Final
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Visit number
1
2a1
2b
3
4
5
6
71, 2
8 
9 
10 
11 
12 
13 
14
Un-
sched
uled 
visit 
Time of visit
Weeks
2w
prior to 
visit 2a
0
4 days 
after Visit 
2
4w
8w
12w
20w
28w 
36w
44w
52w
60w
68w
76w 
EOT
Follow
-up
Visit window
Weeks
+1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
SUBJECT RELATED
INFO/ASSESSMENTS
N8-GP binding antibodies 6, 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
   IgE, IgG8
  X
Biochemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation related parameters
Lupus anticoagulant
X
aPTT
X
X
INR
X
X
von Willebrand factor
X
FVIII activity
FVIII trough level
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII recovery
X
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis
X
X
HIV
X
X
Viral load10
X
CD4+ T cells10
X
Urinalysis
X
X
OTHER ASSESSMENTS
Body measurements
X
X11
X11
X11
X11
X11
X11
X11
X11
X11
X11
X11
X11
X11
PRO questionnaires
X
X5
X5
X5
X5
X5
X5
X
TRIAL MATERIAL
Administration of trial product12
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
IV/IWRS call
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispensing trial product
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispensing trial card
X
Dispensing eDiary
X
REMINDERS


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
Date:
30 September 2011
Status:
Final
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Visit number
1
2a1
2b
3
4
5
6
71, 2
8 
9 
10 
11 
12 
13 
14
Un-
sched
uled 
visit 
Time of visit
Weeks
2w
prior to 
visit 2a
0
4 days 
after Visit 
2
4w
8w
12w
20w
28w 
36w
44w
52w
60w
68w
76w 
EOT
Follow
-up
Visit window
Weeks
+1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
SUBJECT RELATED
INFO/ASSESSMENTS
Affirmation statement
X5
X5
X5
X5
X5
X5
X
End of trial Form
X5
X5
X5
X5
X5
X5
X
X
e-Diary training
X
X
X
X
X
X
X
X
X
X
X
X
X
e-Diary data review
X
X
X
X
X
X
X
X
X
X
X
X
X
Home treatment training
X
X
X
X
X
X
X
X
X
X
X
X
X
Footer
Description
1
Please refer to Table 2-2 for the patients that need to undergo PK
2
Patients in the on-demand arm can switch into prophylaxis treatment after 6 months treatment
3
Confirmation of screening visit 1 in- and exclusion criteria
4
If applicable, i.e. following patient consent and in accordance with local law
5
Only if this visit is EOT visit – dependent on when the patient entered the trial.  
6
Antibody samples will only be drawn from patients in the on-demand arm at Visit 3-13 if they have received treatment since last visit
7
A wash-out period of minimum 96 hrs is needed before the sample (except visit 1 and visit 2a where wash out is minimum 72 hours)
8
Only in case of an unexpected allergic/anaphylactic reaction
9
Not for patients in the on demand arm
10
Only to be taken if HIV status is positive
11
Only BW will be measured
12
From visit 3-13, only for patients in the prophylaxis arm


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
Date:
30 September 2011
Status:
Final
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Version:
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Table 2-2  PK Flow Chart for Selected Patients having PK Sampling Performed at Visit 2a and Visit 7
Day(s)
0
1
2
3
4
Nominal Time1
Pre-dose
0
30
1 hr
4 hrs
12 hrs
24 hrs
48 hrs
72 hrs
96 hrs
Visit Window
-1h2
% 5 min
% 5 min
% 30 min
%30 min
+ 8 hrs
+ 8 hrs
+ 8 hrs
+ 8 hrs
Inclusion / Exclusion Criteria
X3
Withdrawal Criteria
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
Date and time of last coagulation factor administration
X
e-Diary data review 
X
Adverse Events
X
X
X
X
X
X
X
X
X
Body measurements (weight)
X
Physical examination
X
Vital signs
X
X
X
Haematology
X
Urinalysis
X4
Biochemistry
X
X
Coagulation related parameters
X
FVIII activity  
X
X
X
X
X
X
X
X
X
N8-GP binding antibodies
X
FVIII inhibitors
X
Adm. of N8-GP
X
N8-GP accountability
X
TRAINING AND REMINDERS
Home treatment and e-Diary training
X
eDiary dispensing
X
IW/VRS 
X
X5
Footer
Description
1
Time values refer to time elapsed after N8-GP has been administered (completion of the injection)
2
Time window of 1h pre-dose, only applicable for blood samples. Any other assessments must be performed prior to dosing at the day of dosing.
3
Confirmation of Screening visit (Visit 1) in- and exclusion criteria (only visit 2a)
4
Only visit 2a
5
Only visit 7


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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30 September 2011
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3
Introduction
In this document the Investigator refers to the individual overall responsible for the conduct of the 
clinical trial at a trial site.
3.1
Basic Information
3.1.1
Haemophilia A
Haemophilia A is a recessive X-linked congenital bleeding disorder caused by mutations in the 
coagulation factor VIII gene on the long arm of the X-chromosome. According to the World 
Federation of Haemophilia (WFH), there are globally 320,000 – 340,000 patients with haemophilia 
A of which only approximately one quarter receives adequate care1.
With a deficiency or absence of FVIII, activation of coagulation factor X becomes severely 
impaired, and consequently, the thrombin burst becomes delayed and insufficient for normal 
haemostasis2. The haemostatic plug formed in these patients is, if formed, fragile and easily 
dissolved by normal fibrinolytic activity, leading to impaired haemostasis, prolonged bleeding 
episodes and re-bleeding. The bleeding episodes in patients with severe haemophilia A are typically 
spontaneous or after mild trauma in joints, muscles and soft tissues. The bleeding episodes often 
occur in the muscles and joints of the elbows, knees and ankles, causing acute haemarthrosis. In 
repeated cases this is followed by synovitis in the affected joint. Recurrent bleeding episodes in the 
same location, may lead to chronic arthropathy, muscular atrophy and deformities3. Bleeding 
episodes may occur in all parts of the body including life-threatening bleeding episodes in the 
central nervous system (CNS), throat, neck, gastrointestinal tract, retroperitonaeum or external 
injuries. As the Human Immunodeficiency Virus (HIV) and Hepatitis C (HCV) epidemics have 
subsided, the most serious complication to haemophilia treatment is inhibitor development. 
Inhibitors are allogeneic antibodies to FVIII that reduce or eliminate the activity of FVIII proteins in 
clotting factor concentrates. This condition develops in as many as 30–35% of previously untreated 
patients (PUPs) with severe haemophilia A4,5. Hence, the risk of inhibitor development related to 
the individual product should be initially evaluated in PTPs as these patients have been exposed to 
previous FVIII products and considered to be at a low risk of developing inhibitors and therefore 
the most suitable for trial population.
Haemophilia A is classified according to the plasma activity of FVIII (FVIII:C), as severe (FVIII:C 
&1% of normal), moderate (FVIII:C 1-5%) or mild (FVIII:C 6-40%)6.The distribution of severity 
among patients with haemophilia A in the world is difficult to estimate since many of the mild cases 
remain undiagnosed but in countries with registers the numbers are about 50 % severe, 20 % 
moderate and 30 % mild.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
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30 September 2011
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With current treatment the life expectancy for Haemophilia A patients is estimated to 65 – 72 years. 
The major cause of death is intra-cerebral haemorrhage.
Haemophilia care is based on treatment of an active bleed with a haemostatic agent (on-demand 
use) or haemostatic agents are administered for longer periods to prevent bleeding (bleeding 
prophylaxis). The standard treatment of patients with haemophilia is replacement of the FVIII 
protein. Currently available FVIII products are all lyophilised products for i.v. infusion and either 
plasma derived or recombinant. This replacement therapy can be provided either as prophylaxis or 
as on-demand treatment of bleeding episodes. turoctocog alfa
3.1.2
N8-GP
N8-GP represents a new recombinant FVIII (rFVIII) with a longer half life and clinical areas of 
interest include the prophylaxis and treatment of bleeding in patients with Haemophilia A without 
inhibitors, and the prevention of bleeding in surgery undertaken in these patients.
N8-GP is a rFVIII covalently coupled to a single 40K-PEG (polyethylen glycol) at a unique B-
domain O-glycan of turoctocog alfa (Novo Nordisk rFVIII product) resulting in a product consisting 
of one exact molecular form. Glycopegylation is carried out enzymatically whereby terminal sialic 
acids on the O-glycan structures are replaced with another sialic acid conjugated to a branched 
2x20K PEG through a glycine-based linker. Since the O-glycan in turoctocog alfa is located in the 
B-domain, N8-GP is converted to native rFVIIIa upon activation by thrombin at the site of injury. 
In this process, the pegylated activation peptide is released. 
Recombinant human FVIII is synthesised at Novo Nordisk A/S in CHO cells, a mammalian cell line 
that is well characterised and has been used in the production of other recombinant proteins such as
turoctocog alfa.
The No Observed Adverse Effect Level (NOAEL) after multiple dosing with N8-GP in male and 
female rats and male cynomolgus monkeys was 2500 U/kg. 
3.1.3
N8-GP Clinical Data
In accordance with the European Medicines Agency (EMA) Guidelines7, the clinical programme for 
N8-GP was initiated by a pharmacokinetic (PK) trial to document the essential PK characteristics of 
the product and to achieve initial safety information. 
By April 2011, 26 PTPs were dosed with N8-GP in the NN7088-3776 (pathfinder™1) trial and had 
undergone a safety and PK investigation. The phase 1 trial has successfully been concluded with no 
safety concerns. No FVIII inhibitors were detected and no treatment related SAEs were reported. 
The half-life was pro-longed with approx 1.6-fold compared to the patients previous FVIII product. 
For further information on medicinal aspects, non-clinical data and quality of N8-GP, please refer to 
the Investigator’s Brochure (IB)8.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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Date:
30 September 2011
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3.1.4
Risk and Benefits
N8-GP has a longer half-life and thus the potential to improve the quality of life for the haemophilia 
A patients by offering a convenient prophylaxis treatment, reducing the burden of frequent 
infusions.
The glycopegylation of rFVIII has in animal models, and in a first human dose trial, been shown to 
result in a product with equivalent activity of FVIII but with a longer t½.. PEG is allowed in foods
and drugs and it is also used in other licensed products. Overall, it is evaluated as unlikely that 
adverse events will occur in humans specifically as a result of the PEG used to pegylate a biological 
product9. Non-clinical and clinical data does not suggest any alteration to the established rFVIII 
safety profile, or any additional risk of thromboembolic complications.
The primary concern in the clinical development of a new rFVIII product is the potential risk of the 
development of neutralising antibodies to FVIII. The N8-GP clinical trial has been designed in 
order to minimise the risk of inhibitor development. Selection of patients for the clinical trials is in 
accordance with current regulatory guidelines and recommendations and intends to minimise the 
risk of inhibitor formation and the variation in response parameters. Therefore, the clinical risk of 
patients developing antibodies against N8-GP is regarded as low. 
Potentially fragile patients where the treatment with N8-GP may present a risk will not be included 
in the study. Therefore, patients with severe cardiovascular disease, severe renal or hepatic 
dysfunction are excluded. The safety of the patients enrolled in the clinical trial will be carefully 
and closely monitored. 
To minimise the switching between FVIII products, the patients, will upon completion of the 
present trial, be offered to continue treatment with N8-GP in the extension trial (pathfinder™4), 
where patients have the opportunity to continue with N8-GP treatment until commercially 
availabilityb.
3.2
Rationale for the Trial
This trial is part of a clinical development programme that at present includes a completed phase 1 
trial (pathfinder™1), the present pivotal phase 3a trial (pathfinder™2), an extension phase 3b trial 
(pathfinder™4) and a surgery phase 3a trial (pathfinder™3). The phase 3 trials are offered as one 
package to each investigational site to ensure that patients are offered to continue N8-GP until 
commercially available3 and patients in need of surgery can undergo surgery without having to 
switch product. The clinical programme is illustrated in Figure 3-1.
                                                
b For UK only: The end of the extension trial will be defined by exact date and not when commercially available
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
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In the preceding phase 1 trial (pathfinder™1), 26 patients with haemophilia A had one PK session 
with their current FVIII product followed by one PK session with N8-GP. The trial was completed 
on 18 April 2011 and the results formed the basis for the doses selected in the present trial.
The rationale for this trial is to investigate the safety and efficacy, including PK and long-term 
safety of N8-GP in Haemophilia A patients from 12 years of age. 
Figure 3-1 Overview of the pathfinder™clinical trial programme.
Arrows indicate possible transfer of patients between trials. Patients completing the phase 1 trial 
may also be enrolled in the coming trials if found eligible.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
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Version:
1.0
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4
Objective(s) and Endpoint(s)
4.1
Objectives
4.1.1
Co-Primary Objectives
!
To evaluate the immunogenicity of N8-GP in previously treated patients with Haemophilia A
!
To evaluate the clinical efficacy of N8-GP in bleeding prophylaxis (number of bleeds during 
prophylaxis)
4.1.2
Secondary Objectives
!
To evaluate the clinical efficacy of N8-GP when treating bleeds in patients with haemophilia A
!
To evaluate the safety of N8-GP when used for prevention of bleeds and treatment of bleeds in 
patients with haemophilia A
!
To evaluate PK properties of N8-GP 
!
To evaluate Patient Reported Outcomes (PRO)
!
To evaluate the health economic impact of N8-GP treatment
!
Generation of a population based PK-model for N8-GP
4.2
Endpoint(s)
4.2.1
Co-Primary Endpoints
!
The incidence rate of FVIII-inhibitors ∀0.6 BU
!
Annualised bleeding rate in the prophylaxis arm
4.2.2
Secondary Endpoints
4.2.2.1
Confirmatory Secondary Efficacy Endpoint
!
The haemostatic effect of N8-GP when used for treatment of bleeds, assessed on a four-point 
scale for haemostatic response (excellent, good, moderate and none) by counting excellent and 
good as success and moderate and none as failure.
4.2.2.2
Additional Supportive Efficacy Endpoints
! Consumption of N8-GP (number of infusions and U/kg) per bleed 
! Consumption of N8-GP (number of infusions and U/kg per month and per year) during 
prophylaxis and on-demand treatment
! Haemostatic effect as measured by recovery and trough levels FVIII:C (in all patients in the 
prophylaxis treatment arm)
! Patient Reported Outcomes and Health Economic Endpoints
∋
PRO scores and their changes from baseline to the end of the trial 
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
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30 September 2011
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∋
Bleed related health economic resource use and patient/caregiver burden 
4.2.2.3
Safety Endpoints
!
Adverse Events (AEs) and Serious Adverse Events (SAEs) reported during the trial 
!
Changes in vital signs (BP, pulse, temperature, respiratory rate)
4.2.2.4
Pharmacokinetic Endpoints
! Incremental recovery ( [U/mL] / [U/kg] )(single dose and steady state)
! Trough level ( [U/mL]) (single dose and steady state)
! Area Under the Curve (AUC), (h*U/mL)
! Terminal half-life (t½), (h)
! Clearance (mL/h/kg)
! Mean Residence time (MRT) 
! Vss (Volume of distribution at steady state)
4.2.3
Exploratory Endpoints
! Incidence of binding, non-inhibitory antibodies to N8-GP/ turoctocog alfa
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
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5
Trial Design
5.1
Type of Trial
This phase 3 trial is a multi-centre, multi-national, open-label, non-randomised trial evaluating 
safety, pharmacokinetics and clinical efficacy of N8-GP when used for treatment of bleeding 
episodes and for long-term prophylaxis. 
A minimum of 115 patients must complete the trial including at least 10 patients in on-demand 
treatment and 105 patients in prophylaxis treatment with N8-GP every 4 days. In order to ensure 
recruitment of patients for PK it is planned that the first patients (approximately 10) entering the 
prophylaxis arm must undergo PK sessions. Whether a patient will receive prophylaxis treatment or 
on-demand treatment is non randomised and will be the choice of the patient and Investigator. This 
will be based on medical needs and decided at the Screening visit. For the US, recruitment will open 
for the on-demand arm before enrolling patients in the prophylaxis arm, whereas both arms will 
open concurrently at non-US sites. The distribution of patients will be as follows:
!
It is expected that approximately 120 patients will be dosed in the prophylaxis arm in order 
to obtain 105 completed patients on prophylaxis treatment. These patients will receive 
treatment with 50 U/kg of N8-GP every 4 days during a period of approximately 7-19
months. In case of a bleed the patients will be treated with doses between 20-75 U/kg BW.
!
It is expected that approximately 12 patients will be enrolled in the on-demand arm to 
obtain 10 completed patients who have been treated on-demand with N8-GP during a 
period of approximately 6 months. In case of a bleed the patients will be treated with doses 
between 20-75 U/kg BW. When they have completed approximately 6 months on-demand 
treatment, the on-demand patients will be offered to switch to the prophylaxis arm if, the 
prophylaxis arm is still open for enrollment, or to continue on-demand treatment until the 
end of trial.
A minimum of 15 of the patients in the prophylaxis arm must undergo 2 PK sessions to obtain 13 
patients with two usable PK profiles each. The first PK session will take place at Visit 2a and the 
second will take place at Visit 7. When 15 patients have successfully completed the two PK 
sessions and data is available, no additional patients will be required to undergo PK assessments. 
Furthermore, recovery and trough levels of FVIII will be followed throughout the trial at all visits 
for all patients on prophylaxis to evaluate steady-state and indications of inhibitor formation.
Treatment duration is approximately 6 months in the on-demand arm and from approximately 7
(200 days plus screening period of 2-3 weeks) to approximately 19 months in the prophylaxis arm.
The maximum treatment period in this trial is 24 months. In the prophylaxis arm, all patients will 
continue in the trial until the last patient has received at least 50 EDs of N8-GP, thus all patients in 
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
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Version:
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the prophylaxis arm will receive at least 50 EDs of N8-GP and the average exposure to N8-GP will 
be more than 1 year. When this trial is completed, all patients will be offered to continue treatment 
in the extension trial pathfinder™4, if approved by country. As all patients will complete the present 
trial at the same time (or within a short timeframe) the transition of patients from pathfinder™2 to 
pathfinder™4 will be gradual and within a window of approximately 1 month.
Furthermore, if the patients need to undergo surgery during the present trial they can switch into the 
surgery trial pathfinder™3 and upon completion of the surgery they can return to the pathfinder™2c
trial. Recruitment into the surgery trial pathfinder™3 will begin after successful treatment of 
bleeding episodes with N8-GP in at least 5 patients in the pivotal trial pathfinder™2. For US the 
surgery trial will not be initiated until at least 20 bleeding episodes in at least 10 patients are treated 
with N8-GP.
The flow of patients between trials is illustrated in Figure 3-1.
The screening period will add approximately 2-3 weeks to each patient’s trial participation.
The clinical efficacy assessment for treatment of bleeding episodes will be based on the treatment of 
all bleeding episodes (spontaneous, traumatic, re-bleed and after minor surgery). Haemostatic effect 
of N8-GP in treatment of bleeding episodes will be assessed on a four-point scale (excellent, good, 
moderate and none).
5.2
Rationale for Trial Design
The purpose of the prophylaxis arm is to provide sufficient exposure to N8-GP to evaluate 
immunogenicity and to provide efficacy data from 50-100 EDs of prophylaxis treatment with N8-
GP in at least 105 patients with severe haemophilia A >12 years. The reason for not having a 
prophylaxis control is that no FVIII product is globally approved for prophylaxis treatment.
The purpose of the on-demand arm is to ensure that sufficient bleeding treatment data is collected in 
the trial. Additional safety data will also be generated in these on-demand treated patients. It is not a 
comparator to the prophylaxis arm. The reason for not having an on-demand control is that most 
patients are on prophylaxis treatment and it is considered unethical to randomise prophylaxis 
patients to on-demand treatment. In addition, a comparator arm is not required for registration in the 
EU.
The purpose of continuing all patients in the prophylaxis arm in the trial until the last patient has 
completed at least 50 EDs of N8-GP is to ensure that the average exposure to N8-GP will be above 
1 year for a considerable portion of the patients.
                                                
c patients that enter the surgery trial as on-demand patients will continue in the pivotal trial in the on-demand arm
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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The trial is not controlled by a placebo group. It is considered unethical to administer an ineffective 
treatment to patients with haemophilia. The rationale for choosing a multi-centre design is to ensure 
a sufficient number of patients with this rare disorder. 
For clinical efficacy of N8-GP in the prevention of bleeding episodes, historical data on annualised 
bleeding frequency during on-demand treatment and prophylaxis will be used for comparison. The 
historical data derive from a recent review by an independent board of haemophilia treaters within 
the Swedish Council on Health Technology Assessment, including all published clinical studies on 
treatment of severe haemophilia A during the last 25 years which were comprised of at least 20 
patients10. The review selected in total 37 separate studies of haemophilia A replacement therapy, 
seven of which contained data on bleeding frequency in an adult and/or adolescent population11.
5.3
Treatment of Patients
Approximately 150 patients are planned to be screened in order to dose approximately 132 patients 
in the trial out of which 105 patients are expected to complete the prophylaxis part of the trial and a 
minimum of 10 patients are expected to complete approximately 6 months in the on-demand part of 
the trial. 
The two initial doses of N8-GP will be administered in a hospital setting in order to observe for 
adverse reactions. Thereafter, home treatment can be initiated. All patients must previously have 
received at least 150 doses of FVIII and must be familiar with or instructed in home treatment of 
both prophylaxis and treatment of bleeding episodes. 
A severe bleed should be treated immediately at home and the haemophilia site must be contacted 
without delay for further instructions and/or transport to the site.
The following medications are not allowed during the course of the trial until after the EOT visit:
! Bypassing products: rFVIIa, pd-PCC and pd-aPCC
! Coagulation Factors containing products: FVIII, FIX and FVII other than N8-GP.
! Anti-coagulants such as Heparin and vitamin-K antagonists. Heparin is allowed for sealing of 
central venous access ports
5.3.1
Prophylaxis
In the prophylaxis arm, one single bolus dose of 50 U/kg BW of N8-GP is administered 
intravenously every 4 days (96 hours interval). The dose chosen is based on phase 1 data from the 
pathfinder™1 trial and is chosen to ensure a trough level of >1% FVIII:C activity in the majority of 
patients in the prophylaxis arm. During treatment a shortening of the dosing interval for prophylaxis 
to twice weekly may be undertaken at the Investigator’s discretion, if deemed necessary for the 
individual patient (see section 5.3.2). If the dosing regimen is changed to twice weekly, doses 
should be separated with at least 3 calendar days and no more than 4 calendar days. Other changes 
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Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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of the dose or dosing interval for prophylaxis are not allowed within the trial. However, extra doses 
of N8-GP will be administered if a patient experiences a treatment requiring bleeding episode or in 
case of minor surgery.
5.3.2
Treatment of Bleeding episodes
A treatment requiring bleeding episode is in this trial defined as a bleed that require treatment with a 
coagulation factor product e.g. N8-GP. If a patient experiences a treatment requiring bleed it must 
be treated as soon as it is identified (refer to Section 8.2.1).The Investigator must always be 
contacted in case of a severe bleed and the patient should visit the site within 24 hours. 
Mild/moderate bleeding episodes can be treated at home without contacting the site. For definition 
of the severity of a bleed please refer to section 8.2.1.1.
For the treatment of bleeding episodes, doses will be based on World Federation of Haemophilia 
(WFH) guidelines1 (see Section 8.2.1). For treatment of a bleed all on demand and prophylaxis 
patients will be treated with doses between 20-75 U/kg BW (the recommended standard dose will 
be 50 U/kg). Due to individual patient’s bleeding pattern during the trial, an adaptation in dosing 
regimen to 50 U/kg twice weekly will be permitted at the investigator’s discretion. If the dosing 
regimen is changed to twice weekly, doses should be separated by at least 3 calendar days and no 
more than 4 calendar days.
The dose for treatment of bleeding episodes is aimed to achieve an expected post injection level of 
at least 0.50 U/mL of FVIII.
Any dose used for treatment of a known active bleed must be recorded as treatment of bleed and not 
as prophylaxis treatment. When the bleed has resolved, the patient can resume the prophylaxis 
treatment.
If a dose for treatment of a bleed is taken, the next prophylaxis dose should follow the original 
dosing scheme and not be altered by the additional treatment of bleed administration. If a bleed 
occurs on the same day as the planned prophylaxis, the dose must be registered for the bleed and not 
as prophylaxis.
Number of doses and frequency of dosing is decided by the Investigator in relation to the particular 
bleed. The maximum dose to be administered to a patient within 24 hours (hrs) is 200 U/kg BW. 
The dose is recommended to be divided and only considered under exceptional circumstance such 
as serious trauma or severe bleeding episodes.
If a haemostatic response cannot be achieved after 48 hours using adequate doses of N8-GP
treatment when treating bleeding episodes, another FVIII product may be selected at the discretion 
of the Investigator. The use of other FVIII products will result in withdrawal of the patient.
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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An electronic diary (eDiary) will be kept to register all bleeding episodes and their treatment. The 
investigator must review the eDiary data and rate the bleeding episodes at every visit. If the patient 
or caregiver is unable to fill in information for severe bleeding episodes in the eDiary or is 
hospitalised, this information can be entered in the patient’s medical record and hereafter in the 
eCRF by site personnel. The dose, dose interval, number of doses and efficacy of treatment will be 
registered in the eDiary. The dose level can be decided based on the patient’s FVIII recovery or 
trough data. All phone contacts with the site must be documented by the study personnel.
5.3.3
Patients Participating in PK procedures
Patients will be administered a single i.v. bolus injection of 50 U/kg BW of N8-GP at Visit 2a and 
at Visit 7. The PK sessions are 4 days long and with multiple site visits. Overnight stay is not 
required. After completion of the PK sessions the patients will continue treatment in the prophylaxis
arm with the next visit in line. 
Patients must not have received current FVIII product for at least 4 days prior to the PK session at 
visit 2a and N8-GP for at least 7 days prior to the PK session at visit 7. The lines/tubes must be 
flushed immediately after administration of the trial product.
5.3.4
Surgery
Patients in need of major surgery may qualify for the surgical trial (pathfinder™3) being conducted 
in parallel to the present pivotal trial. The patient can undergo a surgery when he has received a 
minimum of 5 N8-GP EDs. If a patient transfers to the surgery trial a surgery transfer visit must be 
scheduled (see section 8.1.6). Minor surgery can be performed while participating in this trial by 
administering an additional dose of 50-75 U/kg N8-GP or a dose sufficient to increase the FVIII 
level to 100% prior to the minor surgery to prevent peri-operative bleeding.
Definition of Minor Surgery
Minor surgery is defined as any invasive operative procedure where only the skin, the mucous 
membranes or superficial connective tissue is manipulated. Examples of minor surgery include 
implanting pumps or ports in subcutaneous tissue, skin biopsies, simple dental procedures and 
uncomplicated emergent procedures.
5.3.5
Patients Continuing Into Other N8-GP Trials
All patients in the prophylaxis arm will continue in the trial until the last patient initiated in the 
prophylaxis arm has received at least 50 EDs. After completion of the trial, all patients will be 
offered to continue prophylaxis or on-demand treatment in the extension trial pathfinder™4 for up to 
approximately two years or until N8-GP becomes commercially availabled in the patient’s country. 
As all patients will complete the present trial at the same time the transition of patients from 
                                                
d For UK only: The end of the extension trial will be defined by exact date and not when commercially available.
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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pathfinder™2 to pathfinder™4 will be gradual and within a window of approximately 1 month.
Please refer to Figure 3-1 for an overview of the flow of patients between trials in the clinical 
development programme.
If the N8-GP programme is terminated or if the health authorities in the patient’s country reject the 
marketing application or if the commercialisation of N8-GP is not possible in the country, the 
extension trial will be stopped and treatment with N8-GP will be ended. Data collected up to the 
point where the patient is transferred to the extension trial will be used in the data analysis in the 
present trial.
5.4
Rationale for Treatment
In the preceding phase 1 trial (pathfinder™1) 26 patients with haemophilia A had one PK session 
with their current FVIII product followed by one PK session with N8-GP. The trial was completed 
on 18 April 2011 and the results formed the basis for the doses selected in the present trial.
The phase 1 trial has successfully been concluded with no safety concerns. No FVIII inhibitors were 
detected and no treatment related SAEs were reported. The half-life was prolonged with approx 1.6-
fold compared to the patients previous FVIII product
Lack of compliance with a frequent injection schedule is one of the most commonly cited reasons 
for failure of prophylaxis with factor treatments, and frequent dosing interrupts and restricts daily 
activities12. The longer half-life of N8-GP will allow for prophylaxis with fewer injections and 
presumably better compliance.
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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30 September 2011
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6
Trial Population
6.1
Number of Patients to be Studied
Countries planned to participate: Australia, Brazil, Croatia, Denmark, France, Germany, Hungary, 
Italy, Japan, Korea, Malaysia, Netherlands, Norway, Spain, Sweden, Switzerland, Taiwan, Turkey, 
United Kingdom and United States
Planned number of patients to be screened (i.e. documented informed consent) approximately: 150
Planned number of patients to be started on trial product(s) approximately:  132
Planned number of patients to complete the trial: ≥ 115
! Minimum 15 patients must be 12-17 years old at screening
! Minimum 10 patients must be in the on-demand arm
! Minimum 105 patients must be in the prophylaxis arm
Planned number of trial sites (approximately): 55
6.2
Inclusion Criteria
1. Informed consent obtained before any trial-related activities. (Trial-related activities are any 
procedure that would not have been performed during normal management of the subject.)
2. Male patients with severe congenital haemophilia A (FVIII activity <1%, according to medical 
records) 
3. Documented history of at least 150 exposure days to other FVIII productse
4. Age >12 years (except for Croatia where the lower age limit will be 18 years)
5. Body Mass Index (BMI) # 35
6. The patient and/or caregiver is capable of assessing a bleed, capable of home treatment of 
bleeding episodes and otherwise following the trial procedures
6.3
Exclusion Criteria
1. Known or suspected hypersensitivity to trial product including allergy to hamster protein or 
related products
                                                
e Prophylaxis, prevention, on-demand and treatment during surgery counts as exposure days.
If not possible to count the actual number of exposures in the medical chart, the Investigator
should make a written statement with an estimate based on eg. patient age, treatment frequency,
medical history, discussion with previous doctor/transfer note and other relevant information. This
statement should be filed either with the patient chart or separately with the Investigator Trial File.
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Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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2. Previous participation in this trial defined as withdrawal after administration of N8-GP.
3. The receipt of any investigational drug (with the exception of turoctocog alfa) within 30 days 
prior to enrolment into the trial (For Brazil, only: Participation in a previous clinical trial within 
one year prior to screening for this trial (Visit 1), unless there is a direct benefit to the research 
subject, at the investigator discretion).
4. Any history of FVIII inhibitors, see section 8.4.4.1
5. FVIII inhibitors > 0.6 BU/mL at screening
6. HIV positive, defined by medical records with CD4+ count #200/∃L or a viral load of >400000 
copies/mL If the data is not available in medical records within last 6 months, CD4+ will be 
measured at the screening visit
7. Congenital or acquired coagulation disorders other than haemophilia A
8. Previous significant thromboembolic events (e.g. myocardial infarction, cerebrovascular disease 
or deep venous thrombosis) as defined by available medical records
9. Platelet count < 50,000 platelets/∃L (laboratory value at the screening visit)
10. ALAT > 3 times above the upper limit of normal reference ranges at central laboratory
11. Creatinine level ∀1.5 times above the upper normal limit (according to central laboratory 
reference ranges)
12. Ongoing immune modulating or chemotherapeutic medication 
13. Any disease (liver, kidney, inflammatory  and mental disorders included) or condition which, 
according to the Investigator’s judgement, could imply a potential hazard to the patient, interfere 
with trial participation or trial outcome
14. Unwillingness, language or other barriers precluding adequate understanding and/or cooperation 
For the UK: Patients who are sexually active and have partners who are or could become pregnant 
must be willing and are required to use a barrier method of contraception (e.g. condom) for the 
duration of the trial and for 90 days following the last dose of trial medication. 
Patients who are non-compliant with any of the eligibility criteria, but included in the trial, should 
be excluded immediately. If extraordinary circumstances speak in favour of maintaining the subject 
in the trial then this is only acceptable if justified and approved by the IEC/IRB, and if the 
regulatory authorities are notified according to local requirements.
6.4
Criteria for rescheduling planned visits
1. Major surgery within one month prior to the first injection of N8-GP and PK evaluation
2. Subjective signs of illness or fever within 48 hours prior to the first injection of N8-GP and 
to PK sessions
3. In a bleeding state (all visits including PK)
4. Less than 72 hours wash out prior the screening visit 1 and visit 2a (except patients who 
undergo PK session at visit 2a) 
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Protocol/UTN: U1111-1119-7416
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5. Less than 96 hours wash out prior to inhibitor and antibody testing when treated with N8-GP 
(all patients)
6. 4 days wash out before the 1st PK evaluation and 7 days wash out before the 2nd  PK 
evaluation (Patients undergoing PK evaluation at visit 2a and 7)
7. Mild/moderate bleed within one week or a severe bleed within one month prior to PK 
evaluation visits
6.5
Withdrawal Criteria
The patient may withdraw at will at any time.
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.
A patient must be withdrawn if the following applies:
1. Haemostasis not achievable with N8-GP: The bleed cannot be controlled after 48 hours using 
adequate doses of N8-GP
2. FVIII inhibitor (≥0.6 BU/mL) as confirmed by re-testing by Central Laboratory
3. Allergy/anaphylaxis to the trial product 
4. Use of Coagulation Factors: FVIII, FIX and FVII-containing products other than N8-GP and 
other FVIII-containing products like fresh frozen plasma or cryoprecipitate. (Exception: current 
FVIII allowed until 72 hours before Visit 2a)
5. Incapacity or unwillingness to follow the trial procedures
6.6
Patient Replacement
Patients withdrawn from the trial can be replaced until 105 patients in the prophylaxis arm have had 
at least 50 EDs, and 10 patients have had 20 bleeding episodes in the on-demand and/or the 
prophylaxis arm.
6.7
Rationale for Trial Population
The present phase 3 trial will enrol patients with haemophilia A aged ≥12 years who are likely to 
benefit from the treatment in the trial. The trial is global and should include different ethnicities. 
Children in the age groups 12 to 17 years are amongst those who might benefit significantly from 
prophylaxis treatment. Adherence to current prophylaxis regimens drops dramatically during the 
teenage years where the compliance rate may be as low as 13%12. Fewer injections are therefore 
likely to improve compliance.
The trial population characterised through the inclusion criteria:
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∋
Criterion no. 1 is included in accordance with ICH-GCP
∋
Criterion no. 2 is included to select patients most likely to benefit from the treatment
∋
Criterion no. 3 is included for selecting previously FVIII treated patients and is in 
accordance with the EMA guideline
∋
Criterion no. 6 is included to ensure compliance with treatment and protocol requirements
∋
Criteria nos. 2, 3, 4, 5, are included in order to limit to a well characterised patient 
population
The trial population characterised through the exclusion criteria:
∋
Criteria nos 1, 4, 5, 6, 8, 9, 10, 11, 12, 13 and 14 are to prevent exposure of potentially 
fragile patients to a new compound and to prevent exposure of FVIII to patients with FVIII 
inhibitors
∋
Criterion no 2 is to ensure that a patient only counts once in the data analyses
∋
Criteria nos. 3 and 12 are selected to minimise any effect of external compounds on the 
patient's coagulation and immune system.
∋
Criteria nos. 7, 9, 10 and 11 are chosen to exclude patients with endogenous abnormalities 
of the coagulation system other than haemophilia A and to exclude patients with severely
impaired liver or kidney function.
∋
Criterion no. 8 is chosen to minimise the risks of thrombotic manifestations
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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7
Trial Schedule
Planned duration of recruitment period: 12 months
After a period of 12 weeks, patient recruitment will be competitive between countries and trial sites
unless otherwise agreed. If a trial site or country has not enrolled the planned number of patients 
according to the recruitment strategy, the remaining patients may be reallocated. All Investigators 
will be notified immediately when the enrolment period comes to an end, after which no patients 
may be screened unless required due to patient withdrawals.
Planned date for FPFV:
01-Feb-2 012
Planned date for LPLV:
01-Oct-2013
The end of the clinical trial is defined as LPLV.
Planned completion of clinical trial report: within 6 months after LPLV
Protocol information for this trial will be subject to public disclosure at external web sites 
(www.clinicaltrials.gov and www.novonordisk-trials.com) according to international regulations 
e.g. the International Committee of Medical Journal Editors (ICMJE)13, the Food and Drug 
Administration Amendments Act (FDAAA)14 - as reflected in Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure.
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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30 September 2011
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8
Methods and Assessments
8.1
Visit Procedures
Figure 8-1 Overview of visits and home treatment periods
All patients will complete at least 8 visits depending on when they are enrolled in the trial as the 
trial will be completed when the last prophylaxis patient has had 50 EDs. The last patient will have 
EOT visit at visit 7 after having received at least 50 EDs whereas the first patient enrolled in the 
trial will have the EOT visit at Visit 13. Therefore, the EOT visit can be all visits from visit 7 to 
visit 13. More visits may be added depending on when the last patient has had at least 50 EDs.
The trial includes the following visits:
! Visit 1: Screening visit
! Visit 2a and 2b: Visits at the site.
∋
All patients will have their first and second dose administered at the site. 
∋
Patients in the prophylaxis arm undergoing PK evaluation will undergo first PK 
evaluation at Visit 2a.  
! Visit 3-13: Visits at the site. 
∋
Patients in the prophylaxis arm will be dosed during the visits
∋
Patients in the prophylaxis arm undergoing PK evaluation will undergo second PK 
evaluation at Visit 7
∋
Patients in the on-demand arm will not be dosed during the visits
Follow-up visit (FU), not shown in Figure 8-1: only for patients withdrawn due to development of 
FVIII inhibitors
Procedures for the scheduled visits are described in the section below and in the flowcharts (please 
refer to section 2). If a visit window is exceeded due to a bleed, this will not be considered a 
protocol deviation.
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Trial Participation: It must be stated in the medical record that the patient is participating in the 
trial. Patients enrolled will also be provided with a card stating that they are participating in the trial, 
and contact addresses and telephone numbers. The patients should be instructed to carry the card 
with them at all times and to return the card to the Investigator at the last visit of the patient or 
destroy the card after the last trial visit.
Screening and Enrolment Log: The Investigator must keep a Subject Identification List and a 
Subject screening and Enrolment log/ Informed Consent Log (these can be combined in one 
document).
Informed Consent Procedure: The patient and/or the patient’s legally acceptable representative 
(LAR) will receive verbal and written information about the trial prior to conduct of any trial related 
procedures/activities. The information will include e.g. descriptions of N8-GP, the procedures 
involved, the practical consequences of participating, responsibilities and rights while participating 
in the trial including the possible advantages and disadvantages. Qualified site staff will ensure that 
patients and caregivers are fully informed both verbally and in writing. Patients and LAR(s) will 
have the opportunity to ask questions and have ample time to consider participation. If the patient 
wishes to participate in the trial, the patient and/or the patients LAR(s) will be requested to sign and 
date the Informed Consent Form. If the patient is a minor, he can in addition sign a child assent 
form, as per local regulations. When signing consent for this trial the patient and /or the patients
LAR(s) should be informed about the surgery and the extension trials as well.
It must be emphasised that any change in a patient’s normal treatment routine is a trial-related 
activity, which is not allowed before the patient has consented to participate in the trial. For 
example: If a patient is taken off prophylaxis to allow for 72 hours without FVIII treatment before 
screening and the interval between the patient’s normal prophylaxis doses is less than 72 hours, it is 
a trial related activity. In such case, it is essential that the informed consent procedure is completed 
prior to the trial related activities undertaken at the screening visit.
For screening failures: Screening failures are defined as patients who have signed the Informed 
Consent Form, but fail to comply with the inclusion and exclusion criteria or if patients withdraw 
consent prior to dosing. Data in respect to the screening visit (Visit 1) will be entered in the 
screening failure form in the electronic case report form (eCRF) preferably 3 days after data are 
available. A screening failure call must be made in the interactive voice/web response system 
(IV/WRS). Serious and non-serious AEs from screening failures will be entered by the Investigator 
in the eCRF, and consequently transferred to the clinical database. When the trial related procedures 
have been finalised for screening failures, no more AEs should be entered in the eCRF. Follow-up 
of AEs should be made according to section 12.
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Screening failures may be re-evaluated for participation in the trial and is allowed once. This will 
require a renewed informed consent to be obtained from the patient, a new eCRF should be started
and the patient should be allocated a new patient number.
For withdrawn patients: Withdrawn patients are defined as patients who meet the withdrawal 
criteria after dosing, see section 6.5. In case a patient is prematurely withdrawn from the trial the 
Investigator must aim at undertaking procedures for the last visit (EOT visit) as soon as possible, if 
possible. The primary reason (AE, non-compliance with protocol or other) for discontinuation must 
be specified in the eCRF. The end-of-trial form must be completed, and final drug accountability 
must be performed even if the patient is not able to attend. All data collected in the period the 
patient participated in the trial will be entered into the eCRF. A withdrawal session must be 
performed in IV/WRS. If a patient is withdrawn due to inhibitor development, the patient must be 
followed according to section 8.1.4.
End of trial visit: The EOT visit can be all visits from visit 7 until visit 13 depending on when the 
patient is enrolled in the trial. For patients continuing in the extension trial (pathfinder™4) the EOT 
visit will also be Visit 1 in this trial. If a patient is withdrawn prior to completion of the trial, all 
attempts must be made to schedule an EOT visit for the patient. The EOT form should be signed at 
the EOT visit. If a patient continues in FU the EOT form will be signed at the FU Visit.
8.1.1
Visit 1 – Screening Visit for All Patients
Before enrolment in the trial and prior to conduct of any trial related procedures/activities the 
patient and/or the LAR must have signed the informed consent form after having received written 
and verbal information about the trial. 
The Screening visit should be planned taking the patients FVIII dose regimen in consideration since 
there should be at least 72 hours after the last administration of coagulation factor products. 
All screened patients will receive a unique patient number, which will be assigned to the patient 
throughout the trial.
Prior to any assessments (laboratory and clinical) at Visit 1, baseline PRO data must be collected.
The patient should be registered for screening by the use of IV/IWRS.
At the Screening visit the following assessments will be performed and/or recorded in the 
eCRF:
! Informed consent form, signed, dated, see section 19.1
! Pharmacogenomic (FVIII genotype) consent (if applicable), see section 8.3.7.5
! Inclusion and exclusion criteria, see section 6.2 and 6.3
!
PRO questionnaire, see section 8.4.5
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! Demography, see section 8.4.1
! Medical history and Concomitant illness, see section 8.4.4
! Haemophilia treatment history and History of Bleeding Episodes, see section 8.4.4.2
! Haemophilia details, see section 8.4.4.2 and Inhibitors status, see section 8.4.4.1
! Concomitant medication, see section 11
! Check date and time of last coagulation factor administration (see section 8.4.3)
! AEs, see section 12.1
! Body measurements, see section 8.4.2
! Physical examination, see section 8.3.3
! Vital signs, see section 8.3.4
! ECG, see section 8.3.5
! Dispense trial card
! Enrolment session in IV/IWRS, see section 10
Blood sampling/Urinalysis for local laboratory assessments:
! Haematology, see section 8.3.6.1
! Urinalysis with sticks provided by the central laboratory, see section 8.3.6.2
Blood sampling for central laboratory assessments:
! Biochemistry, see section 8.3.7.1
! Coagulation related parameters (Lupus anticoagulant, Von Willebrand Factor, aPTT and INR) 
see section 8.3.7.2
! FVIII activity (trough level), see section 8.3.7.3
! FVIII inhibitors, see section 8.3.2.2
! N8-GP binding antibodies, see section 8.3.2.1
! Hepatitis, see viral assessments in section 8.3.7.4
! HIV, see viral assessments in section 8.3.7.4
! FVIII genotype (if documentation is not available in the patient chart and as allowed per local 
law. In addition, the Investigator, patient or LAR has the right to refuse), see section 8.3.7.5
All results necessary for evaluating the inclusion and exclusion criteria, from local and central 
laboratory analyses must be available before determining whether or not the patient can continue in 
the trial in accordance with inclusion and exclusion criteria.
Training and Reminders:
! An appointment for Visit 2a, 2-3 weeks after visit 1, should be made
! Patient should continue with current coagulation factor product until 72 hours prior to Visit 2a. If 
treated with coagulation factors within the last 72 hours the visit should be rescheduled
! Patients in the prophylaxis arm participating in the PK session should be reminded that Visit 2a
will require 4 days wash-out and consist of 4 visits to the site during a period of 4 days
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Patients will be assigned to on-demand treatment or the prophylaxis arm. The decision to enrol into 
either the on-demand arm or the prophylaxis arm lies with the patient and Investigator. 
8.1.2
Visit Schedule for Patients on Prophylaxis not Undergoing PK Evaluation and for 
Patients on On-Demand treatment
Visit 2a should take place as soon as possible upon confirmation of eligibility and 2-3 weeks after 
the Screening visit (Visit 1).
At visit 2a the patients will have their first dose of N8-GP (50 U/kg) BW administered at the site. 
The second dose (50 U/kg BW) is given at visit 2b 4 days after visit 2a. If a bleeding occurs during 
this period the patient must come to the site for treatment with N8-GP.
The samples taken post-dose must not be taken from the same vein as previously used for 
administration of N8-GP.
Patients will be provided with an eDiary and will be carefully trained in the use of this eDiary 
including instruction in reporting details of bleeding episodes and prophylactic treatment including 
doses administered at visits.
At Visit 2a the following assessments will be performed and/or recorded in the eCRF
! Confirmation of inclusion and exclusion criteria, see section 6.2 and 6.3
! Withdrawal criteria, see section 6.5
! Concomitant medication, see section 11
! Check date and time of last coagulation factor administration (see section 8.4.3)
! AEs: before and after dosing, see section 12.1
! Body measurements (weight only), see section 8.4.2
! Physical examination, see section 8.3.3
! Vital signs (before dosing and 30 min (% 10 min) after dosing), see section 8.3.4
! e-Diary training, see section 5.3 and 8.4.3
! e-Diary dispensing
! Dispensing of N8-GP in IV/WRS, see section 10
! Administration of first dose of N8-GP (Stop time of injection must be recorded in the eCRF, this 
corresponds to time “0”) 
Blood sampling for local laboratory assessments
! Haematology, see section 8.3.6.1
! Urinalysis with sticks provided by the central laboratory, see section 8.3.6.2
Blood sampling for central laboratory assessments
! Biochemistry, see section 8.3.7.1
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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! Coagulation related parameters (before dosing and  30 min (%10 min) after the first dose), see 
section 8.3.7.2
! FVIII activity (trough and recovery), i.e. before dosing and  30 min (%5 min) after dosing), see 
section 8.3.7.3
! FVIII inhibitors, see section 8.3.2.2
! N8-GP binding antibodies, see section 8.3.2.1
At Visit 2b (4 days after first dose) the following assessments will be performed and/or 
recorded in the eCRF
! Withdrawal criteria, see section 6.5
! Concomitant medication, see section 11
! AEs: before and after dosing, see section 12.1
! Drug accountability for the trial medication dispensed or returned from the previous visits must 
be recorded in IV/WRS, see section 10.
! Dispensing of N8-GP in IV/WRS, see section 10
! Home treatment/e-Diary training, see section 5.3 and 8.4.3
! Administration of second dose of N8-GP 
! e-Diary data review and rating severity of bleeding episodes, see section 8.2.1
Reminders:
! An appointment for Visit 3 (4 weeks ± 1 week after visit 2a) should be made.
! Withhold N8-GP minimum 96 hours prior to next visit 
8.1.2.1
Visit 3-13 for Patients on Prophylaxis not Undergoing PK Evaluation and 
Patients on On-Demand Treatment
The home treatment period for patients on prophylaxis and on-demand is approximately 4 weeks ± 
1 week between Visit 3, 4 and 5 and approximately 8 weeks ± 1 weeks between Visit 6, 7, 8, 9, 10, 
11, 12 and 13, see section Table 2-1. At the EOT visit patients will not be dosed at the site.
Antibody samples will only be drawn from patients in the on-demand arm at Visit 3-13 if they have 
received treatment during the home treatment period since last visit
The samples taken post dose, must not be taken from the same vein as previously used for 
administration of N8-GP.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
41 of 112
The following will be performed and/or recorded in the eCRF:
! Withdrawal criteria, see section 6.5
! PRO questionnaires, EOT visit only, see section 8.4.5
! Concomitant medication, see section 11
! Check date and time of last coagulation factor administration (see section 8.4.3)
! AEs: Since previous visit, see section 12.1
! Body measurements (weight only at all visits except EOT visit),  see section 8.4.2
! Physical examination (only at visit 5, 9 and EOT visit), see section 8.3.3
! Vital signs, (before dosing), see section 8.3.4
! ECG (only at EOT visit), see section 8.3.5
! e-Diary data review and rate severity of bleeding episodes, see section 8.2.1
! Home treatment/e-Diary training (not at EOT)
! N8-GP administration, not at EOT visit and not for on-demand patients (Stop time of injection 
must be recorded in the eCRF, this corresponds to time “0”)
! Drug accountability for the trial medication dispensed or returned from the previous visits must 
be recorded in IV/WRS, see section 10
! Dispensing of N8-GP for clinic dosing/home treatment must be performed via IV/WRS (except 
at EOT visit), see section 10
! EOT form (at last visit)
! Affirmation statement (at EOT only)
! Completion session in IV/WRS (at EOT only)
! Return eDiary (at EOT only)
Blood sampling for local laboratory assessments:
! Haematology (to be taken within 1 hour prior to dosing), see section 8.3.6.1
Blood sampling for central laboratory assessments:
! Biochemistry, see section 8.3.7.1
! FVIII activity (trough level and recovery), i.e. before dosing and 30 min (%5 min) after dosing. 
Recovery not to be done in the on-demand arm and not at EOT visit, see section 8.3.6.3
! FVIII inhibitors, see section 8.3.2.2
! N8-GP binding antibodies, see section 8.3.2.1
Reminders for each visit: 
! An appointment for the next visit should be made.
! Withhold N8-GP minimum 96 hours prior to next visit 
! For patients continuing in the pathfinder™4, the EOT Visit will be the first visit in the extension 
trial, therefore informed consent must be obtained prior to EOT Visit.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
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Version:
1.0
Status:
Final
Page:
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8.1.3
Visit Schedule for Patients on Prophylaxis Undergoing PK Evaluation
The PK procedures will take place at visit 2a and visit 7. 
All other visits, i.e. visits 1, 3-6, 8-13 (except for the PK visits) are identical to the visits described 
in section 8.1.2. 
After completion of the PK sessions the patients will continue treatment in the prophylaxis arm.
8.1.3.1
Visit 2a for Patients on Prophylaxis Undergoing PK Evaluation
Visit 2a should take place as soon as possible upon confirmation of eligibility 2-3 weeks after the 
screening visit (Visit 1).Overnight stay is not required during the PK evaluation. 
At visit 2a the patients will receive their first dose of N8-GP (50 U/kg BW) at the site and nine PK 
samples will be taken during the following 4 days. 
The additional assessments and blood samples for PK patients are outlined in the flowchart in Table 
2-2.
Samples taken pre-dose may be taken from the same arm as the one used for N8-GP administration.
The samples taken 30 min post dose must not be taken from the same vein as previously used for 
administration of N8-GP. The lines/tubes must be flushed immediately after administration of the 
trial product.
The following will be performed and/or recorded in the eCRF:
Assessments to be made before the PK session at the day of dosing
! Confirmation of inclusion and exclusion criteria, see section 6.2 and 6.3
! Withdrawal criteria, see section 6.5
! Concomitant medication at all time points during PK, see section 11
! Check date and time of last coagulation factor administration (see section 8.4.3)
! AEs, see section 12.1
! Body measurements (weight only), see section 8.4.2
! Physical examination, see section 8.3.3
! Vital signs, see section 8.3.4
! e-Diary dispensing
Blood sampling for local laboratory assessments to be taken within 1 hour prior to dosing:
! Haematology, see section 8.3.6.1
! Urinalysis with sticks provided by the central laboratory, see section 8.3.6.2
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Blood sampling for central laboratory assessments to be taken within 1 hour prior to dosing:
! Biochemistry, see section 8.3.7.1
! Coagulation related parameters (aPPT and INR) (before dosing and  30 min (%10 min) after the 
first dose) see section 8.3.7.2
! FVIII activity (trough level),see section 8.3.7.3
! N8-GP binding antibodies, see section 8.3.2.1
! FVIII inhibitors, see section 8.3.2.2
First N8-GP administration
!
Dispensing of N8-GP for PK evaluation in IV/WRS
!
Patients will receive 50 U/kg BW of N8-GP (Stop time of injection must be recorded in the 
eCRF, this corresponds to time “0”)
The following will be performed and/or recorded in the eCRF for the PK session:
! FVIII activity: 30 min (%5 min), 1 hr (%5 min), 4 hours (%30 min), 12 hours (% 30 min.), 24 hours 
(+ 8 hours), 48 hours (+ 8 hours), 72 hours (+ 8 hours) and 96 hours (+ 8 hours) after dosing, see 
section 8.3.7.3
! AEs, within 1 hour before dosing, 30 min (%5 min), 1 hr (%5 min), 4 hours (%30 min), 12 hours 
(%30 min) 24 hours (+ 8 hours), 48 hours (+ 8 hours), 72 hours (+ 8 hours) and 96 hours (+ 8 
hours) after dosing, see section 12.1
! Vital signs: within 1 hour before dosing and 30 minutes (%5 min) and 96 hours (+ 8 hours) after 
dosing, see section 8.3.4
Laboratory assessments are to be analysed at central Laboratory
Training
! e-Diary training, see 5.3 and 8.4.3
8.1.3.2
Visit 2b for Patients on Prophylaxis Undergoing PK Evaluation
The second dose of N8-GP will be administered at the site after the last PK sample is taken.
Four days after first dose the following assessments will be performed and/or recorded in the 
eCRF 
! Withdrawal criteria, see section 6.5
! AEs: before and after dosing, see section 12.1
! e-Diary data review and rate severity of bleeding episodes 8.2.1
! Home treatment/e-Diary training, see section 5.3 and 8.4.3
! Drug accountability for the trial medication dispensed or returned from the previous visits must 
be recorded in IV/WRS, see section 10.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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! Dispensing of N8-GP in IV/WRS, see section 10
! Administration of second dose of N8-GP 
Reminders:
! An appointment for Visit 3 (4 weeks ± 1 week after) should be made.
! Withhold N8-GP minimum 96 hours prior to next visit 
! The patients who underwent a PK evaluation at Visit 2a must undergo an additional PK 
evaluation at Visit 7.
8.1.3.3
Visit 7 for Patients on Prophylaxis Undergoing PK Evaluation
Patients who underwent a PK evaluation at Visit 2a must undergo an additional PK evaluation at 
Visit 7. If the patient received N8-GP within the last 7 days prior to Visit 7, the visit should be 
rescheduled. Overnight stay is not required during the PK evaluation.
Samples taken pre-dose may be taken from the same arm as the one used for N8-GP administration. 
The samples taken 30 min post dose must not be taken from the same vein as previously used for 
administration of N8-GP. The lines/tubes must be flushed immediately after administration of the 
trial product.
The following will be performed and/or recorded in the eCRF:
Assessments to be made before the PK session at the day of dosing
! Withdrawal criteria, see section 6.5
! Concomitant medication, see section 11
! Check date and time of last coagulation factor administration (see section 8.4.3)
! AEs, since previous visits, see section 12.1
! Body measurements (weight only), see section 8.4.2
! Physical examination, see section 8.3.3
! Vital signs, see section 8.3.4
Blood sampling for local laboratory assessments to be taken within 1 hour prior to dosing:
! Haematology, see section 8.3.6.1
! Urinalysis with sticks provided by the central laboratory, see section 8.3.6.2
Blood sampling for central laboratory assessments to be taken within 1 hour prior to dosing:
! Biochemistry, see section 8.3.7.1
! Coagulation related parameters, see section 8.3.7.2
! FVIII activity (trough level), see section 8.3.7.3
! N8-GP binding antibodies, see section 8.3.2.1
! FVIII inhibitors, see section 8.3.2.2
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
45 of 112
N8-GP administration
! Dispensing of N8-GP for PK evaluation in IV/WRS
! Patients will receive 50 U/kg BW of N8-GP (Stop time of injection must be recorded in the 
eCRF, this corresponds to time “0”)
The following will be performed and/or recorded in the eCRF for the PK session:
! FVIII activity: 30 min (%5 min), 1 hr (%5 min), 4 hours (%30 min), 12 hours (% 30 min.), 24 hours 
(+ 8 hours), 48 hours (+ 8 hours), 72 hours (+ 8 hours) and 96 hours (+ 8 hours) after dosing, see 
section 8.3.7.3
! AEs, within 1 hour before dosing, 30 min (%5 min), 1 hr (%5 min), 4 hours (%30 min), 12 hours 
(%30 min), 24 hours (+ 8 hours), 48 hours (+ 8 hours), 72 hours (+ 8 hours)and 96 hours (+ 8 
hours) after dosing, see section 12.1
! Vital signs: within 1 hour before dosing, 30 minutes (± 5 min) and 96 hours (+ 8 hours) after 
dosing, see section 8.3.4
Laboratory assessments are to be analysed at Central Laboratory.
Training/review
! e-Diary data review and rating of severity of bleeding episodes, see section 8.2.1
! Home treatment/e-Diary training, see section 5.3 and 8.4.3
IV/WRS
! Drug accountability for the trial medication dispensed or returned from the previous visits must 
be recorded in the IV/WRS, see section 10
! Dispensing of N8-GP for home treatment must be performed via IV/WRS, see section 10
Reminders:
! An appointment for Visit 8 (8 weeks %1 week later) should be made.
! Withhold N8-GP minimum 96 hours prior to next visit 
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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8.1.4
Follow-up visit (only for patients withdrawn due to development of FVIII 
inhibitors)
In case of withdrawal due to FVIII inhibitor development, the patient should be scheduled for an 
EOT Visit as soon as possible and within 1 week after a positive inhibitor test is confirmed via 
re-testing, preferably prior to initiation of treatment with another FVIII product. One month (4 
weeks % 2 weeks) after the EOT Visit the patient must attend a FU Visit, please see Section 8.3.6.
At each FU Visit, it will be evaluated if further FU Visits are required. The additional FU Visits will 
be arranged at intervals of 4 weeks ± 2 week as long as clinically warranted up until 3 months after 
confirmation of the FVIII inhibitor.
The following will be performed and/or recorded in the eCRF:
! Follow up on any AEs according to section 12.1
! Vital signs, see section 8.3.4
! Bleeding episodes since last visit
! Affirmation statement
! EOT form
Blood sampling for central laboratory assessments:
! FVIII inhibitors, see section 8.3.2.2
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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8.1.5
Unscheduled Visits
It is possible to perform Unscheduled visits during the trial. The Unscheduled visit can be 
performed any time after enrolment and until the EOT visits as either a telephone visit or a site visit. 
Patients can attend an unscheduled visit due to a bleeding episode, suspicion of inhibitor 
development, any AE, sampling for laboratory test etc.
Visits/contacts to the site for the purpose of non-trial related activities do not need to be reported as 
an Unscheduled visit.
The following can be performed/reported at an Unscheduled visit:
! Withdrawal criteria, see section 6.5
! Concomitant medication, see section 11
! Bleeding episodes including date, severity and location see section 8.2.1
! E-Diary compliance review, see section 8.2.1
! AEs: Since previous visit, see section 12.1
! Dispensing of N8-GP for dosing/home treatment must be performed via IV/WRS, see section 10
! Body measurements, see section 8.4.2
! Physical examination, see section 8.3.3
! Vital signs, see section 8.3.4
! ECG, see section 8.3.5
! Biochemistry, see section 8.3.7.1
! Haematology, see section 8.3.6.1
! HIV (viral assessments), see section 8.3.7.4
! Hepatitis (viral assessments), see section 8.3.7.4
! Coagulation-related parameters, see section 8.3.7.2
! FVIII activity (trough level and recovery), see section 8.3.7.3
! FVIII inhibitors, see section 8.3.2.2
! N8-GP binding antibodies, see section 8.3.2.1
! IgE, IgG, see section 8.3.2.3
! N8-GP administration, not for on-demand patients 
! Home treatment/E-Diary training, see section 5.3 and 8.4.3
! Drug accountability of N8-GP, see section 10
! Surgery transfer session
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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8.1.6
Transfer of Patients due to Major Surgeries
In case major surgery is needed the patients should be transferred to the pathfinder™3 trial. To 
enable patients to be transferred the following assessments have to be performed: 
! To ensure that N8-GP is available for the surgery, notify the IVRS system at least 14 days prior 
to a planned surgery by using the IVRS “Dispensing session”. This can be done both at planned 
and unscheduled visits. 
!
At the day of transferring to the pathfinder™3 trial the IVRS ”surgery transfer session” should be 
used in order to transfer the patient into pathfinder™3
! Drug accountability – the patient must return and account for all drug dispensed in the current 
trial before entering pathfinder™3
! After completion of pathfinder™3 trial an IVRS ”surgery transfer session” should be performed 
in order to transfer the patient into pathfinder™2
! Fill in the Surgery transfer form in the e-CRF
Upon completion of pathfinder™3, patients will return to pathfinder™ 2, re-entering the 
prophylactic or on-demand treatment arm as per their prior participation in the trial. The patient will 
return to the next visit in line in Pathfinder™ 2 and the visit assessement performed at the EOT visit
in pathfinder™3 will be used.
8.2
Efficacy Assessments   
8.2.1
Bleeding Episodes
During the entire trial period all treatment requiring bleeding episodes will be entered by the patient
or caregiver in the patient’s eDiary. In case a patient is unable to enter a bleeding episode in the 
eDiary or hospitalised the Investigator will have to report it in the eCRF as an unscheduled visit, 
please refer to section 8.1.5.
If a patient experience a bleeding episode at home, treatment with N8-GP should be initiated 
irrespective of severity of the bleeding episode, please refer to section 5.3.2 for details. If the bleed 
is mild/moderate, the treatment responsibility is with the patient, patient’s caregiver(s) and/or 
Investigator. For severe bleeding episodes, the treatment responsibility is always with the 
Investigator and the patient should contact the site and come to an unscheduled visit. Treatment of 
severe bleeding episodes should be initiated as soon as possible by the patient or caregiver, before 
coming to the site. It is the responsibility of the Investigator to assess the severity of the bleeding 
episodes and to ensure that all data is recorded correctly in the patient’s eDiary.
Joint bleeds are either categorised as target joint or non-target joint bleeds. Target joints are defined 
as 3 or more bleeding episodes in the same joint within 6 months. When there has been no bleed in 
this same joint for 12 months, such a joint is no longer considered a target joint.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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For bleeding episodes the following will be recorded in Patient’s eDiary or eCRF:
!
Prophylaxis or treatment of bleed
!
Date and time of onset of bleed
!
Location of the bleed
!
Cause of bleed (spontaneous, traumatic, minor surgery)
!
Haemostatic drug used for 
!
Pain relieving medication
!
Dose(s) and Time(s) of administration
!
Other therapy used (compression, ice or other)
!
Stop of bleed (date and time)
!
Categorisation of the bleeding episode (mild/moderate or severe), in the eCRF
!
Clinical evaluation of the haemostatic response (excellent, good, moderate or none)
!
Bleed related days away from work or school
!
Bleed related days using mobility aids
A need for haemostatic rescue therapy with another FVIII product will be assessed by the 
Investigator via phone or during the site visit. Patients treated with FVIII products other than N8-
GP must be withdrawn from the trial.
8.2.1.1
Definition of Severity of Bleeding episodes
!
Mild/Moderate: Bleeding episodes that are uncomplicated joint bleeds, muscular bleeds 
without compartment syndrome, mucosal- or subcutaneous bleeds
!
Severe: All intracranial, retroperitoneal, iliopsoas and neck bleeds must be categorised as 
severe. Muscle bleeds with compartment syndrome and bleeds associated with a significant 
decrease in the haemoglobin level (>3g/dl) should also be reported as severe. These bleeding 
episodes must be treated immediately or at the local emergency room and the trial personnel 
must be contacted. The details of severe bleeding episodes must be entered in the eDiary or if 
the patient is unable to fill in the e-Diary or hospitalized, the Investigator or trial personnel can 
enter the data in the eCRF as an unscheduled visit. Traumatic bleeds at other locations than 
described above can always be considered severe at the investigators discretion.
8.2.1.2
Definition of Haemostatic Response:
!
Excellent: abrupt pain relief and/or unequivocal improvement in objective signs of bleeding 
within approximately 8 hours after a single infusion.
!
Good: definite pain relief and/or improvement in signs of bleeding within approximately 8 
hours after one infusion, but possible requiring more than one infusion for complete resolution
!
Moderate: probable or slight beneficial effect within approximately 8 hours after the first 
infusion; usually requiring more than one infusion
!
None: no improvement, or worsening of symptoms
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
CONFIDENTIAL
Date:
30 September 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Classification of a bleeding episode
!
Spontaneous, traumatic, re-bleed, minor surgery
Classification of re-bleed will be performed by the trial statistician at the time of the statistical 
analysis according to the following criteria:  A re-bleed is defined as a worsening of symptoms in 
the same location after an initial period of improvement, either on treatment or within 72 hours after 
stopping treatment. If a bleed occurs in the same location later than 72 hours after stopping the 
treatment it is considered a new bleed.
8.3
Safety Assessments
8.3.1
Adverse Events
Monitoring of AEs will be performed from the first trial related activity (screening) to the EOT 
visit, according to the procedures described in section 12.
For recording of bleeding episodes, please refer to sections 8.2.1 and 12.1.3.
8.3.2
Antibody Assessments
Blood samples for assessment of antibody formation against N8-GP will be drawn at the screening
visit, pre-dose of N8-GP administration at all visits (except visit 2b) and at the follow-up visit 
approximately one month after the End of Trial visit. Antibody samples will only be drawn from 
patients in the on-demand arm at Visit 3-13 if they have received treatment during the home 
treatment period since last visit. The samples will be analysed both using the Bethesda assay 
identifying inhibitory antibodies towards FVIII and using an assay capable of identifying the 
occurrence of any antibodies towards both rFVIII and N8-GP.
8.3.2.1
N8-GP antibody assay
Binding antibodies towards N8-GP and rFVIII in plasma will be analysed on an ongoing basis.
The presence of N8-GP binding antibodies will be determined by a radioimmunoassay and is 
validated according to internationally recognised guidelines and recommendations. For samples 
with a result above the cut-off the presence of anti-N8-GP antibodies will be confirmed in a 
confirmatory assay by addition of excess of unlabelled N8-GP. Furthermore, cross-reactivity to 
rFVIII will be measured in the confirmatory assay in parallel with excess of un-labelled rFVIII. 
Only samples positive in the confirmatory assay will be characterized as anti-N8-GP or anti-rFVIII 
antibody positive. 
Levels of N8-GP binding antibodies will be compared to pre-dose samples throughout the trial. If a 
patient develops N8-GP binding antibodies and the incremental recovery value at that visit is less
than 60% of screening value, a new inhibitor sample will be taken after a 7 days wash out period.
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Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
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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 N8-GP binding antibodies 
and will not be triggered more than twice for an individual patient. Furthermore, a 7 days wash out 
period will only be applied if the 96 hours wash out is not sufficient to avoid drug interference in 
the inhibitor assay.
8.3.2.2
FVIII inhibitors
All patients will be examined for the development of FVIII inhibitors at scheduled visits. A positive 
inhibitor test is defined as ∀0.6 BU/mL. If FVIII inhibitor development is suspected (increased 
number of bleeding episodes, bleeding episodes difficult to treat, recovery and trough levels below 
expected values) during the course of the trial, additional inhibitor tests can be taken at 
Unscheduled Visits. All inhibitor tests must be analysed by the Central Laboratory.
In the event that a patient has a positive inhibitor test (∀0.6 BU/mL), the patient must attend an 
Unscheduled Visit as soon as possible or within 1 week after the result is available to take a 
confirmatory inhibitor test on a separately drawn sample. This second sample should preferably be 
taken prior to any change of treatment. At this Unscheduled Visit, a recovery test must also be 
performed. If the second inhibitor test is also positive, the patient must be withdrawn by 
discontinuing trial product and attending the EOT Visit within 1 week after the result is available.
A patient has inhibitor (≥0.6 BU/mL) if the patient has been tested positive for inhibitors at two 
consecutive test samples performed at the central laboratory preferably with no more than 2 weeks 
between the tests.
A follow-Up Visit must be scheduled 1 month after the EOT Visit and additional monthly follow-
up visits may be arranged at intervals as long as clinically warranted up to 3 months after the EOT
Visit.
All per protocol inhibitor laboratory samples are to be analysed in the central laboratory, and only 
these results will be used in the trial data analysis.
If the Investigator decides to send a sample for inhibitor testing to a local laboratory, the 
Investigator must also send a duplicate sample for inhibitor testing to the Central Laboratory. The 
data from the Central Laboratory will then be used in the official analysis. A positive inhibitor test 
must be reported as a MESI (please refer to section 12.1.2)
Blood samples for measurement of inhibitors towards FVIII will be analysed according to the 
Nijmegen modification of the Bethesda assay15. Any sampling for the inhibitor test must be 
performed at least 96 hours after last administration of N8-GP to allow for maximum wash-out of 
the drug.
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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An inhibitor test with a result ≥0.6 BU/ml will be considered as a positive inhibitor test. A patient is 
verified inhibitor positive if two independent samples from same patient are inhibitor positive 
(≥0.6BU) – and the patient should discontinue the trial including an EOT Visit and FU Visits.
A patient having an initial positive inhibitor positive test and a second negative inhibitor test, will 
be reported as a MESI and continue in the trial.
If more than two patients are verified inhibitor positive an unscheduled Safety Committee Meeting 
will be called by Global Safety – and a decision whether to continue, modify or stop the trial will 
made, see Section 12.5.3.
8.3.2.3
Antibody Assessments in case of Allergic/Anaphylactic Reaction  
Any patient who experiences an unexpected allergic/anaphylactic reaction will be assessed for
inhibitors and antibodies against drug product content, such as IgG/IgE against N8-GP and Host 
Cell Proteins (HCP). Additional blood samples may be requested for this purpose. If it is deemed 
necessary, the same analyses will be performed for all patients enrolled in the trial using available 
blood samples.
8.3.3
Physical Examination
The physical examinations will be performed according to local procedure and will include:
! General appearance
! Ears, Eyes, Nose, Throat and Neck
! Respiratory System
! Cardiovascular System
! Gastrointestinal System, including mouth
! Musculoskeletal System
! Central and Peripheral Nervous System (general evaluation)
! Skin
! Lymph node palpation
Any changes in the examination between the visits which fulfil the criteria of an AE must be 
recorded as such (see section 12).
Clinically significant findings present at screening must be documented as concomitant illness and 
during the trial as AEs.
8.3.4
Vital Signs
Before measurement of vital signs the patient must rest comfortably for at least three minutes and 
all measurements should, if possible, be performed using the same method and position (e.g. sitting 
or lying down) throughout the trial for each individual patient. 
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
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Vitals signs include assessment of:
! Body temperature (according to local standard practice)
! Pulse
! Blood pressure
! Respiratory rate (resp./min)
Elevated BP is defined as a systolic BP >160 mmHg or a diastolic BP >95 mmHg. Decreased BP is 
defined as a systolic BP <90 mmHg or a decrease from pre-dose of more than 30 mmHg.
Results of vital signs must be reported in the eCRF. Clinically significant findings present at 
screening must be documented as concomitant illness and during the trial as AEs.
8.3.5
ECG
ECG must be performed at Screening (Visit 1) and EOT visit. ECGs will be performed using a 12-
lead Electro Cardiogram. For the ECG recording the patients must be resting and in a horizontal 
position. Any irregularities observed during the ECG e.g. cough, should either induce a re-run of the 
ECG and/or be annotated in the eCRF page with description of the occurrence. Print-outs must 
include date, time, patient’s identification, and initials of the Investigator, and at least 2 complexes 
for each lead and a single rhythm strip of 6 beats. Electronic capture of these measurements may 
also be performed.
The interpretation of result must follow the categories “normal”, “abnormal, not clinically 
significant” or “abnormal, clinically significant”. The evaluation should be made by the Investigator 
or delegated to a cardiologist.
Results of the ECG recording must be reported in the eCRF. Clinically significant findings present 
at screening must be documented as concomitant illness and during the trial as AEs.
8.3.6
Local Laboratory Tests
The local laboratory will analyse and report all laboratory safety tests related to haematology and 
urinalysis performed in this trial. Laboratory results from the local laboratory will be reported in the 
eCRF.
An investigator must sign, date and categorise the local laboratory results. Categorisation will be 
either “normal”, “out of normal range, not clinically significant” or “out of normal range, clinically 
significant”. Clinically significant findings must be recorded as Concomitant Illness (blood samples 
during visit 1) or as an AE (blood samples taken at visit 2-13 incl. unscheduled visits). 
Abnormalities should only be recorded as AEs if not present or worsened from baseline/previous 
assessments. Laboratory results should be signed and dated. Local laboratory result (reports) are 
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Protocol/UTN: U1111-1119-7416
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considering source data and should be kept in the patient file for source data verification (carried 
out by the monitor).
The administration of N8-GP will be performed after collection of all blood samples for the 
laboratory tests, except the recovery samples which must be collected 30 minutes after 
administration of N8-GP.
Storage, handling, and disposition of samples analysed at local laboratories, will be performed 
according to local laboratory procedures. It will be possible for the site to report in other predefined 
units than listed below.
The local laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses. Such data will not be transferred to the 
trial database or the eCRF, but may be reported to the investigator according to specifications in the 
laboratory standard operating procedures and requirements. The investigator must review all 
laboratory results for concomitant illnesses and AEs and report these according to this protocol.
8.3.6.1
Haematology
! Platelet count (thrombocytes) (x 109/L)
! Haemoglobin (mmol/L)
! Red cell count (erythrocytes) (x 1012/L)
! Mean corpuscular volume (MCV) (fL)
! Packed cell volume (haematocrit) (PCV) (%)
! White cell count (leucocytes) (x 109/L)
! Differential white cell count (%)
∋
Lymphocytes
∋
Monocytes
∋
Neutrophils
∋
Eosinophils
∋
Basophils
8.3.6.2
Urinalysis
Qualitative examination (stick):
! pH
! Proteins
! Glucose
! Bilirubin
! Blood
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NNC 0129-0000-1003 
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Protocol/UTN: U1111-1119-7416
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Urinalysis will be performed locally with sticks provided by the central laboratory and should be 
recorded directly in the eCRF. Results from the urinalysis other than pH, proteins, glucose, bilirubin 
and blood should not be reported to Novo Nordisk.
Clinical significant findings must be recorded as concomitant illness at screening and as AEs at the 
following visits if it is new finding or a change relative to a previous visit.
8.3.6.3
FVIII activity (local laboratory)
! FVIII:C (U/mL)
The patient is enrolled in the trial based on the FVIII activity reported in the medical records. 
The Investigator can at any time during the trial perform FVIII activity at his/her discretion. When 
FVIII activity measurements are made clot or chromogenic assays must be used. Moreover, a 
reference standard provided by Novo Nordisk should also be analysed when running the assay. The 
reference standard will be provided by Novo Nordisk together with a description of how to handle, 
store and use it.
8.3.7
Central Laboratory Assessments
A Central Laboratory will analyse and report all laboratory safety tests performed in this trial 
related to coagulation parameters, biochemistry, viral assessments, and FVIII inhibitor assessments. 
Laboratory data from the Central Laboratory will be reported to Novo Nordisk electronically. 
Laboratory data will be reported to Novo Nordisk in a manner that anonymity of patients will be 
maintained. Central Laboratory data will be reported to the investigators by fax or e-mail. Upon 
review of the central laboratory results the investigator must sign and date the laboratory reports.
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.
A detailed description of procedures for sampling, handling, particulars of instrumentation, 
shipment of laboratory samples and all materials such as test tubes and labels will be provided by 
the central lab in the Central Laboratory Manual. The Central Laboratory Manual and the results 
reported will include all reference ranges. 
The central laboratory is requested only to report the analyses dictated by this protocol. 
The central laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses. Such data will not be transferred to the 
trial database or the eCRF, but may be reported to the investigator according to specifications in the 
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Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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laboratory standard operating procedures and requirements. The investigator must review all 
laboratory results for concomitant illnesses and AEs and report these according to this protocol.
8.3.7.1
Biochemistry
! Sodium (mmol/L)
! Potassium (mmol/L)
! Total calcium (mmol/L)
! Chloride (mmol/L)
! Creatinine (micromol/L)
! Urea (mmol/L)
! Albumin (g/L)
! Total Proteins (g/L)
! Total bilirubin (micromol/L)
! Cholesterol (mmol/L)
! Aspartate aminotransferase (AST) (IU/L)
! Alanine aminotransferase (ALT) (IU/L)
! Gamma glutamyltransferase (GGT) (IU/L)
! Alkaline phosphatase (IU/L)
! C-reactive protein (CRP) (mg/L)
8.3.7.2
Coagulation related Parameters
! aPTT (activated partial thromboplastin time) (s)
! INR (prothrombin time) (sec, INR)
! Lupus anticoagulant 
! Von Willebrand’s factor  
8.3.7.3
FVIII Activity (central laboratory)
The analysis of plasma FVIII activity will be performed at laboratory selected by Novo Nordisk by 
three different assays (see below). Blood samples for analysis of FVIII activity will be collected 
from all patients in the prophylaxis arms at the dosing visits pre-dosing (trough level)f and 30 
minutes post-dosing (FVIII recovery)g. For patients on prophylaxis undergoing PK evaluation (at 
Visit 2a and Visit 7), additional samples will be taken post-dose (30 min, 1, 4, 12, 24, 48, 72 and 96 
hours post). Exact date and time of sampling must be documented. The sampling time points are 
relative to completion of N8-GP administration. 
                                                
f The trough level is defined as the lowest level of FVIII measured immediately prior to dosing and reported as (U/mL). 
g Incremental recovery is the FVIII level 30 minutes after trial product administration relative to the dose administered 
and will be reported as [U/mL]/[U/kg]
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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For on-demand patients only one sample will be taken at each visit for analysis of plasma FVIII
activity. The primary analysis of PK will be based on the chromogenic method; however, the 
samples will also be assayed using a modified one-stage clotting assay.
One-stage clot activity assay
The one-stage bioassay (FVIII:C assay, clot assay) measures the activity of the compound in a 
specific process (clot formation). The FVIII:C assay is a modified one-stage clotting assay
(modified aPTT assay) calibrated with an internal N8-GP reference standard for N8-GP and/or with 
an international standard.
Chromogenic activity assay
A bioassay (FVIII:C chromogenic assay), which measures the activity of the compound with a two-
stage method. The FVIII:C is determined by measuring the FVIIIa/FIXa-mediated FX activation 
with a chromogenic FXa substrate. It is a validated assay calibrated with an internal N8-GP 
reference standard for N8-GP and/or with an international plasma standard. 
Exploratory assays for measuring N8-GP activity 
A non validated exploratory Thrombin generation assay (TGA) and/or other assays can be applied 
for measuring activity of N8-GP and analysed by the end of the trial. The results from these assays
will be reported separately.
8.3.7.4
Viral assessments (HIV, Hepatitis B and C)
Viral assessments should be performed if status is unknown or the investigator considers there is an 
indication to test.
! Surface antigen of hepatitis B (HBsAg)
! Anti-HCV antibodies (Hepatitis C) 
! HIV 1 & 2 antibodies (If known to be HIV positive, last CD4+ T cell count and date of test. If 
the CD4+ T cell count test is more than 6 months old, a new test must be taken and send to the 
central laboratory before determining whether or not the patient is eligible in accordance with 
inclusion and exclusion criteria)
! Viral load 
8.3.7.5
FVIII genotype testing (Not applicable to Brazil)
At visit 1, all patients/LARs will be asked about documentation of previous FVIII genotype tests. If 
not available or if it needs to be re-tested FVIII genotype testing will be offered at visit 1. 
Investigator and patients/LARs have the right to refuse to provide patient’s FVIII genotype
documentation or to refuse genotyping.
Applicable for Japan and Taiwan only: If documentation of the patients’ genotype already exists, 
the patients are offered to provide their data for the trial. Only FVIII genotype is analyzed by using 
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Protocol/UTN: U1111-1119-7416
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DNA, isolated from patients’ leucocytes at the laboratory in Germany. No further analysis will be 
carried out for other genotype. Samples will be disposed appropriately after the test. All test results 
are kept strictly confidential in sufficient consideration of individual information.
8.4
Other Assessments
The following assessments should preferably be performed prior to blood sampling and prior to 
administration of N8-GP unless it is clearly stated otherwise. All assessments should be recorded in 
the eCRF unless stated otherwise.
8.4.1
Demographic data
Collected as allowed per local law
! Date of birth and age (for Germany only: Year of Birth and Age)
! Race
! Ethnicity 
8.4.2
Body Measurements
All body measurements (weight, height and BMI) will be performed at Visit 1. On all other visits 
only weight will be measured. The weight measured at the respective visits should be the weight 
used for calculation of the dose administered.
! Weight, wearing light clothing only (kg/pounds) and without shoes
! Height, without shoes (cm/inches), (visit 1 only)
! BMI calculation (kg/m2) (visit 1 only)
8.4.3
eDiaries
eDiaries will be used in this trial. The patient should bring the eDiary to every visit to the site. 
The following data will, as a minimum, be captured by the patient or the caregiver in the e-Diary:
!
Treatment
∋
FVIII product used 
∋
Prophylaxis or treatment of bleed
∋
Dose level
∋
Date and time of dose administration
!
Bleeding episodes 
∋
Onset of bleed (date and time)
∋
Haemostatic drug used for treatment (dose and time of administration) 
∋
Pain relieving medication
∋
Cause of bleed (spontaneous, traumatic, minor surgery) 
∋
Location of bleed
∋
Other therapy used (compression, ice or other)
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Protocol/UTN: U1111-1119-7416
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∋
Evaluation of haemostatic response (excellent, good, moderate, none)
∋
Stop of bleed (date and time)
∋
Bleed related days away from work or school
∋
Bleed related days using mobility aids
The Investigator must carefully instruct the patient in how to evaluate a bleeding episode, the 
haemostatic response after treatment and how to complete the eDiary. 
The entries made by the patient in the eDiary will be reviewed by the Investigator together with the 
patient and/or caregiver during every visit to ensure consistency/compliance. The information in the 
patient’s eDiary is regarded as source data. In case information missing in the eDiary is available in 
the medical records, this information can be used.
It is the investigator responsibility to rate the severity of all reported bleeding episodes in the eCRF.
Trial product administration performed at the site should also be entered in the eDiary by the 
patient.
8.4.4
Medical History/Concomitant Illness
Complete medical history is to be obtained during the screening procedure. If a diagnosis is 
unknown the description of symptoms will be recorded. Onset date including year for all illnesses 
within the last two years should be recorded.
The following organ systems should be assessed and included from medical record:
! Central and peripheral nervous systems
! Eyes-ears-nose-throat
! Cardiovascular
! Respiratory
! Gastrointestinal
! Renal-genitourinary
! Endocrine-metabolic
! Muscolo-skeletal
! Dermatologic
! Haematopoietical-lymphatic including blood type parameter (0 type or non-0) as allowed by 
local law and if available
! Immunological
Conditions related to the following items should be assessed:
! Allergies, including any drug allergies or sensitivities
! Psychiatric disorders
! Abuse of drug, alcohol or any substance
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Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
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Haemophilia Details (including history) 
! Diagnosis of haemophilia A (date)
! Other coagulation related diseases
! Classification of haemophilia A (severe form requested in this trial) and FVIII:C activity level 
(%) from medical history
! Underlying gene defect (if known)
! Clinical suspicion of inhibitors data from medical history
! Number of inhibitor tests and/or FVIII:C recovery tests within the last 8 years
! History of switching FVIII products (type of products (from/ to) and age at switching) if 
available
! Relatives with haemophilia A (yes/no)
∋
If yes – specify any relatives with haemophilia A and inhibitors (as recalled by patient)
8.4.4.1
Documentation of Inhibitor Status
A positive inhibitor test excludes the patient. The historical laboratory cut-off value (assay 
sensitivity or lower limit of quantification) for a positive Bethesda inhibitor titre must not be higher 
than 1.0 BU/mL.
Documentation of inhibitor status must include the following:
•
two inhibitor test result should be documented within the period since diagnosis, not 
necessary within the last 8 years
•
FVIII recovery test performed at least every third year during the last 8 years + evaluation of 
the bleeding history AND/OR negative inhibitor testing at least every third year during the 
last 8 years. 
8.4.4.2
Bleeding Treatment History including History of Bleeding Episodes
For patients currently on prophylaxis treatment, the following should be recorded
∋
Number of months on prophylaxis
∋
Dose and frequency of dosing
∋
Recombinant or plasma FVIII product
∋
Number of bleeding episodes within the last 12 months (number of treatment requiring 
bleeding episodes)
∋
Estimated amount and number of doses used to treat a bleed
∋
Bleeding pattern prior to prophylaxis therapy was initiated 
For patients currently on on-demand treatment the following should be recorded
∋
Number of bleeding episodes within the last 12 months (number of treatment requiring 
bleeding episodes)
∋
Recombinant or plasma FVIII product
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∋
Estimated amount and number of doses used to treat a bleed
For all patients the following should be recorded
! History of Surgery (Surgeries within the last 5 years)
∋
Date of surgery
∋
Indication (surgery)
∋
Recombinant or plasma FVIII product
! Number of EDs prior to trial entry: must be at least150 days (yes/no)
! Vaccinations in the last 12 months 
! Planned vaccinations in the next 12 months from time of screening visit (should be recorded as 
concomitant medication at the time of vaccination)
8.4.5
PRO Questionnaires and Health Economics
PROs will be collected at screening visit (Visit 1) and at EOT visit for all patients. The 
questionnaires should preferably be completed prior to any other trial related activities during the 
two visits. Health economic data will be collected after treatment starts in connection with bleeding 
episodes. 
Several questionnaires will be used to assess disease and age-group specific quality of life and 
treatment satisfaction from the screening and EOT Visits.
The following questionnaires should be completed by the patients and, where relevant, also by the 
parent/LAR:
For trial patients aged 12-16: 
HAEMO-QOL: Questionnaire for children/adolescents (8-12 years, 13-16 years)
EQ-5D: Questionnaire (13 years and above)
HAEMO-QOL: Parents proxy; Questionnaire for parents/LARs of Children/adolescents (8-12 
years, 13-16 years)
HEMO-SAT(P): Parents proxy; Questionnaire for parents/LARs of adolescents (13-16 years)
For trial patients aged 17 and above:
HAEM-A-QOL: Questionnaire for adults aged 17 and above
HEMO-SAT(A): Questionnaire for adults aged 17 and above
EQ-5D: Questionnaire (13 years and above)
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Protocol/UTN: U1111-1119-7416
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The PRO questionnaires are generic as well as disease and age-group specific and are designed to 
minimise the burden on the patient/parent/LAR in providing the information. The questionnaires are 
originally developed and validated in UK English, and have been translated and linguistically 
validated into other languages. However, a translated and linguistically validated questionnaire may 
not be available for all patients in all countries in which case the questionnaire is not to be 
completed. It is the responsibility of the investigator to review the PRO questionnaires for possible 
AEs 
To characterise the impact of on-demand and prophylaxis treatment on health economics aspects,
the following data will be collected as part of the patient eDiaries:
! Number of days not able to attend school or work if related to bleeding episodes or sequelae of 
bleeding episodes
! Number of days requiring use of mobility aids (cane, crutches, wheelchair) if related to bleeding 
episodes or sequelae of bleeding episodes
Furthermore, the following will be recorded in the eCRF:
! Number of hospital admissions and hospitalisation days due to a bleeding episode or sequelae of 
bleeding episodes
! Visits to an emergency room if related to a bleeding episode or sequelae of bleeding episodes
8.5
Patient Compliance
Assessment of patient compliance with the protocol procedures for determination of the 
continuation of the trial will be done at the Investigator’s discretion. The Investigator or his 
designee can at any time access the patient data from the eDiary in a web portal.
Failure of compliance with scheduled visits and trial product administration may result in 
withdrawal in accordance with the protocol withdrawal criteria.
Compliance with the N8-GP treatment should be addressed at each visit. In the prophylaxis 
treatment, doses should not be separated by more than 96 hours. If patients experience bleeding 
episodes due to exceeding the time between doses indicated above, the Investigator must retrain the 
patient/parent/caregiver. The training must be documented in the medical records.
If a patient deviates from the 96 hours dose intervals mentioned above, but the dose is administered 
on the correct day, this is not considered a protocol deviation.
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Protocol/UTN: U1111-1119-7416
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8.5.1
Definition of Treatment Compliance
Good compliance: If the prophylaxis infusions of N8-GP is 50 U/kg BW ± 5 U/kg BW for at least 
80% of the prophylaxis infusions and the time interval between two prophylaxis infusions is 4 days 
for at least 80% of the time. 
Less compliance: If the prophylaxis infusions of N8-GP is outside 50 U/kg BW± 5 U/kg BW for 
more than 20% of the prophylaxis infusions or if there is more or less than 4 days between two 
prohylaxis dosis for more than 20% of the time.
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Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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9
Trial Supplies
9.1
Trial Product(s)
The following trial products will be supplied by Novo Nordisk:
! N8-GP 2000 U/vial 211μg/vial as a sterile, freeze-dried powder in a 2-8 (C (36-46(F) stable 
formulation single use vial of 2000 U/vial to be reconstituted with 4.3 mL of 0.9% Sodium
Chloride (NaCl) for i.v. injection.
N8-GP 2000 U/vial 211μg/vial powder must be reconstituted prior to administration. After 
reconstitution with 4.3 mL Sodium Chloride 0.9% solution each 2000 U vial contains 500 U/mL of 
N8-GP (4 mL can be withdrawn from the vial). Sodium Chloride 0.9% will be provided by Novo 
Nordisk.
The reconstituted solution is colourless and clear to almost clear with a pH of 6.9. The reconstituted 
solution must not be further diluted. It is recommended to use N8-GP immediately after 
reconstitution. Exposure to direct sunlight and/or freezing must be avoided.
Detailed instructions regarding reconstitution of N8-GP will be provided in the Trial Materials 
Manual (TMM). The reconstitution procedure will be translated into local language(s) and given to 
the patient together with the trial product.
The BW for dose calculation will be measured at all relevant visits. After reconstitution, the 
appropriate volume will be drawn into a syringe. The content of several vials may be combined in 
one syringe. N8-GP must not be added to or mixed with other material (other than NaCl).
9.2
Trial Product Administration
The trial product should be administered as a slow bolus i.v. injection over approximately 2 mins 
(from start to completion of injection) for all trial product administrations.
These administrations will primarily be performed at home. All patients and/or caregivers will be 
instructed by the Investigator how to handle home administration before the first dose 
administration at home.
9.3
Packaging and Labelling of Trial Product(s)
Novo Nordisk A/S will label and pack the trial product.
N8-GP drug product and sodium chloride will be provided in separate boxes. All trial products will 
be packed open labelled.
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Protocol/UTN: U1111-1119-7416
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The boxes will be provided with pre-printed labels. Each drug product vial will have a unique 
Dispensing Unit Number (DUN) for identification and traceability.
Labelling will be in accordance with GCP Annex 1316, local law and trial requirements. 
The details of the packaging and labelling of N8-GP drug product will be provided in the TMM 
supplied by Clinical Supplies Coordination, Novo Nordisk A/S.
9.4
Storage, Handling, Accountability and Destruction of Trial Product(s)
N8-GP 2000 U/vial 211μg/vial must be stored at 2-8 °C, protected from light. It is recommended to 
use the trial product immediately following reconstitution. If not used immediately, the 
reconstituted product can be stored for up to 4 hours at room temperature (below 30°C) or 24 hours 
at 2–8°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 Investigator must ensure the availability of proper storage conditions at site and monitor, record 
and evaluate the temperature. The storage facilities must be checked frequently using a calibrated 
temperature logging device. A temperature log for temperature recording (actual, min., and max. 
temperature on working days) must be kept at the Investigator site. The Investigator must contact 
the Monitor in case of deviation from the acceptable temperature range.
The temperature recorder should be either: 
!
electronic with minimum interval of logging of 1 hour or
!
manual with a min-max calibrated thermometer; the actual, minimum and maximum 
temperatures must be logged
The site must carefully instruct the patient in how to store the trial product at home and to read the 
labels with special attention to storage conditions. 
Dispensing and Drug Accountability
The IV/WRS will allocate the trial product in uniquely packed DUNs to the patient at each 
dispensing visit. According to the patient’s BW, the correct number of DUNs will be allocated to 
the patient.
!
No trial product should be dispensed to any person not enrolled in the trial
!
Unused trial product must be stored separately from used trial product
!
All vials (used, partially used, unused, returned, and lost/damaged)(except NaCl vials) must 
be recorded in the IV/WRS drug accountability module
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Protocol/UTN: U1111-1119-7416
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The Investigator or delegated person e.g. trial nurse will perform drug accountability in the IV/WRS 
Drug Accountability module. 
Drug accountability must be performed for all delivered trial products (except NaCl). Trial product 
will be dispensed at dispensing or assessments visits as appropriate.
All used, partly used and unused trial products returned by the patient must be stored separately 
from non-allocated trial products. Returned/used trial products can be stored at room temperature. 
All trial products must be retained for inspection by the Monitor. The Monitor will, upon 
completion of drug accountability, arrange for the destruction of used, expired unused and broken 
vials of the supplied trial product.
The TMM detailing the handling of the trial materials will be provided by Novo Nordisk.
For Japan only: Responsibility for storage and drug accountability of the trial products at the study 
site rests with the head of the study site. The head of the study site should assign some or all of the 
responsibilities for accountability of the trial products at the sites to a trial product storage manager 
(a pharmacist in principle). The trial product storage manager should control and take accountability 
of the trial products in accordance with procedures specified by the sponsor. The head of the study 
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
All medical devices used in this trial will be provided by Novo Nordisk such as syringes, butterflies, 
sterile swabs, vial adapters etc. 
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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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 the internet. Some 
sessions may be available through a toll-free telephone number. Accessibility to the IV/WRS must 
be restricted to and controlled by authorised persons. As a minimum, the system will be used for:
!
screening of patients, 
!
dispensing of trial product, 
!
controlling of expiry date of trial product, 
!
ordering of trial product, 
!
drug accountability
!
screening failure data 
!
Completion of the trial and
!
withdrawal information
!
surgery transfer session
Since drug will not be shipped to the site before screening, the investigator should be encouraged to 
perform screening call in the IV/WRS immediately upon screening of the patient, otherwise the 
drug may not be available for visit 2.
An IV/WRS site user Guide will be provided to the site.
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NNC 0129-0000-1003 
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Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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11 Concomitant Illnesses and Concomitant Medication
Definitions:
Concomitant illness:
any illness that is present at the start of the trial (i.e. at the first visit or 
re-entering from pathfinder™3).
Concomitant medication: any medication, other than the trial product(s), that is taken during the 
trial, including the screening periods.
Details of all concomitant illnesses and medication must be recorded at trial entry (i.e. at the first 
visit or re-entering from pathfinder™3). Any changes in concomitant medication must be recorded 
at each visit. If a change is due to an AE then this must be recorded and reported according to 
section 12. If the change influences the subject’s eligibility to continue in the trial then the Monitor 
must be informed.
The information collected for each concomitant medication preferably includes generic name and 
dose, and at a minimum start date, stop date or continuation and indication.
Prohibited Medication
The following medications are not allowed during the course of the trial until after the EOT visit. 
! Bypassing products: activated recombinant factor VII (rFVIIa), plasma-derived prothrombin 
complex concentrates (pd-PCC) and plasma-derived activated prothrombin complex concentrates 
(pd-aPCC)
! Coagulation Factors: FVIII, FIX and FVII-containing products other than N8-GP and other 
FVIII-containing products like fresh frozen plasma or cryoprecipitate. (Exception: current FVIII
allowed until 72 hours before Visit 2a)
! Anti-coagulants such as Heparin and vitamin-K antagonists. Heparin is allowed for sealing of 
central venous access ports according to local practice
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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12 Adverse Events and Pregnancies
12.1
Definitions
Adverse Event (AE):
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product, and which does not necessarily have a causal relationship with this 
treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.
Note: This includes events from the first trial related activity after the subject has signed the 
informed consent and until post treatment follow-up period as defined in the protocol.
An AE can also be a clinical laboratory abnormality regarded as clinically significant i.e. an 
abnormality that suggests a disease and/or organ toxicity, and is of a severity that requires active 
management (i.e. change of dose, discontinuation of trial product, more frequent follow-up or 
diagnostic investigation).
A worsening in concomitant illness must be recorded as an AE. A worsening of an ongoing AE 
should be reported on a new AE form by making a new assessment for seriousness and/or severity.
The following should not be recorded as AEs: 
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent
!
Pre-existing conditions found as a result of screening procedures. These should be recorded as 
medical history/concomitant illness. 
Serious Adverse Event (SAE):
A SAE is an experience that at any dose results in any of the following:
!
Death
!
A life-threatening experience a)
!
In-patient hospitalisation or prolongation of existing hospitalisation b)
!
A persistent or significant disability/incapacity c)
!
A congenital anomaly/birth defect
!
Important medical events d) that may not result in death, be life-threatening a) or require 
hospitalisation may be considered a SAE when, based upon appropriate medical judgement, 
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they may jeopardise the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.
a)  The term “life-threatening” in the definition of SAE refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death if it were more severe.
b)  The term “hospitalisation” describes a period of at least 24 hours. Over-night stay for 
observation, treatment at emergency room or treatment on an out-subject basis does not 
constitute a hospitalisation. However, medical judgement must always be exercised and when in 
doubt the case should be considered serious.
Hospitalisations for administrative, trial related and social purposes do not constitute 
hospitalisations as defined by the seriousness criteria, and should therefore not be reported as 
such. Likewise, hospital admissions for surgical procedures planned prior to trial inclusion are 
not considered AEs.
c)  The term “disability/incapacity” means that following the event the patient or clinical 
investigation patient has significant, persistent or permanent change, impairment, damage or 
disruption in his body function or structure, physical activity and/or quality of life.
d)  The term “important medical events” means events which may jeopardise the subject or 
require intervention to prevent a seriousness criterion. It can be AEs which suggest a significant 
hazard or puts the subject or clinical investigation subject at risk, such as drug-interactions, 
contra-indications or precautions, occurrence of malignancies or development of drug 
dependency or drug abuse.
Non-Serious Adverse Event:
A non-serious AE is any AE which does not fulfil the definition of a serious AE.
Severity Assessment Definitions:
!
Mild – No or transient symptoms, no interference with the subject’s daily activities
!
Moderate – Marked symptoms, moderate interference with the subject’s daily activities
!
Severe – Considerable interference with the subject’s daily activities, unacceptable.
Relationship to Trial Product N8-GP Assessment Definitions:
!
Probable – Good reasons and sufficient documentation to assume a causal relationship
!
Possible – A causal relationship is conceivable and cannot be dismissed
!
Unlikely – The event is most likely related to aetiology other than the trial product.
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Outcome Categories and Definitions: 
!
Recovered – Fully recovered, or by medical or surgical treatment the condition has returned to 
the level observed at the first trial related activity after the subject signed the informed consent
!
Recovering – The condition is improving and the subject is expected to recover from the event. 
This term should only be used when the subject has completed the trial
!
Recovered with sequelae – As a result of the AE the patient suffered persistent and significant 
disability/incapacity (e.g. became blind, deaf, paralysed). If the sequelae meet seriousness 
criteria the AE must be reported as serious.
!
Not recovered
!
Fatal
!
Unknown – This term should only be used in cases where the subject is lost to follow-up.
12.1.1
Technical Complaint
A technical complaint is any written, electronic, or oral communication that alleges defects on trial 
products - listed as trial supplies in this protocol (section 9). The technical complaint may be 
associated with an AE, but does not concern the AE itself. 
A technical complaint may for example concern:
! the physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
! the packaging material (e.g. leakage, cracks, problems with rubber membrane in the cartridge or 
errors in labelling text)
12.1.2
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 should reported following the same reporting requirements and timelines for SAEs (see 
SAE sections) irrespective of if the MESI fulfils a SAE criterion.
The following events are defined as MESIs in this trial;
1. Medication error
o
Administration of wrong drug
o
wrong route of administration such as intramuscular instead of intravenous
o
Administration of an accidental overdose, ie dose which may lead to significant health 
consequence as judged by the investigator irrespective of whether a SAE criterion is met.
o
Administration of a high dose with the intention to cause harm
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Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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2. Inhibitor formation against FVIII
o
blood samples for measurement of FVIII inhibitors will be analysed at the central laboratory 
selected by Novo Nordisk and if positive (BU ≥0.6/mL) at two consecutive tests - sampled 
preferably within 2 weeks - this should be reported by the investigator as a MESI
3. Allergic reaction including Anaphylactic reaction as defined by Sampson et al 200617 (see 
below). Allergic reactions included but are not limited to any acute immunoglobulin E (IgE) 
mediated reaction or delayed type hypersensitivity (clinical signs may include various types of 
skin rashes) that do not meet the definition of anaphylaxis as described by Sampson et al.17. All 
hypersensitivity reactions reported as MESI will be followed up with a hypersensitivity follow 
up form..
4. Thromboembolic events
o
clinical signs or laboratory indications of arterial and venous thrombosis
including myocardial infaction, pulmonary embolism, cerebral infaction/thrombosis, deep 
vein thrombosis, other clinically significant thromboembolic events and peripheral artery 
occlusion, see definitions)
5. Other events for expedited reporting
o
Suspected transmission of an infectious agent via a trial product
Complete the AE form in the eCRF. If for any reason the EDC application is unavailable, then fax, 
telephone or email Novo Nordisk. Complete the safety information forms on paper CRFs. Forward 
a copy electronically in PDF format by fax or courier to Novo Nordisk.
Clinical Criteria for Diagnosing Anaphylaxis (Sampson et al. 200617)
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalised hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT 
LEAST ONE OF THE FOLLOWING:
o
Respiratory compromise (eg, dyspnea, wheese-bronchospasm, stridor, reduced peak 
     expiratory flow (PEF), hypoxemia)
o
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):
o
Involvement of the skin-mucosal tissue (eg, generalised hives, itch-flush, swollen lips-
tongue-uvula)
o
Respiratory compromise (eg, dyspnea, wheese-bronchospasm, stridor, reduced PEF, 
hypoxemia)
o
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
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Protocol/UTN: U1111-1119-7416
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o
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
o
Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic 
BP (<90 mm Hg in children ≥10 years of age)
o
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s 
baseline PEF, BP.
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 of biochemical markers of myocardial necrosis with at least one of the 
following:
o
Ischaemic symptoms
o
Development of pathologic Q waves on the ECG
o
ECG changes indicative of ischaemia (ST segment elevation or depression)
o
Coronary artery intervention (e.g. angioplasty)
2. Pathologic findings of an acute myocardial infarction (i.e., pathologic findings of an acute 
myocardial infarction will be defined when criteria 1 and 2 below are fulfilled):
o
Increase in Troponin T above the "diagnostic" limit: i.e. > 0.03 μg/L
o
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)
o
ST-segment depression and or T-wave inversion in two or more contiguous leads >=    0.1 
mV
Definition of Pulmonary Embolism
Obstruction of a pulmonary artery or one of its branches, most frequently by detached fragments of 
thrombus from a leg or pelvic vein, diagnosed by at least one of the following:
!
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
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Protocol/UTN: U1111-1119-7416
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!
Cerebral angiography
Deep Vein Thrombosis
Venous thrombosis demonstrated by compression ultrasound, duplex ultrasound, or colour Doppler 
imaging.
Definition of Other Clinically Significant Thromboembolic Events
Clinically significant signs or suspicion of a thromboembolic event, e.g. visceral arterial 
embolus/thrombus, extremity arterial embolus/thrombus or portal venous thrombosis.
Thrombophlebitis is not considered a clinically significant thromboembolic event unless evaluated 
by the Investigator as related to trial product.
Peripheral Artery Occlusion
Clinical signs of acute arterial occlusion verified by either ankle-brachial index test, Doppler and 
ultrasound (Duplex) imaging, computed tomographic angiography, magnetic resonance 
angiography, or conventional angiography.
12.1.3
Disease-related Bleeding
Disease-related bleeding episodes evaluated by the Investigator as part of the underlying disease 
should not be reported as AEs or SAEs unless evaluated by the Investigator as related to trial 
product. 
In case of fatal outcome, the bleeding episode must be reported as a SAE. All bleeding episodes and 
other symptoms related to the underlying disease will be captured in the eCRF/eDiary.
12.2
Collection, Recording and Reporting of Adverse Events
All events meeting the definition of an AE must be collected and reported for all medicinal 
products. 
At each contact with the trial site (visit or telephone, excluding the follow up visits due to inhibitor 
development, where the patient is not seeing the Investigator or his staff e.g. visit to the laboratory) 
the patient must be asked about AEs, 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 recorded by the 
Investigator and evaluated. Novo Nordisk’ assessment of expectedness is done according to the 
reference documents:
!
Investigator’s Brochure, N8-GP8
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The Investigator should record the diagnosis, if available. If no diagnosis is available then the 
Investigator should record each sign and symptom as individual AEs.
All AEs must be recorded by the Investigator on the standard AE form. If more than one sign or 
symptom is to be reported, use a separate AE form for each sign and symptom. For serious AEs, the 
safety information form must also be completed. If several signs or symptoms occur as part of the 
same clinical picture only one set of safety information pages need be used to describe these SAEs.
MESIs must always be reported to the department responsible for global product safety on the AE
form and the safety information form, irrespective of seriousness within the same timelines as for 
SAEs.
The Investigator must report initial information on all SAEs and MESIs to Novo Nordisk within 24 
hours of obtaining knowledge about the event.
The Investigator must complete and forward electronically in pdf format/fax copies to Novo 
Nordisk:
!
AE form in the eCRF within 24 hours
!
safety information form on the paper CRFs within 5 calendar days
of obtaining knowledge about the SAE.
If for some reason the EDC application is unavailable then the AE information should be reported 
to Novo Nordisk by fax, telephone or e-mail within the same timelines.
Novo Nordisk must inform the regulatory authorities and IECs/IRBs in accordance with the local 
requirements in force and ICH GCP18.
Novo Nordisk will notify the Investigator of trial product related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with the local requirements. In addition, the Investigator 
will be informed of any trial related procedure SAEs that may warrant a change of any trial 
procedure.
For Japan only: Novo Nordisk must inform the health authorities and the relevant parties of SAE 
information in accordance with the Japanese requirements in force and ICH GCP19.
Investigators will be notified of trial-related SAEs in accordance with the local requirements in 
force and ICH GCP20.
12.2.1
Follow-up of Adverse Events
During and following a subject’s participation in a clinical trial, the Investigator should ensure that 
adequate medical care is provided to the subject for any AE, including clinically significant 
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laboratory values related to the trial. The Investigator should inform the subject when medical care 
is needed for AE(s) of which the Investigator becomes aware.
The follow up information should only include new (updated and/or additional) information that 
reflects the situation at the time of the Investigator’s signature.
Follow-up information (corrections, new or additional information) should be reported within 24 
hours of obtaining knowledge of the information for SAEs, and if previously non-serious AEs 
become SAEs.
All non-serious AEs classified as severe or possibly/probably related to the trial product must be 
followed until the subject has “recovered” or “recovered with sequelae”, and all queries have been 
resolved. Cases of chronic conditions or cancer or AEs ongoing at time of death (i.e. subject dies 
from another AE) can be closed with an outcome of “recovering” or “not recovered”. Cases can be 
closed with an outcome of “recovering” when the subject has completed the post-trial follow-up 
period and is expected by the Investigator to recover.
All other non-serious AEs must be followed until the outcome of the event is “recovering”, 
“recovered” or “recovered with sequelae” or until the end of the post-treatment follow-up stated in 
the protocol, whichever comes first, and until all queries related to these AEs have been resolved. 
AEs ongoing at time of death (i.e. subject dies from another AE) can be closed with an outcome of 
“recovering” or “not recovered”. 
The Investigator must ensure that the worst case severity and seriousness is kept consistent.
The Investigator must record follow-up information on non-serious AEs by updating the AE form in 
the eCRF. The follow-up information should only include new (updated and/or additional) 
information that reflects the situation at the time of the Investigator’s signature.
Queries or follow-up requests from Novo Nordisk should be responded to within 14 calendar days, 
unless otherwise specified. The Investigator must forward follow-up information on SAEs and 
MESIs within 5 calendar days of obtaining the information. This must be done by updating the AE 
form in the eCRF and/or completing a new safety information form marked follow-up on paper 
CRF and forwarding these to Novo Nordisk. If for any reason the EDC application is unavailable, 
then fax, telephone or e-mail to Novo Nordisk.
All SAEs and MESIs must be followed up until the outcome of the event is “recovered”, “recovered 
with sequelae” or “fatal” and until all queries have been resolved. Cases of chronic conditions or 
cancer or AEs ongoing at time of death (i.e. the subject dies form another AE) can be closed with 
the outcome of “recovered” or “not recovered”. Cases can be closed with an outcome of 
“recovering” when the subject has completed the trial and is expected by the Investigator to recover.
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After access to update the AE form in EDC is removed the Investigator must record any SAE and 
MESI follow-up information, if required, on the paper CRFs provided at trial closure.
Details on how to handle AEs that were not Recovered/Recovering in the pathfinder™3 
Surgery Trial when patients are included in the pathfinder™2 Trial
An AE (including SAEs and MESIs), that is not recovered/recovering in the Surgical Trial 
pathfinder™3 when the patient is enrolled into the present trial (pathfinder™2), will be followed up 
in the preceding Surgical Trial (pathfinder™3) and entered by the Investigator as concomitant 
illness in the present trial.
Non-serious AEs that are reported as not related and not severe in the Surgery Trial will not be 
followed-up when enrolling into the pathfinder™2) trial. Details on how to handle unresolved non-
serious AEs when patients are transfer from the pathfinder™3 (Surgery Trial) into the present trial 
(pathfinder™2) are described below and in Table 12-1. 
A not recovered AE from the preceding Surgery Trial which has worsened during participation in 
the pathfinder™2 must be entered as an AE in the present pathfinder™2by the Investigator.
Table 12-1 Handling of Not Recovered Non-Serious AEs from pathfinder™3
Severity
Outcome Categories
Relationship
AE follow-
up in:
NN7088-60 
(Surgery)
AE in 
NN7088-
3859 
(Present)
Concomi-
tant illness 
in NN7088-
3859 
(Present)
Mild/
Moderate
Severe
Recovered/
Recovered 
with 
sequelae/
Fatal/
Unknown
Not 
recovered/
Recovering
Probable/
Possible
Unlikely
X
X
X
Yes
No*
Yes
X
X
X
Yes
No*
Yes
X
X
X
No
No*
No
X
X
X
Yes
No*
Yes
* Unless worsened during participation in pathfinder™2 (Present Trial)
12.3
Technical Complaints and Technical Complaint Samples
12.3.1
Collection and Reporting of Technical Complaints 
All technical complaints, as defined in Section 12.1.1 - occuring from the time of first and until the 
last usage of trial supplies - must be collected and reported to Novo Nordisk.
The Investigator must assess whether the technical complaint is related to:
!
AE(s), SAE(s) and/or MESI(s) 
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The AE(s), SAE(s) and MESI(s) related to technical complaint(s) must be reported by the 
investigator following the same reporting requirements and timelines as for other AEs, SAEs and 
MESIs (see section 12.2). 
Technical complaints must be reported on the technical complaint form by the Investigator, as 
described in the following:
One technical complaint form must be completed for each trial product, non investigational 
medicinal product (NIMP) or auxiliary supply. If the technical complaint involves more than one 
batch number, a technical complaint form for each batch number must be completed. 
The Investigator must fax the technical complaint form to Customer Complaint Center, Novo 
Nordisk, fax: +45 44 42 13 70, within the following timelines of the trial site obtaining knowledge 
of the technical complaint:
!
technical complaint assessed as related to a SAE and/or MESI within 24 hours
!
all other technical complaints within 5 calendar days
12.3.2
Collection, Storage and Shipment of Technical Complaint Samples
The Investigator must collect the technical complaint sample. If the technical complaint sample is 
not collected, the investigator must specify why it was not collected on the technical complaint 
form. 
The technical complaint sample and a paper copy of the technical complaint form must be sent 
to Novo Nordisk within 5 calendar days of receiving the technical complaint sample at trial site by 
using the following address:
∋
Novo Nordisk A/S, 
Att.: Customer Complaint Center, 
Krogshøj 55, 
DK-2880 Bagsværd, 
Denmark
The investigator must ensure that the technical complaint sample is labelled with the batch number 
and, if available, the DUN number. 
Storage and shipment of the technical complaint sample should be done in accordance with the 
conditions described for the product (see section 9). For further details on the shipment conditions 
of technical complaint samples please contact the monitor.
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12.3.3
Pregnancies in Partners of Trial Patients
In the case of an AE (with a causal relationship evaluated as possible or probable by the 
Investigator) in the foetus, newborn infant(s) or infant(s)/toddler(s) of a trial subject’s partner, who 
is potentially exposed to the trial product via the trial subject, the pregnancy and the AE should be 
reported on pregnancy form A and B and AE and Safety information forms as appropriate. This 
information can only be requested after informed consent from the partner.
12.4
Precautions
As with any protein injected i.v., hypersensitivity reactions may occur. The possible events include 
rash, pruritus, fever, nausea, headache, vomiting and changes in BP. 
If any of these events are suspected further FVIII administration should be stopped and the patient 
should receive treatment as appropriate according to the hospital practice and guidelines. 
12.5
Safety Committee(s)
12.5.1
Internal 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. The Safety Committee is responsible 
for reviewing any safety concern, signal or alert and determining actions to be taken according to 
the guidelines for the Safety Committee.
12.5.2
Data Monitoring Committee
As this is an open label trial, the patient group is not particularly vulnerable, and the investigational 
drug is not expected to show toxicity, no data monitoring committee (DMC) will be established for 
this trial. Rather, an internal Novo Nordisk Safety Committee will be established with the overall 
responsibility of overseeing the safety of the patients enrolled in the trial.
12.5.3
Stopping Rules
Any event occurring after administration of N8-GP fulfilling the SAE/MESI criteria must be 
reported to Novo Nordisk within 24 hours. If the stopping criteria mentioned below is fulfilled, 
enrolment of additional patients will be put on hold. All Investigators will be informed in writing. 
An unscheduled Safety Committee meeting will be called for to decide whether or not the trial can 
continue with or without modifications. During the evaluation of the stopping rules the trial will be 
on hold meaning no new patients will be recruited. Dosing of patients on treatment may continue 
while further evaluation of the SAE/MESI is made by the Safety Committee unless otherwise 
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decided by the Safety Committee. The evaluation of fulfilment of the stopping rules by the Safety 
Committee will take into consideration whether or not the patient was dosed according to protocol.
The following will result in enrolment in the phase III trials being put on hold:
!
Inhibitor formation (Bethesda Unit (BU) of ≥ 0.6 BU) in more than 2 patients. A patient has 
inhibitor formation if the patient has been tested positive for inhibitors at two consecutive tests 
from the central laboratory
!
Death related to trial product assessed by Novo Nordisk or by the Investigator
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13 Case Report Forms
Novo Nordisk will provide a system for electronic data capture (EDC). This system and support 
services to the system will be supplied by a vendor. The activities of this vendor will be under the 
direction and supervision of Novo Nordisk.
13.1
Rules for Completing eCRFs
Ensure that all relevant questions are answered, and that no empty data blocks exist.
If a test/assessment has not been done and will not be available, or if the question is irrelevant (e.g. 
is not applicable) indicate this according to the data entry instructions.
The Investigator must ensure that all information derived from source documentation is consistent 
with the source information. By signing the case book electronically, the Investigator confirms that 
the information is complete and correct.
13.2
Corrections to eCRFs
Corrections to the CRF data will be made by the Investigator or the Investigator’s authorised staff. 
An audit trail will be maintained in the EDC application containing as a minimum: identification of 
the person entering the data, date and time of the entry and reason for the correction.
If corrections are made by the Investigator’s authorised staff after the date of the Investigator’s 
signature on the case book then the case book must be signed again by the Investigator.
13.3
eCRF Flow
The Investigator must ensure that data is recorded in the CRFs as soon as possible after the visit 
(preferably within 3 days). When data is entered it will be available to Novo Nordisk for data 
verification activities.
Site specific CRF data (in an electronic readable format) will be provided to the Investigator after 
the trial database is released, and access to update the trial data in EDC has been removed. This data 
will be retained by the site.
When the final clinical trial report (CTR) is available the data will be archived by Novo Nordisk
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13.4
eDiary
Novo Nordisk will provide patients with an eDiary for electronic recording of details of their 
bleeding episodes, see section 8.4.3. The eDiary and related support services will be supplied by a 
vendor that will be working under the direction and supervision of Novo Nordisk. 
At Visit 2a, the patients will be provided with the eDiary and trained in the use hereof. The eDiary 
will be returned by the patient at the EOT visit.
Data will be entered by the patient or caregiver in the eDiary device. All data entered will be 
automatically transferred from the device to the ePRO database, where it is kept as a certified copy 
of the source data. Data entered in the device will upon confirmation of a successful back-up be 
deleted from the device.
The eDiary will contain built in edit checks, to ensure that all relevant questions are answered. 
The eDiary device is not intended to support the subsequent review and modification of completed 
entries.  In case of need for corrections to the transferred data, a query flow must be initiated by the 
investigator. Upon review by Novo Nordisk, data will be corrected accordingly by the vendor. An 
audit trail will be maintained.
Data in the ePRO database will be viewable to relevant site and Novo Nordisk personnel on a 
secure web portal, which is password protected. Data will be transferred to the Novo Nordisk 
clinical database at defined intervals.
Figure 13-1 eDiary Data Flow
Oracle Clinical
ePRO Vendor
Investigator site
Subject
Novo Nordisk
ePRO database
Device
Web Portal
Trial  
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14 Monitoring procedures
During the course of the trial the Monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The visit intervals will depend on the outcome of the remote monitoring of the 
eCRFs, the trial site's recruitment rate and the compliance of the trial site to the protocol and GCP. 
The monitor should visit a site soon after a patient has been screened. The intervals between visits 
must not exceed 12 weeks.
The Monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. In addition the Monitor should be 
available for discussions e.g. by telephone.
For Screening Failures: Data in respect to the Screening visit must be entered in the eCRF within 
preferably 3 days after data are available. The Screening Failure Form must be completed. These 
data will be transferred into the trial database.
For withdrawn patients: All data collected in the period the patient participated in the trial will be 
entered in the eCRF.
It must be possible to verify data in the eCRF against source documents.
eDiaries will be provided by PHT. Information on treatment and bleeding episodes will be collected 
in the eDiaries (please refer to section 8.4.3).
The completed Diaries are considered source data. The patient will only be identified by patient 
number. The Monitor will verify and ensure that the eCRFs and diaries are completed.
For all data recorded the source document must be defined in a source document agreement at each 
site.
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15 Data Management
Data management is the responsibility of Novo Nordisk Headquarters. Data management may be 
delegated under an agreement of transfer of responsibilities to another data management unit within 
Novo Nordisk or external clinical research organisation (CRO). 
Appropriate measures such as encryption of data files will be used to assure confidentiality of 
subject data when it is transmitted over open networks. 
Laboratory data will be transferred electronically from the central laboratory performing clinical 
analyses. In cases where laboratory data are transferred via non-secure electronic networks, data 
will be encrypted during transfer. The electronic laboratory data will be considered source data.
The central and local laboratories will provide laboratory reports to the Investigator. The laboratory 
report must be signed and dated by the Investigator and stored at the trial site as source data.
Data will be entered and delivered in an Oracle Clinical file and loaded into Oracle Clinical.
The patient and biological material obtained from the patient will be identified by patient number, 
trial site and trial identification number. Appropriate measures such as encryption or deletion will 
be enforced to protect the identity of human patients in all presentations and publications as 
required by local/regional/national requirements.
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16 Computerised Systems
Novo Nordisk will capture and process clinical data using computerised systems which are 
described in NN Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data. 
Novo Nordisk will collect information on the practical use of these systems within the conduct of 
this clinical trial. 
Novo Nordisk will use the Global Haemophilia Network Investigator Portal to distribute and share 
trial related documents and information with the participating sites.
The eDiary software and hardware implementation are compliant with the requirements of FDA 21 
CFR Part 11 and ICH E6 (EU directive for personal data protection). After trial finalisation, each 
trial site will be supplied with long-life DVDs. These DVDs will contain site-specific patient 
records including the patient’s diaries 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 50 years or as required by local data retention laws for trial data.
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17 Evaluability of Patients for Analysis
17.1
Safety Analysis Set
The Safety Analysis Set consists of all patients exposed to N8-GP. The analyses of the safety 
endpoints will be based on the Safety Analysis Set and all available information until the last visit.
17.2
Full Analysis Set
The Full Analysis Set (FAS) consists of all patients exposed to N8-GP. The efficacy analysis and 
the PK analysis will be based on the FAS and all available information until EOT visit. 
Handling of Exceptional PK Outlier Data
Exceptional outlier pharmacokinetic profiles and/or individual plasma concentrations may be 
excluded when analysing pharmacokinetic endpoints based on the FAS. If exceptional outlier data 
are identified, a sensitivity analysis including the outlier data will be conducted. 
Unless otherwise stated, analysis results obtained from FAS excluding exceptional outliers will be 
presented with reference to the “Full Analysis Set excluding outliers”. The results of the sensitivity 
analysis including the exceptional outliers will refer to “Full Analysis Set incl. all data”. 
17.3
Documentation of Analysis Sets
The decision to exclude data points from analysis of PK endpoints based on the Full Analysis Set 
will be made from a review prior to Database Lock. It will be the joint responsibility of the Clinical 
Pharmacology Scientist and the Trial Statistician.
The profiles or observations to be excluded from the FAS and the reason for their exclusion will be 
documented and signed by the Clinical Pharmacology Scientist and the Trial Statistician as part of 
the Database Lock minutes. The documentation will be stored together with the remaining trial 
documentation. This will also be described in the CTR.
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18 Statistical Considerations
18.1
Sample Size Calculation
The study has two co-primary endpoints that both need to succeed for the study to succeed. The two 
endpoints can reasonably be considered approximately independent and combined power then 
becomes the product of the individual power for each co-primary endpoint.
Co-Primary Endpoint: Incidence Rate of Inhibitory Antibodies against FVIII Defined as Titre 
∀0.6 BU/mL
Given the rarity of the disease, a sample size of 105 patients treated for a minimum of 50 exposure 
days will allow for a reasonable evaluation of inhibitor formation in this pivotal trial. 
The aim is to demonstrate that the upper confidence limit for the inhibitor rate is below 6.8%. In 
practical terms this will happen if 2 or less inhibitors are observed in the planned 105 patients with 
50 exposure days (3 or less if the trail should end with 127 patients with 50 EDs). If the true 
inhibitor rate of N8-GP is 1% then the chance/power to achieve a maximum 2 inhibitor out of 132 
patients entered into the trial will be 85%.
Co-Primary Endpoint: Annualised bleeding rate in the prophylaxis arm 
The clinical efficacy of N8-GP in long term bleeding prophylaxis will be evaluated based on all the 
prophylaxis period data. This will give different period lengths for the different patients but on 
average it is expected to give about 12 month prophylaxis treatment per patient (~7 months for the 
last recruited patients and ~17-19 months for the first recruited patients). Prophylactic effect will be 
concluded if the upper 97.5% confidence limit for the annualised bleeding frequency is < 8.5. The 
model will be a Poisson regression allowing for over-dispersion (using Pearson’s chi-square divided 
by the degrees of freedom (i.e. Scale=Pearson in SAS)) and using log observation time as offset to 
account for the differing treatment lengths. Based on an approximation to the normal distribution 
and assuming that the patients bleed 6.8 times per year and an over-dispersion of 5 (so variance 34)
120 patients entered on prophylaxis will give a power of 89%. 
The following table shows the power for various relevant assumptions of bleeding rates and over-
dispersions (OD). 
True rate
OD
Prophylaxis power
6.8
5
89%
6.5
5
97%
6
5
99.9%
6.8
4
83%
6.8
6
95%
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Combined power
With 85% power for the first co-primary endpoint and 89% power for the second co-primary 
endpoint the combined power for the study with the given sample size is expected to be about 
85%*89% = 76%.  
Confirmatory Secondary Endpoint: Haemostatic effect of N8-GP when used for treatment of 
bleeding episodes, assessed on a four-point scale for haemostatic response (excellent, good, 
moderate and none) by counting excellent and good as success and moderate and none as 
failure.
Clinical efficacy of haemostasis (treatment of bleeding episodes) of N8-GP will be demonstrated by 
showing that the success rate (with success defined as scoring excellent or good and failure as 
scoring none or moderate) on the four point scale for haemostatic response is acceptably close to 
80% (defined as statistically significantly larger than 65%). 
Operationally the null-hypothesis will be rejected and a success rate acceptably close to 80% is 
considered confirmed if the lower bound of the 1-sided 97.5% confidence interval for the rate is 
above 65%. By assuming that the observations are independent, the power may be calculated exact 
using the binomial distribution. The power will depend on the number of bleeding episodes actually 
observed. It is expected that more than 200 bleeding episodes will occur in the trial in the on-
demand arm and the prophylaxis arms combined. Assuming a true response rate of 80% the power
for this endpoint is greater than 95%. Correlation between observations corresponding to the same 
patient may reduce this power but is not expected to affect it too much.
18.2
Statistical Methods
18.2.1
General Considerations
Novo Nordisk A/S will be responsible for the statistical analysis. All tests will be performed as 1-
sided tests on 2.5% significance level.
18.2.2
Primary Endpoint(s)
The study has two co-primary endpoints that both have to succeed.
Incidence Rate of Inhibitory Antibodies against FVIII defined as Titre ∀0.6 BU/ml.
The rate of neutralising 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 
inhibitor rate the nominator will include all patients with neutralising antibodies while the 
denominator will include all patients with a minimum of 50 exposures plus any patients with less 
than 50 exposures but with neutralising inhibitors. Adequate safety with regard to neutralising 
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inhibitors will be concluded if the upper 1-sided 97.5% confidence limit is below 6.8% roughly 
corresponding to the upper 97.5% confidence limit if 2 inhibitors out of 105 patients are observed (3 
or less if the study should get 127 or more patients with 50 exposure days).
In terms of actual observed number of neutralising antibodies the consequence of this is that with 
the planned trial size of 105 patients with 50 or more exposure days 2 or less patients with a 
neutralising antibody will be considered acceptable, whereas 3 or more neutralising antibodies will 
be considered unacceptable. Should the study end up with 127 or more patients with 50 exposure 
days 3 or less inhibitors would be acceptable
Number of bleeding episodes (total bleeding episodes assessed as Annualised Bleeding Rate) 
per patient in the prophylaxis arm 
A review of historical data has found that haemophilia A patients on on-demand treatment on 
average bleed 24 times per year while they bleed 6.8 times per year when treated on prophylaxis. 
Historical Control for Hypothesis Test for Prophylaxis
Based on the studies referenced below, Novo Nordisk suggests that representative numbers for 
mean annual bleeding rate (ABR) in severe haemophilia patients is 24 bleeds/year for patients 
treated on-demand and 6.8 for patients on prophylactic treatment. 
Novo Nordisk has based the estimate of historical annual bleeding rate on a systematic review of 
the treatment of Haemophilia A and B and von Willebrand disease, performed by the Swedish 
Council on Health Technology Assessment.
The referenced report is based on review of 3710 abstracts in total, covering treatment of 
Hemophilia A, B or von Willebrand disease. Articles were then selected for full review according to 
specific criteria such as administration of recombinant or plasma-derived Factor concentrate, 
outcome (eg number of bleeding episodes, inhibitor development or quality-of-life measurements), 
and number of patients included. For hemophilia A, only studies comprising 20 patients or more 
were selected. The main objectives of the SBU review is to evaluate the short- and long-term effects 
with different treatment strategies with coagulation factor concentrates in Hemophilia A and B and 
von Willebrand disease.
In the search, SBU identified 37 references dealing with “replacement therapy with factor 
concentrates in treating severe, moderate, and mild hemophilia A”. All these references identified 
by SBU were reviewed as full length articles at Novo Nordisk, and only the original papers with a 
mean total ABR reported (or at least possible to calculate) in patients with an endogenous FVIII:C 
activity <2% were included in our analysis.
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Table 18-1 Historical mean total annual bleeding rate in Haemophilia A patients with an 
endogenous FVIII:C activity <2% 
SBU 
Ref 
No
Reference
On-demand 
(mean ABR)
Number of 
patients
Prophylaxis 
(mean ABR)
Number of 
patients
4
Courter, 200121
18
27
4
27
5
Lusher, 200322
23
85
10
85
5
Lusher, 200322
N.R.
N.R
6
45
9
Tarantino, 200423
N.R.
N.R.
6.3
107
10
Nemes, 200724
N.R.
N.R.
4.9
49
11
Recht, 200925
N.R.
N.R.
3.9
94
15
Abshire, 200011
34
38 
8.3
27
17
Smith, 2005*26
N.R.
N.R.
10.3
32
18
Manco-Johnson, 
20074
18
33 
3.3
32
25
Schwartz, 1990**27
19
56
N.R.
N.R.
Weighted Mean
24
179
6.8
394
ABR = Annual Bleeding Rate. N.R. = not reported. Studies in italics have not included adults. No = Reference number 
in SBU report, chapter 3.1.1. * 5/32 are moderate Hemophilia A, **4/56 are moderate Hemophilia A
In the studies, the mean ABR in patients on prophylaxis is consistently lower than in patients treated 
on-demand, as expected. The studies have ABR in the range of 18 – 34 and 3.3 – 10, for on-demand 
and prophylaxis treatment, respectively, and include different numbers of subjects. To arrive at a 
representative ABR number from the various studies, we weighted the estimates from each study 
based on the number of subjects included. 
As the proposed trial with N8-GP will only include patients aged 12 years and above, we further 
suggest to exclude 3 of the 9 historical studies21,22,4 that only include children below age 6, in order 
to better reflect the study population. The historical mean ABR for on-demand and prophylaxis in 
haemophilia A with <2% will then be estimated at 24 and 6.8, respectively. However, if also the 
studies including children below 6 years of age are included, the estimated ABR for on-demand and 
prophylaxis are 23 and 6.4, respectively. The 2% cut off is often used in clinical studies and will 
give a conservative estimate of the ABR in the study population in the proposed trial with a cut off 
of <1%.
Prophylactic effect of N8-GP will be concluded if the bleeding rate is significantly below 50% of 
the historical on-demand bleeding rate (i.e. significantly lower than 12) as well as within 25% of the 
historical prophylaxis bleeding rates (i.e. significantly lower than 6.8*1.25 = 8.5). Since both must 
be met in practice it must be shown that the bleeding rate is significantly lower than 8.5.
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Let AR be the observed yearly bleeding rate. The null-hypothesis will be tested against the 
alternative hypothesis as given by:
H0: AR ≥ 8.5 against HA: AR < 8.5
The endpoint will be analysed by a Poisson regression model on number of bleeding episodes per 
patient allowing for over-dispersion (using Pearson’s chi-square divided by the degrees of freedom 
(i.e. Scale=Pscale in SAS)) and using log planned observation duration as an offset. Estimates of the 
annualised bleeding rates will be provided with 95% confidence intervals.
For patients withdrawing prematurely the number of bleeding episodes counting in the analysis will 
be imputed up to what they could be expected to have had if they had completed the trial. If e.g. a 
patient withdraws after 2 months with 3 bleeding episodes, but the patient should have been in the 
study for 12 months, then this patient will in the analysis count as having had 18 bleeding episodes 
in 12 months. This is similar to LOCF and will avoid positive bias occurring from patients with 
many bleeding episodes withdrawing early.
For patients who withdraw within 1 month this method is considered to give too uncertain LOCF 
values, hence imputation will not be attempted for such patients and such patients will only 
contribute with the observed bleeding episodes and observation time.
Sensitivity analyses:
Analysis without imputation to planned trial duration
The primary prophylaxis analysis will be repeated but without imputing number of bleeding 
episodes from early withdrawals. Instead only the observed bleeding episodes will be counted and 
the offset will be actual observation duration rather than planned. 
Analysis of 12 months data from patients that could have had 12 months prophylaxis 
Since patients will stay in the trial until the same end date some patients will get only about 7 
months prophylactic treatment while others may get as much as 19 months. To investigate if the 
varying durations have any impact on the results a sensitivity analysis will be performed looking 
only at 12 months data from patients with planned trial duration of 12 or more months. Otherwise 
this analysis will be performed similarly to the primary analysis.
To investigate the effect over time the bleeding rates per month will be calculated and summarised 
numerically and graphically. For months after month 7 not all patients will be available since the 
last patients recruited will only receive about 7 months treatment. This may create an apparent time 
effect really caused by fewer and fewer patients being available. This will be investigated by also 
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summarising by month only for the first 12 months data from patients that could have received 12 
months treatment (i.e. patients recruited earlier than 12 months before LPLV).
Similarly the bleeding rate by calendar month will be calculated and presented. If there is a calendar 
effect it is conceivable that it would be reversed in the southern hemisphere compared to the 
northern. For that reason by calendar month summaries will as best possible be presented by 
northern hemisphere, tropical region and southern hemisphere separately.
18.2.3
Confirmatory Secondary Endpoints
Haemostatic effect of N8-GP when used for treatment of bleeding episodes, assessed on a four-
point scale for haemostatic response (excellent, good, moderate and none) by counting 
excellent and good as success and moderate and none as failure.
In order to protect against false significances this endpoint will only be analysed as a confirmatory 
secondary endpoint if the analyses of the co-primary endpoints are both successful. Otherwise this 
endpoint will be analysed only as a supportive secondary endpoint.
This is assessed as success/failure based on a four-point scale for haemostatic response (excellent, 
good, moderate and none). Excellent and good counts as success and moderate and none as failure. 
In addition any bleeding episodes with missing response information will be counted as failures.
A success rate of 80% is considered the goal. Due to variation it is not certain that N8-GP will 
achieve an observed 80% success rate in this trial even if the true success rate is 80%. For that 
reason it will be demonstrated that the success rate for N8-GP is at most 15% (absolute) worse than 
80%. 
Let R be the observed success rate. The null-hypothesis will be tested against the alternative 
hypothesis as given by:
H0: R ≤ 65% against HA: R > 65%
Specifically this will be done by a logistic regression. The analysis will be performed by use of Proc 
Genmod in SAS. Correlation within patients will be taken into account using a Generalized 
Estimation Equations approach with a working correlation matrix with a compound symmetry 
structure. Adequate efficacy will be concluded if the 1-sided lower 97.5% confidence limit for the 
success rate is above 65%.
Response as measured by the four point scale will also be summarised and listed. Bleeding episodes
will come both from the on-demand periods and from prophylaxis periods. This will be analysed 
together in the statistical analysis but will also be summarised by treatment regimen.
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Sensitivity analysis
A sensitivity analysis will be performed similar to the primary analysis but only analysing bleeding 
episodes with recorded responses (i.e. not counting any bleeding episodes with missing response as 
failures).
18.2.4
Supportive Secondary Endpoints
18.2.4.1
The Number of Injections of N8-GP required per Bleed
This endpoint will be summarised and listed.
18.2.4.2
Amount of N8-GP required per Bleed
Amount of N8-GP required per bleed (U/kg BW/bleeding episode) will be summarised and listed
18.2.4.3
PK Endpoints
! Incremental recovery, ([U/mL] / [U/kg] )(single dose and steady state)
! Trough level, ( U/mL) (single dose and steady state)
! AUC, (h*U/mL)
! Terminal half-life (t½), (h)
! Clearance (mL/h/kg)
! Mean Residence time (MRT) (h)
! Vss (Volume of distribution at steady state) (mL)
Single dose PK will be based on the subgroup of patients with full PK sessions at visits 2 and 7. 
Steady state PK will be based on the periodic recovery and trough measurements on all patients 
from visits 3 to 13:
Single dose PK
The PK parameters will be calculated using plasma concentration obtained from chromogenic assay 
and clot assay. The PK parameters will be derived according to a non-compartmental method, as 
described in Table 18-2. The actual time points will be used in the calculations.
If any profiles and/or individual plasma concentrations are excluded from the primary 
pharmacokinetic analysis, a sensitivity pharmacokinetic analysis will also be performed and 
reported based on all observed data. The primary pharmacokinetic analysis is based on the full 
analysis set excluding outliers. 
Specifically which data points and profiles that will be excluded will be defined prior to database 
lock. It should exclude profiles with pre-dosing activity > 5% (possibly indicating inadequate 
washout) and profiles that are not indicative of a normal i.v. short infusion administration (e.g. 
clearly increasing plasma concentrations initially). If a patient is treated with an additional dose 
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during the PK session, the plasma concentrations after the occurrence will then be excluded. 
Furthermore, if the profile shows indications of an additional dose (e.g. clearly increased plasma 
concentration), the plasma concentrations after the occurrence will then also be excluded. 
All pharmacokinetic endpoints will be modelled and analysed by an ANOVA on the log 
transformed parameter by visit. Estimates of each endpoint with 95% confidence intervals will be 
provided back-transformed to the natural scale.
All PK profiles will be presented graphically by subject and by visit.
Furthermore, the mean PK endpoints will be summarised and individual PK endpoints will be
listed.
Table 18-2 Definition and Calculation of PK Parameters
Parameter
Description
Calculation
Incremental 
Recovery
Dose-normalised activity recorded 
30 min after end of infusion and 
reported as [U/mL]/[U/kg]. 
Expected to be the highest dose-
normalised activity observed.
The incremental recovery is calculated by 
dividing the FVIII activity (U/mL) 
measured in plasma 30 min after dosing by 
the dose injected at time 0 expressed as 
U/kg BW
Trough 
level 
Activity recorded immediately 
before next dose is given and 
reported as [U/mL]. Expected to 
be the lowest dose-normalised 
activity observed.
t½
Terminal half-life
t½ = ln(2) / λz, where λz is the terminal 
elimination rate. The terminal elimination 
rate will be estimated using linear 
regression on the terminal part of the 
log(activity) versus time profile
CL
Total plasma clearance of drug 
after intravenous administration
CL= Dose / AUC
AUC
Area under the activity versus 
time profile from time zero to 
infinity. Measure of total plasma 
exposure. 
AUC = AUC(0-t) + C(t) / λz ,
where C(t)  is the last measurable activity.
18.3
Safety Endpoints
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 
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patients with any event. Similar summaries cross-classified by severity and by causal relation to 
trial product will be made. 
Furthermore, listings will be provided displaying all TEAEs and TESAEs including pertinent 
clinical information.
HCP-antibodies will be listed.
All additional safety parameters such as laboratory parameters, vital signs and physical 
examinations will be summarised and listed.
18.4
Interim Analysis
In order to obtain regulatory permission to start surgery treatment in the US, prophylaxis treatment 
in the US and paediatric trial in the EU lists of acute treatment responses will be prepared at certain 
time-points. They will include patient details as well as dose given and response to treatment.
18.5
Sequential Safety Analysis/Safety Monitoring
Not applicable (NA).
18.6
Explorative Statistical Analysis for Pharmacogenetics and Biomarkers
NA.
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18.7
PK and/or PD Modelling
The relationship between plasma concentration and bleeding frequency will be investigated.
Based on each individuals PK assessments (full PK from some patients but only recovery and 
troughs for most patients) the time to 5%, 3% and 1% FVIII activity after each dose given will be 
calculated and the bleeding rates for each period (>5%, 3-5%, 1-3% and <1%) will be calculated 
and listed and summarised. 
A statistical comparison will be made between the bleeding rates above and below 1% FVIII 
activity. This will be done based on a Poisson regression with patient above or below 1% activity as 
fixed effects. The model will allow for over-dispersion (estimated using Pearsons chi-square 
divided by the degrees of freedom) and will use log duration (above 1% activity and below 1% 
activity respectively) as offset. For computational reasons only patients with at least one bleeding 
episode will be included and similarly only patients with at least 2 weeks cumulative time under 1% 
activity and 2 weeks cumulative time over 1% activity will be included.
The following PK parameters will be estimated using a one-compartment population PK model:
! CL70kg (L/h)
Population median clearance in a patient of weight 70 kg 
! V70kg (L)
Population median volume of distribution in a patient of weight 70 kg 
! )CL,BW
Allometric exponent for relation between median CL and BW
! )V,BW
Allometric exponent for relation between median V and BW
Extrapolated population PK parameters:
! Cmax,SS
Predicted maximal plasma level of FVIII activity in steady state
AUC∗
Predicted total exposure to FVIII activity during a single dosing interval 
in steady state
PK and possible PK/PD modelling are considered exploratory analyses that may not be reported in 
the CTR. The PK assay results to be used for modelling are chromogenic FVIII activities measured 
against N8-GP reference material.
Population PK modelling will be done as a combined analysis with data from the first human dose
trial pathfinder™1 with the main scope of assessing the influence of demographic covariates such as 
BW and possibly race on PK properties of N8-GP. The population PK model of which maximum-
likelihood parameter values are to be estimated is a linear one-compartment model parameterised 
with clearance CL and volume of distribution V. 
The final output of the PK modelling is predictions of FVIII activity exposure parameters (Cmax and 
AUC∗) at steady state in proposed prophylaxis dosing regimes for patients of BW 10 kg, 25 kg, 50 
kg, 70 kg and 100 kg and of any race sufficiently well represented in the trial to allow for 
assessment (min. 20 PK samples from min. 5 different patients). 
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18.8
Health Economics and/or Patient Reported Outcome
PROs will be assessed through PRO questionnaires at screening visit (Visit 1) and EOT visit for 
patients in the on-demand arm for patients in the prophylaxis arm. 
The main PRO endpoint will be subgroup total scores. Changes in scores over time of the main 
PRO endpoints at Visit 1 to EOT visit will be explored and presented graphically. Evaluations of 
PRO data will alone be based on descriptive statistics, i.e. summary tables, listings and figures. 
HE calculations will be performed separately by the Novo Nordisk HE department. Novo Nordisk 
A/S will be responsible for the statistical analysis. 
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19 Ethics
The trial will be conducted in compliance with ICH GCP28, applicable regulatory requirements, and 
in accordance with the Declaration of Helsinki29.
When a patient’s participation in the trial ends due to completion of the trial, the patient will be 
offered to continue in the extension trial (NN7088-3861) upon consent. No patient will consent to a 
trial in the N8-GP clinical programme before all required IRB/IEC and regulatory approvals have 
been obtained for the trial. If the patient does not wish to continue in the extension trial (NN7088-
3861), the patient will consult with the Investigator to decide on the best available treatment.
19.1
Informed Consent Form for Trial Patients
In seeking and documenting informed consent, the Investigator must comply with the applicable 
regulatory requirement(s), and adhere to the ICH GCP30 and the requirements in the Declaration of 
Helsinki29.
Prior to any trial-related activity, the Investigator must give the subject and/or the subject’s legally 
acceptable representative (LAR) oral and written information about the trial in a form that the 
subject or the subject’s LAR can read and understand. This includes the use of impartial witness 
where required.
A voluntary, signed and personally dated, including time, informed consent form will be obtained 
from the patient prior to any trial-related activity.
The responsibility for seeking informed consent must remain with the Investigator or an adequately 
medically qualified person delegated by the Investigator. The written informed consent must be 
signed and personally dated, including time, by the person who seeks the informed consent.
If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the Investigator must inform the subject and/or the subject’s LAR in a 
timely manner, and a revised written informed consent must be obtained.
A separate signed and dated informed consent must be obtained from the patient’s partner when 
collecting data from the patient’s partner, if the patient’s partner becomes pregnant during the trial.
FVIII Genotype Testing / Collection of Previous Genotype Documentation ( Not applicable to 
Brazil)
Genotype testing is offered to the patients participating in this trial. If documentation of the 
patients’ genotype already exists, the patient should give their consent before the data is collected 
for trial purpose. Prior to any trial-related activity, the Investigator must provide the patient the 
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possibility to abstain from the genetic testing/collection of previous documentation but still be able 
to participate in the trial.
19.2
Data Handling
If the patient or the patient’s LAR withdraws the previously given informed consent or if the patient 
dies or if the patient is lost to follow up then the patient’s data will be handled as follows:
!
Data collected will be retained by Novo Nordisk and entered into the database
!
Safety events will be reported to the department responsible for global product safety, Novo 
Nordisk/regulatory authorities according to local/national requirements.
If data is used, it will always be in accordance with local law and IRB/IEC procedures.
19.3
Institutional Review Boards/Independent Ethics Committee
Prior to commencement of the trial the protocol, any protocol amendments, patient
information/informed consent form, any other written information to be provided to the subject, 
subject recruitment procedures (incl. advertisement), if any, IB, available safety information, 
information about payments and compensation available to patients if not mentioned in the patient
information, the Investigator’s current curriculum vitae and/or other documentation evidencing 
qualifications, and other documents as required by the local IRB/IEC should be submitted. The 
submission letter should clearly identify the trial identification number, version, EudraCT no., title 
and/or the date of the documents that have been submitted to the IRB/IEC. Written 
approval/favourable opinion must be obtained from IRB/IEC prior to commencement of the trial.
During the trial, the Investigator or sponsor, as applicable, must promptly report the following to the 
IRB/IEC, in accordance with local requirements: unexpected SAEs where a causal relationship 
cannot be ruled out, substantial protocol amendments to the protocol, non-substantial protocol 
amendments according to local requirements, deviations to the protocol implemented to eliminate 
immediate hazards to the patients, new information that may affect adversely the safety of the 
patients or the conduct of the trial (including new risk/benefit analysis in case it will have an impact 
on the planned follow-up of the patients), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
Substantial protocol amendments must not be implemented before approval/favourable opinion, 
unless necessary to eliminate immediate hazards to the patients.
The Investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records should be filed in the Investigator’s trial file and copies must be sent to Novo 
Nordisk.
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19.4
Regulatory Authorities
Regulatory authorities will receive the clinical trial application (CTA), substantial/non-substantial 
protocol amendments, reports on SAEs, and the CTR according to national requirements.
For Japan only: Regulatory authorities will receive the clinical trial notification (CTN), 
notifications of protocol amendments, reports on SAEs, and the clinical trial reports according to 
the national requirements.
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20 Premature Termination of the Trial/Trial Site
Novo Nordisk, Investigator or a pertinent regulatory authority may decide to stop the trial/trial site 
or part of the trial at any time, but agreement on procedures to be followed must be obtained.
If a trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the Investigator and/or Novo 
Nordisk should promptly inform the IEC/IRB and provide a detailed written explanation. The 
pertinent regulatory authorities should be informed according to national regulations.
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation should 
be provided to the IEC/IRB in case it will have an impact on the planned follow-up of the patients
who have participated in the trial. If so, the actions needed to protect the patients should be 
described.
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21 Protocol Compliance 
Deviations from the protocol should be avoided.
If deviations occur then the Investigator must inform the Monitor, and the implications of the 
deviation must be reviewed and discussed.
Protocol deviations must be documented stating the reason, date, the action(s) taken, and the impact 
for the patients and/or the trial except for protocol deviations where no corrections are required as 
described in the trial specific validation checks in the approved TVP. The Investigator must approve 
these as outlined in the TVP. 
The documentation for the protocol deviations must be kept in the Investigator’s trial file and Novo
Nordisk’s trial master file.
21.1
Audits and Inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk internal Quality 
Audit System or an inspection from domestic or foreign regulatory authorities. The Investigator and 
the site staff as well as Novo Nordisk clinical staff have an obligation to cooperate and assist in 
such audits and inspections. This includes giving Auditors and Inspectors direct access to all source 
documents and other documents relevant to the conduct of the clinical trial at the site.
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22 Critical Documents
Before the Investigator starts the trial (i.e. the site has green light for screening patients), the 
following documents must be available to Novo Nordisk:
!
regulatory approval and/or notification as required 
!
curricula vitae of Investigator and Sub-investigator(s) (current, dated and signed and/or 
supported by an official regulatory document)
!
signed receipt of IB 
!
signed and dated agreement on the final protocol
!
signed and dated agreement on any substantial protocol amendment(s), if applicable
!
approval/favourable opinion from IEC/IRB clearly identifying the documents reviewed: the 
protocol, any substantial protocol amendments, subject information/informed consent form and 
any other written information to be provided to the subject, subject recruitment procedures
!
copy of IEC/IRB approved subject information/informed consent form/any other written 
information/advertisement
!
list of IEC/IRB members/constitution
!
financial agreement(s)
!
laboratory reference ranges
!
laboratory certification/QA scheme/other documentation
!
laboratory methods
!
Verification under disclosures per CFR of Financial Conflict of Interest11.
For US:
!
Signed and dated FDA form 1572 for each US Investigator (and individual US clinical trial staff 
if directly involved in the treatment or evaluation of research making a direct and significant 
contribution to the data).
Protocol NN7088-3859 (US sites): 
!
Intended for US sites 
!
Conducted under the IND 
!
All US investigators will sign FDA Form 1572 
Protocol NN7088-3859 (sites outside the US): 
!
Intended for participating sites outside the US 
!
Not conducted under the IND 
!
All investigators outside the US will not sign FDA Form 1572 
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23 Responsibilities
All staff (Novo Nordisk, site, lab, CRO etc.) must conduct the trial in compliance with ICH GCP31, 
applicable regulatory requirements, and in accordance with the Declaration of Helsinki29.
The Investigator is accountable for the conduct of the trial. If any tasks are delegated, the 
Investigator should maintain a list of appropriately qualified persons to whom he/she has delegated
specified significant trial-related duties.
A qualified physician, who is an Investigator or a sub-investigator for the trial, should be 
responsible for all trial-related medical decisions.
The Investigator will follow the instructions from Novo Nordisk when processing data.
The Investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The Investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law.
In case the Investigator is not able to fulfil the role as Investigator (e.g. retirement), a new 
Investigator must be appointed in collaboration with Novo Nordisk. 
Upon request from Novo Nordisk, the Investigator will provide Novo Nordisk with the necessary 
information to enable Novo Nordisk to ensure that such technical and organisational safety 
measures have been taken.
Plasma samples will be analysed by either central laboratories selected by Novo Nordisk or at Novo 
Nordisk A/S.
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24 Reports and Publications
The information obtained during the conduct of this trial is considered confidential, and can be used 
by Novo Nordisk for regulatory purposes and for the general development of the trial product. All 
information supplied by Novo Nordisk in connection with this trial shall remain the sole property of 
Novo Nordisk and is to be considered confidential information. No confidential information shall be 
disclosed to others without prior written consent from Novo Nordisk. Such information shall not be 
used except in the performance of this trial. The information obtained during this trial may be made 
available to other physicians who are conducting other clinical trials with the trial product, if 
deemed necessary by Novo Nordisk.
The Investigator to be designated with the responsibility to review and sign the Clinical Trial Report 
(Signatory Investigator) will be a member of the Advisory Board and Investigator in this trial. 
24.1
Communication and Publication
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or by 
other means.
Novo Nordisk reserves the right to not release data until specified milestones, e.g. when the clinical 
trial report is available. This includes the right to not release interim results of clinical trials, 
because the release of such information can invalidate the results of the entire trial.
At the end of the trial, one or more manuscripts for publication will be prepared collaboratively 
between Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication 
and/or communication for less than 60 days to protect intellectual property.
24.1.1
Authorship
Authorship of publications should be in accordance with guidelines from The International 
Committee of Medical Journal Editors’ Uniform Requirements (sometimes referred to as the 
Vancouver Criteria32).
24.1.2
Publications
The results of this trial will be subject to public disclosure at external web sites according to 
international regulations, which is reflected in Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure.
In all cases, the trial results shall be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations of the trial. All Authors will be given the 
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relevant statistical tables, figures, and reports needed to support the planned publication. In the 
event of any disagreement about the content of any publication, both the Investigators’ and Novo 
Nordisk’s opinions shall be fairly and sufficiently represented in the publication.
In a multi-centre trial based on the collaboration of all trial sites, any publication of results must 
acknowledge all trial sites.
Novo Nordisk maintains the right to be informed of any Investigator plans for publication and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
the Novo Nordisk Trial Manager prior to submission for comments. Comments will be given within 
four weeks from receipt of the planned communication.
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24.1.3
Site-Specific Publication(s) by Investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations, and frequently do not provide meaningful information for healthcare professionals or 
patients; and therefore may not be supported by Novo Nordisk. It is Novo Nordisk’s policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications and to ask for deferment of 
publication of individual site results until after the primary manuscript is accepted for publication.
24.2
Investigator Access to Data and Review of Results
As owners of the trial database, Novo Nordisk has discretion to determine who will have access to 
the database. Generally, trial databases are only made available to regulatory authorities.
Individual Investigator(s) will have their own research participants' data, and will be provided with 
the randomisation code after results are available.
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25 Retention of Clinical Trial Documentation
Subject notes must be kept for the maximum period permitted by the hospital, institution or private 
practice.
The Investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The Investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the Investigator cannot archive the documents at the trial site after trial 
completion, Novo Nordisk can refer the Investigator to an independent archiving provider who has 
a system in place that allows only the Investigator to access the files.
The Investigator must be able to get hold of his/her trial documents without involving Novo 
Nordisk in any way. 
Clinical trial documentation must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the IMP. 
For Japan, the Clinical trial site should retain clinical trial documentation until approval, or 3 years 
after the date of premature termination or completion of the clinical trial. The sponsor should retain 
clinical trial documentation for 5 years after the approval (in case of drug subject to re-examination, 
until re-examination is completed), or 3 years after the date of premature termination or completion 
of the clinical trial.
Novo Nordisk will maintain Novo Nordisk’s documentation pertaining to the trial as long as the 
product is on the market plus 20 years. The files from the Investigator site/institution will be 
retained 15 years after the completion of the trial, or longer if required by national regulations. 
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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26 Indemnity Statement
Novo Nordisk carries product liability for its products and liability assumed under the special laws, 
acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability by the clinics or 
Doctors conducting experiments, or by persons for whom the said clinic or Doctors are responsible.
Novo Nordisk accepts liability in accordance with local country laws and guidelines.
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 or the fault of any intervening party, without the sponsor's 
being entitled to call on acts by a third party or the voluntary withdrawal of the person who had 
initially consented to cooperating in the research.
Only applicable to The Netherlands: Novo Nordisk accepts liability in accordance with:
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 Patients 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 patients (Medical Research (Human 
Patients) Compulsory Insurance Decree).”
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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Version:
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References
1 Guidelines for the Management of Hemophilia. 2005.
2 Vander AJ, Sherman JH, Luciano. Hemostasis:The Prevention of Blood Loss. In: Vander AJ, 
Sherman JH, Luciano DS, editors. Human Physiology. McGraw-Hill, Inc., 1994: 741-750.
3 Mancojohnson MJ, Nuss R, Geraghty S, Funk S, Kilcoyne R. Results of secondary 
prophylaxis in children with severe hemophilia. Am J Hematol 1994; 47(2):113-117.
4 Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R et al. 
Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. 
N Engl J Med 2007; 357(6):535-544.
5 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Gungor T et al. Incidence of 
development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 
339(8793):594-598.
6 White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Definitions in 
hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of 
the scientific and standardization committee of the International Society on Thrombosis and 
Haemostasis. Thromb Haemost 2001; 85(3):560.
7 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 Investigator's Brochure. 40K PEG-N8, 1st edition. Novo Nordisk A/S. 2010.
9 Webster R, Didier E, Harris P, Siegel N, Stadler J, Tilbury L et al. PEGylated proteins: 
Evaluation of their safety in the absence of definitive metabolism studies. DRUG METAB 
DISPOS 2007; 35(1):9-16.
10 Treatment-of-Hemophilia-A-and-B-and-von-Willebrand-disease. A systematic review.  2011. 
11 Abshire TC, Brackmann HH, Scharrer I, Hoots K, Gazengel C, Powell JS et al. Sucrose 
formulated recombinant human antihemophilic factor VIII is safe and efficacious for 
treatment of hemophilia A in home therapy--International Kogenate-FS Study Group. Thromb 
Haemost 2000; 83(6):811-816.
12 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.
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NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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Version:
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Page:
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13 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.
14 Food and Drug Administration Amendments Act.  2007. 
15 Giles AR, Verbruggen B, Rivard GE, Teitel J, Walker I. A detailed comparison of the 
performance of the standard versus the Nijmegen modification of the Bethesda assay in 
detecting factor VIII:C inhibitors in the haemophilia A population of Canada. Association of 
Hemophilia Centre Directors of Canada. Factor VIII/IX Subcommittee of Scientific and 
Standardization Committee of International Society on Thrombosis and Haemostasis. Thromb 
Haemost 1998; 79(4):872-875.
16 European Union; The rules governing medicinal products in the European Union, volume 4, 
Annex 13, Manufacture of Investigational Medicinal Products - Brussels, July 2003.  2010. 
17 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.
18 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline: Guideline 
for Good Clinical Practice E6 (R1), Step 4.  10-6-1996. 
19 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline: Guideline 
for Good Clinical Practice E6 (R1), Step 4.  10-6-1996. 
20 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline: Guideline 
for Good Clinical Practice E6 (R1), Step 4.  10-6-1996. 
21 C.G.Courter and C.L.Bedrosian.  Clinical Evaluation of B-Domain Deleted Recombinant
Factor VIII in Previously Untreated Patients. Semin Hematol 2001; 38 Suppl 4;52-59.
22 Lusher JM, Lee CA, Kessler CM, Bedrosian CL. The safety and efficacy of B-domain deleted 
recombinant factor VIII concentrate in patients with severe haemophilia A. Haemophilia 
2003; 9(1):38-49.
23 Tarantino MD, Collins PW, Hay CR, Shapiro AD, Gruppo RA, Berntorp E et al. Clinical 
evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-
free method: pharmacokinetics, efficacy, and safety in previously treated patients with 
haemophilia A. Haemophilia 2004; 10(5):428-437.
24 Nemes L, Lissitchkov T, Klukowska A, Dobaczewski G, Komrska V, Zimmermann R et al. 
Evaluation of pharmacokinetics, efficacy and safety of Immunate solvent detergent in 
previously treated patients with severe haemophilia A. Haemophilia 2007; 13(1):9-11.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859
Protocol/UTN: U1111-1119-7416
EudraCT No.:2011-001142-15
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Version:
1.0
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25 Recht M, Nemes L, Matysiak M, Manco-Johnson M, Lusher J, Smith M et al. Clinical 
evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant 
factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, 
and pharmacokinetic equivalence to full-length recombinant factor VIII. Haemophilia 2009; 
15(4):869-880.
26 Smith MP, Giangrande P, Pollman H, Littlewood R, Kollmer C, Feingold J. A postmarketing 
surveillance study of the safety and efficacy of ReFacto (St Louis-derived active substance) in 
patients with haemophilia A. Haemophilia 2005; 11(5):444-451.
27 Schwartz RS, Abildgaard CF, Aledort LM, Arkin S, Bloom AL, Brackmann HH et al. Human 
recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia 
A. recombinant Factor VIII Study Group. N Engl J Med 1990; 323(26):1800-1805.
28 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline: Guideline 
for Good Clinical Practice E6 (R1), Step 4.  10-6-1996. 
29 World Medical Association. World Medical Association Declaration of Helsinki: Ethical 
principles for medical research involving human subjects - Last amended by the 59th WMA 
General Assembly, Seoul.  2008. 
30 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline: Guideline 
for Good Clinical Practice E6 (R1), Step 4.  10-6-1996. 
31 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline: Guideline 
for Good Clinical Practice E6 (R1), Step 4.  10-6-1996. 
32 Clever L, Colaianni LA, Davidoff F, Horton R, Kassirer JP, Angell M et al. Uniform 
requirements for manuscripts submitted to biomedical journals. New Engl J Med 1997; 
336(4):309-315.
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
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NNC 0129-0000-1003
NN7088-3859 Ext 2 final
Clinical Trial Report
Appendix 16.1.1
0D\2019

)LQDO
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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Page:
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Substantial Protocol Amendment 
no. 1-NL
to Protocol, final version 1.0
dated 30 September 2011
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003 
when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A
Trial phase: 3
Applicable to The Netherlands
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
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Page:
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Table of Contents
Page
Table of Contents .............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes......................................................................................................................................................4
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Substantial Protocol Amendment 
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UTN: U1111-1119-7416
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1
Introduction including rationale for the substantial protocol 
amendment
In this substantial protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
The reason for this amendment is to change the inclusion criterion 4 regarding age in order to 
include only adult patients in the trial in the Netherlands.
In the original protocol previously treated patients aged 12 and older were included. 
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
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2
Changes
1 Summary
Key Inclusion Criteria
!
Age ≥12 years (except for Croatia and The Netherlands where the lower age limit will be 18 
years) 
6 Trial Population
6.2 Inclusion Criteria
4. Age ≥12 years (except for Croatia and The Netherlands where the lower age limit will be 18 
years) 
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
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Substantial Protocol Amendment 
no 2
to Protocol, Final version 1.0, dated 30-Sep-2011 and Sample Subject 
Information Informed Consent Form, Final version 1.0, dated 30-Sep-2011
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003
when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A
Trial phase: 3
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
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Table of Contents
Page
Table of Contents .............................................................................................................................................2
Table of tables....................................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes to Protocol ..................................................................................................................................5
3
Changes to Sample Subject Information Informed Consent forms ...................................................16
Table of tables 
Page
Table 2–1 Guide for dosing in bleeding episodes.............................................................................................7
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
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1
Introduction including rationale for the substantial protocol 
amendment
This global substantial amendment is being issued primarily as a response to a Voluntary 
Harmonised Procedure (VHP) assessment, which involve the CTA submission of the NN7088-3859 
(pathfinderTM 2) and NN7088-3860 (pathfinderTM 3) protocol in 8 European countries. 
The following changes have been made to the protocol:
!
VHP recommend a more detailed guidance on the treatment of bleeds. Therefore section 5.3.2 
has been updated accordingly
!
VHP recommend a more clear guidance for the required observation period for adverse 
reactions in connection to administration of the two first doses of N8-GP. This has been added
in the relevant sections
!
Anti-coagulants and heparin have been added in section 6.5 as prohibited medication to the 
protocols withdrawal criteria to make this more consistent.
!
VPH expressed concerns regarding the blood volume planned to be collected during scheduled 
visits - especially for adolescents participating in the PK evaluation. This has been clarified in 
the protocol. Due to the total amount of blood volume planned to be drawn at the screening 
visit, the genotype blood sampling has been moved to visit 3. Moreover inclusion criterion no 4 
has been adjusted only to enroll patients with body weight > 35 kg. This is to ensure that the 
blood volume collected from the patients for all tests do not exceed 1% of the whole blood 
volume at any single collection and 3% of the whole blood volume in 28 days. Please refer to 
section 6.2.
!
As N8-GP is not considered to be mutagenic or considered toxic to the reproductive system, no 
contraception is considered required by males exposed to N8-GP who are sexually active.
Therefore the UK requirement on contraception has been deleted in Section 6.3.
!
Planned number of sites has been updated to reflect the current plan for number of sites in the 
trial
!
In section 8.4.4.2 (Hemophilia Treatment History including History of Bleeding Episodes), one
additional question has been added to collect number of months for patients on on-demand 
treatment. This will ensure alignment with the historical data collected for the patients currently 
on prophylaxis treatment. Furthermore one question has been updated to make it more specific 
with regards to collecting number of bleeding episodes prior to initiation of prophylaxis 
treatment
!
In section 19.1 collection of time in the consent form has been deleted. This is not required as
the patients will be informed about the trial at least 14 days prior to the first dosing visit,.
!
The flow charts (Table 2-1 and Table 2-2) have been updated to reflect the changes to the 
protocol and to correct inconsistencies
!
One additional country added to the list of countries (section 6.1)
!
Mandatory safety text has been updated due to updates in the Novo Nordisk protocol template 
(section 12.1)
!
Some inconsistencies and minor corrections have been updated in the protocol
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Substantial Protocol Amendment 
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The following updates have been made to the Sample Subject Information Informed Consent 
Forms:
!
An error in the title of the subject information consent form has been corrected in all forms in 
order to be consistent with the protocol title
!
Genotype sampling has been moved to visit 3 and correct ml for this sample have been added,
number of sites have been updated, one additional country has been added, total blood volume 
collection has been updated and observation time for adverse reactions for the first two doses of 
N8-GP has been updated to reflect the amendment changes
!
Precautionary advice in connection to the reconstitution of trial product has been added for 
clarification
Minor typographical changes not affecting the content of text, e.g. grammatical and spelling errors, 
will not be disclosed in the following sections.
Any new text in this amendment is written in “Italic”. Any text deleted from the protocol is written 
with a strike through.
The Protocol version 2 incorporates all changes.
The Sample Subject Information Informed Consent form version 2.0, the The Sample Subject 
Information Informed Consent form for minor version 2.0, the Sample Subject Information 
Informed Consent form without PK version 2.0 and Sample Subject Information Informed Consent 
form for partners version 2.0 incorporates all changes described above.
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
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2
Changes to Protocol
List of Abbreviations
…
pd-PCC
plasma derived plasma pcoagulation factor concentrates
1 Summary
…
Key Inclusion Criteria
• Age >12 years and body weight ≥35 kg (except for Croatia and The Netherlands where the lower 
age limit will be 18 years)
2 Flow Chart
The Flow Chart table 2-1 has been updated with the following:
!
Genotype testing has been moved from visit 1 to visit 3
!
The possibility of measuring ECG has been added to unscheduled visit
!
Date and time of last coagulation factor administration not to be recorded at visit 2b
!
HCP to be measured at unscheduled visits in case of an allegic reaction
The Flow Chart table 2-2 has been updated with the following:
!
Coagulation related parametres (aPTT, INR) to be sampled 30  ± 5 min post dose
!
Bleeding episodes severity to be rated during PK session at visit 7
Footer added for Date and time of last coagulation factor administration
6 Wash-out is 4 days prior to visit 2a and 7 days prior to visit 7
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Substantial Protocol Amendment 
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EudraCT No.: 2011-001142-15
Date:
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Table 2-1 footer:
Footer
Description
1
Please refer to Table 2-2 for the patients that need to undergo PK
2
Patients in the on-demand arm can switch into prophylaxis treatment after 6 months treatment
3
Confirmation of screening visit 1 in- and exclusion criteria
4
If applicable, i.e. following patient consent and in accordance with local law
5
Only if this visit is EOT visit – dependent on when the patient entered the trialTo be measured before dosing and 30 min (±10min) after dosing.  
6
Antibody samples will only be drawn from patients in the on-demand arm at Visit 3-13 if they have received treatment since last visit
7
A wash-out period of minimum 96 hrs is needed before the sample (except visit 1 and visit 2a where wash out is minimum 72 hours)
8
Only in case of an unexpected allergic/anaphylactic reaction
9
Trough to be sampled before dosing and recovery to be sampled 30 min (± 5min ) after dosingNot for patients in the on demand arm
10
Only to be taken if HIV status is positive
11
From visit 2a -13 only BW will be measured 
12
From visit 3-123, only for patients in the prophylaxis arm
13
Assessements to be performed at the EOT visit. The EOT visit can be any visit from visit 7 to  visit 13 depending on when the patient entered the trial. This current trial will be terminated when 
the last patient has received 50 exposure days.  


Substantial Protocol Amendment 
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3 Introduction
3.1 Basic Information
3.1.1 Haemophilia A
…
This replacement therapy can be provided either as prophylaxis or as on-demand treatment of 
bleeding episodes. turoctocog alfa
5 Trial Design
…
5.3 Treatment of Patients
…
The two initial doses of N8-GP will be administered in a hospital setting in order to observe for 
adverse reactions.The patient must be observed for at least 1hr after dosing.
5.3.2 Treatment of Bleeding episodes
A treatment requiring bleeding episode is in this trial defined as a bleed that require treatment with 
a coagulation factor product e.g. N8-GP. If a patient experiences a treatment requiring bleed it must 
be treated as soon as it is identified (refer to Section 8.2.1).
…
For the treatment of bleeding episodes, doses will be based on World Federation of Haemophilia 
(WFH) guidelines1 (see Section 8.2.1).For treatment of a bleed, all on demand and prophylaxis 
patients will be treated with doses between 20-75 U/kg BW (the recommended standard dose will 
be 50 U/kg). to achieve a desired dose level based on the severity and location of the bleeding 
episode. Each unit of N8-GP will raise the FVIII level with approximately 2%. For recommended 
dose levels see table 1. Further guidance on the treatment of bleeds may be found in WFH 
guideline1.
The dosage is calculated by multiplying the patient’s weight in kilograms by the factor level desired 
multiplied by 0.5. This will indicate the number of N8-GP units required.  
Example: 50 kg x 40 (% level desired) x 0.5 = 1 000 units of N8-GP.
Table 2–1 Guide for dosing in bleeding episodes
Type of haemorrhage
Desired level
Recommended dose
Joint, muscle (except iliopsoas)
40% - 60%
20 - 30 U per kg
CNS/head, Throat and neck, 
Gastrointestinal, Iliopsoas
80% - 100%
40 – 50 U per kg
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Substantial Protocol Amendment 
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Based on recommendations WFH guidelines.
The effect of initial N8-GP dose on the clinical symptoms should be closely monitored and the need 
for a second dose should be evaluated within 8 hours after the initial N8-GP dose. If further doses 
are considered necessary to treat the bleeding episode, the patient is recommended to contact the 
investigator.
The maximum dose to be administered to a patient within 24 hours (hrs) is 200 U/kg BW. The dose 
is recommended to be divided and only considered under exceptional circumstance such as serious 
trauma or severe bleeding episodes.
Age and body weight are markedly correlated in children and adolescents. As the dosing of N8-GP 
takes body weight into account no further adjustment is needed in the adolescents included in this 
trial.
Due to individual patient’s bleeding pattern during the trial, an adaptation in dosing regimen to 50 
U/kg twice weekly will be permitted at the investigator’s discretion. If the dosing regimen is 
changed to twice weekly, doses should be separated by at least 3 calendar days and no more than 4 
calendar days.
The dose for treatment of bleeding episodes is aimed to achieve an expected post injection level of 
at least 0.50 U/mL of FVIII.
Any dose used for treatment of a known active bleed must be recorded as treatment of bleed and not 
as prophylaxis treatment. When the bleed has resolved, the patient can resume the prophylaxis 
treatment.
If a dose for treatment of a bleed is taken, the next prophylaxis dose should follow the original 
dosing scheme and not be altered by the additional treatment of bleed administration. If a bleed 
occurs on the same day as the planned prophylaxis, the dose must be registered for the bleed and 
not as prophylaxis.
Number of doses and frequency of dosing is decided by the Investigator in relation to the particular 
bleed. The maximum dose to be administered to a patient within 24 hours (hrs) is 200 U/kg BW. 
The dose is recommended to be divided and only considered under exceptional circumstance such 
as serious trauma or severe bleeding episodes.
6 Trial Population
6.1 Number of Patients to be Studied
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Countries planned to participate: Australia, Brazil, Croatia, Denmark, France, Germany, Hungary, 
Italy, Japan, Korea, Malaysia, Netherlands, Norway, Russia, Spain, Sweden, Switzerland, Taiwan, 
Turkey, United Kingdom and United States
…
Planned number of trial sites (approximately): 5575
6.2 Inclusion Criteria
…
4. Age >12 years and body weight >35 kg (except for Croatia and The Netherlands where the lower 
age limit will be 18 years)
6.3 Exclusion Criteria
…
For the UK: Patients who are sexually active and have partners who are or could become pregnant 
must be willing and are required to use a barrier method of contraception (e.g. condom) for the 
duration of the trial and for 90 days following the last dose of trial medication.
6.5 Withdrawal Criteria
…
6. Use of Anti-coagulants such as Heparin and vitamin-K antagonists (Heparin is allowed for 
sealing of central venous access ports according to local practice)
6.7 Rationale for Trial Population
…
The trial population characterised through the inclusion criteria:
∀
Criterion no. 1 is included in accordance with ICH-GCP
∀
Criterion no. 2 is included to select patients most likely to benefit from the treatment
∀
Criterion no. 3 is included for selecting previously FVIII treated patients and is in 
accordance with the EMA guideline
∀
Criterion no 4 Weight is applied in order to ensure that the blood volume collected from the
patients for all tests should not exceed 1% of the whole blood volume at any single time and 
3% of whole blood volume in 28 days. This requirement is in line with European regulatory 
requirements) and FDA requirements
8 Methods and Assessments
8.1.1 Visit 1 – Screening Visit for All Patients
…
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Trial ID: NN7088-3859
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At the Screening visit the following assessments will be performed and/or recorded in the 
eCRF:
...
! History of surgery, see section 8.4.4.2
! FVIII genotype documentation, if applicable, see section 8.3.7.5
…
Blood sampling for central laboratory assessments:
…
! FVIII genotype (if documentation is not available in the patient chart and as allowed per local 
law. In addition, the Investigator, patient or LAR has the right to refuse), see section 8.3.7.5
8.1.2 Visit Schedule for Patients on Prophylaxis not Undergoing PK Evaluation and for 
Patients on On-Demand treatment
…
Visit 2a should take place as soon as possible upon confirmation of eligibility and 2-3 weeks after 
the Screening visit (Visit 1).
At visit 2a the patients will have their first dose of N8-GP (50 U/kg) BW administered at the site. 
The second dose (50 U/kg BW) is given at visit 2b 4 days after visit 2a.
After each of the 2 initial doses of N8-GP, patients must be observed for adverse reactions for at 
least 1hr after dosing.
…
At Visit 2a the following assessments will be performed and/or recorded in the eCRF 
! Confirmation of inclusion and exclusion criteria, see section 6.2 and 6.3
! Withdrawal criteria, see section 6.5
! Concomitant medication, see section 11
! Check date and time of last coagulation factor administration (see section 8.4.3)
…
! Administration of first dose of N8-GP (Stop time of injection must be recorded in the eCRF, this 
corresponds to time “0”. Moreover patients must be observed for at least 1 hr after 
administration for adverse reactions)
…
Blood sampling for central laboratory assessments
! Biochemistry, see section 8.3.7.1
! Coagulation related parameters, aPTT and INR before dosing and  30 min (#10 min) after the 
first dosinginge, see section 8.3.7.2
…
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
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At Visit 2b (4 days after first dose) the following assessments will be performed and/or 
recorded in the eCRF 
…
! Administration of second dose of N8-GP (patients to be observed for at least 1 hr after 
administration for adverse reactions)
…
The following will be performed and/or recorded in the eCRF:
…
! Body measurements (weight only at all visits except EOT visit),  see section 8.4.2
…
Blood sampling for central laboratory assessments:
! Biochemistry, see section 8.3.7.1
! FVIII activity (trough level and recovery), i.e. before dosing and 30 min (#5 min) after dosing 
8.3.7.3. Recovery not to be done in the on-demand arm and not at EOT visit, see section 8.3.6.3
! FVIII inhibitors, see section 8.3.2.2
! N8-GP binding antibodies, see section8.3.2.1
! FVIII genotype (only visit 3). If documentation is not available in the patient chart and as 
allowed per local law. In addition, the Investigator, patient or LAR has the right to refuse, see 
section 8.3.7.5
8.1.3.1 Visit 2a for Patients on Prophylaxis Undergoing PK Evaluation
…
Blood sampling for central laboratory assessments to be taken within 1 hour prior to dosing:
! Biochemistry, see section 8.3.7.1
! Coagulation related parameters, aPPT and INR before dosing and  30 min (#10 min) after the 
first dosinge see section 8.3.7.2
…
First N8-GP administration
!
Dispensing of N8-GP for PK evaluation in IV/WRS
Patients will receive 50 U/kg BW of N8-GP (Stop time of injection must be recorded in the eCRF, 
this corresponds to time “0”. Moreover patients must be observed for at least 1 hr after 
administration for adverse reactions)
8.1.3.2 Visit 2b for Patients on Prophylaxis Undergoing PK Evaluation
Four days after first dose the following assessments will be performed and/or recorded in the 
eCRF 
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
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...
! Administration of second dose of N8-GP (patients must be observed for at least 1 hr after 
administration for adverse reactions)
Reminders:
! An appointment for Visit 3, 4 weeks ± 1 week after visit 2a should be made.
8.1.3.3 Visit 7 for Patients on Prophylaxis Undergoing PK Evaluation
…
Blood sampling for local laboratory assessments to be taken within 1 hour prior to dosing:
! Haematology, see section 8.3.6.1
! Urinalysis with sticks provided by the central laboratory, see section 8.3.6.2
Blood sampling for central laboratory assessments to be taken within 1 hour prior to dosing:
! Biochemistry, see section 8.3.7.1
! Coagulation related parameters, aPPT and INR before dosing and  30 min (#10 min) after 
dosing, see section 8.3.7.2
…
Reminders:
! An appointment for Visit 8, 36 (8 weeks #1 after visit 2aweek later) should be made.
Withhold N8-GP minimum 96 hours prior to next visit 
8.4.1 Follow-up visit (only for patients withdrawn due to development of FVIII inhibitors)
In case of withdrawal due to FVIII inhibitor development, the patient should be scheduled for an 
EOT Visit as soon as possible and within 1 week after a positive inhibitor test is confirmed via 
re-testing, preferably prior to initiation of treatment with another FVIII product. One month (4 
weeks # 2 weeks) after the EOT Visit the patient must attend a FU Visit, please see Section 8.3.6
8.3.2.2
8.1.5 Unscheduled Visits
…
! IgE, IgG, HCP see section 8.3.2.3
! N8-GP administration, not for on-demand patients
8.2 Efficacy Assessments
…
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Substantial Protocol Amendment 
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• Health Economic questions, see section 8.4.5
8.2.1 Bleeding Episodes
…
For bleeding episodes the following will be recorded in Patient’s eDiary or eCRF:
...
!
Haemostatic drug used for 
!
Pain relieving medication
!
Dose(s) and Time(s) of administration
!
Other therapy used (compression, ice or other)
!
Stop of bleed (date and time)
!
Categorisation of the bleeding episode (mild/moderate or severe), in the eCRF 
!
Clinical evaluation of the haemostatic response (excellent, good, moderate or none)
!
Bleed related days away from work or school
Bleed related days using mobility aids
8.4.2 Body Measurements
All body measurements (weight, height and BMI) will be performed at Visit 1. On all other visits 
only weight will be measured. The weight measured at the respective visits should be the weight 
used for calculating the amount on of N8-GP to be dispensed and the dose of N8-GP to be
administered.
! Weight (registered with one decimal), wearing light clothing only (kg/pounds) and without shoes
! Height, without shoes (cm/inches), visit 1 only
! BMI calculation (kg/m2), visit 1 only
8.4.3 eDiaries
eDiaries will be used in this trial. The patient should bring the eDiary to every visit to the site. 
The following data will, as a minimum, be captured by the patient or the caregiver in the e-Diary:
!
Treatment
! FVIII product used 
…
!
Bleed related days away from work or school
!
Bleed related days using mobility aids 
•
Health Economic questions, see section 8.4.5
8.4.4.2 Bleeding Haemophilia Treatment History including History of Bleeding Episodes
For patients currently on prophylaxis treatment, the following should be recorded
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
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…
∀
Number of Bbleeding pattern episodes within the last 12 months prior to initiation of
prophylaxis therapy was initiated 
For patients currently on on-demand treatment the following should be recorded
Number of months on on-demand
12 Adverse Events and Pregnancies
12.1 Definitions
…
b)  The term “hospitalisation” describes a period of at least 24 hours. Over-night stay for 
observation, treatment at emergency room or treatment on an out-subject basis does not constitute a 
hospitalisation. However, medical judgement must always be exercised and when in doubt the case 
should be considered serious.
Hospitalisations for administrative, trial related and social purposes do not constitute 
hospitalisations as defined by the seriousness criteria, and should therefore not be reported as such. 
Likewise, hospital admissions for surgical procedures planned prior to trial inclusion are not 
considered AEs. is used when a subject is:
!
Admitted to a hospital/in-subject (irrespective of the duration of physical stay), or
!
Not admitted to a hospital/not in-subject, but stays at the hospital for treatment or
observation for more than 24 hrs.
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes 
do not constitute AEs and should therefore neither be reported as AEs or SAEs. Likewise, hospital 
admissions for surgical procedures planned prior to trial inclusion are not considered AEs or 
SAEs.
19 Ethics
…
19.1 Informed Consent Form for Trial Patients
...
A voluntary, signed and personally dated, including time, informed consent form will be obtained 
from the patient prior to any trial-related activity.
The responsibility for seeking informed consent must remain with the Investigator or an adequately 
medically qualified person delegated by the Investigator. The written informed consent must be 
signed and personally dated, including time, by the person who seeks the informed consent.
22 Critical Documents
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
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Version:
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…
For US sites:
Signed and dated FDA form 1572 must be completed and signed for by each US Investigator (and 
individual US clinical trial staff if directly involved in the treatment or evaluation of research 
making a direct and significant contribution to the data).
24 Reports and Publications
…
24.2 Investigator Access to Data and Review of Results
As owners of the trial database, Novo Nordisk has discretion to determine who will have access to 
the database. Generally, trial databases are only made available to regulatory authorities.
Individual Investigator(s) will have their own research participants' data, and will be provided with 
the randomisation code after results are available..
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
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Date:
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Version:
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3
Changes to Sample Subject Information Informed Consent forms
Changes that concerns the following Sample Subject Information Informed Consent forms:
Sample Subject Information Informed Consent form 
Sample Subject Information Informed Consent form for minor
Sample Subject Information Informed Consent form without PK
Sample Subject Information Informed Consent form for partners
Front page, title of protocol:
A Multi-National Trial Evaluating Safety and Efficacy Including Pharmacokinetics, of NNC 0129-
0000-1003 when Administered for Treatment and Prophylaxis of Bleeding in Patients with 
Haemophilia A
Changes to Sample Subject Information Informed Consent form, Sample Subject Information 
Informed Consent without PK and Sample Subject Information Informed Consent form for 
minor:
1 Information about the Trial and the Trial Product
1.3 Procedures during the trial conduct
…
Visits and tests during the trial
Changes to Sample Subject Information Informed Consent form and Sample Subject 
Information Informed Consent without PK:
1 Information about the Trial and the Trial Product
1.1 Why are we conducting this trial?
…
Tests to be performed
Visit 1
Visit 2a
14-21days 
after visit 
1
Visit 2b
4 days 
after visit 
2a
Visit 3-5
Every 4 
weeks
Visit 6-12
Every 8 
weeks
Last trial visit
Any time 
between 6-19 
month after 
visit 1
Blood sample for 
genotyping, if consented 
to
X
X ( only at 
visit 3)
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Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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Page:
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We expect that 132 patients worldwide will enrolled in this trial in approximately 5575 haemophilia 
centres. The planned participating countries are: Australia, Brazil, Croatia, Denmark, France, 
Germany, Hungary,  Italy, Japan, Korea, Malaysia, Netherlands, Norway, Russia, Spain, Sweden, 
Switzerland, Taiwan, Turkey, United Kingdom and United States
1.3 Procedures during the trial conduct
…
You are also separately asked to give your consent for a blood sample (56 ml) to perform genotype 
testing. 
First doses with N8-GP
…
The first dose of N8-GP will take place approximately 14-21 days after your first visit and the 
second dose will take place four days after the first dose. These first 2two doses are not dependent 
on bleeding episodes but are done as prophylactic treatment to ensure that the new drug is safe for 
you to take. You will need to stay at the clinic one hour after you have received the first two doses 
with N8-GP to be observed for any possible adverse reactions.
1.4 How to handle trial medication, N8-GP
The clinic will supply you with the required amount of trial medication, solvent for reconstitution 
and infusion sets. If you are treated prophylactically every 4th day, we recommend you take N8-GP 
in the morning at approximately the same time. The trial medication must be stored refrigerated and 
handled as described in the medication label and in the instructions provided. When reconstituted 
N8-GP is a clear /almost clear colourless solution Please note that you must not use the solution if 
there are any solid particles to be seen.
1.9 Withdrawal from the Trial
…
In case you are withdrawn due to inhibitor development we will ask you to come to an end of trial 
visit one week after detection of the inhibitor and for follow up visits monthly at least monthly in 
the following three month up to three month after the end of trial visit.
Changes to Sample Subject Information Informed Consent form 
2 Information about the Risks/Benefits
The total estimated ml of blood that will be taken from you during this trial will be approximately 
280360 ml which is approximately the same as one unit of blood. If you participate in the 
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
09 December 2011
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Version:
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Page:
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pharmacokinetic part the total estimated blood volume will be approximately 320420 ml during the 
trial.
Changes to Sample Subject Information Informed Consent form without PK 
2 Information about the Risks/Benefits
The total estimated ml of blood that will be taken from you during this trial will be approximately 
280360 ml which is approximately the same as one unit of blood.
CONFIDENTIAL


Substantial protocol amendment
Trial No: : NN7088-3859
UTN: 01111-1119-7416
Eudra CT No.: 2011-001142-15
CONFIDENTIAL
Date:
03 January 2012
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Version:
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Substantial Protocol Amendment no 3
to Protocol Attachment II-TR specific, Final version 1.0, dated 17 Oct 2011
Trial ID : NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, including Pharmacokinetics, 
of NNC 0129-0000-1003 when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A
Trial Phase: 3
Author:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be
restricted to relevant parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Substantial protocol amendment
Trial No: : NN7088-3859
UTN: 01111-1119-7416
Eudra CT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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Page:
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Table of Contents
Page
Table of Contents .............................................................................................................................................2
1
Introduction including retionale for the substantial protocol amendment..........................................3
2
Changes......................................................................................................................................................4
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Substantial protocol amendment
Trial No: : NN7088-3859
UTN: 01111-1119-7416
Eudra CT No.: 2011-001142-15
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1
Introduction including retionale for the substantial protocol 
amendment
In this substantial Subject Information/Informed Consent amendment:
Any new text is written in italic.
 Any text deleted from the protocol is written with a strike through..
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Substantial protocol amendment
Trial No: : NN7088-3859
UTN: 01111-1119-7416
Eudra CT No.: 2011-001142-15
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Date:
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2
Changes
The following changes to Attachment II to NN7088-3859:
Principle Investigator:
Title:
Name:
Surname
Tel:
Fax:
Mobile
E-mail:
Investigator:
Title/
qualification:
Name: 
Surname:
Tel:
Fax:
Mobile:
E-mail:
CONFIDENTIAL


Substantial Protocol Amendment no. 4-ES
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
26 January 2012
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Version:
1.0
Status:
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Page:
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Substantial Protocol Amendment 
no 4-ES
to Protocol, final version 1.0
dated 30-Sep-2011
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003
when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A
Trial phase: 3
Applicable to Spain
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Substantial Protocol Amendment no. 4-ES
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
26 January 2012
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Table of Contents
Page
Table of Contents .............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes......................................................................................................................................................4
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Substantial Protocol Amendment no. 4-ES
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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Page:
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1
Introduction including rationale for the substantial protocol 
amendment
This local substantial amendment is being issued to include a new site in Spain
 
 
The Substantial Amendment No. 4-ES to the protocol will be submitted to the Ethic Committees for 
approval, before its implementation. According to local regulation, the amendment information will 
be notified to Competent Authority along with the Ethics Committees opinion.
Any new text in this amendment is written in “Italic”. Any text deleted from the protocol is written 
with a strike through.
The Attachment II– Spain List of Key Staff and Relevant Departments version 2/ES incorporates all
changes.
CONFIDENTIAL


Substantial Protocol Amendment no. 4-ES
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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2
Changes
Attachment II – Spain List of Key Staff and Relevant Departments
Investigator:
National Coordinating 
Investigator:
Name:
Investigator:
Name: 
Title:
Address:
Tel:
Local laboratory(ies):
Name:
Address:
Tel:
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
3 February 2012
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Version:
1.0
Status:
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Page:
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Substantial Protocol Amendment-Local France
N° 5-FR
to Protocol, Final version 1.0, dated 30-Sep-2011, and Global substantial 
amendment N°2, dated 9-Dec-2011
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003
when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A
Trial phase: 3
Applicable to France
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
3 February 2012
Novo Nordisk
Version:
1.0
Status:
                              Final
Page:
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Table of Contents
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes to Protocol ..................................................................................................................................4
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
3 February 2012
Novo Nordisk
Version:
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Status:
                              Final
Page:
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1
Introduction including rationale for the substantial protocol 
amendment
This local substantial amendment is being issued following Ethics Committee decision: due to 
absence of data from clinical trials in adult population, patients below 18 years of age cannot 
be included in this trial.
The following change has been made to the protocol:
!
Inclusion criterion N° 4 has been modified to exclude patients of age < 18 years in France.
Any new text in this amendment is written in “Italic”. Any text deleted from the protocol is written 
with a strike through.
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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Status:
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2
Changes to Protocol
1 Summary
Key Inclusion Criteria
• Age >12 years and body weight ≥35 kg (except for Croatia and, The Netherlands and France
where the lower age limit will be 18 years)
6 Trial Population
6.2 Inclusion Criteria
…
4. Age >12 years and body weight >35 kg (except for Croatia, and The Netherlands and France
where the lower age limit will be 18 years)
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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Substantial Protocol Amendment 
no 6
to Final Protocol, version 2, dated 09 December 2011
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003
when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A
Trial phase: 3
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
30 March 2012
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Table of Contents
Page
Table of Contents .............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes to Protocol ..................................................................................................................................5
2.1
List of Abbreviations .....................................................................................................................5
2.2
Section 1 Summary........................................................................................................................5
2.3
Section 2 ........................................................................................................................................5
2.4
Section 5 Trial design ....................................................................................................................5
2.5
Section 6 Trial Population .............................................................................................................7
2.6
Section 8 Methods and Assessments .............................................................................................7
2.7
Section 11 Concomitant Illness and Concomitant Medication....................................................11
2.8
Section 12 Adverse Events and Pregnancies ...............................................................................11
2.9
Section 18 Statistical Considerations...........................................................................................13
3
Changes to Sample Subject Information Informed Consent Form....................................................19
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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Status:
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1
Introduction including rationale for the substantial protocol 
amendment
This global substantial protocol amendment is being issued primarily as a response to a Special 
Protocol Assessment (SPA) request sent to the US FDA in connection with submission of the 
NN7088-3859 protocol in the United States and includes the following:
Section 18:
!
Annualised bleeding rate in prophylaxis arm. The calculation of annualised bleeding rate 
for withdrawals has been changed. Imputation will also be performed for withdrawals 
within the first month. An annualised bleeding rate of 24 will be used for imputation for all 
patients withdrawing in the first month, including those with zero bleeds
!
Sample size calculations have been changed. For the inhibitor test a true inhibitor rate of 
0.5% instead of 1% is now assumed. This is based on the experience with clinical trials 
with turoctocog alfa. For the prophylaxis test, the impact on the power of the change in 
imputation rule for early withdrawals without bleeding episodes is accounted for
!
An interim analysis has been added in order to evaluate the over-dispersion (only) once 
approximately 90 patients have entered into the prophylaxis arm. If the estimated over-
dispersion is greater than 6 then the planned sample size will be adjusted up to include 160 
prophylaxis patients instead of 120 patients. The planned sample size will not be increased 
without issuing a further amendment 
!
Additional sensitivity analyses have been added both for haemostatic response and for 
annualised bleeding rate
!
Other editorial adjustments have been made to the statistical section of the protocol (section 
18) to better align with the wording of the protocol endpoints in section 4 of the protocol.
In connection with this protocol amendment other clarifications to the protocol have been made:
!
Sections 1 and 6: France has been added to the list of countries that will not allow 
adolescents to participate in the trial
!
Section 1: Clarification of the definition Exposure Days (ED) has been added
!
Sections 5, 6 and 11: Changes to these sections have been made in order to allow patients to 
use their current FVIII product in case they need to treat a bleeding episode immediately at 
home in the period between the first two doses of N8-GP (visit 2a and visit 2b). The changes 
have been made in consideration of patients’ safety
!
Sections 5: The conditions for starting up pathfinderTM3 (NN7088-3860) has been aligned 
with the conditions stated in the pathfinderTM3 protocol
!
Sections 5 and 8: Symptoms that can relate to stop of a bleeding episode have been added.
This in order to guide investigators and patients on how to determine the stop time of a 
bleeding episode
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!
Sections 5 and 6: Guidance for rescheduling of PK sessions in case of a bleeding episode 
during a PK sampling session has been added
!
Section 5: Requirement for documentation of investigators review of the patient’s eDiary at 
every visit has been added
!
Section 8: text regarding Documentation of Inhibitor Status clarified
!
Section 8: Clarifications have been made to the viral assessments. 
!
Section 8: Recording the urine analysis results has been changed from recording the results 
directly into the eCRF to recording this on the laboratory requisition form. This has been 
changed to reflect the current trial set up
!
Section 8: Time point for genotype testing has been corrected from visit 1 to visit 3 in order 
to align with the rest of the protocol
!
Section 8: The first two doses of N8-GP administrated at the hospital will be documented in 
the e-CRF and not in the eDiary. This has been changed due to the current set up of the trial
!
Sections 8 and 12: Reporting of a MESI in case of one positive inhibitor test has been 
clarified
!
Section 12: Some text has been amended to make the text more clear
!
Other editorial corrections have been made to the protocol
!
Attachment I to the protocol has been updated due to changes in key personnel
The following changes have been made to the Subject Information/Informed Consent Form and are 
therefore reflected in this global substantial amendment:
!
Section 1.3: guidance on treatment of a bleeding episode between visit 2a and 2b 
!
Section 3.2: update to the identification of lab samples
In this substantial protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through
!
Minor typographical changes not affecting the content of the text, e.g. grammatical and spelling 
errors will not be disclosed in the following sections
The protocol version 4 incorporates all the above changes.
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2
Changes to Protocol
2.1
List of Abbreviations
pd-aPCC
plasma derived activated plasma prothrombin complex oagulation factor concentrates
pd-PCC
plasma derived prothrombin complex plasma coagulation factor concentrates
2.2
Section 1 Summary
Trial Population:
Foot note added: An “exposure day” is defined as any day the patient has been exposed to N8-GP
including on demand, prophylaxis, during surgery and in PK sessions. If N8-GP is administered 
more than once during the same day, this will still count as one exposure day 
Key Inclusion criteria:
Age ≥12 years and body weight ≥35 kg (except for Croatia, and The Netherlands and France where 
the lower age limit will be 18 years)
2.3
Section 2
Table 2–1
Flow Chart for Patients on Prophylaxis and On-Demand Treatment
‘X’ has been added to the follow-up visit in the flowchart to indicate that N8-GP binding antibodies
must be measured.
2.4
Section 5 Trial design
5.1 Type of Trial:
…
Furthermore, if the patients need to undergo surgery during the present trial they can switch into the 
surgery trial pathfinder™3 and upon completion of the surgery they can return to the pathfinder™2d
trial. Recruitment into the surgery trial pathfinder™3 will begin after successful treatment of 
bleeding episodes with N8-GP in at least 5 patients in the pivotal trial pathfinder™2. For US t The 
surgery trial will not be initiated until at least 20 bleeding episodes in at least 10 patients are treated 
with N8-GP in the present trial.
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5.3 Treatment of Patients
…
The following medications are not allowed during the course of the trial until after the EOT visit:
! Bypassing products: rFVIIa, pd-PCC and pd-aPCC
! Coagulation factors containing products FVIII, FIX, FVII and FVIII other than N8-GP 
(exception: current FVIII is allowed until 72 hours before visit 2a and in case of home treatment 
of a bleeding episode that requires immediate treatment between visit 2a and 2b)
5.3.2 Treatment of Bleeding Episodes
…
Any dose used for treatment of a known active bleed must be recorded as treatment of bleed and not 
as prophylaxis treatment. When the bleed has resolved (e.g. pain reduction and no increase in 
swelling), the patient can resume the prophylaxis treatment.
If a dose for treatment of a bleed is taken, the next prophylaxis dose should follow the original 
dosing scheme and not be altered by the additional treatment of bleed administration. If a bleed 
occurs on the same day as the planned prophylaxis, the dose must be registered for the bleed and 
not as prophylaxis.
If a bleeding episode occurs between visit 2a and 2b, the patient must contact the site and 
preferably come to the site for treatment with N8-GP. In case of a bleeding episode between visit 2a 
and 2b that requires immediate treatment or the Investigator judges it as necessary, the patient can 
treat the bleed at home with his previous FVIII product..
If a haemostatic response cannot be achieved after 48 hours using adequate doses of N8-GP 
treatment when treating bleeding episodes, another FVIII product may be selected at the discretion 
of the Investigator. The use of other FVIII products will result in withdrawal of the patient
(exception: current FVIII product is allowed until 72 hours before visit 2a and in case of home 
treatment of a bleeding episode that requires immediate treatment between visit 2a and 2b).
An electronic diary (eDiary) will be kept to register all bleeding episodes and their treatment
(except treatment with the patients’ current FVIII product between visit 2a and 2b in case of a 
bleeding episode that requires immediate treatment at home. In this case the information will be 
entered into the eCRF). The Investigator must review the eDiary data and rate the bleeding episodes 
at every visit. The review of the eDiary must be documented.
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2.5
Section 6 Trial Population
6.2 Inclusion criteria:
Age ≥12 years and body weight ≥35 kg (except for Croatia, and The Netherlands and France where 
the lower age limit will be 18 years)
6.4 Criteria for rescheduling planned visits:
Criteria 3: In a bleeding state (all visits including PK). If a patient experiences a bleeding episode 
during a PK session between visit 2a and 2b, PK sampling will be stopped and the patient will 
receive treatment with N8-GP, (or the patients’ previous FVIII product if the bleeding episode 
occurs at home and requires immediate treatment)g. In case of mild or moderate bleeding episodes,
rescheduling of PK sessions can be done at the discretion of the Investigator taking the patient’
safety into account. In case of a severe bleeding episode the PK session must be discontinued.
Footnote g: A 7 days wash-out is needed before the rescheduled PK session if the bleeding episode 
was treated with N8-GP and a 4 days wash-out is needed if the bleding episode was treated with 
previous FVIII product.
6.5 Withdrawal Criteria:
! Criteria 4: Use of Coagulation Factors FVIII, FIX and FVII-containing products other than N8-
GP and other FVIII-containing products like fresh frozen plasma or cryoprecipitate (Exception: 
current FVIII is allowed until 72 hours before visit 2a and in case of home treatment of a 
bleeding episode that requires immediate treatment between visit 2a and 2b)  
2.6
Section 8 Methods and Assessments
8.1.2 Visit Schedule for Patients on Prophylaxis not Undergoing PK Evaluation and for 
Patients on On-Demand Treatment
At visit 2a, the patients will have their first dose of N8-GP (50 U/kg) BW) administered at the site. 
The second dose (50 U/kg BW) is given at visit 2b 4 days after visit 2a. If a bleeding occurs during 
this period the patient must contact the site and preferably come to the site for treatment with N8-
GP. If the patient has a bleeding episode that requires immediate treatment or the Investigator 
judges it as necessary, the patient can treat himself at home with his previous FVIII product.
After each of the 2 initial doses of N8-GP, patients must be observed for adverse reactions for at 
least 1hr after dosing.
The samples taken post-dose must not be taken from the same vein as previously used for 
administration of N8-GP.
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Patients will be provided with an eDiary and will be carefully trained in the use of this eDiary 
including instructions in reporting details of bleeding episodes and prophylactic treatment including 
doses administered at all visits after visit 2b.
8.1.3.1 Visit 2a for Patients on Prophylaxis Undergoing PK Evaluation
……
At visit 2a the patients will receive their first dose of N8-GP (50 U/kg BW) at the site and 9 PK 
samples will be taken during the following 4 days. If a bleeding occurs between visit 2a and 2b the 
patient must contact the site and preferably come to the site for treatment with N8-GP. If the patient 
has a bleeding episode that requires immediate treatment or the Investigator judges it as necessary,
the patient can treat himself at home with his previous FVIII product.
…….
Patients will be provided with an eDiary and will be carefully trained in the use of this eDiary 
including instruction in reporting details of bleeding episodes and prophylactic treatment including 
doses administered at all visits after visit 2b.
8.1.4 Follow-up visit (only for patients withdrawn due to development of FVIII inhibitors)
…….
Blood sampling for central laboratory assessments:
! FVIII inhibitors, see section 8.3.2.2
! N8-GP binding antibodies, see section 8.3.2.1
8.1.5 Unscheduled Visits
…
The following can be performed/reported at an unscheduled visit:
…
!
Check date and time of last coagulation factor administration (see section 8.4.3)
8.2.1 Bleeding episodes
For bleeding episodes the following will be recorded in Patient’s eDiary or eCRF:
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…….
!
Date and time for Sstop of bleed (e.g. pain reduction with no increase in swelling) (date and 
time)
A need for haemostatic rescue therapy with another FVIII product will be assessed by the 
Investigator via phone or during the site visit. Patients treated with FVIII products other than N8-
GP must be withdrawn from the trial (exception: current FVIII is allowed until 72 hours before visit 
2a and in case of home treatment of a bleeding episode that requires immediate treatment between 
visit 2a and 2b).
8.3.2.2 FVIII inhibitors
…
If the Investigator decides to send a sample for inhibitor testing to a local laboratory, the 
Investigator must also send a duplicate sample for inhibitor testing to the Central Laboratory. The 
data from the Central Laboratory will then be used in the official analysis. Any single A positive 
inhibitor test must be reported as a MESI (please refer to section 12.1.2).
...
A patient having an initial positive inhibitor positive test and a second negative inhibitor test, will 
be regarded as inhibitor negative and can will be reported as a MESI and continue in the trial.
8.3.6.2 Urinalysis
…
Urinalysis will be performed locally with sticks provided by the central laboratory and should be 
recorded on the laboratory requisition form directly in the eCRF. Results from the urinalysis other 
than pH, proteins, glucose, bilirubin and blood should not be reported to Novo Nordisk.
8.3.7 Central Laboratory Assessments
……
All blood samples including genotyping blood sample will be destroyed after finalisation of the trial 
report. Blood samples of patients who are suspected of inhibitors or who have developed inhibitors 
will be stored at least until evaluation of the clinical trial data by the authorities in the patient’s 
country. 
8.3.7.4 Viral Assessments (HIV, Hepatitis B and C):
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Viral assessments should must be performed if status is unknown or if known or the investigator 
consider there is an indication to test
8.3.7.5 FVIII genotype testing:
At visit 1, all patients/LARs will be asked about documentation of previous FVIII genotype tests. If 
not available or if it needs to be re-tested FVIII genotype testing will be offered at visit 31. 
Investigator and patients/LARs have the right to refuse to provide patient’s FVIII genotype
documentation or to refuse genotyping.
8.4.3 eDiaries:
...
!
Bleeding episodes 
…
∀
Date and time for Sstop of bleed (e.g. pain reduction with no increase in swelling)(date and 
time)
Trial product administration performed at the site should also be entered in the eDiary by the 
patient, except the first two doses of N8-GP administrated at visit 2a and 2b. These will be entered 
into the eCRF by the site. If the patient have used their previous FVIII product to treat a bleeding 
episode between visit 2a and 2b, this information will be entered in the eCRF.
8.4.4.1 Documentation of Inhibitor Status
A positive inhibitor test excludes the patient. The historical laboratory cut-off value (assay 
sensitivity or lower limit of quantification) for a positive Bethesda inhibitor titre must not be higher 
than 1.0 BU/mL.
Documentation of inhibitor status must include the following:
•
two inhibitor test result should be documented within the period since diagnosis, not 
necessary within the last 8 years
•
FVIII recovery test + evaluation of the bleeding history AND/OR negative inhibitor testing 
performed at least every third year during the last 8 years + evaluation of the bleeding 
history AND/OR negative inhibitor testing at least every third year during the last 8 years.
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2.7
Section 11 Concomitant Illness and Concomitant Medication
Coagulation Factors: FVIII, FIX and FVII-containing products other than N8-GP and other FVIII-
containing products like fresh frozen plasma or cryoprecipitate (exception: current FVIII is allowed 
until 72 hours before visit 2a and in case of home treatment of a bleeding episode that requires 
immediate treatment between visit 2a and 2b)
2.8
Section 12 Adverse Events and Pregnancies
12 Adverse Events, Technical Complaints and Pregnancies
12.1.2 Medical event of Special interest
…
A MESI should be reported following the same reporting requirements and timelines for SAEs (see 
section 12.2) irrespective of if the MESI fulfils an SAE criterion.
The following events are defined as MESIs in this trial;
1. Medication error
o
Administration of wrong drug or use of wrong device
o
wrong route of administration such as intramuscular instead of intravenous
o
Administration of an accidental overdose, ie dose which may lead to significant health 
consequence as judged by the investigator irrespective of whether a SAE criterion is met.
o
Administration of a high dose with the intention to cause harm e.g. suicide attempt
2. Inhibitor formation against FVIII
!
Blood samples for measurement of FVIII inhibitors will be analysed at the central laboratory 
selected by Novo Nordisk and if positive (BU ≥0.6/mL) should be reported as a MESI. A 
patient is only considered to be inhibitor positive (BU ≥0.6/mL) if the inhibiotor test is 
positive at two consecutive tests - sampled preferably within 2 weeks.
…
MESIs are reported by completing an AE form and safety information form. Complete the AE form 
in the eCRF. If for any reason the EDC application is unavailable, then fax, telephone or email 
Novo Nordisk. Complete the safety information forms on paper CRFs.
12.2 Collection, Recording and Reporting of Adverse Events
All events meeting the definition of an AE must be collected and reported for all medicinal 
products. 
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12.2.1 Follow up of Adverse Events:
…
Non-serious AEs must be followed until outcome of the event is “recovering”, “recovered” or 
“recovered 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 or cancer or AEs ongoing at time of death (where death is due to another AE) may be 
closed with an outcome of “recovering” or “not recovered” All non-serious AEs classified as 
severe or possibly/probably related to the trial product must be followed until the subject has 
“recovered” or “recovered with sequelae”, and all queries have been resolved. Cases of chronic 
conditions or cancer or AEs ongoing at time of death (i.e. subject dies from another AE) can be 
closed with an outcome of “recovering” or “not recovered”. Cases can be closed with an outcome of 
“recovering” when the subject has completed the post-trial follow-up period and is expected by the 
Investigator to recover.
All other non-serious AEs must be followed until the outcome of the event is “recovering”, 
“recovered” or “recovered with sequelae” or until the end of the post-treatment follow-up stated in 
the protocol, whichever comes first, and until all queries related to these AEs have been resolved. 
AEs ongoing at time of death (i.e. subject dies from another AE) can be closed with an outcome of 
“recovering” or “not recovered”. 
12.3.2 Collection, Storage and Shipment of Technical Complaint Samples
…
The technical complaint sample and a paper copy of the technical complaint form must be sent 
to Novo Nordisk within 5 calendar days of receiving the technical complaint sample at trial site by 
using the following address:
∀
Novo Nordisk A/S, 
Att.: Customer Complaint Center, 
Krogshøjvej 55, 
DK-2880 Bagsværd, 
Denmark
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2.9
Section 18 Statistical Considerations
18.1 Sample Size Calculations
Co-Primary Endpoint: Incidence Rate of FVIII-inhibitors Inhibitory Antibodies against FVIII 
Defined as Titre  ≥0.6 BU/mL
Given the rarity of the disease, a sample size of 105 patients treated for a minimum of 50 exposure 
days will allow for a reasonable evaluation of inhibitor formation in this pivotal trial. 
The aim is to demonstrate that the upper confidence limit for the inhibitor rate is below 6.8%. In 
practical terms this will happen if 2 or less inhibitors are observed in the planned 105 patients with 
50 exposure days (3 or less if the trial should end with 127 patients with 50 EDs). If the true 
inhibitor rate of N8-GP is 0,5 1% then the chance/power to achieve a maximum of 2 inhibitors out 
of 132 patients entered into the trial will be 85% 97%. 
Co-Primary Endpoint: Annualised bleeding rate in the prophylaxis arm 
The clinical efficacy of N8-GP in long term bleeding prophylaxis will be evaluated based on all the 
prophylaxis period data. This will give different period lengths for the different patients but on 
average it is expected to give about 12 month prophylaxis treatment per patient (~7 months for the 
last recruited patients and ~17-19 months for the first recruited patients). Prophylactic effect will be 
concluded if the upper 97.5% confidence limit for the annualised bleeding frequency is < 8.5. 
Annualised bleeding rate for withdrawals will be imputed for the missing period based on their 
observed bleeding rate except for patients withdrawn within one month where imputation will be 
performed based on an annualised bleeding rate of 24. The true bleeding rate will be assumed to be 
6.8 as for historical prophylaxis data but for the sample size calculation it will be assumed that 1 
patient will withdraw within 1 month and that will lift the effective annualised bleeding rate for the 
power calculation by 24/120 = 0.2, i.e. from 6.8 to 7.0. 
The model will be a Poisson regression allowing for over-dispersion (using Pearson’s chi-square 
divided by the degrees of freedom (i.e. Scale=Pearson in SAS)) and using log observation time as 
offset to account for the differing treatment lengths. Based on an approximation to the normal 
distribution and assuming that the patients bleed 7.0 6.8 times per year and an over-dispersion of 5 
(so variance 34 35) 120 patients entered on prophylaxis will give a power of 89% 79%. 
The power calculation is sensitive to the assumed over-dispersion (OD) of 5. For this reason, an 
interim analysis will be performed to evaluate the OD when approximately 90 patients have been 
recruited to prophylaxis: If the estimated OD for the full study is larger than 6, then the sample size 
will be adjusted up to 160 on prophylaxis to ensure that the power holds. The sample size will not 
be increased without issuing a protocol amendment.
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The following table shows the power for the various assumptions of bleeding rates and over-
dispersions (OD).
True ABR
OD
Power for the 
Pprophylaxis test 
power
7.0 6.8
5
79% 89%
6.8 6.5
5
89% 97%
6.5 6
5
97% 99,9%
7.0 6,8
4
87% 83%
7.0 6,8
6
72% 95%
Combined pPower
With 97% power for the first co-primary endpoint and 79% power for the second co-primary 
endpoint, the combined power for the study with the given sample size is expected to be about 
97%*79% = 76% 
With 85% power for the first co-primary endpoint and 89% power for the second co-primary 
endpoint the combined power for the study with the given sample size is expected to be about 
85%*89% = 76%.  
18.2.2 Primary Endpoint(s)
Incidence Rate of FVIII inhibitors ≥Inhibitory Antibodies against FVIII defined as Titre 
0.6 BU/ml.
The rate of inhibitors neutralising 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.
…
Annualised bleeding rate (total number of bleeding episodes per patient assessed as annualised 
bleeding rate) in the prophylaxis arm 
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Number of bleeding episodes (total bleeding episodes assessed as Annualised Bleeding Rate) 
per patient in the prophylaxis arm 
…
For patients withdrawing prematurely the number of bleeding episodes counting in the analysis will
be imputed up to what they could be expected to have had if they had completed the trial. If e.g. a 
patient withdraws after 2 months with 3 bleeding episodes, but the patient should have been in the 
study for 12 months, then this patient will in the analysis count as having had 18 bleeding episodes 
in 12 months. This is similar to LOCF and will avoid positive bias occurring from patients with 
many bleeding episodes withdrawing early.
For patients who withdraw within 1 month this method is considered to give too uncertain LOCF 
values, hence imputation will not be attempted for such patients and such patients will only 
contribute with the observed bleeding episodes and observation time imputation, will be conducted
by assuming an annualised bleeding rate of 24 for the missing period. 
Sensitivity analyses:
Analysis without imputation to planned trial duration 
The primary prophylaxis analysis will be repeated but without imputing number of bleeding 
episodes from early for any withdrawals. Instead only the observed bleeding episodes will be 
counted and the offset will be actual observation duration rather than planned. 
Analysis imputing by LOCF without imputation for withdrawals occurring within the first month
The primary analysis will be repeated but without using imputation of 24 bleeding episodes for 
withdrawals within the first month. Instead only the observed bleeds and the observed duration will 
be used for such subjects.
Analysis imputing a minimum of 24 bleeds per year to planned trial duration
A conservative sensitivity analysis will be performed imputing for all withdrawals the observed 
bleeding rate into the missing period if it is greater than 24 per year and otherwise 24 per year. As 
an example a patient with 3 bleeds in 2 months (observed ABR 18) that should have been in the 
study for 12 months will have 20 bleeds imputed for the missing 10 months. Patients with 6 bleeds 
in 2 months (observed ABR 36) will have 30 bleeds imputed into the missing 10 months.
18.2.3 Confirmatory Secondary Endpoints
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Haemostatic effect of N8-GP when used for treatment of bleeding episodes, assessed on a four-
point scale for haemostatic response (excellent, good, moderate and none) by counting 
excellent and good as success and moderate and none as failure.
Sensitivity analyses
Analysis on observed responses only (i.e. excluding missing observations)
A sensitivity analysis will be performed similar to the primary analysis but only analysing bleeding 
episodes with recorded responses (i.e. not counting any bleeding episodes with missing response as 
failures).
Analysis imputing missing haemostatic response based on number of infusions used
A sensitivity analysis will be performed using the number of infusions given to impute the 
haemostatic response for missing data. Specifically missing responses where only 1 dose was used 
will be counted as success while missing responses where 2 doses were used will be counted as 
failures.
Analysis imputing missing haemostatic response based on patients recorded responses on other 
bleeding episodes
A sensitivity analysis will be performed where missing treatment responses will be imputed based 
on recorded treatment responses from that particular patients recorded treatment responses. The 
imputation will be done randomly based on the recorded success rate. As an example if a patient 
has 2 missing responses and 4 treatment successes in 5 treated bleeds with recorded response then 
the missing responses will be imputed randomly based on an 80% success chance. Patients with 
missing responses for all treated bleeding episodes will be imputed as failures for all bleeding 
episodes.
18.2.4 Supportive Secondary Endpoints
Consumption of N8-GP (number of infusions and U/Kg) per bleed
The Number of Infusions per bleed will be summarised and listed.
The number of U/Kg per bleed will be summarised and listed. 
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Consumption of N8-GP (number of infusions and U/Kg per month and per year) during 
prophylaxis and on-demand treatment
The number of infusions per month and per year will be summarised and listed by treatment 
regimen (prophylaxis and on-demand)
The number of U/Kg per month and per year will be summarised and listed by treatment regimen 
(prophylaxis and on-demand)
Haemostatic effect as measured by recovery and trough levels FVIII:C (in all patients in the 
prophylaxis treatment arm)
Recovery and trough levels measured at scheduled visits will be summarised and listed.
A sensitivity analysis will be performed excluding troughs > 30% and excluding recoveries < 30%. 
This will aim to eliminate any troughs recorded as recoveries and vice versa that has not been 
possible to clarify during data cleaning.
18. 2.4.1 The Number of Injections of N8-GP required per Bleed 
This endpoint will be summarised and listed.
Amount of N8-GP required per Bleed 
Amount of N8-GP required per bleed (U/kg BW/bleeding episode) will be summarised and listed
18.3 Safety Endpoints
Adverse Events (AEs) and Serious Adverse Events (SAEs) reported during the trial
Treatment Emergent AEs (TEAEs defined as AEs occurring after dosing with trial product) and 
Treatment Emergent SAEs (TESAEs) will be summarised by frequency of events and frequency of 
patients with any event. Similar summaries cross-classified by severity and by causal relation to 
trial product will be made. 
Furthermore, listings will be provided displaying all TEAEs and TESAEs including pertinent 
clinical information.
HCP-antibodies will be listed.
Changes in vital signs (BP, pulse, temperature, respiratory rate)
These endpoints will be summarised and listed.
All additional safety parameters such as laboratory parameters and physical examinations will be 
summarised and listed. 
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
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18.4 Exploratory endpoints
Incidence of binding, non-inhibitory antibodies to N8-GP/ turoctocog alfa
Binding non-inhibitory antibodies will be listed.
18.5 Interim analysis
In order to obtain regulatory permission to start the surgery treatment in the US, prophylaxis 
treatment in the US and paediatric trial in the EU lists of acute treatment responses will be prepared 
at certain time-points. They will include patient details as well as dose given and response to 
treatment.
Interim analysis to decide if the sample size should be adjusted
The power calculation for the annualised bleeding rate analyses assumes an over-dispersion (OD) 
of 5. This is based on experience from similar studies with turoctocog alfa but is nevertheless a 
somewhat uncertain assumption that can have major impact on the power of the study. For that 
reason, the OD will be estimated when approximately 90 patients have entered prophylaxis.
This interim analysis will only be based on number of bleeding episodes and exposure time on 
prophylaxis regimen. These data will be cleaned for the interim and archived but not locked in the 
sense that any errors in these data discovered later may still be corrected for the final analysis.
The most likely explanation for the over-dispersion is a patient level effect on the annualised 
bleeding rates. Some patients bleed more often than others. Since such an effect will induce a 
higher over-dispersion in studies of longer duration, it is essential to adjust the OD estimate from 
an interim up to what it can be expected to be for the whole trial where the trial duration will be 
longer. With Exp_int denoting average exposure time at the interim and Exp_full denoting the 
expected average exposure time at end of trial the expected OD at end of trial (OD_full) for the so 
far recruited (100) patients can be estimated from the OD at the interim (OD_int) as 
OD_full=1+(OD_int-1)*(Exp_full/Exp_int). As an example if the estimated OD is 3 and the 
exposure is expected to double before end of trial, OD_full will be estimated as 5.
To ensure proper detachment from the data in the trial while it is still ongoing this analysis will be 
performed by a project independent statistician and only the exposure and the OD will be 
communicated to the project - not the annualised bleeding rate. 
If the OD estimate for the full study is greater than 6, then a decision will be taken to amend the 
protocol to increase the sample size to 160 patients recruited to prophylaxis treatment.
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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3
Changes to Sample Subject Information Informed Consent Form
Changes to Sample Subject Information Informed Consent form and Sample Subject
Information Informed Consent without PK:
Section 1.3 Procedures during the trial conduct
…
Note that if a bleeding episode occurs during the period between your first and second dose you 
must contact your trial doctor and preferably go to the clinic to be treated with trial medication. In 
case of a bleeding episode between visit 2a and 2b that requires immediate treatment or the trial 
doctor judges it as necessary, you can treat the bleed at home with your previous FVIII product. 
Section 3.2 Will your participation in the trial be kept confidential?
…
None of your trial data will be identified by your name. Your trial data will be identified only by a 
trial assigned subject number, and by your date of birth (if allowed by local law). Any laboratory 
samples taken including the test for genotyping, will be identified in the same way. 
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
12 April 2012
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Version:
1.0
Status:         
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Page:
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Substantial Protocol Amendment 
No. 7
to Protocol, Final version 1.0, dated 30-Sep-2011
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003
when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A
Trial phase: 3
Applicable for Brazil
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties.
CONFIDENTIAL
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
12 April 2012
Novo Nordisk
Version:
1.0
Status:         
Final
Page:
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Table of Contents
Page
Table of Contents .............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes to Protocol ..................................................................................................................................4
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
12 April 2012
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Version:
1.0
Status:         
Final
Page:
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1
Introduction including rationale for the substantial protocol 
amendment
In this substantial protocol amendment:
!
Any new text is written in italic.
!
Any text deleted from the protocol is written with a strike through.
This substantial amendment is being issued as a response to a query from the Brazilian National 
Ethics Committee (CONEP) where it states that the protocol does not specify what are the 
acceptable contraception procedures for the Brazilian population. 
This substantial amendment is applicable for Brazil only.
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Changes to Protocol
6.3 Exclusion Criteria
The following text has been added to the end of section 6.3 in the protocol. However, it is not to be 
considered an exclusion criteria.
For Brazil only: Patients who are sexually active and have partners who could become 
pregnant must be willing and are required to use a barrier method of contraception (e.g. 
condom). Furthermore, the patient´s partner must also use a contraceptive method. The 
contraceptive methods should be used for the duration of the trial and for 3 months 
following the last dose of trial medication. 
Patients who declare sexual abstinence due to personal decision will have their decision 
documented and respected and the use of a contraceptive method will not be applicable in 
this case.
CONFIDENTIAL


Substantial Protocol Amendment
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
  Su
to Protoco
A Multi-national T
including Pharmac
Administered for T
Patients with Haem
Amendment originator:
This confidential document is the pr
disclosed without prior written appro
parties.
CONFIDENTIAL
Date:
Version:
Status:
Page:
ubstantial Protocol Amendment
no 8_RU
ol, final version 2.0, dated 09 December
Trial ID: NN7088-3859
Trial Evaluating Safety and E
cokinetics, of NNC 0129-0000
Treatment and Prophylaxis o
mophilia A
Trial phase: 3
Applicable to Russia
roperty of Novo Nordisk. No unpublished information
oval from Novo Nordisk. Access to this document mu
21 June 2012
Novo Nordisk
1.0
Final
1 of 4
r 2011 
Efficacy, 
0-1003 when 
of Bleeding in 
n contained herein may be 
ust be restricted to relevant 
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Substantial Protocol Amendment
CONFIDENTIAL
Date:
21 June 2012
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
2 of 4
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes......................................................................................................................................................4
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
21 June 2012
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
Page:
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1
Introduction including rationale for the substantial protocol 
amendment
This local substantial amendment is being issued as a response to conclusion by Ministry of Health 
and Social Development of the Russian Federation in connection with submission of the     
NN7088-3859 protocol: due to absence of data from clinical trials in population from 12 to 17 years 
old, patients below 18 years of age cannot be included in this trial.
The following change has been made to the protocol:
!
Inclusion criterion number 4 has been modified to exclude patients of age < 18 years in Russia.
In this substantial protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
21 June 2012
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
Page:
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2
Changes
1 Summary
Key Inclusion Criteria
• Age >12 years and body weight ≥35 kg (except for Croatia and ,The Netherlands and Russia
where the lower age limit will be 18 years)
6 Trial Population
6.2 Inclusion Criteria
…
4. Age >12 years and body weight >35 kg (except for Croatia and ,The Netherlands and Russia
where the lower age limit will be 18 years)
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN:U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
19 October 2012
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Version:
1.0
Status:
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Page:
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Substantial Protocol Amendment 
no 9-FR
to Protocol, final version 4.0
dated 30 March 2012
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003
when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A
Trial phase: 3
Applicable to France
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN:U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
19 October 2012
Novo Nordisk
Version:
1.0
Status:
Final
Page:
2 of 4
Table of Contents
Page
Table of Contents .............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes......................................................................................................................................................4
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN:U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
19 October 2012
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Version:
1.0
Status:
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Page:
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1
Introduction including rationale for the substantial protocol 
amendment
The rationale for issuing this substantial amendment is the addition of a new site in France in order 
to help reaching international recruitment target.
Attachment II is updated accordingly.
In this substantial protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7088-3859
UTN:U1111-1119-7416
EudraCT No.: 2011-001142-15
CONFIDENTIAL
Date:
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Version:
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Status:
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Page:
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2
Changes
The following changes to Attachment II to NN7088-3859:
Site added:
Investigator:
Name:
Title:
Address:
Tel:
Fax:
E-mail:
CONFIDENTIAL


Substantial Protocol Amendment
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
Su
A Multi-national Trial Eval
0129-0000-1003 when Adm
Amendment originator:
This confidential document is the pr
disclosed without prior written appro
parties.
CONFIDENTIAL
Date:
Version:
Status:
Page:
bstantial Protocol Amendment
no 10
to Final Protocol, version 4
dated 30 March 2012
Trial ID: NN7088-3859
luating Safety and Efficacy, including Pha
ministered for Treatment and Prophylaxis o
with Haemophilia A
Trial phase: 3
Applicable to all countries 
roperty of Novo Nordisk. No unpublished information
oval from Novo Nordisk. Access to this document mu
03 December 2012
Novo Nordisk
2.0
Final
1 of 6
rmacokinetics, of NNC 
of Bleeding in Patients 
n contained herein may be 
ust be restricted to relevant 
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.


Substantial Protocol Amendment
CONFIDENTIAL
Date:
03 December 2012
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
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Table of contents   
Page
Table of contents...............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes......................................................................................................................................................4
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
03 December 2012
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
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1
Introduction including rationale for the substantial protocol 
amendment
The power calculation is sensitive to an assumed over-dispersion (OD) of 5. For this reason it is 
stated in the protocol that an interim analysis will be performed to evaluate the OD when 
approximately 90 patients have been recruited to prophylaxis: If the estimated OD for the full study 
is larger than 6, then the sample size will be adjusted up to 160 patients on prophylaxis and in that 
way ensure that the power holds. 
It is stated in the protocol that the sample size will not be increased without issuing an amendment 
to the protocol. Therefore, this global substantial protocol amendment is being issued in order to 
allow for an increase in sample size following the described interim analysis, should it be 
determined to be necessary.
The estimated number of enrolled, dosed and completed  patients have therefore changed to reflect 
the maximum number that would be included, should the interim analysis result in an increase in 
sample size. Sections of the protocol reflecting this change include Summary section 1, Trial 
Design sections 5.1, 5.2 and 5.3, Trial Population section 6.1, Patient Replacement section 6.6, 
section 7 and Statistical sections 18.1, and 18.5.
A few spelling errors have been corrected.
In this substantial protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
03 December 2012
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
Page:
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2
Changes
Section 1 Summary
Trial design:
……
A minimum of Approximately 115 (155)1 patients must complete the trial in 2 treatment arms 
including at least 10 patients in on-demand treatment and 105 (145)1 patients in prophylaxis 
treatment with N8-GP every 4 days. Whether a patient will receive prophylaxis treatment or on-
demand treatment is the choice of the patient and Investigator and will be decided at the screening 
visit. 
Trial Population:
Approximately 150 (190)1 previously treated patients (PTPs) with severe (FVIII <1%) haemophilia 
A in a non-bleeding state will be screened to allow for a minimum of approximately 115 (155)1
patients to complete the trial. 
Section 5.1 Type of Trial
……
A minimum of Approximately 115 (155)1 (see section 18.5) patients must complete the trial 
including at least 10 patients in on-demand treatment and 105 (145)1 (see section 18.5) patients in 
prophylaxis treatment with N8-GP every 4 days. 
……
The distribution of patients will be as follows:
It is expected that approximately 120 (160)1 (see section 18.5) patients will be dosed in the 
prophylaxis arm in order to obtain 105 (145)1 (see section 18.5) completed patients on 
prophylaxis treatment. These patients will receive treatment with 50 U/kg of N8-GP every 4 
                                                
1 An interim analysis is planned when approximately 90 patients have been dosed in order to decide if the sample size 
should be adjusted. If the over-dispersion of the annual bleeding rate is greater than 6 then the sample size will 
increase to the patient number stated in brackets (see section 18.5) 
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN7088-3859
Version:
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Status:
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Page:
5 of 6
days during a period of approximately 7-19 months. In case of a bleed the patients will be 
treated with doses between 20-75 U/kg BW.
Section 5.2 Rationale for Trial Design
The purpose of the prophylaxis arm is to provide sufficient exposure to N8-GP to evaluate 
immunogenicity and to provide efficacy data from 50-100 EDs of prophylaxis treatment with N8-
GP in at least approximately 105 (145)1 (see section 18.5) patients with severe haemophilia A ≥12 
years. The reason for not having a prophylaxis control is that no FVIII product is globally approved 
for prophylaxis treatment.
Section 5.3 Treatment of Patients
Approximately 150 (190)1 (see section 18.5) patients are planned to be screened in order to dose 
approximately 132 (172)1 (see section 18.5) patients in the trial out of which 105 (145)1 (see section 
18.5) patients are expected to complete the prophylaxis part of the trial and a minimum of 10 
patients are expected to complete approximately 6 months in the on-demand part of the trial. 
Section 6.1 Number of Patients to be Studied
Countries planned to participate: Australia, Brazil, Croatia, Denmark, France, Germany, Hungary, 
Israel, Italy, Japan, Korea, Malaysia, Netherlands, Norway, Russia, Spain, Sweden, Switzerland, 
Taiwan, Turkey, United Kingdom and Unites States
Planned number of patients to be screened (i.e. documented informed consent) approximately: 150 
(190)1 (see section 18.5)
Planned number of patients to be started on trial product(s) approximately: 132 (172)1 (see section 
18.5) 
Planned number of patients to complete the trial approximately: ≥ 115 (155) (see section 18.5)
!
Minimum 15 patients must be 12-17 years old at screening
!
Minimum 10 patients must be in the on-demand arm
!
Minimum Approximately 105 (145)1 (see section 18.5) patients must be in the prophylaxis arm
Planned number of trial sites (approximately): 75
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
03 December 2012
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Trial ID: NN7088-3859
Version:
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EudraCT No.: 2011-001142-15
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Section 6.6 Patient Replacement
Patients withdrawn from the trial can be replaced until approximately 105 (145)1 (see section 18.5)
patients in the prophylaxis arm have had at least 50 EDs, and 10 patients have had 20 bleeding 
episodes in the on-demand and/or the prophylaxis arm.
Section 7 Trial Schedule
Planned duration of recruitment period: 12 (14)1 months
……
Planned date for LPLV: 
01-Oct (Dec) (See section 18.5)--2013
Section 18.1 Sample Size Calculation
Co-Primary Endpoint: Annualised bleeding rate in the prophylaxis arm 
……
The power calculation is sensitive to the assumed over-dispersion (OD) of 5. For this reason an 
interim analysis will be performed to evaluate the OD when approximately 90 patients have been 
recruited to prophylaxis: If the estimated OD for the full study is larger than 6, then the sample size 
will be adjusted up to 160 on prophylaxis and in that way ensure that the power holds. The sample 
size will not be increased without issuing a protocol amendment.
Section 18.5 Interim Analysis
……
If the OD estimate for the full study is greater than 6, then a decision will be taken to amend the 
protocol increase the sample size up to approximately 160 patients recruited to prophylaxis 
treatment.
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859 
Protocol/UTN: U1111-1119-7416 
EudraCT No.:2011-001142-15 
CONFIDENTIAL 
Date: 
05 December  2012 
Novo Nordisk 
Version: 
1.0 
Status: 
Final 
Page: 
1 of 5 
 
 
 
Substantial Protocol Amendment no. 11  
to Final Protocol version 4.0 dated 30 Mar 2012  
 
 
Trial ID: NN7088-3859 
pathfinder¥2  
 
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003 when 
Administered for Treatment and Prophylaxis of Bleeding in 
Patients with Haemophilia A 
 
 
Trial Phase: 3  
Applicable for Israel only 
 
 
 
 
 
 
Amendment originator:  
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties. 
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


NNC 0129-0000-1003 
Trial ID: NN7088-3859 
Protocol/UTN: U1111-1119-7416 
EudraCT No.:2011-001142-15 
CONFIDENTIAL 
Date: 
05 December  2012 
Novo Nordisk 
Version:
1.0
Status:
Final
Page: 
2 of 5 
Table of Contents  
Table of Contents ............................................................................................................................................. 2
1
Introduction including Rationale for the Substantial Protocol Amendment ....................................... 3
2
Changes ...................................................................................................................................................... 4
Appendix A 
Approval of Final Substantial Protocol Amendment no. 11 
Appendix B 
Agreement on Final Substantial Protocol Amendment no. 11 
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859 
Protocol/UTN: U1111-1119-7416 
EudraCT No.:2011-001142-15 
CONFIDENTIAL 
Date: 
05 December  2012 
Novo Nordisk 
Version: 
1.0 
Status: 
Final 
Page: 
3 of 5 
 
 
1 
Introduction including Rationale for the Substantial Protocol 
Amendment 
 
As genetic approval in Israel is a long process, it was decided for Israel that the genetic testing (or if 
performed previously, to have genotype information made available for this trial) will be indicated 
in the protocol as “Not applicable for Israel”  
 
 
Furthermore, in Israel, adolescents will not be included in the trial which has implications on 
inclusion criteria 4 section 6.2.  
 
In this substantial protocol amendment: 
x Any new text is written in italic. 
x Any text deleted from the protocol is written using strike through. 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859 
Protocol/UTN: U1111-1119-7416 
EudraCT No.:2011-001142-15 
CONFIDENTIAL 
Date: 
05 December  2012 
Novo Nordisk 
Version: 
1.0 
Status: 
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Page: 
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2 
Changes 
 
 
Section Table of Contents  
 
8.3.7.5 
FVIII genotype testing (Not applicable to Brazil and Israel)……17 
 
Section 1 
 
Summary 
 
…. 
 
Key Inclusion Criteria 
Male patients with severe congenital haemophilia A (FVIII activity <1%, according to medical 
records)  
Documented history of at least 150 EDs to other FVIII products  
Age >12 years and body weight ı35 kg (except for Croatia, The Netherlands and France and 
Israel where the lower age limit will be 18 years) 
 
Section 6.2  
Inclusion Criteria 
Informed consent obtained before any trial-related activities. (Trial-related activities are any 
procedure that would not have been performed during normal management of the subject.) 
Male patients with severe congenital haemophilia A (FVIII activity <1%, according to medical 
records)  
Documented history of at least 150 exposure days to other FVIII products   
Age >12 years and body weight ı35 kg (except for Croatia, The Netherlands and France and 
Israel where the lower age limit will be 18 years) 
Body Mass Index (BMI) d 35 
The patient and/or caregiver is capable of assessing a bleed, capable of home treatment of bleeding 
episodes and otherwise following the trial procedures 
 
CONFIDENTIAL


NNC 0129-0000-1003 
Trial ID: NN7088-3859 
Protocol/UTN: U1111-1119-7416 
EudraCT No.:2011-001142-15 
CONFIDENTIAL 
Date: 
05 December  2012 
Novo Nordisk 
Version: 
1.0 
Status: 
Final 
Page: 
5 of 5 
 
 
Section 8.3.7.5 
FVIII genotype testing (Not applicable to Brazil and Israel) 
 
 
 
Section 19.1  
Informed Consent Form for Trial Patients 
 
…  
FVIII Genotype Testing / Collection of Previous Genotype Documentation (Not applicable to 
Brazil and Israel) 
CONFIDENTIAL


Substantial Protocol Amendment
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
Su
                                                 
A Multi-national Trial Eval
0129-0000-1003 when Adm
Amendment originator:
This confidential document is the pr
disclosed without prior written appro
parties.
CONFIDENTIAL
Date:
Version:
Status:
Page:
bstantial Protocol Amendment
no 12
to Protocol, final version 5
dated 03 December 2012
 Trial ID: NN7088-3859
luating Safety and Efficacy, including Pha
ministered for Treatment and Prophylaxis o
with Haemophilia A
Trial phase: 3
Applicable to all countries 
roperty of Novo Nordisk. No unpublished information
oval from Novo Nordisk. Accessto this document mu
05 March 2013
Novo Nordisk
1.0
Final
1 of 6
rmacokinetics, of NNC 
of Bleeding in Patients 
n contained herein may be 
ust be restricted to relevant 
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.


Substantial Protocol Amendment
CONFIDENTIAL
Date:
05 March 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
2 of 6
Table of contents   
Page
Table of contents...............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes......................................................................................................................................................4
2.1
Section 2 Flow Chart .....................................................................................................................4
2.2
Section 5.1 Type of trial ................................................................................................................4
2.3
Section 7 Trial Schedule................................................................................................................4
2.4
Section 8.1 Visit Procedures..........................................................................................................5
2.5
Section 8.1.6  Transfer of Patients to pathfinder™ 3 due to Major Surgeries...............................5
2.6
Section 18.2.2 Primary Endpoint(s)...............................................................................................6
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Substantial Protocol Amendment
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Date:
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1
Introduction including rationale for the substantial protocol 
amendment
This global substantial amendment is being issued in order to extend the maximum treatment period 
with 3 months, from 24 to 27 months, due to an extension of the recruitment period. Therefore 
additional visits Visit 12a to Visit 12j have been added. 
Patients for the surgery trial, NN7088-3860 (pathfinder™ 3), are recruited via this trial where they 
must have had at least 5 exposure days (EDs) before entering the surgery trial. This amendment will 
allow the continued recruitment of major surgery patients after the recruitment of this trial has been 
completed. This is in order to ensure recruitment into the surgery trial and fulfilment of regulatory 
requirements regarding collection of major surgery data. The extension trial will not await these 
patients to complete 50 EDs before it’s initiation.
The following changes has been made to the protocol: Sections 2, 5.1, 7.0, 8.1, 8.1.6 and 18.2.2
In this substantial protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Substantial Protocol Amendment
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Date:
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2
Changes
2.1
Section 2 Flow Chart
Table 2-1
Visit number
1
2a1
2b
3
4
5
6
71, 2
8
9
10
11
1214
1313
14
Un-
schedule
d visit
Footer to table 2-1
14
Additional visits can be added between Visit 12 and 13 if needed. These will be called 
Visit 12a, Visit 12b etc. and contain the same assessments as Visit 12
2.2
Section 5.1 Type of trial
…
Treatment duration is approximately 6 months in the on-demand arm and from approximately 7 
(200 days plus screening period of 2-3 weeks) to approximately 19 months in the prophylaxis arm. 
The maximum treatment period in this trial is 24 27 months. In the prophylaxis arm, all patients will 
continue in the trial until the last patient has received at least 50 EDs of N8-GP, thus all patients in 
the prophylaxis arm will receive at least 50 EDs of N8-GP and the average exposure to N8-GP will 
be more than 1 year. Patients enrolled in pathfinder™2 with the intention of entering the 
pathfinder™3 for major surgery can be enrolled in pathfinder™2 after the end of normal 
recruitment period.  For the purpose of defining LPLV, the definition of LPLV excludes these 
patients and the opening of the extension trial will not await these patients to complete 50 EDs in 
the trial. When this trial is completed, all patients will be offered to continue treatment in the 
extension trial pathfinder™4 , if approved by country. As all patients will complete the present trial 
at the same time (or within a short timeframe) the transition of patients from pathfinder™2 to 
pathfinder™4 will be gradual and within a window of approximately 1 month.
2.3
Section 7 Trial Schedule
…
Planned date for FPFV: 
01-Feb-2 012
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Planned date for LPLV: 
01-Oct (Dec) (see section 18.5) 2013
Patients enrolled in pathfinder™ 2 with the intention of entering the pathfinder™ 3 for major 
surgery can be enrolled in pathfinder™ 2 after the end of normal recruitment period. The definition 
of LPLV excludes these patients and the opening of the extension trial will not await these patients 
to complete 50 EDs in the trial. 
The end of the clinical trial is defined as LPLV.
2.4
Section 8.1 Visit Procedures
…
All patients will complete at least 8 visits depending on when they are enrolled in the trial as the 
trial will be completed when the last prophylaxis patient has had 50 EDs. The last patient will have 
EOT visit at visit 7 after having received at least 50 EDs whereas the first patient enrolled in the 
trial will have the EOT visit at Visit 13. Therefore, the EOT visit can be all visits from visit 7 to 
visit 13. More visits may be added  between Visit 12 and 13 depending on when the last patient has 
had at least 50 EDs (or approval of Extension trial in country). These visits will be called Visit 12a, 
12b, etc.
2.5
Section 8.1.6  Transfer of Patients to pathfinder™ 3 due to Major Surgeries 
…
Upon completion of pathfinder™ 3, patients will may return to pathfinder™ 2, re-entering the 
prophylactic or on-demand treatment arm as per their prior participation in the trial. The patient will 
return to the next visit in line in Pathfinder™ 2 and the visit assessments performed at the EOT visit 
in pathfinder™3, will be used. The patient enrolled in pathfinder™2 with the intention of entering 
the pathfinder™3 for major surgery at the end of normal recruitment period in pathfinder™2 will 
not have to complete Visit 7 and reach 50 EDs before continuing into the Extension trial, if the 
Extension trial is open. Though, a Visit 13 must take place before continuing into the Extension 
trial. Furthermore, the opening of the Extension trial will not await these patients to complete 50 
EDs in the trial.
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Substantial Protocol Amendment
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Date:
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2.6
Section 18.2.2 Primary Endpoint(s)
…
Analysis of 12 months data from patients that could have had 12 months prophylaxis 
Since patients will stay in the trial until the same end date some patients will get only about 7 
months prophylactic treatment while others may get as much as more than 19 months (except for 
patients entering the trial with the intention of major surgery after the end of normal recruitment 
period). To investigate if the varying durations have any impact on the results a sensitivity analysis 
will be performed looking only at 12 months data from patients with planned trial duration of 12 or 
more months. Otherwise this analysis will be performed similarly to the primary analysis.
To investigate the effect over time the bleeding rates per month will be calculated and summarised 
numerically and graphically. For months after month 7 not all patients will be available since the 
last patients recruited will only receive about 7 months treatment (except for patients entering the 
trial with the intention of major surgery after the end of normal recruitment period). This may 
create an apparent time effect really caused by fewer and fewer patients being available. This will 
be investigated by also summarising by month only for the first 12 months data from patients that 
could have received 12 months treatment (i.e. patients recruited earlier than 12 months before 
LPLV).
CONFIDENTIAL


Substantial Protocol Amendment
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
Su
A Multi-nation
including Pharm
Administered for 
Pa
Amendment originator:
This confidential document is the pr
disclosed without prior written appro
parties.
CONFIDENTIAL
Date:
Version:
Status:
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ubstantial Protocol Amendment 
no 13, Global
to Protocol, final version 6
dated 07 March 2013
Trial ID: NN7088-3859
nal Trial Evaluating Safety an
acokinetics, of NNC 0129-00
Treatment and Prophylaxis
atients with Haemophilia A
Trial phase: 3
Applicable to all countries 
roperty of Novo Nordisk. No unpublished information
oval from Novo Nordisk. Access to this document mu
03 May 2013
Novo Nordisk
1.0
Final
1 of 44
nd Efficacy, 
000-1003 when 
s of Bleeding in 
n contained herein may be 
ust be restricted to relevant 
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Substantial Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN7088-3859
Version:
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UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
Page:
2 of 44
Table of contents
Page
Table of contents...............................................................................................................................................2
1
Introduction including rationale for the substantial protocol amendment .........................................3
2
Changes to Protocol ..................................................................................................................................4
2.1
List of Abbreviations .....................................................................................................................4
2.2
Section 1 Summary........................................................................................................................4
2.3
Section 2 Flow Chart .....................................................................................................................7
2.4
Section 3   Introduction................................................................................................................11
2.5
Section 4 Objective(s) and Endpoint(s).......................................................................................12
2.6
Section 5 Trial Design .................................................................................................................13
2.7
Section 6   Trial Population .........................................................................................................18
2.8
Section 7 Trial Schedule..............................................................................................................18
2.9
Section 8 Methods and Assessments ...........................................................................................19
2.10
Section 9 Trial Supply .................................................................................................................34
2.11
Section 10 Interactive Voice/Web Response System (IV/WRS).................................................36
2.12
Section 12   Adverse Events, Technical Complaints and Pregnancies........................................36
2.13
Section 13  Case Report Forms....................................................................................................37
2.14
Section 14  Monitoring procedures..............................................................................................37
2.15
Section 16   Computerised Systems.............................................................................................38
2.16
Section 17    Evaluability of Patients for Analysis ......................................................................38
2.17
Section 18 Statistical Considerations...........................................................................................38
2.18
Section 19 Ethics .........................................................................................................................43
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Substantial Protocol Amendment
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Date:
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Trial ID: NN7088-3859
Version:
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1
Introduction including rationale for the substantial protocol 
amendment
In the current version of the NN7088-3859 (pathfinder™ 2) protocol version 6.0 patients can be 
transferred to the extension trial NN7088-3861 (pathfinder™4) where they can continue treatment 
with N8-GP until it is commercially available.
Instead of setting up a separate trial, the extension trial will be included in the current pathfinder™ 
2 trial as an extension phase which have the following implications:
!
The trial will consist of a Main Phase (the current pathfinder™ 2 protocol) and an Extension 
Phase where patients will be offered to continue treatment with N8-GP until it is commercially 
available 
!
The Extension Phase of will consist of two parts: part 1 and 2:
o
Part 1 will investigate the efficacy and safety of a once weekly (every 7 days) prophylaxis 
dosing regimen in a sub-population. The remainder of the patients will continue with the 4 
days or on-demand treatment regimen as described in the current pathfinder™ 2 protocol 
o
Part 2 will investigate the long-term safety and efficacy of N8-GP for prophylaxis and on-
demand treatment with the possibility of individualised prophylaxis treatment (every 4, 5, 6 
or 7 days treatment) based on the patient’s individual bleeding pattern
!
The dose in the Extension Phase will be 50 U/kg in the every 4 days treatment, as in the Main 
Phase, 60 U/kg for the every 5 and 6 days treatment and 75 U/kg for the every 7 day treatment
!
The statistical section has been updated explaining the analyses of the data collected during the 
Extension Phase
!
Furthermore, minor incorrectness, misspellings and typographical errors have been corrected
In this substantial protocol amendment: 
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN7088-3859
Version:
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UTN: U1111-1119-7416
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2
Changes to Protocol
2.1
List of Abbreviations 
…
EOM
End of Main Phase
…
OD
over- dispersion
…
2.2
Section 1 Summary
…
Co-Primary Endpoints
The Incidence rate of FVIII-inhibitors ∀0.6 BU
Annualised bleeding rate for patients receiving prophylaxis treatment in the prophylaxis arm
Key Secondary Endpoint
Haemostatic effect of N8-GP when used for treatment of bleeds, assessed on a four-point scale for 
haemostatic response (excellent, good, moderate and none) by counting excellent and good as 
success and moderate and none as failure
All efficacy endpoints will be analysed and reported separately for the Main Phase, for the 
Extension Phase part 1 and for the Extension Phase part 2 of the trial. All safety endpoints will be 
reported separately for the Main Phase, for the Extension Phase part 1 and for the Extension Phase 
part 2 as well as based on accumulated data (Main Phase + Extension Phase part 1 and Main 
Phase + both Extension Phases)..The endpoint will be analysed based on all available information 
until the end of trial (EOT) visit and up to approximately 19 months.
Trial design:
This phase 3 trial is a multi-centre, multi-national, open-label, non-randomised trial evaluating 
safety, pharmacokinetics and clinical efficacy of N8-GP when used for treatment of bleeding 
episodes and for long-term prophylaxis. The trial consists of a Main Phase followed by an 
Extension Phase.
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Approximately 115 (155)1 patients must complete the trial in 2 treatment arms including at least 10 
patients in on-demand treatment and 105 (145)1 patients in prophylaxis treatment with N8-GP every 
4 days in the Main Phase of the trial. Whether a patient will receive prophylaxis treatment or on-
demand treatment is the choice of the patient and Investigator and will be decided at the screening 
visit. 
A minimum of 15 of the patients in the prophylaxis arm must undergo two PK sessions to obtain 13 
patients with two PK profiles. In order to ensure recruitment of patients for PK it is planned that the 
first patients (approximately 10) entering the prophylaxis arm must undergo PK sessions.
Main Phase: Treatment duration is approximately 7-19 months. In the prophylaxis arm, all patients 
in the prophylaxis arm will continue in the Main Phase trial until the last patient initiated in the 
prophylaxis arm has received at least 50 exposure days (EDs)2 of N8-GP, thus all patients in the 
prophylaxis arm will receive at least 50 EDs of N8-GP and the average exposure to N8-GP will be 
above 1 year. The purpose of the on-demand arm is to ensure that sufficient bleed treatment data are 
collected in the trial. The on-demand patients can switch to prophylaxis treatment after 
approximately 6 months on-demand treatment if, the prophylaxis arm is still open for enrolment, or 
continue on-demand treatment until end of trial (EOT).
When thisthe Main Phase of this trial is completed, all patients will be offered to continue treatment 
in the Extension trial Phase of the trial NN7088-3861(pathfinder™4) provided approval in the 
respective countries. 
Extension Phase: The Extension Phase will investigate the long-term safety and efficacy of N8-GP 
for prophylaxis patients on a 4-7 day dosing regimen and on-demand treatment. 
If the patients need to undergo surgery during the present trial they can switch into the surgery trial 
NN7088-3860 (pathfinder™3). Upon completion of the surgery the patients can return to the 
NN7088-38593 (pathfinder™2) trial. 
…..
Key Inclusion Criteria
!
Male patients with severe congenital haemophilia A (FVIII activity <1%, according to medical 
records) 
!
Documented history of at least 150 EDs to other FVIII products 
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Substantial Protocol Amendment
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Trial ID: NN7088-3859
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Page:
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!
Age >12 years and body weight ≥35 kg (except for Croatia, The Netherlands, France, Russia 
and Israel where the lower age limit will be 18 years)
….
Trial Product(s):
…
In the prophylaxis arm(s), each patient will receive prophylaxis treatment with a N8-GP dose of 50 
U/kg body weight (BW) every 4 days in the Main Phase. During part 1 of the Extension Phase a 
sub-group of patients will receive prophylaxis treatment every 4 day or every 7 day. In part 2 of the 
Extension Phase patients can be treated on every 4 day to once weekly (every 7 day). In most cases 
this will be home treatment with intravenous (i.v.) self-injection by the patient. Patients 
participating in the on-demand arm and patients in the prophylaxis arm will be treated with 20-75 
U/kg BW in case of bleeding episodes.
CONFIDENTIAL


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Date:
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Version:
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2.3
Section 2 Flow Chart
Table 2-1 Flow Chart for Patients on Prophylaxis and On-Demand Treatment in Main Phase
Visit number
1
2a1
2b
3
4
5
6
71, 2
8 
9 
10 
11 
1214
1313
14
Un-
sched
uled 
visit 
Time of visit
Weeks
2w  
prior to 
visit 2a
0
4 days 
after Visit 
2
4w
8w
12w
20w
28w 
36w
44w
52w
60w
68w
76w 
EO
M
Follow
-up
Visit window
Weeks
+1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
X
X15
…
Footer
Description
1
Please refer to Table 2-2 for the patients that need to undergo PK
2
Patients in the on-demand arm can switch into prophylaxis treatment after 6 months treatment
3
Confirmation of screening visit 1 in- and exclusion criteria
4
If applicable, i.e. following patient consent and in accordance with local law
5
To be measured before dosing and 30 min (±10min) after dosing.  
6
Antibody samples will only be drawn from patients in the on-demand arm at Visit 3-13 if they have received treatment since last visit
7
A wash-out period of minimum 96 hrs is needed before the sample (except visit 1 and visit 2a where wash out is minimum 72 hours)
8
Only in case of an unexpected allergic/anaphylactic reaction
9
Trough to be sampled before dosing and recovery to be sampled 30 min (± 5min ) after dosing only for prophylaxis patients
10
Only to be taken if HIV status is positive
11
From visit 2a -13 only BW will be measured 
12
From visit 3-12, only for patients in the prophylaxis arm
13
Assessments to be performed at the EOTEOM visit. The EOTEOM visit (Visit 13) can take place at any time after be any visit from visit 7 to visit 13 depending on when the patient entered the 
trial. The Main Phase will be terminated when the last patient has received 50 exposure days.
14
Additional visits can be added between Visit 12 and 13 if needed. These will be called Visit 12a, Visit 12b etc and contain the same assessments as Visit 12
15
Addendum Informed Consent on comparison of data from pathfinder™ 1or guardian™ trials


Substantial Protocol Amendment
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Table 2-3
Flow Chart for Patients on Prophylaxis and On-Demand Treatment in Extension Phase
Part 1
Part 2
Visit number
1415
15
16
1715
18-n1,15
EOT
Time of visit
Weeks
same date 
as V13
8w2
16w2
24w2
12w3
12w4
Follow-
up
Un-
scheduled 
Visit14
Visit window
Weeks
±2
±2
±2
±2
±2
Informed Consent
x
Randomisation considerations
x
Withdrawal criteria
x
x
x
x
x
x
Concomitant medication
x
x
x
x
x
x
Date and time of last coagulation 
factor administration
x
x
x
x
x
x
EFFICACY
Bleeding episodes (rating severity)
x 
x
x
x
x
x
x
SAFETY
Adverse events
x
x
x
x
x
x
x
ECG
x
x12
x
x
Physical examination
x
x6
x
x
Vital signs
x
x
x
x
x
x
x
Antibodies
   FVIII inhibitors7,8
x
x
x
x
x
x
x
   N8-GP binding antibodies7,8
x
x
x
x
x
x
x
   IgE, IgG, HCP5
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
   Lupus anticoagulant
x


Substantial Protocol Amendment
UTN: U1111-1119-7416
Date:
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Status:
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Version:
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Part 1
Part 2
Visit number
1415
15
16
1715
18-n1,15
EOT
Time of visit
Weeks
same date 
as V13
8w2
16w2
24w2
12w3
12w4
Follow-
up
Un-
scheduled 
Visit14
Visit window
Weeks
±2
±2
±2
±2
±2
   APTT
x
   von Willebrand factor
x
FVIII activity9
   FVIII trough level
x
x
x
x
x
x
   FVIII recovery10
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Hepatitis
x
HIV13
x
   Viral Load
x
   CD4+ T cells
x
Urinalysis
x
OTHER ASSESSMENTS
Body measurements11
x
x
x
x
x
x
PRO questionnaires
x
x12
x
x
TRIAL MATERIAL
Administration of trial product10
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
IV/IWRS call
x
x
x
x
x
x
x
    Dispensing trial product
x
x
x
x
x
x
Dosing regimen /change
x
x
x
x
x
x
x
Dispensing trial card
x
REMINDERS


Substantial Protocol Amendment
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Date:
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Version:
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Part 1
Part 2
Visit number
1415
15
16
1715
18-n1,15
EOT
Time of visit
Weeks
same date 
as V13
8w2
16w2
24w2
12w3
12w4
Follow-
up
Un-
scheduled 
Visit14
Visit window
Weeks
±2
±2
±2
±2
±2
Affirmation statement
x
x
End of trial
x
x
eDiary training
x
x
x
x
x
x
eDiary data review
x
x
x
x
x
x
Home treatment training
x
x
x
x
x
x
Footer
Description
1
n = visit number from 19 and onwards
2
weeks after Visit 14
3
weeks apart
4
weeks since last visit
5
Only in case of expected unexpected allergic/anaphylactic reaction
6
Only every second visit (V19, V21, V23….)
7
Antibody sample will only be drawn from patients in the on-demand arm if they received treatment since last visit
8
A wash-out period of minimum 96 hrs is needed before the sample
9
Trough to be sampled before dosing and recovery to be sampled 30 min ( ±5 min) after dosing, only for prophylaxis patients
10
Only for patients in prophylaxis treatment
11
Only height every year for patients below 18 years, otherwise only BW
12
Only yearly (at V21, V25…)
13
Only to be taken if HIV status is positive
14
Assessment during unscheduled visit are not mandatory but can be performed
15
It is recommended to contact patients approximately 4 weeks after change of regimen (see section 8.14)


Substantial Protocol Amendment
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2.4
Section 3   Introduction
3.1 Basic Information
….
3.1.4 Risk and Benefits.
….
To minimise the switching between FVIII products, the patients, will upon completion of the 
presentMain Phase of the trial, be offered to continue treatment with N8-GP in the Extension Phase 
of the trial (pathfinder™ 4), where patients have the opportunity to continue with N8-GP treatment 
until commercially availability2.
3.2    Rationale for the Trial
This trial is part of a clinical development programme that at present includes a completed phase 1 
trial (pathfinder™1), the present pivotal (including Main and Extension Phase) phase 3a trial 
(pathfinder™2),  an extension phase 3b trial (pathfinder™4) and a surgery phase 3a trial 
(pathfinder™3). The phase 3 trials are offered as one package to each investigational site to ensure 
that patients are offered to continue N8-GP until commercially available and patients in need of 
surgery can undergo surgery without having to switch product. The clinical programme is illustrated 
in Figure 3-1.
In the preceding phase 1 trial (pathfinder™1), 26 patients with haemophilia A had one PK session 
with their current FVIII product followed by one PK session with N8-GP. The trial was completed 
on 18 April 2011 and the results formed the basis for the doses selected in the present trial. 
The rationale for this trial is to investigate the safety and efficacy, including PK and long-term 
safety of N8-GP in Haemophilia A patients from 12 years of age. In the Main Phase of the trial the 
safety and efficacy of an every 4 day prophylaxis dosing regimen will be investigated. The main 
objective of the Extension Phase part 1 is to investigate the safety and efficacy of once weekly 
prophylaxis dosing of N8-GP in a subset of patients. This option will only be available to patients 
on prophylaxis treatment having a low bleeding rate on an every 4 days dosing regimen in the Main 
Phase of the trial. The main objective of part 2 of the Extension Phase is to collect long term safety 
and efficacy data
2 For UK only: The end of the Extension Phase trial will be defined by exact date and not when commercially available
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Substantial Protocol Amendment
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
New figure:
To be deleted:
Figure 3-1 Overview of the pa
Arrows indicate possible trans
may also be enrolled in the com
2.5
Section 4 Objective(s
….
4.2 Endpoint(s)
4.2.1      Co-Primary Endpoi
The incidence rate of FVIII-in
Annualised bleeding rate for p
CONFIDENTIAL
Date:
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athfinder™clinical trial programme.
sfer of patients between trials. Patients compl
ming trials if found eligible.
s) and Endpoint(s)
nts
nhibitors ∀0.6 BU
patients receiving prophylaxis treatment in the
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eting the phase 1 trial 
e prophylaxis arm
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….
4.2.2.2 Additional Supportive Efficacy Endpoints
! Consumption of N8-GP (number of infusions and U/kg) per bleed 
! Consumption of N8-GP (number of infusions and U/kg per month and per year) during 
prophylaxis and on-demand treatment
! Haemostatic effect as measured by recovery and trough levels FVIII:C (in all patients receiving 
prophylaxis treatment in the prophylaxis treatment arm)
! Patient Reported Outcomes and Health Economic Endpoints
#
PRO scores and their changes in PRO scores in from baseline to the end of the trial phases
#
Bleed related health economic resource use and patient/caregiver burden 
…..
4.2.3 Exploratory Endpoints
Incidence of binding, non-inhibitory antibodies to N8-GP/ turoctocog alfa
4.2.4 Timeframe for evaluation of the endpoints
The pharmacokinetic endpoints will be based on assessments performed from 1 hour prior to and 
up to 96 hours after administration for visit 2a and Visit 7. 
All efficacy endpoints will be analysed and reported separately for the Main Phase, for the 
Extension Phase part 1 and for the Extension Phase part 2 of the trial. All safety endpoints will be 
reported separately for the Main Phase, for the Extension Phase part 1 and for the Extension Phase 
part 2 as well as based on accumulated data (Main Phase + Extension Phase part 1 and Main 
Phase + both Extension Phases).
2.6
Section 5 Trial Design
5.1 Type of Trial
This phase 3 trial is a multi-centre, multi-national, open-label, non-randomised trial evaluating 
safety, pharmacokinetics and clinical efficacy of N8-GP when used for treatment of bleeding 
episodes and for long-term prophylaxis. The trial consists of a Main Phase followed by an 
Extension Phase.
A minimum of 115 (155) (see section 18.5) patients must complete the trial including at least 10 
patients in on-demand treatment and 105 (145) (see section 18.5) patients in prophylaxis treatment 
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with N8-GP every 4 days in the Main Phase of the trial. In order to ensure recruitment of patients 
for PK it is planned that the first patients (approximately 10) entering the prophylaxis arm must 
undergo PK sessions. Whether a patient will receive prophylaxis treatment or on-demand treatment 
is non-randomised and will be the choice of the patient and Investigator. This will be based on 
medical needs and decided at the Screening visit. For the US, recruitment will open for the on-
demand arm before enrolling patients in the prophylaxis arm, whereas both arms will open 
concurrently at non-US sites. 
The distribution of patients in the Main Phase of the trial will be as follows:
…
Treatment duration is approximately 6 months in the on-demand arm and from approximately 7 
(200 days plus screening period of 2-3 weeks) to approximately 19 months in the prophylaxis arm. 
The maximum treatment period in the Main Phase of this trial is 24 27 months. In the prophylaxis 
arm, all patients will continue in the Main Phase trial until the last patient initiated in the 
prophylaxis arm has received at least 50 EDs of N8-GP, thus all patients in the prophylaxis arm will 
receive at least 50 EDs of N8-GP and the average exposure to N8-GP will be more than 1 year. 
Patients enrolled in pathfinder™ 2 with the intention of entering the pathfinder™ 3 for major 
surgery can be enrolled in pathfinder™2 after the end of normal recruitment period. For the purpose 
of defining LPLV, the definition of LPLV in the Main Phase excludes these patients and the 
opening of the Extension Phase will not await these patients to complete 50 EDs in the trial. When
the Main Phase is completed, all patients will be offered to continue treatment in the Extension trial
Phase, if approved by country. As all patients will complete the Main Phase at the same time (or 
within a short timeframe) the transition of patients from the Main Phase to the Extension Phase, 
will be gradual and within a window of approximately 2 months following the patient’s visit 
schedule. When the Extension Phase has opened and has been approved in the country the patient 
must at the next visit end the Main Phase (Visit 13) and continue into the Extension Phase (Visit 
14).
The distribution of patients in the Extension Phase of the trial will be as follows:
The Extension Phase of the trial includes two parts: part 1 and part 2. In part 1, patients who were 
on prophylaxis treatment every 4 days dosing with N8-GP during the Main Phase of the trial and 
with a 0-2 bleeding episodes during the last 6 months (180 days) before entering the Extension 
Phase, will be offered to be randomised to every 7 days or every 4 days treatment (2:1 
randomisation). Patients with 3 or more bleeding episodes within the last 6 months of the Main 
Phase before entering the Extension Phase as well as patients with low bleeding rates who are 
unwilling to be randomised will continue with the same treatment regimen as in the Main Phase of 
the trial. Recruitment into the randomisation sub-group in the Extension Phase part 1 will stop 
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approximately at mid-May 2014, hereafter also patients with a low bleeding rate will continue the 
same treatment as in Main Phase.  
In the part 2 patients can continue being on prophylaxis but can change between dosing regimens 
according to their bleeding episode pattern. When patients randomised to either every 4 or 7 day 
regimen complete the part 1, the part 2 will open also for patients not having completed the 6 
months treatment in part 1.
Patients treated on-demand in the Main Phase will continue with the on-demand regimen.
Furthermore, if the patients need to undergo surgery during the present trial they can switch into the 
surgery trial pathfinder™3 and upon completion of the surgery they can return to the pathfinder™23
trial. Recruitment into the surgery trial pathfinder™3 will begin after successful treatment of 
bleeding episodes with N8-GP in at least 5 patients in the pivotal trial pathfinder™2. The surgery 
trial will not be initiated until at least 20 bleeding episodes in at least 10 patients are treated with 
N8-GP in the present trial.
5.2     Rationale for Trial Design
The purpose of the prophylaxis arm in the Main Phase is to provide sufficient exposure to N8-GP to evaluate 
immunogenicity and to provide efficacy data from 50-100 EDs of prophylaxis treatment with N8-GP in 
approximately 105(145) (see section 18.5) patients with severe haemophilia A >12 years. The reason for not 
having a prophylaxis control is that no FVIII product is globally approved for prophylaxis treatment.
…
The purpose of continuing all patients in the prophylaxis arm in the Main Phase of the trial until the 
last patient has completed at least 50 EDs of N8-GP is to ensure that the average exposure to N8-GP 
will be above 1 year for a considerable portion of the patients. 
…
For clinical efficacy of N8-GP in the prevention of bleeding episodes, historical data on annualised 
bleeding frequency during on-demand treatment and prophylaxis will be used for comparison. The 
historical data derive from a recent review by an independent board of haemophilia treaters within 
the Swedish Council on Health Technology Assessment, including all published clinical studies on 
treatment of severe haemophilia A during the last 25 years which were comprised of at least 20 
patients10. The review selected in total 37 separate studies of haemophilia A replacement therapy, 
seven of which contained data on bleeding frequency in an adult and/or adolescent population11.
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The part 1 of the Extension Phase will include 4 treatment arms: prophylaxis treatment every 4 day, 
a randomised sub-group of treatment every 4 or every 7 day, or on-demand treatment. The primary 
aim of part 1 of the Extension Phase is to investigate the safety and efficacy of every 7 day dosing of 
N8-GP. In the interest of patient safety this treatment will be offered only to a sub-set of patients 
who have low bleeding rates (see section 5.1) from prophylaxis treatment in the Main Phase. In 
order to control for season effects, subjects will continue with every 4 day dosing as control group 
in the randomised group. Allocation to the treatment arms will be done by randomisation. Subjects 
who do not wish to be randomised can continue in the Extension Phase part 1 with the treatment 
regimen from the Main Phase. This ensures that patients with low bleeding rate, who are not 
willing to be on every 7 day treatment, can stay in the trial in the non-randomised arm.
Part 2 of the Extension Phase will consist of a single prophylaxis treatment arm where it will be 
possible to individualise treatment according to recommended guidelines (see section 5.3) taken the 
patients bleeding pattern into account. The single treatment arm design has been chosen as the 
primary objective is to obtain long term safety and efficacy data in more daily life setting.
On demand patient will throughout the Extension Phase continue as previously and will contribute 
with long term safety and efficacy data.
Patients can leave the trial at the End-of-Main Phase Visit without being considered as 
withdrawals. If leaving the trial at any other visits than End-of- Main Phase or End-of-Trial the 
patients will be considered as withdrawals. 
….
5.3.1 Prophylaxis
Main Phase: In the prophylaxis arm, one single bolus dose of 50 U/kg BW of N8-GP is 
administered intravenously every 4 days (96 hours interval). The dose chosen is based on phase 1 
data from the pathfinder™1 trial and is chosen to ensure a trough level of >1% FVIII:C activity in 
the majority of patients in the prophylaxis arm. During treatment a shortening of the dosing interval 
for prophylaxis to twice weekly may be undertaken at the Investigator’s discretion, if deemed 
necessary for the individual patient (see section 5.3.2). If the dosing regimen is changed to twice 
weekly, doses should be separated with at least 3 calendar days and no more than 4 calendar days.
Other changes of the dose or dosing interval for prophylaxis are not allowed within the trial. 
However, extra doses of N8-GP will be administered if a patient experiences a treatment requiring 
bleeding episode or in case of minor surgery.
Extension Phase part 1: The prophylaxis dose of N8-GP is administered in the non-randomised 
group every 4 days or in the randomised group every 4 day or every 7 day depending on which 
treatment arm the patient is allocated to. Based on the bleeding pattern, the Investigator may 
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change the every 7 day prophylaxis treatment to an every 4 day treatment regimen (the non-
randomised arm), but changing vice versa is not permitted. The recommended doses to treat a 
bleeding episode will be the same as in the Main Phase. Patients moving from the randomised 
prophylaxis treatment every 7 day to the non-randomised prophylaxis treatment every 4 day will not 
be replaced in the randomisation distribution. The twice weekly regimen will only be allowed in the 
Extension Phase for patients who already in the Main Phase changed to twice weekly.
Extension Phase part 2: During this period it is possible to adjust the prophylaxis treatment of 
patients to an individualised regimen. Treatment regimens ranging from once weekly to every 4 day 
will be allowed: every 4 day, every 5 day, every 6 day or every 7 day. For deciding to change a 
regimen it is strongly recommended to follow below guidelines for change of regimen:  
!
0-2 bleeding episodes within last 6 months on same regimen would allow a less frequent dosing 
interval to a lowest frequency of every 7 day
!
3 or more bleeding episodes within last 6 months on same regimen allows to stay on regimen or 
change to a more frequent regimen to a highest frequency of every 4 day
!
Change of regimen can only take place after being on the same regimen for at least 6 months
Clinical judgement has to be applied in order to avoid increased risk to the subject’s safety and 
must always overrule guidelines when deemed necessary by the Investigator.
The dose for the Extension Phase part 1 and 2 will be:
!
50 U/kg BW of N8-GP for prophylaxis treatment every 4 day
!
60 U/Kg BW of N8-GP for prophylaxis treatment every 5 and 6 day
!
75 U/Kg of N8-GP for prophylaxis treatment every 7 day
….
5.3.5  Patients Continuing Into Other N8-GP Trials the Extension Phase
All patients in the prophylaxis arm will continue in the Main Phase of the trial until the last patient 
initiated in the prophylaxis arm has received at least 50 EDs. After completion of the Main Phase 
trial, all patients will be offered to continue prophylaxis or on-demand treatment in the Extension 
Phase of the trial pathfinder™ 4 for up to approximately two years or until N8-GP becomes 
commercially available4 in the patient’s country. (For UK only: the end of extension trial will be 
defined by exact date and not when commercially available.) As all patients will complete the Main 
Phase present trial at the same time the continuation transition of patients from the Main Phase to 
the Extension Phase pathfinder™ 2 th pathfinder™ 4will be gradual and within a window of 
approximately 12 months depending on approval of the Extension Phase in the country and of 
4 For UK only: The end of the Extension Phase will be defined by exact date and not when commercially available.
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patients’ next scheduled visit. Please refer to Figure 3.1 for an overview of the flow of patients 
between trials in the clinical development programme.
If the N8-GP programme is terminated or if the health authorities in the patient’s country reject the 
marketing application or if the commercialisation of N8-GP is not possible in the country, the 
extension trial will be stopped and treatment with N8-GP will be ended. All dData collected up to 
the point where the patient is transferred to the extension trial will be used in the data analysis in the 
trial.
2.7
Section 6   Trial Population
6.1 Number of Patients to be Studied
Countries planned to participate: Australia, Brazil, Bulgaria, Croatia, Denmark, France, Germany, 
Hungary, Israel, Italy, Japan, Korea, Malaysia, Netherlands, Norway, Russia, Spain, Sweden, 
Switzerland, Taiwan, Turkey, United Kingdom and United States 
2.8
Section 7 Trial Schedule
….
Planned date for FPFV: 
01-Feb-2012
Planned date for LPLV: 
03-Dec-2018 01-Oct(Dec)(see section 18.5) 2013
Patients enrolled in pathfinder™ 2 with the intention of entering the pathfinder™ 3 for major 
surgery can be enrolled in pathfinder™ 2 after the end of normal recruitment period until 
pathfinder™ 3 has 15 completed surgeries. The definition of LPLV of the Main Phase excludes 
these patients and the opening of the extension trial will not await these patients to complete 50 EDs 
in the trial. 
The end of the clinical trial is defined as LPLV.
Planned completion of clinical trial report: within 6 months after LPLV. Primary completion date 
will be at the end of the part 1 of the Extension Phase in the last quarter of 2014.
…
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2.9
Section 8 Methods and Assessments
8.1 Visit Procedures
New figure:
To be deleted:
Figure 8-1 Overview of visits and home treatment periods in the Main Phase of the trial
All patients will complete at least 8 visits depending on when they are enrolled in the trial as the 
Main Phase of the trial will be completed when the last prophylaxis patient has had 50 EDs. 
Thereafter the Extension Phase will be initiated when approved in the country. All patients need to 
complete at least The last patient will have EOT visit at Visit 7 after having received at least 50 
EDs whereas the first patient enrolled in the trial will have the visits up to EOT visit at Visit 13. 
Therefore, the Visit 13 -End-of-Main Phase EOT visit can take place at any time after be all visits 
from Visit 7 during the Main Phase provided that the last patient has received 50 EDs to visit 13. 
More visits may be added between Visit 12 and 13 (EOM) depending on when the last patient has 
had at least 50 EDs (or approval of Extension Phase trial in country). These visits will be called
Visit 12a, 12b etc. To complete the Main Phase all patients need to have a Visit 13- End-of-Main 
Phase visit.
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New figure:
Figure 8.2
Overview of visits and home treatment periods in the Extension Phase part 1 and 
part 2
OD = on-demand, PPX = prophylaxis, BE = bleeding episodes, ® = randomisation, Q4D = 
prophylaxis every 4 day, Q7D = prophylaxis every 7 day, w = weeks.
The Extension Phase part 1 will for a patient last for 24 weeks, and the Extension Phase part 2 will 
last until the product become available on market in each country or a defined exact date 
depending on country.
The Main Phase of the trial includes the following visits:
! Visit 1: Screening visit
! Visit 2a and 2b: Visits at the site.
-
All patients will have their first and second dose administered at the site. 
-
Patients in the prophylaxis arm undergoing PK evaluation will undergo first PK 
evaluation at Visit 2a.  
! Visit 3-1213: Visits at the site. 
-
Patients in the prophylaxis arm will be dosed during the visits
-
Patients in the prophylaxis arm undergoing PK evaluation will undergo second PK 
evaluation at Visit 7
-
Patients in the on-demand arm will not be dosed during the visits
! Visit 13: End-of-Main Phase visit. Visit at the site
-
End of Main Phase assessments (No patients will be dosed as part of the visit)
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The Extension Phase will include the following visits:
!
Visit 14 (same date as Visit 13 (EOM)): patients are enrolled in Extension Phase
!
Visit 15+16: Visits at the site
-
Patients in the randomised treatment arms will be dosed during the visits
-
Patients on prophylaxis NOT in the randomised treatment arm will be dosed during the 
visits
-
Patients on the on-demand treatment arm will not be dosed during the visits
! Visit 17-n : Visit at site
-
Dosing regimen will be considered
-
Patients on prophylaxis regimen will be dosed at visits
-
Patients on the on-demand arm will not be dosed during the visits
! Visit EOT: Visit at site
-
End of trial assessments, no treatment
Follow-up visit (FU) (not shown in 8.1 and 8-2): only for patients withdrawn due to development 
of FVIII inhibitors
…..
Informed Consent Procedure: The patient and/or the patient’s legally acceptable representative 
(LAR) will receive verbal and written information about the trial prior to conduct of any trial related 
procedures/activities. The information will include e.g. descriptions of N8-GP, the procedures 
involved, the practical consequences of participating, responsibilities and rights while participating 
in the trial including the possible advantages and disadvantages. Qualified site staff will ensure that 
patients and caregivers are fully informed both verbally and in writing. Patients and LAR(s) will 
have the opportunity to ask questions and have ample time to consider participation. If the patient 
wishes to participate in the trial, the patient and/or the patients LAR(s) will be requested to sign and 
date the Informed Consent Form. If the patient is a minor, he can in addition sign a child assent 
form, as per local regulations. When signing consent for the Main Phase of this trial the patient and 
/or the patients LAR(s) should be informed about the surgery trial and the Extension Phase of the
trials as well.
It must be emphasised that any change in a patient’s normal treatment routine is a trial-related 
activity, which is not allowed before the patient has consented to participate in the trial. For 
example: If a patient is taken off prophylaxis to allow for 72 hours without FVIII treatment before 
screening and the interval between the patient’s normal prophylaxis doses is less than 72 hours, it is 
a trial related activity. In such case, it is essential that the informed consent procedure is completed 
prior to the trial related activities undertaken at the screening visit.
Before entering the Extension Phase of the trial a new Informed Consent covering the Extension 
Phase part 1 and 2 must be obtained following the above described procedure. If the patient is part 
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of the group of patients that can be randomised to either prophylaxis treatment every 4th day or 
every 7th day in the part 1 of the Extension Phase, the randomisation procedure must be discussed 
with the patient and an addendum to the informed consent must be signed if the patient agrees to be 
randomised.
Patients having previously participated in Novo Nordisk trials; in guardian™ trials (NN7008-3543 
+ 3545 + 3568) and/or pathfinder™1 (NN7088-3776), must be asked if they give their acceptance 
to compare data from the guardian™/pathfinder™ 1 trial(s) with data from this trial. If patients 
agree they must sign a separate addendum to the informed consent. This must be asked also to 
patients not continuing in the Extension Phase as part of Visit 13. 
For screening failures: Screening failures are defined as patients who have signed the Informed 
Consent Form for the Main Phase of the trial, but fail to comply with the inclusion and exclusion 
criteria or if patients withdraw consent prior to dosing. Data in respect to the screening visit (Visit 
1) will be entered in the screening failure form in the electronic case report form (eCRF) preferably 
3 days after data are available. A screening failure call must be made in the interactive voice/web 
response system (IV/WRS). Serious and non-serious AEs from screening failures will be entered by 
the Investigator in the eCRF, and consequently transferred to the clinical database. When the trial 
related procedures have been finalised for screening failures, no more AEs should be entered in the 
eCRF. Follow-up of AEs should be made according to section 12.
Screening failures may be re-evaluated for participation in the trial and is allowed once. This will 
require a renewed informed consent to be obtained from the patient, a new eCRF should be started 
and the patient should be allocated a new patient number.
For withdrawn patients: Withdrawn patients are defined as patients who meet the withdrawal 
criteria after dosing, see section 6.5. In case a patient is prematurely withdrawn from the trial the 
Investigator must aim at undertaking procedures for the last visit (EOM or EOT visit) as soon as 
possible, if possible. The primary reason (AE, non-compliance with protocol or other) for 
discontinuation must be specified in the eCRF. The end-of-trial form must be completed, and final 
drug accountability must be performed even if the patient is not able to attend. All data collected in 
the period the patient participated in the trial will be entered into the eCRF. A withdrawal session 
must be performed in IV/WRS. If a patient is withdrawn due to inhibitor development, the patient 
must be followed according to section 8.1.4.
Patients can leave the trial at Visit 13 (EOM) at the end of the Main Phase, without being 
considered as withdrawals. If leaving the trial at any other visits than EOM and EOT during the 
Main Phase and during the Extension Phase the patients will be considered as withdrawals. 
End-of-Main Phase of the trial visit (Visit 13): The EOT End-of-Main (EOM) Phase of the trial
visit can take place after be all visits from Visit 7 until Visit 1213 depending on when the patient is 
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enrolled in the trial. For patients continuing in the Extension Phase of the trial (pathfinder™4) the 
EOM of the trial EOTvisit will take place the same day as the also be Visit 14 in the Extension 
Phase part this trial1. If patients end their participation in the trial at the EOM Phase of the trial 
visit, this is not considered as a withdrawal, and the EOT form should be filled in. If a patient is 
withdrawn prior to completion of the Main Phase of the trial a EOM visit should be scheduled if 
possible and EOT form should be filled in.  
End of Trial visit: When a patient ends trial participation of the Extension Phase the assessments 
in the End-of-Trial visit should take place and EOT form must be filled in. If a patient is withdrawn 
prior to completion of the trial If a patient is withdrawn during the Extension Phase, all attempts 
must be made to schedule an EOT visit for the patient. The EOT form should be signed at the EOT 
visit. If a patient continues in FU the EOT form will be signed at the FU Visit.
….
8.1.2 Visit Schedule for Patients on Prophylaxis not Undergoing PK Evaluation and for 
Patients on On-Demand treatment
….
The samples taken post-dose must not be taken from the same vein as previously used for 
administration of N8-GP.
Patients will be provided with an eDiary and will be carefully trained in the use of this eDiary 
including instruction in reporting details of bleeding episodes and prophylactic including doses 
administered at all visits after visit 2b.
At Visit 2a the following assessments will be performed and/or recorded in the eCRF 
! Confirmation of inclusion and exclusion criteria, see section 6.2 and 6.3
! Withdrawal criteria, see section 6.5
! Concomitant medication, see section 11
! Check date and time of last coagulation factor administration 
! AEs: before and after dosing, see section 12.1
! Body measurements (weight only), see section 8.4.2
! Physical examination, see section 8.3.3
! Vital signs (before dosing and 30 min (∃10 min) after dosing), see section 8.3.4
! eDiary training, see section 5.3 and 8.4.3
! eDiary dispensing
! Dispensing of N8-GP in IV/WRS, see section 10
….
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Blood sampling for central laboratory assessments
! Biochemistry, see section 8.3.7.1
! Coagulation related parameters, aPTT and INR before dosing and  30 min (∃10 min) after 
dosing, see section 8.3.7.2
! FVIII activity, trough and recovery, i.e. before dosing and  30 min (∃5 min) after dosing, see 
section 8.3.7.3
! FVIII inhibitors, see section 8.3.2.2
! N8-GP binding antibodies, see section 8.3.2.1
Visit 2b: Patients will be provided with an eDiary and will be carefully trained in the use of this 
eDiary including instruction in reporting details of bleeding episodes and prophylactic treatment 
including doses administered at all visits after Visit 2b.
At Visit 2b (4 days after first dose) the following assessments will be performed and/or 
recorded in the eCRF 
! Withdrawal criteria, see section 6.5
! Concomitant medication, see section 11
! AEs: before and after dosing, see section 12.1 
! Drug accountability for the trial medication dispensed or returned from the previous visits must 
be recorded in IV/WRS, see section 10.
! Dispensing of N8-GP in IV/WRS, see section 10
! e-Diary training, see section 5.3  and 8.4.3
! e-Diary dispensing 
! Home treatment /eDiary training, see section 5.3 and 8.4.3
! Administration of second dose of N8-GP (patients to be observed for at least 1 hr after 
administration for adverse reactions) 
! eDiary data review and rating severity of bleeding episodes, see section 8.2.1
Reminders:
! An appointment for Visit 3 (4 weeks ± 1 week after Visit 2a) should be made.
! Withhold N8-GP minimum 96 hours prior to next visit 
8.1.2.1  Visit 3-13 for Patients on Prophylaxis not Undergoing PK Evaluation and Patients on 
On-Demand Treatment
The home treatment period for patients on prophylaxis and on-demand is approximately 4 weeks ± 
1 week between Visit 3, 4 and 5 and approximately 8 weeks ± 1 weeks between Visit 6, 7, 8, 9, 10, 
11, 12 and 13, see Table 2-1. At the EOT visit Visit 13 EOM Phase the patients will not be dosed at 
the site as part of the visit.
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Antibody samples will only be drawn from patients in the on-demand arm at Visit 3-13 if they have 
received treatment during the home treatment period since last visit
The samples taken post dose, must not be taken from the same vein as previously used for 
administration of N8-GP.
The following will be performed and/or recorded in the eCRF:
! Withdrawal criteria, see section 6.5
! PRO questionnaires, EOT Visit 13 (EOM) only, see section 8.4.5
! Concomitant medication, see section 11
! Check date and time of last coagulation factor administration, see section 8.4.3
! AEs: Since previous visit, see section 12.1
! Body measurements (weight only),  see section 8.4.2
! Physical examination (only at Visit 5, 9 and EOT visit Visit 13 (EOM)), see section 8.3.3
! Vital signs, (before dosing), see section 8.3.4
! ECG (only at EOT visit Visit 13 (EOM)), see section 8.3.5
! e-Diary data review and rate severity of bleeding episodes, see section 8.2.1
! Home treatment/e-Diary training (not at Visit 13 EOMT)
! N8-GP administration, not at EOT visit Visit 13 (EOM) and not for on-demand patients (Stop 
time of injection must be recorded in the eCRF, this corresponds to time “0”)
! Drug accountability for the trial medication dispensed or returned from the previous visits must 
be recorded in IV/WRS, see section 10
! Dispensing of N8-GP for clinic dosing/home treatment must be performed via IV/WRS (except 
at EOT visit Visit 13 (EOM)), see section 10
! EOT form (at last visit, only if not continuing into Extension Phase)
! Affirmation statement (at EO only, only if not continuing into Extension Phase)
! Completion of Main Phase session in IV/WRS (at EOMT only)
! Return eDiary (at EOT only, only if not continuing into Extension Phase)
! Informed Consent for addendum on data comparison (at EOM only)
Blood sampling for local laboratory assessments:
! Haematology (to be taken within 1 hour prior to dosing), see section 8.3.6.1
Blood sampling for central laboratory assessments:
! Biochemistry, see section 8.3.7.1
! FVIII activity (trough level and recovery), i.e. before dosing and 30 min (∃5 min) after dosing 
8.3.7.3. Recovery not to be done in the on-demand arm and not at EOT visit Visit 13 (EOM), see 
section 8.3.7.3
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Date:
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Trial ID: NN7088-3859
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! FVIII inhibitors, see section 8.3.2.2
! N8-GP binding antibodies, see section 8.3.2.1
! FVIII genotype (only Visit 3). If documentation is not available in the patient chart and as 
allowed per local law. In addition, the Investigator, patient or LAR has the right to refuse, see 
section 8.3.7.5
Reminders for each visit: 
! An appointment for the next visit should be made.
! Withhold N8-GP minimum 96 hours prior to next visit 
! For patients continuing in the Extension Phase of the trial pathfinder™ 4, the EOT EOM Visit 
(Visit 13) will take place at the same day asbe the first visit in the Extension Phase of the trial 
(Visit 14), therefore informed consent must be obtained prior to EOT EOM Visit.
…..
8.1.3.1 Visit 2a for Patients on Prophylaxis Undergoing PK Evaluation
….
The samples taken 30 min post dose must not be taken from the same vein as previously used for 
administration of N8-GP. The lines/tubes must be flushed immediately after administration of the 
trial product.
Patients will be provided with an eDiary and will be carefully trained in the use of this eDiary 
including instruction in reporting details of bleeding episodes and prophylactic including doses 
administered at all visits after visit 2b.
The following will be performed and/or recorded in the eCRF:
Assessments to be made before the PK session at the day of dosing
! Confirmation of inclusion and exclusion criteria, see section 6.2 and 6.3
! Withdrawal criteria, see section 6.5 
! Concomitant medication at all time points during PK, see section 11
! Check date and time of last coagulation factor administration (see section 8.4.3) 
! AEs, see section 12.1
! Body measurements (weight only), see section 8.4.2
! Physical examination, see section 8.3.3
! Vital signs, see section 8.3.4
! eDiary dispensing
…..
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Substantial Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN7088-3859
Version:
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Laboratory assessments are to be analysed at central Laboratory
Training
! eDairy training, see 5.3 and 8.4.3
8.1.3.2 Visit 2b for Patients on Prophylaxis Undergoing PK Evaluation
The second dose of N8-GP will be administered at the site after the last PK sample is taken.
Patients will be provided with an eDiary and will be carefully trained in the use of this eDiary 
including instruction in reporting details of bleeding episodes and prophylactic treatment including 
doses administered at all visits after Visit 2b.
Four days after first dose the following assessments will be performed and/or recorded in the 
eCRF 
! Withdrawal criteria, see section 6.5
! AEs: before and after dosing, see section 12.1
! e-Diary training, see section 5.3  and 8.4.3
! e-Diary dispensing
! eDiary data review and rate severity of bleeding episodes 8.2.1
! Home treatment/e-Diary training, see section 5.3 and 8.4.3 
! Drug accountability for the trial medication dispensed or returned from the previous visits must 
be recorded in IV/WRS, see section 10.
…..
8.1.4    Visit 14-n and EOT Visit- visit in the Extension Phase of the trial
Before any trial related procedures/activities related to the Extension Phase of the trial, the patient 
and/or the LAR must have signed the informed consent form after having received written and 
verbal information about the Extension Phase part of the trial. 
It should be decided if the patient is eligible to be part of the randomised group in part 1 of the 
Extension Phase before the patient comes for Visit 13 (EOM) and 14. If the patient for the last 6 
months (180 days) prior to Visit 13/14 only has had 0 - 2 bleeding episode the patient is eligible for 
randomisation. If the patient is eligible to be in the randomised part of the Extension Phase part 1 
and the patient has agreed to be part of the randomisation group, the patient should give written 
consent through the informed consent addendum so agreement to randomisation is documented. 
Recruitment into the sub-group of the Extension Phase part 1 will stop approximately at mid-May
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Trial ID: NN7088-3859
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2014, hereafter also patients with a low bleeding rate will continue the same treatment as in the 
Main Phase.   
When patients randomised in part 1 have completed the part 1, all patients can start part 2 at their 
next visit beginning at visit 17. Skipping visit 15 and/or 16 should be entered with a comment in 
EDC.
While performing the EOM visit, IV/WRS will collect the response whether or not the subject will be 
randomised. For the subjects who are willing to be randomised, IV/WRS will then randomise the 
subject to either once weekly prophylaxis or every 4 day prophylaxis arm. For subjects who are not 
eligible or unwilling to be randomised, IV/WRS will dispense the trial product according to their 
chosen treatment regimen. The patient should be instructed to follow the treatment regimen in the 
assigned treatment arm. The numbers of bleeding episodes should be counted before all visits from 
visit 13 in preparation for a potential change in dosing regimen.
The home treatment period for patients on prophylaxis and on-demand is approximately 8 weeks (± 
2 week) between visits during the first 4 visits in the Extension phase part 1 (Visit 14-17)  and 12 
weeks apart in part 2 (from the Visit 17), see Table 2-3. 
Visit 14 will take place at the same day as Visit 13 in the Main Phase of the trial.
Antibody samples will only be drawn from patients in the on-demand arm at visits if they have 
received treatment during the home treatment period since last visit.
The samples taken post dose must not be taken from the same vein as previously used for 
administration of N8-GP.
The following will be performed and/or recorded in the eCRF at all visits during the Extension 
Phase:
! Withdrawal criteria, see section 6.5 (not at Visit 14)
! PRO questionnaires, Visit 17, and every 4th visit approximately every year (Visit 21, 25…) and 
EOT, see section 8.4.5
! Concomitant medication, see section 11 (not at Visit 14)
! Check date and time of last coagulation factor administration, see section 8.4.3 (not at Visit 14)
! AEs: Since previous visit, see section 12.1 (not at Visit 14)
! Body measurements,  see section 8.4.2 (not at Visit 14)
! Physical examination at Visit 17 and every 2nd visit (Visit 19, 21…) and at EOT, see section8.3.3 
! Vital signs, (before dosing if dosing take place at visit, not at Visit 14), see section 8.3.4
! ECG at Visit 17and every 4th visit (Visit 21, 25…) and at EOT, see section 8.3.5
! e-Diary data review and rate severity of bleeding episodes, see section 8.2.1 (not at Visit 14)
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Trial ID: NN7088-3859
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! Home treatment/e-Diary training (not at EOT) if applicable
! N8-GP administration, not for on-demand patients (stop time of injection must be recorded in 
the eCRF, this corresponds to time “0”) (not at EOT)
! Dosing regimen choice or change and reason if change (not at visit EOT)
! Affirmation statement (at EOT Visit)
! End-of-trial form (at EOT Visit)
On EOT form the first date on trial product refers to trial drug in this trial, and not trial drug taken 
as part of pathfinder™ 1, if the patient has participated in pathfinder™ 1.
Blood sampling for local laboratory assessments:
! Haematology (to be taken within 1 hour prior to dosing), see section 8.3.6.1 (not at Visit 14)
Blood sampling for central laboratory assessments:
! Biochemistry, see section 8.3.7.1 (not at Visit 14)
! FVIII activity (trough level and recovery), i.e. before dosing (not at Visit 14) and 30 min (∃5 
min) after dosing. Recovery not to be done in the on-demand arm and at EOT Visit, see section 
8.3.7.3
! FVIII inhibitors, see section 8.3.2.2 (not at Visit 14)
! N8-GP binding antibodies, see section 8.3.2.1 (not at Visit 14)
IV/WRS:
! Drug accountability for the trial medication dispensed or returned from the previous visits must 
be recorded in IV/WRS (not at Visit 14), see section 10
! Dispensing of N8-GP for clinic dosing/home treatment must be performed via IV/WRS (for Visit 
14 done together with Visit 13 (EOM) call, not at EOT) , see section 10
! Completion session in IV/WRS (at EOT Visit)
Reminders for each visit: 
!
An appointment for the next visit should be made (not at EOT Visit).
!
Withhold N8-GP minimum 96 hours prior to next visit (not at EOT Visit)
!
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Telephone Contact:
It is recommended that a phone call is made to patients who have changed prophylaxis treatment 
regimen approximately 4 weeks or at time which seem appropriate after the change.  
No same assessments should be done both at Visit 13 (EOM) and Visit 14. Data may be transferred 
from Visit 13 and to Visit 14 and vice versa.
….
  8.1.7 Transfer of Patients to pathfinder™ 3 due to Major Surgeries 
In case major surgery is needed the patients should be transferred to the pathfinder™3 trial. To 
enable patients to be transferred the following assessments have to be performed: 
! To ensure that N8-GP is available for the surgery, notify the IV/WRS system at least 14 days 
prior to a planned surgery by using the IVRS “Dispensing session”. This can should be done 
both at a planned and unscheduled visits. 
!
At the day of transferring to the pathfinder™3 trial the IV/WRS ”Major surgery transfer” session 
should be used in order to transfer the patient into pathfinder™3
! Drug accountability – the patient must return and account for all drug dispensed in the current 
trial before entering pathfinder™3
! After completion of pathfinder™3 trial an IV/WRS ”surgery transfer session” should be 
performed in order to transfer the patient into pathfinder™2
! Fill in the Surgery transfer form in the eCRF
Upon completion of pathfinder™ 3, patients may return to pathfinder™ 2, re-entering the 
prophylactic or on-demand treatment arm as per their prior participation in the trial. The patient will 
return to the next visit in line in pathfinder™ 2 and the visit assessments performed at the EOT visit 
in pathfinder™3, will be used. The patient enrolled in pathfinder™ 2 with the intention of entering 
the pathfinder™ 3 for major surgery at the end of normal recruitment period in pathfinder™ 2 will 
not have to complete Visit 7 and reach 50 EDs before continuing into the Extension trial Phase of 
the trial if the Extension trial Phase is open. Though, a Visit 13 (EOM) must take place before 
continuing into the Extension trial Phase. Furthermore, the opening of the Extension trial Phase
will not await these patients to complete 50 EDs in the Main Phase of the trial. 
In case patients who had surgery in pathfinder™ 3 cannot follow the normal visits in the flowcharts 
(see figure 8-1 and 8-2) the patient can start at Visit 3, if the trial is in the period of the Main 
Phase, or Visit 14 if the trial is in the Extension Phase. The surgery patients do not have to 
complete all visits in the Main Phase before continuing into the Extension Phase, but need to follow 
the visit frequencies and need to have the Visit 13 (EOM) before continuing into the Extension 
Phase. If patients cannot return to the treatment regimen as before surgery, the investigator must 
choose the most appropriate regimen within the possibilities of the current phase of the trial.
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Trial ID: NN7088-3859
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8.2 Efficacy Assessments 
8.2.1
Bleeding Episodes
During the entire trial period all treatment requiring bleeding episodes (after Visit 2b) will be 
entered by the patient or caregiver in the patient’s eDiary. In case a patient is unable to enter a 
bleeding episode in the eDiary or hospitalised the Investigator will have to report it in the eCRF as 
an unscheduled visit, please refer to section 8.1.6.
…
8.3.2 Antibody Assessments
Blood samples for assessment of antibody formation against N8-GP will be drawn at the screening 
visit, pre-dose of N8-GP administration at all visits (except Visit 2b, Visit 14). Antibody formation 
is also assessed in case of at the follow-up visit approximately one month after the End of Trial 
visit. Antibody samples will only be drawn from patients in the on-demand arm at Visit 3-13 if they 
have received treatment during the home treatment period since last visit. The samples will be 
analysed both using the Bethesda assay identifying inhibitory antibodies towards FVIII and using 
an assay capable of identifying the occurrence of any antibodies towards  both rFVIII and N8-GP.
8.3.2.1  N8-GP antibody assay
…
Levels of N8-GP binding antibodies will be compared by Novo Nordisk to pre-dose samples 
throughout the trial. If a patient develops N8-GP binding antibodies and the incremental recovery 
value at that visit is less than 60% of screening value and FVIII level at time of inhibitor sampling 
(pre-dose) is more than 0.015U/mL, Novo Nordisk will ask the Investigator to call the patient for an 
unscheduled visit for collection of a new inhibitor sample 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 96 
hours wash out is not sufficient to avoid drug interference in the inhibitor assay.
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Substantial Protocol Amendment
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Date:
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Trial ID: NN7088-3859
Version:
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N8-GP antibodies results will be reported to site at EOM and EOT.
….
8.3.2.3 Antibody Assessments in case of Allergic/Anaphylactic Reaction  
Any patient who experiences an unexpected acute severe allergic/anaphylactic reaction will be 
assessed for inhibitors and antibodies against drug product content, such as IgG/IgE against N8-GP 
and Host Cell Proteins (HCP). Additional blood samples may be requested for this purpose. If it is 
deemed necessary, the same analyses will be performed for all patients enrolled in the trial using 
available blood samples.
….
8.3.5 ECG 
ECG must be performed at Screening (Visit 1), End of Main Phase, at Visit 17(end of part 1), every 
year during Extension Phase part 2 (Visit 21, 25...) and EOT visit. ECGs will be performed using a 
12-lead Electro Cardiogram. For the ECG recording the patients must be resting and in a horizontal 
position. Any irregularities observed during the ECG e.g. cough, should either induce a re-run of 
the ECG and/or be annotated in the eCRF page with description of the occurrence. Print-outs must 
include date, time, patient’s identification, and initials of the Investigator, and at least 2 complexes 
for each lead and a single rhythm strip of 6 beats. Electronic capture of these measurements may 
also be performed.
….
8.3.7.3    FVIII Activity (central laboratory)
…
Exploratory assays for measuring N8-GP activity 
A non validated exploratory Thrombin generation assay (TGA) and/or other assays can be applied 
for measuring activity of N8-GP and analysed by the end of main phase and by end of the trial. The 
results from these assays will be reported separately.
…
8.4.2 Body Measurements
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All body measurements (weight, height and BMI) will be performed at Visit 1. During the 
Extension Phase patients under 18 years will have their height measured yearly. On all other visits 
only weight will be measured. The weight measured at the respective visits should be used for 
calculating the amount of N8-GP to be dispensed and the dose of N8-GP to be administered.
! Weight (registered with one decimal), wearing light clothing only (kg/pounds) and without shoes
! Height, without shoes (cm/inches), Visit 1 only
! BMI calculation (kg/m2), Visit 1 only
…
8.4.4
Medical History/Concomitant Illness 
….
Haemophilia Details (including history) 
! Diagnosis of haemophilia A (date)
! Other coagulation related diseases
! Classification of haemophilia A (severe form requested in this trial – only collected as 
confirmation of inclusion criterion 2) and FVIII:C activity level (%) from medical history
! Underlying gene defect (if known)
! Clinical suspicion of inhibitors data from medical history
! Number of inhibitor tests and/or FVIII:C recovery tests within the last 8 years
! History of switching FVIII products (type of products (from/ to) and age at switching) if 
available
! Relatives with haemophilia A (yes/no)
If yes – specify any relatives with haemophilia A and inhibitors (as recalled by patient)
…
8.4.5 PRO Questionnaires and Health Economics
PROs will be collected at screening visit (Visit 1), at Visit 17 (end of part 1) and every year during 
Extension Phase part 2 (Visit 21, 25…) and atEOT End of Trial visit for all patients. The 
questionnaires should preferably be completed prior to any other trial related activities during the 
two visits. Health economic data will be collected after treatment starts in connection with bleeding 
episodes.  
Several questionnaires will be used to assess disease and age-group specific quality of life and 
treatment satisfaction from the screening and until EOT Visits.
The following questionnaires should be completed by the patients and, where relevant, also by the 
parent/LAR:
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For trial patients aged 12-16: 
HAEMO-QOL: Questionnaire for children/adolescents (8-12 years, 13-16 years) 
EQ-5D: Questionnaire (13 years and above)
HAEMO-QOL: Parents proxy; Questionnaire for parents/LARs of Children/adolescents (8-12 
years, 13-16 years)
HEMO-SAT(P): Parents proxy; Questionnaire for parents/LARs of adolescents (13-16 years)
For trial patients aged 17 and above:
HAEM-A-QOL: Questionnaire for adults aged 17 and above
HEMO-SAT(A): Questionnaire for adults aged 17 and above
EQ-5D: Questionnaire (13 years and above)
The patient (and parents or LAR(s) if applicable) should throughout the trial complete the 
questionnaires corresponding to his age group at screening visit despite the patient changes age 
group during the trial.
….
8.5.1 Definition of Treatment Compliance
Good compliance: If the prophylaxis infusions of N8-GP is 50 U/kg BW ± 5 U/kg BW for at least 
80% of the prophylaxis infusions and the time interval between two prophylaxis infusions is as 
prescribed 4 days for at least 80% of the time. 
Less compliance: If the prophylaxis infusions of N8-GP is outside 50 U/kg BW± 5 U/kg BW for 
more than 20% of the prophylaxis infusions or the time interval if there is more or less than 4 days
between two dosis prophylaxis infusions is not as prescribed for more than 20% of the time.
2.10
Section 9 Trial Supply
….
9.3 Packaging and Labelling of Trial Product(s)
Novo Nordisk A/S will label and pack the trial product.
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N8-GP drug product and sodium chloride will be provided in separate boxes. All trial products will 
be packed open labelled.
The boxes will be provided with pre-printed labels. Each drug product box vial will have a unique 
Dispensing Unit Number (DUN) for identification and traceability. 
Labelling will be in accordance with  GCP Annex 1316, local law and trial requirements. 
The details of the packaging and labelling of N8-GP drug product will be provided in the TMM 
supplied by Clinical Supplies Coordination, Novo Nordisk A/S.
….
9.4 Storage, Handling, Accountability and Destruction of Trial Product(s)
……
Dispensing and Drug Accountability
The IV/WRS will allocate the trial product in uniquely packed DUNs to the patient at each 
dispensing visit. According to the patient’s BW, the correct number of DUNs will be allocated to 
the patient.
!
No trial product should be dispensed to any person not enrolled in the trial
!
Unused trial product must be stored separately from used trial product
!
All vials (used, partially used, unused, returned, and lost/damaged)(except NaCl containers 
vials) must be recorded in the IV/WRS drug accountability module
….
The TMM detailing the handling of the trial materials will be provided by Novo Nordisk.
Dispensing in Extension Phase 
For patients entering the randomisation of the Extension Phase part 1 the IV/WRS system will 
randomise the patient to either treatment every 4 day or every 7 day. Hereafter the IV/WRS system 
will dispense the needed number of DUNs for the patient. For non-randomised patients IV/WRS will 
dispense needed number of DUNs according to treatment regimen. 
In the Extension Phase part 2 the investigator will be able to change the treatment regimen for the 
patient in the IV/WRS system and dispense DUNs accordingly.
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Trial ID: NN7088-3859
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2.11
Section 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 the internet. Some 
sessions may be available through a toll-free telephone number. Accessibility to the IV/WRS must 
be restricted to and controlled by authorised persons. As a minimum, the system will be used for:
!
screening of patients,
!
randomising  of patients 
!
dispensing of trial product, 
!
controlling of expiry date of trial product, 
!
ordering of trial product, 
!
drug accountability
!
screening failure data 
!
Completion of the trial and 
!
withdrawal information 
!
surgery transfer session
….
2.12
Section 12   Adverse Events, Technical Complaints and Pregnancies
….
12.2    Collection, Recording and Reporting of Adverse Events 
…
The Investigator should record the diagnosis, if available. If no diagnosis is available then the 
Investigator should record each sign and symptom as individual AEs.
All AEs must be recorded by the Investigator on the standard AE form. If more than one sign or 
symptom is to be reported, use a separate AE form for each sign and symptom. For serious AEs, the 
safety information form must also be completed. If several signs or symptoms occur as part of the 
same clinical picture only one set of safety information pages need be used to describe these SAEs.
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Trial ID: NN7088-3859
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…..
2.13
Section 13  Case Report Forms
….
13.3   eCRF Flow
The Investigator must ensure that data is recorded in the CRFs as soon as possible after the visit 
(preferably within 3 days). When data is entered it will be available to Novo Nordisk for data 
verification activities. Queries to data in the eCRF must be answered in the system preferably 
within 3 days and during interim or DBL preferably daily.
Site specific CRF data (in an electronic readable format) will be provided to the Investigator after 
the trial database is released, and access to update the trial data in EDC has been removed. This data 
will be retained by the site.
When the final clinical trial report (CTR) is available the data will be archived by Novo Nordisk
13.4  eDiary
Novo Nordisk will provide patients with an eDiary for electronic recording of details of their 
bleeding episodes and treatment, see section 8.4.3. The eDiary and related support services will be 
supplied by a vendor that will be working under the direction and supervision of Novo Nordisk. 
At Visit 2ba, the patients will be provided with the eDiary and trained in the use hereof. The eDiary 
will be returned by the patient at the EOT Visit end of the trial.
Data will be entered by the patient or caregiver in the eDiary device. All data entered will be 
automatically transferred from the device to the ePRO database, where it is kept as a certified copy 
of the source data. Data entered in the device will upon confirmation of a successful back-up be 
deleted from the device.
….
2.14
Section 14  Monitoring procedures
During the course of the trial the Monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The visit intervals will depend on the outcome of the remote monitoring of the 
eCRFs, the trial site's recruitment rate and the compliance of the trial site to the protocol and GCP. 
The monitor should visit a site soon after a patient has been screened. The intervals between visits 
must not exceed 12 weeks during the Main Phase and the Extension Phase part 1. During the 
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Extension Phase part 2 the interval must not exceed 16 weeks, as long as the site has active 
patients.
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. In addition the Monitor should be 
available for discussions e.g. by telephone.
…
2.15
Section 16   Computerised Systems
…
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). After trial finalisation, each 
trial site will be supplied with long-life DVDs. These DVDs will contain site-specific patient 
records including the patient’s diaries 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 50 years or as required by local data retention laws for trial 
data.
…
2.16
Section 17    Evaluability of Patients for Analysis
17.1   Safety Analysis Set
The Safety Analysis Set consists of all patients exposed to N8-GP in this trial. The analyses of the 
safety endpoints will be based on the Safety Analysis Set and all available information until the last 
visit.
17.2  Full Analysis Set
The Full Analysis Set (FAS) consists of all patients exposed to N8-GP in this trial. The efficacy 
analysis and the PK analysis will be based on the FAS and all available information until EOT visit.
…..
2.17
Section 18 Statistical Considerations
All efficacy endpoints will be analysed and reported separately for the Main Phase, for the 
Extension Phase part 1 and for the Extension Phase part 2 of the trial. All safety endpoints will be 
reported separately for the Main Phase, for the Extension Phase part 1 and for the Extension Phase 
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part 2 as well as based on accumulated data (Main Phase + Extension Phase part 1 and Main 
Phase + both Extension Phases).
Section 18.1 to 18.9 describes the statistical methods relating to the Main Phase of the trial while 
the statistical methods relating to part 1 and part 2 of the Extension Phase are described in section 
18.10. 
18.1    Sample Size Calculation
The study has two co-primary endpoints for the Main Phase that both need to succeed for the study 
to succeed. The two endpoints can reasonably be considered approximately independent and 
combined power then becomes the product of the individual power for each co-primary endpoint.
…..
Co-Primary Endpoint: Annualised bleeding rate in the prophylaxis arm 
The clinical efficacy of N8-GP in long term bleeding prophylaxis will be evaluated based on all the 
prophylaxis period data. This will give different period lengths for the different patients but on 
average it is expected to give about 12 month prophylaxis treatment per patient (~7 months for the 
last recruited patients and approximately 17 - 19 months for the first recruited patients). 
Prophylactic effect will be concluded if the upper 97.5% confidence limit for the annualised 
bleeding frequency is < 8.5. Annualised bleeding rate for withdrawals will be imputed for the 
missing period based on their observed bleeding rate except for patients withdrawn within one 
month where imputation will be performed based on an annualised bleeding rate of 24. The true 
bleeding rate will be assumed to be 6.8 as for historical prophylaxis data but for the sample size 
calculation it will further be assumed that 1 patient will withdraw within 1 month and that will lift 
the effective annualised bleeding rate for the power calculation by 24/120 = 0.2, i.e. from 6.8 to 7.0.
…..
Operationally the null-hypothesis will be rejected and a success rate acceptably close to 80% is 
considered confirmed if the lower bound of the 1-sided 97.5% confidence interval for the rate is 
above 65%. By assuming that the observations are independent, the power may be calculated exact 
using the binomial distribution. The power will depend on the number of bleeding episodes actually 
observed. It is expected that more than 200 bleeding episodes will occur in the Main Phase of the
trial in the on-demand arm and the prophylaxis arms combined. Assuming a true response rate of 
80% the power for this endpoint is greater than 95%. Correlation between observations 
corresponding to the same patient may reduce this power but is not expected to affect it too much.
18.2 Statistical Methods
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18.2.1  General Considerations
Novo Nordisk A/S will be responsible for the statistical analysis. All tests will be performed as 1-
sided tests on 2.5% significance level. 
All bleeding endpoints will be evaluated based on bleeding episodes requiring treatment with N8-
GP. Non-treatment requiring bleeding episodes that coincide with regular prophylaxis doses are 
not included. 
18.2.2 Primary Endpoint(s)
…..
Let AR be the observed true yearly bleeding rate. The null-hypothesis will be tested against the 
alternative hypothesis as given by:
….
Analysis of 12 months data from patients that could have had 12 months prophylaxis 
Since patients will stay in the Main Phase of the trial until the same end of Main Phase date some 
patients will get only about 7 months prophylactic treatment while others may get more than 19 
months (except for patients entering the trial with the intention of major surgery after the end of 
normal recruitment period). To investigate if the varying durations have any impact on the results a 
sensitivity analysis will be performed looking only at 12 months data from patients with planned 
trial duration of 12 or more months. Otherwise this analysis will be performed similarly to the 
primary analysis.
…..
18.2.3 Confirmatory Secondary Endpoints
….
Let R be the observed true success rate. The null-hypothesis will be tested against the alternative 
hypothesis as given by:
……
18.2.4.1    PK Endpoints
…..
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Table 18-2  Definition and Calculation of PK Parameters
Parameter
Description
Calculation
Incremental 
Recovery
Dose-normalised activity recorded 
30 min after end of infusion and 
reported as [U/mL]/[U/kg]. 
Expected to be the highest dose-
normalised activity observed.
The incremental recovery is calculated by 
subtracting dividing the FVIII activity 
(U/mL) measured in plasma at time 0 from 
that measured at time 30 min after dosing 
and dividing this difference by the dose 
injected at time 0 expressed as U/kg BW
…..
18.4      Exploratory endpoints
Incidence of binding, non-inhibitory antibodies to N8-GP/turoctocog alfa
Binding non-inhibitory antibodies will be listed.
18.5   Interim Analysis
In order to obtain regulatory permission to start the surgery treatment prophylaxis treatment in the 
US and paediatric trial in the EU lists of acute treatment responses will be prepared at certain time-
points. They will include patient details as well as dose given and response to treatment.
All data from the Main Phase of the trial will be analysed and reported when all patients have 
reached 50 EDs (except for patients having had surgery as part of pathfinder™ 3). All main 
conclusions from the trial will be based on this reporting. Furthermore, an interim analysis will be 
performed when the patients enrolled in the randomised part of the Extension have completed part 
1.
….
18.9   Health Economics and/or Patient Reported Outcome
PROs will in the Main Phase be assessed through PRO questionnaires at screening visit (Visit 1) 
and EOT visit for patients in the on-demand arm for patients in the prophylaxis arm. 
The main PRO endpoint will be subgroup total scores. Changes in scores over time of the main 
PRO endpoints at Visit 1 to EOT EOM visit will be explored and presented graphically. Evaluations 
of PRO data will alone be based on descriptive statistics, i.e. summary tables, listings and figures. 
HE calculations will be performed separately by the Novo Nordisk HE department. Novo Nordisk 
A/S will be responsible for the statistical analysis. 
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18.10 Analyses of Extension Phase Data
Data from part 1 of the Extension Phase
The main objective of part 1 of the Extension Phase is to investigate the safety and efficacy of every 
7 day dosing by evaluating ABR for this dosing regimen and comparing it to the same historical 
bleeding episode rates as used in the primary analysis for the co-primary efficacy endpoint in the 
Main Phase. Prophylactic effect of every 7 day dosing will be concluded if the bleeding rate is 
significantly below 50% of the historical on-demand bleeding rate (i.e. significantly lower than 12) 
as well as within 25% of the historical prophylaxis bleeding rates (i.e. significantly lower than 
6.8*1.25 = 8.5). Since both must be met in practice it must be shown that the bleeding rate is 
significantly lower than 8.5. 
An analysis similar to that for the co-primary endpoint in the Main Phase will be carried out for the 
bleeding episodes in the two randomised treatment regimens during the Extension Phase part 1, 
adding treatment regimen as a factor to the model. Subjects switching from the every 7 day dosing 
arm to the non-randomised every 4 day dosing arm will be handled as withdrawals in this analysis. 
The imputation for withdrawals will be similar to that for the Main Phase, except that planned 
maximum duration is now 6 months. 
Estimates of the annualised bleeding rates for each randomised regimen will be provided with 95% 
confidence intervals. Prophylactic effect of every 7 day dosing will be concluded if the upper limit 
of the 95% CI is below 8.5. In addition, the two randomised treatment regimens will be compared 
by reporting the estimated ratio between the two randomised treatment regimens with 
corresponding 95% confidence interval.
As for the co-primary endpoint in the Main Phase, a sensitivity analysis will be carried out where 
bleeding episodes for withdrawals are not imputed.
ABR based on accumulated number of bleeding episodes (Main Phase + Extension Phase part 1) 
will be evaluated for the every 4 day dosing regimens combined, i.e., combining the randomised 
and non-randomised arm. The model used will be the same as for the primary analysis of the Main 
Phase data.
Only treatment requiring bleeding episodes will be considered in the above evaluations of ABR
Incidence rate of FVIII-inhibitor and haemostatic effect of N8-GP when used for treatment of 
bleeding episodes will be evaluated based on accumulated data (Main Phase + Extension Phase 
part 1).
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Adverse events, consumption of N8-GP, recovery and trough levels will be summarised based on 
accumulated data (Main + Extension Phase part 1) by treatment regimen combining the every 4 
day dosing regimens. In addition, separate summaries including data from part 1 only will be 
presented by treatment regimen for the randomised subset of patients to support the main objective 
of part 1of the Extension Phase. 
Other safety endpoints will be summarised based on accumulated data (Main Phase + Extension 
Phase part 1). Binding non-inhibitory antibodies will be listed.
PRO endpoints at end the Extension Phase part 1 will be evaluated and presented as described in 
section 18.9. 
Data from part 2 of the Extension Phase
All evaluations/summaries based on accumulated data in part 1will be repeated in part 2, 
accumulating data from the entire trial (Main Phase + Extension Phase part 1 + part 2). 
In addition, ABR during part 2 will be summarised for the prophylaxis regimens combined. 
Furthermore, ABR during each 6 month interval in this period will be summarised by prophylaxis 
regimen used during that period. 
Frequency and time used of treatment regimens will be summarised for the different treatment 
prophylaxis regimens used during the Extension Phase part 2. 
PRO endpoints at end of each year in Extension Phase part 2 and at end of Extension Phase will be 
evaluated and presented as described in section 18.9. 
18.11 Additional Evaluations
Exploratory analysis comparing results from study NN7008-3543, NN7008-3545, NN7008-3568 
and NN7088-3776 with results from this study will be performed and reported separately. This 
analysis will include overall comparisons as well as individual comparisons for patients 
participating in one of the above listed trials and this NN7088-3859 trial, if the patient through the 
informed consent has given approval of such comparison of data. 
2.18
Section 19 Ethics
…
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When a patient’s participation in the Main Phase of the trial ends due to completion of the trial, the 
patient will be offered to continue in the Extension Phase of the trial (NN7088-3861) upon consent. 
No patient will consent to a trial in the N8-GP clinical programme before all required IRB/IEC and 
regulatory approvals have been obtained for the trial. If the patient does not wish to continue in the 
Extension Phase of the trial (NN7088-3861), the patient will consult with the Investigator to decide 
on the best available treatment.
…
19.1 Informed Consent Form for Trial Patients
….
FVIII Genotype Testing / Collection of Previous Genotype Documentation (Not applicable to 
Brazil and Israel)
Genotype testing is offered to the patients participating in this trial. If documentation of the 
patients’ genotype already exists, the patient should give their consent before the data is collected 
for trial purpose. Prior to any trial-related activity, the Investigator must provide the patient the 
possibility to abstain from the genetic testing/collection of previous documentation but still be able 
to participate in the trial.
Comparison of data in this trial to data in guardian™ trials and/or pathfinder™ 1 (only relevant 
for countries having participated in guardian™ trials and/or the pathfinder™ 1 trial)
Patients having previously participated in Novo Nordisk trials; in the guardian™ programme 
(Trial NN7008-3543 + 3545 + 3568) with FVIII turoctocog alfa and/or in pathfinder™ 1 (NN7088-
3776), will be asked in the informed consent for the Extension Phase of the trial if data from their 
participation in a guardian™/pathfinder trial(s) can be compared to the data in this trial. Patients 
will be asked to sign an addendum to the informed consent specifically addressing this matter. It is 
not a requirement for these patients to give consent to the comparison of data to participate in the 
Extension Phase of the trial.
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Protocol Amendment
Trial ID: NN7088-3859
UTN: U1111-1119-7416
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Protocol Amendment no 14
to Protocol, final version 7.0
dated 03 May 2013
Trial ID: NN7088-3859
nal Trial Evaluating Safety an
acokinetics, of NNC 0129-00
Treatment and Prophylaxis
atients with Haemophilia A
Trial phase: 3
Applicable to all countries
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Table of contents   "Double click to update Table of Content" 
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1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
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1
Introduction including rationale for the protocol amendment
This global substantial amendment no 14 is being issued primarily as a response to a Voluntary
Harmonised Procedure (VHP) assessment, which involve a central EU CTA submission of the 
NN7088-3859 (pathfinderTM 2) protocol version 7.0 in 8 European countries.
The following changes have been made to the protocol version 7.0:
•VHP raised concerns of the risk of break-through bleeding on every 7 day treatment regimen in the 
extension phase. Therefore section 5.3.1 has been updated to describe rules for when a patient 
should be switched from every 7 day to every 4 day treatment regimen. This will be monitored by 
the Investigator and Novo Nordisk. Furthermore section 5.3.1 has been updated with a rule to define 
when the every 7 day treatment arm should be closed. The text regarding telephone contacts has 
been updated in section 2 Table 2-3 and section 8.1.4 and the risk/benefit section 3.1.4 has been 
updated to describe the risk of break-through bleeding in the once weekly treatment arm. 
•The VHP recommended to follow the dosing regimen of the main part in the extension phase. In 
addition, the VHP raised concerns regarding the efficacy of every 5 and 6 day dosing regimen of 60 
U/kg, since this dose regimen has not been tested in clinical trial setting. These dosing regimens 
have therefore been deleted from the protocol. Patients will continue on every 4 day or every 7 day 
dosing throughout the extension. Section 5.3.1 has been updated to reflect this.
•A few updates have been made in section 5.1 and 18.5, to clarify when data will be reported for 
end of main phase. 
•Section 12.1.3 has been updated to ensure alignment across Novo Nordisk haemophilia trials
•Some inconsistencies and minor corrections have been updated in the protocol
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
1
Summary
Trial design:
...
Extension Phase: The Extension Phase will investigate the long-term safety and efficacy of N8-GP 
for prophylaxis patients on a 4 or- 7 day dosing regimen and on-demand treatment. 
Trial Product(s):
...
In the prophylaxis arm(s), each patient will receive prophylaxis treatment with a N8-GP dose of 50 
U/kg body weight (BW) every 4 days in the Main Phase. During part 1 of the Extension Phase a 
sub-group of patients will receive prophylaxis treatment every 4 day or every 7 day. In part 2 of the 
Extension Phase patients can be treated on every 4 day toor once weekly (every 7 day). 
2
Flow Chart 
Table 2-3
Flow Chart for Patients on Prophylaxis and On-Demand Treatment in Extension 
Phase 
Footer
Description
15
It is recommended to contact patients by phone at the 4 and 6-week interval between the site visits approximately 4 weeks after 
change of regimen (see section 8.1.4)
3
Introduction 
3.1.4
Risk and Benefits
…
The burden of disease with current FVIII prophylaxis treatment is high – long-term, intra-venous 
injections, several times a week. Identifying patients that could have adequate bleeding protection 
with a once weekly injection would be an important break-through for FVIII treatment and could 
potentially improve the uptake of prophylaxis.
In the extension part 1, patients with a low bleeding rate on every 4 day prophylaxis in the main 
phase have the possibility of being randomised to once weekly dosing. It cannot be excluded that 
patients changing from every 4 day prophylaxis to every 7 day will have a risk of more frequent 
break-through bleeding episodes. Therefore specific rules for switching patients back to every 4 day 
dosing and for closing the every 7 day treatment arm are included (see section 5.3.1).
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5
Trial Design 
5.1
Type of Trial
…
Treatment duration is approximately 6 months in the on-demand arm and from approximately 7 
(200 days plus screening period of 2-3 weeks) to approximately 19 months in the prophylaxis arm. 
The maximum treatment period in the Main Phase of this trial is approximately 27 months. In the 
prophylaxis arm, all patients will continue in the Main Phase until the last patient initiated in the 
prophylaxis arm has received at least 50 EDs of N8-GP (except for patients having had surgery as 
part of pathfinderTM 3), thus all patients in the prophylaxis arm will receive at least 50 EDs of N8-
GP and the average exposure to N8-GP will be more than 1 year. 
…
In the part 2 patients can continue being on prophylaxis but can change between every 4 or 7 day
dosing regimens in accordance with the rules described in section 5.3.1 according to their bleeding 
episode pattern..
5.2
Rationale for Trial Design
…
Part 2 of the Extension Phase will consist of a single prophylaxis treatment arm where it will be 
possible to individualisechange between every 4 day or 7 day treatment in accordance with the 
rules described in section 5.3.1according to recommended guidelines (see section 5.3) taken the 
patients bleeding pattern into account..
5.3.1
Prophylaxis
…
Other changes of the dose or dosing interval for prophylaxis are not allowed within the main phase 
of the trial. However, extra doses of N8-GP will be administered if a patient experiences a treatment 
requiring bleeding episode or in case of minor surgery.
Extension Phase part 1: The prophylaxis dose of N8-GP is administered in the non-randomised 
group every 4 days or in the randomised group every 4 day or every 7 day depending on which 
treatment arm the patient is allocated to. Based on the bleeding pattern, the Investigator may change 
the every 7 day prophylaxis treatment to an every 4 day treatment regimen (the non-randomised 
arm) at any time. , but cChanging vice versa is not permitted. In addition the Investigator must 
monitor the patient on an on going basis and change patients from every 7 day prophylaxis 
treatment to an every 4 day treatment regimen in accordance with the following rule.
A patient on every 7 day prophylaxis must be switched back to every 4 day prophylaxis if either of 
the following criteria are met over a 8 week period:
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•Two or more spontaneous bleeding episodes 
•One severe bleeding episode requiring hospitalisation.
Novo Nordisk will monitor that patients are switched from the every 7 day prophylaxis treatment to 
an every 4 day treatment regimen adhering to the rule mentioned above. Novo Nordisk will 
furthermore monitor the number of patients switching from every 7 day to every 4 day treatment 
regimen and will terminate the 7 day treatment arm if the below rule is met:
•If at least 15 out of 30 patients (or 50% of 30 or more) whom have been randomised to the 
every 7 day treatment arm are switched back to the every 4 day treatment arm, then the every 
7 day treatment arm will be closed and all remaining patients will be switched to every 4 day 
treatment.
…
Extension Phase part 2: During this period it is possible to adjustchange the prophylaxis treatment 
of patients to every 4 day or 7 day treatmentan individualised regimen. Treatment regimens ranging 
from once weekly to every 4 day will be allowed: every 4 day, every 5 day, every 6 day or every 7 
day. For deciding to change a regimen it is strongly recommended to followthe Investigator must 
monitor the patient on an on going basis and follow the below guidelinesrules for change of 
regimen:  
•0-2 bleeding episodes within last 6 months on same regimen would allow a less frequent 
dosing interval to a lowest frequency of every 7 day. Change to a less frequent treatment 
regimen should be done while the patient is at a site visit
•If a patient on every 7 day treatment regimen over a 8 week period experiences two or 
more spontaneous bleeding episodes or one severe bleeding episode requiring 
hospitalisation, then the patient must be switched back to every 4 day treatment regimen 3 
or more bleeding episodes within last 6 months on same regimen allows to stay on regimen 
or change to a more frequent regimen to a highest frequency of every 4 day
•Change of regimen can only take place after being on the same regimen for at least 6 
months
Clinical judgement has to be applied in order to avoid increased risk to the subject’s safety and must 
always overrule guidelines the above described rules when deemed necessary by the Investigator.
The dose for the Extension Phase part 1 and 2 will be:
50 U/kg BW of N8-GP for prophylaxis treatment every 4 day
60 U/Kg BW of N8-GP for prophylaxis treatment every 5 and 6 day
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75 U/Kg of N8-GP for prophylaxis treatment every 7 day
5.3.2
Treatment of Bleeding episodes
...
Due to individual patient’s bleeding pattern during the main phase of the trial, an adaptation in 
dosing regimen to 50 U/kg twice weekly will be permitted at the investigator’s discretion. 
8
Methods and Assessments
8.1.4
Visit 14-n and EOT Visit- visit in the Extension Phase of the trial
…
When patients randomised in part 1 have completed the part 1, allremaining patients can start part 2 
at their next visit beginning at visit 17. Skipping visit 15 and/or 16 should be entered with a 
comment in EDC. 
…
Telephone Contact:
It is recommended that a phone call is made to patients at the 4 or 6-week interval between the site 
visits. who have changed prophylaxis treatment regimen approximately 4 weeks or at time which 
seem appropriate after the change.
8.1.6
Unscheduled Visits
…
The following can be performed/reported at an Unscheduled visit:
…
•Dosing regimen choice or change and reason if change 
10
Interactive Voice/Web Response System (IV/WRS)
…
As a minimum, the system will be used for:
…
•changing of dosing frequency
12
Adverse Events, Technical Complaints and Pregnancies
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12.1.3
Disease-related Bleeding
…
In case of a life-threatening event or a fatal outcome, the bleeding episode must be reported as an 
SAE. 
18
Statistical Considerations
18.5
Interim Analysis
…
All data from the Main Phase of the trial will be analysed and reported when all patients have 
reached at least 50 EDs (except for patients having had surgery as part of pathfinder™ 3), and all 
patients have had their first visit after 50 EDs where all planned assessments including inhibitors 
have been performed. The analysis of the main phase of the trial will be based on all data up to the 
patient’s last visit at this point. All main conclusions from the trial will be based on this reporting. 
Furthermore, an interim analysis will be performed when the patients enrolled in the randomised 
part of the Extension have completed part 1. 
CONFIDENTIAL


Protocol Amendment
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
A Multi-nation
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Pa
Amendment originator:
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disclosed without prior written appro
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Protocol Amendment
No 15
to Protocol, final version 8.0
dated 12 July 2013
Trial ID: NN7088-3859
nal Trial Evaluating Safety an
acokinetics, of NNC 0129-00
Treatment and Prophylaxis
atients with Haemophilia A
Trial phase: 3
Applicable to all countries 
roperty of Novo Nordisk. No unpublished information
oval from Novo Nordisk. Access to this document mu
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Final
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nd Efficacy, 
000-1003 when 
s of Bleeding in 
n contained herein may be 
ust be restricted to relevant 
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Changes......................................................................................................................................................4
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1
Introduction including rationale for the protocol amendment
The VHP requested that patients  in the every 7 days treatment arm (Q7D) receive the same visit 
schedule as patients in the every 4 days treatment arm (Q4D) of the Main Study Phase i.e. monthly 
visits at the start of treatment, followed by visits every second month. 
In addition, it was agreed with the VHP to also implement this visit schedule for patients 
randomised to Q4D in the extension phase part 1. This is to avoid any bias in the randomised arms. 
Part 1 of the extension is 6 months in duration, therefore monthly visits for the first 4 months have 
been introduced, followed by a visit 2 months later.
The VHP stipulated that this visit schedule should apply for every switch to Q7D independent of the 
part of the extension phase. Therefore, this requirement has also been implemented for Q7D 
patients in Part 2 of the extension. In Part 2, those switching to Q7D, will have visits every month 
for the first 4 months and subsequently every two months while on Q7D.
!
Therefore the flowchart table 2-3 in section 2 describing the extension phase has been updated 
to describe this
!
Section 5.3.1 has been updated accordingly
!
The text regarding telephone contacts has been deleted in Table 2-3 and section 8.1.4 since 
more often visits has been added instead
!
The trial figure 8-2, section 8 and section 8.1.4 describing the visits in extension phase has been 
revised. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
4 of 15
2
Changes
Table 2-3
Flow Chart for Patients on Prophylaxis and On-Demand Treatment in Extension Phase
Part 1
Part 2
Visit number
1415
15
16
1715
18-n1, 15
EOT
Time of visit
Weeks
same date 
as V13
8w2
16w2
24w2
12w3
12w4
Follow-
up
Un-
scheduled 
Visit14
Visit window
Weeks
±2
±2
±2
±2
±2
Informed Consent
x
Randomisation considerations
x
Withdrawal criteria
x
x
x
x
x
x
Concomitant medication
x
x
x
x
x
x
Date and time of last coagulation 
factor administration
x
x
x
x
x
x
EFFICACY
Bleeding episodes (rating 
severity)
x 
x
x
x
x
x
x
SAFETY
Adverse events
x
x
x
x
x
x
x
ECG
x
x12
x
x
Physical examination
x
x6
x
x
Vital signs
x
x
x
x
x
x
x
Antibodies
   FVIII inhibitors7,8
x
x
x
x
x
x
x
   N8-GP binding antibodies7,8
x
x
x
x
x
x
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
Page:
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Part 1
Part 2
Visit number
1415
15
16
1715
18-n1, 15
EOT
Time of visit
Weeks
same date 
as V13
8w2
16w2
24w2
12w3
12w4
Follow-
up
Un-
scheduled 
Visit14
Visit window
Weeks
±2
±2
±2
±2
±2
   IgE, IgG, HCP5
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
   Lupus anticoagulant
x
   APTT
x
   von Willebrand factor
x
FVIII activity9
   FVIII trough level
x
x
x
x
x
x
   FVIII recovery10
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Hepatitis
x
HIV13
x
   Viral Load
x
   CD4+ T cells
x
Urinalysis
x
OTHER ASSESSMENTS
Body measurements11
x
x
x
x
x
x
PRO questionnaires
x
x12
x
x
TRIAL MATERIAL
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
6 of 15
Part 1
Part 2
Visit number
1415
15
16
1715
18-n1, 15
EOT
Time of visit
Weeks
same date 
as V13
8w2
16w2
24w2
12w3
12w4
Follow-
up
Un-
scheduled 
Visit14
Visit window
Weeks
±2
±2
±2
±2
±2
Administration of trial product10
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
IV/IWRS call
x
x
x
x
x
x
x
    Dispensing trial product
x
x
x
x
x
x
Dosing regimen /change
x
x
x
x
x
x
x
Dispensing trial card
x
REMINDERS
Affirmation statement
x
x
End of trial
x
x
eDiary training
x
x
x
x
x
x
eDiary data review
x
x
x
x
x
x
Home treatment training
x
x
x
x
x
x
Footer
Description
1
n = visit number from 19 and onwards
2
weeks after Visit 14
3
weeks apart
4
weeks since last visit
5
Only in case of expected unexpected allergic/anaphylactic reaction
6
Only every second visit (V19, V21, V23….)
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
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Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
Page:
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7
Antibody sample will only be drawn from patients in the on-demand arm if they received treatment since last visit
8
A wash-out period of minimum 96 hrs is needed before the sample
9
Trough to be sampled before dosing and recovery to be sampled 30 min ( ±5 min) after dosing, only for prophylaxis patients
10
Only for patients in prophylaxis treatment
11
Only height every year for patients below 18 years, otherwise only BW
12
Only yearly (at V21, V25…)
13
Only to be taken if HIV status is positive
14
Assessment during unscheduled visit are not mandatory but can be performed
15
It is recommended to contact patients by phone at the 4 and 6-week interval between the site visits (see section 8.1.4)
CONFIDENTIAL


Protocol Amendment
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Date:
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Trial ID: NN7088-3859
Version:
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UTN: U1111-1119-7416
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EudraCT No.: 2011-001142-15
Page:
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Extension Part 1
Extension Part 2
Visit number
14
14a
15
15a
16
17
Visit 
number
17a4
18
18a4
19-n2/
19a-n2
EOT
Follow-
up
Un-scheduled 
Visit14
Non-randomised 
PPX/
On-Demand patients
Time of visit (weeks)
same 
date as 
V13
-
8w1
-
16w1
24w1
Q4D, 
Twice 
weekly 
PPX/
On-
demand
-
12w±23
-
12w±23
12w±23
Randomised PPX 
patients
Time of visit (weeks)
same 
date as 
V13
4w±11
8w±11
12w±11
16w±11
24w±11
Q7D 
PPX 
4w ±13
8w±13
4w±13
8w±13/
4±1
8w±13/
4±1
Informed Consent
x
Randomisation 
considerations
x
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medication
x
x
x
x
x
x
x
x
x
x
x
Date and time of last 
coagulation factor 
administration
x
x
x
x
x
x
x
x
x
x
x
EFFICACY
Bleeding episodes 
(rating severity)
x 
x 
x 
x
x
x
x
x
x
x
x
x
SAFETY
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x
x12
x
x
Physical 
examination
x
x6
x
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
9 of 15
Extension Part 1
Extension Part 2
Visit number
14
14a
15
15a
16
17
Visit 
number
17a4
18
18a4
19-n2/
19a-n2
EOT
Follow-
up
Un-scheduled 
Visit14
Non-randomised 
PPX/
On-Demand patients
Time of visit (weeks)
same 
date as 
V13
-
8w1
-
16w1
24w1
Q4D, 
Twice 
weekly 
PPX/
On-
demand
-
12w±23
-
12w±23
12w±23
Randomised PPX 
patients
Time of visit (weeks)
same 
date as 
V13
4w±11
8w±11
12w±11
16w±11
24w±11
Q7D 
PPX 
4w ±13
8w±13
4w±13
8w±13/
4±1
8w±13/
4±1
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
Antibodies
FVIII inhibitors7,8
x
x
x
x
x
x
x
x
x
x
x
x
N8-GP binding 
antibodies7,8
x
x
x
x
x
x
x
x
x
x
x
x
IgE, IgG, HCP5
x
Biochemistry
x
x
x
x
x
x
x
x
x
x
x
Coagulation 
parameters
Lupus anticoagulant
x
APTT
x
von Willebrand factor
x
FVIII activity9
FVIII trough level
x
x
x
x
x
x
x
x
x
x
x
FVIII recovery10
x
x
x
x
x
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
x
x
x
x
x
Hepatitis
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
10 of 15
Extension Part 1
Extension Part 2
Visit number
14
14a
15
15a
16
17
Visit 
number
17a4
18
18a4
19-n2/
19a-n2
EOT
Follow-
up
Un-scheduled 
Visit14
Non-randomised 
PPX/
On-Demand patients
Time of visit (weeks)
same 
date as 
V13
-
8w1
-
16w1
24w1
Q4D, 
Twice 
weekly 
PPX/
On-
demand
-
12w±23
-
12w±23
12w±23
Randomised PPX 
patients
Time of visit (weeks)
same 
date as 
V13
4w±11
8w±11
12w±11
16w±11
24w±11
Q7D 
PPX 
4w ±13
8w±13
4w±13
8w±13/
4±1
8w±13/
4±1
HIV13
x
Viral Load
x
CD4+ T cells
x
Urinalysis
x
OTHER 
ASSESSMENTS
Body 
measurements11
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x12
x
x
TRIAL MATERIAL
Administration of 
trial product6
x
x
x
x
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
x
x
x
IV/IWRS call
x
x
x
x
x
x
x
x
x
x
x
x
Dispensing trial 
product
x
x
x
x
x
x
x
x
x
x
x
Dosing regimen 
/change
x
x
x
x
x
x
x
x
x
x
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
11 of 15
Extension Part 1
Extension Part 2
Visit number
14
14a
15
15a
16
17
Visit 
number
17a4
18
18a4
19-n2/
19a-n2
EOT
Follow-
up
Un-scheduled 
Visit14
Non-randomised 
PPX/
On-Demand patients
Time of visit (weeks)
same 
date as 
V13
-
8w1
-
16w1
24w1
Q4D, 
Twice 
weekly 
PPX/
On-
demand
-
12w±23
-
12w±23
12w±23
Randomised PPX 
patients
Time of visit (weeks)
same 
date as 
V13
4w±11
8w±11
12w±11
16w±11
24w±11
Q7D 
PPX 
4w ±13
8w±13
4w±13
8w±13/
4±1
8w±13/
4±1
Dispensing trial card
x
REMINDERS
Affirmation 
statement
x
x
End of trial
x
x
eDiary training
x
x
x
x
x
x
x
x
x
x
x
eDiary data review
x
x
x
x
x
x
x
x
x
x
x
Home treatment 
training
x
x
x
x
x
x
x
x
x
x
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
12 of 15
Footer
Description
1
weeks after Visit 14
2
n = additional visit number until end of trial
3
weeks since last visit
4
It is mandatory to attend 2 consecutive a-visits upon switching to every 7 day treatment regimen in order to achieve visits every 4 weeks (± 1 
week) during the first 4 months. After this time period the patient must attend visits every 8 weeks (± 1 week) while on every 7 day treatment 
regimen.
5
Only in case of expected unexpected allergic/anaphylactic reaction
6
Only every second  non a-visits, e.g. visit (V19, V21, V23….)
7
Antibody sample will only be drawn from patients in the on-demand arm if they received treatment since last visit
8
A wash-out period of minimum 96 hrs is needed before the sample
9
Trough to be sampled before dosing and recovery to be sampled 30 min ( ±5 min) after dosing, only for prophylaxis patients
10
Only for patients in prophylaxis treatment
11
Only height every year for patients below 18 years, otherwise only BW
12
Only yearly (at V21, V25…)
13
Only to be taken if HIV status is positive
14
Assessment during unscheduled visit are not mandatory but can be performed
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
13 of 15
5
Trial Design 
…
5.3.1
Prophylaxis
...
Extension Phase part 2: During this period it is possible to change the prophylaxis treatment of 
patients to every 4 day or 7 day treatment. For deciding to change a regimen the Investigator must 
monitor the patient on an on going basis and follow the below rules:  
! 0-2 bleeding episodes within last 6 months on same regimen allow a less frequent dosing interval 
of every 7 day. Change to a less frequent treatment regimen should be done while the patient is 
at a site visit. After switching, the patient must attend the next sequential a-visit in line. The 
a-visits are applicable to attend 2 times following a switch to every 7 day treatment regimen to 
allow for monthly visits the first 4 months and thereafter visits every second month while on 
every 7 day treatment regimen, see Table 2-3 and Figure 8-2
! If a patient on every 7 day treatment regimen over a 8 week period experiences two or more 
spontaneous bleeding episodes or one severe bleeding episode requiring hospitalisation, then the 
patient must be switched back to every 4 day treatment regimen. The patient must attend the next 
sequential visit in line and attend visits every third month while on every 4 day treatment 
regimen, see Table 2-3 and Figure 8-2. 
8
Methods and Assessments
…
Old figure 8-2:
CONFIDENTIAL


Protocol Amendment
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
New figure 8-2
OD = on-demand, PPX = prop
prophylaxis every 4 day, Q7D
mandatory to attend upon swit
during the first 4 months
…
The Extension Phase part 1 w
! Non-randomised prophylax
Visit 14 (same date as Vis
Visit 15+16: Visits at the 
-
Patients in the rand
-
Patients on prophyl
the visits
-
Patients on the on-d
! Randomised PPX patients
Visit 14 (same date as Visi
Visit 14a, 15, 15a +16: Vis
-
Patients in the rando
The Extension Phase part 2 w
Visit 17-n : Visit at site
Visit 17a-visits-n: 2 consecutiv
treatment regimen in order to 
-
Dosing regimen wil
-
Patients on prophyl
Patients on the on-demand a
CONFIDENTIAL
Date:
Version:
Status:
Page:
phylaxis, BE = bleeding episodes, ® = random
D = prophylaxis every 7 day, w = weeks, ○2 
tching to Q7D in order to achieve visits every
will include the following visits:
xis and on-Demand patients
it 13 (EOM)): patients are enrolled in Extensi
site
domised treatment arms will be dosed durin
laxis NOT in the randomised treatment ar
demand treatment arm will not be dosed du
it 13 (EOM)): patients are enrolled in Extens
sits at the site
domised treatment arms will be dosed during 
will include the following visits:
ve a-visits are mandatory to attend upon swit
achieve visits every 4 weeks (± 1 week) durin
ll be considered
laxis regimen will be dosed at visits
arm will not be dosed during the visits
28 August 2013
Novo Nordisk
1.0
Final
14 of 15
misation, Q4D = 
consecutive a-visits are 
y 4 weeks (± 1 week) 
ion Phase
ng the visits
m will be dosed during 
uring the visits
sion Phase
the visits
tching to every 7 day 
ng the first 4 months
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 August 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
15 of 15
…
8.1.4
Visit 14-n and EOT Visit- visit in the Extension Phase of the trial
…
The numbers of bleeding episodes should be counted before all visits from visit 13 in preparation 
for a potential change in dosing regimen, see section 5.3.1.
The home treatment period for patients on non-randomised every 4 day prophylaxis and on-demand 
is approximately 8 weeks (± 2 week) between visits during the first 4 visits in the Extension phase 
part 1 (Visit 14-17). The home treatment period for patients randomised to every 4 or 7 day 
prophylaxis in Extension phase part 1 is 4 weeks (± 1 week) for the first 4 months and thereafter 8 
weeks (± 1 week) (Visit 14-17), see Table 2-3. 
The home treatment period for patients on every 4 day and twice weekly prophylaxis, and on-
demand is and 12 weeks (± 2 weeks) apart in the Extension phase part 2 (from the Visit 17). 
Patients continuing on every 7 day prophylaxis from Extension phase part 1 into Extension phase 
part 2, will continue a home treatment period of 8 weeks (± 1 weeks). Whenever a patient in 
Extension phase part 2 switches to every 7 day prophylaxis, the home treatment period will be 4 
weeks (± 1 weeks) for the first 4 months and thereafter 8 weeks (± 1 week) for the remaining of the 
period on every 7 day prophylaxis, see Table 2-3.
…
The following will be performed and/or recorded in the eCRF at all visits during the 
Extension Phase:
…
Telephone Contact:
It is recommended that a phone call is made to patients at the 4 or 6-week interval between the site 
visits.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
27 September 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
1 of 6
Protocol Amendment
No 16
to Protocol, final version 9.0
dated 28 August 2013
NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, including Pharmacokinetics, of NNC 
0129-0000-1003 when Administered for Treatment and Prophylaxis of Bleeding in Patients 
with Haemophilia A
Trial phase: 3
Applicable to US site 924
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
27 September 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
2 of 6
Table of contents 
Page
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1
Protocol Section 6.5: Withdrawal Criteria.....................................................................................4
2.2
Protocol Section 8.1.5: Follow-up visit (only for patients withdrawn due to development of 
FVIII inhibitors).............................................................................................................................4
2.3
Protocol Section 8.3.2.2: FVIII inhibitors .....................................................................................4
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
27 September 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
3 of 6
1
Introduction including rationale for the protocol amendment
In the current version of the NN7088-3859 (pathfinderTM2) protocol (section 6.5) it is stated that a 
patient must be withdrawn if the following applies:
!
FVIII inhibitor (≥0.6 BU/mL) as confirmed by re-testing by Central Laboratory
With this current wording, a patient with a low titre inhibitor that does not interfere with 
prophylaxis or treatment of bleeding episodes with N8-GP must be withdrawn from the trial. This is 
not in line with current treatment practices in haemophilia A where patients with low titre inhibitors 
continue treatment with FVIII until the inhibitor interferes with prophylaxis or treatment of bleeds 
at standard doses of FVIII (Collins et al 2013, BJH). In addition, some low titre inhibitors may be 
transient, disappearing within 6 months of initial documentation, despite recent antigenic challenge 
with factor concentrate (Srivistava et al 2013, Haemophilia).
Therefore the withdrawal criteria section 6.5 of the protocol will be amended to allow patients with 
a low titre inhibitor (≤5 BU/mL), that does not result in clinically ineffective treatment with N8-
GP, to continue in the trial.
Furthermore section 8.1.5 and 8.3.2.2 are updated to reflect this change of process.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
27 September 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
4 of 6
2
Changes
2.1
Protocol Section 6.5: Withdrawal Criteria
The patient may withdraw at will at any time.
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.
A patient must be withdrawn if the following applies:
2. FVIII inhibitor (≥0.6 >5 BU/mL) as confirmed by re-testing by Central Laboratory
7. FVIII inhibitor (≥0.6 and ≤5 BU/mL)as confirmed by re-testing by Central Laboratory that
makes treatment (prophylaxis or treatment of bleeding episodes) with N8-GP clinically ineffective
2.2
Protocol Section 8.1.5: Follow-up visit (only for patients withdrawn due to 
development of FVIII inhibitors)
In case of withdrawal due to FVIII inhibitor development (that makes treatment, prophylaxis or 
treatment of bleeding episodes, with N8-GP clinically ineffective or inhibitor titre >5 BU/mL), the 
patient should be scheduled for an EOT Visit as soon as possible and within 1 week after a positive 
inhibitor test is confirmed via re-testing, preferably prior to initiation of treatment with another 
FVIII product. One month (4 weeks ± 2 weeks) after the EOT Visit the patient must attend a FU 
Visit, please see Section 8.3.2.2. At each FU Visit, it will be evaluated if further FU Visits are 
required. The additional FU Visits will be arranged at intervals of 4 weeks ± 2 week as long as 
clinically warranted up until 3 months after confirmation of the FVIII inhibitor.
2.3
Protocol Section 8.3.2.2: FVIII inhibitors
All patients will be examined for the development of FVIII inhibitors at scheduled visits. A positive 
inhibitor test is defined as ∀0.6 BU/mL. If FVIII inhibitor development is suspected (increased 
number of bleeding episodes, bleeding episodes difficult to treat, recovery and trough levels below 
expected values) during the course of the trial, additional inhibitor tests can be taken at 
Unscheduled Visits. All inhibitor tests must be analysed by the Central Laboratory.
In the event that a patient has a positive inhibitor test (∀0.6 BU/mL), the patient must attend an 
Unscheduled Visit as soon as possible or within 1 week after the result is available to take a 
confirmatory inhibitor test on a separately drawn sample. In addition the following tests should be 
performed: N8-GP binding antibody, FVIII trough, FVIII recovery and lupus anticoagulant. 
Thisese second samples should preferably be taken prior to any change of treatment, and after a 96 
hours wash-out period. A 7 days wash out period may be applied if the 96 hours wash out is not 
sufficient to avoid drug interference in the inhibitor assay.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
27 September 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
5 of 6
At this Unscheduled Visit, a recovery test must also be performed. If the second (confirmatory)
inhibitor test is also positive, the patient must be withdrawn if FVIII inhibitor >5 BU/mL or FVIII 
inhibitor ≥0.6 and ≤5 BU/mL that makes treatment (prophylaxis or treatment of bleeding episodes) 
with N8-GP clinically ineffective, by discontinuing trial product and attending the EOT Visit within 
1 week after the result is available.
If the second (confirmatory) inhibitor test is positive and ≤ 5 BU/mL and the Investigator judges 
that the inhibitor does not clinically interfere with treatment (prophylaxis or treatment of bleeding 
episodes) the patients may stay in pathfinderTM 2 on current treatment.
A patient has inhibitors (≥0.6 BU/mL) if the patient has been tested positive for inhibitors at two 
consecutive test samples performed at the central laboratory preferably with no more than 2 weeks 
between the tests.
For withdrawn patients: A follow-Up Visit must be scheduled 1 month after the EOT Visit and 
additional monthly follow-up visits may be arranged at intervals as long as clinically warranted up 
to 3 months after the EOT Visit.
For patients continuing in pathfinderTM2 with inhibitor (≥0.6 and ≤5 BU/mL): the patient must 
follow previous dosing schedule and the scheduled visits as described in Flowchart Table 2-.1. 
Additional visits can be scheduled if closer monitoring is needed. In the event of a concern about 
reduced treatment efficacy a PK session may be performed. The PK can be evaluated after a wash 
out period of at least 96 hours. 
All per protocol inhibitor laboratory samples are to be analysed in the central laboratory, and only 
these results will be used in the trial data analysis.
If the Investigator decides to send a sample for inhibitor testing to a local laboratory, the 
Investigator must also send a duplicate sample for inhibitor testing to the Central Laboratory. The 
data from the Central Laboratory will then be used in the official analysis. Any single positive 
inhibitor test must be reported as a MESI (please refer to section 12.1.2)
Blood samples for measurement of inhibitors towards FVIII will be analysed according to the 
Nijmegen modification of the Bethesda assay15. Any sampling for the inhibitor test must be 
performed at least 96 hours after last administration of N8-GP to allow for maximum wash-out of 
the drug. 
An inhibitor test with a result ≥0.6 BU/ml will be considered as a positive inhibitor test. A patient is 
verified inhibitor positive if two independent samples from same patient are inhibitor positive 
(≥0.6BU) – and the patient should may discontinue the trial including an EOT Visit and FU Visits
or remain in pathfinderTM2 as described above.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
27 September 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
6 of 6
A patient having an initial positive inhibitor test and a second negative inhibitor test will be 
regarded as inhibitor negative and can continue in the trial.
If more than two patients are verified inhibitor positive an unscheduled Safety Committee Meeting 
will be called by Global Safety – and a decision whether to continue, modify or stop the trial will 
made, see Section 12.5.3.
CONFIDENTIAL


Substantial Amendment
Trial ID: NN7088-3859
UTN: U1111-1119-7416
EudraCT No.: 2011-001142-15
A Multi-nation
including Pharm
Administered for 
Pa
Amendment originator:
This confidential document is the pr
disclosed without prior written appro
parties.
CONFIDENTIAL
Date:
Version:
Status:
Page:
Substantial Amendment
no 17-FR
Trial ID:NN7088-3859
nal Trial Evaluating Safety an
acokinetics, of NNC 0129-00
Treatment and Prophylaxis
atients with Haemophilia A
Trial phase: 3
Applicable to FRANCE
roperty of Novo Nordisk. No unpublished information
oval from Novo Nordisk. Access to this document mu
21 October 2013
Novo Nordisk
1.0
Final
1 of 5
nd Efficacy, 
000-1003 when 
s of Bleeding in 
n contained herein may be 
ust be restricted to relevant 
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.


Substantial Amendment
CONFIDENTIAL
Date:
21 October 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
2 of 5
Table of contents   "Double click to update Table of Content" 
Page
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
CONFIDENTIAL


Substantial Amendment
CONFIDENTIAL
Date:
21 October 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
3 of 5
1
Introduction including rationale for the protocol amendment
The rationale for issuing this substantial amendment is the address’change for Pr Negrier’s site.
Attachment II is updated accordingly.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Substantial Amendment
CONFIDENTIAL
Date:
21 October 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
4 of 5
2
Changes
The following changes to Attachment II to NN7088-3859 :
Address change:
From:
National 
coordinating 
Investigator
Name:
Title 
/qualification:
Address:
Tel:
Fax:
E-mail:
to
National 
coordinating 
Investigator
Name:
Title 
/qualification:
Address:
CONFIDENTIAL


Substantial Amendment
CONFIDENTIAL
Date:
21 October 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
5 of 5
Tel:
Fax:
E-mail:
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
1 of 14
Protocol Amendment
No 18
to Protocol, final version 9.0
dated 28 August 2013
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, 
including Pharmacokinetics, of NNC 0129-0000-1003 when 
Administered for Treatment and Prophylaxis of Bleeding in 
Patients with Haemophilia A
Trial phase: 3
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
2 of 14
Table of contents
Page
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
3 of 14
1
Introduction including rationale for the protocol amendment
In the current version of the NN7088-3859 (pathfinderTM2) protocol (section 6.5) it is stated that a 
patient must be withdrawn if the following applies:
!
FVIII inhibitor (≥0.6 BU/mL) as confirmed by re-testing by Central Laboratory
With this current wording, a patient with a low titre inhibitor that does not interfere with 
prophylaxis or treatment of bleeding episodes with N8-GP must be withdrawn from the trial. This is 
not in line with current treatment practices in haemophilia A where patients with low titre inhibitors 
continue treatment with FVIII until the inhibitor interferes with prophylaxis or treatment of bleeds 
at standard doses of FVIII (Collins et al 2013, BJH). In addition, some low titre inhibitors may be 
transient, disappearing within 6 months of initial documentation, despite recent antigenic challenge 
with factor concentrate (Srivistava et al 2012, Haemophilia).
Therefore the withdrawal criteria section 6.5 of the protocol will be amended to allow patients with 
a low titre inhibitor (≤ 5 BU/mL), that does not result in clinically ineffective treatment with N8-
GP, to continue in the trial. Furthermore section 8.1.5 and 8.3.2.2 are updated to reflect this change 
of process.
Furthermore a few other updates have been performed concurrently:
!
A new PK endpoint has been added in section 4.2.2.4 and 18.2.4.1
!
Minor update to flowchart in section 2, update to when recruitment into the randomised arm in 
extension phase part 1 will end in section 5.1 and 8.1.4, Bulgaria has been deleted from the 
country list in section 6.1 and update to section 9.3 regarding labelling and packaging of trial 
product.
!
Minor addition to section 8.1.7 regarding major surgery patients.
!
Section 8.3.2.1 has been updated to include an assay to analyse for antibodies towards PEG.
!
Section 8.3.7 has been updated to reflect what the patient has consented to regarding storage of 
samples in pathfinderTM2 main and extension phase.
!
Text regarding adverse events has been updated in section 12.1 and 18.10.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
4 of 14
2
Changes
2 Flow chart
Table 2–3
Flow Chart for Patients on Prophylaxis and On-Demand Treatment in Extension Phase 
Extension Part 1
Extension Part 2
Visit number
14
14a
15
15a
16
17
Visit 
number
17a4
18
18a4
19-n2/
19a-n2
EOT
Follow-
up
Un-
scheduled 
Visit14
Non-randomised 
PPX/On-Demand 
patients
Time of visit (weeks)
same 
date as 
V13
-
8w±21
-
16w±21
24w±21
Q4D, 
Twice 
weekly 
PPX/
On-
demand
-
12w±23
-
12w±23
12w±23
Randomised PPX 
patients
Time of visit (weeks)
same 
date as 
V13
4w±11
8w±11
12w±11
16w±11
24w±11
Q7D 
PPX 
4w ±13
8w±13
4w±13
8w±13/
4±1
8w±13/
4±1
Informed Consent
x
Randomisation 
considerations
x
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medication
x
x
x
x
x
x
x
x
x
x
x
Date and time of last 
coagulation factor 
administration
x
x
x
x
x
x
x
x
x
x
x
EFFICACY
Bleeding episodes 
(rating severity)
x 
x 
x 
x
x
x
x
x
x
x
x
x
SAFETY
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
5 of 14
Extension Part 1
Extension Part 2
Visit number
14
14a
15
15a
16
17
Visit 
number
17a4
18
18a4
19-n2/
19a-n2
EOT
Follow-
up
Un-
scheduled 
Visit14
Non-randomised 
PPX/On-Demand 
patients
Time of visit (weeks)
same 
date as 
V13
-
8w±21
-
16w±21
24w±21
Q4D, 
Twice 
weekly 
PPX/
On-
demand
-
12w±23
-
12w±23
12w±23
Randomised PPX 
patients
Time of visit (weeks)
same 
date as 
V13
4w±11
8w±11
12w±11
16w±11
24w±11
Q7D 
PPX 
4w ±13
8w±13
4w±13
8w±13/
4±1
8w±13/
4±1
ECG
x
x12
x
x
Physical 
examination
x
x6
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
Antibodies
FVIII inhibitors7,8
x
x
x
x
x
x
x
x
x
x
x
x
N8-GP binding 
antibodies7,8
x
x
x
x
x
x
x
x
x
x
x
x
IgE, IgG, HCP5
x
Biochemistry
x
x
x
x
x
x
x
x
x
x
x
Coagulation 
parameters
Lupus anticoagulant
x
APTT
x
von Willebrand factor
x
FVIII activity9
FVIII trough level
x
x
x
x
x
x
x
x
x
x
x
FVIII recovery10
x
x
x
x
x
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
x
x
x
x
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
6 of 14
Extension Part 1
Extension Part 2
Visit number
14
14a
15
15a
16
17
Visit 
number
17a4
18
18a4
19-n2/
19a-n2
EOT
Follow-
up
Un-
scheduled 
Visit14
Non-randomised 
PPX/On-Demand 
patients
Time of visit (weeks)
same 
date as 
V13
-
8w±21
-
16w±21
24w±21
Q4D, 
Twice 
weekly 
PPX/
On-
demand
-
12w±23
-
12w±23
12w±23
Randomised PPX 
patients
Time of visit (weeks)
same 
date as 
V13
4w±11
8w±11
12w±11
16w±11
24w±11
Q7D 
PPX 
4w ±13
8w±13
4w±13
8w±13/
4±1
8w±13/
4±1
Hepatitis
x
HIV13
x
Viral Load
x
CD4+ T cells
x
Urinalysis
x
OTHER 
ASSESSMENTS
Body 
measurements11
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x12
x
x
TRIAL 
MATERIAL
Administration of 
trial product6
x
x
x
x
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
x
x
x
IV/IWRS call
x
x
x
x
x
x
x
x
x
x
x
x
Dispensing trial 
product
x
x
x
x
x
x
x
x
x
x
x
Dosing regimen 
/change6
x
x
x
x
x
x
x
x
x
x
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
7 of 14
Extension Part 1
Extension Part 2
Visit number
14
14a
15
15a
16
17
Visit 
number
17a4
18
18a4
19-n2/
19a-n2
EOT
Follow-
up
Un-
scheduled 
Visit14
Non-randomised 
PPX/On-Demand 
patients
Time of visit (weeks)
same 
date as 
V13
-
8w±21
-
16w±21
24w±21
Q4D, 
Twice 
weekly 
PPX/
On-
demand
-
12w±23
-
12w±23
12w±23
Randomised PPX 
patients
Time of visit (weeks)
same 
date as 
V13
4w±11
8w±11
12w±11
16w±11
24w±11
Q7D 
PPX 
4w ±13
8w±13
4w±13
8w±13/
4±1
8w±13/
4±1
Dispensing trial 
card
x
REMINDERS
Affirmation 
statement
x
x
End of trial
x
x
eDiary training
x
x
x
x
x
x
x
x
x
x
x
eDiary data review
x
x
x
x
x
x
x
x
x
x
x
Home treatment 
training
x
x
x
x
x
x
x
x
x
x
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
8 of 14
Footer
Description
1
weeks after Visit 14
2
n = additional visit number until end of trial
3
weeks since last visit
4
It is mandatory to attend 2 consecutive a-visits upon switching to every 7 day treatment regimen in order to achieve visits every 4 weeks (± 1 
week) during the first 4 months. After this time period the patient must attend visits every 8 weeks (± 1 week) while on every 7 day treatment 
regimen.
5
Only in case of expected unexpected allergic/anaphylactic reaction
6
Only every second  non a-visits, e.g. visit (V19, V21, V23….)Change of dosing regimen from every 4 day to every 7 day treatment regimen can 
only take place at non a-visits in extension phase part 2. Change of dosing regimen from every 7 day to every 4 day treatment regimen can take 
place at all visits in extension phase part 1 and 2
7
Antibody sample will only be drawn from patients in the on-demand arm if they received treatment since last visit
8
A wash-out period of minimum 96 hrs is needed before the sample
9
Trough to be sampled before dosing and recovery to be sampled 30 min ( ±5 min) after dosing, only for prophylaxis patients
10
Only for patients in prophylaxis treatment
11
Only height every year for patients below 18 years, otherwise only BW
12
Only yearly (at V21, V25…)
13
Only to be taken if HIV status is positive
14
Assessment during unscheduled visit are not mandatory but can be performed
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
9 of 14
4 Objective(s) and Endpoint(s) 
4.2.2.4 Pharmacokinetic Endpoints 
!
FVIII activity 30 min post-injection (C30min)
5 Trial Design
5.1. Type of Trial 
…
Recruitment into the randomisation sub-group in the Extension Phase part 1 will stop approximately 
at mid MayApril 2014, hereafter also patients with a low bleeding rate will continue the same 
treatment as in Main Phase.
6 Trial Population
6.1 Number of Patients to be Studied
Countries planned to participate: Australia, Brazil, Bulgaria, Croatia, Denmark, France, Germany, 
Hungary, Israel, Italy, Japan, Korea, Malaysia, Netherlands, Norway, Russia, Spain, Sweden, 
Switzerland, Taiwan, Turkey, United Kingdom and United States 
6.5 Withdrawal criteria
…
2 - FVIII inhibitor (>0.6>5 BU/mL) as confirmed by re-testing by Central Laboratory
…
7 - FVIII inhibitor (≥0.6 and ≤ 5 BU/mL) as confirmed by re-testing by Central Laboratory that 
makes treatment (prophylaxis and/or treatment of bleeding episodes) with N8-GP clinically 
ineffective
8 Methods and Assessments
8.1.4 Visit 14-n and EOT Visit- visit in the Extension Phase of the trial
…
Recruitment into the sub-group of the Extension Phase part 1 will stop approximately at mid 
MayApril 2014, hereafter also patients with a low bleeding rate will continue the same treatment as 
in the Main Phase.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
10 of 14
8.1.5 Follow-up visit (only for patients withdrawn due to development of FVIII inhibitors)
In case of withdrawal due to FVIII inhibitor development that makes treatment (prophylaxis and/or 
treatment of bleeding episodes) with N8-GP clinically ineffective or inhibitor titre >5 BU/mL), the 
patient should be scheduled for an EOT Visit as soon as possible and within 1 week after a positive 
inhibitor test is confirmed via re-testing, preferably prior to initiation of treatment with another 
FVIII product.
8.1.7 Transfer of Patients to pathfinder™3 due to Major Surgeries 
…
Upon completion of pathfinder™3, patients may return to pathfinder™2, re-entering the 
prophylactic or on-demand treatment arm as per their prior participation in the trial. Randomised 
patients in extension part 1 on every 4 or 7 day prophylaxis treatment regimen must return to the 
non-randomised every 4 days prophylaxis treatment regimen
8.3.2.1 N8-GP antibody assay
…
Levels of N8-GP binding antibodies will be compared by Novo Nordisk to pre-dose samples 
throughout the trial. If a patient develops N8-GP binding antibodies and the recovery value at that 
visit is less than 60% of screening value and FVIII level at time of inhibitor sampling (pre-dose) is 
more than 0.0152 U/mL, Novo Nordisk will ask the Investigator to call the patient for an 
unscheduled visit for collection of a new inhibitor sample which should will be taken after a 7 days 
wash out period.
…
A selection of the samples collected for N8-GP binding analysis will only be analysed for PEG 
binding antibodies twice before treatment with N8-GP, approximately every 4 months in main 
phase and extension phase part 1 and every year in extension phase part 2 if sufficient sample 
material is available. The PEG antibodies will be based on a validated assay.
8.3.2.2. FVIII inhibitors
…
In the event that a previously inhibitor negative patient has a positive inhibitor test (∀0.6 BU/mL), 
the patient must attend an Unscheduled Visit as soon as possible or within 1 week after the result is 
available to take a confirmatory inhibitor test on a separately drawn sample. In addition the 
following tests should be performed: N8-GP binding antibody, FVIII trough, FVIII recovery and 
lupus anticoagulant. These samples should preferably be taken prior to any change of treatment, 
and after at least 96 hours wash-out period. A 7 days wash out period may be applied if the 96 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
11 of 14
hours wash out is not sufficient to avoid drug interference in the inhibitor assay. If the second 
(confirmatory) inhibitor test is also positive, the patient must be withdrawn if FVIII inhibitor >5 
BU/mL or if FVIII inhibitor ≥0.6 and ≤ 5 BU/mL that makes treatment (prophylaxis or treatment of 
bleeding episodes) with N8-GP clinically ineffective, by discontinuing trial product and attending 
the EOT Visit within 1 week after the result is available.
If the second (confirmatory) inhibitor test is positive and ≤ 5 BU/mL and the Investigator judges 
that the inhibitor does not clinically interfere with N8-GP treatment (prophylaxis or treatment of 
bleeding episodes) the patients may stay in pathfinderTM2 on per-protocol treatment.
A patient has inhibitor (≥0.6 BU/mL) if the patient has been tested positive for inhibitors at two 
consecutive test samples performed at the central laboratory preferably with no more than 2 weeks 
between the tests.
For withdrawn patients: A follow-Up Visit must be scheduled 1 month after the EOT Visit and 
additional monthly follow-up visits may be arranged at intervals as long as clinically warranted up 
to 3 months after the EOT Visit.
For patients continuing in pathfinderTM2 with inhibitor (≥0.6 and ≤ 5 BU/mL): the patient must 
follow per-protocol treatment schedule and the scheduled visits as described in Flowchart Table 2-
1 and Table 2-3. Additional visits can be scheduled if closer monitoring is needed. Closer 
monitoring is highly recommended but this decision will be at Investigator’s discretion. In the event 
of a concern about reduced treatment efficacy a PK session may be performed. The PK can be 
evaluated after a wash out period of at least 96 hours. Blood sampling during the PK profile 
session can be performed at the following time points: pre-dose, 30 minutes (± 10 min), 24h (± 8 
hours), 48h (± 8 hours), 72h (± 8 hours) and 96h (± 8 hours). 
A confirmed positive inhibitor is considered to have disappeared if the inhibitor titre is <0.6 BU/mL 
on 2 consecutive inhibitor tests (performed at 2 consecutive visits) and the FVIII recovery is ≥66% 
of expected values. A patient with repeated positive inhibitor test result will count only once in the 
determination of the inhibitor incidence rate.
Patients who develop an inhibitor should be classified as high responders (peak inhibitor titre > 5 
BU/mL), low responders (peak inhibitor titre ≤5 BU/mL), and whether the inhibitor is transient 
(disappearing (inhibitor titer <0.6 BU⁄mL on ≥2 consecutive measurements) spontaneously within 6 
months without a change in treatment regimen), or not.
…
An inhibitor test with a result ≥0.6 BU/ml will be considered as a positive inhibitor test. A patient is 
verified inhibitor positive if two independent samples from the same patient are inhibitor positive 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
12 of 14
(≥0.6BU/mL) – and the patient may discontinue the trial including an EOT Visit and FU Visits or 
remain in pathfinderTM2 as described above. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
13 of 14
8.3.7 Central Laboratory Assessments
…
For pathfinderTM2 main phase: All blood samples including genotyping blood sample will be 
destroyed after finalisation of the trial report. Blood samples of patients who are suspected of 
inhibitors or who have developed inhibitors will be stored at least until evaluation of the clinical 
trial data by the authorities in the patient’s country. 
For pathfinderTM2 extension  phase: Laboratory samples will be destroyed after trial completion 
If allowed by local law and consented to, in pathfinderTM2 extension phase addendum ‘Storage of 
blood samples from pathfinderTM2’, samples drawn for analysis of antibodies in pathfinderTM2 main 
and extension phase will be stored until market authorisation in case further characterisation of the 
samples should be required by authorities.
9 Trial Supplies
9.3 Packaging and Labelling of Trial Product(s)
Novo Nordisk A/S will label and pack thebe responsible for labelling and packaging of the trial 
product. Third party vendors may be employed.
12 Adverse Events, Technical Complaints and Pregnancies
12.1 Definitions
…
Serious Adverse Event (SAE):
!
Important medical events d) that may not result in death, be life-threatening a) or require 
hospitalisation may be considered a SAE when, based upon appropriate medical judgement, 
they may jeopardise the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Suspicion of transmission of infectious agents 
via the trial product and formation of inhibitory antibodies must always be considered a 
SAE.
18 Statistical Considerations
18.2.4.1 PK Endpoints
!
FVIII activity 30 min post-injection (C30min)
...
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 November 2013
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
14 of 14
All pharmacokinetic endpoints will be modelled and analysed by an ANOVA on the log 
transformed parameter by visit. Estimates of each endpoint with 95% confidence intervals will be 
provided back-transformed to the natural scale. In addition, the 90% confidence intervals will be 
provided back-transformed to the natural scale for AUC and C30min.
18.10 Analyses of Extension Phase Data
...
Data from part 2 of the Extension Phase
All safety parameters except Adverse Events and Serious Adverse Events, will in Extension Phase 
Part 2 be presented by listings and individual graphical representation only. 
All other evaluations/summaries based on accumulated data in part 1will be repeated in part 2, 
accumulating data from the entire trial (Main Phase + Extension Phase part 1 + part 2).
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
1 of 10
Protocol Amendment
no 19
to Protocol, final version 11
dated 29 November 2013
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, including Pharmacokinetics, of 
NNC 0129-0000-1003 when Administered for Treatment and Prophylaxis of Bleeding in 
Patients with Haemophilia A
Trial phase: 3
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
2 of 10
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......................................................................................................................................................3
2.1
Section 1 Summary........................................................................................................................3
2.2
Section 2 Flow Chart .....................................................................................................................4
2.3
Section 3.2 Rational for trial design ..............................................................................................4
2.4
Section 5.1 Type of Trial ...............................................................................................................5
2.5
Section 5.3.5 Patients Continuing Into the Extension Phase .........................................................5
2.6
Section 8.1.4 Visit 14-n and EOT Visit- visit in the Extension Phase of the trial .........................5
2.7
Section 8.1.8 Transfer of Patients to pathfinder™7......................................................................5
2.8
Section 8.3.2 Antibody assessments..............................................................................................6
2.9
Section 8.3.2.3 HCP antibodies.....................................................................................................6
2.10
Section 8.3.7 Central Laboratory Assessments..............................................................................7
2.11
Section 8.3.7.3 FVIII Activity (central Laboratory)......................................................................7
2.12
Section 8.4.5. PRO Questionnaires and Health Economics...........................................................7
2.13
Section 10 Interactive Voice/Web Response System (IV/WRS)...................................................7
2.14
Section 12.2.1 Follow-up of Adverse Events ................................................................................8
2.15
Section 18.5 Interim Analysis........................................................................................................9
2.16
Section 25 Retention of Clinical Trial Documentation and Human Biosamples...........................9
Table of Figures   
Page
Figure 1 Figure 3-1 Overview of the pathfinder™ clinical trial programme.....................................................4
Table of Tables   
Page
Table 2–1 Table 12-1 Handling of Not Recovered/recovering Non-Serious AEs from pathfinder™3 .............8
Table 2–2
Table 12-2 Handling of Not Recovered/recovering Non-Serious AEs from pathfinder™7 ..........9
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
3 of 10
1
Introduction including rationale for the protocol amendment
This protocol amendment has been prepared to include the following changes to the protocol:
!
Allow some parthfinder™2 patients to participate in a separate PK trial NN7088-4033 
(pathfinder™7). The rational for conducting the pathfinder™7 is to compare the PK profile 
for N8-GP produced at two different manufacturing sites
!
Monitor antibody development against Host Cell Protein (HCP). No new blood samples will 
be required since the samples collected for the N8-GP binding antibody analysis will be 
used. The rational for implementing the HCP antibody analysis is based on a 
recommendation from the U.S. Food and Drug Administration (FDA)
!
Interim analysis including data from the extension phase part 2 are planned prior to 
submission of Biologics License Application and Marketing Authorisation Application
!
Prolonged storage of leftover blood samples to enable further characterisation as new 
biomarkers related to the disease and/or safety, efficacy, or mechanism of action may 
evolve. This might improve the understanding and treatment of haemophilia in the future.
Furthermore minor mistakes and inconsistencies have been corrected.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 1 Summary
…
If the patients need to undergo surgery during the present trial they can switch into the surgery trial 
NN7088-3860 (pathfinder™3). Upon completion of the surgery the patients can return to the 
NN7088-3859 (pathfinder™2) trial. 
In some countries patients will have the possibility to participate in a separate PK trial NN7088-
4033(pathfinder™7). If a patient decides to participate in the pathfinder™7, the patient will return 
to the pathfinder™2 trial after completion of the pathfinder™7.
…
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
4 of 10
!
N8-GP drug product
N8-GP 2000 U/vial 211μg/vial drug product is a lyophilised powder in single use vials with a 
nominal content of 2000 U/vial produced by Novo Nordisk A/S, Denmark.
2.2
Section 2 Flow Chart
…
Footer 12: Approximately every year Only yearly (at V21, V25…)
For ‘N8-GP binding antibodies’ the following footnote is added:
Footer 15: HCP antibodies will be analysed using samples taken for the N8-GP binding antibodies 
at the time points described in section 8.3.2.3
2.3
Section 3.2 Rational for trial design
…
The phase 3 trials are offered as one package to each investigational site to ensure that patients are 
offered to continue N8-GP until commercially available and patients in need of surgery can undergo 
surgery without having to switch product. In addition patients in some countries will be offered to 
participate in a PK trial NN7088-4033 (pathfinder™7). Patients will return to pathfinder™2 after 
completion or withdrawal from pathfinder™7.
…
Figure 1 Figure 3-1 Overview of the pathfinder™ clinical trial programme.
pathfinder™1
Phase 1
pathfinder™2 pivotal
Main Phase
Extension Phase 
Part 1
Extension Phase 
Part 2
Patients
pathfinder™3 
Surgery
pathfinder™7 
PK
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
5 of 10
2.4
Section 5.1 Type of Trial 
…
Recruitment into the surgery trial pathfinder™3 will begin after successful treatment of bleeding 
episodes with N8-GP in at least 5 patients in the pivotal trial pathfinder™2. The surgery trial will 
not be initiated until at least 20 bleeding episodes in at least 10 patients are treated with N8-GP in 
the present trial.
In addition patients in some countries will be offered the opportunity to participate in a PK trial 
(pathfinder™7). Patients will be allowed to return to pathfinder™2 after completion or withdrawal 
from pathfinder™7.
2.5
Section 5.3.5 Patients Continuing Into the Extension Phase
…
As all patients will complete the Main Phase at the same time the continuation of patients from the 
Main Phase to the Extension Phase will be gradual and within a window of approximately 2 months 
depending on approval of the Extension Phase in the country and of patients’ next scheduled visit. 
Please refer to
In the Extension phase part 2 patients already included in the pathfinder™ 2 trial will in some 
countries be offered the opportunity to participate in the pathfinder™ 7 PK trial. 
Please refer to Figure 3-1for an overview of the flow of patients between trials in the clinical 
development programme.
2.6
Section 8.1.4 Visit 14-n and EOT Visit- visit in the Extension Phase of the trial
…
Blood sampling for central laboratory assessments:
!
Biochemistry, see section 8.3.7.1 (not at Visit 14)
!
…
!
Host cell protein (HCP) antibodies, see section 8.3.2.2
2.7
Section 8.1.8 Transfer of Patients to pathfinder™7
To enable patients to be transferred to the pathfinder™7 trial, the Investigator must ensure the 
following:
!
Order trial product for the pathfinder™7 to ensure that trial product is available at trial 
start
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
6 of 10
!
At the day of transferring to pathfinder™7 the IV/WRS ”PK trial transfer” session must be 
used in order to transfer the patient into pathfinder™7
!
The patient must return all drug dispensed in the current trial before entering pathfinder™7 
!
After completion of pathfinder™7 trial the IV/WRS ”PK trial transfer session” must be 
performed in order to transfer the patient into pathfinder™2
Upon completion of pathfinder™7, patients should return to pathfinder™2 re-entering the 
treatment regimen as per their prior participation in the trial. 
If a patient cannot return to the same treatment regimen as before transferring to pathfinder™7, 
the investigator must choose the most appropriate regimen for the patient available in 
pathfinder™2. However, patients in the every 4 day dosing regimen will not be allowed to switch to 
every 7 day dosing regimen until the 6 month evaluation period have been completed and the 
requirements fulfilled see section 5.3.1.
The patient will return to the next visit in line in pathfinder™2 and the visit assessments performed 
at the EOT visit in pathfinder™7, will be used.
2.8
Section 8.3.2 Antibody assessments
…
The samples will be analysed both using the Bethesda assay identifying inhibitory antibodies 
towards FVIII and using an assay capable of identifying the occurrence of any antibodies towards 
N8-GP.
In addition an analysis for antibodies developed against HCP, i.e., HCP-antibodies, will be 
performed. 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.
2.9
Section 8.3.2.3 HCP antibodies
A selection of the samples collected for the N8-GP binding antibody analysis will be analysed for 
HCP antibodies. 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 6-12 months.
If deemed necessary more samples may be analysed to fully characterise the individual patient’s 
HCP antibody profile.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
7 of 10
2.10
Section 8.3.7 Central Laboratory Assessments
…
For pathfinder™2 main phase: All blood samples including genotyping blood sample will be 
destroyed after finalisation of the trial report. Blood samples of patients who are suspected of 
inhibitors or who have developed inhibitors will be stored at least until evaluation of the clinical 
trial data by the authorities in the patient’s country.
For pathfinder™2 extension phase: Laboratory samples will be destroyed after trial completion.
If allowed by local law and consented to, in pathfinderTM2 extension phase addendum ‘Storage of 
blood samples from pathfinderTM2’, samples drawn for analysis of antibodies in pathfinderTM2 
main and extension phase will be stored until market authorisation in case further characterisation 
of the samples should be required by authorities.
However, if allowed according to local law all blood samples might be stored for a maximum of 15 
years from end of trial after which they will be destroyed see section 25.2. 
2.11
Section 8.3.7.3 FVIII Activity (central Laboratory)
The analysis of plasma FVIII activity will be performed at laboratory selected by Novo Nordisk by 
two three different assays (one stage clot and chromogenic assay see below), but only one FVIII 
activity result is reported to the site.
2.12
Section 8.4.5. PRO Questionnaires and Health Economics 
PROs will be collected at screening visit (Visit 1), at Visit 13 (end of main phase), at Visit 17 (end 
of part 1) and approximately every year during Extension Phase part 2 (Visit 21, 25…) and at the 
End of Trial visit for all patients.
2.13
Section 10 Interactive Voice/Web Response System (IV/WRS)
…
As a minimum, the system will be used for:
!
screening of patients
!
…
!
PK trial transfer session
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
8 of 10
2.14
Section 12.2.1 Follow-up of Adverse Events
…
After access to update the AE form in EDC is removed the Investigator must record any SAE and 
MESI follow-up information, if required, on the paper CRFs provided at trial closure.
Details on how to handle AEs that were not Recovered/Recovering in the pathfinder™3 
Surgery & pathfinder™ 7 PK Trials when patients are included in returning to the 
pathfinder™2 Trial
An AE (including SAEs and MESIs), that is not recovered/recovering in the Surgical Trial 
pathfinder™3 when the patient is enrolled into returns to the present trial (pathfinder™2), will be 
followed up in the preceding Surgical Trial (pathfinder™3) and entered by the Investigator as 
concomitant illness in the present trial. An AE (including SAEs and MESIs), that is not 
recovered/recovering in the PK trial (pathfinder™7) will upon return of the patient be followed up 
in the present trial (pathfinder™2).
Non-serious AEs that are reported as not related and not severe in the Surgery and PK Trials will 
not be followed-up when enrolling into returning to the pathfinder™2 trial. Details on how to handle 
unresolved non-serious AEs when patients are transferred from the pathfinder™3 & 7 (Surgery and 
PK Trials) into the present trial (pathfinder™2) are described below and in table 12.1 and table 12.2.
Table 2–1 Table 12-1 Handling of Not Recovered/recovering Non-Serious AEs from 
pathfinder™3
Severity
Outcome Categories
Relationship
AE follow-
up in:
NN7088-
3860 
(Surgery) 
AE in 
NN7088-
3859 
(Present)
Concomitant 
illness in 
NN7088-
3859 
(Present)
Mild/
Moderate
Severe
Recovered/
Recovered 
with sequelae/
Fatal/
Unknown
Not 
recovered/
Recovering
Probable/
Possible
Unlikely
X
X
X
Yes
No*
Yes
X
X
X
Yes
No*
Yes
X
X
X
No
No*
No
X
X
X
Yes
No*
Yes
* Unless worsened during participation in pathfinder™2 (Present Trial)
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
9 of 10
Table 2–2 Table 12-2 Handling of Not Recovered/recovering Non-Serious AEs from 
pathfinder™7
Severity
Relationship
AE follow-
up in:
NN7088-
4033 (PK) 
AE in 
NN7088-
3859 
(Present)
Concomitant 
illness in 
NN7088-3859 
(Present)
Mild/
Moderate
Severe
Probable/
Possible
Unlikely
X
X
No
No
Yes
X
X
No
No
Yes
X
X
No
No
Yes
X
X
No
No
Yes
2.15
Section 18.5 Interim Analysis
…
All main conclusions from the trial will be based on this reporting. Furthermore, an interim analysis 
will be performed when the patients enrolled in the randomised part of the Extension have 
completed part 1. 
In addition interim analyses including data from the extension phase part 2 are planned prior to 
submission of Biologics License Application and Marketing Authorisation Application.
2.16
Section 25 Retention of Clinical Trial Documentation and Human Biosamples
25.1 Retention of Clinical Trial Documentation
...
Novo Nordisk will maintain Novo Nordisk’s documentation pertaining to the trial as long as the 
product is on the market plus 20 years. The files from the Investigator site/institution will be 
retained 15 years after the completion of the trial, or longer if required by national regulations.
25.2 Retention of Human Biosamples
If allowed according to local law leftover blood samples may be retained for later analysis for 
further characterisation until marketing authorisation approval or until the research project 
terminates, but no longer than 15 years from end of trial after which they will be destroyed. As new 
biomarkers related to the disease and/or safety, efficacy, or mechanism of action may evolve the 
analyses may also include biomarkers that are unknown at present or have not been included in the 
scientific hypothesis at initiation of the trial. The samples will be stored at a Novo Nordisk 
designated central laboratory. 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 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
29 April 2016
Novo Nordisk
Trial ID: NN7088-3859
Version:
2.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
10 of 10
with the samples. The analyses will not have any medical consequences for the patients or their 
relatives.
Only Novo Nordisk staff and central laboratory personnel (if applicable) will have access to the
stored blood samples.
In the event that the blood samples are used in the future, the investigator will become directly 
informed by Novo Nordisk about the results if the findings are deemed clinically and analytically 
valid and quantifiable. Patients or parent(s)/LAR may at any time contact the investigator if they 
wish to be informed about results derived from stored blood samples obtained from their own body.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
23 January 2017
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
1 of 3
Protocol Amendment
no 20
to Protocol, final version 12.0
dated 02 May 2016
Trial ID:NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy, including Pharmacokinetics, of NNC 
0129-0000-1003 when Administered for Treatment and Prophylaxis of Bleeding in Patients 
with Haemophilia A
Trial phase: 3
Applicable to: Denmark, Italy, Netherlands and Switzerland
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
23 January 2017
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
2 of 3
Table of Contents
Page
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes to section 9 Trial supplies..........................................................................................................3
9.1 
Trial Product(s)..............................................................................................................................3
9.4 
Storage, Handling, Accountability and Destruction of Trial Product(s)........................................3
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
23 January 2017
Novo Nordisk
Trial ID: NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
3 of 3
1
Introduction including rationale for the protocol amendment
The rationale for this protocol amendment is the introduction of N8-GP in 3000 IU vials instead of 
2000 U vials. The change is evaluated to be convenient for the patients since the use of N8-GP in 
3000 IU vials will reduce the required injection volume compared to the use of N8-GP in 2000 U 
vials. In addition the number of N8-GP vials required for each injection will be reduced for some
patients depending on the patient’s bodyweight.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes to section 9 Trial supplies
9.1 
Trial Product(s)
The following trial products will be supplied by Novo Nordisk:
!
N8-GP 2000 U/vial 211μg/vial as a sterile, freeze-dried powder in a 2-8 ∀C (36-46∀F) stable 
formulation single use vial of 2000 U/vial to be reconstituted with 4.3 mL of 0.9% Sodium 
Chloride (NaCl) for i.v. injection.
!
N8-GP 3000 IU/vial as a sterile, freeze-dried powder in a 2-8°C (36-46°F) stable 
formulation single use vial of 3000 IU/vial to be reconstituted with 4.3 mL of 0.9% Sodium 
Chloride (NaCl) for i.v. injection. The strength is given as IU, however, for N8-GP the 
strength IU equals U and these units can be used interchangeably.
N8-GP 2000 U/vial 211μg/vial powder must be reconstituted prior to administration. After 
reconstitution with 4.3 mL Sodium Chloride 0.9% solution each 2000 U vial contains 500 U/mL of 
N8-GP (4 mL can be withdrawn from the vial).N8-GP 3000 IU/vial powder must be reconstituted 
prior to administration. After reconstitution with 4.3 mL Sodium Chloride 0.9% solution each 3000 
IU vial contains 750 IU/mL of N8-GP (4 mL can be withdrawn from the vial). Sodium Chloride 
0.9% will be provided by Novo Nordisk.
...
9.4 
Storage, Handling, Accountability and Destruction of Trial Product(s)
N8-GP 2000 U/vial 211μg/vial must be stored at 2-8 °C, protected from light.N8-GP 3000 IU/vials
must be stored at 2-8 °C, protected from light
CONFIDENTIAL


Protocol Amendment no 21
CONFIDENTIAL
Date:
04 January 2018
Novo Nordisk
Trial ID:NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT no: 2011-001142-15
Page:
1 of 3
Protocol Amendment
no 21
to Protocol, version 12
dated 02 May 2016 
(for Denmark, Italy, Netherlands and Switzerland: 
Amendment to Protocol, version 13
dated 24 January 2017)
Trial ID: NN7088-3859 
A Multi-national Trial Evaluating Safety and Efficacy, including Pharmacokinetics, of NNC
0129-0000-1003 when Administered for Treatment and Prophylaxis of Bleeding in Patients
with Haemophilia A
Trial phase: 3
Applicable to all countries 
CONFIDENTIAL


Protocol Amendment no 21
CONFIDENTIAL
Date:
04 January 2018
Novo Nordisk
Trial ID:NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT no: 2011-001142-15
Page:
2 of 3
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
CONFIDENTIAL


Protocol Amendment no 21
CONFIDENTIAL
Date:
04 January 2018
Novo Nordisk
Trial ID:NN7088-3859
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT no: 2011-001142-15
Page:
3 of 3
1
Introduction including rationale for the protocol amendment
The purpose of this amendment is to clarify when patients participating in pathfinder2 
(NN7088-3859) can complete the trial.
From May 2018, patients will be offered to complete their visit schedule in NN7088-3859 and 
transfer to a new trial (NN7088-4410), where treatment with N8-GP can be continued. Transfer can 
take place when local authority approvals for the new trial have been obtained.
The planned LPLV date for NN7088-3859 remains unchanged. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
Section 7 Trial Schedule
…….
Planned date for FPFV: 
01-Feb-2012
Planned date for LPLV: 
03-Dec-2018*
*Patients may successfully complete the trial from May 2018, irrespective of their last scheduled
visit.
…….
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical analysis plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT01480180 
Sponsor trial ID: 
NN7088-3859 
Official title of study: 
A multi-national trial evaluating safety and efficacy, including 
pharmacokinetics, of NNC 0129-0000-1003 when 
administered for treatment and prophylaxis of bleeding in 
patients with haemophilia A. 
Document date: 
05-May-2019


Link
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6tatisticalanalysisplan...........................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Turoctocog alfa pegol
NN7088-3859 Ext 2 Final
Clinical Trial Report
Appendix 16.1.9
0D\2019
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16.1.9 Documentation of statistical methods
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Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
1 of 25
Statistical Analysis Plan
Trial ID: NN7088-3859
A Multi-national Trial Evaluating Safety and Efficacy,
including Pharmacokinetics, of NNC 0129-0000-1003 when
Administered for Treatment and Prophylaxis of Bleeding in
Patients with Haemophilia A 
Author:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
2 of 25
Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Scope of the statistical analysis plan..........................................................................................4
2
Statistical considerations .....................................................................................................................6
2.1
Sample Size Calculation............................................................................................................6
2.2
Statistical Methods....................................................................................................................6
2.2.1
General Considerations ............................................................................................6
2.2.2
Primary Endpoint(s).................................................................................................7
2.2.3
Confirmatory Secondary Endpoints........................................................................12
2.2.4
Supportive Secondary Endpoints............................................................................13
2.2.4.1
PK Endpoints ...................................................................................13
2.3
Safety Endpoints .....................................................................................................................18
2.4
Exploratory endpoints .............................................................................................................18
2.5
Interim Analysis......................................................................................................................18
2.6
Sequential Safety Analysis/Safety Monitoring.........................................................................19
2.7
Explorative Statistical Analysis for Pharmacogenetics and Biomarkers....................................19
2.8
PK and/or PD Modelling.........................................................................................................19
2.9
Health Economics and/or Patient Reported Outcome...............................................................20
2.10
Analyses of Extension Phase Data...........................................................................................20
2.11
Additional Evaluations............................................................................................................22
3
Changes to the statistical analyses planned in the protocol..............................................................23
4
References ..........................................................................................................................................25
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
3 of 25
List of abbreviations
AE
Adverse event
ANOVA
Analysis of variance
AUC
Area under the curve
BU
Bethesda unit
BW 
Body weight
C30min
FVIII activity at 30 min post injection
CI
Confidence interval
CL 
Total clearance
CTR
Clinical trial report
ED
Exposure days
EOM
End of Main part of the trial
FVIII
Coagulation factor eight
LOCF
Last observation carried forward
N8-GP 
Glycopegylated recombinant coagulation factor VIII (NCC 0129-0000-1003)
OD
Over-dispersion
PD
Pharmacodynamics
PK
Pharmacokinetics
PPX 
Prophylaxis
PRO 
Patient reported outcome
SAE
Serious adverse event
SAP
Statistical analysis plan
t½ 
Terminal half life
Vss 
Volume of distribution at steady state
Vz 
Apparent volume of distribution
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
4 of 25
1
Introduction
1.1
Trial information
This phase 3 trial is a multi-centre, multi-national, open-label, non-randomised trial evaluating 
safety, pharmacokinetics and clinical efficacy of NNC 0129-0000-1003 (hereafter referred to as N8-
GP) when used for treatment of bleeding episodes and for long-term prophylaxis. The trial consists 
of a Main Phase followed by an Extension Phase part 1 and part 2. In the main phase, patients in the 
prophylaxis arm were receiving one single bolus dose of 50 U/kg body weight (BW) of N8-GP 
every 4 days (96 hours interval). 
In the extension part 1, patients with a low bleeding rate on every 4 day prophylaxis in the main 
phase have the possibility of being randomised to either 50 U/kg BW every 4th day or to 75 U/kg 
BW once weekly dosing. If the patient for the last 6 months (180 days) prior to Visit 13/14 only had 
0 - 2 bleeding episodes, the patient was eligible for randomisation. Patients who were not eligible to 
be in the randomised arm or patients who are eligible but unwilling to be randomised can stay on 
the same regimen as in the Main phase.
In the extension phase part 2, patients with a low bleeding rate (0-2 bleeding episodes during the 
last 6 months) on every 4 day prophylaxis have the possibility of changing to 75 U/kg BW once 
weekly dosing regimen. Patients who has been on 75 U/kg BW once weekly dosing during 
extension phase part 1 can continue on this regimen arm or change back to either 50 U/kg BW 
every 4th day  if the patients want to. Patients on once weekly dosing who have more than 2 
spontaneous bleeds within a 8 week period or are hospitalised due to a bleed need to change back to 
every 4 days regimen according to the protocol.
1.2
Scope of the statistical analysis plan
The scope of this SAP is to clarify the planed analysis for extension phase part 2 described in the 
protocol. 
This SAP is based on the Protocol A Multi-national Trial Evaluating Safety and Efficacy, including 
Pharmacokinetics, of NNC 0129-0000-1003 when Administered for Treatment and Prophylaxis of 
Bleeding in Patients with Haemophilia A version 1.0 (30-Sep-2011) including Final Substantial 
Amendment no 1 version 1.0, NL (24-Oct-2011), Final Substantial Amendment no 2 version 1.0, 
Global (09-Dec-2011), Final Substantial Amendment no 5 version 1.0 FR (3-Feb-2012), Final 
Substantial Amendment no 6 version 1.0, Global (30-Mar-2012), Final Substantial Amendment no 
8 RU (21-Jun-2012), Final Substantial Amendment no 10 version 2.0, Global (03-Dec-2012), Final 
Substantial Amendment no 11 version 1.0 IL (05-Dec-2012),Final Substantial Amendment no 12 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
5 of 25
version 1.0, Global (05-Mar-2013), Final Substantial Amendment no 13 version 1.0, Global (03-
May-2013), Final Substantial Amendment no 14 version 1.0, Global (12-Jul-2013), Final 
Substantial Amendment no 15 version 1.0, Global (28-Aug-2013), Final Substantial Amendment no 
18 version 1.0, Global (29-Nov-2013), Final Substantial Amendment no 19 version 2.0, Global (29-
Apr-2016), and the final version of the protocol for this trial (version 13, 24 January 2017).
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Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
6 of 25
2
Statistical considerations
The Pivotal part of the trial was reported based on all data from the Main Phase where all patients 
have reached at least 50 EDs (except for patients having had surgery as part of pathfinder™3), and 
all patients have had their first visit after 50 EDs where all planned assessments including inhibitors 
have been performed. All main conclusions from the trial are based on this reporting except for 
conclusions regarding every 7 day prophylaxis and long term safety/efficacy. 
In the interim at end of extension phase part 1 all data from main phase up to the end of extension 
phase part 1 was analysed and reported. The main focus was on once weekly prophylaxis with 
every 4 day dosing as control where patients with low bleeding rate could be randomised to the two 
treatment arms.
The main reason for the interim for the ongoing extension phase part 2 including all data from the 
main phase and extension phase up to the cut-off is to collect additional safety and efficacy data.
2.1
Sample Size Calculation
The study has two co-primary endpoints for the Pivotal part that both need to succeed for the study 
to succeed. The co-primary endpoints can reasonably be considered approximately independent and 
combined power then becomes the product of the individual power for each co-primary endpoint.
For further detail, see section 18.1 in the protocol.
2.2
Statistical Methods
2.2.1
General Considerations
Novo Nordisk A/S will be responsible for the statistical analysis. All tests will be performed as 1-
sided tests on 2.5% significance level. All bleeding endpoints will be evaluated based on bleeding 
episodes requiring treatment with N8-GP. Non-treatment requiring bleeding episodes that coincide 
with regular prophylaxis doses are not included in the analyses. 
Multiple bleeding locations occurring from the same event (e.g. due to a bicycle accident) or at the 
same time point will be counted as one bleeding episode and only one haemostatic response will be 
considered for the bleeding episode. In case different responses were registered for different 
bleeding locations in such a bleeding episode, the worst response will be used in the analysis.
As stated in the protocol, a re-bleed is defined as a worsening of symptoms in the same location 
after an initial period of improvement, either on treatment or within 72 hours after stopping 
treatment. If a bleed occurs in the same location later than 72 hours after stopping the treatment it is 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
7 of 25
considered a new bleed. Re-bleeds will only be considered for joint bleeds since the specific 
location for other bleeds e.g. in subcutaneous are not captured in the database.
In the sub analyses of annualised bleeding rate where there are less than 5 patients in a sub-group,
model based estimation will not be done. If no bleedings occur in a sub-group, then the confidence 
interval will not be calculated.
2.2.2
Primary Endpoint(s)
The study has two co-primary endpoints that both have to succeed.
Incidence Rate of FVIII-inhibitors !0.6 BU
The rate of inhibitors will be reported and a 1-sided 97.5% upper confidence limit will be provided 
based on an exact calculation for a binomial distribution. For the calculation of the inhibitor rate the 
nominator will include all patients with neutralising antibodies while the denominator will include 
all patients with a minimum of 50 exposures plus any patients with less than 50 exposures but with 
neutralising inhibitors. Adequate safety with regard to neutralising inhibitors will be concluded if 
the upper 1-sided 97.5% confidence limit is below 6.8% roughly corresponding to the upper 97.5% 
confidence limit if 2 inhibitors out of 105 patients are observed (3 or less if the study should get 127 
or more patients with 50 exposure days).
Annualised bleeding rate (total number of bleeding episodes per patient assessed as 
annualised bleeding rate) in the prophylaxis arm 
A review of historical data has found that haemophilia A patients on on-demand treatment on 
average bleed 24 times per year while they bleed 6.8 times per year when treated on prophylaxis. 
Historical Control for Hypothesis Test for Prophylaxis
Based on the studies referenced below, Novo Nordisk suggests that representative numbers for 
mean annual bleeding rate (ABR) in severe haemophilia patients is 24 bleeds/year for patients 
treated on-demand and 6.8 for patients on prophylactic treatment. 
Novo Nordisk has based the estimate of historical annual bleeding rate on a systematic review of 
the treatment of Haemophilia A and B and von Willebrand disease, performed by the Swedish 
Council on Health Technology Assessment.
The referenced report is based on review of 3710 abstracts in total, covering treatment of 
Haemophilia A, B or von Willebrand disease. Articles were then selected for full review according 
to specific criteria such as administration of recombinant or plasma-derived Factor concentrate, 
outcome (eg number of bleeding episodes, inhibitor development or quality-of-life measurements), 
and number of patients included. For haemophilia A, only studies comprising 20 patients or more 
were selected. The main objectives of the SBU review is to evaluate the short- and long-term effects 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
8 of 25
with different treatment strategies with coagulation factor concentrates in Haemophilia A and B and 
von Willebrand disease.
In the search, SBU identified 37 references dealing with “replacement therapy with factor 
concentrates in treating severe, moderate, and mild haemophilia A”. All these references identified 
by SBU were reviewed as full length articles at Novo Nordisk, and only the original papers with a 
mean total ABR reported (or at least possible to calculate) in patients with an endogenous FVIII:C 
activity <2% were included in our analysis.
Table 2–1
Historical mean total annual bleeding rate in Haemophilia A patients with an 
endogenous FVIII:C activity <2% 
SBU 
Ref 
No
Reference
On-demand 
(mean ABR)
Number of 
patients
Prophylaxis 
(mean ABR)
Number 
of 
patients
4
Courter, 20013
18
27
4
27
5
Lusher, 20034
23
85
10
85
5
Lusher, 20034
N.R.
N.R
6
45
9
Tarantino, 20045
N.R.
N.R.
6.3
107
10
Nemes, 20076
N.R.
N.R.
4.9
49
11
Recht, 20097
N.R.
N.R.
3.9
94
15
Abshire, 20002
34
38 
8.3
27
17
Smith, 2005*8
N.R.
N.R.
10.3
32
18
Manco-Johnson, 
20071
18
33 
3.3
32
25
Schwartz, 1990**9 19
56
N.R.
N.R.
Weighted Mean
24
179
6.8
394
ABR = Annual Bleeding Rate. N.R. = not reported. Studies in italics havenot included adults. No = 
Reference number in SBU report, chapter 3.1.1. * 5/32 are moderate Hemophilia A, **4/56 are 
moderate Hemophilia A
In the studies, the mean ABR in patients on prophylaxis is consistently lower than in patients 
treated on-demand, as expected. The studies have ABR in the range of 18 –34 and 3.3 –10, for on-
demand and prophylaxis treatment, respectively, and include different numbers of subjects. To 
arrive at a representative ABR number from the various studies, we weighted the estimates from 
each study based on the number of subjects included. 
As the proposed trial with N8-GP will only include patients aged 12 years and above, we further 
suggest to exclude 3 of the 9 historical studies1,3,4, that only include children below age 6, in order 
to better reflect the study population. The historical mean ABR for on-demand and prophylaxis in 
haemophilia A with <2% will then be estimated at 24 and 6.8, respectively. However, if also the 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
9 of 25
studies including children below 6 years of age are included, the estimated ABR for on-demand and 
prophylaxis are 23 and 6.4, respectively. The 2% cut off is often used in clinical studies and will 
give a conservative estimate of the ABR in the study population in the proposed trial with a cut off 
of <1%.
Prophylactic effect of N8-GP will be concluded if the bleeding rate is significantly below 50% of 
the historical on-demand bleeding rate (i.e. significantly lower than 12) as well as within 25% of the 
historical prophylaxis bleeding rates (i.e. significantly lower than 6.8*1.25 = 8.5). Since both must 
be met in practice it must be shown that the bleeding rate is significantly lower than 8.5.
Let AR be the true yearly bleeding rate. The null-hypothesis will be tested against the alternative 
hypothesis as given by:
H0: AR ≥ 8.5 against HA: AR < 8.5
The endpoint will be analysed by a Poisson regression model on number of bleeding episodes per 
patient allowing for over-dispersion (using Pearson’s chi-square divided by the degrees of freedom 
(i.e. Scale=Pscale in SAS)) and using log observation duration as an offset. Estimates of the 
annualised bleeding rates will be provided with 95% confidence intervals. 
For patients withdrawing prematurely, the number of bleeding episodes counting in the analysis will 
be imputed up to what they could be expected to have had if they had completed the trial. If e.g. a 
patient withdraws after 2 months with 3 bleeding episodes, but the patient should have been in the 
study for 12 months, then this patient will in the analysis count as having had 18 bleeding episodes 
in 12 months. This is similar to last observation carried forward (LOCF) and will avoid positive 
bias occurring from patients with many bleeding episodes withdrawing early. 
The rules for calculating planned exposure time used for imputation depends on what part of the 
trial the patient is withdrawn from and furthermore what parts of the trial the calculations represent
as described in the following.
Calculations of ABR for the Pivotal part:
Since the planned exposure time for each patient in the Pivotal phase of the trial depends on 
when the patient was recruited in the trial, the maximum expected exposure time based on the 
last visit date included in each part of the analysis will be used as planned exposure time, e.g. 
the date of the last patient’s first visit after his 50EDs will be used for the pivotal part of the 
analysis where all patients should have reached at least 50 EDs (except for patients having 
had surgery as part of pathfinder™3).
Calculations of ABR for extension phase part 1:
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Statistical Analysis Plan
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Date:
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Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
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For patients who were withdrawn in the Pivotal part the planned exposure time will be until 
the end of the pivotal part as described above. For patients who were withdrawn in the main 
part after the pivotal part ended, the maximum expected exposure time will be used, i.e. 100 
weeks as this is the maximum duration for main phase. For patients withdrawn during 
extension phase part 1, the planned exposure is 24 weeks (duration of extension phase part 1) 
added to the actual exposure in main
For calculations only including the randomised period, the planned exposure time will be the 
time from visit 14 to visit 17, i.e. 24 weeks. Patients that change from Q7D to non-
randomised part of Q4D will have their bleeds imputed using a planned exposure time of 24 
weeks using the same approach as in the pivotal part of the trial even though they are not 
withdrawn from the study. This is to avoid bias for randomized Q7D caused by patients 
withdrawing due to high bleeding rate.
Calculations of ABR for extension phase part 2:
For patients withdrawn prior to extension phase part 2, planned exposure is calculated as 
explained above. For patients withdrawing during extension phase part 2, planned exposure in 
extension phase part 2 will be calculated using the overall cut-date (15Aug2017) as planned 
end date. The actual exposure time in main and extension phase part 1 is added to the planned 
exposure time in extension phase part 2, to get the overall planned exposure time for a 
withdrawn patient.
Planned exposure time is only relevant for the treatment regimen the patient is on, when being 
withdrawn. Time on other regimens and time in surgery trial is subtracted when calculating planned 
exposure time.
For patients who withdrew within 1 month, imputation will be conducted by assuming an 
annualised bleeding rate of 24 (bleeds per year) for the missing period. This also applies to change 
from Q7D to Q4D in the randomised part of extension phase part 1.
Estimates of the annualised bleeding rates for each regimen will be provided together with the 95% 
confidence intervals as described in the protocol.
Sensitivity analyses:
Analysis applying a different model
A sensitivity analysis based on a negative binomial regression model with number of bleeding 
episodes requiring treatment as the outcome variable, and adjusting for exposure time will be 
performed.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
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Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
Page:
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Analysis without imputation to planned trial duration 
The primary prophylaxis analysis will be repeated but without imputing number of bleeding 
episodes for any withdrawals. Instead only the observed bleeding episodes will be counted and the 
offset will be actual observation duration rather than planned. 
Analysis imputing by LOCF without imputation for withdrawals occurring within the first 
month
The primary analysis will be repeated but without using imputation of 24 bleeding episodes for 
withdrawals within the first month. Instead only the observed bleeds and the observed duration will 
be used for such subjects.
Analysis imputing a minimum of 24 bleeds per year to planned trial duration
A conservative sensitivity analysis will be performed imputing for all withdrawals the observed 
bleeding rate into the missing period if it is greater than 24 per year and otherwise 24 per year. As 
an example a patient with 3 bleeds in 2 months (observed ABR 18) that should have been in the 
study for 12 months will have 20 bleeds imputed for the missing 10 months. Patients with 6 bleeds 
in 2 months (observed ABR 36) will have 30 bleeds imputed into the missing 10 months.
Analysis of 12 months data from patients that could have had 12 months prophylaxis 
Since patients will stay in the Main Phase of the trial until the same end of Main Phase date some 
patients will get only about 7 months prophylactic treatment while others may get more than 19 
months (except for patients entering the trial with the intention of major surgery after the end of 
normal recruitment period). To investigate if the varying durations have any impact on the results a 
sensitivity analysis will be performed looking only at 12 months data from patients with planned 
trial duration of 12 or more months. Otherwise this analysis will be performed similarly to the 
primary analysis. This sensitivity analysis is not applicable after the interim for extension phase, 
part 1, since no new data for the main phase and extension phase part 1 will be available.
To investigate the effect over time the bleeding rates per month will be calculated and summarised 
numerically and graphically. This will be done by treatment regimen and only including the first 
consecutive period on each treatment regimen. A patient that is on different treatment regimens 
during the trial will therefore have bleeding rate per month calculated for each treatment regimen, 
but only including the first consecutive period on each treatment regimen. Surgery leave is not 
considered change in treatment regimen.
Similarly the bleeding rate by calendar month will be calculated and presented. If there is a calendar 
effect it is conceivable that it would be reversed in the southern hemisphere compared to the 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
12 of 25
northern. Therefore, calendar months for Australia and Brazil are shifted 6 months, i.e. January is 
changed to July, February to August etc.
2.2.3
Confirmatory Secondary Endpoints
Haemostatic effect of N8-GP when used for treatment of bleeding episodes, assessed on a four-
point scale for haemostatic response (excellent, good, moderate and none) by counting excellent 
and good as success and moderate and none as failure.
In order to protect against false significances this endpoint will only be analysed as a confirmatory 
secondary endpoint in the pivotal part if the analyses of the co-primary endpoints are both 
successful. Otherwise this endpoint will be analysed only as a supportive secondary endpoint.
This is assessed as success/failure based on a four-point scale for haemostatic response (excellent, 
good, moderate and none). Excellent and good counts as success and moderate and none as failure. 
In addition any bleeding episodes with missing response information will be counted as failures.
A success rate of 80% is considered the goal. Due to variation it is not certain that N8-GP will 
achieve an observed 80% success rate in this trial even if the true success rate is 80%. For that 
reason it will be demonstrated that the success rate for N8-GP is at most 15% (absolute) worse than 
80%. 
Let R be the true success rate. The null-hypothesis will be tested against the alternative hypothesis 
as given by:
H0: R ≤ 65% against HA: R > 65%
Specifically this will be done by a logistic regression. The analysis will be performed by use of Proc 
Genmod in SAS. Correlation within patients will be taken into account using a Generalized 
Estimation Equations approach with a working correlation matrix with a compound symmetry 
structure. Adequate efficacy will be concluded if the 1-sided lower 97.5% confidence limit for the 
success rate is above 65%.
Response as measured by the four point scale will also be summarised and listed. Bleeding episodes 
will come both from the on-demand periods and from prophylaxis periods. This will be analysed 
together in the statistical analysis but will also be summarised by treatment regimen.
Sensitivity analyses
Analysis on observed responses only (i.e. excluding missing observations)
A sensitivity analysis will be performed similar to the primary analysis but only analysing bleeding 
episodes with recorded responses (i.e. not counting any bleeding episodes with missing response as 
failures).
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Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
13 of 25
Analysis imputing missing haemostatic response based on number of infusions used
A sensitivity analysis will be performed using the number of infusions given to impute the 
haemostatic response for missing data. Specifically missing responses where only 1 dose was used 
will be counted as success while missing responses where 2 doses were used will be counted as 
failures.
Analysis imputing missing haemostatic response based on patients recorded responses on 
other bleeding episodes
A sensitivity analysis will be performed where missing treatment responses will be imputed based 
on recorded treatment responses from that particular patients. The imputation will be done 
randomly based on the recorded success rate. As an example if a patient has 2 missing responses 
and 4 treatment successes in 5 treated bleeds with recorded response then the missing responses will 
be imputed randomly based on an 80% success chance. Patients with missing responses for all 
treated bleeding episodes will be imputed as failures for all episodes.
2.2.4
Supportive Secondary Endpoints
Consumption of N8-GP (number of infusions and U/Kg) per bleed
The number of infusions per bleed will be summarised and listed.
The number of U/Kg per bleed will be summarised and listed. 
Consumption of N8-GP (number of infusions and U/Kg per month and per year) during 
prophylaxis and on-demand treatment
The number of infusions per month and per year will be summarised and listed by treatment 
regimen (prophylaxis and on-demand).
The number of U/Kg per month and per year will be summarised and listed by treatment regimen 
(prophylaxis and on-demand).
Haemostatic effect as measured by recovery and trough levels FVIII:C (in all patients in the 
prophylaxis treatment arm)
Recovery and trough levels measured at scheduled visits will be summarised and listed.
2.2.4.1
PK Endpoints
∀FVIII activity 30 min post-injection (C30min)
∀Incremental recovery, ([IU/mL] / [U/kg] )(single dose and steady state)
∀Trough level, ( IU/mL) (single dose and steady state)
∀Area under the curve (AUC), (h*IU/mL)
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Statistical Analysis Plan
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Date:
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Trial ID: 7088-3859-final
Version:
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UTN: U1111-1119-7416
Status:
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Page:
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∀Terminal half-life (t½), (h)
∀Clearance (mL/h/kg)
∀Mean Residence time (MRT) (h)
∀Volume of distribution at steady state (Vss) (mL)
∀Apparent volume of distribution(Vz) (mL)
∀Percentage of AUC(0-inf) determined by extrapolation (%extrap)
∀Terminal elimination rate constant (λz)
Single dose PK will be based on the subgroup of patients with full PK sessions at Visits 2 and 7. 
Steady state PK will be based on the periodic recovery and pre-dose measurements on all patients 
from Visits 3 to 13:
Single dose PK
The PK parameters will be calculated using plasma concentration obtained from chromogenic assay 
and clot assay. The PK parameters will be derived according to a non-compartmental method, as 
described in Table 2–2. The actual time points will be used in the calculations.
If any profiles and/or individual plasma concentrations are excluded from the primary 
pharmacokinetic analysis, a sensitivity pharmacokinetic analysis will also be performed and 
reported based on all observed data. The primary pharmacokinetic analysis is based on the full 
analysis set excluding outliers. 
Specifically which data points and profiles that will be excluded will be defined prior to database 
lock. It should exclude profiles with pre-dosing activity > 5% (possibly indicating inadequate 
washout) and profiles that are not indicative of a normal intravenously short infusion administration 
(e.g. clearly increasing plasma concentrations initially). If a patient is treated with an additional 
dose during the PK session, the plasma concentrations after the occurrence will then be excluded.  
Furthermore, if the profile shows indications of an additional dose (e.g. clearly increased plasma 
concentration), the plasma concentrations after the occurrence will then also be excluded. 
All pharmacokinetic endpoints (except MRT, Vss, Vz, percentage of AUC(0-inf) determined by 
extrapolation and Terminal elimination rate constant) will be analysed using mixed effects model 
on log-transformed parameters including visit as fixed effect, and patient as random effects. 
Estimates of each endpoint with 95% confidence intervals will be provided back-transformed to the 
natural scale. In addition, AUC and C30min will be compared between the 2 visits as estimated ratio 
between the two visits together with the 90% confidence intervals.
All PK profiles will be presented graphically by subject and by visit.
Furthermore, the mean PK endpoints will be summarised and individual PK endpoints will be 
listed.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
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Table 2–2
Definition and Calculation of PK Parameters
Parameter
Description
Calculation
Incremental 
Recovery
Dose-normalised activity recorded 
30 min after end of infusion and 
reported as [IU/mL]/[U/kg]. 
Expected to be the highest dose-
normalised activity observed.
The incremental recovery is calculated by 
subtracting the FVIII activity (IU/mL) 
measured in plasma at time 0 from that 
measured at time 30 min after dosing and 
dividing this difference by the dose injected 
at time 0 expressed as U/kg BW
C30min
The FVIII activity recorded 30 
min after end of infusion. Measure 
of maximum exposure
The FVIII activity recorded 30 min after 
end of infusion. The value is sensitive to 
deviations from the scheduled sampling 
time. This limits the value of this 
parameter, especially when comparing to 
other studies. 
Trough 
level 
Activity recorded immediately 
before next dose is given and 
reported as [IU/mL]. Expected to 
be the lowest dose-normalised 
activity observed.
t½
Terminal half-life
t½ = ln(2) / λz, where λz is the terminal 
elimination rate. The terminal elimination 
rate will be estimated using linear 
regression on the terminal part of the 
log(activity) versus time profile
CL
Total plasma clearance of drug 
after intravenous administration
CL= Dose / AUC
AUC(0-inf)
Area under the activity versus 
time profile from time zero to 
infinity. Measure of total plasma 
exposure. 
AUC = AUC(0-t) + C(t) / λz ,
where C(t)  is the last measurable activity.
AUC(0-t)
Area under the plasma activity 
versus time profile from time zero 
to the last measurable activity. 
Measure of plasma exposure in the 
time interval 0 to last measurable 
activity.
AUC(0-t) is calculated using the linear 
trapezoidal method from time 0 to the time 
for the last measurable activity. The activity 
at time 0 will be estimated by log-linear 
back extrapolation of the two initial post-
administration activities. If the second value 
is not lower than the first value, the 
concentration at time 0 will be defined as 
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Statistical Analysis Plan
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Date:
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Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
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the highest of these two.
Vz
Apparent volume of distribution 
based on the terminal phase
Vz = CL/λz
Vss
Apparent volume of distribution at 
steady-state
Vss = CL x MRT
%extrap
Percentage of AUC(0-inf) 
determined by extrapolation
AUCt-inf/(AUC(0-inf))
MRT
Mean Residence Time
MRT = AUMC/AUC(0-inf), where AUMC 
is the area under the first moment curve, i.e. 
the area under the curve t∙C(t), calculated 
with the same method as AUC(0-inf) (linear 
trapezoidal method + extrapolated area) 
λz
Terminal elimination rate constant
The terminal elimination rate constant will 
be estimated using linear regression on the 
terminal part of the log(activity) versus time 
profile
Since no new single dose PK profiles have been collected since main phase, PK parameters will not 
be reported for the extension phase part 2 interim. 
Steady state PK
The following rules will be implemented for pre-dose activity, post dose activity and incremental 
recovery:
∀
FVIII activity data will be excluded if post-dose activity is ≤ pre-dose FVIII activity.
∀
Samples drawn more than #2 days from planned time as well as less than twice the 
prophylaxis treatment interval after last treatment of bleed will be excluded.
∀
For patients performing a PK session at Visit 7 (including a wash-out period), the pre- and 
post-dose data will be excluded from calculation of mean trough and mean recovery. The 
incremental recovery will still be calculated.
∀
Samples for randomised patients in extension phase part 1 changing from every 7 day 
dosing to every 4 day dosing will be excluded from change of treatment regimen  and 
onwards. 
∀
Samples taken at “return visit” from the surgery trial (NN7088-3860)
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Statistical Analysis Plan
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Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
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EudraCT No.: 2011-001142-15
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∀
FVIII activity measured in defrosted plasma samples will be excluded.
The pre-dose FVIII activity levels assessed from after at least 4 PPX dosing intervals will be 
analysed to get an estimate of the pre-dose level for N8-GP at steady state. The model will be a 
mixed model on the logarithmic plasma activity levels with dose and age as a factor and patient as a 
random effect. Plasma concentrations below lower limit of quantification (LLOQ) will be set to half 
the value of the LLOQ. The estimated pre-dose FVIII level will be presented together with the 95%
confidence intervals. Trial duration for the main phase differs between patients, but all patients 
reach at least Visit 8 prior to being transferred to Visit 13 (end of main phase). Therefore, the 
analysis will be performed both on pre-dose values from main and extension phase part 1 and 
furthermore including only pre-dose values up  to visit 8.
A sensitivity analysis including all data after at least 4 PPX dosing intervals will also be performed 
for both cases.
Furthermore the same analyses will be performed for measurements from the randomised patients 
in the extension phase part 1.
Pre-dose activity, post-dose activity and incremental recovery will be summarised by visit. 
Furthermore, mean pre-dose activity and mean post-dose activity will be plotted vs. time.
In extension phase part 2, the only PK endpoint that will be summarised by visit is incremental 
recovery for all prophylaxis patients, since incremental recovery is independent of dose and dosing 
frequency. Incremental recovery will be calculated using the same activity measurements as used 
for estimation of recovery and trough levels.
In extension phase part 2 the following rules have been added to the rules for activity measurements 
listed above  (the new rules are also applied to activity measurements from main and extension 
phase part 1)
∀
Samples from visits when changing treatment regimen (e.g. from every 4 day dosing to 
every 7 day dosing) will be excluded (this rule replaces the rule for randomised patients 
changing from every 7 day dosing to every 4 day dosing)
∀
Samples taken at “return visit” from the PK-trial (NN7088-4033) are excluded.
∀
If the FVIII activity is above 3.0 IU/ml based on one of the three clot assays and the ratio of 
Clot PSS (chrom)/Chrom PSS > 1.5, all clot data for this sample time point will be 
excluded. The reason for this rule is that plasma samples can be activated during pre-
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Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
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analytical handling resulting in very high FVIII activity measured with one-stage clot assay 
but not with the chromogenic assay.
2.3
Safety Endpoints
Adverse Events (AEs) and Serious Adverse Events (SAEs) reported during the trial
Treatment emergent AEs (TEAEs defined as AEs occurring after dosing with trial product) and 
treatment emergent SAEs (TESAEs) will be summarised by frequency of events and frequency of 
patients with any event. Similar summaries cross-classified by severity and by causal relation to 
trial product will be made. 
Furthermore, listings will be provided displaying all TEAEs and TESAEs including pertinent 
clinical information.
Changes in vital signs (blood pressures, pulse, temperature, respiratory rate)
These endpoints will be presented and listed
Other safety parameters
All additional safety parameters such as laboratory parameters, vital signs and physical 
examinations will be presented and listed.
2.4
Exploratory endpoints
Incidence of anti-N8-GP antibodies (non-neutralising)
Anti-N8-GP antibodies (non-neutralising) will be listed.
Anti-CHO HCP antibodies
Number of samples with negative/positive will be summarised by visit.
Anti-PEG antibodies
Plots will be created of incremental recovery according to PEG antibody status at baseline and 
during the trial.
2.5
Interim Analysis
All data from the Main Phase of the trial will be analysed and reported when all patients have 
reached at least 50 EDs (except for patients having had surgery as part of pathfinder™3), and all 
patients have had their first visit after 50 EDs where all planned assessments including inhibitors 
have been performed. The analysis of the main phase of the trial will be based on all data up to the 
patient’s last visit at this point. All main conclusions from the trial will be based on this reporting. 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
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Furthermore, an interim analysis was performed when all patients had completed extension phase
part 1. The interim for the extension phase part 2 will cover all data from the main phase and
extension phase 1+2 up to last visit before 15-Aug-2017.
2.6
Sequential Safety Analysis/Safety Monitoring
Not applicable (NA).
2.7
Explorative Statistical Analysis for Pharmacogenetics and Biomarkers
NA.
2.8
PK and/or PD Modelling
The relationship between plasma concentration and bleeding frequency will be investigated.
Based on each individuals PK assessments (full PK from some patients but only recovery and 
troughs for most patients) the time to 5%, 3% and 1% FVIII activity after each dose given will be 
calculated and the bleeding rates for each period (>5%, 3-5%, 1-3% and <1%) will be calculated 
and listed and summarised. 
A statistical comparison will be made between the bleeding rates above and below 1% FVIII 
activity. This will be done based on a Poisson regression with patient above or below 1% activity as 
fixed effects. The model will allow for over-dispersion (estimated using Pearsons chi-square 
divided by the degrees of freedom) and will use log duration (above 1% activity and below 1% 
activity respectively) as offset. For computational reasons only patients with at least one bleeding 
episode will be included and similarly only patients with at least 2 weeks cumulative time under 1% 
activity and 2 weeks cumulative time over 1% activity will be included.
The following PK parameters will be estimated using a one-compartment population PK model:
∀CL70kg (L/h)
Population median clearance in a patient of weight 70 kg 
∀V70kg (L)
Population median volume of distribution in a patient of weight 
70 kg 
∀βCL,BW
Allometric exponent for relation between median CL and BW
∀βV,BW
Allometric exponent for relation between median V and BW
Extrapolated population PK parameters:
∀Cmax,SS
Predicted maximal plasma level of FVIII activity in steady state
∀AUCτ
Predicted total exposure to FVIII activity during a single dosing 
interval in steady state
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
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PK and possible PK/PD modelling are considered exploratory analyses that may not be reported in 
the clinical trial report. The PK assay results to be used for modelling are chromogenic FVIII 
activities measured against N8-GP reference material.
Population PK modelling will be done as a combined analysis with data from the first human dose 
trial pathfinder™1 with the main scope of assessing the influence of demographic covariates such as 
BW and possibly race on PK properties of N8-GP. The population PK model of which maximum-
likelihood parameter values are to be estimated is a linear one-compartment model parameterised 
with clearance CL and volume of distribution V. 
The final output of the PK modelling is predictions of FVIII activity exposure parameters (Cmax and 
AUCτ) at steady state in proposed prophylaxis dosing regimes for patients of BW 10 kg, 25 kg, 50 
kg, 70 kg and 100 kg and of any race sufficiently well represented in the trial to allow for 
assessment (min. 20 PK samples from min. 5 different patients). 
2.9
Health Economics and/or Patient Reported Outcome
PROs will in the Main Phase be assessed through PRO questionnaires at screening visit (Visit 1) 
and end of trial visit for patients in the on-demand arm and for patients in the prophylaxis arm. 
The main PRO endpoint will be subgroup total scores. Changes in scores over time of the main 
PRO endpoints at Visit 1 to end of main visit will be explored and presented graphically. 
Evaluations of PRO data will alone be based on descriptive statistics, i.e. summary tables, listings 
and figures. 
HE calculations will be performed separately by the Novo Nordisk HE department. Novo Nordisk 
A/S will be responsible for the statistical analysis. 
2.10
Analyses of Extension Phase Data
Data from part 1 of the Extension Phase
The main objective of part 1 of the Extension Phase is to investigate the safety and efficacy of every 
7 day dosing by evaluating ABR for this dosing regimen and comparing it to the same historical 
bleeding episode rates as used in the primary analysis for the co-primary efficacy endpoint in the 
Main Phase. Prophylactic effect of every 7 day dosing will be concluded if the bleeding rate is 
significantly below 50% of the historical on-demand bleeding rate (i.e. significantly lower than 12) 
as well as within 25% of the historical prophylaxis bleeding rates (i.e. significantly lower than 
6.8*1.25 = 8.5). Since both must be met in practice it must be shown that the bleeding rate is 
significantly lower than 8.5. 
An analysis similar to that for the co-primary endpoint in the Main Phase will be carried out for the 
bleeding episodes in the two randomised treatment regimens during the Extension Phase part 1, 
adding treatment regimen as a factor to the model. Subjects switching from the every 7 day dosing 
arm to the non-randomised every 4 day dosing arm will be handled as withdrawals in this analysis. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
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The imputation for withdrawals will be similar to that for the Main Phase, except that planned 
maximum duration is now 6 months. 
Estimates of the annualised bleeding rates for each randomised regimen will be provided with 95% 
confidence intervals. Prophylactic effect of every 7 day dosing will be concluded if the upper limit 
of the 95% confidence intervals (CI) is below 8.5. In addition, the two randomised treatment 
regimens will be compared by reporting the estimated ratio between the two randomised treatment 
regimens with corresponding 95% confidence interval.
As for the co-primary endpoint in the Main Phase, a sensitivity analysis will be carried out where 
bleeding episodes for withdrawals are not imputed.
ABR based on accumulated number of bleeding episodes (Main Phase + Extension Phase part 1) 
will be evaluated for the every 4 day dosing regimens combined, i.e., combining the randomised 
and non-randomised arm. The model used will be the same as for the primary analysis of the Main 
Phase data.
Only treatment requiring bleeding episodes will be considered in the above evaluations of ABR
Incidence rate of FVIII-inhibitor and haemostatic effect of N8-GP when used for treatment of 
bleeding episodes will be evaluated based on accumulated data (Main Phase + Extension Phase part 
1).
Adverse events, consumption of N8-GP, recovery and pre-dose levels will be summarised based on 
accumulated data (Main + Extension Phase part 1) by treatment regimen combining the every 4 day 
dosing regimens. In addition, separate summaries including data from part 1 only will be presented 
by treatment regimen for the randomised subset of patients to support the main objective of part 1of 
the Extension Phase. 
Other safety endpoints will be summarised based on accumulated data (Main Phase + Extension 
Phase part 1). Binding non-inhibitory antibodies will be listed.
PRO endpoints at end the Extension Phase part 1 will be evaluated and presented as described in 
section 18.9. 
Data from part 2 of the Extension Phase
The main objective of extension phase part 2 is to collect long term safety and efficacy data.
ABR will be calculated as for the co-primary endpoint in the main phase, but based on the 
accumulated data, i.e. combined data from main phase, extension phase part 1 and extension phase 
part 2. Furthermore, sensitivity analyses are performed based on actual bleeding episodes and 
exposure times (i.e. without imputation for withdrawn patients).
Incidence rate of FVIII-inhibitor and haemostatic effect of N8-GP when used for treatment of 
bleeding episodes will be evaluated based on accumulated data.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
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Adverse events and consumption of N8-GP will be summarised based on accumulated data by 
treatment regimen.
Incremental recovery will be summarised by visit for extension phase part 2 and furthermore be 
presented graphically in the following ways:
∀
By N8-GP production process (extension phase part 2 data)
∀
According to Anti-PEG-antibody status (accumulated data) 
For Anti-CHO HCP-antibodies, the number of negative/positive samples will be summarised by 
visit.
Other safety endpoints will be listed and/or plotted based on accumulated data.
∀
PRO endpoints for extension phase part 2 will be summarised by time since first dose (since timing 
of visits depend on treatment regimen). Time grouping will span a year, i.e. grouping being “1 - <2 
years”, “2 - <3 years”,…. The two prophylaxis regimens will be considered as a combined 
prophylaxis treatment regimen.
2.11
Additional Evaluations
Exploratory analysis comparing results from study NN7008-3543, NN7008-3545, NN7008-3568 
and NN7088-3776 with results from this study will be performed and reported separately. This 
analysis will include overall comparisons as well as individual comparisons for patients 
participating in one of the above listed trials and this NN7088-3859 trial, if the patient through the 
informed consent has given approval of such comparison of data. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
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3
Changes to the statistical analyses planned in the protocol
It has been clarified that treatment requiring bleeding episodes occurring in multiple locations with 
the same start time will be calculated as one bleed. This is in accordance to the initial setup of how
data could be captured in the diary and electronic case report form (eCRF), but some changes have
been made in the eCRF by mistake at a later time point where auto-query has been added to enquire
all bleeding episodes which were associated with multiple locations to be captured as separate
episodes.
As a conservative approach, the worst response will be used in case multiple haemostatic responses
were registered for multiple bleeding locations with the same start time. 
None of the non-joint bleeds will be considered as re-bleeds even if they occurred within 72 hours 
as the specific location is not captured in the database. 
A conservative approach will be used to calculate the planned exposure time for withdrawals such 
that the maximum expected exposure time will be used.
An additional sensitivity analysis is added for the analysis of the ABR to investigate the robustness 
of the assumption that the treatment requiring bleeds can be modelled adequately using a Poisson 
distribution with overdispersion. The additional sensitivity analyses uses modelling based on the 
negative binomial distribution
It was added that ABR will be analysed when there are at least 5 patients in total and when at least 
one bleed was observed, in order to provide reliable estimates.
At the end of trial:
Efficacy data:
As a sensitivity analysis, analysis without imputation to planned duration will be performed. The 
other sensitivity analyses performed in the pivotal reporting are no longer applicable, since this was 
already addressed in the previous interim reportings.  
Calculation of ABR by month for a given treatment regimen has been defined to be based on the 
first consecutive period on the treatment regimen to ensure that a effect over time is not influenced 
by time on other treatment regimens.
Calculation of ABR by calendar month has been defined to be done by shifting calendar month half 
a year for countries in the southern hemisphere (i.e. Brazil and Australia). This is done to take the 
difference in seasons between the southern and northern hemisphere into account. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
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The ABRs defined to be calculated based on a sub-selection consisting of data from extension phase 
part 2, will not be done, since patients have differing trial durations when entering extension phase 
part 2 and therefore ABRs for such a sub-selection is of limited value.
PK data:
Since patients are allowed to change treatment regimen at any time during the extension phase part 
2 and since the visits intervals are different for the prophylaxis treatment regimens, FVIII activity 
data will be summarised by visit only for incremental recovery. Since incremental recovery is dose-
normalised activity increase this will not be affected by a possible regimen and dose change.
Plots of pre-dose activity measurements will not be created since the plots have been evaluated to 
contribute with no relevant information.
PRO data: 
PRO endpoints for extension phase part 2 will be summarised by grouping of time since first dose, 
since timing of visits depend on treatment regimen and since patients are moving between treatment 
regimens.
Safety data:
Adverse Events and Serious Adverse Events will be summarised by treatment regimen and all other 
safety endpoints will be presented by listings and individual graphical representation only. Safety 
data consists of accumulated data from the trial.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 January 2019
Novo Nordisk
Trial ID: 7088-3859-final
Version:
1.0
UTN: U1111-1119-7416
Status:
Final
EudraCT No.: 2011-001142-15
Page:
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4
References
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5 Tarantino MD, Collins PW, Hay CR, Shapiro AD, Gruppo RA, Berntorp E et al. Clinical 
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pharmacokinetic equivalence to full-length recombinant factor VIII. Haemophilia 2009; 15(4):869-
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8 Smith MP, Giangrande P, Pollman H, Littlewood R, Kollmer C, Feingold J. A postmarketing 
surveillance study of the safety and efficacy of ReFacto (St Louis-derived active substance) in 
patients with haemophilia A. Haemophilia 2005; 11(5):444-451.
9 Schwartz RS, Abildgaard CF, Aledort LM, Arkin S, Bloom AL, Brackmann HH et al. Human 
recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. 
recombinant Factor VIII Study Group. N Engl J Med 1990; 323(26):1800-1805.
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