Clinical trial NCT01493778
Conditions: Congenital Bleeding Disorder Haemophilia A
Sponsor: Novo Nordisk A/S
Start date: 2012-09-17; Completion date: 2018-12-05
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial is conducted in Asia, Europe and North America. The purpose of the trial is to evaluate the safety and efficacy of turoctocog alfa in prevention and treatment of bleeds in previously untreated children with haemophilia A.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: turoctocog alfa
Intervention descriptions: intervention 1: Patients will be scheduled to receive treatment with turoctocog alfa for at least 100 exposure days. In most cases, treatment will be given at home with intravenous (i.v., into the vein) self-injection by the parent/caregiver/support person.

Protocol documents:
Prot_SAP_000.pdf: 
Cover Page for Protocol and Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT01493778 
Sponsor trial ID: 
NN7008-3809 
Official title of study: 
Safety and Efficacy of turoctocog alfa in Prevention and 
Treatment of Bleeds in Paediatric Previously Untreated 
Patients with Haemophilia A 
Document date: 
21 September 2017 
 


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List of contents
Protocol ...............................................................................................................................................
Appendix A - Agreement on Final Protocol.....................................................................................
Appendix B - Whole Blood Volume Rules in the Paediatric Population.......................................
Appendix C - Anaphylaxis.................................................................................................................
Appendix D - Body Mass Index Chart .............................................................................................
Appendix E - Patient Reported Outcome Questionnaire................................................................
Attachments 1 & 2..............................................................................................................................
Protocol amendment 01 - Global ......................................................................................................
Protocol amendment 02 - RU ............................................................................................................
Protocol amendment 04 - TR ............................................................................................................
Protocol amendment 05 - Global ......................................................................................................
Protocol amendment 06 - Global ......................................................................................................
Protocol amendment 07 - Global ......................................................................................................
Protocol amendment 08 - AT ............................................................................................................
Protocol amendment 09 - Global ......................................................................................................
Protocol amendment 10 - Global ......................................................................................................
Protocol amendment 11 - AT ............................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
turoctocog alfa
Trial ID: NN7008-3809
Clinical Trial Report
Appendix 16.1.1
 September 2017
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
1.0
Status:
Final
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Protocol
Trial ID: NN7008-3809
Safety and Efficacy of NNC 0155-0000-0004 in 
Prevention and Treatment of Bleeds in Paediatric 
Previously Untreated Patients with Haemophilia A
Trial phase:
3
Author:
Name:
Department:Haemostasis, Clinical Operations FVIII
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 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
2 of 85
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...............................................................................................................................................13
3
Introduction.............................................................................................................................................16
3.1
Basic Information ........................................................................................................................16
3.1.1
Novo Nordisk’ recombinant FVIII, N8.......................................................................17
3.1.1.1
Pre-Clinical and Clinical Data.................................................................17
3.1.1.2
Risks and Benefits ...................................................................................17
3.2
Rationale for the Trial..................................................................................................................18
3.2.1
Clinical Development Programme ..............................................................................18
4
Objective(s) and Endpoint(s)..................................................................................................................20
4.1
Objective(s)..................................................................................................................................20
4.2
Endpoint(s) ..................................................................................................................................20
5
Trial Design..............................................................................................................................................21
5.1
Type of Trial................................................................................................................................21
5.2
Rationale for Trial Design ...........................................................................................................21
5.3
Treatment of Patients...................................................................................................................22
5.3.1
Preventive Treatment and Dose Adjustment...............................................................22
5.3.2
Treatment of Bleeds and Dose Adjustment.................................................................23
5.3.3
Treatment during Surgery ...........................................................................................23
5.3.4
Treatment of Patients with Inhibitors..........................................................................24
5.4
Treatment after End of Trial ........................................................................................................26
5.5
Rationale for Treatment...............................................................................................................26
6
Trial Population ......................................................................................................................................27
6.1
Number of Patients to be Studied ................................................................................................27
6.2
Inclusion Criteria .........................................................................................................................27
6.3
Exclusion Criteria ........................................................................................................................27
6.4
Withdrawal Criteria .....................................................................................................................28
6.5
Patient Replacement ....................................................................................................................28
6.6
Rationale for Trial Population .....................................................................................................28
7
Trial Schedule..........................................................................................................................................30
8
Methods and Assessments ......................................................................................................................31
8.1
Visit Procedures...........................................................................................................................31
8.1.1
Overall Procedures, Assessments and Methods..........................................................31
8.1.2
Visit 1, Screening Visit ...............................................................................................31
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
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8.1.3
Visit 2..........................................................................................................................32
8.1.4
Visit 3 to Visit 7 ..........................................................................................................32
8.1.5
Unscheduled Visit .......................................................................................................32
8.1.5.1
Surgery Visit............................................................................................32
8.1.5.2
Inhibitor Treatment Visit .........................................................................33
8.2
Assessments for Safety................................................................................................................33
8.2.1
Adverse Events............................................................................................................33
8.2.2
FVIII Inhibitors ...........................................................................................................34
8.2.3
FVIII Recovery............................................................................................................34
8.2.4
FVIII (N8) Pharmacokinetic T1/2...............................................................................35
8.2.5
FVIII Trough Level Assessment .................................................................................35
8.2.6
Haematology ...............................................................................................................35
8.2.7
Biochemistry ...............................................................................................................35
8.2.8
Laboratory Tests..........................................................................................................36
8.2.8.1
General Considerations............................................................................36
8.2.8.2
Local Laboratory Tests ............................................................................36
8.2.8.3
Central Laboratory Tests..........................................................................37
8.2.8.4
Blood Sampling Volume .........................................................................37
8.2.9
Physical Examination..................................................................................................38
8.2.10
Vital Signs...................................................................................................................38
8.3
Assessments for Efficacy.............................................................................................................38
8.3.1
Bleeds..........................................................................................................................38
8.3.1.1
Definition of Severity of Bleeds ..............................................................39
8.3.1.2
Definition of Haemostatic Response .......................................................39
8.3.1.3
Bleed Classification.................................................................................40
8.4
Other Assessments.......................................................................................................................41
8.4.1
FVIII genotype testing (not applicable to Brazil)........................................................41
8.4.2
Viral Antibody Information.........................................................................................41
8.4.3
Demography................................................................................................................41
8.4.4
Body Measurements....................................................................................................41
8.4.5
Diaries .........................................................................................................................42
8.4.6
Medical and Haemophilia History...............................................................................42
8.4.6.1
Medical History .......................................................................................42
8.4.6.2
Details of Haemophilia ............................................................................43
8.4.6.3
Haemophilia Treatment History (if applicable).......................................43
8.4.7
HE and PRO data ........................................................................................................43
8.5
Patient Compliance......................................................................................................................43
9
Trial Supplies...........................................................................................................................................45
9.1
Trial Products...............................................................................................................................45
9.2
Packaging and Labelling of Trial Products..................................................................................45
9.3
Storage of Trial Products.............................................................................................................45
9.4
Dispensing and Drug Accountability of Trial Products...............................................................46
9.5
Trial Product Administration.......................................................................................................47
9.6
Auxiliary supply ..........................................................................................................................47
10 Randomisation, Breaking of Blinded Codes and Interactive Voice/Web Response System 
(IV/WRS) .................................................................................................................................................48
10.1
Randomisation .............................................................................................................................48
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NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
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10.2
Breaking of Blinded Codes..........................................................................................................48
10.3
Interactive Voice/Web Response System (IV/WRS) ..................................................................48
11 Concomitant Illnesses and Concomitant Medication...........................................................................49
12 Adverse Events ........................................................................................................................................50
12.1
Definitions ...................................................................................................................................50
12.1.1
Technical Complaints..................................................................................................52
12.1.2
Medical Event of Special Interest and other events for expedited reporting...............52
12.2
Collection, Recording and Reporting of Adverse Events............................................................53
12.2.1
Disease-related Bleeding.............................................................................................55
12.2.2
Follow-up of Adverse Events......................................................................................55
12.3
Technical Complaints and Technical Complaint Samples ..........................................................56
12.3.1
Collection and Reporting of Technical Complaints....................................................56
12.3.2
Collection, Storage and Shipment of Technical Complaint Samples..........................57
Storage and shipment of the technical complaint sample should be done in accordance with the 
conditions prescribed for the product, see Section 9. For further details on the shipment 
conditions of technical complaints, please contact the local monitor..........................................57
12.4
Precautions/Over-Dosage ............................................................................................................57
12.5
Safety Committee(s) ....................................................................................................................58
12.5.1
Internal Novo Nordisk Safety Committee...................................................................58
12.5.2
Rules for putting the enrolment on hold......................................................................58
12.5.3
Data Monitoring Committee .......................................................................................59
13 Case Report Forms .................................................................................................................................60
13.1
Rules for Completing eCRFs.......................................................................................................60
13.2
Corrections to eCRFs...................................................................................................................60
13.3
eCRF Flow...................................................................................................................................60
13.4
Analysis Results...........................................................................................................................60
14 Monitoring Procedures...........................................................................................................................62
15 Data Management...................................................................................................................................63
16 Computerised Systems............................................................................................................................64
17 Evaluability of Patients for Analysis .....................................................................................................65
18 Statistical Considerations.......................................................................................................................66
18.1
Sample Size Calculation..............................................................................................................66
18.2
Statistical Methods.......................................................................................................................66
18.2.1
General Considerations ...............................................................................................66
18.2.2
Primary Endpoint(s) ....................................................................................................66
18.2.3
Confirmatory Secondary Endpoints ............................................................................67
18.2.4
Supportive Secondary Endpoints ................................................................................67
18.3
Interim Analysis...........................................................................................................................69
18.4
Sequential Safety Analysis/Safety Monitoring............................................................................69
18.5
Explorative Statistical Analysis for Pharmacogenetics and Biomarkers.....................................70
18.6
PK and/or PD Modelling .............................................................................................................70
18.7
Health Economics and Patient Reported Outcomes ....................................................................70
19 Ethics........................................................................................................................................................71
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
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Status:
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19.1
Informed Consent Form for Trial Patients...................................................................................71
19.2
Data Handling..............................................................................................................................72
19.3
Institutional Review Boards/Independent Ethics Committee......................................................72
20 Premature Termination of the Trial/Trial Site ....................................................................................74
21 Protocol Compliance...............................................................................................................................75
21.1
Audits and Inspections.................................................................................................................75
22 Critical Documents..................................................................................................................................76
23 Responsibilities........................................................................................................................................77
24 Reports and Publications........................................................................................................................78
24.1
Communication and Publication..................................................................................................78
24.1.1
Authorship...................................................................................................................78
24.1.2
Publications .................................................................................................................79
24.1.3
Site-Specific Publication(s) by Investigator(s)............................................................80
24.2
Investigator Access to Data and Review of Results ....................................................................80
25 Retention of Clinical Trial Documentation...........................................................................................81
26 Indemnity Statement...............................................................................................................................82
27 References................................................................................................................................................83
Appendix A
Agreement on Final Protocol
Appendix B
Whole Blood Volume Rules in the Paediatric Population
Appendix C
Anaphylaxis
Appendix D
Body Mass Index Chart
Appendix E
Patient Reported Outcome Questionnaire
Attachment I - Global
List of Key Staff, Relevant Departments
Attachment II - Country
List of Key Staff and Relevant Departments
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Table of Figures
Page
Figure 2–1 Trial Design .................................................................................................................................15
Figure 5–1 Inhibitor Management..................................................................................................................25
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Table of Tables 
Page
Table 2–1
Visit Flow Chart...........................................................................................................................13
Table 5–1
Overview of Treatment Regimens...............................................................................................26
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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List of Abbreviations
AE
adverse event
BP
blood pressure
BU
Bethesda units
BW
body weight
CD4+
T-lymphocyte subtype
CI
confidence interval
CRF
case report form
CRO
contract research organisation
CTR
clinical trial report
CV
curriculum vitae
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
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FPFV
first patient first visit
GCP
good clinical practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C
HE
health economics
Hemo-Sat P
haemophilia satisfaction questionnaire for parents
HIV
human immunodeficiency virus
IB
Investigator´s brochure
ICH
International Conference on Harmonisation 
IEC 
Independent Ethics Committee
IRB 
Institutional Review Board
IU
international units
IV/WRS
interactive voice/web response system
IVIG
intravenous immunoglobulin
LAR
legally authorised representative
LOD
limit of detection 
LPFV
last patient first visit
LPLV 
last patient last visit
MESI
medical events of special interest
N8
Novo Nordisk’s recombinant FVIII product
NOAEL
no observed adverse effect level
PK
pharmacokinetic
PRO
patient reported outcomes
PTP
previously treated patients
PUP
previously untreated patients 
rFVIII
recombinant Factor Eight product
SAE
serious adverse event
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
1.0
Status:
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T1/2
Pharmacokinetic half life
TMM
trial materials manual
TVP
trial validation plan
NNC 0155-000-004
Novo Nordisk code for N8 (investigational medicinal product)
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
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1
Summary
Objectives and Endpoints
Primary Objective:
!
To evaluate safety of NNC 0155-0000-0004 in paediatric previously untreated patients (PUP) 1
with haemophilia A
Key Secondary Objectives:
!
To evaluate efficacy of NNC 0155-0000-0004 in treatment of bleeds in paediatric PUP with 
haemophilia A 
!
To evaluate preventive effect of NNC 0155-0000-0004 on bleeds in paediatric PUP with 
haemophilia A
Primary Endpoint:
!
Incidence rate of FVIII inhibitors (>0.6 BU/mL) will be evaluated from Visit 1 to End of Trial 
Visit/Visit 7
Key Secondary Endpoints:
!
Haemostatic effect of NNC 0155-0000-0004 on treatment of bleeds assessed on a predefined 
four point scale: Excellent, Good, Moderate and None will be evaluated from Visit 2 to End of 
Trial Visit/Visit 7
!
Annualized bleeding rate will be evaluated from Visit 2 to End of Trial Visit/Visit 7
Trial Design
A multi-centre, multi-national, non-randomised, open-label, safety and efficacy trial in PUP with
haemophilia A.
The patients will receive preventive treatment with NNC 0155-0000-0004 until they reach a 
minimum of 100 exposure days2 (ED). The patients will stay in the trial for approximately 9-24 
months, and the estimated total duration of the trial is approximately 55 months.
                                                
1 Previously untreated patients refers to those patients who have never been treated with clotting factor products (except 
previous exposure to blood components)
2 Exposure day (ED) is any day that the patient has been exposed to trial product. This will be used for reporting 
purposes.
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
1.0
Status:
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The trial is designed in accordance with European Medicines Agency (EMA) draft guideline from 
July 2009 on the Clinical Investigation of Recombinant and Human Plasma-Derived Factor VIII 
Products.1
Trial Population
Approximately 120 PUP with severe (baseline level FVIII ∀1%) haemophilia A without inhibitors 
below 6 years of age in a non-bleeding state will be enroled to allow for at least 100 patients to 
complete the trial.
Key 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 patient)
!
Male patients with congenital severe haemophilia A (baseline level FVIII ∀1%)
!
Age < 6 years
!
No prior use of purified clotting factor products (previous exposure to blood components is 
acceptable)
Key Exclusion Criteria:
!
Known or suspected allergy to hamster protein or intolerance to trial product(s) or related 
products
!
Previous participation in this trial defined as withdrawal after administration of trial product
!
Congenital or acquired coagulation disorders other than haemophilia A
!
FVIII inhibitor (> 0.6 BU/mL) at screening
!
Ongoing treatment or planned treatment during the trial with immunomodulatory agents (e.g. 
intravenous immunoglobulin (IVIG)), routine systemic corticosteroids)
!
Platelet count <50,000 platelets/μL
Main Assessments:
!
Presence of FVIII inhibitors will be tested throughout the trial
!
Evaluation of haemostasis, following NNC 0155-0000-0004 administration, as Excellent, Good, 
Moderate or None
!
Consumption of NNC 0155-0000-0004 IU/kg body weight (BW) will be monitored throughout 
the trial.
Furthermore, physical examination, vital signs, laboratory tests, and recording of AEs and SAEs 
will be performed for safety assessments.
Patients with development of inhibitors
In case of inhibitor development, the clinical evaluation will take into account the inhibitor titre, 
and different patient and treatment characteristics.
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
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Patients with inhibitor formation will be offered continued treatment with NNC 0155-0000-0004.
Surgery
Patients undergoing surgical procedures will receive NNC 0155-0000-0004 bleeding preventive 
treatment before, during and after surgery according to standard of practice of the participating site. 
Trial Product
Each patient will receive bleeding preventive treatment with a dose of NNC 0155-0000-0004 
(hereafter named N8) of 15-60 IU/kg BW. The exact dose of N8 is decided by the Investigator
based on the patient’s clinical profile. It is recommended to have at least one day between each N8 
preventive dose. 
The initial infusions will be administered at the investigational site, but after adequate instruction 
and practice the goal is to implement home treatment with intravenous (i.v.) injections given by the 
parent or a support person. N8 will be supplied as freeze dried powder to be reconstituted with a 
sterile sodium chloride solution for injection. 
The dose for treatment of bleeds is decided by the Investigator but should be approximately 25-50
IU/kg in accordance with Guidelines for the Management of Haemophilia2. The maximum total 
daily dose of N8 for the treatment of bleeds is 200 IU/kg with a maximum dose per infusion of 100 
IU/kg. This maximum limit does not apply during inhibitor treatment for patients with inhibitors.
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
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2
Flow Chart
Table 2–1 Visit Flow Chart
Visit number
Screen.
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Unscheduled
Visit
Visit window
NA
14 # 7 d
post V1
10th -15th
ED
20th -25th
ED
50th -55th
ED
75th -80th
ED
100th -110th
ED
PATIENT RELATED 
INFO / 
ASSESSMENTS
Informed consent
●
Inclusion/Exclusion 
Criteria
●
●
Consent for FVIII 
genotype test
●
Withdrawal Criteria
●
●
●
●
●
●
●b
Haemophilia 
treatment history
●
Concomitant illnesses 
/ Medical history
●
Concomitant 
medication
●
●
●
●
●
●
●
●b
Demography
●
Body measurements
●
●d
●d
●d
●d
●d
●
●b, d
FVIII genotype test
●f
Details of haemophilia ●
EFFICACY
Bleed(s)
●
●
●
●
●
●
●b
SAFETY
Adverse events
●
●
●
●
●
●
●
●b
Physical examination
●
●
●
●
●
●
●
●b
Vital signs
●
●
FVIII activity
●a
FVIII inhibitors
●a
●a
●a
●a
●a
●a
●a, b
FVIII trough level
●b
●b
●b
●b
●b
FVIII recovery
●b, c
FVIII (N8) half life 
(T1/2)
●b
Biochemistry
●
●
Haematology
●
●
OTHER 
ASSESSMENTS
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Visit number
Screen.
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Unscheduled
Visit
PRO questionnaire
●
●
●
HE assessment
●
●
●
●
●
●
●
Viral antibody test (if 
HIV, HBsAg and/or 
HCV status unknown)
●b
T cells subset: CD4+
●h
TRIAL MATERIAL
N8 administration
●b
●
●
●
●
●b
Home treatment 
training
●
Diary and Trial card 
dispensing and/or 
collection
●e
●e
●e
●e
●e
●e
●
●b
Review of patient 
diary and entry of 
data in eCRF
●
●
●
●
●
●b
Enrolment session in 
IV/WRS
●
Completion session in 
IV/WRS
●
Drug dispensing and 
accountability
●g
●
●
●
●
●g
●b
End of trial form
●
a – minimum 48 hours washout period of N8 (or blood component products at Visit 1)
b – if applicable
c – mandatory to confirm clinical relevant inhibitors and inhibitor treatment success
d – weight only
e – Visit 1 trial card only, Visit 2-6 diary card only
f – if not available, if allowed by law and after consent
g – Visit 2 dispensing only, Visit 7 accountability only
h – if HIV positive, last value of CD4+ T-cells (if available), or new cell count
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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150 patients are planned to be screened to get approximately 120 enroled, and 100 completers. Screening will be done 
at Visit 1, 14 # 7 days prior to Visit 2. Preventive treatment with investigational product (N8) starts at Visit 2 (may start 
after the first two bleeds, see Section 5.3 and is completed at V7.
Figure 2–1Trial Design
V2
V7
150 pts screened
120 pts enroled
100 pts completed
100 ED
V1
N8
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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
Haemophilia A is a recessive X-linked congenital bleeding disorder, caused by mutation in the 
coagulation factor eight (FVIII) gene on the long arm of the X-chromosome. Approximately 1 in 
5,000 male births give rise to haemophilia A. Classification of the severity of hemophilia A is based 
on plasma level of FVIII, with patients <1% factor defined as severe; 1–5%  as moderately severe; 
and 5-40%  as mild.3 Patients with haemophilia A lack or have a reduced production of FVIII, or 
they produce biochemically defective FVIII molecules. With a deficiency or absence of these 
factors, the activation of coagulation factor X becomes severely impaired, and consequently, the 
thrombin burst becomes delayed and insufficient for normal haemostasis. The haemostatic plug 
formed in these patients is therefore fragile and easily dissolved by normal fibrinolytic activity, 
leading to impaired haemostasis and prolonged bleeds.4
Recurrent bleeds in the same location, most commonly a weight-bearing joint, lead to chronic 
arthropathy, muscular atrophy, and deformities. Treatment of bleeds as they manifest may delay 
this process, but does not prevent it.5 For this reason, primary prophylaxis with regular FVIII 
injections in the non-bleeding state is standard practice from early childhood to at least 18 years of 
age. The primary goals of haemophilia therapy for patients are the prevention of bleeds, the rapid 
and definitive treatment of bleeds that do occur, and the provision of adequate haemostasis during 
surgery and other major challenges to haemostasis. A most serious complication to haemophilia 
treatment is inhibitor development. Inhibitors are antibodies formed as an immune response to 
allogeneic FVIII and which reduce or eliminate the activity of FVIII proteins. This condition 
develops in about 30% of previously untreated patients (PUP) with severe haemophilia A following 
exposure to FVIII products.6,7
Substitution therapy with FVIII concentrates is the standard care of haemophilia A patients. N8 is a 
“third generation” recombinant FVIII similar to other marketed FVIII products of recombinant 
origin.8
The current document describes a clinical trial designed to demonstrate safety and efficacy of N8 
used for both prevention (prophylaxis) and treatment of bleeds in PUP with haemophilia A.
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3.1.1
Novo Nordisk’ recombinant FVIII, N8
3.1.1.1
Pre-Clinical and Clinical Data
Novo Nordisk is developing a recombinant FVIII (rFVIII) product (N8) for treatment of 
haemophilia A. Please find current key pre-clinical and clinical data presented below.
For the full information on medicinal aspects, non-clinical data and quality of N8, please refer to the 
Investigator’s Brochure (IB)9.
N8 has been investigated in a single dose intravenously (i.v.) escalating dose trial and a 14 day daily 
i.v. toxicity and safety pharmacology trial including toxicokinetics in male cynomolgus monkeys.
There were no adverse findings after a single dose of N8. Therefore the No Observed Adverse 
Effect Level (NOAEL) after the single dose is >5000 IU/kg, which was the highest dose tested.
In accordance with the EMA Guidelines1,10, the clinical programme for N8 was initiated by a 
pharmacokinetic (PK) trial to document the essential PK characteristics of the product and to 
achieve initial safety information. The initial PK trial (NN7008-3522) has been designed as a 
comparative trial to the rFVIII product Advate∃ which is seen as the standard for recombinant FVIII 
treatments.
The First Human Dose and PK trial (NN7008-3522) comparing N8 and Advate® has been 
completed. The trial included a comparison of PK profiles after a single dose administration of 50
IU/kg BW of Advate® and N8 (in this order of dosing) to patients with severe haemophilia A 
without FVIII inhibitors and in a non-bleeding state. The age of the trial population was 13–54
years. The data from the 23 patients showed mean PK profiles of N8 comparable to Advate® within 
the defined limits of comparability. These limits are the standard criteria for bioequivalence. No 
development of FVIII inhibitor activity was detected in these 23 patients and no Severe Adverse 
Events (SAEs) were reported. For further information on PK results and safety of N8 please refer to 
the IB9.
Currently three clinical studies are ongoing in the Novo Nordisk development program, the pivotal 
phase 3 trial (guardianTM 1), the paediatric trial (guardianTM 3) and the extension trial (guardianTM
2), and the accumulated clinical experience with N8 is now approaching 10000 exposure days (ED).
3.1.1.2
Risks and Benefits
FVIII products are used in the standard care of patients with haemophilia A. Although not similar in 
structure, the effect of N8 is similar to other marketed FVIII products which are of either plasma 
derived or recombinant origin. N8 is a recombinant FVIII molecule with a truncated B-domain
manufactured without additional human or animal plasma proteins.8
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It is expected that the safety profile of N8 will be similar to that of other third generation 
recombinant products.
The potential benefits to patients of N8 are more treatment choices and a globally expanded access 
to safe and effective treatment of haemophilia A.
According to the EMA Guideline1 it is stated that treatment with FVIII products in a clinical trial 
including PUP should start when:
!
data are available from 20 previously treated patients (PTP) below 12 years of age with at least 
50 ED of the investigational product
!
a minimum of 10 of these PTP must be below 6 years of age
!
PK data from 26 patients aged 0-12 years is available, including minimum 13 patients below 6 
years of age.
After completing the present trial (guardianTM 4), patients will be offered to continue with N8 in an 
extension trial, see Section 5.4. This serves to minimise the patients’ need of switching to other 
FVIII products.
For further information on risk and benefits and safety of N8 please refer to the IB9.
3.2
Rationale for the Trial
Globally there is still a vast unmet medical need for treatment of haemophilia A. Through the
development of new rFVIII products, the possibility for haemophilia A patients to choose between 
different FVIII products is increased. New products may also contribute to securing product supply, 
thereby increasing the opportunity for improved treatment in haemophilia A.
In order to achieve marketing authorisation for this product, EMA draft guidelines on clinical 
investigation of plasma derived and recombinant FVIII products and review of relevant Food and 
Drug Administration (FDA) approvals of recombinant FVIII and FIX products1,11,12 are applied in 
the clinical development programme (see further details in the IB9). According to the draft EMA
guideline on clinical Investigation of new FVIII products, the clinical programme must include a 
paediatric trial in PUP demonstrating safety and clinical efficacy in at least 100 patients.
The guardianTM 4 trial is a prospective clinical phase 3a trial intended at demonstrating safety and 
efficacy of N8 in PUP < 6 years of age with severe haemophilia A. The trial will continue until at 
least 100 patients have received at least 100 ED to N8.
3.2.1
Clinical Development Programme
The overall clinical development programme for N8 uses a stepwise approach, following the EMA 
draft guideline1, by evaluating experience in older and previously treated patients (guardianTM 1) 
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before investigating in younger children (guardianTM 3) and finally in previously untreated patients, 
the study population of the present trial (guardianTM 4).
In addition, Novo Nordisk is conducting a phase 3b (guardianTM 2) extension trial and is planning 
further trials to collect ongoing longer term efficacy and safety data.
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4
Objective(s) and Endpoint(s)
4.1
Objective(s)
Primary Objective
!
To evaluate safety of N8 in paediatric previously untreated patients (PUP) with haemophilia A
Secondary Objectives
!
To evaluate efficacy and safety of N8 in treatment of bleeds in paediatric PUP with haemophilia 
A 
!
To evaluate preventive effect of N8 on bleeds in paediatric PUP with haemophilia A
!
To evaluate patient reported outcomes (PRO) impact of N8 treatment
!
To evaluate the health economic (HE) impact of N8 treatment
4.2
Endpoint(s)
Primary Endpoint
!
Incidence rate of FVIII inhibitors (≥0.6 BU/mL)
Secondary Endpoint(s)
Safety Endpoints:
!
Frequency of adverse events (AEs) and serious adverse events (SAEs) reported during the trial 
period
!
Incidence rate of clinically relevant inhibitors defined as an inhibitor titre (>0.6 BU/mL) 
combined with a decreased recovery (<66% of expected level) 
!
Incidence rate of high-titre inhibitors defined as inhibitor titre > 5 BU/mL
Efficacy Endpoints:
!
Haemostatic effect of N8 on treatment of bleeds assessed on a predefined four point scale: 
Excellent, Good, Moderate and None
!
Annualized bleeding rate
!
Number of N8 infusions required per bleed
!
Total consumption of N8 per patient (prevention, treatment of bleeds and during surgery) per 
month and annualised value
!
Consumption of N8 (IU/kg/bleed) per bleed 
!
Consumption of N8 (IU/kg/ months) for bleed prevention
Patient Reported Outcomes (PRO) and Health Economics (HE) End points: 
!
Change in total scores for parent reported treatment satisfaction
!
Health resource utlilisation and caregiver burden associated with bleeds
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5
Trial Design
5.1
Type of Trial
This is a multi-centre, multi-national, non-randomised, open-label, safety and efficacy trial in a 
paediatric population of PUP with severe haemophilia A. There will only be one treatment arm and 
no comparator.
The trial comprises 7 planned visits. Patients will attend a screening visit (Visit 1) in order to assess 
their eligibility. At Visit 2 eligible patient will receive their first dose and will be scheduled to 
attend for 5 more visits, if applicable. Details on the trial design can be found in Figure 2–1 and
details on the individual visits can be found in Table 2–1.
The patients will be scheduled to receive treatment with N8 for at least 100 ED, which for the 
individual patient translates into a duration of approximately 9-24 months depending on the dose 
regimens (and bleeding pattern). The total duration of the trial is estimated to be approximately 55
months.
Patients who develop inhibitors during the trial may continue treatment with N8 and will follow an 
alternative visit schedule, see Section 5.3.4
If needed, the patients can undergo minor or major surgical procedures during the trial, see Section
5.3.3. Upon completion of the surgery the patient can continue preventive treatment as before the 
surgery.
5.2
Rationale for Trial Design
This trial design (Figure 2–1) will provide documentation of the safety and efficacy of N8 in 
prevention and treatment of bleeds in paediatric PUP with severe haemophilia A. The trial design is 
in accordance with EMA draft guideline1 from July 2009 for the development of rFVIII products.
The dose levels and preventive treatment regimens chosen in this trial have been based on accepted 
clinical practices for treatment of the PUP population and are standard practise in US and EU2. In 
addition, the doses are chosen to reflect potentially higher clearance in children and in line with the 
recommendations from the International Society for Thrombosis and Haemostasis13.
An active comparator has not been chosen as extensive comparative data from recently registered 
rFVIII products are available in comparable global populations including patients from EU and 
US14,15. Furthermore, the completed PK trial NN7008-3522 confirmed similarity of PK profiles and 
bioequivalence of Advate® and N8, see Section 3.1.1.1. Finally, the pivotal phase 3 trial 
(guardianTM 1) including at least 110 PTP above 12 years of age for at least 75 ED is planned to be
completed before the initiation of the present trial. 
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The rationale for choosing a multi-centre, multi-national design is to ensure a sufficient patient pool 
and relevant ethnic diversity of paediatric patients as N8 is expected to be marketed globally.
5.3
Treatment of Patients
Approximately 120 patients are expected to be enroled into the trial in order to have 100 patients 
completing the trial (estimated drop out rate is 20%). For replacement of withdrawn patients, please 
refer to Section 6.5.
Patients will enter a bleeding preventive regimen as described below, see Section 5.3.1. Preventive 
treatment can be postponed until a maximum of two bleeding episodes have occurred.
For prevention one single bolus dose of N8 is administered intravenously (i.v.) at each 
administration day. N8 should preferably be administered in the morning. The maximum duration 
of treatment of a patient from first to last N8 administration is approximately 24 month.
In most cases, treatment will be given at home with i.v. self-injection by the 
parent/caregiver/support person. However, on days when the patient is attending a trial visit, the 
dose will be administered at the clinic by a health care professional.
For an overview of the treatment regimens, please refer to Table 5–1.
Maximum dose
The maximum total daily dose of N8 for the treatment of bleeds is 200 IU/kg with a maximum dose 
per infusion of 100 IU/kg. This maximum limit does not apply during immune tolerance induction 
treatment for patients with inhibitors.
Prohibited medication
Treatment with FVIII products other than the investigational product, N8, is not allowed.
5.3.1
Preventive Treatment and Dose Adjustment
The preventive treatment regimens are meant to reflect the different dosing regimens applied 
globally for initial and continued treatment of PUP. The recommended dose is 15-50 IU/kg BW 
once weekly at the start of preventive treatment, but higher and more frequent doses may be 
necessary depending on the clinical situation. The regimen should then be gradually increased 
towards 20-50 IU/kg BW every second day or 20-60 IU/kg BW three times weekly.16
The decision to initiate preventive treatment will be made by the Investigator and the child’s parent 
or legal representative with due consideration for the child’s own wishes (if they are capable to 
express these wishes). 
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Changes of the preventive regimen should be documented and rationale for the change should be 
provided in the eCRF (e.g. insufficient dose, increased body weight, improved feasibility of home 
treatment, or ‘other’).
The Investigator can perform FVIII trough level 3 assessments, e.g. as a basis for adjustment of 
dose. If the trough level is below the assay limit of detection (LOD) of the clinic, the dose can be 
adjusted at the discretion of the Investigator.
5.3.2
Treatment of Bleeds and Dose Adjustment
During preventive treatment, break-through bleeds may occur and require extra doses of N8. 
Treatment should be started as soon as a bleed is identified. Mild/moderate bleeds can be treated at 
home, whereas severe bleeds (see Section 8.3.1.1) must always be evaluated by the Investigator, 
preferably at the clinic. However, even with severe bleeds treatment should be started immediately 
at home if possible. All bleeds must be reported to the clinic within 24 hours from onset of the 
bleed. 
The dose for treatment of bleeds should aim at providing a post injection level of FVIII of at least 
0.50 IU/mL. The bleeding pattern of the individual patient, as well as low trough levels described 
above, should be considered in adjustments of the preventive dose and at the Investigator’s 
discretion. 
Number and frequency of doses during bleeds is decided by the Investigator based on local 
guideline or standard of practice. This dosing may be prescribed at a scheduled or unscheduled visit 
at the clinic or by telephone contact to the clinic. 
Blood sampling to assess post injection levels may be undertaken during the visit to the clinic at the 
discretion of the Investigator, and such blood sampling can be analysed by the local laboratory.
If a haemostatic response of bleeds cannot be achieved (i.e. the bleed does not stop) after after 48 
hours using doses of N8 up to 200 IU/kg BW per day, 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 from the trial.
Each administered dose (IU given and time of day) as well as efficacy in treatment of bleeds will be 
registered in the diary and in the eCRF.
5.3.3
Treatment during Surgery
Patients undergoing surgical procedures will receive bleeding prophylaxis with N8 according to 
standard of practice at the participating site. The post injection level of FVIII for major surgery is 
                                                
3 The trough level is defined as the lowest level of FVIII measured immediately prior to the dosing and is reported as 
(IU/mL). The trough level will be determined at the local laboratory.
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recommended to be at least 0.50 IU/mL. In the recovery period the patient should be dosed with N8 
according to local standard of practice or general guidelines for treatment of patients with 
haemophilia A.
Treatment with N8 during surgery will be included in the overall count of ED.
5.3.4
Treatment of Patients with Inhibitors
Several genetic factors, such as FVIII gene mutation type, family history of inhibitors, ethnicity, 
have been associated with inhibitor development in patients with severe haemophilia.15
Management of patients with inhibitors includes the treatment of bleeding episodes by the use of 
by-passing agents (rFVII or activated prothrombin complex concentrates) and the permanent 
eradication of the inhibitor through immune tolerance induction therapy.
Patients who develop inhibitors, within this trial, will be offered continued treatment with N8. The 
duration of the inhibitor treatment will be at least 12 months from the time of diagnosis of inhibitor. 
For patients who develop inhibitors during their first year in the trial (within 12 months) the
inhibitor treatment may continue until a total trial duration of 24 months.
It may also be decided by the Investigator and/or parent/legal representative to withdraw the patient.
All patients, who are diagnosed with inhibitor and continue treatment with N8 will follow an 
alternative visit schedule, see Section 8.1.5.2.
The initiation, dose level and dosing frequency of inhibitor treatment will be decided by the 
Investigator based on clinical evaluation and local standards, and it should be documented in the 
eCRF. Within this trial, ‘inhibitor treatment’ includes Immune Tolerance Induction (ITI) as well as 
smaller dose adjustments with low responding and/or clinical insignificant inhibitors.
Transient inhibitors are defined in this trial as inhibitors which disappear within 3 months after two 
positive inhibitor tests.
Inhibitor treatment success is defined as (not applicable for patients with transient inhibitors):
!
two consecutive blood samples showing inhibitor level <0.6 BU/mL
!
FVIII plasma recovery >66 % of expected level
!
N8 T1/2 of >6 h after a 72 h N8 washout period17
Inhibitor treatment failure is defined as persistence of inhibitor with no consistent decline of the 
inhibitor titer from peak level within 12 months of the inhibitor diagnosis. If inhibitor treatment 
failure occurs, the patient must be withdrawn. 
After completion of the inhibitor treatment, the patient will be called to an End of trial Visit (Visit 
7).
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Treatment of bleeds with by-passing agents i.e. FVIIa or activated prothrombin complex 
concentrate (APCC), is allowed for patients who develop inhibitors.
Please see Section 8.2.2 for definition and diagnosis of inhibitor.
Details on inhibitor management can be found in Figure 5–1
Patients who develop inhibitor will be offered to continue N8 treatment. The regular visit schedule will stop and an 
alternative schedule will be commenced. After 12 months treatment, patients will fall into three categories; a) total trial 
duration % 24 months –treatment may continue up to 24 months, b) total trial duration & 24 months – patients will be 
withdrawn, c) treatment failure as defined in Section 5.3.4 - patients will be withdrawn. Patients may also at any time be 
withdrawn at the discretion of the Investigator or the parents/legal representative, or on the patient´s on will.
Figure 5–1Inhibitor Management
Withdrawal 
Continued
treatment with N8
Trial duration
& 24 months
Treatment 
failure
Inhibitor
End of Trial Visit
(Visit 7)
Alternative visit
schedule
Withdrawal 
12 months
Treatment
Withdrawal
Cont´d N8 
treatment,
∀24 mo
trial
duration
Withdrawal
Trial duration
<24 months
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Table 5–1 Overview of Treatment Regimens
Trial product
Dose
Treatment
Type
Total daily 
Doses, IU/kg
Frequency
Targeted level of FVIII
rFVIII (N8)
Preventive
Individual
15-50
Once weekly
Local practice & guidelines
rFVIII (N8)
Preventive
Individual
20-50
Once every 
second day
Local practice & guidelines
rFVIII (N8)
Preventive
Individual
20-60
3 times weekly Local practice & guidelines
rFVIII (N8)
Treatment of 
bleeds
Individual
Max 2x100
Investigator’s 
discretion
>0.50 IU/mL
rFVIII (N8)
Surgery
Individual
Max 2x100
Investigator’s 
discretion
>0.50 IU/mL*
Local practice & guidelines
rFVIII (N8)
Inhibitor
Individual
Investigator’s 
discretion
Investigator’s 
discretion
NA
* Pre-surgery treatment
5.4
Treatment after End of Trial
It is expected that N8 will be granted marketing authorisation and is commercially available when 
the patients complete this trial. Where no marketing authorisation has been granted, each patient 
will be offered to continue in the phase 3b extension trial (guardianTM 2), see Section 3.2.1, as 
applicable by local regulation and rules.
5.5
Rationale for Treatment
Based on the clinical and preclinical results for N8 presented in Section 3.1.1.1, it is expected that 
dosing will be the same as that of currently marketed recombinant FVIII products and the same 
potency and efficacy is expected for N8.
Please refer to the IB9 and any updates hereof for further preclinical and clinical data.
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6
Trial Population
6.1
Number of Patients to be Studied
Countries planned to participate: Austria, Belgium, Brazil, Canada, China, Croatia, Czech Republic, 
Greece, Hong Kong, Japan, South Korea, Malaysia, Romania, Russia, Serbia, Spain, Thailand, 
Turkey, UK and US.
Planned number of patients to be screened (i.e. documented informed consent):
150
Planned number of patients to be started on trial product(s):
120
Planned number of patients to complete the trial:
100
Planned number of trial sites: 
80
6.2
Inclusion Criteria
1. Informed consent obtained before any trial-related activities (trial-related activities are any 
procedure that would not have been performed during normal management of the patient)
2. Male patients with congenital severe haemophilia A (FVIII level ∀1%)
3. Age < 6 years
4. No prior use of purified clotting factor products (previous exposure to blood components is 
acceptable)
6.3
Exclusion Criteria
1. Known or suspected allergy to hamster protein or intolerance to trial product(s) or related 
products
2. Previous participation in this trial defined as withdrawal after administration of trial product
3. Congenital or acquired coagulation disorders other than haemophilia A
4. FVIII inhibitor (>0.6 BU/mL) at screening
5. Ongoing or planned treatment during the trial with immunomodulatory agents (e.g. intravenous 
immunoglobulin (IVIG)), routine systemic corticosteroids)
6. Platelet count <50,000 platelets/μL
7. Any disease or condition which, judged by the Investigator, could imply a potential hazard to 
the patient, interfere with the trial participation or trial outcome including renal and/or liver 
failure
8. Unwillingness, language or other barriers precluding adequate understanding and/or cooperation 
from parents and/or legal representatives and child 
9. The receipt of any investigational product within 30 days prior to inclusion in this trial
Patients who are non-compliant with any of the eligibility criteria, but included in the trial, should 
be withdrawn immediately. If extraordinary circumstances speak in favour of maintaining the 
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patient in the trial then this is only acceptable if justified and approved by the Independent Ethics 
Committee/Institutional Review Board (IEC/IRB), and if the regulatory authorities are notified 
according to local requirements.
6.4
Withdrawal Criteria
The patient may withdraw at will at any time. The legally responsible person for the patient may 
withdraw the child from the trial at will at any time.
The patient may be withdrawn from the trial at the discretion of the Investigator or the sponsor 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: The bleed cannot be controlled after 48 hours using 
recommended doses of N8
2. Allergy/Anaphylaxis to the trial product 
3. Treatment with FVIII products other than N8
4. For inhibitor patients – inhibitor treatment failure with N8 treatment (refer to Inhibitor 
Treatment Section 5.3.4). 
Withdrawn patients should be scheduled for an End of Trial Visit (Visit 7) as soon as possible and 
within 28 days after the last N8 administration, and preferably prior to initiation of treatment with 
another FVIII product. The Investigator should aim to conduct all procedures as specified in the 
protocol for Visit 7.
6.5
Patient Replacement
Withdrawn patients may be replaced to ensure that 100 patients complete the trial with at least 100 
ED. Assuming a drop-out rate of 20%, it is estimated that 120 patients must be started on N8 to 
obtain the 100 completed patients. This may, however, be adjusted during the trial based on the 
actual drop-out rate.
6.6
Rationale for Trial Population
The inclusion and exclusion criteria are in line with previously studied recombinant FVIII products, 
reflect the general haemophilia A paediatric population that will receive N8 when marketed, and 
address the requirements of the EMA/CHMP draft guideline on the clinical investigation of 
recombinant and human plasma-derived factor VIII products1. According to the EMA guideline, the 
clinical programme must include a paediatric trial in PUP demonstrating safety and clinical efficacy 
in at least 100 patients.
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Rationale for Inclusion Criteria:
!
Criterion no.1 is included in accordance with ICH-GCP18.
!
Criterion no. 2 is included to select patients who will potentially benefit the most from treatment
with N8.
!
Criteria nos. 3 and 4 are included to target the specific population required to meet the 
objectives of this trial.
Rationale for Exclusion Criteria:
!
Criterion no. 1 is chosen to protect patient’s safety
!
Criterion no. 2 is chosen to exclude patients treated with N8 (FVIII product), who are not PUP 
anymore
!
Criteria nos. 3 and 6 are chosen to exclude patients with endogenous abnormalities of the 
coagulation system other than haemophilia
!
Criterion no. 4 is chosen to exclude patients with FVIII inhibitors before starting treatment with 
N8
!
Criterion no. 5 is selected to minimise confounding effects of other drugs and treatments on the 
patient's coagulation and immune system
!
Criteria nos. 7 and 8 are chosen to avoid exposing fragile patients to a new compound
!
Criterion no. 9 is included in accordance with ICH-GCP
Rational for Withdrawal Criteria:
!
Criteria nos. 1, 2 and 4 are included to protect the patient's safety.
!
Criterion no. 3 is selected not to confound the effects of the investigational product.
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Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
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7
Trial Schedule
Planned duration of recruitment period (FPFV-LPFV):
42 months
Planned date for FPFV:
December 2011
Planned date for LPFV:
June 2015
Planned LPLV:
July 2016
The end of the clinical trial is defined as last visit of the last patient.
Planned completion of clinical trial report (CTR): Q3 2016
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)19 the Food and Drug 
Administration Amendments Act (FDAAA)20 - as reflected in Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure. In Japan the trial data will be registered at Clinical Trials 
Information/JapicCTI.
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8
Methods and Assessments
8.1
Visit Procedures
8.1.1
Overall Procedures, Assessments and Methods
Specific procedures, assessments and methods for the scheduled visits are described in the sections
below, and the list of assessments for each visit is presented in the flow chart, see Table 2–1.
8.1.2
Visit 1, Screening Visit
For all patients with a signed Informed Consent Form (ICF), the Investigator will, through IV/WRS,
assign a unique 6 digit patient number. The patient number is maintained throughout the trial and 
continuously maintained should the patient be enroled in the extension trial, see Section 5.4.
The patients will be registered as enroled via telephone or internet by use of the IV/WRS.
Patients should withhold and stop any anti-haemophilic treatment with blood components at least 
48 hours prior to Visit 1.
At Visit 1 the patients’ characteristics will be obtained and eligibility will be assessed. If the 
inclusion and exclusion criteria are fulfilled, the screened patient will be scheduled for Visit 2.
According to local practice, the Investigator should keep a list(s) of participating patients e.g. ICF 
signed, screened and/or enroled etc.
In case a patient is evaluated as not eligible for trial participation by the Investigator, the Screening 
Failure form in the eCRF must be completed. A screening failure call must also be made to the 
IV/WRS, see Section 10
As a minimum the following should be recorded for screening failures:
!
existence of patient (date of birth, ICF-/Screening-/Enrolment List)
!
informed consent
!
confirmation of participation in the trial (i.e. notes in medical records, IV/WRS screening 
confirmation, ICF) 
!
AEs or sign and symptoms (description and duration)
!
reason for screening failure.
Patients will also be provided with a trial card stating that they are participating in the trial. This 
will include the contact addresses and telephone numbers for the clinical center where the patient 
will be seen.
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8.1.3
Visit 2
The visit will be scheduled 14 # 7 days after Visit 1.
Patients should withhold and stop any anti-haemophilic treatment with blood components at least 
48 hours prior to Visit 2.
The main purpose of Visit 2 is to administer N8 for the first time, if applicable, to eligible patients.
Another important purpose is to provide the patient and care giver training for home treatment.
The assessments to be performed at Visit 2 are listed in Table 2–1
8.1.4
Visit 3 to Visit 7
Visits 3 to 7 will be scheduled based on the number of accumulated ED. The planned visit intervals 
and the visit assessment are listed in Table 2–1.
Patients should withhold treatment with N8 at least 48 hours prior to the visits.
Visit 7 should also be completed for withdrawn patients.
8.1.5
Unscheduled Visit
The unscheduled visit can be performed after the enrolment into the trial until the End of Trial Visit
(Visit7) as either telephone visit or a site visit. Unscheduled visits will also be performed during 
inhibitor treatment, see Section 8.1.5.2, and surgery procedures, Section 8.1.5.1. Please find listed 
in Table 2–1 the assessments, which should be performed at an unscheduled visit. The date and 
time of the visit should be recorded in the eCRF.
8.1.5.1
Surgery Visit
Patients undergoing surgery will continue the regular visit schedule, but additional visits may be 
performed in the peri-operative period as decided by the Investigator. Surgery visits will be 
documented as unscheduled visits.
For planned surgery patients, the following data should be collected:
!
Type of surgery
!
Date of surgery
!
N8 doses and dosing schedule in relation to peri-operative period (surgery day and post-surgical 
recovery period)
!
FVIII inhibitor tests on the day of surgery and a second test in the interval 10 - 14 days post-
surgery
!
Clinical narrative of the procedure.
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Emergency surgery is allowed in this trial if adequate supply of N8 is available to ensure 
haemostasis and wound healing. The Investigator will decide which trial assessments to be made in 
an emergency situation.
8.1.5.2
Inhibitor Treatment Visit
All patients, who develop inhibitors will follow an alternative visit schedule prescribed by the 
Investigator according to local standard of practice, irrespective of whether inhibitor treatment is 
being initiated or not, see Section 5.3.4.  Monthly visits are recommended, at least initially, for 
patients who develop inhibitors.
These visits will be recorded as unscheduled visits and the following assessments should be 
performed.
!
Assessment of withdrawal criteria
!
Concomitant Medication
!
Body measurements (weight)
!
Bleeds including classification and site of bleeds
!
Adverse Events
!
Physical examination
!
Collect and review diary
!
Diary dispensing
!
Dispensing of the product
!
Drug accountability
!
Administration of N8
!
FVIII inhibitor test
Recovery test is required at the time of inhibitor diagnosis and for the confirmation of inhibitor 
treatment success, see Section 8.2.3.
Measurement of N8 pharmacokinetic plasma (T1/2) will be performed to confirm inhibitor 
treatment success, see Section 8.2.4.
When the last inhibitor treatment visit has been performed, the patient will be called to an End of 
Trial Visit (Visit 7).
8.2
Assessments for Safety
8.2.1
Adverse Events
Monitoring of Adverse Events will be performed from the first trial-related activity to the End of 
Trial Visit (Visit 7) and at potential follow-up visits, according to procedures described in Section 
12.
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8.2.2
FVIII Inhibitors
All patients will be examined regularly for the development of FVIII neutralising antibodies 
(inhibitors). The tests will be performed at Visit 1 and Visits 3-7. Additional laboratory assessment 
for FVIII neutralising antibodies can be done if inhibitor development is suspected during the 
course of the trial, or if more frequent testing is mandated i.e. during unscheduled visits.
Detection of FVIII inhibitors will be carried out at a central laboratory using the Nijmegen modified 
Bethesda21 assay. A positive inhibitor test is defined as > 0.6 Bethesda Unit (BU)/mL.
In the event of a positive inhibitor test, the patient should attend an (unscheduled) visit within a
week after the result is available to take a blood sample for a confirmatory test.
!
The diagnosis of inhibitor is made if the patient has been tested positive for inhibitors (BU 
>0.6/mL) at two consecutive tests (central lab), sampled preferably within 2 weeks. Inhibitors 
will be classified as low titre (>0.6 BU/mL but <5 BU/mL), or high titre (>5 BU/mL), and as 
clinically significant (recovery <66% of expected level, assessed at inhibitor diagnosis at the 
time of the confirmatory inhibitor test).
Blood sampling for FVIII inhibitor test should be performed at a trough level, i.e. with a minimum 
of 48 hours N8 treatment washout period.
In case of inhibitor development, a clinical evaluation will be performed as described in Section 
18.2.2.
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.
For storage, handling, dispatch, and disposition of samples analysed for FVIII inhibitors at the 
central laboratory, please refer to detailed guidance in the Laboratory Manual.
8.2.3
FVIII Recovery
Recovery is the FVIII plasma level recorded 30 minutes after trial product administration and 
reported as [IU/mL]/[IU/kg]. Recovery assessment is mandatory at inhibitor diagnosis to identify 
clinical relevant inhibitors (see Sections 8.2.2). Likewise, recovery assessment is necessary when 
establishing inhibitor treatment success (see Sections 5.3.4). Additional recovery assessments may 
be requested at the discretion of the Investigator.
Samples for FVIII recovery will be sent to the central laboratory for analysis.
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8.2.4
FVIII (N8) Pharmacokinetic T1/2
The T1/2 of N8 will be based on FVIII activity and the procedures should be according to local 
guidelines. The N8 washout period should be at least 72 hrs. It is recommended that at least three 
time points for blood sampling is chosen, and it should be within 48 hrs of N8 administration. The 
samples should be sent to the central lab for analysis.
The N8 T1/2 will be used to evaluate inhibitor treatment success, see Section 5.3.4.
8.2.5
FVIII Trough Level Assessment
The Investigator can at his/her discretion perform trough level assessments at Visit 3-6. The trough 
level is defined as the lowest level of FVIII measured immediately prior to dosing and reported as 
(IU/mL). The trough level will be determined at the local laboratory.
Trough levels need only to be recorded in the eCRF if it is the reason for dose adjustments.
8.2.6
Haematology
The assessment will be performed at Visit 1 and Visit 7 according to practice of the local laboratory
and includes:
!
Haemoglobin (mmol/L)
!
Red cell count (erythrocytes) (x10∋(/L)
!
Mean corpuscular volume (MCV) (fL)
!
Packed cell volume (haematocrit)(PCV)(%)
!
Mean corpuscular haemoglobin (MCH) (fmol/L)
!
White blood cell count (leucocytes) (x10)/L)
!
Differential white blood cell count (%)
o
Lymphocytes
o
Monocytes
o
Neutrophils
o
Eosinophils
o
Basophils
!
Platelet count (thrombocytes) (x10)/L)
It is recommended that the haematology values are reported in the above listed units. However, in 
the eCRF it will be possible to enter values in other units accepted by Novo Nordisk.
8.2.7
Biochemistry
The assessment will be performed at Visit 1 and Visit 7 according to practices of the central 
laboratory and includes:
! Sodium (mmol/L)
! Potassium (mmol/L)
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! Urea (mmol/L)
! Creatinine (micromol/L)
! Total Proteins (g/L)
! Albumin (g/L)
! Total Bilirubin (micromol/L)
! Cholesterol and LDL (mmol/L)
! Chloride (mmol/L)
! Total calcium (mmol/L) 
! Aspartate aminotransferase (AST) (IU/L)
! Alanine aminotransferase (ALT) (IU/L)
! Gamma-glutamyl Transferase (GGT) (IU/L)
! Alkaline phosphatase (ALP) (IU/L)
8.2.8
Laboratory Tests
8.2.8.1
General Considerations
The collection of all blood samples for the laboratory tests will be performed before administration 
of N8, except the recovery samples which must be collected 30 minutes after administration of N8.
Please find below a summary of the assessments and procedures for the local and central 
laboratories, respectively.
The laboratory equipment used by central and local laboratories may provide analyses not 
requested in the protocol but produced automatically in connection with the requested analyses. 
Such data will not be transferred to the trial database, but may be reported to the Investigator
according to specifications in the laboratory standard operating procedures and requirements. The 
additional data should be specified in the trial specific laboratory manual. The Investigator must 
review all laboratory results for concomitant illnesses and adverse events and report these according 
to this protocol.
8.2.8.2
Local Laboratory Tests
Assessments of haematology and FVIII trough levels will be done at the local laboratory as per 
standard of practice at the participating site. Laboratory results from the local laboratory will be 
recorded in the eCRF.
If the local laboratory is used for analysis of inhibitors and/or FVIII recovery, duplicate sample 
must also be sent to the central laboratory for analysis. The data from the central laboratory will 
then be used in the official analysis.
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 
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significant”. Clinically significant findings must be recorded as concomitant illness (blood samples 
during visit 1) or as an Adverse Event (blood samples taken at visit 2-7, unscheduled visits and
potential follow-up visits). Abnormalities should only be recorded as AEs if not present or 
worsened from baseline/previous assessments. Laboratory results should be signed and dated. 
Laboratory reports (laboratory result) are considered source data and should be kept in patient file 
for source data verification (carried out by the monitor).
The local laboratory must be certified in performing laboratory tests and assessments as requested 
in this trial.
Storage, handling, and disposition of samples analysed at local laboratories, will be performed 
according to local laboratory procedures.
8.2.8.3
Central Laboratory Tests
A central laboratory will analyse and report all laboratory safety tests related to biochemistry, viral 
antibody assessments, FVIII inhibitor and FVIII activity tests performed in this trial. Laboratory 
data from the central laboratory will be reported to Novo Nordisk electronically, and in a manner 
that anonymity of patients will be maintained.
A one-stage FVIII clotting activity assay and a two-stage chromogenic assay will both be used to 
assess the FVIII activity at the central laboratory.
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.
For descriptions of assay methods, particulars of instrumentation, procedures for obtaining 
samples/specimens, who will perform the assessments and the storage, handling conditions, and 
disposition of specimens, please refer to the Laboratory Manual.
8.2.8.4
Blood Sampling Volume
Blood samples for laboratory analysis of efficacy, safety and other parameters will be drawn as 
described for the individual visits. The total volume of blood drawn during the trial will be 
approximately 30 mL per patient. The blood volume collected from the patient 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 (see Appendix B). This is in accordance with European regulatory guidelines (Directive 
2001/20/EC)2,22. During visits, when samples are taken, blood samples will be aliquoted to meet 
above mentioned requirements. Instructions will be provided in the Laboratory Manual.
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8.2.9
Physical Examination
Physical examination should be performed at Visits 1-7 according to practice at the participating 
clinic including assessments of the following:
!
Head, ears, eyes, nose, throat, and neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous systems
!
Skin
Any changes in the examinations between the visits which fulfil the criteria of an Adverse Event
must be recorded as such, see Section 12.1.
8.2.10
Vital Signs
Vital signs will be assessed at Visit 1 and Visit 7 and includes:
! Body temperature (assessed by measuring inner ear temperature or using an oral digital 
thermometer)
! Respiratory rate (resp./min.)
! Pulse: preferably supine
! Blood pressure (BP): preferably supine
BP (systolic and diastolic) and pulse rate will be measured according to local practice at the clinic; 
preferably after the patient has rested comfortably for at least 3 minutes.
Any changes in the vital signs between the two visits which fulfil the criteria of an Adverse Event
must be recorded as such, see Section 12.1.
8.3
Assessments for Efficacy
8.3.1
Bleeds
During the entire trial period all bleeds treated with N8 will be entered in either the eCRF or in the 
patient’s diary. For mild/moderate bleeds, the patient or caregiver must fill in the diary and at visits 
the diary data will be transcribed into the eCRF by trial site personnel. For severe bleeds (see 
definition in Section (8.3.1.1) the Investigator, or designated site staff, must be contacted without 
delay to prescribe the appropriate treatment and any follow-up procedures. It is recommended that 
these direct instructions are followed by, or given at, an unscheduled visit to the clinic. 
Documentation about the severe bleed should be entered in the medical records and eCRF by the 
trial personnel.
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All bleeds should be reported to the clinic within 24 hours. However, if there is no haemostatic 
improvement within 8 h after one dose, immediate contact should be taken with the Investigator/site 
staff for advice.
Joint bleeds are either categorised as target joint or non-target joint bleeds. Target joint bleeds are 
defined as 3 or more bleeds 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.23
For bleeds the following will be recorded in the patient diary:
!
Date and time of onset of bleed
!
Location of the bleeding (central nervous system (CNS), haemarthrosis (joint), 
gastrointestinal, subcutaneous, muscle, mucosal or other)
!
Classification of bleed (spontaneous, traumatic)
!
Haemostatic drug used for treatment (N8 or other drug if haemostasis cannot be achieved, 
i.e. bleed cannot be controlled with N8)
!
Dose(s) and Time(s) of administration
!
Other therapy used (compression/other)
!
Date and time of stop of bleed
!
The bleeds must be categorised as mild/moderate or severe, see Section 8.3.1.1.
!
Clinical evaluation of the haemostasis (Excellent, Good, Moderate or None), see Section 
8.3.1.2
8.3.1.1
Definition of Severity of Bleeds
Mild/Moderate: minor bleeds which are uncomplicated joint bleeds, muscular bleeds without 
compartment syndrome, mucosal or subcutaneous bleeds
Severe: Major bleeds that require hospitalisation. All internal head 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) will also be reported as severe and entered in 
the eCRF. All mild or moderate bleeds which are ongoing 24 hours after start will be redefined as
severe.
8.3.1.2
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 an infusion, but possibly requiring more than one infusion for complete resolution;
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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 within approximately 8 hours after the first 
infusion; usually requiring more than one infusion.
8.3.1.3
Bleed Classification
!
Spontaneous
!
Traumatic
!
Re-bleed
Re-bleeds will be reported by the trial statistician based on the diary data. Re-bleed is defined as 
when after an initial period of improvement, worsening of bleeding site conditions either on 
treatment or within 72 hours after stopping of treatment (therefore, a new bleed is considered 
occurring later than 72 hours after stopping of treatment).
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8.4
Other Assessments
8.4.1
FVIII genotype testing (not applicable to Brazil)
At Visit 2, all patients/parents/legally authorised representative (LAR) 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 as allowed by local law. Investigator, parent(s) or LAR have the 
right to refuse to provide patient’s FVIII genotype documentation or to refuse genotyping. This will 
not stop the patient to continue participation in the remainder of the study.
Applicable for Japan only: If documentation of the patient´s genotype already exists, the patient is 
offered to provide his data for the trial. If no previous data exists and genotyping consent is 
obtained, FVIII genotype analysis is performed at the laboratory in Bonn, Germany, using DNA
isolated from leucocytes from the patient’s blood. No analysis will be performed concerning other 
genes than FVIII. Samples will be disposed appropriately after the test and all test results are kept 
strictly confidential.
8.4.2
Viral Antibody Information
At Visit 1 status of the following viral infections are assessed.
• HBsAg and/or anti-HCV antibodies  if status is unknown or the Investigator considers there is an  
indication to test
• HIV 1 & 2 antibodies if status is unknown or the Investigator considers there is an indication to 
test.
If the patient is HIV positive the last value of CD4+ T-cells, and date of test, should be recorded. If 
not available a new cell count is required.
8.4.3
Demography
Following information will be collected at Visit 1 as allowed by local law.
!
Date of birth
!
Ethnicity
!
Race
8.4.4
Body Measurements
Weight and height will be measured at Visit 1 and 7, for Visit 2-6 only weight is measured. 
!
Weight, light clothing only (kg/lbs) and without shoes
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!
Height without shoes (cm/inches)
8.4.5
Diaries
Diaries will be dispensed at Visits 2-6, and the following data will be collected:
!
Treatment
∗
Preventive or treatment of bleed
∗
N8 dose
∗
Date and time of dose administration
!
Bleeds 
∗
Onset of bleed (date and time)
∗
Stop of bleed (date and time)
∗
Location of bleed
∗
Classification of bleed, see Section 8.3.1.3.
∗
Evaluation of haemostasis, see Section 8.3.1.2.
∗
Other therapy used
∗
Severity of bleed, see Section 8.3.1.1.
Trial product administration performed at the clinic by the Investigator will not be entered into the 
diary, but in the eCRF.
8.4.6
Medical and Haemophilia History 
8.4.6.1
Medical History
Complete medical history is to be obtained during the Screening Visit (Visit 1) including other 
coagulation-related diseases. In the event that a diagnosis is unknown the description of symptoms 
will be recorded. All chronic illnesses should be recorded.
The following organ systems should be considered in medical history (if recorded in the medical 
charts):
!
Central and peripheral nervous system
!
Eyes-ears-nose-throat
!
Cardiovascular
!
Respiratory
!
Endocrine-metabolic
!
Musculoskeletal
!
Dermatologic
!
Gastrointestinal system
!
Genitourinary system
!
Haematopoietic-lymphatic including blood type parameter ( O type or non-O) as allowed by 
local law and if available
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The following conditions should be assessed:
!
Drug allergies or sensitivities
!
Non-drug allergies
8.4.6.2
Details of Haemophilia
Following information about the patients haemophilia to be obtained during the Screening Visit
(Visit 1).
!
Diagnosis of haemophilia A (date)
!
Classification of haemophilia A and FVIII level (%)
!
Underlying gene defect (if known)
!
History of relatives with haemophilia A (as recalled by parent/guardian) including inhibitors
8.4.6.3
Haemophilia Treatment History (if applicable)
Following information about the patients haemophilia treatment to be obtained during the Screening 
Visit (Visit 1).
!
Treatment
∗
Any treatment with blood products 
∗
Number of bleeds prior to screening visit
∗
Number of bleeds into the same joint prior to the screening visit
8.4.7
HE and PRO data
In this trial HE and PRO data will be collected. The HE data include assessments of resource 
utilization and patient/caregiver burdens associated with bleeds. The PRO data use a validated 
questionnaire to assess treatment satisfaction, Hemo-Sat.
Hemo-Sat is a treatment satisfaction survey for parents/caregivers (the P version). Dimensions 
measured include ease and convenience, efficacy, burden, specialists/nurses, centre/hospitals, 
general satisfaction.
The questionnaire was originally developed in UK English and has been translated and 
linguistically validated into other languages. However it might not be available for all countries. 
The questionnaire is to be filled in at Visits 1, 3, and 7, preferably before any other trial related 
procedures.
8.5
Patient Compliance
Assessment of patient compliance with the protocol procedures for determination of the 
continuation of the trial will be done by the Investigator. Full compliance with protocol procedures 
is expected in this trial. 
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Failure of compliance with scheduled visits and trial product administration may result in 
withdrawal in accordance with the protocol withdrawal criteria, see Section 6.4.
Compliance with N8 treatment should be addressed at each visit. If the Investigator considers the 
bleeds a patient experiences are due to exceeding the intended time between doses, the Investigator
must retrain the patient/parent/caregiver.
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Protocol / UTN:U1111-1119-6116
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9
Trial Supplies
9.1
Trial Products
The following products will be supplied by Novo Nordisk:
!
N8, 2000 IU/vial
o
Sterile, freeze-dried powder
o
To be reconstituted with 4.3 mL of 0.9% Sodium Chloride (NaCl) for injection
o
After reconstitution each vial contains 500 IU/mL of N8
o
The reconstituted solution is colourless and clear/almost clear
!
N8, 250 IU/vial
o
Sterile, freeze-dried powder
o
To be reconstituted with 4.3 mL of 0.9% Sodium Chloride (NaCl) for injection
o
After reconstitution each vial contains 62.5 IU/mL of N8 
o
The reconstituted solution is colourless and clear/almost clear
!
Sodium chloride 0.9%, 10 mL
N8 must not be further diluted, added to or mixed with other material.
A leaflet describing the reconstitution procedure will be translated into local language(s) and 
handed over to the patient together with the trial product.
Detailed instructions regarding reconstitution of N8 will be provided in the Trial Materials Manual 
(TMM).
9.2
Packaging and Labelling of Trial Products
Labelling will be in accordance with Annex 1324, local law and trial requirements.
The trial products will be packed open labelled.
Each box will have a Dispensing Unit Number (DUN) for drug accountability and traceability.
9.3
Storage of Trial Products
In use time of the reconstituted N8 is 24 hours at 2-8 +C or 4 hours at 9-25 +C.
!
N8
o
Store at 2-8+C
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o
Protect from direct sunlight
o
Do not freeze
!
NaCl
o
No special storage requirements.
The Investigator must ensure the availability of proper storage conditions and monitor and record 
and evaluate the temperature. A temperature log for daily 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 outside the acceptable temperature 
range during storage at the site.
Returned trial product(s) (partly used or unused including empty packaging material) must be stored 
separately from non-allocated trial product(s). Returned trial products can be stored at room 
temperature.
9.4
Dispensing and Drug Accountability of Trial Products
The IV/WRS will allocate a trial product DUN to the patient at each dispensing visit. The correct 
DUN must be dispensed to the patient. 
!
No trial product(s) should be dispensed to any person not enroled in the trial. 
!
Unused trial product must be stored separately from used trial product.
!
Once a patient is dosed, all vials (used, partially used, unused, returned, and lost/damaged) must 
be recorded in the IV/WRS Drug Accountability module.
Trial product will be dispensed at the visits depicted in the flow chart, see Table 2–1. The patient is 
required to return both used and unused vials at the next visit to the clinic or at the End of Trial 
Visit, as appropriate.
The Investigator or delegated person e.g. trial nurse will perform drug accountability in the 
IV/WRS Drug Accountability module.
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, unused, and broken vials of 
the supplied trial product.
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Protocol / UTN:U1111-1119-6116
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9.5
Trial Product Administration 
The trial product should be administered as a slow bolus i.v. injection over approximately 2 min. 
(from start to completion of injection) for all trial product administrations.
These administrations will primarily be performed at home. All patients and/or parents/caregivers 
will be instructed by Investigator how to handle home administration before first dose.
9.6
Auxiliary supply
All auxiliary supply used in this trial such as syringes, butterflies, sterile swaps etc. will be provided 
by Novo Nordisk.
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Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
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10 Randomisation, Breaking of Blinded Codes and Interactive 
Voice/Web Response System (IV/WRS)
10.1
Randomisation
NA
10.2
Breaking of Blinded Codes
NA
10.3
Interactive Voice/Web Response System (IV/WRS)
A trial specific IV/WRS will be set-up, and can be accessed at any time by 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. For a minimum, the system will be used for 
enrolment of patients, dispensing of trial product, controlling of expiry date of trial product, 
ordering of trial product, drug accountability and screening failure data and withdrawal information. 
An IV/WRS user manual will be provided to the site.
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Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
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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).
Concomitant medication: any medication, other than the trial product(s), that is taken during the 
trial, including the screening and run-in periods. Vaccinations must also 
be recorded as concomitant medication.
(Vaccinations will be included in the evaluation of risk factors for inhibitor development, see 
Section 18.4 ) 
Details of all concomitant illnesses and medication must be recorded at trial entry (i.e. at the first 
visit). Any changes in concomitant medication must be recorded at each visit. If a change is due to 
an AE this must be recorded and reported according to section 12. If the change influences the 
patient’s eligibility to continue in the trial the Monitor must be informed.
The information collected for each concomitant medication includes (at a minimum) start date, stop 
date or continuation and indication.
The following concomitant medications are not permitted during the course of this trial:
! Treatment with FVIII concentrates other than N8, see Section 6.4.
In case these medications are used during the trial, the patient must be withdrawn.
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Protocol / UTN:U1111-1119-6116
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12 Adverse Events
12.1
Definitions
Adverse Event (AE):
Any untoward medical occurrence in a patient 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 patient has signed the 
informed consent and until post treatment follow-up period as defined in the protocol.
An AE can also be a clinical laboratory abnormality regarded as clinically significant i.e. an 
abnormality that suggests a disease and/or organ toxicity, and is of a severity that requires active 
management (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 patient has signed the informed 
consent
!
Pre-existing conditions found as a result of screening procedures. These should be 
recorded as medical history/concomitant illness.
Serious Adverse Event (SAE):
A SAE is an experience that at any dose results in any of the following:
!
Death
!
A life-threatening experience a)
!
In-patient hospitalisation or prolongation of existing hospitalisation b)
!
A persistent or significant disability/incapacity c)
!
A congenital anomaly/birth defect
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!
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.
a)  The term “life-threatening” in the definition of SAE refers to an event in which the patient
was at risk of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death if it were more severe.
b)  The term “hospitalisation” is used when a patient is:
!
Admitted to a hospital/inpatient (irrespective of the duration of physical stay), or
!
Not admitted to a hospital/not inpatient, but stays at the hospital for treatment or 
observation for more than 24 hours.
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social 
purposes do not constitute AEs and should therefore neither be reported as AEs or SAEs. 
Likewise, hospital admissions for surgical procedures planned prior to trial inclusion are not 
considered AEs or SAEs.
c)  The term “disability/incapacity” means that following the event the patient or clinical 
investigation subject has significant, persistent or permanent change, impairment, damage or 
disruption in his body function or structure, physical activity and/or quality of life.
d)  The term “important medical events” means events which may jeopardise the patient or 
require intervention to prevent a seriousness criterion. It can be AEs which suggest a significant 
hazard or puts the patient 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 patient’s daily activities
!
Moderate – Marked symptoms, moderate interference with the patient’s daily activities
!
Severe – Considerable interference with the patient’s daily activities, unacceptable.
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Protocol / UTN:U1111-1119-6116
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Relationship to Trial Product (N8) Assessment Definitions:
!
Probable – Good reasons and sufficient documentation to assume a causal relationship
!
Possible – A causal relationship is conceivable and cannot be dismissed
!
Unlikely – The event is most likely related to aetiology other than the trial product.
Outcome Categories and Definitions: 
!
Recovered* – Fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first trial related activity after the patient signed the 
informed consent
!
Recovering – The condition is improving and the patient is expected to recover from the 
event. This term should only be used when the patient has completed the trial
!
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 
meets a seriousness criterion, the AE must be reported as a SAE
!
Not recovered
!
Fatal
!
Unknown – This term should only be used in cases where the patient is lost to follow-up.
*In Japan “Remitted” will be used
12.1.1
Technical Complaints
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 and other events for expedited reporting
A medical event of special interest (MESI) is an event in which, in the evaluation of safety, has 
special focus. 
A MESI should be reported following the same reporting requirements and timelines as for SAEs, 
irrespective of the MESI fulfils a seriousness criterion.
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The following events are defined as MESIs in this trial;
!
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
!
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
!
Allergic reaction including Anaphylactic reaction as defined by Sampson et al 200625. 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.25
!
Thromboembolic events
o
clinical signs or laboratory indications of arterial and venous thrombosis including 
myocardial infarction, pulmonary embolism, cerebral infarction/thrombosis, deep 
vein thrombosis, other clinically significant thromboembolic events and peripheral 
artery occlusion, see definitions)
Other events for expedited reporting;
!
Suspected transmission of infectious agents via a trial product.
12.2
Collection, Recording and Reporting of Adverse Events
All events meeting the definition of an AE must be collected and reported from screening (visit 1) 
until End of Trial and at potential Follow-Up visits. During each contact with the trial site (visit or 
telephone, excluding safety visits, where the patient is not seeing the Investigator or site staff e.g. 
visits to the laboratory) the patient must be asked about adverse events, 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: N8 Investigator’s Brochure (insert reference)
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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 SAEs complete a 
safety information form for each event. However, if several symptoms or diagnosis occur as part of 
the same clinical picture only one set of safety information form pages can be used to describe all 
the SAEs. 
MESIs and other events for expedited reporting must always be reported to Novo Nordisk 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, MESIs and other events for expedited 
reporting 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.
For US the Investigator, and for all other countries Novo Nordisk, must inform the regulatory 
authorities and IECs/IRBs in accordance with the local requirements in force and ICH  GCP8.
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.
Investigators will be notified of trial-related SAEs in accordance with the local requirements in 
force and ICH GCP8. In Japan, Novo Nordisk must inform the health authorities and the relevant 
parties of SAE information in accordance with the Japanese requirements in force and ICH GCP.8
The monitor must be informed accordingly.
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12.2.1
Disease-related Bleeding
Bleeds and other symptoms (e.g. pain, swelling, synovitis, arthralgia, injection site haematoma) in 
connection to bleeds that are evaluated by the Investigator as part of the underlying disease are AEs. 
However, they should only be reported as AEs if evaluated as related to trial product or trial 
procedure by the Investigator. Furthermore, fatal or life-threatening SAEs must be reported 
regardless of relatedness. All bleeds and other symptoms related to the underlying disease will be 
captured in the eCRF.
12.2.2
Follow-up of Adverse Events
During and following a patient’s participation in a clinical trial, the Investigator should ensure that 
adequate medical care is provided to the patient for any AE, including clinically significant 
laboratory values related to the trial. The Investigator should inform the patient when medical care 
is needed for AE(s) of which the Investigator becomes aware.
The follow up information should only include new (updated and/or additional) information that 
reflects the situation at the time of the Investigator’s signature.
Follow-up information (corrections, new or additional information) should be reported within 24 
hours of obtaining knowledge of the information for SAEs, and if previously non-serious AEs 
become SAEs.
All non-serious AEs classified as severe or possibly/probably related to the trial product must be 
followed until the patient 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. patient 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 patient 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. patient 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.
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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, MESIs 
and other events for expedited reporting 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, MESIs and other events for expedited reporting 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 patient 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 patient has completed the trial and is expected by 
the Investigator to recover.
After access to update the AE form in EDC is removed the Investigator must record any follow-up 
information, if required, of SAE, MESI and other events for expedited reporting on the paper CRFs 
provided at trial closure.
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 - occurring from the time of first and until the 
last usage of trial supplies - must be collected and reported to Novo Nordisk.
The patient must be asked about technical complaints during each contact (visit or telephone) with 
the Investigator or trial site staff. This may be done by posing a simple question such as “have you 
experienced any problems since the last contact?”.
The Investigator must assess whether the technical complaint is related to:
!
AE(s), SAE(s), MESI(s) and/or other events for expedited reporting
The AE(s), SAE(s), MESI(s) and/or other events for expedited reporting related to technical 
complaint(s) must be reported by the Investigator following the same reporting requirements and 
timelines as for other AEs, SAEs, MESIs and other events for expedited reporting (see section 
12.2). 
Technical complaints must be reported on the technical complaint form by the Investigator, as 
described in the following:
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One technical complaint form must be completed for each trial product, non-investigational 
medicinal product 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 from the patient. If the technical 
complaint sample is unobtainable, the Investigator must specify on the technical complaint form 
why it is unobtainable. 
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, 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 prescribed for the product, see Section 9. For further details on the shipment conditions 
of technical complaints, please contact the local monitor.
12.4
Precautions/Over-Dosage
As with any protein injected i.v., hypersensitivity reactions may occur. This might include rash, 
pruritus, fever, nausea, headache, and vomiting; also changes in blood pressure may occur.
If any of the above events occur or if an overdose is suspected, further N8 administration should be 
stopped and the patient should receive treatment as appropriate according to the hospital practice 
and guidelines.
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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. The safety committee works according to a written guideline and will meet regularly to discuss 
and evaluate the overall safety for N8 for this trial and all other N8 trials. The Novo Nordisk safety 
committee can take action with  regard to the patient safety for the trial based upon observations of 
the overall information for N8. Pre-defined rules for setting the enrolment on hold is described in 
Section 12.5.2.
The safety committee might meet to evaluate data at any time point during the conduct of the trial if 
deemed necessary.
12.5.2
Rules for putting the enrolment on hold
There are two pre-planned safety interim analysis. At each interim all patients exposed at the pre-
defined time points determined by number of patients exposed will be evaluated for inhibitor 
development.
!
Safety interim 1: After the first 25 patients have been to Visit 4 (20-25 exposure days)
!
Safety interim 2: After the first 50 patients have been to Visit 5 (50-55 exposure days)
The expected rate of inhibitors is 30–35% in previously untreated patients with severe haemophilia 
A.
The rules for putting the enrolment on hold are as follows;
Inhibitor formation in 12 or more of all exposed patients at safety interim 1, or 22 or more of all 
exposed patients at safety interim 2, will result in the N8 safety committee evaluation of all cases of 
inhibitor formation. During these evaluations, ongoing treatment in the trial will continue, however 
new patients will not be enroled in the trial. The evaluation will provide the basis for a decision on 
any actions required for the trial to allow for continuation of enrolment or decision to terminate the 
trial.
The diagnosis of inhibitor is made if the patient has been tested positive for inhibitors (BU 
≥0.6/mL) at two consecutive tests at central laboratory, sampled preferably within 2 weeks.
During the evaluation the safety committee will evaluate risk factors for inhibitor formation such as 
ethnicity, family history of inhibitors, FVIII gene mutation type, age at first FVIII treatment, reason 
for first treatment, treatment duration after first treatment, the details of any surgery (including type 
of surgery, amount of product used, and outcome), any recent infection and any recent vaccination. 
Furthermore the time of occurrence of inhibitor formation (after how many exposures) and whether 
the inhibitor is a high or low titre will be evaluated
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12.5.3
Data Monitoring Committee
No Data Monitoring Committee will be established for this trial as the trial is open-label, and the 
investigational drug is not expected to show toxicity.
Safety surveillance will be performed by the internal Novo Nordisk safety committee.
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13 Case Report Forms
Novo Nordisk will provide a system for EDC. This system and support services to the system will 
be supplied by a vendor. The activities of this vendor will be under the direction and supervision of 
Novo Nordisk.
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 eCRF 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 are recorded in the eCRFs as soon as possible after the visit 
(preferably within 3 days). When data are 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 site 
after the trial database is released and access to update the trial data on the EDC application is 
removed. These 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
Analysis Results
Laboratory reports from the Local Laboratory must be signed and dated by the Investigator on the 
day of the review of the analysis results. The results from the Local Laboratory should be entered in 
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the eCRF for each patient. A signed and dated copy of Local Laboratory report must be retained at 
the trial site.
Central laboratory results will be transferred electronically to Novo Nordisk.
Laboratory reports from the central laboratory will be provided to the Investigator.
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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 has been 
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 intervals between visits must not exceed 8 weeks when there are patients ongoing in the trial at 
the site. When there are no trial active patients at the sites, 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 will be entered in the eCRF within
preferably 3 days after data are available. The Screening Failure Form will be completed. These 
data will go 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.
The following data can be recorded directly in the eCRF and will then be considered source data:
!
Ethnic origin
!
Race
For all other data in the eCRF, it must be possible to verify these against source documents.
Diaries on paper will be provided by Novo Nordisk. Information on treatment and bleeds will be 
collected in the diaries, please refer to Section 8.4.5. The completed diaries are considered source 
data. The original diary must be stored at site. 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 
patient data when it is transmitted over open networks. 
Laboratory data will be transferred electronically from the central laboratory performing clinical 
analyses. In cases where laboratory data are transferred via non-secure electronic networks, data 
will be encrypted during transfer. The electronic laboratory data will be 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 (OC) file and loading into OC.
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. 
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17 Evaluability of Patients for Analysis
All main descriptions and analyses of efficacy will be based on the Full Analysis Set, as defined in 
ICH E9 Guidelines (Statistical Principles for Clinical Trials)18. The Full Analysis Set includes all 
dosed patients with data after dosing.
The Safety Analysis Set also includes all dosed patients with data after dosing. The analyses of the 
safety endpoints will be based on the Safety Analysis Set.
No formal Per-Protocol analysis is planned. However, the sensibility of the results with respect to 
single patient’s data may be investigated by performing additional analyses on subsets of data.
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18 Statistical Considerations
Novo Nordisk will be responsible for the statistical analysis.
18.1
Sample Size Calculation
No formal sample size calculations have been performed. The sample size is based on the EMA
guideline requirement.
18.2
Statistical Methods
18.2.1
General Considerations
No formal testing of statistical hypotheses will be performed. Evaluation of data will be based on
estimated incidence rates and odds ratios, and confidence intervals for these, as well as descriptive
statistics, i.e. summary tables, listings, and figures.
18.2.2
Primary Endpoint(s)
Incidence rate of inhibitors defined as inhibitor titres ≥ 0.6 Bethesda units/mL
The incidence rate of inhibitors will be calculated 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
incidence rate the numerator will include all patients with inhibitors while the denominator will
include all patients with minimum of 50 ED plus any patients with less than 50 ED but with
inhibitors.
Furthermore, the time to inhibitor development will be presented by a Kaplan Meyer plot.
The relationship between the incidence rate of inhibitors and different patient and treatment
characteristics will be investigated
Patient characteristics include:
!
Ethnicity (White, Asian, African, Other)
!
Family history of inhibitors (Negative, Positive)
!
FVIII gene mutation type (Low risk (small deletions/insertions of < 200 base pairs, missense 
mutations, and other including splite or promoter mutations), High risk (large deletions of 
over 200 base pairs, nonsense mutations, intron 22 or one inversions))
Treatment characteristics include:
!
Age at first treatment (Older than 12 months, between 6-12 months, between 1-6 months, 
before 1 month)
!
Reason for first FVIII treatment (Prevention, Bleed, Surgery)
!
Treatment moment at first treatment (Less than five consecutive days, Five or more 
consecutive days )
The odds ratio for each patient and treatment characteristic will be calculated using a univariate
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logistics regression model and presented together with a 95% confidence interval.
The incidence rate of inhibitors will be calculated and presented by the patient and treatment
characteristics.
18.2.3
Confirmatory Secondary Endpoints
NA
18.2.4
Supportive Secondary Endpoints
For patients that develop inhibitors only the time period until the last negative inhibitor result is 
considered for the efficacy endpoints below. Sensitivity analyses will be made only including 
patients who do not develop inhibitors. Further, tables will be made including only inhibitor 
patients. For these patients the relevant time period is the time period after positive inhibitor test.
Secondary Efficacy Endpoints
!
Haemostatic effect of N8 on treatment of bleeds assessed on a predefined four point scale: 
Excellent, Good, Moderate and None.
The haemostatic effect of N8 will be will be summarised by frequency tables containing count
and percentages of all bleeds.
The haemostatic effect of N8 will also be summarised by the following subgroups: Cause of bleed
(Spontaneous, Traumatic, Re-bleed), Site of bleeding (Central nervous system, Haemarthrosis
(Joint), Gastrointestinal, Subcutaneous, Muscular or other), Classification of bleeding
(Mild/Moderate or Severe) and Time of bleeding (the day is divided into 6 time intervals, each of
4 hours). Details (cause, site, classification and time) about the bleeds will also be summarised and 
listed.
!
Annualized bleeding rate during bleeding prevention period with N8
For this endpoint patients who develop inhibitors will only be included if they have been treated for 
minimum 1 month before the first positive inhibitor test. The reason to exclude these patients from 
the calculations is that if the treatment period is too short, the uncertainty introduced on the 
estimated annualized bleeding rate will be relatively large.
The annualized number of bleeds in total and by cause of bleeding (spontaneous or traumatic) will
be estimated by a Poisson model allowing for over-dispersion and presented with a 95%
confidence interval (CI).
In addition, the annualized number of bleeds in total and by cause of bleeding, excluding all
bleeds occurring more than 72 hours after last N8 dose will be estimated by a Poisson model
allowing for over-dispersion and presented together with a 95% CI.
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The annualized number of bleeds in total and by cause of bleeding, excluding all bleeds occurring
more than 48 hours after last N8 dose will also be estimated by a Poisson model allowing for
over-dispersion and presented together with a 95% CI.
A sensitivity analysis will be made only including data related to the time periods where the 
patients are dosed three times weekly or every second day.
The time interval from last N8 dose to start of a bleed will be summarised. This will be done by a
frequency tables dividing the time interval into the following 5 groups: ≤ 12 hrs, > 12 hrs and ≤ 24
hrs, > 24 hrs and ≤ 48 hrs, > 48 hrs ≤ 72 hrs, > 72 hrs. The time interval from last N8 dose to start
of a bleed will also be illustrated graphically with time from last dose on the x-axis and number of
bleedings on the y-axis.
!
Number of N8 infusions required per bleed
The number of infusions of N8 required per bleed will be calculated as the number of infusions of
N8 used in the time period from start of the bleed to stop of the bleed. The number of infusions
will be presented using count and percentages of all bleeds.
!
Total consumption of N8 per patient (prevention, treatment of bleeds and during surgery) 
per month and annualised value
Total consumption of N8 during the trial will be summarised and listed by patient.
!
N8 consumption per bleed
The consumption of N8 (IU/kg BW/bleed) will be calculated as the consumption of N8 used from
start of the bleed to stop of the bleed. The consumption will be summarised and listed by patient.
!
N8 consumption during bleeding prevention period
The consumption of N8 during bleeding prevention period (IU/kg BW/month) will be calculated as 
the consumption of preventive N8 doses and summarised and listed by patient.
Secondary Safety Endpoints
!
Frequency of adverse events and serious adverse events
All AEs and SAEs will be summarised by frequency of events and frequency of patients with any
event. Similar summaries cross-classified by severity and by causal relation to trial product will
also be made.
Furthermore, listings will be provided displaying all AEs and SAEs including pertinent
clinical information.
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!
Incidence rate of high-titre inhibitors defined as inhibitor titre ≥ 5 Bethesda units/mL
Incidence rate of high-titre inhibitors will be calculated and a 1-sided 97.5% upper confidence
limit will be provided based on an exact calculation for a binomial distribution.
!
Incidence rate of clinically relevant inhibitors defined as an inhibitor titre (≥ 0.6 BU/mL) 
combined with a decreased recovery (<66% of expected level)
The incidence rate of clinically relevant inhibitors will be calculated and a 1-sided 97.5% upper
confidence limit will be provided based on an exact calculation for a binomial distribution
Furthermore, the time to inhibitor development and clinically inhibitor development will be
presented by a Kaplan Meyer plot.
The relationship between the incidence rate of clinically relevant inhibitors and high-titre
inhibitors and different patient and treatment characteristics will also be investigated.
Outcome of inhibitor treatment will be listed and summarised.
All additional safety parameters such as laboratory parameters and physical examinations will be
listed and summarised by visit for all patients.
18.3
Interim Analysis
An interim analysis is planned to occur after the first 50 patients each have 50 ED. The interim
analysis will include a full report of all data for the 50 patient until the cut-off date, which is the
date the 50th patient had his exposure number 50.
The interim analysis is performed to file a marketing authorisation variation application to
include PUP in the N8 label.
Furthermore, the interim will include a safety analysis for all patients exposed before the cut-off
date. The safety analysis will include a Kaplan Meyer plot presenting the time to high titre
inhibitor, clinically relevant inhibitor and inhibitor (≥0.6 BU/mL), respectively. All AEs, SAEs,
MESIs and other abnormal safety parameters such as laboratory parameters and physical
examinations will be presented for all patients.
18.4
Sequential Safety Analysis/Safety Monitoring
There are two pre-planned safety interim analysis. At each interim all patients exposed at the pre-
defined time points determined by number of patients exposed will be evaluated for inhibitor 
development.
!
Safety interim 1: After the first 25 patients have been to Visit 4 (20-25 exposure days)
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!
Safety interim 2: After the first 50 patients have been to Visit 5 (50-55 exposure days)
The expected rate of inhibitors is 30–35% in previously untreated patients with severe haemophilia 
A. 
The rules for putting the enrolment on hold are as follows;
Inhibitor formation in 12 or more of all exposed patients at safety interim 1, or 22 or more of all 
exposed patients at interim 2, will result in the N8 safety committee evaluation of all cases of 
inhibitor formation. During these evaluations, ongoing treatment in the trial will continue, however 
new patients will not be enroled in the trial. The evaluation will provide the basis for a decision on 
any actions required for the trial to allow for continuation of enrolment or decision to terminate the 
trial.
During the evaluation the Safety Committee will evaluate risk factors for inhibitor formation such 
as ethnicity, family history of inhibitors, FVIII gene mutation type, age at first FVIII treatment, 
reason for first treatment, treatment duration after first treatment, the details of any surgery 
(including type of surgery, amount of product used, and outcome), any recent infection and any 
recent vaccination. Furthermore the time of occurrence of inhibitor formation (after how many 
exposures) and whether the inhibitor is a high or low titre will be evaluated.
18.5
Explorative Statistical Analysis for Pharmacogenetics and Biomarkers
N/A
18.6
PK and/or PD Modelling
N/A
18.7
Health Economics and Patient Reported Outcomes
Health economic data will be collected in the eCRF in connection with severe bleeds. Patient 
reported outcomes will be collected using questionnaires at visits 1, 3, and 7. The health economic 
and PRO data will be summarised using descriptive statistics.
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19 Ethics
The trial will be conducted in compliance with ICH GCP18, applicable regulatory requirements, and 
in accordance with the Declaration of Helsinki26.
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 GCP and the requirements in the Declaration of 
Helsinki.
Prior to any trial-related activity, the Investigator must give the patient and/or the patient’s LAR
oral and written information about the trial in a form that the patient or the patient’s LAR can read 
and understand. This includes the use of impartial witness where required. In this trial the notion of 
legal representative should be understood as both parents, or legal representative(s), as defined in 
Member States’ national laws, who consents on behalf of the child.
Consent: As a child is unable to provide legally binding consent, informed consent must be sought 
from the parents/ legal representative (see definition above) on the child’s behalf. The specific and 
written informed consent of the parents/legal representative must be sought prior to enroling a child 
in the trial. Information should be given by an experienced Investigator to each parent, or the legal 
representative, on the purpose of the trial and its nature. 
Assent: When a patient deemed legally incompetent, such as a child, is able to give assent to 
decisions about participation in trial, the Investigator must offer the possibility for the child to give 
assent in addition to the consent of the parents/LAR. An "assent form" will be provided and can be 
used when appropriate and when the child is capable of forming an opinion and assessing.
The requirement for obtaining informed consent from a patient’s LAR is that the patient is unable to 
provide informed consent, and the process has been approved by the relevant IRB/IEC.
Children, incapable of giving consent, are included as patients in this trial in accordance with 
Health Authority guidelines for development of FVIII products.1
A voluntary, signed and personally dated (including time) informed consent form will be obtained 
from the patient and/or the patient’s LAR prior to any trial-related activity.
The responsibility for seeking informed consent must remain with the Investigator or an adequately 
medically qualified person delegated by the Investigator. The written informed consent must be 
signed and personally dated by the parents/LAR, including time by the person who seeks the 
informed consent.
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If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the Investigator must inform the patient and/or the patient’s LAR in a 
timely manner, and a revised written informed consent must be obtained.
FVIII Genotype Testing
A collection of samples for genotype testing is offered to the patients participating in this trial. Prior 
to any trial-related activity, the Investigator must provide the patient and/or the patient’s LAR the 
possibility to abstain from the genetic testing 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 refuses to 
consent to continue in the trial, if the patient dies and no consent is available from a patient’s LAR, 
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 are 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 patient, 
patient recruitment procedures (incl. advertisement), if any, Investigator’s Brochure (IB), available 
safety information, information about payments and compensation available to patients if not 
mentioned in the patient information, the Investigator’s current curriculum vitae (CV) and/or other 
documentation evidencing qualifications, and other documents as required by the local IRB/IEC 
should be submitted. The submission letter should clearly identify the trial identification number, 
version, EudraCT no., title and/or the date of the documents that have been submitted to the 
IRB/IEC. Written approval/favourable opinion must be obtained from IRB/IEC prior to 
commencement of the trial.
During the trial, the Investigator or sponsor, as applicable, must promptly report the following to 
the IRB/IEC, in accordance with local requirements: updates to IB, unexpected SAEs where a 
causal relationship cannot be ruled out, 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.
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Substantial protocol amendments must not be implemented before approval/favourable opinion, 
unless necessary to eliminate immediate hazards to the patients.
The Investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records should be filed in the Investigator’s trial file and copies must be sent to Novo 
Nordisk.
19.4
Regulatory Authorities
Regulatory authorities will receive the clinical trial application (CTA)/clinical trial notification 
(CTN for Japan), substantial/non-substantial protocol amendments (notifications of protocol 
amendments for Japan), reports on SAEs, and the CTR according to 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.
Two pre-planned safety interim analyses will be performed during the trial to monitor the inhibitor 
development. If the pre-determined limit of number of cases is reached, the N8 safety committee 
will evaluate all cases of inhibitor formation. During these evaluations, ongoing treatment in the 
trial will continue, however new patients will not be enroled in the trial. For further information, 
please see Section 18.4.
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 trial validation plan (TVP). The 
Investigator must approve these as outlined in the TVP. 
The documentation for the protocol deviations must be kept in the Investigator’s trial file and Novo 
Nordisk’s trial master file.
21.1
Audits and Inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk internal Quality 
Audit System or an inspection from domestic or foreign regulatory authorities. The Investigator and 
the site staff as well as Novo Nordisk clinical staff have an obligation to cooperate and assist in 
such audits and inspections. This includes giving Auditors and Inspectors direct access to all source 
documents and other documents relevant to the conduct of the clinical trial at the site.
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22 Critical Documents
Before the Investigator starts the trial (i.e. the site has green light for screening patients), the 
following documents must be available to Novo Nordisk:
!
regulatory approval and/or notification as required 
!
curricula vitae of Investigator and sub-Investigator(s) (current, dated and signed and/or 
supported by an official regulatory document)
!
signed receipt of IB 
!
signed and dated agreement on the final protocol
!
signed and dated agreement on any substantial protocol amendment(s), if applicable
!
approval/favourable opinion from IEC/IRB clearly identifying the documents reviewed: the 
protocol, any substantial protocol amendments, patient information/informed consent form and 
any other written information to be provided to the patient, patient recruitment procedures
!
copy of IEC/IRB approved patient information/informed consent form/any other written 
information/advertisement
!
list of IEC/IRB members/constitution
!
financial agreement(s)
∗
Verification under disclosures per CRF of Final Conflict of Interest11 (US sites only)
!
FDA financial disclosure form or local equivalent as applicable.
!
laboratory reference ranges
!
laboratory certification/QA scheme/other documentation
!
laboratory methods
!
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).
∗
All Investigators outside the US will not sign FDA Form 1572. As documented in writing 
by protocol signature, all Investigators will fully comply with ICH GCP18, applicable 
regulatory requirements, and in accordance with the Declaration of Helsinki26.
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23 Responsibilities
All staff (Novo Nordisk, site, lab, CRO etc.) must conduct the trial in compliance with ICH GCP8, 
applicable regulatory requirements, and in accordance with the Declaration of Helsinki26.
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.
The following will be analysed at the local laboratory: haematology and FVIII trough level 
assessment.
A central laboratory will analyse and report all laboratory safety tests related to biochemistry, viral 
antibody assessments, FVIII activity and FVIII inhibitor assessments performed in this trial. 
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.
HE and PRO data will be analysed by Novo Nordisk.
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Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
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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.
Novo Nordisk will designate a trial Investigator with the responsibility to review and sign the CTR, 
the Signatory Investigator.
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 Criteria27).
Not withstanding anything to the contrary in this protocol. Novo Nordisk acknowledges the 
Investigators’ right to publish the entire results of the trial. Any such scientific paper, presentation, 
communication or other information concerning the investigation described in this protocol, must 
be submitted in writing to the Novo Nordisk International Trial Manager prior to submission for 
publication/presentation for comments. Comments will be given within four weeks from receipt of 
the manuscript.
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NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
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24.1.2
Publications
The results of this trial will be subject to public disclosure at external web sites according to 
international regulations, which is reflected in Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure.
In all cases, the trial results shall be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations of the trial. All authors will be given the 
relevant statistical tables, figures, and reports needed to support the planned publication. In the 
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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NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
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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 access to their own research participants' data after the full 
clinical trial report is finalised.
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NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
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25 Retention of Clinical Trial Documentation
Patient notes must be kept for the maximum period permitted by the hospital, institution or private 
practice.
The Investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The Investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the Investigator cannot archive the documents at the trial site after trial 
completion, Novo Nordisk can refer the Investigator to an independent archiving provider who has 
a system in place that allows only the Investigator to access the files.
The Investigator must be able to get hold of his/her trial documents without involving Novo 
Nordisk in any way.
Clinical trial documentation must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the Investigational Medicinal Product.
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 subjected 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. For 
Japan, the files from the Investigator/institution must be retained longer in accordance with national 
regulations.
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NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
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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.
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
EudraCT No.: 2011-001033-16
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27 References
1 Committee for medicinal products for human use (CHMP), Guideline on the Clinical 
Investigation of Recombinant and Human Plasma-derived Factor VIII Products, 
(EMEA/CHMP/BPWP/144533/2009). 2009.
2 Guidelines for the Management of Hemophilia. 2005.
3 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.
4 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.
5 Manco-Johnson MJ, Abshire T, Brown D, buchanan G, Cohen AR, DiMichele D et al. 
Randomized, controlled, multi-year study to evaluate joint outcomes in young children using 
recombinant factor VIII (Kogenate FS). Haemophilia 12[suppl 2], 12-22. 2006. 
6 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.
7 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.
8 Franchini M, Lippi G. Recombinant factor VIII concentrates. Semin Thromb Hemost 2010; 
36(5):493-497.
9 Investigator's Brochure. N8: Recombinant Factor VIII, 3rd edition.  10-12-0009. 
10 Note for Guidance on the Investigation of Bioavailability
and Bioequivalence (CPMP/EWP/QWP/1401/98). 2001.
11 Scientific Discussion on Advate®. 2005.
12 Xyntha Product Monograph. 2008.
13 The Design and Analysis of Pharmacokinetic Studies of Coagulation Factors. Subcommittee 
on Factor VIII and Factor IX of the Scientific and Standardization Committee of the ISTH 
Manuscript. Scientific and Standardization Committee of ISTH. 2001.
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Trial ID: NN7008-3809
Protocol / UTN:U1111-1119-6116
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14 Kreuz W. Full-length sucrose-formulated recombinant factor VIII for
treatment of previously untreated or minimally treated young
children with severe haemophilia A. Thromb Haemost 2005.
15 Gouw SC, van den Berg HM, Le Cessie S, van der Bom JG. Treatment characteristics and the 
risk of inhibitor development: a multicenter cohort study among previously untreated patients 
with severe hemophilia A. J Thromb Haemost 2007; 5(7):1383-1390.
16 Petrini P. What factors should influence the dosage and interval of prophylactic treatment in 
patients with severe haemophilia A and B? Haemophilia : the official journal of the World 
Federation of Hemophilia 2001; 7(1):99-9102.
17 Astermark J, Morado M, Rocino A, van den B, von Depka M, Gringeri A et al. Current 
European practice in immune tolerance induction therapy in patients with haemophilia and 
inhibitors. Haemophilia : the official journal of the World Federation of Hemophilia 2006; 
12(4):363-371.
18 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Good 
Clinical Practice, 01-May-1996, Geneva, Switzerland. 1996.
19 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.
20 Food and Drug Administration Amendments Act.  2007. 
21 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.
22 The ad hoc group for the development of implementingguidelines for Directive 2001/20/EC 
relating to good clinical practice in theconduct of clinical trials on medicinal products for 
human use. ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS ON MEDICINAL
PRODUCTS CONDUCTED WITH THE PAEDIATRIC POPULATION. EC Directive 2008.
23 Blanchette VS, McCready M, Achonu C, Abdolell M, Rivard G, Manco-Johnson M. A survey 
of factor prophylaxis in boys with haemophilia
followed in North American haemophilia treatment centres. Haemophilia 2003; 9(1):19-26.
24 European Union; The rules governing medicinal products in the European Union, volume 4, 
Annex 13, Manufacture of Investigational Medicinal Products - Brussels, July 2003.  2010. 
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Protocol / UTN:U1111-1119-6116
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25 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.
26 World Medical Association Declaration of Helsinki: Ethical principles for medical research 
involving human subjects - Last amended by the 59th WMA General Assembly, Seoul 2008.  
2008. 
27 Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and 
Editing for Biomedical Publication. ULR:http://www.icmje.org/urm_full.pdf. icmje . 2010. 
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol - Appendix A
EudraCT No.: 2011-001033-16
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Date:
29 June 2011
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Version:
1.0
Status:
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Appendix A
Agreement on Final Protocol
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 0155-0000-0004
Trial ID: NN7008-3809
Protocol - Appendix A
EudraCT No.: 2011-001033-16
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Agreement on Final Protocol
Trial ID: NN7008-3809
The Investigator and Novo Nordisk agree to conduct the trial as outlined in this protocol with 
reference to current Good Clinical Practice (GCP), applicable regulatory requirements, and in 
accordance with the Declaration of Helsinki. Any modification to the protocol must be agreed upon 
by both the Investigator and Novo Nordisk and documented in writing. By written agreement to this 
protocol, the Investigator agrees to allow direct access to all documentation, including source data, 
to authorised individuals representing Novo Nordisk (including monitoring staff and auditors), to 
institutional review boards/independent ethics committees (IEC/IRB) and/or to regulatory 
authorities.
Investigator:
Name (printed)
Signature
Date
Head of medical/clinical research or Designee:
Name (printed)
Signature
Date
CONFIDENTIAL


NN 0155-0000-0004
Trial ID: NN7008-3809
Protocol - Appendix B
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
1.0
Status:
Final
Page:
1 of 2
Appendix B
Whole Blood Volume Rules in the Paediatric Population
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.


NN 0155-0000-0004
Trial ID: NN7008-3809
Protocol - Appendix B
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
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1.0
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Whole Blood Volume Rules
The whole blood volume is used as a general guide in estimating reasonable volumes of blood that 
can be removed safely. 
The table below shows values for mean blood volume in children, men and women 
(Geigy Scientific Tables, 7th Ed; 1971): 
Whole Blood Volume
(mL/kg Body Weight)
Newborn, 15-30 minutes of age 76.5
Newborn, 24 hours 
83.3 
Children, 3 months 
87 
Children, 6 months 
86 
Children, 1 year 
80 
Children, 6 years 
80 
Children, 10 years 
75 
Children, 15 years 
71 
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol - Appendix C
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
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Status:
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Appendix C
Anaphylaxis
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 0155-0000-0004
Trial ID: NN7008-3809
Protocol - Appendix C
EudraCT No.: 2011-001033-16
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Date:
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Definition and treatment of anaphylactic reactions
The patient must be monitored carefully for anaphylactic reactions according to the clinical criteria 
for diagnosing as defined by Sampson et al, 2006.
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 (e.g. generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and at 
least one of the following:
!
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia)
!
Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g. hypotonia 
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
!
Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush, swollen lips-
tongue-uvula)
!
Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia)
!
Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
!
Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several 
hours):
!
Infants and children: low systolic blood pressure (age specific) or greater than 30% decrease 
in systolic blood pressure1
!
Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline
Reference
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.
                                                
1 Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg + [2 x age]) 
from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.
CONFIDENTIAL


NNC 0155-0000-0004
Trial ID: NN7008-3809
Protocol - Appendix D
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
29 June 2011
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Version:
1.0
Status:
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Page:
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Appendix D
Body Mass Index Charts
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 0155-0000-0004
Trial ID: NN7008-3809
Protocol - Appendix D
EudraCT No.: 2011-001033-16
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Date:
29 June 2011
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Version:
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Status:
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Page:
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Body Mass Index Charts
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Trial ID: NN7008-3809
Protocol - Appendix D
EudraCT No.: 2011-001033-16
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Date:
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Version:
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Status:
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Page:
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CONFIDENTIAL


Date: 
29 June 2011 
Version: 
1.0 
Status: 
Final 
NNC 0155-0000-0004 
Trial ID: NN7008-3809 
Protocol - Appendix E 
EudraCT No.: 2011-001033-16 
CONFIDENTIAL 
Page: 
1 of 7 
Novo Nordisk 
 
Appendix E 
 
Patients Reported Outcome 
Questionnaires 
 
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.


Date: 
29 June 2011 
Version: 
1.0 
Status: 
Final 
NNC 0155-0000-0004 
Trial ID: NN7008-3809 
Protocol - Appendix E 
EudraCT No.: 2011-001033-16 
CONFIDENTIAL 
Page: 
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Novo Nordisk 
 
 
Table of content 
 
x 
HEMO-SAT Parents; Questionnaires for Parents to Children 
CONFIDENTIAL


Trial ID: NN7008-3809 
 
 
 
VISIT X 
 
 
Centre ID/No.: 
 
Subject No.: 
 
 
 
 
 
 
Hello there! 
 
We would like to know how satisfied you are with your son’s hemophilia treatment. We 
have a few questions that we would like you to answer. This questionnaire was made 
for parents of children with hemophilia. 
Ö Please read each question carefully. 
Ö Choose the answer that fits you best and check the appropriate box. 
Ö There are no right or wrong answers.  
Ö It’s what you think that matters. 
 
For example:  
totally 
agree 
somewhat 
agree  
neither 
agree nor 
disagree
somewhat 
disagree  
totally 
disagree 
I’m satisfied with my son’s 
life in general 
 
 
 
 
 
 
 
Date of completion: __ / __ / __ (month / day / year) 
 
Hemo-SatP - Hemophilia treatment satisfaction questionnaire (ENGLISH FOR THE USA version parents) 15.05.09  
 
Hemo-Sat Parents - United States/English - Version of 15 May 09 - Mapi Research Institute. 
ID5118 / Hemo-SAT-P_AU1.0_eng-US.doc 
CONFIDENTIAL


We would like to know how satisfied you are with the following aspects concerning YOUR 
SON’S HEMOPHILIA TREATMENT? 
1. Ease and convenience 
How much do you agree with the 
following statements? 
totally 
agree 
somewhat 
agree  
neither 
agree nor 
disagree 
somewhat
disagree  
totally 
disagree 
1. 
Treatment does not interfere 
with our everyday life   
 
 
 
 
 
2. 
I am satisfied with the number 
of doctor's appointments 
associated with my son's 
treatment 
 
 
 
 
 
3. 
It is easy to prepare the 
infusion 
 
 
 
 
 
4. 
I am satisfied with the volume 
of the infusion 
 
 
 
 
 
5. 
I am satisfied with the way 
that the medication is 
administered 
 
 
 
 
 
6. 
I am satisfied with the way 
that I have to store the 
medication 
 
 
 
 
 
7. 
I am satisfied with how often 
my son must be infused 
 
 
 
 
 
8. 
I feel that his medication is 
safe 
 
 
 
 
 
9. 
I worry about the risk of 
inhibitors associated with his 
medication  
 
 
 
 
 
10. 
I am bothered by side effects 
caused by his medication  
 
 
 
 
 
11. 
I worry about the risk of 
infection associated with his 
medication  
 
 
 
 
 
Hemo-SatP - Hemophilia treatment satisfaction questionnaire (ENGLISH FOR THE USA version parents) 15.05.09  
Hemo-Sat Parents - United States/English - Version of 15 May 09 - Mapi Research Institute. 
ID5118 / Hemo-SAT-P_AU1.0_eng-US.doc 
CONFIDENTIAL


2. Efficacy 
How much do you agree with the 
following statements? 
totally 
agree 
somewhat 
agree  
neither 
agree nor 
disagree 
somewhat 
disagree  
totally 
disagree 
1. 
I am satisfied with the time 
needed for the medication to 
stop my son’s bleed 
 
 
 
 
 
2. 
I am satisfied with the number 
of injections that are normally 
needed to stop a bleed 
 
 
 
 
 
3. 
I am confident that, if he takes 
the medication in advance, he 
can prevent a bleed 
 
 
 
 
 
4. 
I am satisfied with the ability 
of the medication to control 
my son’s bleeds 
 
 
 
 
 
5. 
I am confident that he can 
have a normal life when he 
follows the prescribed 
treatment 
 
 
 
 
 
6. 
I am satisfied with the 
activities he is allowed to do 
with his treatment 
 
 
 
 
 
3. Burden 
How much do you agree with the 
following statements? 
totally 
agree 
somewhat 
agree  
neither 
agree nor 
disagree 
somewhat 
disagree  
totally 
disagree 
1. 
The medication does not 
cause my son any discomfort 
 
 
 
 
 
2. 
My son doesn’t worry about 
receiving his medication 
 
 
 
 
 
3. 
I have full confidence in his 
medication 
 
 
 
 
 
4. 
I am pleased to be able to 
control his disease myself 
 
 
 
 
 
Hemo-SatP - Hemophilia treatment satisfaction questionnaire (ENGLISH FOR THE USA version parents) 15.05.09  
Hemo-Sat Parents - United States/English - Version of 15 May 09 - Mapi Research Institute. 
ID5118 / Hemo-SAT-P_AU1.0_eng-US.doc 
CONFIDENTIAL


4. Specialist/Nurses 
How much do you agree with the 
following statements? 
totally 
agree 
somewhat 
agree  
neither 
agree nor 
disagree 
somewhat 
disagree  
totally 
disagree 
1. 
I am satisfied with the 
information that I received 
about my son’s medication 
from his doctor 
 
 
 
 
 
2. 
I am satisfied with the 
information I received about 
his options for treatment  
 
 
 
 
 
3. 
I am satisfied with the quality 
of care that he receives 
 
 
 
 
 
4. 
I have confidence in the 
doctor’s recommendations for 
my son’s hemophilia 
treatment 
 
 
 
 
 
5. 
I am satisfied with the doctor's 
explanation of my son’s health 
condition 
 
 
 
 
 
6. 
I am satisfied with the time my 
son’s doctor spends with us 
 
 
 
 
 
7. 
I feel the doctor understands 
us and our problems 
 
 
 
 
 
5. Center/Hospital 
How much do you agree with the 
following statements? 
totally 
agree 
somewhat 
agree  
neither 
agree nor 
disagree 
somewhat 
disagree  
totally 
disagree 
1. 
I am satisfied with the 
availability of the person on 
duty at the center/hospital 
 
 
 
 
 
2. 
We feel comfortable at the 
center/hospital 
 
 
 
 
 
3. 
I am satisfied with our 
relationship with his doctor 
 
 
 
 
 
4. 
I am satisfied with our 
relationships with the nurses 
 
 
 
 
 
5.  
I am confident that his center 
takes good care of him 
 
 
 
 
 
Hemo-SatP - Hemophilia treatment satisfaction questionnaire (ENGLISH FOR THE USA version parents) 15.05.09  
Hemo-Sat Parents - United States/English - Version of 15 May 09 - Mapi Research Institute. 
ID5118 / Hemo-SAT-P_AU1.0_eng-US.doc 
CONFIDENTIAL


Hemo-SatP - Hemophilia treatment satisfaction questionnaire (ENGLISH FOR THE USA version parents) 15.05.09  
Hemo-Sat Parents - United States/English - Version of 15 May 09 - Mapi Research Institute. 
ID5118 / Hemo-SAT-P_AU1.0_eng-US.doc 
6. GENERAL SATISFACTION with the treatment 
How much do you agree with the 
following statements? 
totally 
agree 
rather 
agree  
neither 
agree nor 
disagree 
somewha
t 
disagree  
totally 
disagree 
1. 
I am generally satisfied with 
his treatment  
 
 
 
 
 
2. 
I am satisfied with his 
medication  
 
 
 
 
 
THANK YOU FOR YOUR ASSISTANCE! 
 
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
turoctocog alfa
Trial ID: NN7008-3809
Clinical Trial Report
Appendix 16.1.1
14 September 2017
1.0
Final
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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Substantial Protocol Amendment 
no 1
to Protocol, final version 1.0
dated 29 June 2011
Trial ID: NN7008-3809
Safety and Efficacy of NNC 0155-0000-0004 in Prevention and Treatment of Bleeds 
in Paediatric Previously Untreated Patients with Haemophilia A
Trial phase: 3
Applicable to all countries
Amendment originator:
Name: 
Department: Haemostasis, Clinical Operations FVIII & FXIII
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: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
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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 .........................................4
2
Changes......................................................................................................................................................5
2.1
General...........................................................................................................................................5
2.2
Cover page.....................................................................................................................................5
2.3
1    Summary..................................................................................................................................5
2.4
2    Flow Chart ...............................................................................................................................6
2.5
Figure 2-1 Trial Design..................................................................................................................6
2.6
3.1.1.1    Pre-Clinical and Clinical Data ........................................................................................7
2.7
3.1.1.1    Risks and Benefits ..........................................................................................................7
2.8
3.2    Rationale for the Trial...........................................................................................................7
2.9
3.2.1   Clinical Development Programme......................................................................................7
2.10
5.1    Type of Trial.........................................................................................................................8
2.11
5.2     Rationale for Trial Design ...................................................................................................8
2.12
5.3    Treatments of Patients ..........................................................................................................8
2.13
5.3.4     Treatment of Patients with Inhibitors ...............................................................................9
2.14
5.4     Treatment after End of Trial ..............................................................................................10
2.15
6.1     Number of Patients to be Studied ......................................................................................10
2.16
6.2     Inclusion criteria ................................................................................................................11
2.17
6.4     Withdrawal Criteria ...........................................................................................................11
2.18
6.5     Patient Replacement ..........................................................................................................11
2.19
6.6     Rationale for Trial Population ...........................................................................................11
2.20
8.1.2     Visit 1, Screening Visit...................................................................................................12
2.21
8.1.5    Unscheduled Visit............................................................................................................12
2.22
8.1.5.2    Inhibitor Treatment Visit ..............................................................................................12
2.23
8.2.2    FVIII Inhibitors................................................................................................................13
2.24
8.2.3    FVIII Recovery................................................................................................................13
2.25
8.2.4       FVIII (N8) Pharmacokinetic T1/2 ................................................................................13
2.26
8.2.5        FVIII Trough Level Assessment..................................................................................13
2.27
8.2.8.1     General Consideration .................................................................................................13
2.28
8.2.8.2    Local laboratory Tests ..................................................................................................14
2.29
8.2.8.3    Central Laboratory Tests...............................................................................................14
2.30
8.4.4       Body measurements......................................................................................................14
2.31
8.4.5       Diaries...........................................................................................................................15
2.32
9.1          Trial Products................................................................................................................15
2.33
12.1.2      Medical Event of Special Interest and other events for expedited reporting...............15
2.34
12.5.2      Rules for Putting the enrolment on hold......................................................................15
2.35
18.2.2      Primary Endpoints .......................................................................................................16
2.36
18.2.4    Supportive Secondary Endpoints...................................................................................16
2.37
18.3      Interim analysis...............................................................................................................16
2.38
18.4      Sequential Safety Analysis/Safety Monitoring...............................................................17
2.39
18.7        Health Economics and Patient Reported Outcomes .....................................................17
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
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Version:
1.0
Status:
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Page:
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2.40
27     References...........................................................................................................................17
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
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Version:
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Page:
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1
Introduction including rationale for the substantial protocol 
amendment
Novo Nordisk (NN) has produced a third generation rFVIII product (N8/turoctocog alfa) which is 
similar to other marketed rFVIII molecules of recombinant origin. Turoctocog alfa is produced 
without significant changes to either the molecular structure or manufacturing process of commonly 
derived rFVIII products.
The guardian™ 4/NN7008-3809 clinical trial is a prospective phase III paediatric trial intended to 
further investigate the safety and efficacy profile of turoctocog alfa in PUPs < 6 years of age with 
severe haemophilia A.  The trial will continue until at least 50 subjects have received at least 50 ED 
to turoctocog alfa. The reduction in patient number reflects the industry standard for PUP trials 
taking into consideration haemophilia A being a rare disease.  
This global substantial amendment has been prepared to:
!
adapt the protocol to reduced number of patients and reduced number of exposure days
!
clarify minor inconsistencies and ambiguities, and to correct apparent mistakes and 
misspellings.
In this substantial protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
!
Any section referred from the protocol, which are not complete is depicted -------
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
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Version:
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Page:
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2
Changes
2.1
General
Throughout the protocol the following changes will be made:
!
N8 turoctocog alfa
!
Visit 7 Visit 5
!
Visit 5 and Visit 6 will be deleted.
2.2
Cover page
Department: Haemostasis Clinical Operations FVIII & FXIII
2.3
1    Summary
---------
Primary Endpoint:
Incidence rate of FVIII inhibitors (>0.6 BU/mL) will be evaluated from Visit 1 2 to End of Trial 
Visit
---------
Trial Design
---------
The patients will receive preventive treatment with NNC 0155-0000-0004 until they reach a 
minimum of 100 50 exposure days1 (ED). The patients will stay in the trial for approximately 93-24 
months, and the estimated total duration of the trial is approximately 55 50 months.
The trial is designed in accordance with European Medicines Agency (EMA) draft guideline from 
July 2009 on the Clinical Investigation of Recombinant and Human Plasma-Derived Factor VIII 
Products.1
Trial Population
Approximately 120 60 PUP with severe (baseline level FVIII ∀1%) haemophilia A without 
inhibitors below 6 years of age in a non-bleeding state will be enroled to allow for at least 100 50
patients to complete the trial.
---------
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
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Version:
1.0
Status:
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Page:
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Trial Product
The maximum total daily dose of N8 turoctocog alfa, for the treatment of bleeds and/or during 
immune tolerance induction treatment for patients with inhibitors, is 200 IU/kg with a maximum 
dose per infusion of 100 IU/kg. This maximum limit does not apply during inhibitor treatment for 
patients with inhibitors.
2.4
2    Flow Chart
Following changes will be made in the flow chart:
!
Columns labelled Visit 5 and Visit 6 will be deleted
!
Column labelled Visit 7 will be re-named Visit 5
!
Assessment “FVIII genotype test” will be moved to Visit 3, Visit 4 or unscheduled Visit. Table 
note “b” will be added and table note “f” moved to the “Assessments” column.
!
Assessment “PRO questionnaire” will be removed from Visit 1
!
N8 turoctocog alfa administration will have table note “b” added to Visit 3 and Visit 4
!
Assessment “FVIII recovery” will have table note “b” added to  Visit 2, Visit 3 and Visit 4.
!
Table note
!
c – mandatory to confirm clinical relevant inhibitors and inhibitor treatment success
!
e – Visit 1 trial card only, Visit 2-4 6 diary card only
2.5
Figure 2-1 Trial Design
150 75 patients are planned to be screened to get approximately 120 60 enroled, and 100 50 completers. Screening will 
be done at Visit 1, 14 # 7 days prior to Visit 2. Preventive treatment with investigational product (N8 turoctocog alfa)
starts at Visit 2 (may start after the first two bleeds, see Section 5.3), and is completed at V7 V5.
V2
V7 V5
150 75 pts screened 120 60 pts enroled
100 50 pts completed
100 50 ED
V1
N8 turoctocog alfa
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
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Version:
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Status:
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2.6
3.1.1.1    Pre-Clinical and Clinical Data
---------
Recently Currently three two major clinical trial studies are ongoing were completed in the Novo 
Nordisk turoctocog alfa development program, the pivotal phase 3 trial (guardianTM 1/NN7008-
3543), and the paediatric trial (guardianTM 3NN7008-3545), and another large study is ongoing, the 
extension trial (guardianTM 2/NN7008-3568).and The accumulated clinical experience with N8
turoctocog alfa is now approaching 10000 30000 exposure days (ED).
2.7
3.1.1.1    Risks and Benefits
---------
After completing the present trial (guardianTM 4), eligible patients will be offered to continue with 
N8 turoctocog alfa in an extension trial, see Section 5.4. This serves to minimise the patients’ need 
of switching to other FVIII products.
2.8
3.2    Rationale for the Trial
---------
In order to achieve marketing authorisation for this product, EMA draft guidelines on clinical 
investigation of plasma derived and recombinant FVIII products and review of relevant Food and 
Drug Administration (FDA) approvals of recombinant FVIII and FIX products1,11,12 are applied in 
the clinical development programme (see further details in the IB9). According to the draft EMA 
guideline on clinical Investigation of new FVIII products, the clinical programme must include a 
paediatric trial in PUP demonstrating safety and clinical efficacy in at least 100 patients.
The guardianTM 4 trial is a prospective clinical phase 3ab trial intended at demonstrating safety and 
efficacy of N8 turoctocog alfa in PUP < 6 years of age with severe haemophilia A. The trial will 
continue until at least 100 50 patients have reached a minimum of received at least 100 50 ED to N8
turoctocog alfa.
2.9
3.2.1   Clinical Development Programme
The overall clinical development programme for N8 turoctocog alfa uses a stepwise approach, 
following the EMA draft guideline1, by evaluating experience in older and previously treated 
patients (guardianTM 1) before investigating in younger children (guardianTM 3). The present trial 
(guardianTM 4) will support the programme scientifically with data on inhibitor developmentand 
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
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Version:
1.0
Status:
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Page:
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finally in previously untreated patients and contribute to the overall safety and efficacy profile of 
turoctocog alfa. the study population of
2.10
5.1    Type of Trial
---------
The trial comprises 7 5 planned visits. Patients will attend a screening visit (Visit 1) in order to 
assess their eligibility. At Visit 2 eligible patient will receive their first dose and will be scheduled 
to attend for 5 3 more visits, if applicable. Details on the trial design can be found in Figure 2-1 and 
details on the individual visits can be found in Table 2-1.
The patients will be scheduled to receive treatment with N8 turoctocog alfa for at least 100 50 ED, 
which for the individual patient translates into a duration of approximately 93-24 months depending 
on the dose regimens (and bleeding pattern). The total duration of the trial is estimated to be 
approximately 55 50 months.
2.11
5.2     Rationale for Trial Design
This trial design (Figure 2-1) will provide documentation of the safety and efficacy of N8
turoctocog alfa in prevention and treatment of bleeds in paediatric PUP with severe haemophilia A. 
The trial design is in accordance with EMA draft guideline1 from July 2009 for the development of 
rFVIII products.
---------
Finally, the pivotal phase 3 trial (guardianTM 1) including at least 110 PTP above 12 years of age for 
at least 75 ED is planned to be completed before the initiation of the present trial.
2.12
5.3    Treatments of Patients
Approximately 120 60 patients are expected to be enroled into the trial in order to have 100 50
patients completing the trial (estimated drop out rate is 20%). For replacement of withdrawn 
patients, please refer to Section 6.5.
---------
In most cases, treatment will be given at home with i.v. self-injection by the 
parent/caregiver/support person. However, on days when the patient is attending a trial visit, if 
applicable the dose will may be administered at the clinic by a health care professional.
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
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Version:
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Maximum dose
The maximum total daily dose of N8 turoctocog alfa, for the treatment of bleeds and/or during 
immune tolerance induction treatment for patients with inhibitors, is 200 IU/kg with a maximum 
dose per infusion of 100 IU/kg. This maximum limit does not apply during inhibitor treatment for 
patients with inhibitors
2.13
5.3.4     Treatment of Patients with Inhibitors
Several genetic factors, such as FVIII gene mutation type, family history of inhibitors, ethnicity, 
have been associated with inhibitor development in patients with severe haemophilia.15
Management of patients with inhibitors includes the treatment of bleeding episodes by the use of 
by-passing agents (rFVIIa or activated prothrombin complex concentrates) and the permanent 
eradication of the inhibitor through immune tolerance induction therapy.
Patients who develop inhibitors, within this trial, will be offered continued treatment with N8
turoctocog alfa for 12 months. The duration of the inhibitor treatment will be at least 12 months
from the time of diagnosis of inhibitor.  For patients who develop inhibitors during their first year in 
the trial (within 12 months) the inhibitor treatment may continue until a total trial duration of 24 
months.
It may also be decided by the Investigator and/or parent/legal representative to withdraw the patient.
---------
Transient inhibitors are defined in this trial as inhibitors which disappear within 3 months after two 
positive inhibitor tests.
Inhibitor treatment success is defined as (not applicable for patients with transient inhibitors):
!
two consecutive blood samples showing inhibitor level <0.6 BU/mL
!
FVIII plasma recovery >66 % of expected level
!
N8 T1/2 of >6 h after a 72 h N8 washout period17
Inhibitor treatment failure is defined as persistence of inhibitor with no consistent decline of the 
inhibitor titer from peak level within 12 months of the inhibitor diagnosis. If inhibitor treatment 
failure occurs, the patient must be withdrawn. 
After completion of the inhibitor treatment, or if preventive treatment is resumed, the patient will be 
called to an End of trial Visit (Visit 5 7).
Treatment of bleeds with by-passing agents i.e. rFVIIa or activated prothrombin complex 
concentrate (APCC), is allowed for patients who develop inhibitors.
---------
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
23 January 2012
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Version:
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Details on inhibitor management can be found in Figure 5.1
Patients who develop inhibitor will be offered to continue N8 treatment. The regular visit schedule will stop and an 
alternative schedule will be commenced. After 12 months treatment, patients will fall into three categories; a) total trial 
duration ∃24 months –treatment may continue up to 24 months, b) total trial duration % 24 months – patients will be 
withdrawn, c) treatment failure as defined in Section - patients will be withdrawn. Patients may also at any time be 
withdrawn at the discretion of the Investigator or the parents/legal representative, or on the patient´s on will.
2.14
5.4     Treatment after End of Trial
It is expected that N8 turoctocog alfa will be granted marketing authorisation and is commercially 
available when the patients complete this trial. Where no marketing authorisation has been granted,
each eligible patients will be offered to continue in the phase 3b extension trial (guardianTM 2), see 
Section 3.2.1, as applicable by local regulation and rules.
2.15
6.1     Number of Patients to be Studied
Countries planned to participate: Austria, Belgium, Brazil, Canada, China, Croatia, Czech Republic, 
Greece, Hong Kong, Japan, South Korea, Malaysia, Romania, Russia, Serbia, Spain, Thailand, 
Turkey, UK and US.
Planned number of patients to be screened (i.e. documented informed consent):
15075
Planned number of patients to be started on trial product(s):
12060
Planned number of patients to complete the trial:
10050
Withdrawal 
Continued
treatment with N8
Trial duration
% 24 months
Treatment 
failure
Inhibitor
End of Trial Visit
(Visit 7)
Alternative visit
schedule
Withdrawal 
12 months
Treatment
Withdrawal
Cont´d N8 
treatment,
∀24 mo
trial
duration
Withdrawal
Trial duration
<24 months
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
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Version:
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Page:
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Planned number of trial sites: 
  8050
2.16
6.2     Inclusion criteria
---------
2. Male patient with congenital sever haemophilia A (FVIII level ∀1%)*
*based on the one-stage clotting assay
------------
5. Immunocompetent, defined as either HIV negative or if HIV positive, CD4+ cells >200 cells/μl.
2.17
6.4     Withdrawal Criteria
---------
4.    For inhibitor patients – inhibitor treatment failure with N8 treatment (refer to Inhibitor 
Treatment Section 5.3.4.)
2.18
6.5     Patient Replacement
Withdrawn patients may be replaced to ensure that 10050 patients complete the trial with at least 
10050 ED. Assuming a drop-out rate of 20%, it is estimated that 12060 patients must be enroled
started on N8 to obtain the 10050 completed patients. This may, however, be adjusted during the 
trial based on the actual drop-out rate.
2.19
6.6     Rationale for Trial Population
The inclusion and exclusion criteria are in line with previously studied recombinant FVIII products, 
reflect the general haemophilia A paediatric population that will receive N8 turoctocog alfa when 
marketed. and address the requirements of the EMA/CHMP draft guideline on the clinical 
investigation of recombinant and human plasma-derived factor VIII products1. According to the 
EMA guideline, the clinical programme must include a paediatric trial in PUP demonstrating safety 
and clinical efficacy in at least 100 patients. In addition, PUP in their immunological naïve state
with regard to external FVIII protein, is the optimal population to investigate the development of 
inhibitors.
---------
Rationale for Withdrawal Criteria:
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
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23 January 2012
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Version:
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Page:
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!
Criteria nos. 1 and 2 and 4 are included to protect the patient's safety.
2.20
7         Trial Schedule
Planned duration of recruitment period (FPFV-LPFV):
3942 months
Planned date for FPFV:
December 2011
Planned date for LPFV:
MarchJune 2015
Planned LPLV:
AprilJuly 2016
2.21
8.1.2     Visit 1, Screening Visit
---------
Patients should withhold and stop any anti-haemophilic treatment with blood components at least 
48 hours prior to Visit 1.
2.22
8.1.5    Unscheduled Visit
The unscheduled visit can be performed after the enrolment into the trial until the End of Trial Visit 
(Visit75) as either telephone visitcontact or a site visit. Unscheduled visits will also be performed 
during inhibitor treatment, see Section 8.1.5.2, and surgery procedures, Section. 8.1.5.1 Please find 
listed in Table 2-1 the assessments, which should be performed at an unscheduled visit. The date 
and time of the visit should be recorded in the eCRF.
2.23
8.1.5.2    Inhibitor Treatment Visit
All patients, who develop inhibitors and continue treatment with turoctocog alfa, will follow an 
alternative visit schedule prescribed by the Investigator according to local standard of practice, 
irrespective of whether inhibitor treatment is being initiated or not, see Section 5.3.4. Monthly visits 
are recommended, at least initially, for patients who develop inhibitors.
---------
Recovery test is required at the time of inhibitor diagnosis and for the confirmation of inhibitor 
treatment success, see Section 8.2.3.
Measurement of N8 pharmacokinetic plasma (T1/2) will be performed to confirm inhibitor 
treatment success, see Section 2.26.
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
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Version:
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When the last inhibitor treatment visit has been performed, the patient will be called to an End of 
Trial Visit (Visit 5 7).
2.24
8.2.2    FVIII Inhibitors
---------
All per protocol inhibitor laboratory samples analyses are to be analysed coordinated by in the 
central laboratory, and only these results will be used in the trial data analysis.
2.25
8.2.3    FVIII Recovery
Recovery is the FVIII plasma level recorded 30 # 5 minutes after trial product administration and 
reported as [IU/mL]/[IU/kg]. Recovery assessment is mandatory at inhibitor diagnosis to identify 
clinical relevant inhibitors (see Sections 8.2.2). Likewise, recovery assessment is necessary when 
establishing inhibitor treatment success (see Sections 5.3.4). Additional recovery assessments may 
be requested at the discretion of the Investigator.
2.26
8.2.4       FVIII (N8) Pharmacokinetic T1/2
The T1/2 of N8 will be based on FVIII activity and the procedures should be according to local 
guidelines. The N8 washout period should be at least 72 hrs. It is recommended that at least three 
time points for blood sampling is chosen, and it should be within 48 hrs of N8 administration. The 
samples should be sent to the central lab for analysis.
The N8 T1/2 will be used to evaluate inhibitor treatment success, see Section 5.3.4.
2.27
8.2.5        FVIII Trough Level Assessment
The Investigator can at his/her discretion perform trough level assessments at visits 3 and 4 6.
2.28
8.2.6       Haematology
---------
!
Mean corpuscular haemoglobin (MCH) (fmol/L)
2.29
8.2.8.1     General Consideration
The collection of all blood samples for the laboratory tests will be performed before administration 
of N8 turoctocog alfa, except the recovery samples which must be collected after (approximately 30 
minutes) administration of N8 turoctocog alfa.
CONFIDENTIAL


Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
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Version:
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2.30
8.2.8.2    Local laboratory Tests
Assessments of haematology and, FVIII trough levels and CD4+ T-cell count (if applicable) will be 
done at the local laboratory* as per standard of practice at the participating site. Laboratory results 
from the local laboratory will be recorded in the eCRF.
*not applicable for Serbia
2.31
8.2.8.3    Central Laboratory Tests
A central laboratory will coordinate analyseis and reporting of all laboratory safety tests related to 
biochemistry, viral antibody assessments (except CD4+ T-cell count), FVIII inhibitor and FVIII 
activity tests, and genotyping performed in this trial. Laboratory data from the central laboratory 
will be reported to Novo Nordisk electronically, and in a manner that anonymity of patients will be 
maintained.
A one-stage FVIII clotting activity assay and a two-stage chromogenic assay will both be used to 
assess the FVIII activity, but only the one-stage clotting activity assay result will be reported to the 
Investigator. at the central laboratory.
---------
For descriptions of assay methods, particulars of instrumentation, procedures for obtaining 
samples/specimens, who will perform the assessments and the storage, handling conditions, and 
disposition of specimens, please refer to the Laboratory Manual.
2.31.1.1
8.2.8.4     Blood Sampling Volume
Blood samples for laboratory analysis of efficacy, safety and other parameters will be drawn as 
described for the individual visits. The total volume of blood drawn during the trial will be 
approximately 30 20-50 mL per patient (the higher range is for patients in inhibitor treatment). The 
blood volume collected from the patient 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 (see Appendix B). This is in 
accordance with European regulatory guidelines (Directive 2001/20/EC)2,22. During visits, when 
samples are taken, blood samples will be aliquoted to meet above mentioned requirements. 
Instructions will be provided in the Laboratory Manual
2.32
8.4.1       FVIII genotype testing (not applicable to Brazil)
At Visit 2, all patients/parents/legally authorised representative (LAR) 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 as allowed by local law. The blood sample should be taken at Visit 
3, Visit 4 or an unscheduled Visit. Investigator, parent(s) or LAR have the right to refuse to provide 
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Trial ID: NN7008-3809
UTN: U1111-1119-6116
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patient’s FVIII genotype documentation or to refuse genotyping. This will not stop the patient to 
continue participation in the remainder of the study.
2.33
8.4.4       Body measurements
Weight and height will be measured at Visit 1 and 75, for Visit 2-4 6 only weight is measured.
2.34
8.4.5       Diaries
Diaries will be dispensed at Visits 2-4 6, and the following data will be collected:
2.35
9.1          Trial Products
NNC 0155-0000-0004, N8 and turoctocog alfa are all synonym trial product names in this trial.
2.36
12.1.2      Medical Event of Special Interest and other events for expedited reporting
---------
Allergic reaction including Anaphylactic reaction as defined by Sampson et al 200625. 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 al25. All hypersensitivity reactions 
reported as MESI will be followed up with a hypersensitivity questionnaire.
2.37
12.5.2      Rules for Putting the enrolment on hold
There are two is one pre-planned safety interim analysis. At each this interim all patients exposed at 
the pre-defined time point, determined by number of patients exposed, will be evaluated for 
inhibitor development.
!
Safety interim 1: After the first 25 patients have been to Visit 4 (20-25 exposure days)
!
Safety interim 2: After the first 50 patients have been to Visit 5 (50-55 exposure days)
The expected rate of inhibitors is 30–35% in PUP previously untreated patients with severe 
haemophilia A. 
The rules for putting the enrolment on hold are as follows;
Inhibitor formation in 12 or more of all exposed patients at the safety interim 1, or 22 or more of all 
exposed patients at interim 2, will result in the N8 turoctocog alfa safety committee evaluation of 
all cases of inhibitor formation. During these evaluations, ongoing treatment in the trial will 
continue, however new patients will not be enroled in the trial. The evaluation will provide the basis 
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Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
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Version:
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Status:
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Page:
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for a decision on any actions required for the trial to allow for continuation of enrolment or decision 
to terminate the trial.
2.38
18.1         Sample Size Calculation
No formal sample size calculations have been performed, but 50 patients are expected to give 
adequate precision for the estimate of inhibitor formation in PUP. The sample size is based on the 
EMA guideline requirement.
2.39
18.2.2      Primary Endpoints
---------
Furthermore, the time to inhibitor development will be presented by a Kaplan Meyer plot.
The relationship between the incidence rate of inhibitors and different patient and treatment
characteristics will be investigated
Patient characteristics include:
!
Ethnicity (White, Asian, African, Other)
!
Family history of inhibitors (Negative, Positive)
!
FVIII gene mutation type (Low risk (small deletions/insertions of < 200 base pairs, missense 
mutations, and other including splite splice or promoter mutations), High risk (large 
deletions of over 200 base pairs, nonsense mutations, intron 22 or one1 inversions))
2.40
18.2.4    Supportive Secondary Endpoints
---------
Outcome of inhibitor treatment will be listed and summarised.
2.41
18.3      Interim analysis
An interim analysis is planned to occur after the first 50 patients each have 50 ED. The interim
analysis will include a full report of all data for the 50 patient until the cut-off date, which is the
date the 50th patient had his exposure number 50.
The interim analysis is performed to file a marketing authorisation variation application to
include PUP in the N8 label.
Furthermore, the interim will include a safety analysis for all patients exposed before the cut-off
date. The safety analysis will include a Kaplan Meyer plot presenting the time to high titre
inhibitor, clinically relevant inhibitor and inhibitor (≥0.6 BU/mL), respectively. All AEs, SAEs,
MESIs and other abnormal safety parameters such as laboratory parameters and physical
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Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
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examinations will be presented for all patients.
2.42
18.4      Sequential Safety Analysis/Safety Monitoring
There are two is one pre-planned safety interim analysis. At each this interim all patients exposed at 
the pre-defined time point, determined by number of patients exposed, will be evaluated for 
inhibitor development.
!
Safety interim 1: After the first 25 patients have been to Visit 4 (20-25 exposure days)
!
Safety interim 2: After the first 50 patients have been to Visit 5 (50-55 exposure days)
The expected rate of inhibitors is 30–35% in previously untreated patients with severe haemophilia 
A. 
The rules for putting the enrolment on hold are as follows;
Inhibitor formation in 12 or more of all exposed patients at the safety interim 1, or 22 or more of all 
exposed patients at interim 2, will result in the N8 turoctocog alfa safety committee evaluation of 
all cases of inhibitor formation. During these evaluations, ongoing treatment in the trial will 
continue, however new patients will not be enroled in the trial. The evaluation will provide the basis 
for a decision on any actions required for the trial to allow for continuation of enrolment or decision 
to terminate the trial.
2.43
18.7        Health Economics and Patient Reported Outcomes
Health economic data will be collected in the eCRF in connection with severe bleeds. Patient 
reported outcomes will be collected using questionnaires at visits 1, 3, and 75. The health economic 
and PRO data will be summarised using descriptive statistics.
2.44
27     References
---------
Committee for medicinal products for human use (CHMP), Guideline on the Clinical Investigation 
of Recombinant and Human Plasma-derived Factor VIII Products, 
(EMEA/CHMP/BPWP/144533/2009). 2009 2011.
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Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
CONFIDENTIAL
Date:
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Version:
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Page:
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2.45
Appendix B    Whole Blood Volume Rules in the Paediatric Poulation
---------
The blood volume collected from the subject 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 (Directive 2001/20/EC) and FDA requirements. The table 
below shows the estimated blood volume in children weighing from 6-25 kg and the blood volume 
that can be taken at any single time and in 28 days according to European regulatory requirements 
(Directive 2001/20/EC) and FDA requirements.
Total Blood volume according to Geigy Scientific Table
Children 1-5 years of age
Weight (kg)
Blood volume 
(ml/kg)
Total Blood 
volume (ml)
Volume/blood 
sample (1%)
Volume /28 
days (3%)
6
80
480
4,8
14,4
7
80
560
5,6
16,80
8
80
640
6,4
19,2
9
80
720
7,2
21,3
10
80
800
8.0
24.0
11
80
880
8.8
26.4
12
80
960
9.6
28.8
13
80
1040
10.4
31.2
14
80
1120
11.2
33.6
15
80
1200
12.0
36.0
16
80
1280
12.8
38.4
17
80
1360
13.6
40.8
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Substantial Protocol Amendment 
Trial ID: NN7008-3809
UTN: U1111-1119-6116
EudraCT No.: 2011-001033-16
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Weight (kg)
Blood volume 
(ml/kg)
Total Blood 
volume (ml)
Volume/blood 
sample (1%)
Volume /28 
days (3%)
18
80
1440
14.4
43.2
19
80
1520
15.2
45.6
20
80
1600
16.0
48.0
21
80
1680
16.8
50.4
22
80
1760
17.6
52.8
23
80
1840
18.4
55.2
24
80
1920
19.2
57.6
25
80
2000
20.0
60.0
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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 No.4-
TR 
CONFIDENTIAL 
Date: 
24 May 2012 
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Trial ID: NN7008-3809 
Version: 
1.0 
UTN:2011-001033-16 
Status: 
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EudraCT No.:2011-001033-16 
Page: 
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  Substantial Protocol Amendment 
No.4-TR 
to Protocol Attachment II-TR, final version 1.0 
dated 26 September 2011 
NN7008-3809 
 
Safety and Efficacy of NNC 0155-0000-0004 in 
Prevention and Treatment of Bleeds in Paediatric 
Previously Untreated Patients with Haemophilia A 
 
Trial phase: 3 
Applicable to Turkey 
Amendment originator: 
Name:
 
Department:
 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
 
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Substantial Protocol Amendment No.4-
TR 
CONFIDENTIAL 
Date: 
24 May 2012 
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Trial ID: NN7008-3809 
Version: 
1.0 
UTN:2011-001033-16 
Status: 
Final 
EudraCT No.:2011-001033-16 
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
 
 
 
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Substantial Protocol Amendment No.4-
TR 
CONFIDENTIAL 
Date: 
24 May 2012 
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Trial ID: NN7008-3809 
Version: 
1.0 
UTN:2011-001033-16 
Status: 
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EudraCT No.:2011-001033-16 
Page: 
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1 
Introduction including rationale for the substantial protocol 
amendment 
In this substantial protocol amendment: 
x Any new text is written in italics. 
x Any text deleted from the protocol is written using strike through. 
 
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Substantial Protocol Amendment No.4-
TR 
CONFIDENTIAL 
Date: 
24 May 2012 
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Trial ID: NN7008-3809 
Version: 
1.0 
UTN:2011-001033-16 
Status: 
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EudraCT No.:2011-001033-16 
Page: 
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2 
Changes 
In Turkey, the Priniciple Investigator of the site 
 -  
 
changed in NN7008-3809 trial. 
Previously, it was Assoc. Prof. 
. The responsibility had been transferred to Assoc. Prof.  
. There is no change in local laboratory informations. 
Old text: 
Investigator: 
Title/ 
qualification 
Assoc. Prof 
 
Name: 
 
 
 
Address: 
 
 
 
Tel: 
 
 
 
Fax: 
 
 
 
Mobile: 
 
 
 
E-mail: 
 
 
New text: 
Investigator: 
Title/ 
qualification 
Assoc. Prof 
 
Name:
 
 
 
Address:
 
 
 
Tel:
 
 
 
Fax:
 
 
 
Mobile: 
 
 
 
E-mail: 
 
 
 
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Substantial Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN7008-3809
Version:
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Substantial Protocol Amendment no 5
to Protocol, final version 2.0
dated 01 February 2012
Trial ID: NN7008-3809
(NNC0155-0000-0004)
Safety and Efficacy of NNC 0155-0000-0004 in Prevention and Treatment of Bleeds in 
Paediatric Previously Untreated Patients with Haemophilia A
Trial phase: 3b
Applicable to all countries 
Amendment originator:
Name: 
Department: Haemophilia, Clinical Operations FVIII & FXIII
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
CONFIDENTIAL
Date:
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Trial ID: NN7008-3809
Version:
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UTN:1111-1119-6116
Status:
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EudraCT No.:2011-001033-16
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Table of contents
Page
Table of contents...............................................................................................................................................2
Table of tables...................................................................................................................................................3
1
Introduction including rationale for the substantial protocol amendment .........................................4
2
Changes......................................................................................................................................................5
2.1
1 Summary.....................................................................................................................................5
2.2
2 Flow Chart ..................................................................................................................................6
2.3
3.1.1.1 Pre-Clinical and Clinical Data ...........................................................................................9
2.4
3.1.1.2 Risks and Benefits ...........................................................................................................10
2.5
3.2   Rationale for the Trial..........................................................................................................10
2.6
4.2   Endpoint(s)...........................................................................................................................10
2.7
5.1   Type of Trial........................................................................................................................10
2.8
5.3   Treatment of Patients...........................................................................................................11
2.9
5.3.2  Treatment of Bleeds and Dose Adjustment .......................................................................11
2.10
5.3.4  Treatment of Patients with Inhibitors.................................................................................11
2.11
5.4   Treatment after End of Trial ................................................................................................12
2.12
6.1   Number of Patients to be studied.........................................................................................12
2.13
6.4   Withdrawal Criteria .............................................................................................................12
2.14
6.5   Patient Replacement.............................................................................................................13
2.15
6.6   Rationale for Trial Population .............................................................................................13
2.16
7   Trial Schedule.........................................................................................................................13
2.17
8.1.1  Overall Procedures, Assessments and Methods.................................................................13
2.18
8.1.2  Visit 1, Screening Visit......................................................................................................13
2.19
8.1.4  Visit 3 to Visit 5.................................................................................................................13
2.20
8.1.5  Unscheduled Visit..............................................................................................................14
2.21
8.1.6  Extension phase Visits........................................................................................................14
2.22
8.1.7  EoT Visit ............................................................................................................................14
2.23
8.1.5.2 Inhibitor Treatment Visit .................................................................................................14
2.24
8.2.1  Adverse Events ..................................................................................................................14
2.25
8.2.2  FVIII Inhibitors..................................................................................................................14
2.26
8.2.3  FVIII Recovery..................................................................................................................14
2.27
8.2.4  FVIII Trough Level Assessment........................................................................................15
2.28
8.2.5  Haematology......................................................................................................................15
2.29
8.2.6  Biochemistry......................................................................................................................15
2.30
8.2.7.2 Local Laboratory Test......................................................................................................15
2.31
8.2.7.3 Central Laboratory Tests..................................................................................................15
2.32
8.2.7.4 Blood Sampling Volume..................................................................................................15
2.33
8.2.8  Physical Examination.........................................................................................................16
2.34
8.2.9  Vital Signs..........................................................................................................................16
2.35
8.3.1 Bleeds..................................................................................................................................16
2.36
8.4.1  FVIII genotype testing (not applicable to Brazil)..............................................................17
2.37
8.4.2  Viral Antibody Information...............................................................................................17
2.38
8.4.4  Body Measurements...........................................................................................................17
2.39
8.4.5  Diaries................................................................................................................................17
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2.40
8.4.7  HE and PRO data...............................................................................................................17
2.41
9.4 Dispensing and Drug Accountability of Trial Products.........................................................17
2.42
14 Monitoring Procedures............................................................................................................17
2.43
18.2.2 Primary Endpoint(s)..........................................................................................................18
2.44
18.2.4 Supportive Secondary Endpoints......................................................................................18
2.45
18.6  Health Economics and Patient Reported Outcomes ...........................................................20
2.46
23  Responsibilities......................................................................................................................20
2.47
27  References..............................................................................................................................20
2.48
Appendix B..................................................................................................................................20
Table of tables
Page
Table 2–1
Visit Flow Chart main trial phase..........................................................................................6
Table 2–2
Visit Flow Chart trial extension phase.....................................................................................7
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Substantial Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN7008-3809
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EudraCT No.:2011-001033-16
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1
Introduction including rationale for the substantial protocol 
amendment
This global substantial amendment has been prepared to:
!
change the treatment after end of trial
!
introduce the concept of two different phases of the trial, a main phase and an extension phase
!
present the results from previous trials in the guardianTM clinical programme
!
extend the trial duration
!
make it optional to conduct a phone “visit” for severe bleedings.
The current clinical trial, guardianTM 4 (NN7008-3809), includes Previously Untreated Patients 
(PUP), treated with turoctocog alfa for at least 50 exposure days (ED). To preserve the homogeneity 
of the patient cohort, patients will not be transferred to guardianTM 2 (NN7008-3568), which holds a 
trial population consisting of Previously Treated Patients (PTP) > 100 ED.
In this substantial protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
The below changes will not be disclosed in the following sections due to they are minor changes 
that do not affect the content of the text;
!
minor inconsistencies and ambiguities, and typographical errors.
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Substantial Protocol Amendment
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Date:
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Trial ID: NN7008-3809
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EudraCT No.:2011-001033-16
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2
Changes
2.1
1
Summary
Objectives and Endpoints
---
Primary Endpoint:
!
Incidence rate of FVIII inhibitors (>0.6 BU/mL) will be evaluated for the main phase of the trial
from Visit 2 to End of Trial (EoT) Visit/Visit 5
Key Secondary Endpoints:
The secondary endpoints will be evaluated for the main phase of trial, for the extension phase of 
trial, and for the combined main and extension phases.
!
Haemostatic effect of NNC 0155-0000-0004 on treatment of bleeds assessed on a predefined 
four point scale: Excellent, Good, Moderate and None will be evaluated from Visit 2 to EoT 
Visit/Visit 5
!
Annualized bleeding rate will be evaluated from Visit 2 to EoT Visit/Visit 5
!
Incidence rate of FVIII inhibitors (>0.6 BU/mL)
Trial Design
---
The trial consists of two phases. In the main phase The an aggregated number of at least 50 
patients will receive preventive treatment with NNC 0155-0000-0004 until they reach a minimum 
of 50 exposure days2 (ED) or until they develop inhibitors. After that the patient will continue in the 
extension phase, which will last for approximately 3.5 years. The patients will stay in the trial for 
approximately 3-24 months, and The estimated total duration of the trial is approximately 50
months years.
The trial  is designed in accordance with European Medicines Agency (EMA) guideline on the 
Clinical Investigation of Recombinant and Human Plasma-Derived Factor VIII Products1.
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Substantial Protocol Amendment
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Date:
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Trial ID: NN7008-3809
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EudraCT No.:2011-001033-16
Page:
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2.2
2
Flow Chart
(Clarification note: For Table 2-1 only information that are subjected to changes are presented.)
Table 2–1
Visit Flow Chart main trial phase
Visit number
Screen.
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Unscheduled 
Visit
Visit window
NA
14 ∀7 d
post V1
10th -15thED
20th -25th ED
50100th –
55110th ED
FVIII trough level
●b
●b
●b
FVIII recovery
●b
●b
●b
●b
●b,c
T cells subset: CD4+
●b,h
●b,h
●b,h
turoctocog alfa administration
●b
●b
●b
●b
●b
Diary and Trial card dispensing and/or 
collection
●e
●e
●e
●e
●e
●b
Completion session in IV/WRS
-●-
Drug dispensing and accountability
●g
●
●
●g
●b
End of trial form
●
Table 2-2 presents the rolling visit schedule in the extension phase over the period of one year. It 
comes to effect after Visit 5 or after ITI treatment.
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Substantial Protocol Amendment
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Date:
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Trial ID: NN7008-3809
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Table 2–2
Visit Flow Chart trial extension phase
Visit type
Dispensing
Assessment&
Dispensing
Dispensing
Assessment&
Dispensing
End of 
Trial
Unsch
Visit
Visit number#
6
7
8
9
10
11
Previous visit time(w)
-8
-8
-10
-8
-8
-10
< 8
Visit window
± 1w
± 1w
± 1w
± 1w
± 1w
± 1w
NA
NA
ASSESSMENTS
Withdrawal Criteria
●
●
●
●
●
●
Concomitant medication
●
●
●
●
●
●
●
●b
Body measurements
●c
●c
●
EFFICACY
Bleed(s)
●b
●b
●b
●b
●b
●b
●b
●b
SAFETY
Adverse events
●
●
●
●
●
●
●
●b
Physical examination
●a
●a
●
Vital signs
●a
●a
●
FVIII inhibitors
●a
●a
●
●a
●a
●
●
●a
FVIII trough level
●a
●a
FVIII recovery
●a
●a
●a
●a
●a
●a
●a
Biochemistry & 
Haematology
●
●
●
●a
OTHER ASSESSMENTS
PRO questionnaire
●
●
HE assessment
●b
●b
●b
●b
●b
●b
●b
●b
Viral antibody test (if HIV, 
HBsAg and/or HCV status 
unknown)
●
●b
T cells subset: CD4+
●b
TRIAL MATERIAL
turoctocog alfa
administration
●a
●a
●a
●a
●a
●a
Diary card dispensing 
and/or collection
●
●
●
●
●
●
●d
●a
Review of patient diary 
and entry of data in eCRF
●
●
●
●
●
●
●
●a
Completion session in 
IV/WRS
●
Drug dispensing and 
accountability
●
●
●
●
●
●
●e
●a
EoT form
●
# - Presented numbers are for the first 12 months. Visit numbers for future years will be in consecutive order
a – Optional, at discretion of investigator
b – If applicable
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c – Weight only
d – Collection only
e – Accountability only
Figure 2-1 Trial Design
75 patients are planned to be screened to get approximately 60 enroled, and 50 completers. Screening will be done at 
Visit 1, 14 ∀7 days prior to Visit 2. At Visit 2 eligible patients are enroled and preventive treatment with investigational 
product (turoctocog alfa) starts if applicable at Visit 2 (may start after the first two bleeds)., see Section 5.3 and is 
completed at V5. At visit 5, after ≥ 50 ED, patients will leave the main phase of the trial and continue in the extension 
V2
V5/50 ED
turoctocog alfa
EoT
V1
main phase
extension phase
ITI treatment
inhibitor cohort
preventive 
treatment
V2
V5
75 pts screened
60 pts enroled
50 pts completed
50 ED
V1
turoctocog alfa
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phase. Patients who develop inhibitors can continue with ITI treatment with an alternative visit schedule (down ward 
arrows). If ITI treatment is successful these patients can continue with preventive treatment according to the extension 
phase (upward arrows). The patients will belong to either of the groups main-phase, extension phase or inhibitor 
cohort.
2.3
3.1.1.1
Pre-Clinical and Clinical Data
---
Two phase 3 trials were completed in 2011, i.e. the pivotal trial guardian™ 1 (NN7008-3543) and 
the paediatric trial guardian™ 3 (NN7008-3545) in PTP with severe haemophilia A (FVIII<1 %). 
In both trials, the primary objective was to assess safety, including the incidence rate of FVIII 
inhibitors (≥0.6 BU). 
A total of 150 male patients aged 12 to 60 years were dosed in the guardian™ 1 trial, whereof 148 
patients had at least 50 ED and 142 patients had at least 75 preventive ED in the trial. No clinically 
significant safety issues were identified and no FVIII inhibitors were detected. The success rate for 
treatment of bleeds was 84.5% (excluding bleeds for which there was no outcome reported).
A total of 63 male patients below 12 years of age were dosed in guardian™ 3 whereof 59 patients 
(28 children [0#<6 years] and 31 children [6#<12 years]) had at least 50 ED in the trial. No 
clinically significant safety issues were identified and no FVIII inhibitors were detected. The 
success rate for treatment of bleeds was 94.3% (excluding bleeds for which there was no outcome 
reported).
Further PK data have been obtained in the NN7008-3600 trial with six Japanese patients and in the 
NN7008-3893 trial with four additional adult patients. Both these trials used two different lots of 
drug product. In the NN7008-3600 trial, the PK properties of a single dose of turoctocog alfa in the 
Japanese population of patients with severe haemophilia A were successfully characterised. In the 
NN7008-3893 trial, three of the patients were of Asian and 1 was of Caucasian racial origin, and 
all patients completed the trial. No safety concerns were observed.
After completing the guardian™ 1 and guardian™ 3 trials, 189 of the 206 completing patients have 
continued treatment with turoctocog alfa within the extension trial guardian™ 2 (NN7008-3568), 
and the total clinical experience as of Nov 21 2011 exceeds 30000 ED. Despite regular monitoring 
and testing, no safety concerns have yet been detected and no patient has developed a FVIII 
inhibitor within the trials.
Recently two major clinical trials were completed in the Novo Nordisk turoctocog alfa development 
program, the pivotal phase 3 trial (guardianTM1/NN7008-3543), the paediatric trial 
(guardianTM3/NN7008-3545), and another large study is on-going, the extension trial 
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(guardianTM2/NN7008-3568). The accumulated clinical experience with turoctocog alfa is now 
approaching 30000 exposure days (ED).
2.4
3.1.1.2
Risks and Benefits
---
After completing the present trial (guardianTM 4), eligibleThe patients will be offered to continue
with  turoctocog alfa in an extension the trial until product launch or until the end of trial, should 
market authorisation not be obtained, see Section 7 5.4 for details. This serves to minimise the 
patients’ need of switching to other FVIII products.
2.5
3.2
Rationale for the Trial
----
The guardianTM4 trial is a prospective clinical phase 3b trial intended at demonstrating safety and 
efficacy of turoctocog alfa in PUP < 6 years of age with severe haemophilia A. The trial will 
continue until at least 50 patients have received at least 50 ED to turoctocog alfa.
2.6
4.2
Endpoint(s)
Primary Endpoint
!
Incidence rate of FVIII inhibitors (>0.6 BU/mL) will be evaluated for the main phase of the trial
Secondary Endpoint(s)
The secondary endpoints will be evaluated for the main phase of trial, for the extension phase of 
trial, and for the combined main and extension phases..
Safety Endpoints:
!
---
!
Incidence rate of FVIII inhibitors (>0.6 BU/mL).
----
2.7
5.1
Type of Trial
---
The trial comprises 5 planned visits consists of two phases i.e. main and extension, respectively. In 
the main phase the patients will attend a screening visit (Visit 1) in order to assess their eligibility. 
At Visit 2 eligible patient will receive their first dose, if applicable, and will be scheduled to attend
for 3 more visits. After Visit 5 the patients will enter the extension phase, and a rolling visit 
schedule will apply with 6 planned visits (including 4 dispensing visits) per year.
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The main trial phase will be completed when the aggregated number of patients will be scheduled 
to , who have either received treatment with turoctocog alfa for at least 50 ED or developed 
inhibitors, are at least 50. which For the individual patient it translates into duration of the main 
phase of approximately 3-24 months depending on the dose regimens (and bleeding pattern). The 
duration of the extension phase may be up to 3.5 years, and the total duration of the trial is 
estimated to be approximately 50 months years, please see Section 7.
Patients who develop inhibitors during the trial may continue treatment with turoctocog alfa and 
will follow an alternative visit schedule, see Section 5.3.4. These patients will be considered as a 
separate cohort and will be evaluated accordingly, please refer to Section 18.2.2.
---
Details on the trial design can be found in Figure 2-1 and details on the individual visits can be 
found in Table 2-1 and 2-2, and in Section 8.
2.8
5.3
Treatment of Patients
Approximately 60 patients are expected to be enroled into the trial in order to have 50 evaluable
patients completing in the main phase of the trial (estimated dropout rate is 15 20%). For 
replacement of withdrawn patients, please refer to Section 6.5. 
---
The maximum duration of treatment of a patient from first to last turoctocog alfa administration is 
approximately 24 4 years month.
2.9
5.3.2
Treatment of Bleeds and Dose Adjustment
During preventive treatment, break-through bleeds may occur and require extra doses of turoctocog 
alfa. Treatment should be started as soon as a bleed is identified. All bleeds, mild/moderate and 
severe, bleeds can be treated at home. whereas For severe bleeds (see Section 8.3.1.1) must always 
be evaluated by the Investigator should evaluate if the patient should be seen preferably at the 
clinic. However, even with severe bleeds treatment should be started immediately at home if 
possible. All bleeds must be reported to the clinic within 24 hours from onset of the bleed.
2.10
5.3.4
Treatment of Patients with Inhibitors
---
Patients who develop inhibitors, within this trial, will be offered continued treatment with 
turoctocog alfa for 12 months. It may also be decided by the Investigator and/or parent/legal 
representative to withdraw the patient.
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---
The initiation, dose level and dosing frequency of inhibitor treatment will be decided by the 
Investigator based on clinical evaluation and local standards, and it should be documented in the 
eCRF. Within this trial, ‘inhibitor treatment’ includes Immune Tolerance Induction (ITI) as well as 
smaller dose adjustments with low responding and/or clinical insignificant inhibitors.
If needed and decided by the Investigator, the initiation of the inhibitor treatment with turoctocog 
alfa can be delayed for up to 6 months from the time of diagnosis of inhibitor.
If the inhibitor disappears (BU <0.6/mL) during the ITI treatment, the patient should resume 
preventive treatment as recommended in this protocol, see Table 5-1, following the visit schedule in 
the extension phase. For patients still with positive inhibitors after 12 months ITI treatment, 
continued trial participation will be evaluated based on the level of inhibitors. After completion of 
the inhibitor treatment, or if preventive treatment is resumed, the patient will be called to an End of 
trial Visit (Visit 5).
2.11
5.4
Treatment after End of Trial
It is expected that turoctocog alfa will be granted marketing authorisation and is commercially 
available when the patients complete this trial. Where no marketing authorisation has been granted, 
eligible patients will be offered to continue in the phase 3b extension trial (guardianTM 2), see 
Section 3.2.1, as applicable by local regulation and rules.
2.12
6.1
Number of Patients to be studied
Countries planned to participate: Austria, Brazil, China, Croatia, Czech Republic, Greece, Hong 
Kong, Japan, Malaysia, Russia, Serbia, Spain, Turkey, UK and US.
Planned number of patients to be screened (i.e. documented informed consent):
7565
2.13
6.4
Withdrawal Criteria
---
1. Haemostasis not achievable with turoctocog alfa: The bleed cannot be controlled after 48 hours 
using recommended doses of turoctocog alfa
---
Withdrawn patients should be scheduled for an EoT Visit (Visit 5) as soon as possible and within 
28 days after the last turoctocog alfa administration, and preferably prior to initiation of treatment 
with another FVIII product. The Investigator should aim to conduct all procedures as specified in 
the protocol for the EoT Visit 5.
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2.14
6.5
Patient Replacement
Withdrawn patients may be replaced to ensure that 50 patients complete the trial with at least 50 
ED. Assuming a drop-out rate of 2015%, it is estimated that 60 patients must be enroled to obtain 
the 50 completed patients. This may, however, be adjusted during the trial based on the actual drop-
out rate.
2.15
6.6
Rationale for Trial Population
---
Rational for Withdrawal Criteria:
!
Criteriona nos. 1 is included to protect the patient's safety
!
Criterion no. 23 is selected not to confound the effects of the investigational product.
2.16
7
Trial Schedule
---
Planned LPLV:
April QIII 2016
The duration of the trial for the individual country is dependent upon the timelines of market 
authorisation and commercial availability of the trial product. Should market authorisation not be 
obtained, the maximum trial duration is approximately 5 years.
2.17
8.1.1
Overall Procedures, Assessments and Methods
Specific procedures, assessments and methods for the scheduled visits are described in the sections 
below, and the list of assessments for each visit is presented in the flow charts, see Table 2-1 and 2-
2.
2.18
8.1.2
Visit 1, Screening Visit
For all patients with a signed Informed Consent Form (ICF), the Investigator will, through IV/WRS,
assign a unique 6 digit patient number. The patient number is maintained throughout the trial and 
continuously maintained should the patient be enroled in the extension trial, see Section 5.4.
2.19
8.1.4
Visit 3 to Visit 5
---
Visit 5 should also be completed for withdrawn patients.
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2.20
8.1.5
Unscheduled Visit
The unscheduled visit can be performed after the enrolment into the trial until the EoT Visit (Visit5)
as either telephone contact or a site visit. Unscheduled visits will also be performed during inhibitor 
treatment, see Section 8.1.5.2, and for surgeryical procedures, Section 8.1.5.1. Please find listed in 
Table 2–1 and Table 2-2 the assessments, which should be performed at an unscheduled visit. The 
date and time of the visit should be recorded in the eCRF.
2.21
8.1.5.2
Inhibitor Treatment Visit
---
The alternative visit schedule will remain as long as the patient is treated for inhibitor.When the 
last inhibitor treatment visit has been performed, the patient will be called to an End of Trial Visit 
(Visit 5).
2.22
8.1.6
Extension phase Visits
These are visits to be performed for patients, who have completed the main phase and after Visit 5 
continue in the extension phase. Patients, who resume preventive treatment after completed ITI 
treatment, will also follow the visit schedule in the extension phase. The patients will be called to 
the visits according to a rolling visit schedule, which runs over one year. There are two kinds of 
visits, Dispensing (4) and Assessment&Dispensing (2), and the aggregated planned number of visits 
over one year is 6.
Please also see Table 2-2 for your reference.
2.23
8.1.7
EoT Visit
Within 8 weeks of the last scheduled visit in the extension phase the patient should be called to an 
EoT Visit. For patients, who discontinue the trial, an EoT visit should be performed within 28 days.
2.24
8.2.1
Adverse Events
Monitoring of Adverse Events will be performed from the first trial-related activity to the EoT Visit 
(Visit 5) and at potential follow-up visits, according to procedures described in Section 12.
2.25
8.2.2
FVIII Inhibitors
All patients will be examined regularly for the development of FVIII neutralising antibodies 
(inhibitors). The tests will be performed at Visit 1 and Visits 3-5 in the main phase of the trial, and 
at the Assessment&Dispensing Visits in the extension phase, i.e. at least twice annually.
2.26
8.2.3
FVIII Recovery
---
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Samples for FVIII recovery will be sent to the central laboratory for analysis, see Section 8.2.7.2.
2.27
8.2.4
FVIII Trough Level Assessment
The Investigator can at his/her discretion perform trough level assessments at any time during the 
trial. Visit 3-4
2.28
8.2.5
Haematology
The assessment will be performed at Visit 1 and Visit 5 in the main phase, the 
Assessment&Dispensing Visits in the extension phase, EoT Visit and optionally at unscheduled 
visits. It is performed according to practice of the local laboratory and includes:
2.29
8.2.6
Biochemistry
The assessment will be performed at Visit 1 and Visit 5 in the main phase, the 
Assessment&Dispensing Visits in the extension phase, EoT Visit and optionally at unscheduled 
visits. It is performed according to practice of the central laboratory and includes:
2.30
8.2.7.2
Local Laboratory Test
Assessments of haematology, FVIII trough levels and CD4+ T-cell count (if applicable) will be 
done at the local laboratory* as per standard of practice at the participating site. Laboratory results 
from the local laboratory will be recorded in the eCRF.
                                                                           *in Russia and Hong Kong, CD4+ T-cell count is done centrally
not applicable for Serbia
---
Clinically significant findings must be recorded as concomitant illness (blood samples during visit 
1) or as an Adverse Event (blood samples taken during the course of the trial. at visit 2-5, 
unscheduled visits and potential follow-up visits)
2.31
8.2.7.3
Central Laboratory Tests
A central laboratory will coordinate analysis and report of all laboratory safety tests related to 
biochemistry, viral antibody assessments (except CD4+ T-cell count), FVIII inhibitor, FVIII 
activity and genotyping tests performed in this trial. Laboratory data from the central laboratory will 
be reported to Novo Nordisk electronically, and in a manner that anonymity of patients will be 
maintained.
2.32
8.2.7.4
Blood Sampling Volume
Blood samples for laboratory analysis of efficacy, safety and other parameters will be drawn as 
described for the individual visits. The total volume of blood drawn during the trial will be 
approximately 2040- 5065 mL per patient (the higher range is for patient in inhibitor treatment 
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and/or for patient, who stay in the trial for a longer duration of time). According to the European 
regulatory guidelines (Directive 2001/20/EC)2,19 the recommended blood volume collected from the 
patient 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 (see Appendix B). . This is in accordance with Where this guideline
is not applicable, local guidelines for blood sampling volumes will apply. During visits when 
multiple samples are taken, blood samples will be aliquoted to meet above mentioned requirements. 
Instructions will be provided in the Laboratory Manual and in Appendix B.
2.33
8.2.8
Physical Examination
Physical examination should be performed at Visits 1-5 and at EoT (additional examinations can be 
performed as appropriate) according to practice at the participating clinic including assessments of 
the following:
2.34
8.2.9
Vital Signs
Vital signs will be assessed at Visit 1 and ,Visit 5 and at EoT (additional assessments can be 
performed as needed) and includes:
!
Body temperature (assessed by measuring inner ear temperature or using an oral digital 
thermometer)
!
Respiratory rate (resp./min.)
!
Pulse: preferably supine
!
Blood pressure (BP): preferably supine
BP (systolic and diastolic) and pulse rate will be measured according to local practice at the clinic; 
preferably after the patient has rested comfortably for at least 3 minutes.
Any changes in the vital signs between the two visits which fulfil the criteria of an Adverse Event 
must be recorded as such, see Section 12.1.
2.35
8.3.1Bleeds
During the entire trial period all bleeds treated with turoctocog alfa will be entered in either the 
eCRF or in the patient’s diary. For mild/moderate bleeds treated at home, the patient or caregiver 
must fill in the diary and during visits the diary data will be transcribed into the eCRF by trial site 
personnel. For severe bleeds (see definition in Section (8.3.1.1) the Investigator, or designated site 
staff, must be contacted without delay to prescribe the appropriate treatment and any follow-up 
procedures. It is recommended that these direct instructions are followed by, or given at, an 
unscheduled visit to the clinic. Documentation about the severe bleeds treated at the clinic should 
be entered in the medical records and eCRF by the trial personnel.
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2.36
8.4.1
FVIII genotype testing (not applicable to Brazil)
At Visit 1 2, all patients/parents/legally authorized representative (LAR) 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 as allowed by local law. The blood sample should be taken at Visit
3, 4 or an unscheduled Visit. The FVIII genotype analysis is performed at the laboratory in Bonn, 
Germany. Investigator, parent(s) or LAR have the right to refuse to provide patient’s FVIII 
genotype documentation or to refuse genotyping. This will not stop the patient to continue 
participation in the remainder of the study trial.
2.37
8.4.2
Viral Antibody Information
At Visit 1 and at EoT status of the following viral infections are assessed.
2.38
8.4.4
Body Measurements
Weight and height will be measured at Visits 1, 5 and EoT. For Visits 2-4 and for the 
Assessment&Dispensing Visits in the extension part only weight is measured. 
2.39
8.4.5
Diaries
Diaries will be dispensed and reviewed at all visits 2-4, except Visits 1, 2 and EoT. The following 
data will be collected.
2.40
8.4.7
HE and PRO data
---
The questionnaire is to be filled in at Visits 1, 3 and 5 in the main phase, annually in the extension 
phase and at EoT Visit preferably before any other trial related procedures.
2.41
9.4
Dispensing and Drug Accountability of Trial Products
---
       •No trial product(s) should be dispensed to any person not enroled in the trial (excluding 
parents/LAR)
Trial product will be dispensed at the visits depicted in the flow chart, see Table 2-1 and 2-2. The 
patient is required to return both used and unused vials at the next visit to the clinic or at the End of 
Trial Visit, as appropriate.
2.42
14
Monitoring Procedures
During the course of the trial, the Monitor will visit the trial site to ensure that the protocol has been
adhered to, that all issues have been recorded, to perform source data verification and to monitor
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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, 
but The intervals between visits must not exceed 8 weeks when there are patients ongoing in the 
trial at the site. When there are no trial active patients at the sites, intervals between visits must not 
exceed 12 weeks.
2.43
18.2.2
Primary Endpoint(s)
!
Incidence rate of inhibitors defined as inhibitor titres ≥ 0.6 Bethesda units/mL for the main 
phase of the trial
The incidence rate of inhibitors will be calculated 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
incidence rate the numerator will include number of all patients with inhibitors while the 
denominator will include number of all patients with confirmed inhibitors during the main phase of 
trial or completed the main phase without confirmed minimum of 50 ED plus any patients with less 
than 50 ED but with inhibitors.
2.44
18.2.4
Supportive Secondary Endpoints
All the below efficacy endpoints will be evaluated for the main phase of trial, for the extension 
phase of trial, and for the combined main and extension phases. Sensitivity analyses will be made 
only including patients who do not develop inhibitors during the main phase of the trial and during 
the extension phase of the trial.For patients that develop inhibitors only the time period until the last 
negative inhibitor result is considered for the efficacy endpoints below. Sensitivity analyses will be 
made only including patients who do not develop inhibitors. Further, tables will be made including 
only inhibitor patients. For these patients the relevant time period is the time period after positive 
inhibitor test.
Secondary Efficacy Endpoints
---
!
Annualized bleeding rate during bleeding prevention period with turoctocog alfa
For this endpoint patients who develop inhibitors will only be included if they have been treated 
with at least two doses of trial product for minimum 1 month before the first positive inhibitor test. 
The reason to exclude these patients from the calculations is that if the treatment period is too short,
that the information from the treatment with one dose is too small and the uncertainty introduced on 
the estimated annualized bleeding rate will be relatively large.
---
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Substantial Protocol Amendment
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Trial ID: NN7008-3809
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Separate reports and listings will be made for the above efficacy endpoints for patients developing 
inhibitors. Data used in these reports and listings will include data from the first time patient is
confirmed with inhibitors until the end of the main phase of trial as well as until the end of trial. 
Furthermore, each of these reports will also be generated for different method for management of 
patients with inhibitors.
Secondary Safety Endpoints
!
Incidence rate of inhibitors defined as inhibitor titres ≥ 0.6 Bethesda units/mL for the 
extension part of trial and the combined main and extension phases of the trial. 
The incidence rate of inhibitors will be calculated and analyzed in the similar way as the primary 
endpoint. 
Furthermore, Kaplan Meyer plots and the additional analyses outlined in Section 18.2.2 for the 
primary endpoint will be generated using data from the extension phase and the combined main 
and extension phases of the trial.
!
Frequency of AEs adverse events and SAEs serious adverse events
AEs and SAEs will be analyzed for the main phase of the trial and the combined main and extension 
phases.
---
Separate reports and listings will be made for AEs and SAEs for patients developing inhibitors. 
Data used in these reports and listings will include data from the first time patient is confirmed with 
inhibitors until the end of the main phase of trial as well as until the end of trial.
---
The incidence rate of clinically relevant inhibitors and high-titre inhibitors will be evaluated for the 
main phase of trial, for the extension phase of trial, and for the combined main and extension 
phases.
---
All additional safety parameters such as laboratory parameters and physical examinations will be 
listed and summarized by visit for all patients for the main phase of trial, for the extension phase of 
trial, and for the combined main and extension phases
Separate reports and listings will be made for the above safety endpoints for patients developing 
inhibitors. Data used in these reports and listings will include data from the first time patient is 
confirmed with inhibitors until the end of the main phase of trial as well as until the end of trial. 
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Trial ID: NN7008-3809
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2.45
18.6
Health Economics and Patient Reported Outcomes
Health economic data will be collected in the eCRF in connection with severe bleeds. Patient 
reported outcomes will be collected using questionnaires at Visits 3 and 5 in the main phase, and 
annually during the extension phase.
2.46
23
Responsibilities
---
The following will be analysed at the local laboratory: haematology, FVIII trough level assessment 
and CD4+ T-cell (excluding Russia).
ACentral and specialized laboratoryies will analyse and report all laboratory safety tests related to 
biochemistry, viral antibody assessments, FVIII activity, FVIII inhibitor assessments and potential 
genotyping performed in this trial. 
2.47
27
References
---
9
Investigator's Brochure. N8: Recombinant Factor VIII, 3rd4th edition.  10-12-000915 
May 2012
2.48
Appendix B
---
The blood volume collected from the subject 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 according to This requirement 
is in line with European regulatory guidelines requirements (Directive 2001/20/EC)2,19 and FDA 
requirements, or it should be according to local guidelines for blood sampling volumes. As a 
reference, the table below shows the estimated blood volume in children weighing from 6 -25 kg 
and the blood volume that can be taken at any single time and within 28 days, respectively,
according to EMA, European regulatory requirements (Directive 2001/20/EC) and over a 24h 
period according to FDA requirements guidelines.
Total Blood volume according to Geigy Scientific Table and maximum blood sampling volume 
according to EMA and FDA.
Weight 
(kg)
Blood volume 
(ml/kg)
Total Blood 
volume (ml)
Volume/blood sample 
(1%)        EMA
Volume/28 days (3%)
EMA
Volume/ 24h
FDA
6
80
480
4.8
14.4
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7
80
560
5.6
16.8
14
---
---
---
---
---
10
80
800
8.0
24.0
20
---
---
---
---
---
15
80
1200
12.0
36.0
30
---
---
---
---
---
20
80
1600
16.0
48.0
40
---
---
---
---
---
25
80
2000
20.0
60.0
50
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
1 of 11
Substantial Protocol Amendment no 6
to Protocol, final version 3.0
dated 27 August 2012
Trial ID: NN7008-3809
(turoctocog alfa)
Safety and Efficacy of turoctocog alfa in Prevention and Treatment of Bleeds in Paediatric
Previously Untreated Patients with Haemophilia A
Trial phase: 3b
Applicable to all countries 
Amendment originator:
Name: 
Department: Haemophilia, Clinical Operations FVIII & FXIII
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
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
2 of 11
Table of contents
Page
Table of contents...............................................................................................................................................2
Table of tables...................................................................................................................................................2
1
Introduction...............................................................................................................................................3
1.1
Substantial protocol amendment....................................................................................................3
1.2
Rationale for amendment No. 6.....................................................................................................3
2
Changes......................................................................................................................................................5
2.1
1 Summary.....................................................................................................................................5
2.2
2 Flow Chart ..................................................................................................................................6
2.3
3.1.1.2 Risks and Benefits .............................................................................................................7
2.4
5.1   Type of Trial..........................................................................................................................7
2.5
5.3   Treatment of Patients.............................................................................................................8
2.6
6.2   Inclusion Criteria ...................................................................................................................8
2.7
6.3   Exclusion Criteria ..................................................................................................................8
2.8
6.5   Patient Replacement...............................................................................................................8
2.9
6.6   Rationale for Trial Population ...............................................................................................8
2.10
7   Trial Schedule...........................................................................................................................9
2.11
8.1.3  Visit 2...................................................................................................................................9
2.12
8.1.3.1 Combining Visit 1 and Visit 2............................................................................................9
2.13
8.2.2  FVIII Inhibitors....................................................................................................................9
2.14
8.2.3  FVIII Recovery Assessments ...............................................................................................9
2.15
8.2.3.1 FVIII Activity .....................................................................................................................9
2.16
8.2.3 8.2.3.2 FVIII Recovery.........................................................................................................9
2.17
8.2.4 8.2.3.3 FVIII Trough Level Assessment.............................................................................10
2.18
8.2.5  Haematology......................................................................................................................10
2.19
8.2.7.2 Local Laboratory Tests ....................................................................................................10
2.20
8.2.7.3 Central Laboratory Tests..................................................................................................10
2.21
8.4.5  Diaries................................................................................................................................10
2.22
12.1.2 Medical Event of Special Interest and other events for expedited reporting....................11
2.23
23   Responsibilities.....................................................................................................................11
2.24
Appendix D Body Mass Index Charts .........................................................................................11
Table of tables
Page
Table 2–1
Visit Flow Chart main trial phase.............................................................................................6
Table 2–2
Visit Flow Chart trial extension phase......................................................................................6
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
3 of 11
1
Introduction
1.1
Substantial protocol amendment
This global substantial amendment has been prepared to:
!
enable performing Visit 1 and Visit 2 at the same day
!
revise inclusion criterion no.2 and exclusion criterion no. 4
!
delete inclusion criterion no.5 and exclusion criterion no. 6
!
extend the number of required exposure days (ED) from 50 to 100
!
analyse haematology samples at the central lab.
In this substantial protocol amendment:
!
any new text is written in italics
!
any text deleted from the protocol is written using strike through.
Minor changes that do not affect the content of the protocol will not be disclosed in the following 
sections e.g.:
!
the substance code NNC 0155-0000-0004 will be exchanged for turoctocog alfa
!
minor inconsistencies and ambiguities
!
typographical errors.
1.2
Rationale for amendment No. 6
The main focus of this amendment is enabling performing Visits 1 and 2 at the same day. The 
current clinical trial includes Previously Untreated Patients (PUP), and the protocol demands blood 
sampling at the first visit in the trial. This constitutes a risk for bleeds. For the safety of these 
untreated patients, we will make it possible to administer trial product already at the first visit to the 
clinic. This can be accomplished if Visit 1 and Visit 2 are performed at the same time, without 
waiting for lab result from screening assessments.
Changes to the eligibility criteria, i.e. deletion of inclusion criterion #5 and exclusion criteria and 
#6, and revising inclusion criterion #2 and exclusion criterion #4, are following considerations of 
relevance. Immune competency will be present in the vast majority of PUPs and inclusion criterion 
#5 can thus be regarded as unnecessary. Presence of FVIII inhibitors, 0.6 ≥ BU, (exclusion criterion 
#4) can be considered as highly improbable in a true PUP population. Similarly, thrombocytopenia 
with platelets ≤ 50000/μl (exclusion criterion #6) will also very rarely, if ever, be seen in these 
haemophilic patients. The above mentioned parameters will be captured as baseline characteristics, 
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
4 of 11
but not for eligibility.
It is our strong opinion that changing the above criteria will in not compromise the safety of the 
patients enrolled in the trial. Patients with any disease or condition which might pose a potential 
hazard are not eligible according to the unchanged exclusion criterion #7.
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
5 of 11
2
Changes
2.1
1
Summary
Trial Design
---
The trial consists of two phases. In the main phase, an aggregated number of at least 50 patients will 
receive preventive treatment with turoctocog alfa NNC 0155-0000-0004 until they reach a 
minimum of 50 exposure days (ED) or until they develop inhibitors. After that the patient will 
continue in the extension phase until at least 100 ED has been achieved, which will translate into a 
maximum of last for approximately 3.5 years. The estimated total duration of the trial is 
approximately 5 years.
Trial Population
Approximately 60 PUP with severe (baseline level FVIII ∀1%) haemophilia A without no history of
inhibitors below 6 years of age in a non-bleeding state will be enroled to allow for at least 50 
patients to complete the trial.
Key Inclusion Criteria:
!
---
!
Male patients diagnosed with congenital severe haemophilia A (baseline level FVIII < 1%)
Key exclusion Criteria:
!
---
!
Any history of FVIII inhibitor (> 0.6 BU/mL) at screening
!
---
!
Platelet count <50,000 platelets/μL
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
6 of 11
2.2
2
Flow Chart
(Clarification note: For Table 2-1 and 2-2 only information that is subjected to changes is
presented.)
Table 2–1
Visit Flow Chart main trial phase
Visit number
Screen.
Visit 1
Visit 2#
Visit 3
Visit 4
Visit 5
Unscheduled 
Visit
Visit window
NA
<2114 # 7
d
post V1
10th -15thED
20th -25th
ED
50100th –
55110th ED
# Visit 2 can be performed at the same day as Visit 1
Table 2–2
Visit Flow Chart trial extension phase
Visit type
Dispensing
Assessment&
Dispensing
Dispensing
Assessment&
Dispensing
End of 
Trial
Unsch 
Visit
Visit number#
6
7
8
9
10
11
Previous visit time(w)
-8
-8
-10
-8
-8
-10
< 8
Visit window
± 1w
± 1w
± 1w
± 1w
± 1w
± 1w
NA
NA
ASSESSMENTS
SAFETY
FVIII trough level
●a
●a
●a
●a
●a
●a
●a
a – optional, at discretion of investigator
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
7 of 11
Screening will be done at Visit 1., 14 # 7 days prior to Visit 2 will be performed within 21 days post Visit 1, and it 
could be the same day as Visit 1. At Visit 2 eligible patients are enrolled and preventive treatment with investigational 
product (turoctocog alfa) starts if applicable (may start after the first two bleeds). At Visit 5, after ≥ 50 ED, patients will 
leave the main phase of the trial and continue in the extension phase. Patients who develop inhibitors can continue with 
ITI treatment with an alternative visit schedule (down ward arrows). If ITI treatment is successful these patients can 
continue with preventive treatment according to the extension phase (upward arrows). The patients will belong to either 
of the groups main-phase, extension phase or inhibitor cohort.
Figure 2–1
Trial Design
2.3
3.1.1.2
Risks and Benefits
---
After the patients have achieved the required number of ED, they may will continue in the trial until 
product launch or until the end of trial, should market authorisation not be obtained, see Section 7. 
This serves to minimise the patients’ need of switching to other FVIII products
2.4
5.1
Type of Trial
---
The trial consists of two phases i.e. main and extension, respectively. In the main phase the patients 
will attend a screening visit (Visit 1) in order to assess their eligibility. At Visit 2 eligible patients
will receive their first dose, if applicable. It is an option to perform Visit 1 and Visit 2 at the same 
day for the purpose of immediate administration of the trial product. After Visit 2 the patients and
will be scheduled for 3 more visits in the main phase. After Visit 5 the patients will enter the 
extension phase, and a rolling visit schedule will apply with 6 planned visits (including 4 dispensing 
visits) per year.
V2
V5/50 ED
turoctocog alfa
EoT/>100 ED
V1
main phase
extension 
ITI treatment
inhibitor cohort
preventive 
treatment
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
8 of 11
The main trial phase will be completed when the aggregated number of patients, who have either 
received treatment with turoctocog alfa for at least 50 ED or developed inhibitors, are at least 50. In 
the extension phase the patients will be followed until at least 100 ED has been achieved. For the 
individual patient it translates into duration of the main phase of approximately 3-24 months 
depending on the dose regimens (and bleeding pattern). The duration of the extension phase may be 
up to 3.5 years, and the total duration of the trial is estimated to be approximately 5 years, please 
see Section 7.
2.5
5.3
Treatment of Patients
Approximately 60 patients are expected to be enrolled (trial drug administered) into the trial in 
order to have 50 evaluable patients, who complete in the main phase of the trial (estimated drop-out 
rate is 15%). For replacement of withdrawn patients, please refer to Section 6.5.
2.6
6.2
Inclusion Criteria
-----
2.    Male patients diagnosed with congenital severe haemophilia A (FVIII level ∀1%)*
----
5.    Immunocompetent, defined as either HIV negative or if HIV positive, CD4+ cells > 200   
cells/μl.
*based on the one-stage clotting assay
2.7
6.3
Exclusion Criteria
4.   Any history of FVIII inhibitor (> 0.6 BU/mL) at screening
----
6.    Platelet count <50,000 platelets/μL
2.8
6.5
Patient Replacement
Withdrawn patients may be replaced to ensure that 50 patients complete the trial with at least 50
100 ED. Assuming a drop-out rate of 15%, it is estimated that 60 patients must be enroled to obtain 
the 50 completed patients. This may, however, be adjusted during the trial based on the actual drop-
out rate.
2.9
6.6
Rationale for Trial Population
---
Rational for Exclusion Criteria:
----
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
9 of 11
!
Criteriaon nos. 3 and 6 are is chosen to exclude patients with endogenous abnormalities of the 
coagulation system other than haemophilia
2.10
7
Trial Schedule
---
Planned completion of clinical trial report (CTR): Q3 2016 Q1 2017
2.11
8.1.3
Visit 2
The visit will be scheduled within 21 14 # 7 days after Visit 1.
The main purpose of Visit 2 is to administer turoctocog alfa for the first time, if applicable, or 
alternatively dispense the trial product to eligible patients. 
2.12
8.1.3.1
Combining Visit 1 and Visit 2 
Visit 1 and Visit 2 can be performed at the same day. It will allow for immediate administration of 
trial product should, this be preferred or deemed necessary.
Please ensure that all assessments required for Visit 1 and Visit 2 are performed and that all 
required blood samples for the central laboratory is taken before the administration of the trial
product.
2.13
8.2.2
FVIII Inhibitors
All patients will be examined regularly for the development of FVIII neutralising antibodies 
(inhibitors). The tests will be performed at Visit 1 (baseline characteristics) and Visits 3-5 in the 
main phase of the trial, and at the Assessment&Dispensing and EoT Visits in the extension phase, 
i.e. at least twice annually. Additional laboratory assessment for FVIII neutralising antibodies can 
be done if inhibitor development is suspected during the course of the trial, or if more frequent 
testing is mandated i.e. during unscheduled visits.
2.14
8.2.3
FVIII Recovery Assessments
2.15
8.2.3.1
FVIII Activity
In order to establish patient characteristics, baseline FVIII activity will be taken at Visit 1. Any
anti-haemophilic treatment with blood components should be withdrawn at least 48 hours prior to 
blood sampling.
2.16
8.2.3 8.2.3.2
FVIII Recovery
Recovery is the FVIII plasma level recorded 30 # 5 minutes after trial product administration and 
reported as [IU/mL]/ [IU/kg]. Recovery assessment is mandatory at inhibitor diagnosis to identify 
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
10 of 11
clinical relevant inhibitors (see Section 8.2.2). Additional recovery assessments may be requested at 
the discretion of the Investigator.
Samples for FVIII recovery will be sent to the central laboratory for analysis, see Section 8.2.7.2.
2.17
8.2.4 8.2.3.3
FVIII Trough Level Assessment
The Investigator can at his/her discretion perform trough level assessments at any visit during the 
trial, except Visit 3-4 1-2. The trough level is defined as the lowest level of FVIII measured 
immediately prior to dosing and reported as (IU/mL). The trough level will be determined at the 
local laboratory.
Trough levels need only to be recorded in the eCRF if it is the reason for dose adjustments.
2.18
8.2.5
Haematology
The assessment will be performed at Visit 1 and Visit 5 in the main phase, the 
Assessment&Dispensing Visits in the extension phase, EoT Visit and optionally at unscheduled 
visits. It is performed according to practice of the central local laboratory and includes:
---
It is recommended that the haematology values are reported in the above listed units. However, in 
the eCRF it will be possible to enter values in other units accepted by Novo Nordisk.
2.19
8.2.7.2
Local Laboratory Tests
Assessments of haematology, FVIII trough levels and CD4+ T-cell count (if applicable) will be 
done at the local laboratory* as per standard of practice at the participating site. Laboratory results 
from the local laboratory will be recorded in the eCRF.
                                                                                                        *in Russia and Hong Kong, CD4+ 
T-cell count is done centrally 
2.20
8.2.7.3
Central Laboratory Tests
A central laboratory will coordinate analysis and report of all laboratory safety tests related to 
biochemistry, viral antibody assessments except CD4+ T-cell count, FVIII inhibitor, FVIII activity
and genotyping performed in this trial. Laboratory data from the central laboratory will be reported 
to Novo Nordisk electronically, and in a manner that anonymity of patients will be maintained.
2.21
8.4.5
Diaries
Diaries will be dispensed and reviewed at all visits, except visits 1, 2 and EoT starting from Visit2.
CONFIDENTIAL


Substantial Protocol Amendment
CONFIDENTIAL
Date:
28 November 2012
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN:1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
11 of 11
2.22
12.1.2
Medical Event of Special Interest and other events for expedited 
reporting
---
!
Inhibitor formation against FVIII
o
Inhibitor formation is always considered a MESI. Blood samples for measurements 
of FVIII inhibitors will be analysed at the central laboratory selected by Novo 
Nordisk. However, if an investigator obtains any indication of inhibitor formation by 
clinical signs or local laboratory results, it should be reported as MESIs.
The diagnosis of inhibitor is made, if the patient has been tested positive for 
inhibitors (BU≥0.6/mL) at two consecutive tests at the central laboratory, sampled 
preferably within 2 weeks. this should be reported by the Investigator as a MESI 
However, if the first inhibitor test is positive, it should also be reported as a MESI 
even though the confirmatory test is negative.
2.23
23
Responsibilities
---
The following will be analysed at the local laboratory: haematology, FVIII trough level assessment 
and CD4+ T-cell (excluding Russia).
Central and specialized laboratories will analyse and report all laboratory safety tests 
related to biochemistry, haematology, viral antibody assessments, FVIII activity, FVIII 
inhibitor assessments and potential genotyping performed in this trial. 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.
2.24
Appendix D
Body Mass Index Charts
Appendix D will be deleted.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
1 of 23
Protocol Amendment
no 7
to Protocol, final version 4
dated 30 November 2012
Trial ID:NN7008-3809
Safety and Efficacy of turoctocog alfa in Prevention and Treatment of Bleeds in Paediatric 
Previously Untreated Patients with Haemophilia A
Trial phase: 3a
Applicable to all countries
Amendment originator:
Name: 
Department: Haemophilia, Clinical Operations 1
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:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
2 of 23
Table of contents
Page
1
Introduction including rationale for the protocol amendment.............................................................4
2
Changes......................................................................................................................................................5
2.1
1  Summary....................................................................................................................................5
2.2
2  Flow Chart .................................................................................................................................6
(Clarification note: For Table 2-1 and 2-2 only information that is subjected to changes is 
presented.)......................................................................................................................................6
2.3
5.1 Type of Trial............................................................................................................................7
2.4
5.3  Treatment of Patients..............................................................................................................7
2.5
5.3.1   Preventive Treatment and Dose Adjustment ......................................................................7
2.6
5.3.2  Treatment of Bleeds and Dose Adjustments........................................................................8
2.7
5.3.4   Treatment of patients with Inhibitors..................................................................................8
2.8
5.4 Treatment after End of Trial ....................................................................................................9
2.9
6.1 Number of patients to be Studied.............................................................................................9
2.10
6.2 Inclusion Criteria .....................................................................................................................9
2.11
6.4 Withdrawal criteria ..................................................................................................................9
2.12
6.6  Rationale for Trial Population ..............................................................................................10
2.13
7  Trial Schedule..........................................................................................................................10
2.14
8.1.3   Visit 2................................................................................................................................10
2.15
8.1.5.   Unscheduled Visit............................................................................................................11
2.16
8.2.2   FVIII antibodies Inhibitors ...............................................................................................11
2.17
8.2.2.1  FVIII Inhibitors...............................................................................................................11
2.18
8.2.2.2  Non-neutralising antibodies............................................................................................11
2.19
8.2.4   Haematology.....................................................................................................................11
2.20
8.2.6.1  General Considerations...................................................................................................11
2.21
8.2.6.2  Local Laboratory Tests ...................................................................................................12
2.22
8.2.6.3  Central Laboratory Tests.................................................................................................12
2.23
8.3.1   Bleeds................................................................................................................................12
2.24
8.3.1.1  Definition of Severity of Bleeds .....................................................................................12
2.25
8.3.1.3  Bleed Classification ........................................................................................................13
2.26
8.4.1  FVIII Genotype testing ......................................................................................................13
2.27
9.1 Trial Products.........................................................................................................................13
2.28
9.4 Dispensed and Drug Accountability of Trial Products..........................................................14
2.29
11  Concomitant Illnesses and Concomitant Medication.............................................................14
2.30
12.1  Definitions ..........................................................................................................................14
2.31
12.1.2  Medical Event of Special Interest and other events for expedited reporting ...................15
2.32
12.2 Collection, Recording and Reporting of Adverse Event......................................................16
2.33
12.2.2.  Follow-up of Adverse Events .........................................................................................18
2.34
12.3.1  Collection and Reporting of Technical Complaints.........................................................19
2.35
13.4  Analysis Results..................................................................................................................20
2.36
14 Monitoring Procedures............................................................................................................20
2.37
18.2.1  General Considerations....................................................................................................20
2.38
18.4  Explorative Statistical Analysis for Pharmacogenetics and Biomarkers............................20
2.39
19.1  Informed Consent Form for Trial Patients..........................................................................20
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
3 of 23
2.40
19.4 Regulatory Authorities.........................................................................................................21
2.41
20 Premature Termination of the Trial/Trial Site ........................................................................21
2.42
23  Responsibilities......................................................................................................................21
2.43
25 Retention of Clinical Trial Documentation.............................................................................22
2.44
Attachment I – Global..................................................................................................................22
Table of figures
Page
Figure 12–1
17
Table of tables
Page
Table 2–1
Visit Flow Chart main trial phase.........................................................................................6
Table 2–2
Visit Flow Chart trial extension phase..................................................................................6
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
4 of 23
1
Introduction including rationale for the protocol amendment
The main reasons for this amendment is to re-define the duration and conditions for treatment of 
patients with inhibitors, restrict the number of previous exposures to blood components (to keep a 
homogenous PUP population), re-define the trial duration and revise the date of end of trial. In 
addition, the possibility to further investigate immunogenicity of turoctocog alfa e.g. non-
neutralising antibodies assessment and Human Leucocyte Antigen (HLA) genotyping will be 
introduced. Some changes are administrative to align with updated guidelines and Novo Nordisk 
Standard Operation Procedures e.g. the requirement to list the participating countries has been 
removed.
The Patient Information and Informed Consent will be adapted accordingly.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
!
Corrections of minor inconsistencies and ambiguities, and typographical errors will not be 
listed.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
5 of 23
2
Changes
2.1
1  Summary
Trial Design
---
The trial consists of two phases. In the main phase, an aggregated number of at least 50 patients will 
receive preventive treatment with turoctocog alfa until they reach a minimum of 50 exposure days2
(ED) or until they develop inhibitors. After that the patients will continue in the extension phase 
until where at least 50 patients should achieve at least 100 ED has been achieved, which will 
translate into a maximum trial duration of up to 3.5 5 years (including any potential inhibitor 
treatment). The estimated total duration of the trial is approximately 5 7 years.
Trial Population
Approximately 60 PUP with severe (FVIII ≤ 1%) haemophilia A with no history of inhibitors below 
6 years of age in a non-bleeding state will be enrolled to allow for at least 50 patients to complete 
the trial
Key Inclusion  Criteria
!
---
!
No prior use of purified clotting factor products (previous exposure, equal to or less than 5 ED
to blood components, e.g. cryoprecipitate, fresh frozen plasma is accepted)
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
6 of 23
2.2
2  Flow Chart
(Clarification note: For Table 2-1 and 2-2 only information that is subjected to changes is 
presented.)
Table 2–1 Visit Flow Chart main trial phase
Visit number#
Screen.
Visit 1
Visit 2#
Visit 3
Visit 4
Visit 5
Unscheduled 
Visit
Visit window
NA
≤21 d
post V1
10th -15thED
20th -25th ED
50th -55th ED
SAFETY
Consent for FVIII genotype test
●
Antibodies
- FVIII inhibitors
- FVIII non-neutralising 
antibodies
●a
●a
●a
●a
●a, b
Trial Material
Diary and Trial card dispensing 
and/or collectione
●e
●e
●e
●e
●e
●b
Drug dispensing and 
accountability
●g
●
●
●
●b
Diary card training
●
# - Visit 2 can be performed at the same day as Visit 1
a – minimum 48 hours washout period of turoctocog alfa (or blood component products at Visit 1)
b – if applicable
---
e - Visit 1 trial card only, Visit 2-4 2-5 diary card only
---
g - Visit 2 dispensing only, Visit 5 accountability only
Table 2–2 Visit Flow Chart trial extension phase
Visit type
Dispensing
Assessment&
Dispensing
Dispensing
Assessment&
Dispensing
End of 
Trial
Unsch 
Visit
Visit number#
6
7
8
9
10
11
Previous visit time(w)
-8
-8
-10
-8
-8
-10
< 8
Visit window
± 1w
± 1w
± 1w
± 1w
± 1w
± 1w
NA
NA
SAFETY
Antibodies
- FVIII inhibitors
- FVIII non-neutralising 
antibodies
●a
●a
●
●a
●a
●
●
●a
# - Presented numbers are for the first 12 months. Visit numbers for future years will be in consecutive order
a – optional, at discretion of investigator
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
7 of 23
---
Caption text (Figure 2–1 Trial Design)
Screening will be done at Visit 1. Visit 2 will be performed within 21 days post Visit 1, and it could 
be the same day as Visit 1. At Visit 2 eligible patients are enrolled and preventive treatment with 
investigational product (turoctocog alfa) starts if applicable (may be delayed, see section 5.3.1 start 
after the first two bleeds). At Visit 5, after ≥ 50 ED, patients will leave the main phase of the trial 
and continue in the extension phase. Patients who develop inhibitors can continue with ITI 
treatment with an alternative visit schedule (down ward arrows). If ITI treatment is successful these 
patients can continue with preventive treatment according to the extension phase (upward arrows). 
The patients will belong to either of the groups main phase, extension phase or inhibitor cohort.
2.3
5.1
Type of Trial
---
The main trial phase will be completed when the aggregated number of patients, who have either 
received treatment with turoctocog alfa for at least 50 ED or developed inhibitors, are at least 50. In 
the extension phase, at least 50 the patients will be followed until at least 100 ED has been 
achieved. For the individual patient it translates into duration of the main phase of approximately 3-
24 months depending on the dose regimens (and bleeding pattern). The duration of the extension 
phase may be up to 3.5 years, and the total duration of the trial is estimated to be approximately 5 7 
years, please see Section 7.
2.4
5.3  Treatment of Patients
---
Patients will enter a bleeding preventive regimen as described below, see Section 5.3.1. Preventive 
treatment can be postponed until a maximum of two bleeding episodes have occurred. For 
prevention one single bolus dose of turoctocog alfa is administered intravenously (i.v.) at each 
administration day. Turoctocog alfa should preferably be administered in the morning. The 
maximum duration of treatment of a patient from first to last turoctocog alfa administration is 
approximately 4 years.
2.5
5.3.1  Preventive Treatment and Dose Adjustment
---
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
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EudraCT No.:2011-001033-16
Page:
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The decision to initiate preventive treatment will be made by the Investigator and the child’s parent 
or legal representative with due consideration for the child’s own wishes (if they are capable to 
express these wishes). However, the preventive treatment has to be commenced no later than when 
the patient reaches 24 months old, or after a maximum of two treatment requiring bleeding episodes 
(joint, muscle or severe bleeding episode) have occurred, whatever comes first. Should a patient be 
older than 24 months of age at enrolment, preventive treatment needs to start immediately.
2.6
5.3.2  Treatment of Bleeds and Dose Adjustments
---
If a haemostatic response of bleeds cannot be achieved (i.e. the bleed does not stop) after 48 hours 
using doses of turoctocog alfa up to 200 IU/kg BW per day, 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 from the trial.
2.7
5.3.4  Treatment of patients with Inhibitors
---
Patients who develop inhibitors, within this trial, will be offered continued treatment with 
turoctocog alfa for 12 months, including ITI treatment for a maximum period of 24 months. It may 
also be decided by the Investigator and/or parent/legal representative to withdraw the patient.
---
Patients will be evaluated after 12 months of ITI treatment, based on the level of inhibitors. If 
inhibitors are still positive after 12 months, but the decline from peak titer level is ≥ 20%, ITI may 
continue for a maximum period of 24 month in totals.
---
If needed and decided by the Investigator, the initiation of the inhibitor treatment with turoctocog 
alfa can be delayed, for up to but it has to start within 6 months from the time of diagnosis of 
inhibitor.
If the inhibitor disappears (BU <0.6/mL) during the ITI treatment, the patient shouldwill continue in 
the extension phase at a time point decided by the Investigator, resuming/starting preventive 
treatment as recommended in this protocol, see Table 5–1. However, if the inhibitor persists after 
24 months of ITI treatment, the patient will be withdrawn from the trial. following the visit schedule 
in the extension phase. For patients still with positive inhibitors after 12 months ITI treatment, 
continued trial participation will be evaluated based on the level of inhibitors.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
9 of 23
Treatment of bleeds with by-passing agents i.e. FVIIa or activated prothrombin complex 
concentrate (APCC) according to local label, is allowed for patients who develop inhibitors.
Bypassing agents are not considered trial medication
2.8
5.4
Treatment after End of Trial
When discontinuing trial product, patients should be switched to a suitable marketed product at the 
discretion of the Investigator. It is expected that turoctocog alfa will be granted marketing 
authorisation and is commercially available when the patients complete this trial. However, this 
cannot be guaranteed.
Novo Nordisk will not provide any patient with trial medication after the end of the trial unless 
required in accordance with local law or regulation. 
2.9
6.1
Number of patients to be Studied
Countries planned to participate: Austria, Brazil, China, Croatia, Greece, Hong Kong, Japan, 
Russia, Spain, Turkey, and US.
---
Planned number of patients to complete the main phase of the trial:
50
2.10
6.2
Inclusion Criteria
----
4. No prior use of purified clotting factor products (previous exposure, equal to or less than 5 ED to
blood components, e.g. cryoprecipitate, fresh frozen plasma, is accepted)
2.11
6.4
Withdrawal criteria
---
A patient must be withdrawn if the following applies:
1. Not in use
2. Allergy/Anaphylaxis to the trial product 
3. Treatment with FVIII products other than turoctocog alfa
4. Not in use
5. Inhibitor treatment has not been started within 6 months from the date of confirmation of 
positive FVIII inhibitor (BU ≥0.6/mL)
6. FVIII inhibitor titer decline from peak level is less than 20% after 12 months of inhibitor
treatment
7. FVIII inhibitor is positive (BU ≥0.6/mL) after 24 months of inhibitor treatment.
8. After completed inhibitor treatment (maximum 24 months), preventive treatment as described in 
the protocol is not resumed/started.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
10 of 23
2.12
6.6  Rationale for Trial Population
---
Rational for Withdrawal Criteria
---
!
Criterion no. 5-8 are selected for the safety of patients, who do not benefit from inhibitor
treatment with turoctocog alfa 
2.13
7 Trial Schedule
---
Planned date for LPLV:
QIII 30 June 20162018
The duration of the trial for the individual country is dependent upon the timelines of market 
authorisation and commercial availability of the trial product. Should market authorisation not be 
obtained, the maximum trial duration is approximately 5 years.
The duration of turoctocog alfa treatment in this trial is a minimum total 100 EDs for a particular 
patient. Once a patient has achieved 100 EDs, they may be offered the option to continue in the trial 
until either turoctocog alfa is commercially available in the relevant country or until the marketing 
authorisation application for turoctocog alfa is rejected in the relevant country unless the trial, part 
of the trial or a trial site is terminated by Novo Nordisk or a relevant authority for any reason. In 
any event, the LPLV for the trial will be no later than 30 June 2018 whether or not the product is 
commercially available in the relevant country.
The following exceptions will be made to the date for LPLV:
!
patients will be allowed to achieve at least 100 ED with trial product.
!
patients with inhibitor will be allowed to receive ITI treatment for up to 24 months.
---
Planned completion of main clinical trial report (CTR): Q1 2017 2016
Planned completion of updated clinical trial report: Q4 2018
2.14
8.1.3  Visit 2
---
OtherAnother important purposes are to provide the patient and care giver training for home 
treatment and training for how to fill out the diary.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
11 of 23
2.15
8.1.5.   Unscheduled Visit
---
If the patient visits the site for additional dispensing of trial product and/or auxiliary supplies, or if 
a scheduled visit is postponed, it is not considered as an unscheduled visit.
2.16
8.2.2  FVIII antibodies Inhibitors
2.17
8.2.2.1  FVIII Inhibitors
---
2.18
8.2.2.2  Non-neutralising antibodies
Plasma samples for analysis of non-neutralising antibodies against FVIII will be taken at the same 
time point as for inhibitor testing. The results will be used to characterise the underlying 
immunogenicity towards FVIII. The samples will be frozen and stored and the analysis will be 
carried out by a validated antibody assay. The samples may be used for further FVIII antibody 
characterisations (e.g. isotyping, binding properties).
It will not be possible to review the results of non-neutralising antibody measurements in relation to 
potential AEs because the results will be available after LPLV.
Determination of non-neutralising antibodies against FVIII will be performed by Novo Nordisk A/S
or by a laboratory appointed by Novo Nordisk A/S.
If requested by the regulatory authorities antibody samples may be stored for a longer period until 
drug approval by Food and Drug Administration (FDA) and/or European Medicines Agency 
(EMA).
2.19
8.2.4   Haematology
---
!
Haemoglobin (mmolg/L)
2.20
8.2.6.1  General Considerations
---
Laboratory results should be signed and dated by the Investigator. Laboratory reports (laboratory 
result) are considered source data and should be kept in patient file for source data verification 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
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EudraCT No.:2011-001033-16
Page:
12 of 23
(carried out by the monitor). Clinically significant findings must be recorded as concomitant illness 
(blood samples during visit 1) or as an Adverse Event (blood samples taken during the course of the 
trial). Abnormalities should only be recorded as AEs if not present or worsened from 
baseline/previous assessments.
2.21
8.2.6.2  Local Laboratory Tests
---
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 Adverse Event (blood samples taken during the course of the trial). 
Abnormalities should only be recorded as AEs if not present or worsened from baseline/previous 
assessments. Laboratory results should be signed and dated. Laboratory reports (laboratory result) 
are considered source data and should be kept in patient file for source data verification (carried out 
by the monitor).
2.22
8.2.6.3  Central Laboratory Tests
A central laboratory will coordinate analysis and report of all laboratory safety tests and will 
perform related to the biochemistry, haematology and viral antibody assessments. FVIII inhibitor, 
turoctocog alfa antibodies, FVIII activity and genotyping assessments will be performed by
different specialized laboratories. in this trial. Laboratory data from the central and specialized 
laboratories will be reported to Novo Nordisk electronically, and in a manner that ensures
anonymity of patientswill be maintained.
---
The quality control of the central and specialized laboratory test results will be performed according 
to the regulations and specifications set by the authorities at the location of the central laboratories 
used for this trial.
2.23
8.3.1  Bleeds
---
!
Dose(s) (trial product volume and vial strength) and Time(s) of administration
2.24
8.3.1.1  Definition of Severity of Bleeds
---
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
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EudraCT No.:2011-001033-16
Page:
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Severe: Major bleeds that require hospitalisation. All internal head 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) will also be reported as severe and entered in 
the eCRF.All mild or moderate bleeds which are on-going 24 hours after start will be redefined as 
severe.
2.25
8.3.1.3  Bleed Classification
---
Re-bleeds will be reported by the trial statistician based on the diary data. Re-bleed is defined as a
bleedwhen after an initial period of improvement, (worsening of bleeding site conditions e.g. 
swelling, pain) either on treatment or within 72 hours after stopping of a previous bleed at the same
anatomical location.treatment (therefore, a new bleed is considered occurring later than 72 hours 
after stopping of treatment.
2.26
8.4.1  FVIII Genotype testing
At Visit 1, all patients/parents/legally authorised representative (LAR) will be asked about 
documentation of previous FVIII and Human Leucocyte Antigen (HLA) genotype tests. If not 
available or if it needs to be re-tested, based on the Investigators discretion, FVIII and HLA 
genotype testing will be offered as allowed by local law. The blood sample should be taken at Visit 
3, 4 or an unscheduled Visit. The FVIII genotype analysis is performed at the laboratory in Bonn, 
Germany. 
Investigator, parent(s) or LAR have the right to refuse to provide patient’s FVIII genotype 
documentation or to refuse genotyping. This will not stop prevent the patient’s to continued
participation in the remainder of the trial.
Applicable for Japan only: If documentation of the patient´s genotype already exists, the patient is 
offered to provide his data for the trial. If no previous data exists and genotyping consent is 
obtained, FVIII genotype analysis is performed at the laboratory in Bonn, Germany, using DNA 
isolated from leucocytes from the patient’s blood. No analysis will be performed concerning other 
genes than FVIII and HLA. Samples will be disposed appropriately after the test and all test results 
are kept strictly confidential.
2.27
9.1
Trial Products
---
Novo Nordisk will not supply any non-investigational products (NIMPs).
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
14 of 23
2.28
9.4
Dispensed and Drug Accountability of Trial Products
---
Once a patient is dosed, the allvials (used, partially used, unused, returned, and lost/damaged) must 
be recorded in the IV/WRS Drug Accountability module.
2.29
11 Concomitant Illnesses and Concomitant Medication
---
Concomitant medication: any medication, other than the trial product(s), that is taken during the 
trial, including the screening and run-in periods. Vaccinations must also 
be recorded as concomitant medication, and it should include 
vaccinations performed 1 year prior to Visit 1.
NB Vaccinations planned ahead of trial participation should be 
postponed to 3 months after the first turoctocog alfa treatment, as 
vaccination activates the immune system of the patient, thereby 
potentially increasing the risk of inhibitor development
2.30
12.1 Definitions
---
Serious Adverse Event (SAE):
--
!
Important medical eventsd) that may not result in death, be life-threateninga) or require 
hospitalisationb 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 the definition SAEd. Suspicion of transmission of infectious agents via 
trial product and formation of inhibitory antibodies must always be considered an SAE.
---
d) The term “important medical events” means events which may jeopardise the patient or require 
intervention to prevent a seriousness criterion. It can be AEs which suggest a significant hazard or 
puts the patient 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. For 
example intensive treatment in an emergency room or at home of allergic bronchospasm, blood 
dyscrasiasis or convulsions that do not result in hospitalisation or development of drug dependency 
or drug abuse.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
15 of 23
---
Relationship to Trial Product (turoctocog alfa) Assessment Definitions Causality assessment
The following terms are used when assessing the relationship between an AE and the relevant trial 
product(s):
Probable – Good reasons and sufficient documentation to assume a causal relationship
Possible – A causal relationship is conceivable and cannot be dismissed
Unlikely – The event is most likely related to aetiology other than the trial product.
Outcome Categories and Definitions Final outcome of an AE
!
Recovered/resolved* – Fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first trial related activity after the patient signed the 
informed consent.
!
Recovering/resolving – The condition is improving and the patient is expected to recover from 
the event. This term should only be used when the patient has completed the trial or has died 
from another AE.
!
Recovered/resolved with sequelae – As a result of the AE the patient suffered persistent and 
significant disability/incapacity (e.g. became blind, deaf, paralysed).The patient has recovered 
from the condition, but with lasting effect due to a disease, injury, treatment or procedure If the 
sequelae meets a seriousness SAE criterion, the AE must be reported as a SAE 
!
Not recovered/not resolved - The condition of the patient has not improved and the symptoms 
are unchanged, or the outcome is not known
!
Fatal - This term is only applicable if the subject died from a condition related to the reported 
AE. Outcomes of other reported AEs in a subject before he/she died should be assessed as 
“recovered/resolved”,“recovering/resolving”,“recovered/resolved with sequelae” or “not 
recovered/not resolved”. An AE with fatal outcome must be reported as an SAE.
!
Unknown – This term should only be used in cases where the patient is lost to follow-up.
*In Japan “Remitted” will be used
2.31
12.1.2  Medical Event of Special Interest and other events for expedited reporting
---
!
Medication error
o
Administration of wrong drug
o
Wrong route of administration such as intramuscular instead of intravenous
o
Administration of an accidental overdose i.e. dose which may lead to significant 
health consequence as judged by the Investigator irrespective of whether a SAE 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
16 of 23
criterion is met lower or higher dose than intended. The administered dose must 
deviate from the intended dose to an extent where clinical consequences for the trial 
subject were likely to happen as judged by the Investigator, although not necessarily
did happen.
o
Administration of a high dose with the intention to cause harm (e.g. suicide attempt)
2.32
12.2 Collection, Recording and Reporting of Adverse Event
All events meeting the definition of an AE must be collected and reported; from screening (visit 1) 
this includes events from the first trial related activity after the patient has signed the informed 
consent until End of Trial and at potential Follow-Up visits. The events must be recorded in the 
applicable CRF forms in a timely manner, see timelines below and Figure 12.1
During each contact with the trial site staff(visit or telephone, excluding safety visits, where the 
patient is not seeing the Investigator or site staff e.g. visits to the laboratory) the patient must be 
asked about adverse events, e.g. “Have you experienced any problems since the last contact?”
---
MESIs and other events for expedited reporting must always be reported to Novo Nordisk on the 
AE form and the safety information form, irrespective of seriousness. within the same timelines as 
for SAEs.
The AE form for a non-serious AE should be signed when the event is resolved or at the end of the 
trial.
Timelines for initial reporting of AEs:
The Investigator must report initial information on all SAEs, MESIs and other events for expedited 
reporting to Novo Nordisk within 24 hours of obtaining knowledge about the event.
The Investigator must complete the following forms in the CRF/eCRF within the specified timelines 
and forward electronically in pdf format/fax copies to Novo Nordisk:
!
SAEs: The AE form in the eCRF within 24 hours and the paper safety information form within 
5 calendar days of the Investigator’s first knowledge of the SAE.
The AE form in the eCRF must be signed within 7 calendar days from the date the information 
was entered in the eCRF.
!
Non-serious AE fulfilling the MESI criteria: The AE form and safety information form within 
14 calendar days of the Investigator’s first knowledge of the event.
!
safety information form on the paper CRFs within 5 calendar days
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
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EudraCT No.:2011-001033-16
Page:
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The paper safety information form must be forwarded to NovoNordisk either by fax, email or 
courier.
Contact details (fax, telephone, e-mail and address) are provided in the Investigators trial file.
Figure 12–1
Reporting of trial product-related SUSARs by the sponsor:
For US the Investigator, and for all other countries Novo Nordisk, must inform the regulatory 
authorities and IECs/IRBs in accordance with the local requirements in force and ICH  GCP8.
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 any trial related SAEs that may warrant a change of any trial procedure.
Investigators will be notified of trial-related SAEs in accordance with the local requirements in 
force and ICH GCP8. In Japan, Novo Nordisk must inform the health authorities and the relevant 
parties of SAE information in accordance with the Japanese requirements in force and ICH GCP.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and GCP, unless 
locally this is an obligation of the Investigator.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
18 of 23
2.33
12.2.2.  Follow-up of Adverse Events
During and following a patient’s participation in a clinical trial, the Investigator should ensure that 
adequate medical care is provided to the patient for any AE, including clinically significant 
laboratory values related to the trial. The Investigator should inform the patient when medical care 
is needed for AE(s) of which the Investigator becomes aware.
The follow up information should only include new (updated and/or additional) information that 
reflects the situation at the time of the Investigator’s signature.
The Investigator must record follow-up information updating the forms in the eCRF, and/or as 
corrections to the original paper CRF or by using a new paper form marked as follow-up.
Follow up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs, MESIs and other events for expedited reporting must be followed until the 
outcome of the event is “recovered/resolved”, “recovered/resolved with sequelae” or “fatal”, 
and until all queries have been resolved. Cases of chronic conditions, cancer or AEs on-going at
time of death (where death is due to another AE) can may be closed with the outcome
“recoveredrecovering/resolving” or “not recovered/not resolved”. Cases can be closed with the
outcome of “recovering/resolving” when the patient has completed the trial follow-up period
and is expected by the Investigator to recover.
The SAE follow-up information should only include new (e.g. corrections, or additional)
information should must be reported within 24 hours of obtaining knowledgethe Investigator’s 
first knowledge of the information for SAEs. This is also the case for previously non-serious 
AEs which subsequently become SAEs.
!
Non-serious AEs: AllNon-serious AEs classified as severe or possibly/probably related to the 
trial product must be followed until the patient has outcome of the event is
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions or cancer or AEs on-going 
at time of death (where death is due to another AE) can may be closed with an outcome of 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with an outcome of 
“recovering/resolving” when the patient 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 on-going at time of death (i.e. patient dies from another AE) can be closed with an outcome of 
“recovering” or “not recovered”. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
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!
Non-serious AE fulfilling the MESI criteria: Follow-up information on MESIs should only 
include new (e.g. corrections or additional) information and must be reported within 14 
calendar days of the Investigator’s first knowledge of the information. This is also the case for 
previously reported non-serious AEs which subsequently fulfil the MESI criteria.
The Investigator must 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.
The Investigator must ensure that the worst case severity and seriousness of an event is kept 
consistentthroughout the trial. A worsening of an unresolved AE must be reported as follow up with 
re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days 
from the date of receipt of the request, unless otherwise specified in the follow-up request. The 
Investigator must forward follow-up information on SAEs, MESIs and other events for expedited 
reporting 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.
2.34
12.3.1  Collection and Reporting of Technical Complaints
---
The patient must be asked about technical complaints during each contact (visit or telephone) with 
the Investigator or trial site staff. This may be done by posing a simple question such as “have you 
experienced any problems since the last contact?”.
---
The AE(s), SAE(s), MESI(s) and/or other events for expedited reporting related to technical 
complaint(s) must be reported by the Investigator following the same reporting requirements and 
timelines as for other AEs, SAEs, MESIs and other events for expedited reporting (see section 
12.2). 
---
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
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
20 of 23
!
all other technical complaints within 5 calendar days
2.35
13.4 Analysis Results
Laboratory reports from the central, specialized and local laboratories must be signed and dated by 
the Investigator on the day of the review of the analysis results. The Potential results from the local 
laboratory should be entered in the eCRF for each patient. A signed and dated copy of Local the 
laboratory reports must be retained at the trial site.
2.36
14
Monitoring Procedures
During the course of the trial, the Monitor will visit the trial site to ensure that the protocol has been 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV and 
no later than 4 weeks after. 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, but and must not exceed 12 weeks after preventive treatment has been commenced. Prior to 
initiation of preventive treatment monitoring should be performed when a patient has been screened 
and after each treatment requiring bleed.
2.37
18.2.1  General Considerations
---
The main CTR will be conducted when at least 50 patients have completed the main phase of the 
trial (completed visit 5 or has a confirmed inhibitor). The main CTR will present data for the main 
phase, the extension phase and the combined main and extension phases of the trial. An updated 
CTR will be conducted when all patients have completed the extension phase of the trial. The 
updated CTR will also present data for the main phase, the extension phase and the combined main 
and extension phases of the trial.
2.38
18.4 Explorative Statistical Analysis for Pharmacogenetics and Biomarkers
The data from genotyping and immunogenicity assessment will be summarised using descriptive 
statistics.
2.39
19.1 Informed Consent Form for Trial Patients
---
Prior to any trial-related activity, the Investigator must give the patient and/or the patient’s LAR 
oral and written information about the trial in a form that the patient or the patient’s LAR can read 
and understand. This includes the use of impartial witness where required. In this trial the notion of 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
21 of 23
legal representative should be understood as both parents, or legal representative(s), as defined in 
Member States’ national laws, who consents on behalf of the child.
Consent: As a child is unable to provide legally binding consent, informed consent must be sought 
from the parents/ legal representative (see definition above) on the child’s behalf. The specific and 
written informed consent of the parents/legal representative must be sought prior to enrolling a child 
in the trial. Information should be given by an experienced Investigator to each parent, or the legal 
representative, on the purpose of the trial and its nature. 
The patients or the patient’s LAR must be fully informed of their rights and responsibilities while 
participating in the trial as well as possible disadvantages of being treated with the trial products.
The Investigator must ensure the patient or the patient’s LAR ample time to come to a decision
whether or not to participate in the trial.
2.40
19.4 Regulatory Authorities
Regulatory authorities will receive the clinical trial application (CTA)/clinical trial notifications 
(CTN for Japan), substantial/non-substantial protocol amendments (notifications of protocol 
amendments for Japan), reports on SAEs, and the CTR according to national requirements.
2.41
20
Premature Termination of the Trial/Trial Site
---
Two One pre-planned safety interim analysis will be performed during the trial to monitor the 
inhibitor development.
2.42
23
Responsibilities
---
Central and specialized laboratories will analyse and report all laboratory safety tests related to 
biochemistry, haematology, viral antibody assessments, FVIII activity, FVIII inhibitor antibody 
assessments and potential genotyping performed in this trial. Laboratory data from the central and 
specialized laboratories 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.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
22 of 23
2.43
25 Retention of Clinical Trial Documentation
---
The Investigator must be able to get hold of access his/her trial documents without involving Novo 
Nordisk in any way. Site-specific CRFs and other subject data (in an electronic readable format or 
as paper copies or prints) will be provided to the Investigator before access is revoked to the 
systems supplied by Novo Nordisk. These data must be retained by the trial site. If the Novo Nordisk 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the Investigator
can request a new copy. A copy of all data will be stored by Novo Nordisk.
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 Investigational Medicinal Product.
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 subjected to 
reexamination, until re-examination is completed), or 3 years after the date of premature 
termination or completion of the clinical trial.
2.44
Attachment I – Global
List of Key Staff, Relevant Departments and CRO(s)
---
Sponsor´s medical expert
Name
Address
Novo Allé 
DK-2880 Bagsvaerd
Tel:
Fax:
+45 44436740
E-mail:
International Trial Manager:
Name:
Address:
Novo Allé 
DK-2880 Bagsvaerd
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 October 2013
Novo Nordisk
Trial ID:NN7008-3809 
Version:
2.0
UTN:u1111-1119-6116
Status:
Final
EudraCT No.:2011-001033-16
Page:
23 of 23
Tel:
Fax:
+45 44436740
E-mail:
Special Laboratory
Name:
NovoNordisk Laboratory
Contact
person:
Address:
Cell and Antibody Analysis
Novo Nordisk Park G8 S.10
DK-2760 Måløv
Denmark
Tel:
E-mail:
IVRS vendor:
Name:
Program 
Manager:
Address:
Tel:
Fax:
E-mail:
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
18 February 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
1 of 4
Protocol Amendment
No 08_AT
to Protocol, final version 5.0
dated 11 Nov 2013
Trial ID: NN7008-3809
Safety and Efficacy of turoctocog alfa in Prevention and
Treatment of Bleeds in Paediatric Previously Untreated
Patients with Haemophilia A
Trial phase: 3a
Applicable to Austria
Amendment originator:
Name: 
Department: 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
18 February 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
2 of 4
Table of contents  
Page 
1 
Introduction including rationale for the protocol amendment ............................................................. 3 
2 
Changes ...................................................................................................................................................... 4 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
18 February 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
In this protocol amendment: A new site will be added. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
18 February 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
4 of 4
2
Changes
An additional site will be opened: 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
1 of 35
Protocol Amendment
no 9
to Protocol, final version 5
dated 11 November 2013
Trial ID:NN7008-3809
Safety and Efficacy of turoctocog alfa in Prevention and Treatment of Bleeds in Paediatric 
Previously Untreated Patients with Haemophilia A
Trial phase: 3a
Applicable to all countries
Amendment originator:
Haemophilia, Clinical Operations 1 
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:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
2 of 35
Table of contents   
Page
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
Overview of changes: ....................................................................................................................3
1.2
Rational for the changes: ...............................................................................................................3
2
Changes......................................................................................................................................................5
2.4
Withdrawal criteria ......................................................................................................................13
2.4.1
Authorship .................................................................................................................24
Table of figures   
Page
Figure 2–1
Trial Design ..............................................................................................................................9
Table of tables   
Page
Table 2–2
Visit Flow Chart trial extension phase..................................................................................7
Table 5–1
Guide for dosing in bleeding episodes1 ................................................................................11
Table 5–2
Overview of Treatment Regimens..........................................................................................12
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
3 of 35
1
Introduction including rationale for the protocol amendment
1.1
Overview of changes:
1. Clarified that commercially available FVIII must not be infused prior to enrolment
2. Added withdrawal criteria: Preventive treatment not initiated at age of 24 months
3. Recruitment period has been prolonged 
4. Added a new laboratory test: Lupus Anticoagulant
5. Added long term retention of remaining blood samples (Biospecimens)
6. Changed the timing of interim analysis by including inhibitor patients in the “25 patients who 
need to completed visit 4 before the interim analysis”.
7. Added a new preventive treatment frequency of twice weekly
8. Number of planned sites increased
9. Added monitoring visits every 12 weeks also before patients have been recruited at a site
10. Changed definition of disease related bleedings from being AEs to not being AEs
11. Clarification that the maximum of 2 treatment requiring bleeding episodes, before preventive 
treatment must start, must be treated with trial product (turoctocog alfa)
12. Clarified dosing for treatment of bleeds
13. Clarified publications of results
14. Clarified dosing guidelines for ITI treatment
15. Clarified timing of CD4+T cells sampling
16. Changed minor inconsistencies, ambiguities and typographical errors
Subject information/Informed consent:
17. Changed minimum mandatory safety text 
18. Changed inconsistencies. These changes are considered minor and do not affect the content of 
the SI/IC and thus will not be listed in this amendment:
!
your treatment changed to your child’s treatment
!
investigator changed to trial doctor
!
drug changed to medication
!
doctor changed to trial doctor
1.2
Rational for the changes:
1. The trial product (turoctocog alfa) will be commercially available during the conduct of this trial 
and must not be used prior to trial enrolment due to that potentially patients that are excluded 
due to inhibitor developed using turoctogoc alfa will bias the primary endpoint
2. It has previously been stated in the protocol that preventive treatment must be initiated before 
the age of 24 months. This has now been emphasised by adding this to the withdrawal criteria.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
4 of 35
3. To ensure possibility of recruiting Chinese patients as the CTA in China has been delayed 
4. To align with other PUP trials in haemophilia and to ensure better evaluation of inhibitor 
patients
5. To ensure a possibility of exploratory analysis in the future on remaining blood samples and to 
align with other PUP trials in haemophilia
6. To ensure timely interim analysis independent of number of inhibitor patients
7. The gap from once weekly to 3 times weekly infusion of preventive treatment was to big so 
sites have requested twice weekly frequency to avoid overdosing of patients
8. To ensure the number of planned recruited patients are fulfilled the number of sites are
increased
9. 12 weeks between monitoring visits even if there are no patients at site have been reintroduced 
to ensure a check of trial supplies at site and thus possibility to enrol patients
10. To align with other guardian protocols and Global Safeties current definition of disease related 
bleedings
11. Ensure no misunderstanding regarding treatment requirering bleeds must be treated with trial 
product (turoctocog alfa)
12. Sites have requested a guideline for treatment of bleeding episodes
13. Align with current procures for publication of results
14. To guide sites if dosing during ITI treatment
15. Align flow chart with text in protocol
16. Enhance quality of protocol
Subject information/Informed consent:
17. Minimum mandatory safety text has been updated
18. Enhance quality of SI/IC
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:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
5 of 35
2
Changes
1 Summary
….
Primary Endpoint:
Incidence rate of FVIII inhibitors (> ≥0.6 BU/ml) will be evaluated for the main phase of the trial 
Key Secondary Endpoints:
….
Incidence rate of FVIII inhibitors (>≥0.6 BU)
Key Inclusion Criteria:
….
!
No prior use of purified clotting factor FVIII products (previous exposure, equal to or less than 
5 ED to blood components, e.g. cryoprecipitate, fresh frozen plasma is accepted) including 
commercially available NovoEight® /Novoeight®
Trial Product
…
The dose for treatment of bleeds is decided by the Investigator but should be approximately 25-50 
IU/kg in accordance with Guidelines for the Management of Haemophilia1. The maximum total 
daily dose of turoctocog alfa for the treatment of bleeds is 200 IU/kg with a maximum dose per 
infusion of 100 IU/kg.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
6 of 35
2 Flow chart
Table 2-1 Visit Flow Chart main trial phase
Visit number
Screen.
Visit 1
Visit 2#
Visit 3
Visit 4
Visit 5
Unsche
duled 
Visit
Visit window
NA
< ≤21 
d
post 
V1
10th -
15thED
20th -25th
ED
50th -55th
ED
PATIENT RELATED INFO / 
ASSESSMENTS
Consent for  genotype test
●,b
Biospecimen consent
●,b
FVIII gGenotype test f
●b
●b
●b
Lupus Anticoagulant
●b
HE assessment
●
●
●
●
●b
Viral antibody test (if HIV, 
HBsAg and /or HCV status 
unknown)
●i ,b
●b
T cells subset: CD4+
●b,h
●b,h
●b,h
TRIAL MATERIAL
Completion session in IV/WRS
Diary card training
●
# - Visit 2 can be performed at the same day as Visit 1
a – minimum 48 hours washout period of turoctocog alfa (or blood component products at Visit 1)
b – if applicable or optional
c – mandatory to confirm clinical relevant inhibitors
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
7 of 35
d – weight only
e – Visit 1 trial card only, Visit 2-5 diary card only
f – if previous tests are not available, if allowed by local law and after consent
g – Visit 2 dispensing only
h – if HIV positive, last value of CD4+ T-cells (if available), or new cell count 
i  - if HIV, HBsAg and/or HCV status unknown
Table 2-2 presents the rolling visit schedule in the extension phase over the period of one year. It 
comes to effect after Visit 5 or after ITI inhibitor treatment.
Table 2-2
Visit Flow Chart trial extension phase
Visit type
Dispensing
Assessment 
&
Dispensing
Dispensing
Assessment
&
Dispensing
End 
of 
Trial
Unsc
h 
Visit
Visit number#
6
7
8
9
10
11
Previous visit time(w)
-8
-8
-10
-8
-8
-10
< 8
Visit window
± 1w
± 
1w
± 1w
± 1w
± 
1w
± 1w
NA
NA
ASSESSMENTS
Withdrawal Criteria
●
●
●
●
●
●
●b
Body measurements
●c
●c
●
●a
SAFETY
Lupus Anticoagulant
●b
FVIII trough level
●a
●a
●a
●a
●a
●a
●a
FVIII recovery
●a
●a
●a
●a
●a
●a
●a
Biochemistry & 
Haematology
●
●
●
●a
Haematology
●
●
●
●a
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
8 of 35
OTHER ASSESSMENTS
HE assessment
●b
●b
●b
●b
●b
●b
●b
●b
Viral antibody test (if HIV, 
HBsAg and /or HCV status 
unknown)
●
●a,b
T cells subset: CD4+
●
●b
TRIAL MATERIAL
turoctocog alfa 
administration
●a
●a
●a
●a
●a
●a
●a
Diary card dispensing 
and/or collection
●
●
●
●
●
●
●d
●b
Review of patient diary and 
entry of data in eCRF
●
●
●
●
●
●
●
●b,a
Drug dispensing and 
accountability
●
●
●
●
●
●
●e
●b,a
# - Presented numbers are for the first 12 months. Visit numbers for future years will be in consecutive order
a – optional, at discretion of  investigator
b – if applicable 
c – weight only
d – collection only
e – accountability only
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
9 of 35
Figure 2–1
Trial Design
3.2 Rationale for the Trial
…
The guardianTM 4 trial is a prospective clinical phase 3ab trial intended at demonstrating safety and 
efficacy of turoctocog alfa in PUP < 6 years of age with severe haemophilia A. 
4.2 Endpoint
…..
Primary Endpoint
1. Incidence rate of FVIII inhibitors (≥0.6 BU/ml) will be evaluated for the main phase of the trial.
………….
Safety Endpoints:
…………
!
Incidence rate of clinically relevant inhibitors defined as an inhibitor titre (≥0.6 BU/mL) 
combined with a decreased recovery (<66% of expected level) 
V
2
V5/50 
ED
turoctocog 
alfa
EoT/>100 
V
main phase
extension phase
iITI 
inhibitortreat
ment
inhibitor cohort
preventive 
treatment
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
10 of 35
!
Incidence rate of high-titre inhibitors defined as inhibitor titre ≥ 5 BU/mL.
!
Incidence rate of FVIII inhibitors (>≥0.6 BU/mL)
5.3.1 Preventive Treatment and Dose Adjustment
The preventive treatment regimens are meant to reflect the different dosing regimens applied 
globally for initial and continued treatment of PUP. The recommended dose is 15-50 IU/kg BW 
once weekly at the start of preventive treatment, but higher and more frequent doses may be 
necessary depending on the clinical situation. The regimen should then be gradually increased 
towards 20-50 IU/kg BW every second day or 20-60 IU/kg BW two or three times weekly.14
The decision to initiate preventive treatment will be made by the Investigator and the child’s parent 
or legal representative with due consideration for the child’s own wishes (if they are capable to 
express these wishes). However, the preventive treatment has to be commenced no later than when 
the patient reaches 24 months old, or after a maximum of two treatment requirering bleeding 
episodes have occurred which require treatment with turoctocog alfa (joint, muscle or severe 
bleeding episode) have occurred, whatever comes first. Should a patient be older than 24 months of 
age at enrolment, preventive treatment needs to start immediately
5.3.2 Treatment of Bleeds and dose adjustment
…….
The dose for treatment of bleeds should aim at providing a post injection level of FVIII of at least 
0.50 IU/mL or 50 IU/dL. The bleeding pattern of the individual patient, as well as low trough levels 
described above, should be considered in adjustments of the preventive dose and at the 
Investigator’s discretion. 
The individual dose is determined by the investigator, using the recommendations in the World 
Federation of Haemophilia (WFH) guidelines.10
The required dosage can be determined using the following formula
Dose (IU) = weight (kg) x desired factor level (IU/dL) x 0.5
The WFH guideline10 may be used to guide dosing. FVIII activity should not fall below the lower 
range for the given plasma activity level (in % of normal or IU/dl) until the bleeding episode is 
resolved. As the guidelines are recommendations non-compliance with them will not require 
protocol deviations. The maximum dose per injection mentioned in this protocol must though be 
followed.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
11 of 35
Table 5-1
Guide for dosing in bleeding episodes1
Degree of 
haemorrhage
FVIII level required 
(%) (IU/dl)
Frequency of doses 
(hours)/ Duration of 
therapy (days)
Early 
haemarthrosis, 
muscle bleeding or 
oral bleeding
20-40
Repeat every 12 to 24 
hours until the 
bleeding episode as 
indicated by pain is 
resolved or healing 
achieved
More extensive 
haemarthrosis, 
muscle bleeding or 
haematoma
30-60
Repeat injection every 
12 to 24 hours for 3-4 
days or more until 
pain and acute 
disability are resolved
Life-threatening 
haemorrhages
60-100
Repeat injection every 
8 to 24 hours until 
threat is resolved
X1 Novo Nordisk company core data sheet for turoctocog alfa
This formula may be used to calculate resulting factor levels:
IU/dL (or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 [IU/dL]/[IU/kg]
……
Each administered dose (mL IU given, vial strength and time of day) as well as efficacy in 
treatment of bleeds will be registered in the diary and in the eCRF.
5.3.3 Treatment during surgery
……..
Doses should aim at securing haemostasis without reaching super-physiological FVIII levels.
5.3.4 Treatment of patients with inhibitors
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
12 of 35
……
An ITI protocol with high-dose or low-dose regimen can be chosen by the Investigator, depending 
on the patient's peak inhibitor titre and the titre before the start of the ITI. International consensus 
guidelines and local practice guidelines should be used when selecting optimal ITI regimen.15,16,17
……
Patients will be evaluated after 12 months of ITI inhibitor treatment, based on the level of 
inhibitors. If inhibitors are still positive after 12 months, but the decline from peak titer level is ≥ 
20%, ITI inhibitor treatment may continue for a maximum period of 24 months in total.
The dose level and dosing frequency of inhibitor treatment will be decided by the Investigator based 
on clinical evaluation and local standards, and it should be documented in the eCRF. Within this 
trial, ‘inhibitor treatment’ includes Immune Tolerance Induction (ITI) as well as smaller dose 
adjustments with low responding and/or clinical insignificant inhibitors.
If needed and decided by the Investigator, the initiation of the inhibitor treatment with turoctocog 
alfa can be delayed, but it has to start within 6 months from the time of diagnosis of inhibitor.
Inhibitor treatment with turoctocog alfa will be included in the overall count of ED.
If the inhibitor disappears (BU<0.6 BU/mL) during the inhibitor ITI treatment, the patient will 
continue in the extension phase at a time point decided by the Investigator, resuming/starting 
preventive treatment as recommended in this protocol, see Table 2–1. However, if the inhibitor 
persists after 24 months of ITI inhibitor treatment, the patient will be withdrawn from the trial.
Table 2–1
Overview of Treatment Regimens
Trial product
Dose
Treatment
Type
Total daily 
Doses, IU/kg
Frequency
Targeted level of FVIII
rFVIII 
(turoctocog 
alfa)
Preventive
Individual
15-50
Once weekly
Local practice & guidelines
rFVIII 
(turoctocog 
alfa)
Preventive
Individual
20-60
Two times 
weekly
Local practice & guidelines
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rFVIII 
(turoctocog 
alfa)
Preventive
Individual
20-60
3 times weekly Local practice & guidelines
rFVIII 
(turoctocog 
alfa)
Preventive
Individual
20-50
Once every 
second day
Local practice & guidelines
rFVIII 
(turoctocog 
alfa)
Treatment of 
bleeds
Individual
Investigator’s 
discretion **. 
See section 
max 2x100
Investigator’s 
discretion
>0.50 IU/mL
rFVIII 
(turoctocog 
alfa)
Surgery
Individual
Investigator’s 
discretion**  
max 2x100
Investigator’s 
discretion
>0.50 IU/mL*
Local practice & guidelines
rFVIII 
(turoctocog 
alfa)
Inhibitor
Individual
Investigator’s 
discretion**
Investigator’s 
discretion
NA
* Pre-surgery and during surgery treatment
** Please see section 5.3 for the maximum allowed dose
6 Trial population
6.1 Number of Patients to be studied
……
Planned number of trial sites: 
505
6.2 Inclusion Criteria
……
4. No prior use of purified clotting factor FVIII products (previous exposure, equal to or less than 5 
ED to blood components, e.g. cryoprecipitate, fresh frozen plasma, is accepted) including 
commercially available NovoEight® /Novoeight®
2.4
Withdrawal criteria
……
5. Inhibitor treatment has not been started within 6 months from the date of confirmation of positive 
FVIII inhibitor ( BU≥ 0.6 BU/mL)
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6. FVIII inhibitor titer decline from peak level is less than 20% after 12 months of inhibitor 
treatment
7. FVIII inhibitor is positive (BU ≥ 0.6 BU/mL) after 24 months of inhibitor treatment.
8. After completed inhibitor treatment (maximum 24 months), preventive treatment as described in 
the protocol is not resumed/started.
9. Preventive treatment not initiated at the patient’s age of 24 months.
6.6 Rationale for Trial Population
……
Rational for Withdrawal Criteria:
!
Criterion no. 21 is included to protect the patient's safety.
!
Criterion no. 3 2 is selected not to confound the effects of the investigational product
7 Trial schedule
Planned duration of recruitment period (FPFV-LPFV):
39 months
Planned date for FPFV:
December 2011
Planned date for LPFV:
31 DecemberMarch 2015
……
!
patients with inhibitor will be allowed to receive inhibitor ITI treatment for up to 24 months
8.1.2 Visit 1, Screening Visit
……
The assessments to be performed at Visit 1 are listed in Table 2-1
8.1.5.1 Surgery Visit
Patients undergoing surgery will continue the regular visit schedule, but additional visits may be 
performed in the peri-operative period as decided by the Investigator. Surgery visits will be 
documented as unscheduled visits.
For planned surgery patients, the following data should be collected: 
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!
Type of surgery
!
Date of surgery
!
turoctocog alfa doses and dosing schedule in relation to peri-operative period (surgery day and 
post-surgical recovery period)
!
FVIII inhibitor tests on the day of surgery and a second test in the interval 10 - 14 days post-
surgery
!
Clinical narrative of the procedure
!
Concomitant medication
!
Adverse events
!
Assessment of withdrawal criteria
8.1.5.2 Inhibitor Treatment Visit
All patients, who develop inhibitors and continue treatment with turoctocog alfa, will follow an 
alternative visit schedule prescribed by the Investigator according to local standard of practice, 
Monthly visits are recommended, at least initially, for patients who develop inhibitors.
These visits will be recorded as unscheduled visits and the following assessments should be 
performed.
!
Assessment of withdrawal criteria
!
Concomitant Medication
!
Body measurements (weight)
!
Bleeds including classification and site of bleeds
!
Adverse Events 
!
Physical examination
!
Collect and review diary
!
Diary dispensing
!
Dispensing of trial product
!
Drug accountability
!
Administration of turoctocog alfa, if applicable
!
FVIII inhibitor test
!
Performing drug accountability
8.1.6 Extension phase Visits
These are visits to be performed for patients, who have completed the main phase and after Visit 5 
continue in the extension phase. Patients, who resume preventive treatment after completed ITI 
inhibitor treatment, will also follow the visit schedule in the extension phase. The patients will be 
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called to the visits according to a rolling visit schedule, which runs over one year. There are two 
kinds of visits, Dispensing (4) and Assessment & Dispensing (2), and the aggregated planned 
number of visits over one year is 6.
8.1.7 EoT Visit
Within 8 weeks of the last scheduled visit in the extension phase the patient should be called to an 
EoT Visit. For patients, who discontinue the trial, an EoT visit should be performed within 28 days. 
Please also see Table 2-2 for your reference.
8.2.2.1 FVIII inhibitors
Detection of FVIII inhibitors will be carried out at a central laboratory using the Nijmegen modified 
Bethesda21 assay. A positive inhibitor test is defined as ≥ 0.6 Bethesda Unit (BU)/mL.
In the event of a positive inhibitor test, the patient should attend an (unscheduled) visit preferably
within a 2 weeks of the first blood sample after the result is available to take a new blood sample 
for a confirmatory inhibitor test.
!
The diagnosis of inhibitor is made if the patient has been tested positive for inhibitors ( >≥0.6 
BU/mL) at two consecutive tests (central lab), sampled preferably within 2 weeks. Inhibitors 
will be classified as low titre (≥0.6 BU/mL but <5 BU/mL), or high titre (≥5 BU/mL), and as 
clinically significant (recovery <66% of expected level, assessed at inhibitor diagnosis at the 
time of the confirmatory inhibitor test).
8.2.2.2 Non neutralising antibodies
Plasma samples for analysis of non-neutralising antibodies against FVIII will be taken at the same 
time point as for inhibitor testing. The results will be used to characterise the underlying 
immunogenicity towards FVIII. The samples will be frozen and stored and the analysis will be 
carried out by a validated antibody assay. The samples may be used for further FVIII antibody 
characterisations (e.g. isotyping, binding properties), see section 25.2
It might will not be possible to review the results of non-neutralising antibody measurements in 
relation to potential AEs because some of the results will may be available after LPLV.
Determination of non-neutralising antibodies against FVIII will be performed by Novo Nordisk A/S 
or by a laboratory appointed by Novo Nordisk A/S.
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If requested by the regulatory authorities antibody samples may be stored for a longer period until 
drug approval by Food and Drug Administration (FDA) and/or European Medicines Agency 
(EMA).
8.2.3.2 FVIII Recovery
……
Samples for FVIII recovery will be sent to the central laboratory for analysis, see Section 8.2.7.3
8.2.6.2
8.2.6 Lupus Anticoagulant
Lupus Anticoagulant will be sampled together with the confirmatory inhibitor test at an 
unscheduled visit. 
In the event that a patient has both a positive Lupus Anticoagulant and a positive confirmatory 
inhibitor test Lupus Anticoagulant must be taken at every consecutive inhibitor test thereafter until 
the inhibitor test is negative (<0.6 BU).
8.2.7.3 Central Laboratory Tests
------
For descriptions of procedures for obtaining samples/specimens, and the storage, handling and 
disposition of specimens, please refer to the Laboratory Manual, and section 25.2
8.3.1.3 Bleed Classification
Re-bleeds will be reported by the trial statistician Novo Nordisk based on the diary data. Re-bleed is 
defined as a bleed (worsening of bleeding site conditions e.g. swelling, pain) within 72 hours after 
stopping of a previous bleed at the same anatomical location.
8.4.1 Bleed Classification
At Visit 1, all patients/parents/legally authorised representative (LAR) will be asked about 
documentation of previous FVIII and Human Leucocyte Antigen (HLA) genotype tests. If not 
available or if it needs to be re-tested, based on the Investigators discretion, FVIII and HLA 
genotype testing will be offered as allowed by local law. The blood sample should be taken at Visit 
3, 4 or an unscheduled Visit. The genotype analysis is performed at the laboratory in Bonn, 
Germany.
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Investigator, parent(s) or LAR have the right to refuse to provide patient’s genotype documentation 
or to refuse genotyping. This will not prevent the patient’s continued participation in the remainder 
of the trial.
Applicable for Japan only: If documentation of the patient´s genotype already exists, the patient is 
offered to provide his data for the trial. If no previous data exists and genotyping consent is 
obtained, genotype analysis is performed at the laboratory in Bonn, Germany, using DNA isolated 
from leucocytes from the patient’s blood. No analysis will be performed concerning other genes 
than FVIII and HLA. Samples will be disposed appropriately after the test and all test results are 
kept strictly confidential.
8.4.2 Viral Antibody Information
At Visit 1 and at EoT status of the following tests viral infections are assessed.
!
HBsAg and/or anti-HCV antibodies if status is unknown or the Investigator considers there is an 
indication to test
!
HIV 1 & 2 antibodies if status is unknown or the Investigator considers there is an indication to 
test.
At Visit 1 the above tests are only mandatory in case the patient’s status is unknown or the 
Investigator considers there is an indication to test. If the patient is HIV positive the last value of 
CD4+ T-cells, and date of test, should be recorded. If not available a new cell count is required
8.4.2.1 CD4+T cells
If the patient is HIV positive at Visit 1 the most recent value in the medical records of CD4+ T-
cells, and date of test, should be recorded at either Visit 1 or Visit 2. If this is not available a new 
cell count is required.
At the EoT visit CD4+T cell count must be obtained.
8.4.4 Body measurements
Weight and height will be measured at Visits 1, 5 and EoT. For Visit 2-4 and for the Assessment &
Dispensing Visits in the extension part only weight is measured. Additional assessments can be 
performed as needed
8.4.6.2 Details of haemophilia
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Following information about the patient’s haemophilia to be obtained during the Screening Visit 
(Visit 1):
!
Diagnosis of haemophilia A (date)
!
Classification of haemophilia A and FVIII level (%)
!
Underlying gene defect (if known and patients/LAR’s consent has been obtained) 
!
History of relatives with haemophilia A (as recalled by parent/guardian) including inhibitors
8.4.7 HE and PRO data
In this trial HE and PRO data will be collected. 
The HE data include assessments of resource utilization and patient/caregiver burdens associated 
with bleeds. HE questions are available in the eCRF. The HE assessments should be completed at 
every scheduled and every inhibitor unscheduled visit in case the patient has had a bleed between 
visits. In case of a severe bleed additional HE questions should be completed.
The PRO data use a validated questionnaire to assess treatment satisfaction, Hemo-Sat. (See 
Appendix E). Hemo-Sat questionnaire is a treatment satisfaction survey for parents/caregivers (the 
P version). Dimensions measured include ease and convenience, efficacy, burden, 
specialists/nurses, centre/hospitals, general satisfaction. The HEMO-Sat questionnaire was 
originally developed in UK English and has been translated and linguistically validated into other 
languages. However it might not be available for all countries. The HEMO-Sat questionnaire is to 
be filled in at Visits 3 and 5 in the main phase, annually in the extension phase and at EoT Visit, 
preferably before any other trial related procedures.
9.3 Storage of Trial Products
……
NaClSodium chloride
……
Returned trial product(s) (used, partly used or unused vials including empty packaging material) 
must be stored separately from non-allocated trial product(s). Returned trial products can be stored 
at room temperature.
9.4 Dispensing and Drug Accountability of Trial Products
Drug accountability is the responsibility of the investigator.
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The IV/WRS will allocate a trial product DUN to the patient at each dispensing visit. The correct 
DUN must be dispensed to the patient. 
!
No trial product(s) should be dispensed to any person not enrolled in the trial (excluding 
parents/LAR).
!
Unused trial product must be stored separately from used trial product.
!
Once a patient is dosed, the vials (used, unused,returned and lost/damaged) must be recorded in 
the IV/WRS Drug Accountability module.
9.5 Trial Product Administration
The IV/WRS will report the dosing volume of turoctocog alfa to be injected based on the patient’s 
weight and dose IU/kg. 
10.3 Interactive Voice/Web Response System (IV/WRS)
A trial specific IV/WRS will be set-up, and can be accessed at any time by 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. For a minimum, the system will be used for 
enrolment of patients, dispensing allocation of trial product with sufficient expiry until the next
scheduled visit, facilitation of expiry monitoring dosing volume calculation of turoctocog alfa, 
controlling of expiry date of trial product, ordering of trial product, drug accountability and 
screening failure data and withdrawal information. An IV/WRS user manual will be provided to the 
site.
11 Concomitant Illnesses and Concomitant Medication
……
!
Treatment with FVIII concentrates other than the turoctocog alfa the trial product, see Section 
6.4.
12.1.1 Technical Complaint
……
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 and other events for expedited 
reporting
……
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!
Inhibitor formation against FVIII
!
Inhibitor formation is always considered a MESI. Blood samples for measurement of FVIII 
inhibitors will be analysed at the central laboratory selected by Novo Nordisk. However, if 
an investigator obtains any indication of inhibitor formation by clinical signs or local 
laboratory results, it should be reported as MESIs.
The diagnosis of inhibitor is made, if the patient has been tested positive for inhibitors (BU
≥0.6 BU/mL) at two consecutive tests at the central laboratory, sampled preferably within 2 
weeks. However, if the first inhibitor test is positive, it should also be reported as a MESI 
even though the confirmatory test is negative.
……
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: turoctocog alfa Investigator’s Brochure7 (insert reference)
……
!
SAE: The AE form within 24 hours and the paper safety information form within 5 calendar 
days of the Investigator’s first knowledge of the SAE.
The AE form in the eCRF must be signed by the Investigator within 7 calendar days from the 
date the information was entered in the eCRF. The AE form must be signed regardless of how 
complete it is. If the AE form is updated after it has been signed it must be signed again by the 
principal Investigator. 
12.2.1 Disease related Bleeding
Disease related bBleeds and other symptoms (e.g. pain, swelling, synovitis, arthralgia, injection site 
haematoma) in connection to bleeds that are evaluated by the Investigator as part of the underlying 
disease should not be reported as are AEs or SAEs unless . However, they should only be reported 
as AEs if evaluated as related to trial product or trial procedure by the Investigator. Furthermore 
However, fatal or life-threatening SAEs bleeds must be reported as a SAE regardless of relatedness. 
All bleeds and other symptoms related to the underlying disease will be captured in the eCRF and 
diary.
12.5.2 Rules for putting the enrolment on hold
There is one pre-planned safety interim analysis. At this interim all patients exposed at the pre-
defined time points determined by number of patients exposed will be evaluated for inhibitor 
development.
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!
Safety interim: After the first 25 patients either have been to Visit 4 (20-25 exposure days) or 
have developed inhibitors before visit 4
……
The diagnosis of inhibitor is made if the patient has been tested positive for inhibitors (BU ≥0.6 
BU/mL) at two consecutive tests at central laboratory, sampled preferably within 2 weeks.
13.4 Analysis Results
……
Laboratory reports from the central laboratory will be provided to the Investigator except the two-
stage chromogenic assay.
14 Monitoring Procedure
During the course of the trial, the Monitor will visit the trial site to ensure that the protocol has been 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first A monitoring visit must will be performed as soon as possible after 
screening of a patient FPFV and no later than 4 weeks after. 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, and must not exceed 12 weeks. after preventive treatment 
has been commenced. Prior to initiation of preventive treatment monitoring should be performed 
when a patient has been screened and after each treatment requiring bleed.
18.2.2 Primary Endpoint(s)
Incidence rate of inhibitors defined as inhibitor titres ≥ 0.6 BUethesda units/mL for the main phase 
of the trial
18.2.4 Supportive Secondary Endpoints
…….
Incidence rate of inhibitors defined as inhibitor titres ≥ 0.6 Bethesda units BU/mL for the extension 
part of trial and the combined main and extension phases of the trial.
……
!
Incidence rate of high-titre inhibitors defined as inhibitor titre ≥ 5 Bethesda units BU/mL
……
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!
Incidence rate of clinically relevant inhibitors defined as an inhibitor titre (≥ 0.6 BU/mL) 
combined with a decreased recovery (<66% of expected level)
The incidence rate of clinically relevant inhibitors will be calculated and a 1-sided 97.5% upper 
confidence limit will be provided based on an exact calculation for a binomial distribution 
Furthermore, the time to inhibitor development and clinically relevant inhibitor development will 
be presented by a Kaplan Meyer plot.
18.3 Sequential Safety Analysis/Safety Monitoring
!
Safety interim: After the first 25 patients either have been to Visit 4 (20-25 exposure days) or 
have developed inhibitors before visit 4
18.4 Explorative Statistical Analysis for Pharmacogenetics and 
Biomarkers
The data from genotyping and immunogenicity non-neutralising antibody assessment will be 
summarised using descriptive statistics.
19.1 Informed Consent Form for Trial Patients
……
FVIII Genotype Testing
A collection of samples for genotype testing is offered to the patients participating in this trial. Prior 
to any trial-related activity, the Investigator must provide the patient and/or the patient’s LAR the 
possibility to abstain from the genetic testing but still be able to participate in the trial.
Retention of blood samples
The patients parents are requested to give consent to retain the remaining blood samples after the 
primary analysis mentioned in this protocol for later exploratory analysis, see section 25.2 The 
Investigator must provide the patient and/or the patient’s LAR the possibility to abstain from the 
retention of blood samples but still be able to participate in the trial.
24.1 Communication and Publications of results
No permission to publish shall be granted to any clinical research organisation involved in the 
trial.
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 
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scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure.
Novo Nordisk reserves the right to not defer the release of data until specified milestones are 
reached,e.g. for example. when the clinical trial report is available. This includes the right to not to
release the results of interim results of clinical trials analyses, because the release of such 
information can invalidate may influence the results of the entire trial.
At the end of the trial, one or more manuscripts scientific publications will may be prepared 
collaboratively between by the Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right 
to postpone publication and/or communication for less than up to 60 days to protect intellectual 
property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of 
any disagreement on the content of any publication, both the investigators’ and Novo Nordisk 
opinions will be fairly and sufficiently represented in the publication.
Where required by the journal, the principal investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
24.1.1Authorship
Authorship of publications should be in accordance with guidelines from the Uniform 
Requirements of Tthe International Committee of Medical Journal Editors’ Uniform Requirements 
(sometimes referred to as the Vancouver Criteria)27
Notwithstanding anything to the contrary in this protocol. Novo Nordisk acknowledges the 
Investigators’ right to publish the entire results of the trial. Any such scientific paper, presentation, 
communication or other information concerning the investigation described in this protocol, must 
be submitted in writing to the Novo Nordisk International Trial Manager prior to submission for 
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publication/presentation for comments. Comments will be given within four weeks from receipt of 
the manuscript.
24.1.2 Publications
The results of this trial will be subject to public disclosure at external web sites according to 
international regulations, which is reflected in Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure.
In all cases, the trial results shall be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations of the trial. All authors will be given the 
relevant statistical tables, figures, and reports needed to support the planned publication. In the 
event of any disagreement about the content of any publication, both the Investigators’ and Novo 
Nordisk’s opinions shall be fairly and sufficiently represented in the publication.
In a multi-centre trial based on the collaboration of all trial sites, any publication of results must 
acknowledge all trial sites.
Novo Nordisk maintains the right to be informed of any Investigator plans for publication and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
the Novo Nordisk Trial Manager prior to submission for comments. Comments will be given within 
four weeks from receipt of the planned communication
24.1.2 Site-Specific Publication(s) by Investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations, and frequently do not provide meaningful information for healthcare professionals or 
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 Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy.
Submission for publication of such primary policy will take place no later than 18 months after trial 
completion. and to ask for deferment of publication of individual site results until after the primary 
manuscript is accepted for publication.
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25 Retention of Clinical Trial Documentation and Human 
Biospecimens
25.1Retention 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. The 
deletion process must ensure confidentiality of data and must be done in accordance with local 
regulatory requirements. For Japan, the files from the Investigator/institution must be retained 
longer in accordance with national regulations.
25.2 Retention of blood samples
Storage and disposition of blood samples analysed at local laboratories will be performed 
according to local laboratory procedures. 
Remaining blood not used for the primary analysis mentioned in this protocol will be stored for 
future exploratory analysis until the trial has been evaluated by appropriate authorities or the 
project terminates or until the exploratory analysis has been performed, but no longer than 15 
years from the end of the trial. As new biomarkers related to the disease and/or safety, efficacy, or 
mechanism of action of turoctocog alfa may evolve during the conduct of the trial, the analyses of 
the stored blood samples may also include biomarkers that are unknown at present or have not 
been included in the scientific hypotheses at initiation of the trial. 
Parents will be requested to consent to the long-time retention and exploratory analysis of blood 
samples, see section 19.1
The samples will be stored at Novo Nordisk or a Novo Nordisk designated referral bio-repository 
with access to the samples. Samples might be transferred to other countries, if not prohibited by 
local regulations. The patient’s identity will remain confidential and samples will only be marked 
and identified by a unique sample ID. No direct identification of the patient will be stored together 
with the samples. The analyses will not have any medical consequences for the patients or their 
relatives. Only Novo Nordisk staff and bio-repository personnel (if applicable) will have access to
the stored bio specimens. 
In the event that the collected blood samples will be used in the future, the investigator will become 
directly informed by Novo Nordisk about the results if the findings are deemed clinically and 
analytically valid and quantifiable. In such case, a written summary of the findings, including 
listings of subject specific values, will be provided once a firm conclusion from the results has been 
drawn by Novo Nordisk. Potentially, observations of neoplastic diseases, serious genetically 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
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hereditary diseases, other un-treatable diseases, or any other abnormal findings could be part of 
the observations. Subjects 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.
Subject information/Informed consent
1 Information about the trial and the trial product
The purpose of this trial is to collect information about a blood clotting factor (FVIII) medication 
called turoctocog alfa, hereafter also called trial medication. Turoctocog alfa is produced by Novo 
Nordisk A/S (using genetic recombinant methods without use of any animal products) for use in 
people with haemophilia A. The trial is focused on evaluating the safety of turoctocog alfa in young 
children who have not been treated with FVIII products previously. The effect of the trial 
medication for prevention and treatment of bleeds will also be assessed.
Treatment
In this trial, your child will receive preventive treatment with turoctocog alfa. It should be given 
once weekly, twice or three times weekly or every second day, according to your child´s doctor’s 
advice. The treatment could begin before your child suffers a bleed or alternatively after the first 
one or two second bleeds that requires treatment with turoctocog alfa, whichever is according to the 
usual practice at your child’s treatment centre. However, the preventive treatment has to start once 
your child has reached the age of 2 years (24 months). The trial medication is administered by 
injection in a vein. Most of the injections will be performed at home by the parents, supported by 
the haemophilia centre. Your child´s doctor will instruct you how to manage the administration, and 
you and your child will receive a set of written instructions that you can take home.
Please be aware that you must handle store the trial medication according to the information on the 
label.
If your child experiences a bleed during this trial you should always call the trial hospital within 24 
hours. All bleeding episodes can be treated at home but in case of a severe bleed, you might be 
advised by your child´s doctor to visit the trial hospital. Your child´s doctor will explain how you 
can tell which bleeds are considered mild, moderate and severe in this trial. All treatment requiring 
bleeds during this trial will be treated with turoctocog alfa.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
28 of 35
Your consent to allow the genotype information to be recorded, or to perform the genotype testing, 
will be done on a separate form, the addendum 1. 
The following will take place during visit 3 and 4
At these visits your child’s weight will be measured and if applicable necessary the doctor will 
administer an injection of the trial drug medication.
The following will take place at Visit 5
Your child’s weight will be measured and if applicable necessary the doctor will administer an 
injection of the trial drug medication.
Extension phase visits
In the extension phase six annual visits are planned and the interval between visits range from 8-10 
weeks. Your child’s weight will be measured and if applicable necessary the doctor will administer 
an injection of the trial medication drug.
Unscheduled visits
Your child´s doctor or you might decide that your child needs to attend the haemophilia clinic for 
medical reasons for additional visits, which are not scheduled in advance
2 Risks and benefits
What are the possible risks if we participate in this trial?
The medicine that is being tested in this trial, turoctocog alfa, a recombinant Factor VIII (rFVIII), is 
an experimental medication drug in this setting. There may be potential side effects of the trial 
medication, and it is important that you consider all the options before you and your child decide to 
participate in this trial.
Based on data from more than 200 patients exposed to turoctocog alfa during completed clinical 
trials, approximately 9 % of the patients have reported adverse drug reactions. The most frequently 
reported adverse reactions were elevated hepatic enzymes and injection site reactions. Less 
frequent adverse reactions included insomnia, headache, dizziness, increased blood pressure, rash, 
stiffness and pain in muscles, pain in legs and arms, bruising, joint disease, swelling of legs and 
feet, fatigue, feeling hot, and fever.
2.1.1 Inhibitor development
There is a risk of development of antibodies against FVIII that could decrease the effectiveness of 
the treatment with turoctocog alfa and future treatments with products containing FVIII. In patients 
not previously treated with any FVIII product the risk for development of antibodies is 
approximately 30% while the risk is approximately 2% in patients previously treated with a FVIII 
product (>150 exposure days). 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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2.1.2 Allergic/hypersensitivity reactions
An allergic response to turoctocog alfa could develop. As turoctocog alfa is produced in a hamster 
ovary cell line patients with a known allergy to hamster protein should not be treated with 
turoctocog alfa. If you experience early signs of an allergic reaction such as hives, rashes, itching, 
tightness of chest, generalised urticaria (a pale red, itchy, raised skin rash on larger parts of the 
body), wheezing or sudden weakness please let your child’s trial doctor know immediately.
2.1.3 Other inconveniences
In order to take blood samples, your child’s trial doctor will need to draw blood from your child’s 
vessels. You may feel a little discomfort, bruising, bleeding or swelling at the place of the needle. 
There is also a slight risk of infection at the place where the needle goes into your child’s vein.
In the trial a maximum of 40 mL blood will be taken for laboratory testing. If your child develops 
inhibitors then the trial doctor will decide how often you should visit the clinic. In this event, the 
amount of trial related blood samplings will increase but the total volume of blood collected will 
not exceed 65 mL
Your child’s trial doctor will monitor you closely regarding possible side effects. Please inform 
him/her about all unexpected medical events and about any indispositions, even though you think 
that there is no causal relation with the trial medication. As with all medications, unforeseen risks 
may occur. You should not hesitate to report any side effects or health-related problems you may 
experience or report any questions you may have.
If information becomes available which might affect your willingness to participate you will be 
informed about this by your child’s trial doctor.
The blood samples taken during the trial may cause a little discomfort, bruising, bleeding or 
swelling at the sampling site. There is also a slight risk of infection. Since this trial involves 
children the volume of blood drawn during the trial follow the European regulatory guidelines 
(Directive 2001/20/EC) or the local guideline in your country. The blood volume collected from 
your child for all tests in the trial will not exceed 40 mL if your child follows the regular visit 
schedule. If your child develops inhibitors then the doctor decide how often you should visit the 
clinic. In this event, the amount of trial related blood samplings will increase but the total volume of 
blood collected should not exceed 65 mL.
Your child´s doctor will monitor your child closely regarding possible adverse events. Please 
inform him/her about all unexpected signs and symptoms, even if you think that there is no 
connection with the trial medication. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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The most frequently reported adverse events are expected to include headache, nasopharyngitis, 
upper respiratory tract infection, arthralgia and fever. Less frequent adverse events may include 
cough, abdominal pain, oropharyngeal pain, inhibitor development and allergic reactions. 
As mentioned above, there is a risk of developing inhibitors (neutralising antibodies) against FVIII 
that could decrease the effectiveness of future treatments with medications containing FVIII. 
However, this risk is not expected to be greater than with other FVIII medications. 
Allergic response to turoctocog alfa could develop as rFVIII is produced in a hamster ovary cell 
line. Patients with a known allergy to hamster protein should not receive turoctocog alfa. If your 
child experience early signs of an allergic reaction such as hives, rashes, itching, tightness of chest, 
generalised urticaria, wheezing or sudden weakness please let your doctor know immediately.
It is also possible that turoctocog alfa may not prevent your child’s tendency to bleed or effectively 
stop the bleeding. This risk is also not expected to be greater than with other FVIII medications.
As required by the regulatory authorities, experimental studies with turoctocog alfa in animals have 
been completed and did not indicate any unexpected risks for humans. 
Two previous trials with turoctocog alfa involving more than 200 haemophilia A patients, whereof 
about 30 children under the age of 6 years, have been completed without any safety concerns and 
without any inhibitor formation. If information becomes available which might affect your 
willingness to participate you will be informed about this by your trial doctor.
……
If your child develops inhibitors during the course of the trial, payment for medical care related to 
the inhibitors will be limited to continued treatment with the trial medication for a maximum of 24 
months
3 Data privacy
Will our participation in this trial be kept confidential?
……
At novonordisk-trials.com you will be able to find an anonymised version of the clinical trial report, 
where you can find descriptions of all main results and conclusions of the trial. This report will be 
available 6 months after the last patient has attended the last visit in the trial.
Any information transferred electronically will be coded to protect your child’s confidentiality. 
Laboratory samples will be destroyed after analysis/trial completion. The remaining of your child’s 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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laboratory samples may be stored for a longer periode for future analyses not currenlty defined. A 
request for your consent to perform this will be requested in addedum 2. If you do not consent to 
this it will not have any consequences for your child’s future involvement in the trial. The reason for 
these future analysis is that they may benefit the understanding of haemophilia, and thereby in the 
future may benefit treatments for the disease 
Trial documentation will be kept and securely archived for at least 15 years. 
If you consent to participate in this trial in an EU country, please note that coded information from 
this trial may be archived or transferred outside of the EU for data processing and analysis 
purposes. 
You and your child will be informed of any plans for new analyses on retained identifiable material 
that were not foreseen at time of consent and that a new consent will be asked for. You will have 
the right to refuse further analyses.
4 The consent procedure
……
!
Have the time and willingness to attend the clinic according to the  visit schedule plus any 
additional visits if necessary visits required on-demand (unscheduled visits)
……
!
Visit the clinic in case of severe bleeds if the trial doctor evaluates this as it is necessary
How do I agree to participate in this trial?
……
You do not have to participate in this trial to obtain treatment for your child’s condition.
6 Signature Page
……
Subject, if applicable
……
Subject's Legally Acceptable Representative, if applicable
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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Addendum 1 – Genotyping
……
Your child’s data will be kept confidential and nobody besides the trial doctor, and clinic staff and 
Novo Nordisk staff quality checking the data will know his identity and  or have access to the result 
of the genotyping test. 
Addendum 2: Future blood analysis and long term storage of blood 
samples 
In addition to this trial we would like to ask you to consider if we may perform future analysis not 
currently defined on your child’s remaining blood after the primary analysis mentioned in this 
informed consent and if we may store these samples up to 15 years after this trial is finalised.
Your child will not have additional blood samples performed due to this consent.
What is the procedure?
These blood samples will be used to explore any additional test that may be of interest that we 
currently cannot foresee. 
Your child’s data will be kept confidential and nobody besides the trial doctor and clinic staff will 
know your child’s identity or have access to the result of these future tests.
Your child’s trial doctor will only receive these results if they show any new information in regards 
to your child’s illness or any other new illness and Novo Nordisk can come into contact with your 
child’s trial doctor. It may though take up to several years before these tests are performed and 
your child’s trial doctor receives any results.
In the event that these long term stored blood samples will be used in the future, the trial doctor will 
become directly informed by Novo Nordisk about the results if the findings are evaluated to be 
correct. Potentially, any other abnormal findings could be part of the observations. You may at any 
time contact your child’s trial doctor if you wish to be informed about these results.
Can I say no to this?
Yes, this is entirely voluntary and it is up to you to decide if this is something you would like to have 
done or not. If you decide not to have this performed, your child can continue in the trial as planned 
and the laboratory samples will be destroyed at trial completion.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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Is there anything else I need to know?
Should you regret this consent, you just need to say this to the trial doctor and he/she will ensure 
that the samples are destroyed after the trial is finalised, unless the tests already have been 
performed. 
All information regarding conditions for participating in a clinical trial explained to you in the 
patient information sheet for this trial are also valid for this part.
Informed Consent – Signature page for future analysis and long term storage of blood samples
Title of trial: Safety and Efficacy of turoctocog alfa in Prevention and Treatment of Bleeds in 
Paediatric Previously Untreated Patients with Haemophilia A.
I hereby confirm that I have been given oral and written information about the above mentioned 
long term storage and future analysis of my child’s remaining blood samples and that I have 
received a copy of this information. I have had enough time to consider my participation in this part 
of the trial. I have had the possibility to ask all questions I have about the long term retention of my 
child’s blood samples and analysis of these, and they have been answered to my satisfaction. I know 
the long term retention of my child’s blood samples and future analysis of these is completely 
voluntary and I can at any time withdraw my consent without it having any consequence for my 
child’s future treatment or participation in the trial.
I know that the above mentioned data are collected and kept confidential, and my data may be 
transferred securely to other countries for analyses. Representatives from Novo Nordisk A/S and the 
IEC/IRB and international regulatory authorities will have access to my data to oversee the trial 
conduct.
I will receive a copy of this information signed and dated
Person who conducted the information discussion:
(If the information discussion about the trial was conducted by a person other than the trial doctor 
then this signature/date is required)
Date:
Time:
Signature:
(hh:mm)
Name (print):
Subject, if applicable:
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
34 of 35
Date:
Time:
Signature:
(hh:mm)
Name (print):
Trial doctor or appropriately medically qualified designee seeking the informed consent:
(If the information discussion about the trial was conducted by the trial doctor or an appropriately 
medically qualified person delegated by the trial doctor ONLY this signature/date is required)
Date:
Time:
Signature:
(hh:mm)
Name (print):
Subject's Legally Acceptable Representative:
Date:
Time:
Signature:
(hh:mm)
Name (print):
Relationship to Subject:
Impartial Witness, if applicable:
Date:
Time:
Signature:
(hh:mm)
Name (print):
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
19 June 2014
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
35 of 35
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
1 of 19
Protocol Amendment
no 10
to Protocol, final version 6.0
dated 12 June 2014
Trial ID: NN7008-3809
Safety and Efficacy of turoctocog alfa in Prevention and Treatment of Bleeds in Paediatric
Previously Untreated Patients with Haemophilia A
Trial phase: 3a
Applicable to all countries
Amendment originator:
Haemophilia, Clinical Operations 1
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:
07 December 2015
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
2 of 19
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................7
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
3 of 19
1
Introduction including rationale for the protocol amendment
The  main reason for amending the protocol is to update the trial timelines to reflect an extension in 
the recruitment period. In addition other changes have also been applied with the purpose of 
clarifying the protocol and correcting minor inconsistencies, ambiguities and typographical errors. 
The list of changes and the related rationales is provided in section 1.1 and 1.2.
1.1
Overview of changes
1. Deleted appendix A (Table of contents)
2. Added items in list of abbreviations. (List of abbreviations)
3. Deleted sentence in the Summary stating that initial infusions of trial product should be done 
at investigational site. (Summary)
4. Clarified and corrected footnotes in visit flow charts. (Section 2)
5. Clarified in the visit flow chart for the extension trial phase that genotype can be tested at 
unscheduled visits. (Section 2)
6. Added visit flow chart table describing which assessments to be done at the unscheduled 
visit for inhibitor confirmation, and at the inhibitor unscheduled visit(s). (Section 2)
7. Clarified that eligible patients can receive first dose at Visit 2. (Section 5.1)
8. Changed the maximum duration of treatment of a patient from first to last turoctocog alfa 
administration.(Section 5.3)
9. Clarified how patients can be treated with turoctocog alfa. (Sections 5.3 and 9.5)
10. Clarified in section 5.3.2 that all treatments administered in relation to bleeds must be 
recorded as ‘treatment of bleeds’.
11. Updated trial timelines. (Section 7)
12. Clarified that the main purpose of Visit 2 is to enrol eligible patients, to dispense the trial 
product and to administer turoctocog alfa for the first time, if applicable. (Section 8.1.3)
13. Added that patients with inhibitors must attend inhibitor unscheduled visit at least every 
third month. (Section 8.1.5.2)
14. Clarified in the list of assessments to be performed at inhibitor unscheduled visit, that Lupus 
anticoagulant and FVIII Non-neutralising antibodies should be performed. (Section 8.1.5.2)
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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15. Clarified that the minimum 48 hours washout period of turoctocog alfa does not apply for 
inhibitor patients on ITI treatment. (Section 8.2.2.1)
16. Added that ‘used’ vials should be recorded in the IV/WRS Drug Accountability module.
(Section 9.4)
17. Added that treatment with blood and blood component products containing FVIII, e.g. 
cryoprecipitate and plasma except during surgery should be avoided during the course of the 
trial. (Section 11)
18. Deleted MESI reporting timelines in section 12.1.2 Medical Event of Special Interest and 
other events for expedited reporting. (Section 12.1.2)
19. Changed minor inconsistencies, ambiguities and typographical errors.
Subject information/Informed consent:
No changes to the Subject information/Informed consent.
1.2
Rational for changes
1. Appendix is not required to be included in the protocol and has therefore been deleted.
2. Description of two abbreviations were missing.
3. The sentence was inserted in error and the deletion is in accordance with the Protocol.
4. To ensure alignment with the Methods and Assessments section of the Protocol.
5. To ensure alignment with the Methods and Assessments section of the Protocol.
6. To make it clear how to conduct Unscheduled Visit with inhibitor confirmation and 
Inhibitor Unscheduled Visit.
7. To make it clear that patients will not necessarily be administered the first dose at Visit 2. 
The first dose may be administered at a later time point.
8. To reflect the expected maximum treatment duration.
9. To clarify that patients can be treated at non-investigational site in addition to treatment at 
investigational site and at home. Furthermore the section describing that investigator needs 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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to  instruct patients/parents/caregivers/support persons in how to handle administration of 
turoctocog alfa has been moved from Section 9.5 Trial Product Administration to Section 
5.3 Treatment of Patients.
10. To ensure that all treatments of turoctocog alfa administered in relation to bleeds are 
reported as ‘treatment of bleeds’. This ensures consistent reporting of the treatment of 
bleeds.
11. Timelines have been revised to reflect an extension of the recruitment period.
12. To detail that the main purpose of Visit 2 is to enrol eligible patients and to dispense trial 
product in addition to administer trial product for the first time, if applicable.
13. To ensure that patients with inhibitors attends inhibitor unscheduled visits with a frequency 
that allows close follow up on safety and efficacy status and on the inhibitor status.
14. To clarify that Lupus anticoagulant and FVIII non-neutralising antibodies should be 
performed at inhibitor unscheduled visit. This is in accordance with the visit flow chart and 
with the description of the two assessments Lupus anticoagulant and FVIII non-neutralising 
antibodies.
15. The 48 hours washout period is not applicable for patients on ITI treatment,  where the 
treatment regimen require daily administration of turoctocog alfa.
16. All vials; used, unused and lost should be recorded in the IV/WRS Drug Accountability 
module. The word ‘used’ was by error deleted in the former version of the protocol.
17. To avoid the use of blood and blood component products containing FVIII as these 
treatments may confound the effects of the investigational product.
18. MESI reporting timelines were not correctly defined in section 12.1.2. The correct MESI 
reporting timelines are defined in section 12.2 Collection, Recording and Reporting of 
Adverse Events.
19. To enhance the quality of the Protocol.
Subject information/Informed consent:
Not applicable.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
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Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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2
Changes
Table of Contents
…
Appendix A
Agreement on Final Protocol
Appendix B
Whole Blood Volume Rules in the Paediatric Population, Version 6.0
dated 12 June 2014
Appendix C
Anaphylaxis, Version 6.0 dated 12 June 2014
Appendix E
Patient Reported Outcome Questionnaire, Version 6.0 dated 12 June
2014
…
List of abbreviations
…
NB
nota bene (take notice)
PUP
previously untreated patients
1 Summary
…
Trial Product
…
The initial infusions will be administered at the investigational site, but after adequate instruction 
and practice the goal is to implement home treatment with intravenous (i.v.) injections given by the 
parent or a support person. Turoctocog alfa will be supplied as freeze dried powder to be 
reconstituted with a sterile sodium chloride solution for injection.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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2 Flow Chart
Table 2-1 Visit Flow Chart main trial phase
Visit number
Screen.
Visit 1
Visit 2#
Visit 3
Visit 4
Visit 5
Unsche
duled 
Visit
Visit window
NA
≤ 21 d
post V1
10th -15thED
20th -25th ED
50th -55th ED
PATIENT RELATED INFO / 
ASSESSMENTS
Informed consent
●
Inclusion/Exclusion Criteria
●
●
Consent for  genotype test
●b
Biospecimen consent
●b
Withdrawal Criteria
●
●
●
●
●b
Haemophilia treatment history
●
Concomitant illnesses / Medical history
●
Concomitant medication
●
●
●
●
●
●b
Demography
●
Body measurements
●
●d
●d
●d
●
●ba,d
Genotype test f
●b, f
●b, f
●b, f
Details of haemophilia
●
EFFICACY
Bleed(s)
●
●
●
●
●b
SAFETY
Adverse events
●
●
●
●
●
●b
Physical examination
●
●
●
●
●
●ba
Vital signs
●
●
FVIII activity
●ac
Antibodies
- FVIII inhibitors
- FVIII non-neutralising antibodies
●ac
●ac
●ac
●ac
●a, c, b
Lupus Anticoagulant
●b
FVIII trough level
●ab
●ab
●ab
●ab
FVIII recovery
●ab
●ab
●ab
●ab
●a b, c
Biochemistry
●
●
●a
Haematology
●
●
●a
OTHER ASSESSMENTS
PRO questionnaire
●
●
HE assessment
●b
●b
●b
●b
●b
Viral antibody test 
●i
●ab
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
Novo Nordisk
Trial ID: NN7008-3809
Version:
2.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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Visit number
Screen.
Visit 1
Visit 2#
Visit 3
Visit 4
Visit 5
Unsche
duled 
Visit
Visit window
NA
≤ 21 d
post V1
10th -15thED
20th -25th ED
50th -55th ED
T cells subset: CD4+
●b, h
●b, h
●b, h
TRIAL MATERIAL
turoctocog alfa administration
●ab
●a b
●a b
●ab
●ab
Home treatment training
●
Diary and or Trial card dispensing and/or 
collection e
●e
●e
●e
●e
●e
●b, e
Review of patient diary and entry of data 
in eCRF
●
●
●
●b
Enrolment session in IV/WRS
●
Drug dispensing and accountability
●g
●
●
●
●b
Diary  training
●
# - Visit 2 can be performed at the same day as Visit 1
a – minimum 48 hours washout period of turoctocog alfa (or blood component products at Visit 1).
a – optional, at discretion of Investigator
b – if applicable or optional
c – mandatory to confirm clinical relevant inhibitorscd
c – Minimum 48 hours washout period of turoctocog alfa (or blood component products at Visit 1). Not a requirement 
for patients on ITI treatment.
d – weight only
e – Visit 1 trial card only, Visit 2-5 diary only
f – if previous tests are not available, if allowed by local law and after consent
g – Visit 2 dispensing only
h – if HIV positive, last value of CD4+ T-cells (if available), or new cell count 
i  - if HIV, HBsAg and/or HCV status unknown
Table 2-2 presents the rolling visit schedule in the extension phase over the period of one year. It 
comes to effect after Visit 5 or after inhibitor treatment.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
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Trial ID: NN7008-3809
Version:
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UTN: U1111-1119-6116
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EudraCT No.: 2011-001033-16
Page:
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Table 2-2 Visit Flow Chart trial extension phase
Visit type
Dispensing
Assessment 
&
Dispensing
Dispensing
Assessment
&
Dispensing
End 
of 
Trial
Unsch 
Visit
Visit number#
6
7
8
9
10
11
Previous visit time(w)
-8
-8
-10
-8
-8
-10
< 8
Visit window
± 1w
± 1w
± 1w
± 1w
± 1w
± 1w
NA
NA
ASSESSMENTS
Withdrawal Criteria
●
●
●
●
●
●
●b
Concomitant medication
●
●
●
●
●
●
●
●b
Body measurements
●c
●c
●
●a, c
Genotype
●b
EFFICACY
Bleed(s)
●b
●b
●b
●b
●b
●b
●b
●b
SAFETY
Adverse events
●
●
●
●
●
●
●
●b
Physical examination
●a
●a
●
Vital signs
●a
●a
●
Antibodiesf
- FVIII inhibitors
- FVIII non-neutralising antibodies
●a, f
●a, f
●, f
●a, f
●a, f
●, f
●, f
●a, f
Lupus Anticoagulant
●b
FVIII trough level
●a
●a
●a
●a
●a
●a
●a
FVIII recovery
●a
●a
●a
●a
●a
●a
●a
Biochemistry 
●
●
●
●a
Haematology
●
●
●
●a
OTHER ASSESSMENTS
PRO questionnaire
●
●
HE assessment
●b
●b
●b
●b
●b
●b
●b
●b
Viral antibody test 
●
●a
T cells subset: CD4+
●
●b
TRIAL MATERIAL
turoctocog alfa administration
●a
●a
●a
●a
●a
●a
●a
Diary dispensing and/or collection
●
●
●
●
●
●
●d
●b
Review of patient diary and entry of 
data in eCRF
●
●
●
●
●
●
●
●b
Completion session in IV/WRS
●
Drug dispensing and accountability
●
●
●
●
●
●
●e
●b
EoT form
●
# - Presented numbers are for the first 12 months. Visit numbers for future years will be in consecutive order
a – optional, at discretion of  investigator
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
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Trial ID: NN7008-3809
Version:
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UTN: U1111-1119-6116
Status:
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EudraCT No.: 2011-001033-16
Page:
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b – if applicable 
c – weight only
d – collection only
e – accountability only
f - Minimum 48 hours washout period of turoctocog alfa. Not a requirement for patients on ITI treatment.
Table 2-3 presents the assessments to be made at unscheduled visit with inhibitor confirmation and 
at inhibitor unscheduled visit.
Table 2-3 Visit Flow Chart inhibitor related visits
Visit type
Inhibitor 
confirmation at 
Unscheduled 
Visit
Inhibitor 
Unscheduled Visit
PATIENT RELATED INFO / ASSESSMENTS
Withdrawal Criteria
●b
Concomitant medication
●b
Body measurements
Assessments 
●a, c
EFFICACY
according to 
Bleed(s)
normal 
●b
SAFETY
Unscheduled 
Visit
Adverse events
●
Physical examination
●b
Antibodies
- FVIII inhibitors
- FVIII non-neutralising antibodies
●e
●a, e
Lupus Anticoagulant
●
●d
FVIII trough level
●a
●a
FVIII recovery
●
●a
OTHER ASSESSMENTS
HE assessment
Assessments 
●b
TRIAL MATERIAL
according to 
turoctocog alfa administration
normal 
●a
Diary dispensing and/or collection
Unscheduled 
Visit
●b
Review of patient diary and entry of data in eCRF
●b
Drug dispensing and accountability
●b
a – optional at discretion of investigator
b – if applicable
c – weight only
CONFIDENTIAL


Protocol Amendment
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Date:
07 December 2015
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Trial ID: NN7008-3809
Version:
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UTN: U1111-1119-6116
Status:
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EudraCT No.: 2011-001033-16
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d – In the event that a patient has both a positive Lupus Anticoagulant and a positive confirmatory inhibitor test, Lupus 
Anticoagulant must be taken at every subsequent inhibitor test thereafter until the inhibitor test is negative (<0.6 BU).
e – Minimum 48 hours washout period of turoctocog alfa. Not a requirement for patients on ITI treatment.
…
5 Trial Design
5.1 Type of Trial
…
The trial consists of two phases i.e. main and extension, respectively. In the main phase the patients 
will attend a screening visit (Visit 1) in order to assess their eligibility. At Visit 2 eligible patients
will can receive their first dose, if applicable.
…
5.3 Treatment of Patients
…
Patients will enter a bleeding preventive regimen as described below, see Section 5.3.1. 
For prevention one single bolus dose of turoctocog alfa is administered intravenously (i.v.) at each 
administration day. Turoctocog alfa should preferably be administered in the morning. The 
maximum duration of treatment of a patient from first to last turoctocog alfa administration is 
approximately 5 4 years.
…
In most cases, treatment will be given at home with i.v. self-injection by the 
parent/caregiver/support person. However, on days when the patient is attending a trial visit, if 
applicable the dose may be administered at the clinic by a health care professional.Initially 
treatment with turoctocog alfa will typically be carried out by the staff at the clinic. Treatment can 
also be given at home with i.v. injection by the parent/caregiver/support person and/or at a non-
investigational site. All patients and/or parents/caregivers/support persons will be instructed by 
Investigator how to handle administration of turoctocog alfa before first dose is administered at 
home or at non-investigational site.
…
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Protocol Amendment
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Date:
07 December 2015
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Trial ID: NN7008-3809
Version:
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UTN: U1111-1119-6116
Status:
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EudraCT No.: 2011-001033-16
Page:
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5.3.2 Treatment of Bleeds 
During preventive treatment, break-through bleeds may occur and require extra doses of turoctocog 
alfa. Treatment of bleeds should be started as soon as a bleed is identified. All bleeds, 
mild/moderate and severe, can be treated at home. For severe bleeds (see Section 8.3.1.1) the 
Investigator should evaluate if the patient should be seen at the clinic. All bleeds must be reported 
to the clinic within 24 hours from onset of the bleed.
The dose for treatment of bleeds should aim at providing a post injection level of FVIII according 
to Table 5-1of at least 0.50 IU/mL or 50 IU/dL.
…
Each administered dose (mL given, vial strength and time of day) as well as efficacy in treatment of 
bleeds will be registered in the diary and in the eCRF. All treatments (excluding ITI treatment) 
administered in relation to bleeds must be recorded as ‘treatment of bleeds’, e.g. scheduled 
preventive treatment administered between start and stop time of a bleed must be registered as 
‘treatment of bleed’.
…
5.3.4 Treatment of Patients with Inhibitors
…
Treatment of bleeds with by-passing agents e.g.i.e. FVIIa or activated prothrombin complex 
concentrate (APCC) according to local label, is allowed for patients who develop inhibitors. 
Bypassing agents are not considered trial medication.
…
7 Trial Schedule
Planned duration of recruitment period (FPFV-LPFV): 3945 months
Planned date for FPFV:
December 2011
Planned date for LPFV:
31 December 2015Q2 2016
Planned date for LPLV:
30 June Q2 2018
The duration of turoctocog alfa treatment in this trial is a minimum total 100 EDs for a particular 
patient. Once a patient has achieved 100 EDs, they may be offered the option to continue in the trial 
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Protocol Amendment
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Date:
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Trial ID: NN7008-3809
Version:
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UTN: U1111-1119-6116
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until either turoctocog alfa is commercially available in the relevant country or until the marketing 
authorisation application for turoctocog alfa is rejected in the relevant country unless the trial, part 
of the trial or a trial site is terminated by Novo Nordisk or a relevant authority for any reason. In 
any event, the Last Patient Last Visit for the trial will be no later than 30 June 2018 whether or not 
the product is commercially available in the relevant country.
The following exceptions will be made:
!
patients will be allowed to achieve at least 100 ED with trial product
!
patients with inhibitor will be allowed to receive inhibitor treatment for up to 24 months.
The end of the clinical trial is defined as last visit of the last patient.
Planned completion of main clinical trial report (CTR): Q1 2016Q3 2017
Planned completion of updated clinical trial report: Q4 2018
…
8 Methods and Assessments
8.1 Visit Procedures
8.1.1 Overall Procedures, Assessments and Methods
Specific procedures, assessments and methods for the scheduled visits are described in the Sections 
below, and the list of assessments for each visit is presented in the flow chart, see Table 2-1,and
Table 2-2 and Table 2-3.
…
8.1.3 Visit 2
…
The main purpose of Visit 2 is to enrol eligible patients, to dispense the trial product and to
administer turoctocog alfa for the first time, if applicable, or alternatively dispense the trial product 
to eligible patients.
…
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
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Trial ID: NN7008-3809
Version:
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UTN: U1111-1119-6116
Status:
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EudraCT No.: 2011-001033-16
Page:
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8.1.5.2 Inhibitor Treatment Unscheduled Visit
All patients, who develop inhibitors and continue treatment with turoctocog alfa, will follow an 
alternative visit schedule prescribed by the Investigator according to local standard of practice, 
Monthly visits are recommended, at least initially, for patients who develop inhibitors. These 
patients must attend inhibitor unscheduled visits at least every 3rd month. However, initially 
monthly visits are recommended.
These visits will be recorded as inhibitor unscheduled visits and the following assessments should 
be performed. Please see also Table 2-3.
!
Assessment of withdrawal criteria
!
Concomitant Medication
!
Body measurements (weight)
!
Bleeds including classification and site of bleeds
!
Adverse Events 
!
Physical examination
!
Collect and review diary
!
Diary dispensing
!
Dispensing of trial product
!
Drug accountability
!
Administration of turoctocog alfa, if applicable
!
FVIII inhibitor test
!
FVIII Non-neutralising antibodies
!
Lupus Anticoagulant
!
Performing drug accountability
…
8.2 Assessments for Safety
8.2.2 FVIII antibodies 
8.2.2.1 FVIII Inhibitors
Blood sampling for FVIII inhibitor test should be performed at a trough level, i.e. with a minimum 
of 48 hours turoctocog alfa treatment washout period. The 48 hours washout period does not apply 
for patients on ITI treatment.
…
CONFIDENTIAL


Protocol Amendment
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Date:
07 December 2015
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Trial ID: NN7008-3809
Version:
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8.2.6 Lupus Anticoagulant
Lupus Anticoagulant will be sampled together with the confirmatory inhibitor test at an 
unscheduled visit. 
In the event that a patient has both a positive Lupus Anticoagulant and a positive confirmatory 
inhibitor test Lupus Anticoagulant must be taken at every consecutive subsequent inhibitor test 
thereafter until the inhibitor test is negative (<0.6 BU).
…
9 Trial Supplies
…
9.4
Dispensing and Drug Accountability of Trial Products
Drug accountability is the responsibility of the investigator.
The IV/WRS will allocate a trial product DUN to the patient at each dispensing visit. The correct 
DUN must be dispensed to the patient. 
!
No trial product(s) should be dispensed to any person not enrolled in the trial (excluding 
parents/LAR).
!
Unused trial product must be stored separately from used trial product.
!
Once a patient is dosed, the vials (used, unused and lost) must be recorded in the IV/WRS 
Drug Accountability module.
… 
9.5 Trial Product Administration 
The IV/WRS will report the dosing volume of turoctocog alfa to be injected based on the patient’s 
weight and dose IU/kg. 
The trial product should be administered as a slow bolus i.v. injection over approximately 2 min. 
(from start to completion of injection) for all trial product administrations.
These administrations will primarily be performed at home. All patients and/or parents/caregivers
will be instructed by Investigator how to handle home administration before first dose.
…
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Protocol Amendment
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Date:
07 December 2015
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Trial ID: NN7008-3809
Version:
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UTN: U1111-1119-6116
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EudraCT No.: 2011-001033-16
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11 Concomitant Illnesses and Concomitant Medication
…
The following concomitant medications are not permitted during the course of this trial:
!
Treatment with FVIII concentrates other than the trial product, see Section 6.4.
Treatment with blood and blood component products containing FVIII, e.g. cryoprecipitate and 
plasma, except during surgery, should be avoided.
In case these medications are used during the trial, the patient must be withdrawn.The use of these 
medications during the course of the trial may lead to patient withdrawal as described in Section 
6.4.
…
12 Adverse Events
12.1 Definitions
…
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 defectImportant medical events that may not result in death, 
be life-threatening a) or require hospitalisationb) 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 
of SAEd). Suspicion of transmission of infectious agents via trial product and/or
formation of inhibitory antibodies must always be considered an SAE
…
12.1.2 Medical Event of Special Interest and other events for expedited reporting
A medical event of special interest (MESI) is an event in which, in the evaluation of safety, has 
special focus. 
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Protocol Amendment
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Date:
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Trial ID: NN7008-3809
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A MESI should be reported following the same reporting requirements and timelines as for SAEs, 
irrespective of the MESI fulfils a seriousness criterion.
…
18 Statistical Considerations
…
18.6 Health Economics and Patient Reported Outcomes
Health economic data will be collected in the eCRF in connection with severe bleeds. Patient 
reported outcomes will be collected using questionnaires at visits 3 and 5 in the main phase, and 
annually during the extension phase. The health economic and PRO data will be summarised using 
descriptive statistics.
…
19 Ethics
19.1 Informed Consent Form for Trial Patients
…
Retention of blood samples
The patients parents and/or the patient’s LAR  are requested to give consent to retain the remaining 
blood samples after the primary analysis mentioned in this protocol for later exploratory analysis, 
see Section 25.2. The Investigator must provide the patient and/or the patient’s LAR the possibility
to abstain from the retention of blood samples but still be able to participate in the trial.
…
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Protocol Amendment
CONFIDENTIAL
Date:
07 December 2015
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Trial ID: NN7008-3809
Version:
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EudraCT No.: 2011-001033-16
Page:
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25 Retention of Clinical Trial Documentation and Human 
Biospecimens
…
25.2 Retention of blood samples
…
Parents and/or LAR will be requested to consent to the long-time retention and exploratory analysis 
of blood samples, see Section 19.1.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
20 January 2016
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
1 of 5
Protocol Amendment
No 11_AT
to Protocol, final version 6.0
dated 12 June 2014
Trial ID: NN7008-3809
Safety and Efficacy of turoctocog alfa in Prevention and
Treatment of Bleeds in Paediatric Previously Untreated
Patients with Haemophilia A
Trial phase: 3a
Applicable to Austria
Amendment originator:
Name: 
Department: 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
20 January 2016
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
2 of 5
Table of contents  
Page 
1 
Introduction including rationale for the protocol amendment ............................................................. 3 
2 
Changes ...................................................................................................................................................... 4 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
20 January 2016
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Trial ID: NN7008-3809
Version:
1.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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1
Introduction including rationale for the protocol amendment
A new principal investigator at trial site 
 will start to work due to retirement of the previous PI. 
At site 
 a new principal investigator will start to work due to relocation of the previous PI. 
Substantial Protocol Amendment No. 11_AT will be forwarded to Health Authority and the Ethics 
Committees for approval prior to implementation. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
20 January 2016
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
4 of 5
2
Changes
At site 
 (Prof. Dr. 
) the principal investigator will change due to retirement.
Principal Investigator: 
Title: 
Prof. Dr.
Name: 
Address: 
,
Tel: 
Fax: 
Email: 
Principal Investigator: 
Title: 
Dr.
Name: 
Address: 
Tel: 
Fax: 
Email:
At site 
 (OA Dr. 
) the principal investigator will change due to relocation.
Principal Investigator: 
Title: 
Dr.
Name: 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
20 January 2016
Novo Nordisk
Trial ID: NN7008-3809
Version:
1.0
UTN: U1111-1119-6116
Status:
Final
EudraCT No.: 2011-001033-16
Page:
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Address: 
Tel: 
Fax: 
Email: 
Principal Investigator: 
Title: 
Dr.
Name: 
Address: 
Tel: 
Fax: 
Email: 
CONFIDENTIAL