Clinical trial NCT03196297
Conditions: Haemostasis Haemophilia A
Sponsor: Novo Nordisk A/S
Start date: 2017-08-16; Completion date: 2020-06-03
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial is conducted in Asia, Europe and the United States of America (USA). The aim of the trial is to assess the efficacy of concizumab administered s.c. (subcutaneously, under the skin) once daily in preventing bleeding episodes in patients with severe haemophilia A without inhibitors.

Detailed description:

Arms: arm 1: Daily administration of concizumab to both on-demand and prophylaxis patients
Interventions: intervention 1: Concizumab intervention 2: Turoctocog alfa
Intervention descriptions: intervention 1: 0.15 mg/kg (with potential stepwise dose administration to 0.25 mg/kg) administered daily s.c (subcutaneously, under the skin). Treatment duration is 24 weeks in the main phase, and 52 weeks in the extension phase intervention 2: Breakthrough bleeding episodes will be treated by the patients at home with turoctocog alfa at the discretion of the study doctor, who will also choose dose levels

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03196297 
Sponsor trial ID: 
NN7415-4255 
Official title of study: 
A Multi-Centre Trial Evaluating Efficacy and Safety of 
Prophylactic Administration of Concizumab in Patients with 
Severe Haemophilia A without Inhibitors 
Document date: 
28 August 2018 
 


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CONFIDENTIAL
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
1 of 122
Protocol
Trial ID: NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of Prophylactic 
Administration of Concizumab in Patients with Severe Haemophilia A 
without Inhibitors
Trial phase: 2
Protocol originator
, 
Biopharm, Trial 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 No unpublished information contained herein may be 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.
3URWRFROY_
_
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
2 of 122
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................7
Table of Tables..................................................................................................................................................7
List of abbreviations.........................................................................................................................................8
1
Summary..................................................................................................................................................14
2
Flow chart ................................................................................................................................................17
3
Background information and rationale for the trial............................................................................20
3.1
Background information..............................................................................................................20
3.1.1
Haemophilia...............................................................................................................20
3.1.2
Concizumab ...............................................................................................................21
3.2
Rationale for the trial...................................................................................................................23
4
Objective(s) and endpoint(s) ..................................................................................................................25
4.1
Objective(s)..................................................................................................................................25
4.1.1
Primary objective.......................................................................................................25
4.1.2
Secondary objectives .................................................................................................25
4.2
Endpoint(s)...................................................................................................................................25
4.2.1
Primary endpoint........................................................................................................25
4.2.2
Secondary endpoints..................................................................................................25
4.2.2.1
Supportive secondary endpoints..........................................................25
4.2.3
Exploratory endpoints................................................................................................26
4.2.3.1
Exploratory safety endpoints...............................................................26
4.2.3.2
Exploratory patient-reported outcome endpoints................................27
5
Trial design ..............................................................................................................................................28
5.1
Type of trial .................................................................................................................................28
5.1.1
Surgery.......................................................................................................................29
5.2
Rationale for trial design..............................................................................................................29
5.3
Treatment of patients ...................................................................................................................32
5.3.1
Dose escalation ..........................................................................................................33
5.3.2
Treatment of bleeding episodes during the trial.........................................................34
5.3.3
Prohibited medication................................................................................................34
5.4
Treatment after discontinuation of trial product ..........................................................................35
5.5
Rationale for treatment ................................................................................................................35
6
Trial population.......................................................................................................................................36
6.1
Number of patients.......................................................................................................................36
6.2
Inclusion criteria ..........................................................................................................................36
6.3
Exclusion criteria.........................................................................................................................36
6.4
Criteria for premature discontinuation of trial product................................................................37
6.5
Withdrawal from trial ..................................................................................................................37
6.6
Patient replacement......................................................................................................................37
6.7
Rationale for trial population.......................................................................................................38
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
3 of 122
7
Milestones.................................................................................................................................................39
8
Methods and assessments .......................................................................................................................40
8.1
Visit procedures...........................................................................................................................40
8.1.1
Informed consent, long-term storage consent............................................................41
8.1.2
Screening log, enrolment log, trial card and patient number.....................................41
8.1.3
Screening failures and re-screening...........................................................................41
8.1.4
Premature discontinuation of trial product ................................................................42
8.1.5
Withdrawal from trial ................................................................................................42
8.1.6
Review/evaluation of clinical outcome......................................................................42
8.1.7
Visit 1 (Screening part)..............................................................................................43
8.1.8
Training of patients visit 1 and visit 2 .......................................................................44
8.1.9
Treatment period - Main part.....................................................................................44
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site) .......................44
8.1.9.2
Treatment period at home....................................................................45
8.1.9.3
Visit 3 (Phone visit).............................................................................45
8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits)...........................................46
8.1.9.5
Visit 9 (Assessment visits) ..................................................................46
8.1.10
Extension Part............................................................................................................47
8.1.10.1
Visit 10 (Assessment visits) ................................................................47
8.1.10.2
Visit 11, 12, 13, 14 and 15 (Assessment visits)...................................48
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) -
Extension part......................................................................................49
8.1.11
Follow-up Part ...........................................................................................................50
8.1.11.1
Visit 17 (End of trial) ..........................................................................50
8.1.12
Unscheduled Visit......................................................................................................51
8.2
Patient related information/assessments ......................................................................................51
8.2.1
Demography...............................................................................................................51
8.2.2
Concomitant illness and medical history other than haemophilia .............................51
8.2.3
Concomitant medication............................................................................................52
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History........................52
8.3
Efficacy assessments....................................................................................................................53
8.3.1
Bleeding episodes ......................................................................................................53
8.4
Safety assessments.......................................................................................................................57
8.4.1
Physical examination.................................................................................................57
8.4.2
Body measurements...................................................................................................58
8.4.3
Vital signs ..................................................................................................................58
8.4.4
Electrocardiogram......................................................................................................58
8.4.5
Adverse events...........................................................................................................59
8.4.5.1
Medication error..................................................................................59
8.4.5.2
Adverse events requiring additional data collection ...........................59
8.5
Laboratory assessments ...............................................................................................................61
8.5.1
Laboratory assessments for efficacy..........................................................................62
8.5.1.1
Thrombin generation...........................................................................62
8.5.1.2
Free TFPI.............................................................................................62
8.5.2
Laboratory assessments for safety .............................................................................63
8.5.2.1
Urinalysis ............................................................................................63
8.5.2.2
Haematology .......................................................................................63
8.5.2.3
Biochemistry .......................................................................................64
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
4 of 122
8.5.2.4
FVIII activity.......................................................................................64
8.5.2.5
Coagulation parameters.......................................................................64
8.5.2.6
FVIII inhibitor test ..............................................................................65
8.5.2.7
Anti-concizumab antibodies................................................................65
8.5.2.8
Concizumab ELISA ............................................................................67
8.5.2.9
Total TFPI ...........................................................................................67
8.5.3
Human biosamples.....................................................................................................67
8.6
Other assessments........................................................................................................................68
8.6.1
Patient reported outcomes..........................................................................................68
8.6.2
Training......................................................................................................................69
8.6.2.1
Concizumab and NovoPen® 4 .............................................................69
8.6.2.2
Turoctocog alfa ...................................................................................69
8.6.2.3
eDiary..................................................................................................70
8.6.3
Surgery.......................................................................................................................70
8.7
Patient compliance.......................................................................................................................70
8.8
Treatment compliance: ................................................................................................................71
9
Trial supplies ...........................................................................................................................................72
9.1
Trial products...............................................................................................................................72
9.2
Labelling......................................................................................................................................72
9.3
Storage .........................................................................................................................................73
9.4
Drug accountability and destruction............................................................................................74
9.5
Auxiliary supplies........................................................................................................................74
10 Interactive voice/web response system ..................................................................................................75
11 Randomisation procedure and breaking of blinded codes..................................................................76
Randomisation...........................................................................................................................................76
12 Adverse events, and technical complaints.............................................................................................77
12.1
Definitions ...................................................................................................................................77
12.1.1
Adverse event ............................................................................................................77
12.1.2
Serious adverse event.................................................................................................78
12.1.3
Non-serious adverse event.........................................................................................79
12.1.4
Medication errors.......................................................................................................79
12.1.5
Adverse events requiring additional data collection..................................................80
12.1.6
Adverse event of special interest ...............................................................................81
12.1.7
Technical complaints.................................................................................................85
12.2
Reporting of adverse events.........................................................................................................85
12.3
Follow-up of adverse events........................................................................................................87
12.4
Technical complaints and technical complaint samples ..............................................................88
12.4.1
Reporting of technical complaints .............................................................................88
12.4.2
Collection, storage and shipment of technical complaint samples ............................89
12.5
Pregnancies..................................................................................................................................90
12.5.1
Pregnancies in female partners of male patients........................................................90
12.6
Precautions and/or overdose ........................................................................................................91
12.7
Rules for putting enrolment on hold............................................................................................91
12.8
Committees related to safety........................................................................................................92
12.8.1
Novo Nordisk safety committee ................................................................................92
12.8.2
Data monitoring committee .......................................................................................92
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
5 of 122
13 Case report forms....................................................................................................................................93
13.1
Corrections to case report forms..................................................................................................93
13.2
Case report form flow..................................................................................................................93
13.3
Electronic diary............................................................................................................................94
13.3.1
Investigator review of eDiary data.............................................................................94
14 Monitoring procedures ...........................................................................................................................94
15 Data management....................................................................................................................................97
16 Computerised systems.............................................................................................................................97
17 Statistical considerations ........................................................................................................................98
17.1
Sample size calculation................................................................................................................99
17.2
Definition of analysis sets..........................................................................................................100
17.3
Primary endpoint........................................................................................................................100
17.4
Sensitivity analyses....................................................................................................................100
17.5
Additional analyses....................................................................................................................101
17.6
Secondary endpoints..................................................................................................................101
17.6.1
Supportive secondary efficacy endpoints ................................................................101
17.6.3
Supportive secondary pharmacokinetic endpoints...................................................102
17.6.4
Supportive secondary pharmacodynamic endpoints................................................103
17.7
Exploratory endpoints................................................................................................................103
17.7.1
Exploratory safety endpoints ...................................................................................103
17.7.2
Exploratory patient reported outcome endpoints.....................................................103
17.8
Interim analysis..........................................................................................................................105
18 Ethics......................................................................................................................................................106
18.1
Benefit-risk assessment of the trial............................................................................................106
18.2
Informed consent .......................................................................................................................107
18.3
Data handling.............................................................................................................................108
18.4
Information to patients during trial............................................................................................108
18.5
Premature termination of the trial and/or trial site.....................................................................108
19 Protocol compliance..............................................................................................................................109
19.1
Protocol deviations ....................................................................................................................109
19.2
Prevention of missing data.........................................................................................................109
20 Audits and inspections ..........................................................................................................................110
21 Critical documents ................................................................................................................................110
22 Responsibilities......................................................................................................................................111
23 Reports and publications......................................................................................................................112
23.1
Communication of results..........................................................................................................113
23.1.1
Authorship ...............................................................................................................113
23.1.2
Site-specific publication(s) by investigator(s) .........................................................114
23.2
Investigator access to data and review of results.......................................................................114
24 Retention of clinical trial documentation and human biosamples....................................................115
24.1
Retention of clinical trial documentation...................................................................................115
24.2
Retention of human biosamples.................................................................................................116
24.2.1
Antibody samples ....................................................................................................117
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
6 of 122
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............118
26 Indemnity statement .............................................................................................................................119
27 References..............................................................................................................................................120
Appendix I Patient Reported Outcome
Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments, if applicable for the individual 
country
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
7 of 122
Table of Figures
Page
Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous 
(circles) and traumatic (triangles) bleeding episodes during the dosing period and 
follow-up period. ....................................................................................................................23
Figure 5–1
Schematic diagram of the trial design.....................................................................................28
Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated 
patients in explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal 
lines indicate 100 ng/mL, and the shaded areas represent the full range (min-max) of the 
individual predicted profiles...................................................................................................30
Figure 5–3
Dose escalation of concizumab for one individual patient.....................................................34
Figure 8–1
Overview of visit structure in explorer™5.............................................................................40
Figure 12–1
Reporting of AEs....................................................................................................................87
Figure 17–1
Definition of main and extension part ..................................................................................105
Table of Tables   
Page
Table 2–1
Flow chart...............................................................................................................................17
Table 2–2
Flow chart explanatory descriptions.......................................................................................19
Table 5–1 
List of products provided by Novo Nordisk...........................................................................32
Table 8–1
Definition of stop of bleeding episode....................................................................................54
Table 8–2
Definitions of bleeding episodes (cause of bleed)..................................................................54
Table 8–3
Definition of bleeding episode severity and treatment recommendation ...............................55
Table 8–4
Guide for dosing in bleeding episodes and surgery................................................................56
Table 9–1
Trial products..........................................................................................................................72
Table 9–2
Storage conditions ..................................................................................................................73
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion.............................99
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
8 of 122
List of abbreviations
ABI
ankle-brachial index
ABR
annualised bleeding rate 
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest 
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
antithrombin
BP
blood pressure
BU
Bethesda unit
CLAE
clinical laboratory adverse event
Cmax
maximum plasma concentration
CNS
central nervous system
concizumab B
the name concizumab is being used as an 
abbreviation for concizumab B. B is the 
formulation 
CPoC
clinical proof of concept
CRF
case report form
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
9 of 122
CRO
contract research organisation
CRP
c-reactive protein
CT
computerized tomography
cTn
cardiac troponin
CTR
clinical trial report
DFU
direction for use
DIC
disseminated intravascular coagulation
DMC
data monitoring committee
DUN
dispensing unit number
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EMA
European medicines agency
EOT
end of trial
ETP
endogenous thrombin potential 
FAS
full analysis set
FDA
U.S. Food and Drug Administration
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
10 of 122
FDAAA
U.S. Food and Drug Administration 
Amendment Act
FIX
coagulation factor IX
FPFV
first patient first visit
FVIII
coagulation factor VIII
FX
coagulation factor X
FXa
activated coagulation factor X
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GHN
global haemophilia network
HCP
host cell protein
IB
investigator’s brochure
IC
informed consent 
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal 
Editors
ID
identification
IEC
independent ethics committee
IgG4
immunoglobulin G4
IMP
investigational medicinal product
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
11 of 122
INN
International Non-Proprietary Names for 
Pharmaceutical Substances 
IRB
institutional review board
ISTH
International Society on Thrombosis and 
Haemostasis
i.v.
intravenous(-ly)
IWRS
interactive web response system
LBBB
left bundle branch block
LPFV
last patient first visit
LPLV
last patient last visit
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory 
Activities
MI
myocardial infarction
MRA
magnetic resonance angiogram
MRI
magnetic resonance imaging
NIMP
non investigational medicinal product
PCD
PD
primary completion date
pharmacodynamic
PEF
peak expiratory flow
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
12 of 122
PK
pharmacokinetic
PP
per protocol
PRO
patient reported outcome
PT
prothrombin time
QA
Q4D
quality assurance
every 4th day
rFVIII
the name ‘rFVIII’ will be used throughout 
the protocol and the product is identical to 
‘turoctocog alfa’
SAE
serious adverse event
SAS
safety analysis set
sBE
s.c.
spontaneous Bleeding Episode
subcutaneous(-ly)
SI
international system of units
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse 
reaction
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
TF
tissue factor
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
13 of 122
TFPI
tissue factor pathway inhibitor
TG
thrombin generation
TMM
trial materials manual
TPA
trial product administration
UTN
Universal Trial Number
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
14 of 122
1
Summary
The main objective for the phase 2 trial NN7415-4255, explorer™5, is to assess the efficacy of 
concizumab administered s.c. once daily to prevent bleeding episodes in patients with severe 
haemophilia A without inhibitors. Furthermore, this trial aims to assess the longer-term efficacy and 
safety of concizumab in severe haemophilia A patients without inhibitors. 
Objective(s) and endpoint(s):
Primary objective 
!
To assess the efficacy of concizumab administered  s.c. once daily in preventing bleeding
episodes in patients with severe haemophilia A without inhibitors
Secondary objectives 
!
To assess the longer-term efficacy of concizumab in patients with severe haemophilia A without
inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without
inhibitors
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset..
Key secondary endpoints
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of treatment emergent adverse events (TEAEs) during at least 24 weeks from
treatment onset.
Time frames for evaluation of objectives/endpoints:
All endpoints referring to the time frame of at least 24 weeks will be evaluated in the main part of 
the trial, defined to end when the last patient has completed a minimum of 24 weeks of treatment 
with trial product (or have withdrawn). In addition, number of bleeding episodes during 76 weeks 
of treatment with prophylactic concizumab will be analysed. The extension part of the trial will 
provide additional safety and long-term efficacy data.
Trial design:
The trial is a multi-centre single arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation) administered daily s.c. in patients with 
severe haemophilia A without inhibitors. This is done by comparing the annual bleeding rate (ABR) 
to an ABR of 12.The selected dose regimen is based on relevant PK and TFPI data as well as 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
15 of 122
pharmacokinetic/pharmacodynamic (PK/PD) modelling from the preceding explorer™ trials. Both 
on-demand and prophylaxis patients will be eligible for the trial.
The total trial duration for the individual patient will be approximately 86 weeks, consisting of a 2 
week screening period, a subsequent 76 week treatment period and an 8 week follow-up period. 
The 76 weeks treatment period is split into a main part which lasts at least 24 weeks and an 
extension part which lasts up to 52 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 30 patients have completed at least 24 weeks of concizumab 
dosing or have discontinued trial treatment. The analysis of the main part of the trial aims to 
substantiate clinical proof of concept (CPoC) that concizumab has the potential to prevent bleeding 
episodes in severe haemophilia A patients without inhibitors. 
rFVIII (turoctocog alfa) for treatment of breakthrough bleeding episodes will be provided by Novo 
Nordisk during the trial. The patient will not be provided with trial product or rFVIII (turoctocog 
alfa) after the end of the trial.
Trial population:
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product: 33
Number of patients expected to complete the trial: 30
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine the 
suitability for the trial
!
Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at screening
Key exclusion criteria
!
Known or suspected hypersensitivity to trial product(s) or related products
!
Known inherited or acquired bleeding disorder other than haemophilia A
!
Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at 
screening measured by the Nijmegen method 
Key Efficacy assessment
!
The number of bleeding episodes during at least 24 weeks.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
16 of 122
Key Safety assessment
!
Number of TEAEs during at least 24 weeks.
Trial product(s):
The following products will be used in the trial:
!
Investigational Medicinal Product (IMP):
Concizumab B, 100 mg/mL to be administered s.c. with NovoPen®4 and needles 
!
Non Investigational Medical Product (NIMP):
Turoctocog alfa (rFVIII) 2000 IU/vial and isotonic sodium chloride (solvent). Turoctocog 
alfa (rFVIII) is for intravenous administration.
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CONFIDENTIAL


Protocol
UTN:U1111-1179-3872
Date:
15 March 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
1.0
Page:
17 of 122
2
Flow chart
Table 2–1
Flow chart
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
Timing of visit (d) d
14 to 21 days 
before Visit2
1
8
29
57
85
113
141
169
225
281
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 21 days 
before Visit 
2
0
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not applicable
-7
Treatment week (w)
---
0
1w
4w
8w
12w
16w
20w
24w
32w
40w
48w
56w
64w
72w
76w
---
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/Genotyping and Long-term storage consent
●
In/exclusion criteria
●
●e
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial 
product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
EFFICACY ASSESSMENTS 
Bleeding episodes f, g
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Free TFPI (central lab)  
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
SAFETY ASSESSMENTS
Physical examination
●
●
●
●
●
●
●
Body measurements 
●
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
Vital signs
●
●j
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Biochemistry (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII activity (central lab)
●k
●l
Coagulation parameters (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII inhibitors (central lab)
●
●l
Anti-concizumab antibodies (ADA) (special lab)m
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Concizumab ELISA (special lab)
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Total TFPI (special lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
TRIAL MATERIALS
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Protocol
UTN:U1111-1179-3872
Date:
15 March 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
1.0
Page:
18 of 122
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
IWRS call
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab, turoctocog alfa) (IWRS)
●n
●
●
●
●
●
●
●
●
●
●
●
●
●
●n
●
Administration of trial product (concizumab) 
●o
Drug Accountability (concizumab, turoctocog alfa) 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product c, p
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires
●
●
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
Hand out ID Card 
●
Training (trial product, e-Diary and NovoPen® 4) q
●
●
●
Compliance (e-Diary)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
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Protocol
UTN:U1111-1179-3872
Date:
15 March 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
1.0
Page:
19 of 122
Table 2–2
Flow chart explanatory descriptions
Footer
Description
a
Concizumab administration is performed at home except for visit 2 where concizumab administration will take place at the trial site.
b
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 will be 
a phone call to the patient. 
c
For patients being dose escalated a phone call is recommended 1 week after first new dose of concizumab.
d
Daily dosing preferably at the same time in the morning.
e
Evaluation of laboratory results obtained from samples taken at screening.
f
Bleeding episodes occurring between visit 1 and visit 2 or at site should be registered in the eCRF. All bleeding episodes except for severe occurring after visit 
2 at home should be registered in the eDiary. Severe bleeding episodes must be registered in the eCRF.
g
Turoctocog alfa will be given to treat breakthrough bleeding episodes either in the clinic or at home.
h
At visit 9 and 16 all blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been performed.
i
Only body weight should be measured.
j
Vital signs should be evaluated before and after trial drug administration at visit 2. 
k
Sampling for FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours and medical records documenting the severity of 
haemophilia are not available.
l
FVIII activity and FVIII inhibitor tests should only be collected if reduced effect of turoctocog alfa or FVIII inhibitor development is suspected.
m
In case of clinical signs of e.g. hypersensitivity reactions or immune related events are seen, additional samples for ADAs may be taken. All antibody samples 
from the affected patient will be analysed on an ongoing basis. If antibodies are detected additional samples will be taken and stored for characterisation of the 
antibodies.
n
Only dispensing of turoctocog alfa and sodium chloride.
o
The trial patient must be in a non-bleeding state at the time of the first trial product administration (TPA), and should not have received any haemostatic drug
(e.g. FVIII) for prophylaxis or treatment of a bleeding episode within a period of 48 hours prior to first TPA.
p
Patient should be dose escalated at next scheduled visit if he experiences ≥3 spontaneous bleeding episodes within the preceding 12 weeks of treatment with 
concizumab. If investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose escalation.
q
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Home treatment training comprises handing out of Direction 
for Use (DFU), training in administration of concizumab with NovoPen®4, turoctocog alfa and data entry in eDiary. Further the patients will be trained in 
recognition of signs/symptoms of thrombosis.
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
20 of 122
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP)1 and applicable regulatory requirements, and in 
accordance with the Declaration of Helsinki2 and ISO 141553.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
The International Non-Proprietary Names for Pharmaceutical Substances (INN) name of the active 
pharmaceutical ingredient is concizumab (synonyms used during early development are NNC0172-
2021, anti-TFPI, NN7415 or mab2021). Throughout this document “concizumab” is used as the 
name of the trial drug.
3.1
Background information
3.1.1
Haemophilia
Haemophilia is an inherited bleeding disorder characterised by an increased bleeding tendency, 
typically in weight bearing joints. Haemophilia A is caused by a partial or complete deficiency of 
blood coagulation factor VIII (FVIII) and haemophilia B is caused by defect factor IX (FIX).  
Inheritance is chromosome X-linked and recessive; therefore the disease mainly affects males. The 
incidence of haemophilia A and B on average is estimated to be about 1 in 5000 live male births4. 
According to the World Federation of Haemophilia global survey of 2014, about 178,500 persons 
are diagnosed with haemophilia worldwide. Of these, about 80% have haemophilia A.
Haemophilia is classified as “severe”, “moderate” or “mild” according to the plasma activity of the 
affected coagulation factor5.With a deficiency of FVIII or FIX, the degree of activation of 
coagulation factor X (FX) becomes insufficient. Consequently, the thrombin burst is delayed and 
insufficient for normal haemostasis6.The haemostatic plug, if formed, in these patients is fragile and 
easily dissolved by normal fibrinolytic activity. This leads to impaired haemostasis and spontaneous 
prolonged bleeding episodes. In severe haemophilia, bleeding in joints occurs spontaneously and is 
the most frequent symptom of the disease. Recurrent bleeding episodes in the same location - most 
commonly a weight bearing joint - lead to chronic arthropathy, muscular atrophy and deformities. 
Treatment of bleeding episodes as they manifest (on-demand treatment) may delay arthropathy, but 
does not prevent it. The majority of children with severe haemophilia experience their first bleeding 
episode in a joint prior to the age of 4 years. Many children also bleed from other body sites, also 
before this age is reached7. For this reason, primary prophylaxis treatment with regular FVIII 
injections in the non-bleeding state is the recommended from early childhood.
The most common complication of replacement therapy is development of antibodies binding to 
FVIII. These binding antibodies might neutralise the exogenous of FVIII and are then called
inhibitors. In patients who have developed inhibitors towards FVIII, replacement therapy is 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
21 of 122
rendered ineffective. These patients may be treated with bypassing agents, activated FVII 
(NovoSeven®) and activated prothrombin complex concentrate (FEIBA®) given as intravenous 
(i.v.) injections.
Current treatment options in haemophilia A, includes replacement therapy or by-passing therapy are 
hampered by the fact that these products must be given as i.v. injections. Bypassing agents are 
characterized by relatively short half-lives, therefore prophylactic treatment is burdensome. A new 
therapeutic agent that can be administered subcutaneously will represent a major improvement in 
the treatment of these patients in a prophylaxis setting. 
3.1.2
Concizumab
The trial product, concizumab, is a humanised recombinant monoclonal antibody (mAb) of the 
immunoglobulin G4 (IgG4) isotype with a molecular weight of 149 kilo Daltons. Like other 
antibodies, concizumab is composed of two light chains and two heavy chains linked together by 
disulfide bridges. To prevent formation of half-antibodies, the serine at position 241 in the heavy 
chain has been replaced with a proline (S241P (Kabat annotation)) . The mechanism of action of 
concizumab is based on the concept of inhibiting the activity of a natural coagulation inhibitor, 
tissue factor pathway inhibitor (TFPI). TFPI is a potent inhibitor of the initiation phase of the 
coagulation process, i.e. the activation of FX to FXa by the tissue factor (TF)/factor VIIa (FVIIa) 
complex. TFPI first binds to and inhibits activated FXa and subsequently binds to and inhibits the 
TF/FVIIa complex, forming a TF/FVIIa/FXa/TFPI complex. Thus, concizumab prevents both 
inhibition of FXa and inhibition of FVIIa/TF by TFPI. In this manner, sufficient amounts of FXa to 
ensure effective haemostasis in the absence of a functional activated factor IX/activated factor VIII 
(FIXa/ FVIIIa) complex may be generated. This is a new concept that remains to be documented 
safe and efficacious in patients with haemophilia. More information about the physiological role of 
TFPI and the mode of action of concizumab is provided in the Investigator’s Brochure (IB). 
Key differentiator is thus a new mode of action (MoA), and the key benefit of concizumab in 
patients with severe haemophilia A is reduced treatment burden due to subcutaneous (s.c.) 
administration potentially leading to better adherence, more patients on prophylactic treatment and 
ultimately better outcome.
Four clinical trials with concizumab have been completed thus far: the first-human-dose trial 
(NN7415-3813, explorer™1), a single dose trial in Japanese healthy subjects (NN7415-3981), a 
multiple dose trial NN7415-3986 (explorer™2), and NN7415-4159 (explorer™3). When the first 
cohort with four healthy subjects in explorer™2 was completed, prior to the initiation of the 2nd 
cohort, the trial was halted due to findings related to thrombosis in an ongoing 26-week toxicity 
study in primates. In this study animal had plasma concentrations several hundred folds above 
clinically relevant concentrations. Follow up investigations confirmed that the animal’s condition 
was related to thrombosis in the lungs caused by exaggerated pharmacology at these high plasma 
concentrations. Before the initiation of the fourth phase 1 trial (, explorer™3) a new 52-week non-
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
22 of 122
clinical toxicology study was conducted in primates to investigate the findings in the previous 
study. The conclusion from this new non-clinical study was that the results from non-clinical 
studies support further clinical development of concizumab. Explorer™3 was a multiple-dose 
clinical trial, which aimed to investigate the safety, pharmacokinetics and pharmacodynamics of 
concizumab at five different dose levels in adult severe haemophilia A patients without inhibitors. 
In this trial multiple doses of concizumab were administered s.c. over a period of six weeks. Doses 
of up to 0.8 mg/kg administered every four days did not raise safety concerns and a decision not to 
dose-escalate to a 1.1 mg/kg dose-cohort was taken. For further information, please refer to the 
Investigator’s Brochure.
The explorer™3 trial was finalised following the completion of cohort 3 (0.8 mg/kg sc every 4 days 
for 6 weeks). Blinded preliminary safety and PK/PD data from the cohort was reviewed by the 
concizumab safety committee. Marked changes in coagulation parameters were observed including 
a decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range. In addition, a substantial inter subject variation in pro-coagulant response to the drug 
was observed. Based on this, the Novo Nordisk safety committee (see section 12.8.1) decided not to 
proceed to cohort 4 (1.1 mg/kg sc every 4 days for 6 weeks). No clinical consequences or serious 
adverse were seen in the completed cohorts in explorer3.
The PK results from explorer™3 showed exposure-response in terms of fewer bleeding episodes 
recorded for patients who reached plasma concentrations of concizumab above 100 ng/mL. 
Individual predicted PK profiles merged with recorded spontaneous and traumatic bleeding 
episodes are shown in Figure 3–1.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
23 of 122
Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous (circles) and 
traumatic (triangles) bleeding episodes during the dosing period and follow-up period. 
All data originates from explorer™3 (N=24 patients). PK of concizumab is subdivided into three exposure levels of 
≤20 ng/mL, 20-100 ng/mL, and > 100 ng/mL together with the number of contributing patients. LLOQ: lower limit of 
quantification. a ‘Time in trial’ refers to the time that the patients spent on each concizumab exposure level, and the 
≤20 ng/mL level therefore also includes the screening period (not shown on this figure).
A large difference between the peak and trough plasma concentrations of concizumab were 
observed as well, especially in the highest dose group (0.80 mg/kg) of explorer™3. In patients who 
received 0.25, 0.5 and 0.8 mg/kg doses a significant overlap in plasma concentrations of 
concizumab was seen due to high between-patient variability in concizumab.
Single doses of concizumab up to 9 mg/kg have been administered to haemophilia patients in the 
first human dose trial with concizumab, explorer™1. These doses resulted in plasma concentrations 
of concizumab that were significantly higher than the ones that are modelled to be reached in the 
highest escalated daily dose (0.25 mg/kg) of explorer™5.
For an assessment of benefits and risks of the trial, see Section 18.1.
For further information, please refer to the Investigator’s Brochure.
3.2
Rationale for the trial
Four phase 1 clinical trials with concizumab have been finalised. Key safety and preliminary 
efficacy results from these phase 1 trials support further development of concizumab in haemophilia 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
24 of 122
patients. Therefore, the main objective in the phase 2 of concizumab development is to assess 
efficacy and safety and provide data that will guide for the confirmatory phase 3 concizumab trials. 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
25 of 122
4
Objective(s) and endpoint(s)
4.1
Objective(s)
4.1.1
Primary objective
!
To assess the efficacy of concizumab administered s.c. once daily in preventing bleeding 
episodes in patients with severe haemophilia A without inhibitors
4.1.2
Secondary objectives
!
To assess the long-termer efficacy of concizumab in patients with severe haemophilia A 
without inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without 
inhibitors
4.2
Endpoint(s)
4.2.1
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset
!
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary endpoints
!
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during 76 weeks from treatment onset
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of  spontaneous bleeding episodes during 76 weeks from treatment onset
!
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during 76 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during 76 weeks from treatment onset
!
!
Change from baseline of fibrinogen during 24 weeks from treatment onset
!
Change from baseline of fibrinogen during 76 weeks from treatment onset
!
Change from baseline of D-dimer during 24 weeks from treatment onset
!
Change from baseline of D-dimer during 76 weeks from treatment onset
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
26 of 122
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset
!
Change from baseline of F1 + 2 during 76 weeks from treatment onset
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset
!
Change from baseline of PT during 76 weeks from treatment onset
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset
!
Change from baseline of APTT during 76 weeks from treatment onset
!
Change from baseline of antithrombin (AT) during 24 weeks from treatment onset
!
Change from baseline of AT 76 weeks from treatment onset
!
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks
!
Concentration of concizumab prior to the last dose administration at 76 weeks
Supportive secondary pharmacodynamic endpoints
Plasma free TFPI concentration
!
Value prior to the last dose administration at 24 weeks 
!
Value prior to the last dose administration at 76 weeks 
Thrombin generation
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks 
!
Peak thrombin generation (nM) prior to the last dose administration at 76 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 76 weeks 
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks 
!
Velocity index (nM/min) prior to the last dose administration at 76 weeks 
4.2.3
Exploratory endpoints
4.2.3.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
27 of 122
4.2.3.2
Exploratory patient-reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 24 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Change in PGI-C after 24 weeks from treatment onset
!
Change in PGI-C after 76 weeks from treatment onset
!
Change in H-DAT after 24 weeks from treatment onset
!
Change in H-DAT after 76 weeks from treatment onset
All endpoints referring to a time frame of either 24 weeks or of at least 24 weeks will be evaluated 
in the main part of the trial. 
All endpoints referring to a time frame of 76 weeks will be evaluated in the extension part of the 
trial.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
28 of 122
5
Trial design
5.1
Type of trial
The trial is a multicentre single-arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation to 0.20 and 0.25 mg/kg) administered daily 
s.c. in patients with severe haemophilia A without inhibitors. The selected dose regimen is based on
relevant PK and TFPI data as well as PK/PD modelling from the preceding explorer™ trials. Both
on-demand and prophylaxis patients will be eligible for the trial.
Figure 5–1
Schematic diagram of the trial design
The total trial duration for the individual patient will be approximately 86 weeks, including a 2-
week screening period, a subsequent 76-week treatment period and an 8-week follow-up period, see 
Figure 5–1.
The76 weeks treatment periodis further split into a main part which lasts at least 24 weeks for all 
patients in the trial and an extension part which lasts 52 weeks.After completion ofthe main part of 
the trial, patients will continue into the extension part. All available data up to the time point where 
the last patients ends 24 weeks of treatment (or have withdrawn) will be used in the analysis of the 
main part, see Section 17.7.
Breakthrough bleeding episodes occurring from visit 1 to end-of-trial visit will be treated by the 
patients at home with FVIII at the discretion of the investigator, who will also choose dose levels. 
Only turoctocog alfa/NovoEight®will be provided and paid by Novo Nordisk for this purpose.
The analysis of the main part (after 24 weeks) of the trial aims to substantiate CPoC that 
concizumab has the potential to prevent bleeding episodes in patients with severe haemophilia A 
without inhibitors. The extension part will provide additional safety data on 52 weeksdosing of 
concizumab.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
29 of 122
Human biosamples (plasma, serum, and/or DNA for genotyping) will be collected in this trial  for 
future exploratory analysis to pursue a deeper insight into the biology of TFPI, coagulation, and 
effect of concizumab on joint health that may include coagulation parameters and markers of joint 
status or damage. Acceptance of storage of human biological specimens is voluntary and will not 
affect the patients’ participation in the trial. Therefore, patients will have the possibility to sign the 
informed consent for the trial and participate, while refusing permission for biological specimens to 
be stored for future exploratory analysis. Please refer to Section 24.1 for further information.
An independent data monitoring committee (DMC) will be established for this trial. The DMC will 
review all safety data from all ongoing trials with concizumab exposure, see Section 12.8.2.
5.1.1
Surgery
Minor surgery is allowed in this trial. Major surgery conducted more than one month (30 days) 
prior to trial start is allowed, see exclusion criterion no 6.
Minor surgery is defined as an invasive operative procedure where only the skin, the mucous 
membranes or superficial connective tissue is manipulated. Examples of minor surgery include 
implanting of central venous access devices (ports, CVC, pumps and other CVADs) in 
subcutaneous tissue, skin biopsies or simple dental procedures.
5.2
Rationale for trial design
Explorer™5 is a phase 2, clinical proof of concept (CPoC) and safety trial. The trial aims to 
substantiate CPoC that concizumab has the potential to prevent bleeding episodes in haemophilia 
patients without inhibitors. A dose escalation design will allow cautious dose escalation in order to 
choose the efficacious and safe concizumab dose for the individual patient from the selected dose 
regimenConcizumab 0.15 mg/kg (with two potential dose-escalation steps, 0.20mg/kgand 0.25 
mg/kg) given s.c. once daily will be investigated.
The duration of 24 weeks for the main part of the trial is deemed necessary in order to obtain 
information on the annual bleeding rate (ABR)during concizumab prophylaxis. The duration of the 
extension part of the trial will be 52 weeks and will provide further information on long-term 
efficacy, i.e. ABR, and also provide additional safety data upon 76 weeks treatment with 
concizumab.
A total of 33 patientsare planned to receive concizumab s.c.once daily in this single arm trial,
please see Figure 5–1.
The concizumab dose regimentswill be startingwith0.15 mg/kg with the possibilityto escalate to 
0.20 mg/kg and 0.25 mg/kg, see section 5.3.1.
Daily dosing with 0.15 mg/kg aims to ensure steady-state levels of concizumab plasma 
concentrations above 100 ng/mL for the majority of the patients starting on this dose. The PK 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
30 of 122
results from explorer™3 showed exposure-response in terms of fewer bleeding episodes recorded 
for patients who reached plasma concentrations of concizumab above 100 ng/mLsee Figure 3–1. 
The minority of patients which are predicted to have steady-state plasma concentrations below this 
threshold are expected to experience bleeding episodes and therefore will have the opportunity to be 
dose-escalated to the dose of 0.2 mg/kg. A further dose escalation to 0.25 mg/kg per day is 
permitted, again based on the bleeding rate,see section 5.3.1.
Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated patients in 
explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal lines indicate 100 ng/mL, 
and the shaded areas represent the full range (min-max) of the individual predicted profiles1.
1 Plasma concentrations in the same range as those in explorer™3 are expected to be reached in this trial with daily dose 
administration. The starting dose for all patients will be 0.15 mg/kg daily. The plasma steady-state exposure for a typical subject at 
this dose level is predicted to fourfold lower compared to a typical subject on 0.8 mg/kg Q4D (cohort 3 of explorer3) in terms of both 
Cmax and AUC 0-24h. For 0.20 mg/kg daily and 0.25 mg/kg, the plasma steady-state exposure levels for a typical subject are 
predicted to be less than 40% and 70% respectively, compared to the typical subject exposure in the 3rd cohort of explorer™3 (AUC 
and Cmax). The maximum predicted plasma exposure levels (Cmax and AUC 0-24h) for the 0.15 mg/kg daily dose level is predicted 
to be more than 8 fold lower than for 0.80 mg/kg Q4D. For 0.20 mg/kg daily both Cmax and AUC 0-24h are predicted to be more 
than 3 times lower than for 0.80 mg/kg Q4D. For 0.25 mg/kg daily, the maximum Cmax and AUC 0-24h are predicted to be 35 % 
lower than for 0.80 mg/kg Q4D.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
31 of 122
Due to the high between-patient variability in concizumab concentration observed in explorer™3, a 
significant overlap in plasma concentrations of concizumab in patients who received 0.25, 0.5 and 
0.8 mg/kg doses was seen, see Figure 5–2. Therefore, choosing three doses that would lead to 
reasonably distinct mean plasma concentrations of concizumab, and thus different efficacy at each 
dose level was not deemed possible. For this reason, a traditional parallel arm design was not 
chosen for the phase 2 trials. In contrast, the titration trial design allows patients to start on a low 
dose, which is expected to ensure prophylaxis but not marked changes in coagulation parameters, 
for the majority of patients. Escalation to the next dose level will only occur in the case of lack of 
efficacy (≥3 spontaneous bleeding episodes within the preceding 12 weeks. In addition, the PK of 
concizumab is heavily influenced by target mediated drug disposition, which means that small 
differences in concizumab dose ultimately leads to large differences in plasma concentrations. 
Therefore, daily dosing is proposed for the phase 2 trial, explorer™5. Daily dosing will allow for 
the increase in trough levels and thus better efficacy may be expected with a lower dose. 
Embryonic exposure in pregnant female partners of men treated with concizumab is highly unlikely 
and there is no need for protocol requirements for use of contraception in phase 2 and 3 trials.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
32 of 122
5.3
Treatment of patients
Table 5–1
List of products provided by Novo Nordisk
Compound Name 
Strength
Dosage form 
Route of 
administration
Treatment period
Concizumab B2, 
100 mg/mL
3 mL solution in 
a 3 mL 
cartridge3. 
S.c.
administration
using NovoPen® 4
For prophylactic 
treatment for 76 
weeks. 
Turoctocog alfa 
(NovoEight®)4, 
Sodium chloride 
solution 4ml  
2000 
IU/vial
Powder for 
solution for 
injection
Solvent for 
solution for i.v. 
injection used 
for 
reconstitution of 
turoctocog alfa.
I.v. administration
For treatment of 
breakthrough 
bleeding episodes 
(or prophylaxis in 
the screening and 
follow-up phases), 
at the discretion of 
the treating 
physician (patients 
may choose to use 
other familiar pre-
trial FVIII drug).
For further 
information see 
section 5.3.2
Concizumab will be given s.c., once daily for a total dosing period of 76 weeks. 
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. It will be labelled in accordance with national legislation and a copy of the label can 
be found within the Trial Materials Manual, see Section 9.1.
The first dose of concizumab will be given at the trial site under medical supervision. After the 
initial dose the patient must be observed for potential emergence of AEs/safety signals for at least 2 
hours at the trial site. At the screening visit and the first scheduled treatment visit patients will be 
trained in s.c. administration of concizumab with NovoPen® 4 and in the use of eDiary.
Investigational medicinal product (IMP)
3 Not to be confused with the daily injected volume (~150 μL, depending on dose strength and body weight)
4 Non-investigational medicinal product (NIMP)
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
33 of 122
In case safety concerns meet the criteria(See section12)for putting enrolment of additional 
patients on hold,further enrolment in the trial will be halted. Dosing of patients on treatment may 
continue while further evaluation is made by the safety committee. In case of other safety concerns 
all available data will be evaluated by the DMCsee Section 12.8.2.
5.3.1
Dose escalation
Bleeding episodes will be assessed during the trial both at scheduled visits and also between visits.
The first 2 weeks of the treatment with concizumab 0.15 mg/kg is considered as a run-in period. 
Hence the bleeding episodes occurring during the first 2 weeks should not influence a dose 
escalation decision.
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (first-dose visit) 
until visit 16 (end-of-treatment visit), i.e. a total of 74 weeks. Dose-escalation will be based on the 
number of spontaneous, treated bleeding episodes in patients within preceding 12 weeks. However, 
before dose-escalation can occur, to ensure the safety of the patients, the investigator must take into 
account the full clinical picture the patient is presenting with and all available laboratory results, 
including coagulation parameters.
Dose 0.15 mg/kg:
When a sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the preceding 
12 weeks since visit 2+2weeks (including the current sBE). If yes, and if investigator deems it safe, 
the patient will have to be dose escalated from 0.15 to 0.20 mg/kg at the next scheduled visit. If the 
investigator judges that this visit is scheduled too late, he/she should contact the patient for an 
unscheduled visit.
Dose 0.20 mg/kg:
When an sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the 
preceding 12 weeks (including the current sBE), counting only new sBEs from the beginning of the 
0.20 mg/kg treatment period. If yes, and if investigator deems it safe, the patient will have to be 
dose escalated from 0.20 to 0.25 mg/kg at the next scheduled visit. If the investigator judges that 
this visit is scheduled too late, he/she should contact the patient for an unscheduled visit.
Dose 0.25 mg/kg:
Patients are not dose escalated further regardless of the number of sBEs
Since the patient may have to wait up to 8 weeks for the next scheduled visit (in the extension part), 
the possibility of dose escalation at unscheduled visits is necessary for the dose-escalation eliciting 
bleeding episode to occur soon after previous scheduled visit.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
34 of 122
Figure 5–3
Dose escalation of concizumab for one individual patient
5.3.2
Treatment of bleeding episodes during the trial
Bleeding episodes (main part, extension part, and follow-up part):
Breakthrough bleeding episodes during the course of the trial will be treated at the discretion of the 
treating physician, with either turoctocog alfa/Novoeight® (rFVIII) (provided by Novo Nordisk) or 
other non-modified FVIII products (not provided by Novo Nordisk). Treatment dose is chosen at 
the discretion of the investigator. The patient can treat himself and then he must call the site. 
Bleeding episodes classified as severe must be recorded in the electronic case report form (eCRF)
as serious adverse events (SAEs) see Table 8–3. The bleeding episodes must be recorded in the 
eDiary.
FVIII prophylactic treatment (follow-up part):
During the follow-up part of the trial (i.e. from concizumab end-of-treatment visit to end-of-trial 
visit) patients will receive pre-trial FVIII medication at the discretion of the treating investigator, 
who will also choose dose levels. Only turoctocog alfa/NovoEight® will be provided by Novo 
Nordisk for this purpose.
5.3.3
Prohibited medication 
!
Treatment with anti-fibrinolytics (e.g. tranexamic acid, aminocaproic acid)
!
Heparin, except for sealing of central venous access ports according to local practice
!
Vitamin-K antagonists
!
Direct oral anti-coagulants (DOACs)
!
Modified FVIII products with extended half-life
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
35 of 122
5.4
Treatment after discontinuation of trial product
When discontinuing trial products the patient should be switched to a suitable marketed product at 
the discretion of the investigator. The patient will not be provided with concizumab or FVIII 
(turoctocog alfa/NovoEight®) by Novo Nordisk after end of trial (visit 17). 
5.5
Rationale for treatment
Concizumab is a monoclonal antibody and as such offers the possibility of s.c. administration. S.c. 
administration of an effective prophylactic drug has potential to reduce treatment burden 
significantly compared to the currently approved prophylactic drugs which have to be administered 
i.v.
The treatment period of 24 weeks (the main part of the trial) is considered necessary for providing 
data that allow demonstration of CPoC and to support decision-making regarding a phase 3 
confirmatory trial. Dosing for an additional 52 weeks will provide valuable long-term efficacy and 
safety.
Breakthrough bleeding episodes may occur during prophylactic regimens with conventional FVIII 
replacement therapy. Therefore, it is expected that breakthrough bleeding episodes will also occur 
during prophylaxis with concizumab even if clinical proof of concept is demonstrated. 
Consequently turoctocog alfa (FVIII ) will be provided by Novo Nordisk A/S in this trial for 
treatment of breakthrough bleeding episodes. 
Patients are not obliged to use turoctocog alfa (FVIII) and can use their previously used FVIII 
concentrate for treatment of breakthrough bleeding episode. Novo Nordisk A/S will not provide or 
reimburse these products.
Please refer to the Investigator’s Brochure for further information.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product(s): 33
Number of patients planned to complete the trial: 30
Discontinued patients will not be replaced.
6.2
Inclusion criteria
For an eligible patient, all inclusion criteria must be answered “yes”.
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at 
screening.
3. For patients being treated on-demand with FVIII replacement therapy, a minimum of six 
documented and treated bleeding episodes during the 24 weeks (or twelve bleeds during 52 
weeks) prior to screening.
6.3
Exclusion criteria
For an eligible patient, all exclusion criteria must be answered “no”.
1. Known or suspected hypersensitivity to trial product(s) or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within the last 30 days or 5 half-lives (whichever is longer) from the last drug 
administration before screening.
4. Any disorder, which in the investigator’s opinion might jeopardise patient’s safety or 
compliance with the protocol.
5. Known inherited or acquired bleeding disorder other than haemophilia A.
6. Major surgery conducted within one month prior to the initiation of trial activities or major 
surgery planned to occur during the trial.
7. Previous history of thromboembolic disease. Current clinical signs of thromboembolic 
disease, or patients who in the judgement of the investigator are considered at high risk of 
thromboembolic events.
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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8. Mental incapacity, unwillingness to cooperate or language barrier precluding adequate
understanding and cooperation.
9. Patients who, at screening, have a significant infection or known systemic inflammatory
condition which require systemic treatment according to the investigator’s judgement.
10. Hepatic dysfunction defined as elevated liver transaminases (ALT) >3 times the upper limit
of normal laboratory reference ranges at screening.
11. Renal impairment defined as estimated glomerular filtration rate (eGFR)≤60
mL/min/1.73m2 based on serum creatinine measured at screening or evidence of renal
damage.
12. Platelet count ≤ 100x109/L at screening.
13. Fibrinogen level < the lower limit of normal at screening
14. Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at
screening measured by the Nijmegen method.
15. History of inhibitors towards FVIII based on investigator’s knowledge or documentation in
available medical records.
6.4
Criteria for premature discontinuation of trial product
The patient may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
The patient must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria
2. Simultaneous participation in another clinical trial of an approved or non-approved
investigational medicinal product.
3. Incapacity or unwillingness to follow the trial procedures
4. Anaphylactic reaction
5. Thromboembolic event
6. Event of disseminated intravascular coagulation (DIC)
7. Development of inhibitors to Factor VIII (≥0.6 BU)
8. Loss of efficacy due to neutralising antibodies towards concizumab
See Section8.1.4 for procedures to be performed for patients discontinuing trial product 
prematurely.
6.5
Withdrawal from trial
The patientmay withdraw consent at will at any time.
See Section 8.1.5for procedures to be performed for patients withdrawing consent.
6.6
Patientreplacement
Patients who discontinue trial product prematurely will not be replaced.
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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6.7
Rationale for trial population 
The most important reason for choosing the trial population, haemophilia A without inhibitors, is 
that there is a significant unmet medical need in this patient population for a treatment option which 
reduces the burden associated with the current care, including small volume s.c. administration 
instead of i.v. Finally, the trial population reflects the patient population that will be selected in a 
potential subsequent phase 3 trial in which the efficacy and safety of concizumab is to be 
confirmed.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
39 of 122
7
Milestones
Planned duration of recruitment period first patient first visit – last patient first visit (FPFV-LPFV): 
4 months
Planned FPFV: 
16-Aug-2017
Planned FPFT: 
30-Aug-2017
Planned LPFV: 
16-Dec-2017
Planned LPLV: 
11-Sep-2019
The total duration of concizumab treatment in the trial is 76 weeks for an individual patient enrolled 
in the trial for concizumab treatment at visit 2.
End of trial is defined as last patient last visit (LPLV).
Recruitment:
The screening and enrolment rate will be followed closely via the interactive web response system 
(IWRS) in order to estimate when to stop screening. All investigators will be notified immediately 
when the recruitment period ends, after which no further patients may be screened and the IWRS 
will be closed for further screening. All patients screened during the recruitment period and found 
eligible for enrolment can be enrolled within the timelines specified in the flow chart (see Section 
2).
Trial registration:
Information about the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and clinical 
trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure, how-we-
disclose-trial-information8, it will also be disclosed according to other applicable requirements such 
as those of the International Committee of Medical Journal Editors (ICMJE) 9, the Food and Drug 
Administration Amendment Act (FDAAA)10 , European Commission Requirements 11, 12 and other 
relevant recommendations or regulations 13. If a patient requests to be included in the trial via the 
Novo Nordisk e-mail contact at these web sites, Novo Nordisk may disclose the investigator’s 
contact details to the patient. As a result of increasing requirements for transparency, some 
countries require public disclosure of investigator names and their affiliations.
Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
protocol Last Patient First Treatment LPFT (visit2) + 24 weeks ( i.e. last patient visit 9) If the last 
patient is withdrawn early the PCD is the date when the last patient would have completed visit 9. 
The PCD determines the deadline for results disclosure at ClinicalTrials.gov according to 
FDAAA.10
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CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
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8
Methods and assessments
Assessments to be performed at the scheduled and at unscheduled visits in this trial are described in 
this section and in the trial flow chart (section 2).
Figure 8–1
Overview of visit structure in explorer™5
8.1
Visit procedures
For each patient the trial consists of the following scheduled parts and visits:
Screening Part:
Visit 1 (screening visit)
Main Part:
Visit 2 (1st treatment visit with concizumab at site)
Home treatment with concizumab daily
Visit 3 (phone visit with site)
Visit 4 (Assessment visit, patients treat themselves at home)
Visit 5 (Assessment visit, patients treat themselves at home)
Visit 6 (Assessment visit, patients treat themselves at home)
Visit 7 (Assessment visit, patients treat themselves at home)
Visit 8 (Assessment visit, patients treat themselves at home)
Visit 9 (Assessment visit, after the visit patients treat themselves at home)
Extension Part:
Visit 10 (Assessment visit, patients treat themselves at home)
Visit 11 (Assessment visit, patients treat themselves at home)
Visit 12 (Assessment visit, patients treat themselves at home)
Visit 13 (Assessment visit, patients treat themselves at home)
Visit 14 (Assessment visit, patients treat themselves at home)
Visit 15 (Assessment visit, patients treat themselves at home)
Visit 16 (Assessment visit and End of treatment)
Follow-up part
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Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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Visit 17 (Assessment visit and End of trial)
Unscheduled visits can occur e.g. for dispensing of trial products, when an assessment of bleeding 
episodes is necessary at site or at the discretion of the investigator.
The duration of the visits (V1-V17) will depend on the assessments and the patient’s individual 
training and/or discussion need on concizumab administration, NovoPen® 4, usage of e-Diary, 
completion of the patient reported outcome(PRO) etc.
8.1.1
Informed consent, long-term storage consent
Informed consent must be obtained before any trial related activity, see Section 18.2.
The trial includes a separate informed consent for long-term storage of human biosamples, see 
Section 24.2. 
Storage of human biosamples and genotyping is voluntary and will not affect the patients’ 
participation in the trial. Therefore, patients will have the possibility to sign the informed consent 
for the trial and participate, while refusing permission for biological specimens and /or genotyping 
to be stored for future exploratory analysis.
8.1.2
Screening log, enrolment log, trial card and patient number
The investigator must keep a patient screening log, a patient identification (ID) code list and a 
patient enrolment log. Only patients who have signed the informed consent form should be included 
on the logs. The patient screening log and patient enrolment log may be combined in one log.
At screening, patients will be provided with a card stating that they are participating in a trial and 
given contact address(es) and telephone number(s) of relevant trial clinic staff. Patients should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each patient will be assigned a unique 6-digit patient number which will remain the same 
throughout the trial.
8.1.3
Screening failures and re-screening
For screening failures the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial. Serious and non-serious adverse events 
from screening failures must be transcribed by the investigator into the eCRF. Follow-up on serious 
adverse events (SAEs) must be carried out according to Section 12.
A screening failure session must be made in the IWRS. The case book must be signed in the eCRF.
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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Re-screening is NOT allowed if the patient has failed one of the inclusion or exclusion criteria; this 
includes re-sampling if the patient has failed one of the inclusion or exclusion criteria related to 
laboratory parameters.
8.1.4
Premature discontinuation of trial product
If a patient prematurely discontinues trial product, the investigator must undertake procedures 
similar to those for visit 9 (the last treatment in the main part) or visit 16 (the last treatment visit in 
the extension part) as soon as possible. The follow up visit (visit 17) must be performed 8 weeks 
(window minus 7 days) after last dose of trial drug.
The primary reason for premature discontinuation of trial product must be specified in the end of 
treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
Permanent premature discontinuation of treatment with trial product will lead to patient withdrawal 
from the trial.
8.1.5
Withdrawal from trial
If a patient withdraws consent, the investigator must aim to undertake procedures similar to those 
for visit 9 (the last visit in the main part) or visit 16 (the last visit in the extension part) as soon as 
possible depending on where the patient is in the trial schedule.
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the patient is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS and the case book must be signed in the eCRF.
Although a patient is not obliged to give his reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the patient’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.6
Review/evaluation of clinical outcome
Novo Nordisk has constituted an internal concizumab safety committee and established an external 
DMC to perform ongoing safety surveillance of safety data relevant for concizumab, see Section 
12.8.
Review of eDiary data and laboratory reports etc. must be documented either on the documents or 
in the patient’s medical record.
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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If unclear entries or discrepancies in the eDiary or PRO are identified and a clarification is needed, 
the patient must be asked for clarification and a conclusion made in the patient’s medical record. 
Care must be taken not to bias the patient.
8.1.7
Visit 1 (Screening part)
Informed consent must be obtained before any trial related activity, see Section 18.2.
In cases where a patient's baseline FVIII level is not documented in medical records, sampling for 
FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours.
Screening can take place between 14 to 21 days prior to planned enrolment day (visit 2).
All assessments to be performed at screening are listed in Table 2–1, see Section 2.
Apart from informed consent patients will be asked to complete the ePRO questionnaires before any 
other trial related activities are performed according to section 8.6;
!
Hemo-TEM,
!
VERITAS-Pro® orVERITAS-PRN®
Assessment results from physical examination, body measurements, as well as measurements of 
vital signs, urinalysis electrocardiogram (ECG) and details of any contemporary adverse events 
must be entered into the eCRF.
A screening confirmation call must be performed in the IWRS, at the day of the visit.
The investigator must review all information obtained from the screening procedures. If a patient
does not meet all inclusion criteria or meets one or more of the exclusion criteria for the trial the 
patient does not qualify to be enrolled.
Patients will be provided with turoctocog alfa (rFVIII) trial injection kits and directions for use
(DFU) to cover the potential FVIII treatment in the screening part of the trial and investigator will 
ensure that the patients are capable of treating themselves with rFVIII (turoctocog alfa). Patients on 
any previous FVIII prophylaxis can continue with this treatment until 48 hours before visit 2.
Dispensing of rFVIII (turoctocog alfa) should be performed in the IWRS
For bleeding episodes that occur in the period from Screening visit (Visit1) to enrolment visit (Visit 
2) information about the bleeding episode is to be entered in the eCRF at visit 2. 
The patient should be instructed to call the site if any bleeding episodes, questions or issues arise 
after he has left the site.
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CONFIDENTIAL
Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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8.1.8
Training of patients visit 1 and visit 2
During the site visits 1 and 2 patients must be trained in self administration of concizumab in the 
home setting using NovoPen® 4. The dose of concizumab to be administered must be 
communicated to the patient at visit 2. Furthermore patients must be instructed and trained in the 
importance and reporting of all home treatment with concizumab, details of the bleeding episodes 
and the turoctocog alfa (FVIII) treatment associated with these bleeding episodes in the eDiary,(See 
section 8.6.2).
Patients should be trained on how to recognize and react to signs of thromboembolic events, so that 
the patient without any delay contacts the site.
8.1.9
Treatment period - Main part
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site)
Visit 2 should be scheduled 14 to 21 days after visit 1. The date of visit 2 will be considered as trial 
day 1.
Before any concizumab administration it is important to verify the in/exclusion criteria again and 
review central laboratory test results from screening. 
The patient must be in a non-bleeding state at the time of first administration with concizumab and 
should not have received any FVIII treatment for prophylaxis or for treatment of a bleeding episode 
within a period of 48 hours prior to dosing.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
Hemo-TEM,
o
SF-36v2, 
o
SDS, 
o
TSQM, 
o
SIAQ-ISRQ
All protocol assessments must be performed before 1st administration of concizumab. Vital signs 
must be assessed both before and after concizumab administration.
Assessment results from concomitant medication, vital signs, Body measurements (weight only)
and details of adverse events must be entered into the eCRF.
At this, the 1st treatment visit, the allocated dose of concizumab will be given. Concizumab will be 
administered at the trial site supervised by medically trained trial staff.
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CONFIDENTIAL
Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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The time point at which the completion of the first dose takes place corresponds to Time on 
treatment = 0 and must be recorded in the eCRF.
The patient must be observed at the trial site for at least 2 hours after the administration of the first 
dose of concizumab.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.
Investigator will communicate any the daily dose of concizumab to the patient and record the dose 
for the coming home treatment period in the eCRF. 
Prior to the first dose a dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits as well as an eDiary device to be able to conduct and report 
home treatment until the next scheduled visit.
The patient will be reminded to report bleeding episodes and home treatment in the eDiary device.
The patient will be asked to return all used, partly used and unused turoctocog alfa (FVIII) during 
the trial as instructed by the investigator. Drug accountability must be performed for turoctocog alfa
(rFVIII), including injection kits if applicable, according to section 9.4.
8.1.9.2
Treatment period at home
Home treatment is defined as self-administration of trial product, performed independently by the 
patient, preferablyin the morning.Home treatment starts after visit 2 or when the patient is 
comfortable self-administrating trial product subcutaneously (concizumab) and intravenously 
(turoctocog alfa(FVIII)).
8.1.9.3
Visit 3 (Phone visit)
Visit 3 is to be scheduled as a phone contact (or similar) 7days after visit 2 (with a visit window of 
+1 day).
All relevant protocol assessments listed in table 2-1 must be discussed. Assessment results from 
concomitant medication and details of adverse events must be entered into the eCRF.
Patients should be informed to treat themselves at home according to the dosing schedule regardless 
of when visits 4, 5, 6, 7 and 8 are scheduled. 
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits)
Visits 4, 5, 6, 7 and 8 are to be scheduled on trial day 29 (4 weeks), day 57 (8 weeks), day 85 (12 
weeks), day 113 (16 weeks) and day 141 (20 weeks) respectively with a visit window of ± 7days.
Patients should treat themselves at home according to the dosing schedule regardless of when visits 
4, 5, 6, 7 and 8 are scheduled
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6;
o
PGI-C
o
Hemo-TEM
Assessments are to be performed according to Table 2–1and the assessment results from 
concomitant medication, vital signs, Body measurements (weight only) and details of adverse 
events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewingcollected data from the eDiary.Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab dosesis needed 
according the escalationrules described in section 5.3.1. All decisionsto escalate the concizumab 
dosemust be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocogalfa) including injection kits, if 
applicable.
At visit 8 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 9.
8.1.9.5
Visit 9(Assessment visits)  
Visit 9is to be scheduled on trial day 169(24 weeks) with a visit window of ± 7days.
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Treatment with concizumab must take place after the blood sampling at this visit.
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
PGI-C
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
Assessments are to be performed according to Table 2–1and the assessment results from physical 
examination, concomitant medication, vital signs, Body measurements (weight only) and details of 
adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through the available access to collected data from the eDiary. Based on the assessment of any 
spontaneous bleeding episodes the investigator must evaluate if an escalation of the concizumab 
doses is needed according the escalation rules described in section 5.3.1. All decisions to escalate 
the concizumab dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
8.1.10
Extension Part
8.1.10.1
Visit 10 (Assessment visits) 
Visit 10 is to be scheduled on trial day 225 (32 weeks), with a visit window of ± 7days.
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Assessments are to be performed according to the flowchart section 2 and the assessment results 
from concomitant medication, vital signs, Body measurements (weight only)and detailsof adverse 
events must be entered into the eCRF.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performedaccording tosection 8.6.1;
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
SIAQ-ISRQ
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable.
8.1.10.2
Visit 11, 12, 13, 14 and 15 (Assessment visits)
Visits 11 to 15 are to be scheduled on trial day 281 (40 weeks), day 337 (48 weeks), day 393 (56 
weeks), day 449 (64 weeks) and day 505 (week 72) respectively with a visit window of ± 7days.
Assessments are to be performed according to Table 2–1 and the assessment results from physical 
examination (applicable for V12), concomitant medication, vital signs, Body measurements (weight 
only) and details of adverse events must be entered into the eCRF.
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
At visit 15 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 16.
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) - Extension part
Visit 16 is to be scheduled on trial day 533 (76 weeks) with a visit window of ± 7days.
Visit 16 should be scheduled to be conducted at the last day of treatment with concizumab.
Treatment with concizumab must take place after the blood sampling at this visit.
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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Assessments are to be performed according to Table 2–1 and the assessment results from 
concomitant medication, vital signs and details of adverse events (AE) must be entered into the 
eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. 
In the period from visit 16 to visit 17 the patient can be treated with turoctocog alfa (rFVIII) at the 
discretion of the investigator. Treatment can either be prophylactically and/or treatment of eventual 
bleeding episodes. Only turoctocog alfa will be provided by Novo Nordisk.
If necessary, a dispensing call must be performed in the IWRS. At the visit the patient will be 
provided with rFVIII (turoctocog alfa) and injection kits to be able to conduct home treatment until 
final visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. NovoPen 4 must be 
returned. Drug accountability must be performed at all visits for concizumab and rFVIII (turoctocog 
alfa) including injection kits, if applicable.
8.1.11
Follow-up Part
8.1.11.1
Visit 17 (End of trial)
Visit17is to be scheduled on trial day 589(84 weeks) with a visit window of minus 7days 
Assessments are to be performed according to Table 2–1and the assessment results from
concomitant medication,physical examination, body measurements(weight only), vital signsand 
details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Patients must be asked if their female partner has 
become pregnant during the trial (see Section 12.5.1).
The patient will be asked to return all used, partly used and unusedturoctocog alfa (rFVIII), eDiary
deviceand Trial card.Drug accountability must be performed for turoctocog alfa (rFVIII)including 
injection kits, if applicable.
End of trial information must be entered in the End of Trial form in the eCRF.
End of trial Call must be made in the IWRS.
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
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8.1.12
Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Table 2–1.
The purpose of the unscheduled visit must be documented in the eCRF. During unscheduled visits 
assessments and blood sampling must be performed according to Table 2–1. Assessment results 
must be recorded in the eCRF. Assessments and blood sampling can be omitted if the only reason 
for the unscheduled visit is dispensing of trial product. 
If trial product administration or dispensing is required, dispensing of trial product must be 
performed via IWRS.
The following forms can be found in the unscheduled visit in the eCRF:
!
Bleeding episodes
!
Dosing with FVIII, concizumab including dose escalation section 5.3.1
!
Surgery
!
Local, special and central laboratory (re-) sampling/results
!
Body measurements
8.2
Patient related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Concomitant illness and medical history other than haemophilia
A concomitant illness is any illness, other than haemophilia A, that is present at the start of the trial 
(i.e. at the first visit) or found as a result of a screening procedure or other trial procedures 
performed before first exposure to trial product. All concomitant illnesses should be reported in the 
Concomitant illness forms in the eCRF except information on haemophilia A which is to be 
reported in the Haemophilia Medical history section of the eCRF.
Medical history is a medical event, other than haemophilia A, which the patient has experienced in 
the past. Only relevant medical history should be reported. The information collected for 
concomitant illness and medical history should include diagnosis, date of onset and date of 
resolution or continuation, as applicable. Any change to a concomitant illness should be recorded 
during the trial. A clinically significant worsening of a concomitant illness must be reported as an 
AE. 
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It must be possible to verify the patient’s medical history in source documents such as patient’s
medical record:
If a patient is not from the investigators own practice; the investigator must make a reasonable 
effort to obtain a copy of the patient’s medical record from relevant party e.g. primary physician. 
See section 6.2 and 6.3 for full description of the selection criteria. The investigator must document 
any attempt to obtain external medical information by noting the date(s) when information was 
requested and who has been contacted.  
8.2.3
Concomitant medication
A concomitant medication is any medication, other than concizumab and turoctocog alfa (rFVIII)
(and connected 0.9% Isotonic Sodium Chloride) used for rescue treatment, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the patient’s eligibility to continue in the trial, the monitor must be informed.
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History
All available information on haemophilia, prior to screening should be recorded in the eCRF. 
!
Diagnosis of haemophilia (date)
!
Classification of haemophilia type (haemophilia A)
!
Severity of haemophilia (severe, moderate or mild)
!
Etiology of haemophilia (congenital or acquired)
!
Family history of haemophilia [yes or no in eCRF]
!
Family history of Prothrombotic disorders [yes or no in eCRF]
!
Family history of Thromboembolism [yes or no in eCRF]
!
Family history of inhibitors [yes or no in eCRF]
!
Deficiency factor level
The following information on bleeding episodes one year prior to screening should be recorded in 
the eCRF:
!
Type of treatment 
o
Prophylaxis or on-demand
o
Start date 
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o
Stop date 
!
Number of bleeding episodes 
o
If possible specify number of spontaneous bleeding episodes.
!
Coagulation factor product(s) 
o
Brand name, or if the brand is not known, the type of product, (plasma derived or 
recombinant)
!
Dosage used for prophylaxis  (for prophylaxis patients only) 
!
Dosing frequency during prophylaxis (only for prophylaxis patients) 
!
Approximate dose to treat a bleeding episode 
!
Approximate number of doses to treat a bleeding episode
!
Target joint listing (definition: a target joint is a joint in which 3 or more spontaneous 
bleeding episodes have occurred within a consecutive 6-month period)
o
Location
o
Position (left/right)
o
Number of bleeding episodes
8.3
Efficacy assessments
8.3.1
Bleeding episodes
All bleeding episodes treated with FVIII and symptoms related to the underlying disease must be 
captured in the eDiary by the patient or in the eCRF by the investigator. The trial site should be 
informed of the details of all bleeding episodes, including those that are treated outside of the trial 
site. All information captured including severe bleeding episodes, during visits at the trial site will 
be collected in the eCRF.
When home treatment is initiated at visit 2 all bleeding episodes and injections with concizumab 
and turoctocog alfa (rFVIII) infusions occurring outside the trial site should be entered in the eDiary 
by the patient (Section 8.6.2.3). The completed eDiary is considered source data.
The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with rFVIII (turoctocog alfa):
!
Start date and time
!
Stop date and time (see Table 8–1 for definition) 
!
Anatomical location(s)
o
Position (left/ right)
!
Cause (see Table 8–2 for definitions)
o
spontaneous
o
traumatic
o
post-surgical
!
Severity (see Table 8–3 for definitions)
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o
mild/moderate, severe

classification and of severe bleeding episodes is the responsibility of the 
investigator
!
Treatment, if any 
o
rFVIII (turoctocog alfa) administration(s) or other product administrations

dose, date, time 
o
other medicinal treatments related to the bleeding episode (e.g. pain relieving 
medication, non-medical therapy etc.)

record as concomitant medication (see section 8.2.3)
!
Symptoms during bleeding episodes 
o
Pain 
o
Blood in urine
o
Tingling sensation
o
Swelling
o
Mouth/Gum bleed
o
Warmth
o
Loss of movement
o
Bruises
o
Nose bleed
Only report the bleeding episode as an AE/SAE if fatal, life threatening or evaluated as related to 
trial product (see section 12.1)
Table 8–1
Definition of stop of bleeding episode
Stop time is:
When the patient experiences/observes signs of cessation of the active 
bleeding episode such as; pain relief, no increase in swelling/limitation of 
motion and improvement in other objective signs of the bleeding episode
Stop time is not:
When pain and objective signs of the bleeding episode are completely 
resolved
Table 8–2
Definitions of bleeding episodes (cause of bleed)
Category
Definition
Spontaneous
Not linked to a specific, known action or event
Traumatic
Caused by a specific, known action or event (e.g. injury or exercise)
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Post-surgical
Bleeding episodes after surgery from the surgical wound. Bleeding 
episodes during surgery does not fall under this category 
Table 8–3
Definition of bleeding episode severity and treatment recommendation
Category
Definition
Treatment recommendation
Mild/Moderate
Examples: uncomplicated musculoskeletal 
bleeding episodes (joint, muscular bleeds 
without compartment syndrome), mucosal- or 
subcutaneous bleeding episodes
Mild/moderate bleeding episodes may occur in 
other anatomical locations
Mild/moderate bleeding 
episodes can be treated at home 
before contact to the 
investigator
Severe
Examples: intracranial, retroperitoneal, 
iliopsoas and internal neck bleeding episodes; 
muscle bleeding episodes with compartment 
syndrome; bleeding episodes associated with a 
significant decrease in the haemoglobin level 
(>3g/dl)
Severe bleeding episodes may occur in other 
anatomical locations 
Bleeding episodes that require hospitalisation
All life-threatening bleeding episodes 
Severe bleeding episodes must 
be treated immediately 
Instruction for 
patients
The patient must be instructed to contact the investigator immediately if in doubt 
regarding treatment of a bleeding episode and to discuss what other actions may 
need to be taken
Information about bleeding episodes prior to visit 2 will be recorded in eCRF.
The trial site should be informed of the details of all bleeding episodes, including those that are 
treated outside of the trial site. After visit 2 bleeding episodes must be recorded either in the eDiary 
(if treated at home) or in the eCRF (if treated at the trial site), see section 12.3.
Severity of bleeding episodes must be evaluated by the investigator according to Table 8–3and 
reported in the eDiary database.
Prophylactic treatment with concizumab should continue independent of bleeding episodes and 
their treatment, i.e. the original dosing schedule should be maintained unless investigator judges 
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otherwise. Decisions to alter dosing schedule, including the rationale for the alteration, should be 
documented. If applicable, investigator must instruct the patient to use rFVIII (turoctocog alfa) as 
rescue medication to treat bleeding episodes.
Treatment of bleeding episodes will be at the discretion of the investigator. In countries where 
turoctocog alfa is approved for the market it is recommended to follow the approved labelling for 
NovoEight®. For countries where turoctocog alfa is not approved it is recommended to follow the 
instructions in the EU-SMPC for turoctocog alfa (FVIII): “The calculation of the required dose of 
factor VIII is based on the empirical finding that 1 IU factor VIII per kg body weight raises the 
plasma factor VIII activity by 2 IU/dl. The required dose is determined using the following formula:
Required units (IU) = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5 (IU/kg per 
IU/dl).
The amount to be administered and frequency of administration should always be oriented to the 
clinical effectiveness in the individual case.
In case of the following haemorrhagic events, the factor VIII activity should not fall below the 
given plasma activity level (in % of normal or IU/dl) in the corresponding period. The following 
table can be used to guide dosing in bleeding episodes and surgery:”
Table 8–4
Guide for dosing in bleeding episodes and surgery
Degree of haemorrhage/ Type of
surgical procedure
FVIII level required (%)
(IU/dl)*
Frequency of doses (hours)/ 
Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding
or oral bleeding
More extensive haemarthrosis, muscle
bleeding or haematoma
Life threatening haemorrhages
20-40 
30-60 
60-100
Repeat every 12 to 24 hours, at least1 
day, until the bleeding episode as
indicated by pain is resolved or
healing achieved
Repeat infusion every 12-24 hours for 
3-4 days or more until pain and acute 
disability are resolved
Repeat infusion every 8 to 24 hours
until threat is resolved
Surgery
Minor surgery including tooth
extraction
Major surgery
30-60 
80-100 (pre- and postoperative)
Every 24 hours, at least 1 day, until
healing is achieved
Repeat infusion every 8-24 hours
until adequate wound healing, then
therapy for at least another 7 days to
maintain a factor VIII activity of 30%
to 60% (IU/dl)
*however in this trial any given single dose should not exceed 50 IU/kg 
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Furthermore investigator must instruct the patient to contact the site when a bleeding episode occurs 
to discuss the bleed.
It is the responsibility of the investigator to instruct the patient when to contact the site according 
toTable 8–3 .
In absence of apparent effect of turoctocog alfa (rFVIII) the site must be contacted for further 
advice and before any further dosing. In case of a bleeding episode that requires treatment occurring 
outside the trial site’s opening hours the patient must be treated according to local procedure. All 
contacts to the patient must be recorded in the patient’s medical chart. 
It is the responsibility of the investigator to instruct the patient about the timelines for timely 
completion of the eDiary. Furthermore the investigator must review the bleeding and treatment data 
collected by the eDiary according to section 13.3.
For in-between visit administrations of trial drug, patients will self-administer concizumab (and 
turoctocog alfa (rFVIII) as rescue medication)) and will record treatment in the hand-held, eDiary, 
which will be reviewed during periodic calls to/contact with the patient and at each visit by trial site
staff and the sponsor staff.
8.4
Safety assessments 
8.4.1
Physical examination
Performed as standard physical examination and include the following:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Genito-Urinary system, breasts 
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
The investigator must evaluate the results of the examination and classify the outcome as either:
!
Normal or abnormal.
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at Screening: record as Medical History (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
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!
Measurements will be reported in the eCRF
8.4.2
Body measurements
Height (cm), at screening
Body Weight (kg),with 1 decimal.
The body weight assessed at each visit will be used for determination of the concizumab dose to be 
administered until next visit.
Measurements will be reported in the eCRF
8.4.3
Vital signs
Before measurement of vital signs the patient should preferably rest comfortably for at least five
minutes and all measurements should, if possible, be performed using the same method and sitting 
position throughout the trial. 
Measurements at visits must be performed prior to any trial product administration unless otherwise 
specified
!
Body temperature (°C)
!
Systolic and diastolic blood pressure, sitting (BP) (mmHg)
!
Pulse, sitting (beats/min)
!
Respiratory rate
Exception: At visit 2, the measurement is also performed after concizumab administration.
The investigator must evaluate the results and classify the outcome as either: 
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2.)
o
If observed after screening: report an AE/SAE (section 12)
Measurements will be reported in the eCRF.
8.4.4
Electrocardiogram 
The investigator must evaluate the ECG (standard 12 lead) at screening and classify the outcome as
either:
!
Normal or Abnormal. 
!
If Abnormal the investigator must: 
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o
Specify the abnormality 
o
Record if the result is clinically significant? (Yes/No)
o
If observed before or at Screening: record as Medical History (Section 8.2.1)
o
If observed after screening: report an AE/SAE (Section 12)
The ECG results must be dated and signed by the investigator to verify that the data have been 
reviewed. Outcome will be reported in the eCRF.
8.4.5
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12.
8.4.5.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form: 
!
Trial product(s) involved 
!
Classification of medication error
!
Whether the patient experienced any adverse event(s) as a result of the medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4.
8.4.5.2
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section12.
Injection site reaction 
Investigation of injection site reactions will be performed locally at visit 2 based on patient 
feedback and by following visual inspections of injection sites for concizumab administration:
Symptoms e.g.
!
Pain 
!
Numbness 
!
Itching
!
Burning
Signs e.g.:
!
Redness (mm x mm)
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!
Induration (mm x mm)
!
Swelling
!
Dimpling
!
Macula
!
Haematoma
!
Bleeding
!
Other (visual reactions) 
Any injection site reaction symptom (evaluated between visit 2-16) should be recorded in the AE 
form and the injection site reaction form, see section 12.1.5. 
A separate AE should be recorded for each injection site reaction symptom. The affected area 
should also be evaluated for redness and induration in mm using a ruler. To ensure all local 
injection site assessments are performed at the injection site, the area around the site will be marked 
with a pen prior to injection. 
In the event of a local reaction, additional visual assessments (as described above) will be 
performed until resolution as judged necessary by the investigator.
Assessment of injection site reactions can be performed at any time, if deemed necessary by the 
investigator.
Hypersensitivity reaction
If suspicion of a hypersensitivity reaction occurs the patients should be instructed to contact the site
staff as soon as possible for further guidance.
All events of hypersensitivity reactions must be reported and the following information must be 
obtained if available on the hypersensitivity reaction form: 
!
Signs and symptoms associated with the event
!
Time of appearance after administration of trial drug
!
Relevant immunological tests performed (See section 8.5.2.7)
!
Treatment given for the reaction
!
Previous history of similar reactions
!
Association with the trial product(s)
!
Relevant risk factors associated with the event
!
Storage condition of the trial product
!
Total number of doses, from first day on trial product, up to the time of this event
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8.5
Laboratory assessments
An approximate total blood volume of 450 mL will be taken from each patient in the trial. Ports 
cannot be used for blood sampling.
A laboratory manual will be provided for detailed description of obtaining and processing blood 
samples.
All laboratory blood samples collected for this trial except for haematology samples are to be 
shipped for analysis at central laboratories or further distribution to special laboratories.
Haematology samples are to be analysed locally.
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in international system of units (SI) .
Laboratory reports listing results from centrally analysed samples will be made available for the 
investigator. Investigator must review and evaluate the results and report AEs for results which are 
clinical significant. Laboratory reports will where possible indicate normal ranges 
Categorisation of clinical significance for out of range results may not be required for the following 
laboratory parameters and the investigator is therefore not required to perform a categorisation even 
though these parameters are listed in the laboratory report: FVIII activity, FVIII inhibitor test, 
Thrombin generation, TFPI not bound to concizumab, concizumab concentration in plasma, Anti-
concizumab binding antibodies, and Total TFPI.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to section 8.2.2 and section 12.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory except for biomarkers and anti-drug antibodies (anti-concizumab IgE antibodies and 
anti-concizumab binding antibodies).
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report (CTR).
Antibody samples and human bio-samples, if applicable will be stored as described in section 24.2. 
The investigator may not be able to review the results of antibody measurements in relation to AEs 
as these are often analysed after LPLV.
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8.5.1
Laboratory assessments for efficacy
8.5.1.1
Thrombin generation
The Thrombin Generation Assay (TGA) will be performed at all visits, except visit 3.
The TGA is included as an exploratory PD assessment.
The generation of thrombin is a fundamental part of the haemostatic system, and is a key 
measurable parameter of the formation of a clot under bleeding or thrombotic conditions. The 
thrombin burst is crucial for the formation of a stable fibrin clot. 
The Calibrated Automated Thrombogram (CAT) method (used by Thrombinoscope BV) will be 
used to measure thrombin generation (TG). This method uses a slow acting fluorogenic substrate 
that allows continuous measurement of thrombin generation in double centrifuged citrated plasma. 
In this assay set-up thrombin generation is initiated by low-dose tissue factor that is combined with 
phospholipid. The result is obtained by comparison to a constant known thrombin activity in a 
parallel non tissue factor initiated sample. The assay has been validated fit-for-purpose.
The thrombin generation endpoints are defined, but not limited to,
!
The Endogenous Thrombin Potential (ETP) – the area under the curve 
!
Peak thrombin generation
!
Velocity Index 
8.5.1.2
Free TFPI
Free TFPI measures TFPI not bound to concizumab. This enzyme-linked immunosorbent assay 
(ELISA) test will be will be sampled for at all assessment visits.
The free TFPI ELISA assay is an enzyme immunoassay measuring levels of TFPI not bound to 
concizumab from Diagnostica Stago (named and referred to Asserachrom TOTAL TFPI) and will 
be used for PD assessments. 
Free TFPI is included as a PD assessment.
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8.5.2
Laboratory assessments for safety
8.5.2.1
Urinalysis
!
pH
!
Protein
!
Glucose
!
Bilirubin
This is a semi qualitative measurement which will be performed (locally) at the screening visit by 
the site by using the appropriate reagent strips for urinalysis. The results will be recorded in the 
eCRF.
Clinically significant findings must be recorded as: 
!
Normal or abnormal
o
if abnormal the investigator must:
o
record if the result is clinically significant? (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
8.5.2.2
Haematology
Haematology samples are to be sampled and analysed locally at all visits, except visit 3. 
!
Haemoglobin 
!
Erythrocytes (cell count) 
!
Thrombocytes (Platelet count)
!
Leucocytes (cell count) 
!
Differential leucocytes cell count 
o
Lymphocytes
o
Monocytes
o
Neutrophils
o
Eosinophils 
o
Basophils
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
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Haematology results are to be entered into the eCRF.
8.5.2.3
Biochemistry
!
Creatinine 
!
Albumin 
!
Bilirubin; total, direct and indirect)
!
Aspartate aminotransferase (AST) 
!
Alanine aminotransferase (ALT)
!
Gamma glutamyltransferase (GGT) 
!
Alkaline phosphatase
!
C-reactive protein (CRP) 
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
8.5.2.4
FVIII activity
!
FVIII activity (IU/ml)
8.5.2.5
Coagulation parameters 
!
Fibrinogen
!
Prothrombin time  (PT) including INR
!
D-dimer 
!
Prothrombin fragment 1+2 
!
Activated partial thromboplastin time (APTT)
!
Antithrombin (AT)
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
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8.5.2.6
FVIII inhibitor test
The inhibitor level of the patient will be measured by the Nijmegen method at visit 1 (screening). 
!
FVIII inhibitor titre (BU)
8.5.2.7
Anti-concizumab antibodies
Sampling will be performed at all visits except at visit 3. Samples will be collected pre-dose at visit 
2, 9 and 16.
Assessment of binding antibodies against concizumab (anti-drug antibodies (ADA)) will be 
performed at specialised laboratories whereas assessment of neutralising antibodies will be 
performed at Novo Nordisk A/S.
Analysis for ADA will be done as listed in Table 2–1, with a bridging ECL assay (binding ADA 
assay), using labelled concizumab for antibody capture and detection. Confirmed positive samples 
will be characterised for binding to IgG backbone, CDR region or the S241P mutation. 
Furthermore, positive samples will be characterised for neutralising activity using a modified TFPI 
functionality assay (neutralising ADA assay). All antibody assays are validated according to 
international guidelines and recommendations.
The following analyses will be available:
!
Anti-concizumab antibody assay
!
Specificity assay (Anti-concizumab antibodies cross reacting with IgG4 backbone, CDR region
or S241P mutation) 
!
Anti-concizumab neutralising antibody assay
Samples will be drawn at all visits except at visit 3. The samples will be analysed in batches during 
the trial and results will be available to the data monitoring committee approximately every third 
month after the first patient has been dosed (Section 12). Neutralising antibodies will be analysed 
and reported at the end of trial. A detailed description of the assay methods will be included in the 
antibody analysis report at the end of the trial.
Investigators will be notified in case their patient is shown to have developed neutralising 
antibodies against concizumab.
Samples for the determination of anti-drug antibodies collected during the treatment period must be 
drawn prior to administering trial products.
In the event that a trial patient develops binding ADAs towards concizumab during the course of the 
trial and has measurable binding ADAs at his End of Trial visit, the patient may attend an ADA 
follow-up visit. The ADA positive patients will be called for additional visits, e.g. every 4 to 6 
weeks, for safety assessment and blood sampling for ADA and PD markers (free TFPI and 
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Thrombin generation). The ADA positive patients will be followed no longer than one year after 
End of Trial.
Hypersensitivity
If suspicion of a hypersensitivity reaction occurs, patients should be instructed to contact the site 
staff as soon as possible for further guidance, see Section 12.1.5.
In the event of a severe local and/or systemic hypersensitivity reaction possibly or probably related 
to trial product, blood sampling for assessment of anti-concizumab IgE antibodies as well as anti-
concizumab antibodies should be conducted in relation to the reaction and no later than 1-2 weeks 
after the event. Additional testing may be performed if deemed relevant (e.g. anti-Host Cell Proteins 
(HCP) antibodies). 
In the event of a severe systemic hypersensitivity reaction to trial product it is recommended also to 
test for tryptase (total and/or mature tryptase) within 3 hours of the reaction. Moreover, a baseline 
tryptase measurement is necessary 1-2 weeks after the immediate severe hypersensitivity reaction 
due to individual to individual variation in tryptase baseline concentration. 
A follow up visit should be conducted 3-4 weeks post the allergic reaction with repeated blood 
sampling for assessment of anti-concizumab IgE antibodies as well as anti-concizumab antibodies 
and if possible also at a visit 3 months post the hypersensitivity reaction for assessing the 
persistence of the IgE response. Tryptase measurements are not required at the follow up visits.
Additionally, basophil activation testing may be performed if deemed relevant. This can be 
performed using existing samples and/or by analysing the patient’s basophil cells from an additional 
blood sample taken 3-4 weeks and no later than 2 months after the event. Similarly, prick tests 
and/or intra-dermal tests may be performed if relevant using trial product or components of trial 
product. Complement may be measured in case of suspicion of immune complex mediated 
hypersensitivity reactions.
Results from the following additional tests will be reported to Novo Nordisk Safety Operations for 
inclusion in the ARGUS database and included in the narratives, if measured:
Test to be performed in case of severe hypersensitivity
!
Anti-concizumab IgE antibodies
!
Anti-concizumab antibodies (additional to scheduled time points)
Additional testing may be performed if deemed relevant e.g
!
Anti-Host Cell Proteins (HCP) antibodies
!
Anti-HCP IgE antibodies
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!
Basophil activation results
!
Prick test/intra-dermal test
!
Complement test results
Furthermore, it is recommended locally to test for
!
Tryptase (total and/or mature tryptase)
8.5.2.8
Concizumab ELISA
Concizumab ELISA will be performed at all visits except at screening and at visit 3. Samples will 
be collected pre-dose at visit 2, 9 and 16.
Concizumab will be quantified using a validated ELISA assay. Recombinant human TFPI will be 
used to capture concizumab. A colorimetric detection signal is obtained by the enzymatic reaction 
of horseradish peroxidase labelled anti-human IgG4 specific antibodies with the chromogenic 
substrate TMB (3,3´,5,5´-tetramethylbenzidine). The amount of anti-TFPI present in the calibration, 
quality control and test samples correlates with the obtained signal strength.
Validation of the assay follows current guidelines for bioanalytical method validation. Bioanalytical 
data will be reported in a bioanalytical report.
8.5.2.9
Total TFPI
Total TFPI ELISA sampling will be performed at all visits except at visit 3. Samples will be 
collected pre-dose at visit 2, 9 and 16.
The Total TFPI ELISA is included as an exploratory PD assessment.
The total TFPI level (free and concizumab bound) will be included as an exploratory biomarker 
assessment. The assay is an ELISA, where TFPI is captured by polyclonal anti-TFPI antibody, 
distanced from the binding site of concizumab, meaning that both free TFPI and concizumab bound 
TFPI will be captured. Detection will be obtained with a monoclonal antibody against TFPI, which 
does not bind to the concizumab epitope. Data will be reported in ng/mL TFPI.
Total TFPI ELISA will be performed at all visits, except visit 3. Sample will be collected pre-dose 
at visit 2.
Data will be reported in mg/ml TFPI
8.5.3
Human biosamples
If patient permission is obtained, plasma, serum and/or DNA for genotyping samples are to be taken 
for long term retention. The blood samples can be stored up to 15 years, for future potential 
exploratory purposes please refer to section 24.2.
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Antibody samples storage and retention see section 24.2.1. The investigator is not able to review the 
results of antibody measurements in relation to AEs as these are analysed after LPLV.
If applicable, samples will be collected at visit 1 and at visit 17.
8.6
Other assessments
8.6.1
Patient reported outcomes
In this trial a newly developed disease specific PRO -the Hemophilia Treatment Experience 
Measure (Hemo-TEM) -is being validated. In order to assess the psychometric properties of Hemo-
TEM,  other questionnaires will be provided; see further appendix 1.
The following ePRO questionnaires are used:
- Haemophilia Treatment Experience Measure (Hemo-TEM)
- Validated Hemophilia Regimen Treatment Adherence Scale – Prophylaxis (VERITAS-
Pro®)/Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
- 36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
- Patient Global Impression of Change (PGI-C)
- Sheehan Disability Scale (SDS)16
- Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
- Haemophilia - Device Assessment Tool (H-DAT)
- Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
The PROs should be assessed at the scheduled visits following the order listed below:
!
visit 1 (Hemo-TEM, VERITAS-Pro® or VERITAS-PRN®)
!
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 4 (PGI-C, Hemo-TEM)a
!
visit 5 (PGI-C, Hemo-TEM)
!
visit 6 (PGI-C, Hemo-TEM)
!
visit 7 (PGI-C, Hemo-TEM)
!
visit 8 (PGI-C, Hemo-TEM)
!
visit 9 (PGI-C, Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
!
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 16 (Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
At visit 1 before any visit-related activities all patients should complete Hemo-TEM and 
VERITAS-Pro® (if the patient at baseline receives prophylactic treatment) / VERITAS-PRN® (if 
patient at baseline receives on demand treatment).   
At visit 2 before any visit-related activities all patients should complete Hemo-TEM, SF36v2, SDS, 
TSQM and SIAQ-ISRQ.
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At visit 4-8: before any visit-related activities the patient should complete the PGI-C before the 
Hemo-TEM. These are the rules that apply:
!
If the patient responds “1” to question 1 in the PGI-C, the patient should also complete the
Hemo-TEM. In this case the patient should not fill in the PGI-C any more in the trial and the
Hemo-TEM only again at visit 9.
!
If the patient responds “0” or “2” to question 1 in the PGI-C, the patient should not complete
any other questionnaires at this visit, but should repeat the procedure at next visit.
At visit 9 if the patient has responded “0”or “2”in the PGIC at all previous visits, the patient 
should complete PGI-C. All patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT
and SIAQ-ISRQ.
At visit 10 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and SIAQ-ISRQ.
At visit 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT and SIAQ-
ISRQ. The investigator mustcheck the ePROs for potential AEs and SAEs.
The completed ePROs should be transmitted to the ePRO database by the investigator at each visit.
All PROs can be found in Appendix I. 
8.6.2
Training 
The patients must be trained in how to handle bleeding episodes and how to recognize the signs and 
symptoms of thrombosis. The training must be recorded in the medical records. 
8.6.2.1
Concizumab and NovoPen® 4
A direction for use (DFU) will be available as hand out for patients at visit 2. Training in 
NovoPen®4 can start at screening (visit 1) and s.c. administration of concizumab using the 
NovoPen®4 can start at the first dose at the trial site (visit 2). Patients must be instructed that 
injections are to be performed subcutaneously, not intravenously. Concizumab and NovoPen®4 will 
be dispensed to patients at visit 2. Training must be performed at site until patients feel comfortable
using the device or performing the treatment. The training must be documented in the medical 
records.
Detailed instructions can be found in the DFU.
8.6.2.2
Turoctocog alfa
A direction for use (DFU) will be available as hand out for patients at visit 1. Training must be 
performed at site until patients feel comfortable performing the treatment. The training must be 
documented in the medical records. 
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Detailed instructions can be found in the DFU.
8.6.2.3
eDiary
Training on the use of the eDiary can start at visit 1. The eDiary will be provided to the patients at 
visit 2.
Training must be repeated at the site until patients feel comfortable using the device. The training 
must be documented in the medical records.
During the home treatment period the patient must ensure that all home treatments of concizumab, 
details of bleeding episodes and the turoctocog alfa (FVIII) treatment associated with these bleeding 
episodes are captured in the eDiary as instructed and trained by investigator or delegated staff.
It will be the responsibility of the investigator or delegated staff to assess the eDiary data 
throughout the conduct of the trial and to ensure data entry compliance (timely entry, no duplicates 
data, no missing data etc.) and retraining if necessary.
For patients completing the trial or in case of withdrawal, the eDiary will be collected at the end of 
trial.
8.6.3
Surgery
Minor surgery can be performed within this trial at the investigator’s discretion according to local 
guidelines. Definition of minor surgery, see section 5.1.1. Major surgery is not allowed, see 
exclusion criteria no 6.
For minor surgery the following should be recorded in the eCRF:
!
Date, stop time and dose of preventive treatment with turoctocog alfa before surgery, if this was
deemed necessary by the investigator
!
Indication for surgery
!
Location of surgery
!
Date of surgery
!
Start and stop time of surgery
8.7
Patient compliance
Throughout the trial, the investigator will remind the patients to follow the trial procedures and 
requirements to ensure patient compliance. If a patient is found to be non-compliant, the 
investigator will remind the patient in the importance of following the instructions given including 
taking the trial products as prescribed.
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Assessment of patient compliance with protocol procedures for determination of continuation of the 
trial will be done by the investigator on an ongoing basis.
8.8
Treatment compliance:
Treatment compliance will be monitored and documented through timely review of eDiary data and 
drug accountability. 
Concizumab will be administered at the trial site at visit 2 supervised by medically trained trial staff
and administration at home can be initiated after visit 2 if the patient feels comfortable with the s.c. 
administration. Administration of turoctocog alfa (rFVIII) for bleeding episodes will be 
administered at the trial site by a medically trained trial staff or at home by the patient, see section 
8.3.1. 
The patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator. Drug accountability will be performed and will be used to assess 
patient compliance together with the patient’s adherence to trial procedures. 
Compliance check includes a cross check between records in EDC/eDiary (number of 
administrations and bleeding episodes) and the used/returned cartridges/vials. 
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
The trial product, concizumab B, appears clear to slightly opalescent and colourless to slightly 
yellow. The trial product must not be used if it contains visible particles or discolouration.
The reconstituted turoctocog alfa (FVIII) solution appears as a clear or slightly opalescent solution. 
Do not use the reconstituted solution if it has visible particles or discoloration. 
Trial products must not be dispensed to any person not included in the trial.
9.1
Trial products
The following trial products will be provided by Novo Nordisk, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
concizumab B 
(IMP a)
100 mg/mL
Solution for injection
s.c. injection
3 ml cartridge
turoctocog alfa
(NIMP b)
2000 IU/vial
Powder for solution for 
injection
i.v. injection
Vial
0.9% Sodium Chloride 
Solution
(NIMP b)  
N/A
Solvent for solution for
injection 
i.v. injection
4 ml prefilled 
syringe
a Investigational Medicinal Product (IMP) 
b Non-Investigational Medical Product (NIMP) given as NIMP for bleeding episodes
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. NovoPen®4 will be labelled in accordance with the EMA directive on medical devices 
annex I 21 and similar national legislation. A description on how to use the device is given in the
DFU.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 22, local regulations and trial 
requirements.
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Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial products will be distributed to the trial sites according to enrolment 
and drug dispensing of distribution.
The investigator must document that direction for use is given to the patient orally and in writing at 
the first dispensing visit (see flow chart section 2). 
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time a
concizumab B 100 mg/mL
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
Store at room temperature 
(below 30°C)
Do not refrigerate
Protect from light
Use within 4 weeks 
(28 days)
turoctocog alfa
2000 IU/vial
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
May be stored at room 
temperature (9-30oC) for a 
single period not exceeding 9
months. Do not return the 
product to the refrigerator.
Write the start date for the 
storage at room temperature on 
the label
For single use
To be used immediately after 
reconstitution
Use within 4 hours after 
reconstitution when stored at 
room temperature
N/A
0.9% sodium chloride 
solution
Store at 2°-30°C
Do not freeze
Protect from light
For single use
N/A
a In-use time for concizumab starts when first dose is administrated from an individual cartridge and for turoctocog alfa 
when the product is reconstituted
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any patient before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
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Investigator must instruct the patient to use and store trial product according to the label.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator. The 
patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator except for the sodium chloride solution which should be discarded at 
home and not accounted for.
All cartridges (concizumab) and vials (FVIII) must be accounted for as used, partly used, or unused. 
The investigator will perform drug accountability using the IWRS Drug Accountability module.
Returned trial product (used/partly used and unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Destruction of concizumab can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
For Japan only: Responsibility for storage and drug accountability of the trial drug product at the 
trial site rests with the head of the trial site. The head of the trial site could assign some or all of the 
responsibilities for accountability of the trial drug product at the trial sites to a trial product storage 
manager (a pharmacist in principle). The trial product storage manager should control and take 
accountability of the trial drug product in accordance with procedures specified by Novo Nordisk. 
The head of the trial site or the trial product storage manager must ensure the availability of proper 
storage conditions, and record and evaluate the temperature.
9.5
Auxiliary supplies
Novo Nordisk will provide the auxiliaries for this trial: 
!
For concizumab administration: NovoPen®4, needles, and DFU
!
For turoctocog alfa reconstitution and administration: Trial Injection Kit and DFU
Only needles and trial injection kits provided by Novo Nordisk must be used for administration of 
trial product.  
For further guidance please see the TMM.
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for:
!
Screening
!
Screening failure
!
Medication arrival
!
Dispensing
!
Dispensing verification
!
Treatment discontinuation 
!
Completion
!
Drug accountability
!
Data change
An IWRS user manual will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
Randomisation 
Not applicable for this trial
Breaking of blinded codes
Not applicable for this trial.
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12 Adverse events, and technical complaints
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial 
procedures performed before exposure to trial product (pre-existing conditions should be 
reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the patient has signed the informed 
consent.
!
Bleeding episodes and other symptoms (e.g. pain, swelling, synovitis, arthralgia, injection 
site haematoma) in connection with bleeding episodes should not be reported as AEs/SAEs 
unless the event is fatal, life-threatening or evaluated by the investigator as related to trial 
product or trial procedure. All bleeding episodes and other findings related to underlying 
disease will be captured in the eCRF/eDiary
The following three definitions are used when assessing an AE:
!
Severity 
o
Mild – no or transient symptoms, no interference with the patient’s daily activities.
o
Moderate – marked symptoms, moderate interference with the patient’s daily activities.
o
Severe – considerable interference with the patient’s daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial product(s): 
o
Probable - Good reason and sufficient documentation to assume a causal relationship.
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o
Possible - A causal relationship is conceivable and cannot be dismissed.
o
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome 
o
Recovered/resolved - The patient has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the patient signed the informed consent.
o
Recovering/resolving - The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the trial 
or has died from another AE.
o
Recovered/resolved with sequelae - The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
o
Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known.
o
Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he 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.
o
Unknown - This term is only applicable if the patient is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
a. The term “life threatening” in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
b. The term “hospitalisation” is used when a patient: 
o
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
o
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c.A substantial disruption of a patient’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the patient has significant, persistent or permanent change, 
impairment, damage or disruption in his body function or structure, physical activity and/or quality 
of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
Suspicion of transmission of infectious agents via the trial product 
!
Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative 
aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error unless 
it results in administration of wrong drug.
!
Wrong route of administration, 
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. However, the 
administered dose must deviate from the intended dose to an extent where clinical 
consequences for the trial patient were likely to happen as judged by the investigator, 
although they did not necessarily occur
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1
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12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
In this trial the following AEs require the completion of specific event forms in the eCRF:
!
Injection site reaction (see section 8.4.5.2)
!
Hypersensitivity type reactions, incl. anaphylactic reactions, as defined below 
Injection site reactions:
Any injection site reaction symptom must be reported on the AE form and the injection site reaction 
form, See section 8.4.5.2.
Hypersensitivity type reactions:
In cases where clinical signs of a severe and immediate hypersensitivity reaction resembling a type
I hypersensitivity reaction are present, blood should be sampled for central laboratory assessment of 
anti-drug IgE antibodies and anti-drug binding antibodies. In the event of an immediate systemic 
hypersensitivity reaction to the trial product, it is recommended to also test for tryptase (total and/or 
mature tryptase) within 3 hours of the reaction. Moreover, a baseline tryptase measurement is 
necessary ~1 week after the immediate severe hypersensitivity reaction due to individual to 
individual variation in tryptase baseline concentration. Tryptase concentrations (if measured) must 
be interpreted and considered in the context of a complete workup of each patient.
Special attention should be given to clinical signs and symptoms of hypersensitivity reactions of 
type II and III. Common clinical signs and symptoms characteristic for these types of reactions may 
include but are not limited to: fever/malaise, cutaneous eruptions, arthralgia, lymphadenopathy, 
itching, headaches and myalgia. Related laboratory findings may include but are not limited to: mild 
proteinuria or haematuria, leukopenia or leucocytosis, decreased complement levels or increased 
complement split products and transient elevations of serum creatinine levels. In cases where there 
is a suspicion of hypersensitivity reaction that requires systemic treatment, additional sampling for 
the purpose of measuring ADA is to be performed.
Definition of anaphylaxis23
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
!
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (e.g. generalised hives, pruritus or flushing, swollen lips-tongue-uvula) and 
at least one of the following:
a) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)
b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.
hypotonia [collapse], syncope, incontinence)
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!
Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):
a) Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush, swollen 
lips-tongue-uvula)
b) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
!
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
Systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
BP.
If a patient fulfils any of the three criteria of anaphylaxis outlined above, the patient should receive 
epinephrine/adrenalin immediately. Dose regimen should be according to hospital operating 
procedure, and the patient should be transferred to an emergency department or intensive care unit, 
if clinically warranted.
Events not fulfilling the criteria for an anaphylactic reaction and other allergic reactions must be 
treated at the discretion of the investigator. If according to the investigators judgment, 
hypersensitivity type reactions that require systemic treatment are suspected, dosing with 
concizumab should be stopped immediately and treatment at the discretion of the treating physician 
initiated.
12.1.6
Adverse event of special interest
An adverse event of special interest (AESI) is an event, which in the evaluation of safety, has a 
special focus. In this trial, the following AEs fulfil the AESI criteria:
!
Thromboembolic events including but not limited to,
o
disseminated intravascular coagulation (DIC) (A), 
o
clinical signs or laboratory indications of arterial and venous thrombosis including 
myocardial infarction (B), 
o
pulmonary embolism (C), 
o
stroke (D), 
o
deep vein thrombosis (E), 
o
other clinically significant thromboembolic events (F) and peripheral artery 
occlusion (see below G), see definitions below.
The AESIs must be reported on an AE form and a safety information form.
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A) Definition of disseminated intravascular coagulation (DIC), as defined below:
The definition of DIC in this trial should be made according to the International Society on
Thrombosis and Haemostasis (ISTH) criteria. Thus, a DIC diagnosis may be based on 
clinical signs and symptoms of a bleeding tendency or thrombotic tendency, organ 
dysfunction and the laboratory parameters criteria as listed below:
o
Platelet count (>100 × 109/L = 0, <100 × 109/L = 1, <50 × 109/L = 2)
o
Elevated D-dimer (no increase = 0, moderate increase = 2, strong increase = 3)
o
Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
o
Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
o
Calculate score: ≥5 compatible with overt DIC
(B) Myocardial infarction is defined according to the “Third Universal Definition of
Myocardical Infarction” 24
Criteria for acute myocardial infarction - The term acute myocardial infarction (MI) should be used 
when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial 
ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI:
!
Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin
(cTn)] with at least one value above the 99th percentile upper reference limit (URL) and
with at least one of the following:
o
Symptoms of ischemia.
o
New or presumed new significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB).
o
Development of pathological Q waves in the ECG.
o
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality.
o
Identification of an intracoronary thrombus by angiography or autopsy.
Criteria for prior myocardial infarction- Any one of the following criteria meets the diagnosis for
prior MI:
!
Pathological Q waves with or without symptoms in the absence of non-ischemic causes.
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to
contract, in the absence of a non-ischemic cause.
!
Pathological findings of a prior MI.
Recurrent myocardial infarction - Incident MI’ is defined as the individual’s first MI. When features 
of MI occur in the first 28 days after an incident event, this is not counted as a new event for 
epidemiological purposes. If characteristics of MI occur after 28 days following an incident MI, it is
considered to be a recurrent MI.
C) Definition of pulmonary embolism:
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The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends diagnostic
imaging studies for patients with intermediate or high pre-test probability of pulmonary embolism25.
Accordingly, the definition of pulmonary embolism is the following: obstruction of a pulmonary 
artery or one of its branches, most frequently by detached fragments of thrombus from a leg or 
pelvic vein, diagnosed by at least one of the following:
!
Positive findings in ventilation/perfusion scan
!
Positive findings in a spiral (helical) computerised tomography (CT) or angiography
!
Positive findings in a magnetic resonance imaging (MRI)
!
Positive findings in a pulmonary angiography
D) Definition of stroke:
The definition of central nervous infarction is according to the American Heart
Association/American Stroke Association Expert Consensus Document:  “An Updated Definition of 
Stroke for the 21st Century”26.
Accordingly, the term “stroke” should be broadly used to include all of the following:
Definition of central nervous system (CNS) infarction: CNS infarction is brain, spinal
cord, or retinal cell death attributable to ischemia, based on:
o
1. pathological, imaging, or other objective evidence of cerebral, spinal cord, or
retinal focal ischemic injury in a defined vascular distribution; or
o
2. clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on
symptoms persisting 24 hours or until death, and other etiologies excluded.
Note: CNS infarction includes haemorrhagic infarctions, types I and II; see “Haemorrhagic
Infarction”.
Definition of ischemic stroke: An episode of neurological dysfunction caused by focal cerebral,
spinal, or retinal infarction. Note: Evidence of CNS infarction is defined above.
Definition of silent CNS infarction: Imaging or neuropathological evidence of CNS infarction,
without a history of acute neurological dysfunction attributable to the lesion.
Definition of intracerebral haemorrhage: A focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma. Note: Intracerebral haemorrhage includes
parenchymal haemorrhages after CNS infarction, types I and II - see “Haemorragic Infarction”.
Definition of stroke caused by intracerebral haemorrhage: Rapidly developing clinical signs of
neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma.
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Definition of silent cerebral haemorrhage: A focal collection of chronic blood products within the
brain parenchyma, subarachnoid space, or ventricular system on neuroimaging or neuropathological
examination that is not caused by trauma and without a history of acute neurological dysfunction
attributable to the lesion.
Definition of subarachnoid haemorrhage: Bleeding into the subarachnoid space (the space between
the arachnoid membrane and the pia mater of the brain or spinal cord).
Definition of stroke caused by subarachnoid haemorrhage: Rapidly developing signs of
neurological dysfunction and/or headache because of bleeding into the subarachnoid space (the
space between the arachnoid membrane and the pia mater of the brain or spinal cord), which is not
caused by trauma.
Definition of stroke caused by cerebral venous thrombosis: Infarction or haemorrhage in the brain,
spinal cord, or retina because of thrombosis of a cerebral venous structure. Symptoms or signs
caused by reversible edema without infarction or haemorrhage do not qualify as stroke.
Definition of stroke, not otherwise specified: An episode of acute neurological dysfunction 
presumed to be caused by ischemia or haemorrhage, persisting ≥24 hours or until death, but without
sufficient evidence to be classified as one of the above.
Definition of a Transient Ischemic Attack: The definition of Transient Ischemic Attack is according
to the American Heart Association/American Stroke Association. Accordingly: a Transient 
ischemic attack (TIA) is a transient episode of neurological dysfunction caused by focal brain, 
spinal cord, or retinal ischemia, without acute infarction 27.
E) Definition of deep vein thrombosis:
The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends
ultrasound scanning for patients with intermediate or high pre-test probability of deep vein 
thrombosis (DVT) in the lower extremities 25. Accordingly, venous thrombosis should be 
demonstrated by compression ultrasound,
duplex ultrasound, colour Doppler imaging or venography (phlebography).
F) Definition of other clinically significant thromboembolic events:
Signs or suspicion of a clinically significant thromboembolic event (e.g. visceral arterial 
embolus/thrombus, extremity arterial embolus/thrombus, or portal venous thrombosis).
Superficial thrombophlebitis is not considered a clinically significant thromboembolic event unless 
evaluated as such by the investigator.
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G) Definition of peripheral artery occlusion:
Clinical signs of acute arterial occlusion verified by ankle-brachial index (ABI) test, Doppler and
ultrasound (Duplex) imaging, computerised tomographic angiography, magnetic resonance 
angiogram (MRA), or conventional angiography. The 2011 American College of Cardiology 
Foundation/American Heart Association Focused Update of the Guideline for the Management of 
Patients With Peripheral Artery Disease could serve as a reference for the diagnosis of lower 
extremity peripheral artery disease 28
12.1.7
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between pen and needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the patient has signed the informed consent until the end of 
the post-treatment follow-up period (visit 17). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12–1
During each contact with the trial site staff, the patient must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?
All AEs, either observed by the investigator or patient, must be reported by the investigator and 
evaluated. All AEs must be recorded by the investigator on an AE form. The investigator should 
report the diagnosis, if available. If no diagnosis is available, the investigator should record each 
sign and symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
AESIs regardless of the seriousness, must be reported using the AE form and safety information 
form
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For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the case report form (CRF)/eCRF within the 
specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator’s first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in the 
eCRF. 
For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
!
Non-serious AEs fulfilling the AESI criteria: The AE form and safety information form 
within 14 calendar days of the investigator’s first knowledge of the event.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: Investigator’s Brochure; Current version and any updates thereto.
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP 1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the
International Review Boards/Independent Ethics Committees (IRBs/IECs) of trial product-related 
SUSARs in accordance with local requirement and ICH GCP 1, unless locally this is an obligation 
of the investigator.
Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
non-investigational medicinal product rFVIII (turoctocog alfa) or concomitant medication in the 
trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to report this 
adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. 
Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is 
“recovered/resolved”, “recovered/resolved with sequelae” or “fatal”, and until all queries 
have been resolved. Cases of chronic conditions, cancer or AEs ongoing at time of death 
(where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the 
outcome of “recovering/resolving” when the patient has completed the follow-up period 
and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
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information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or 
until the end of the follow-up period stated in the protocol, whichever comes first, and 
until all queries related to these AEs have been resolved. Cases of chronic conditions, 
cancer or AEs ongoing at time of death (where death is due to another AE) may be 
closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the patient has 
completed the follow-up period and is expected by the investigator to recover.
!
Non-serious AEs fulfilling the AESI criteria: Non-serious AE fulfilling the AESI 
criteria must be followed as specified for non-serious AE. Follow-up information on 
AESIs 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 AESI criteria.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a patient after the patient has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 
!
Concizumab B 100 mg/mL, solution for injection in a 3 ml cartridge
!
NovoPen®4
!
Novo Nordisk needles
!
Turoctocog alfa 2000 IU/vial, powder for solution for injection in a vial  
!
0.9 % sodium chloride 4.0 mL prefilled syringe
!
Novo Nordisk trial injection kit
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which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Centre, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, AESIs and/or 
SAEs.
Technical complaints must be reported on a separate technical complaint form: 
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each batch, code or lot number
must be completed
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not patient related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Centre, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. 
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12.5
Pregnancies 
12.5.1
Pregnancies in female partners of male patients
Male patients must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period (from visit 1 to dosing at visit 2). At the last 
scheduled visit, male patients must be asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male patient and assess, if the pregnancy 
outcome is normal or abnormal. 
When the pregnancy outcome is normal this information is recorded in the patient’s medical record 
only, no further information is collected and reported to Novo Nordisk. When the pregnancy 
outcome is abnormal (i.e. congenital anomalies, foetal death including spontaneous abortion and/or 
any anomalies of the foetus observed at gross examination or during autopsy), the following must 
be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
1. Reporting of pregnancy information
Information from the male patient has to be reported on the Paternal Form. Furthermore, 
information from the female partner (including information about the pregnancy outcome and 
health status of the infant until the age of one month) has to be reported on the Maternal Forms 
1A, 1B and 2, after an informed consent has been obtained from the female partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information. 
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
o
Non-serious AEs evaluated as possible/probably related to the father’s treatment 
with the trial product(s). 
o
SAEs in the foetus and newborn infant - whether or not related to the father’s 
treatment with the trial product(s). This includes an abnormal outcome - such as 
foetal death (including spontaneous abortion) and congenital anomalies (including 
those observed at gross examination or during autopsy of the foetus).
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
Paper AE forma within 14 calendar days of the investigator’s first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
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!
Paper AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
Paper safety information form within 5 calendar days of the investigator’s first knowledge 
of the SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information.
a It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
patient, foetus or new born infant. 
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Dose limiting toxicities of concizumab has not been investigated in clinical trials.
There have been no reports about overdosing of concizumab and therefore no experience with 
overdose and overdose reactions exists. In case of a concizumab overdose, symptomatic medical 
treatment according to the clinical condition should be applied. No antidote exists in case of 
concizumab overdose.
Any overdose should be reported as an AE, with or without clinical manifestations. Overdoses are 
considered medication errors.
Treatment should be as appropriate and in accordance with hospital practice and guidelines.
12.7
Rules for putting enrolment on hold
If one of below mentioned criteria is fulfilled, enrolment of additional patients in the clinical trial 
program will be placed on hold. An urgent safety committee meeting will be scheduled to decide 
further actions. Dosing of patients on treatment may continue while further evaluation is made by 
the safety committee. 
!
Significant thromboembolic event* 
!
Event of DIC 
!
Anaphylactic reaction related to trial drug administration 
!
Death of trial patient which may be related to the trial product
* Superficial thrombophlebitis or venous thrombosis associated with indwelling catheters is not considered a significant 
thromboembolic event unless evaluated as such by the investigator
If two or more other trial product related SAEs similar in nature have been reported and/or detected 
by laboratory measurements, or if trends in AEs, clinical observations or laboratory parameters 
raise concerns about the safety of continued treatment, the safety committee (see section 12.8.1) 
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will then decide whether further dosing of any patients in the clinical trial program should be 
continued, paused or discontinued.
12.8
Committees related to safety
12.8.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal concizumab safety committee to perform ongoing safety 
surveillance of safety data relevant to concizumab. The safety committee is a cross functional group 
within Novo Nordisk.
12.8.2
Data monitoring committee
The DMC is an independent, external committee composed of members whose expertise covers 
relevant specialties including statistics. The DMC is established to review and evaluate accumulated 
data from the trial at predefined time points as well as ad-hoc. This is in order to protect the safety 
of the patients and to evaluate the benefit-risk balance. The DMC will have access to the unblinded
data, and will provide recommendations on trial continuation, modification or termination.
In case there is any safety concern data will be compiled and the DMC will review these data. Their 
recommendation will go to the Novo Nordisk Safety committee for final decision of what next step 
is in this trial.
The DMC members will only have direct contact with the Novo Nordisk Global Safety department 
through the safety surveillance representatives, and will have no direct interaction with those in trial 
management. The DMC recommendations should be addressed directly to the Novo Nordisk Global 
Safety department and the internal Novo Nordisk safety committee for concizumab. It is the 
responsibility of the Novo Nordisk internal safety committee for concizumab to take action(s) for
patient safety based on the DMC recommendations.
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter.
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13 Case report forms 
For this trial a combination of electronic case report forms (eCRFs) and paper CRFs will be used.
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
Safety information forms
!
Technical complaint forms 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
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Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
13.3
Electronic diary
Novo Nordisk will provide the patient with an eDiary for electronic recording of details of their 
home treatment, bleeding episodes and treatment of bleeding episodes (i.e. use of FVIII). The 
eDiary and related support services will be supplied by a vendor working under the direction and 
supervision of Novo Nordisk. 
Patients will be instructed in the use of the eDiary by the investigator or delegated person before 
entering of any data. The eDiary will be dispensed to the patient at visit 2. After visit 2 and 
onwards, data will be entered by the patient in the eDiary device during home treatment.
The eDiary will be returned by the patient at the end of trial (EOT) visit.
All data entered will be transferred from the device to an electronic database, where it is kept as a 
certified copy of the source data by the eDiary vendor. Data entered in the device will upon 
confirmation of a successful back-up be deleted from the device. 
The eDiary will have built in edit checks and reminders, to ensure that all relevant questions are 
answered. 
eDiary data transferred to the electronic database will be viewable to relevant trial site staff and 
Novo Nordisk personnel on a secure, password protected web portal.
13.3.1
Investigator review of eDiary data
It is the responsibility of the Investigator or delegated staff to review the eDiary data reported by the 
patient. As a minimum it must be verified that the eDiary data is complete, consistent and according 
to the requirements defined in this protocol. This also includes that the number of doses reported in 
the eDiary is reviewed against the number of vials/cartridge accounted for as used by the patient.  
Upon review the Investigator must document that the review has taken place and any actions 
required e.g. retraining of the patient or decision to amend or correct the data reported by the 
patient. 
If the Investigator finds it necessary to amend or correct eDiary data, the patient must be consulted 
prior to requesting the actual data change. A Data Correction Request must be submitted to the 
eDiary vendor. An audit trail will be maintained.
14 Monitoring procedures 
Monitoring will be conducted using a risk based approach including risk assessment, monitoring 
plans, centralised monitoring and visits to trial sites. During the course of the trial, the monitor will 
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visit the trial site to ensure that the protocol is adhered to, that all issues have been recorded, to 
perform source data verification and to monitor drug accountability. The first monitoring visit will 
be performed as soon as possible after FPFV at the trial site and no later than 4 weeks after. The 
monitoring visit intervals will depend on the outcome of the centralised monitoring of the eCRFs 
(remote assessment of data by Novo Nordisk), the trial site's recruitment rate and the compliance of 
the trial site to the protocol and GCP, but will not exceed 12 weeks until LPLV at the trial site. This 
only applies to sites with scheduled, ongoing and/or discontinued patients.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone or text message).
All data must be verifiable in source documentation other than the eCRF. eDiary data is entered by 
the patient and will also be treated as source data. 
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
For historical data such as medical history, details of haemophilia and haemophilia treatment 
history, a reasonable effort must be made by the investigator, considering local requirements, to 
obtain this information from external sources, if not known by the patient. It is accepted that the 
earliest practically retainable record should be considered as the location of the source data and 
therefore the source document. This means that for laboratory results (e.g. biochemistry and 
haematology) a signed printout of the electronic results must be available.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated
by the person making the correction.
The monitor will ensure that the eCRFs are completed and paper CRFs (if any) collected, that PROs 
and eDiaries are completed and reviewed by the investigator at the relevant scheduled visits and 
needed action has been taken and documented, if any.
The following data will be source data verified for screening failures:
!
Date for obtaining informed consent
!
Inclusion and exclusion criteria
!
Screen failure reason if possible
!
Date patient left the trial
!
Data relating to AEs if applicable
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!
Demography (See section 8.2.1)
!
Date of visit
Monitors will review the patient’s medical records and other source data (e.g. eDiaries and ePROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract reseach organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of patientdata, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The laboratory will provide all laboratory reports to the investigator for filing at the trial site. The 
laboratory report must be signedand dated by the investigator or delegated person and stored at the 
trial siteas source data.
The patientand any biological material obtained from the patientwill be identified by patient
number and trial ID. Appropriate measures such as encryption orleaving out certain identifiers will 
be enforced to protect the identity of patients in all presentations and publications as required by 
local, regional and national requirements
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk 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 use the Global Haemophilia Network (GHN) Investigator Portal to distribute 
and share trial-related documents and information with the participating sites.
After trial completion, Novo Nordisk will supply each trial site with long-life CDs or other relevant 
electronic archiving containing the electronic Investigator Trial Master File (eITMF) for each trial 
site. These CDs or other relevant electronic archiving will contain site-specific trial documentation 
as well as trial specific news and other relevant trial information, including audit trail on documents 
and site staff users. The GHN Portal software and hardware implementation are compliant with the 
requirements of U.S. Food and Drug Administration (FDA)21 CFR Part11 and ICH E6 (EU 
directive for personal data protection)1,29.
Novo Nordisk will provide electronic tablets for reporting of all PROs questionnaires described in 
section8.6.1and in Appendix 1. In case the electronic tablet is revoked the questionnaires will be 
available in paper.
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The eDiary software and hardware implementation are compliant with the requirements of FDA 21
CFR Part 11 and ICH E6 (EU directive for personal data protection)1, 29.After trial completion, each 
trial site will be supplied with long-life CDs. These CDs will contain site-specific patient records 
including the patient’s eDiaries and ePROs as PROs are handled seperately from eDiary and audit 
trail including any data additions and corrections made on each form. The eDiary vendor will 
furthermore retain and securely store copies of all archived documents and data for 15 years or as 
required by local data retention laws for trial data
17 Statistical considerations
All endpoints referring to a time frame of at least 24 weeks will be evaluated in the main part of the 
trial, defined to end when the last patient have completed a minimum of 24 weeks of dosing or at 
LPFT (visit 2)+24 weeks if the last patient has withdrawn before visit 9. Please refer to Figure 17–1
for further information. All available data up to the time point where the last patient ends 24 weeks 
of treatment or has withdrawn will in such case be used in the analysis of the main part.
Endpoints comprising number of bleeding episodes will be evaluated based on treated bleeding 
episodes only. Multiple bleeding locations occurring from the same event (e.g., due to a bicycle 
accident) or at the same time point will be counted as one bleeding episode. Further, the endpoints 
will not include re-bleed.
A re-bleed is defined as a bleeding episode (worsening of bleeding site conditions e.g. swelling, 
pain) within 72 hours after stopping of a previous bleeding episode at the same (or subset of the 
same) anatomical location. If a bleeding episode occurs in the same location 72 hours after 
stopping, the treatment is defined as a new bleeding episode.
Clinical proof of concept
The statistical analysis of the collected data aims to establish CPoC that concizumab is efficacious 
in preventing bleeding episodes in haemophilia A patients without inhibitors. The objective will be 
assessed when the last of the 30 patients have completed 24 weeks of dosing (or have withdrawn). 
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the ABR of all patients with a threshold of 12, irrespective of individual dose 
titration. The primary CPoC criterion aims at evaluating the effect of concizumab at the last dose 
level reached for a patient. Hence, for this evaluation, only observations from the period where 
patients are on their end dose at time of analysis will contribute to the analysis. Furthermore, 
observations from the 2 week run-in period will be not be included. Since this evaluation disregards 
a subset of data collected the result should be viewed taking in to account the potential bias. The 
second CPoC criterion aims at evaluating the effect of concizumab when given as an escalation 
regimen. Hence, this will compare the ABR of haemophilia A patients treated with concizumab 
with the typical historical ABR of haemophilia A patients being treated on-demand using all data 
after enrolment. The second CPoC criterion will only be evaluated if the first one succeeds.
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The referred comparisons will be made using a negative binomial model with log of exposure time 
in main phase as offset. For each criterion, evidence of effect will be concluded if the 95% 
confidence interval of the estimated ABR is below 12. 
The value of 12 bleeds per year reflects conservatively a 50% reduction from the bleeding rate 
during on-demand treatment, which in previous trials typically has been reported to be above 30 
bleeds per year 30-32. A confidence limit lower than 12 will also to a certain extent substantiate that 
the prophylactic efficacy of concizumab may be similar to that of FVIII replacement therapy where 
an estimated mean of 6.5 bleeds per year was observed33.
Clinical arguments for the hierarchical test approach
Concizumab exhibits non-linear PK due to target mediated drug disposition and it is expected that 
the dose response curve of the ABR is rather steep. This implies that patients that are on a dose 
which is not efficacious are likely to bleed as patients that are not treated at all. The subset of data 
collected from the last dose clinically deemed as efficacious would reflect the efficacy of 
concizumab in the given patient.
17.1
Sample size calculation
The sample size calculation has been determined taking the small patient population into account, 
while also aiming for an acceptably narrow 95% confidence interval for the ABR. 
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be
accommodated by 30 patients. 
It is expected that the treatment duration of the main part allowing for escalation time for some 
patients is on average 6 months in the below calculations. 
When evaluating the power of the negative binomial analysis referred above, an annual bleeding 
rate of 4 is assumed for the end dose concizumab regimen, respectively in combination with an 
over-dispersion of 6. The power for concluding a bleeding rate lower than 12 then becomes 
approximately 95%. The power under varying values of true ABR and over-dispersion for the 
primary CPoC criterion are shown below in Table 17–1.
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion.
Power
Over-dispersion
ABR
5
6
7
4
99%
95%
92%
5
95%
90%
86%
6
87%
81%
72%
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For the secondary CPoC criterion that includes data prior to potential dose escalation, it is expected 
that the treatment duration of the main part is on average 8 months with an average ABR of 5.4 for 
the concizumab treated patients. This yields a marginal power of approximately 87% for the 
secondary CPoC criterion. 
In prior Novo Nordisk trials conducted in haemophilia patients, the typical 1-year over-dispersion 
for non-inhibitor patients on prophylaxis with FVIII or FIX has been in the range 4-8, implying 24 
weeks over-dispersion of 3-5 (e.g. in NN7008-3543, NN7088-3859 and NN7999-3747). On that 
background, an over-dispersion of 6 over the 24 weeks in the main part of the current trial is 
deemed realistic.
17.2
Definition of analysis sets
All dosed patients will be included in the Full Analysis Set (FAS) as well as in the Safety Analysis 
Set (SAS).
17.3
Primary endpoint
The primary endpoint is the number of bleeding episodes during at least 24 weeks from treatment 
onset.
The primary endpoint will be estimated using negative binomial regression with log of exposure 
time in main phase as offset, providing an actual estimate of the ABR as well as a corresponding 
95% confidence interval.
This analysis has the underlying assumption that the missing data mechanism is “missing at 
random”, i.e. MAR. Under this assumption, the statistical behaviour of the missing data (given the 
observed responses and the mean value structure) is assumed to be the same as for the observed 
data. The endpoint will be estimated based on the full analysis set (FAS) and only data collected 
prior to discontinuation of trial product or initiation of alternative treatment options will be used to 
draw inference.
17.4
Sensitivity analyses
To evaluate the robustness of the MAR assumption implied in the primary analysis, a modified 
tipping point analysis will be performed where patients having discontinued before finalization of 
the main part are assumed to have a worse outcome compared to what was observed during the 
main part of the trial. This will be done by adding a value Δi to the observed bleeding episodes in 
the main part of the trial before analysing the data. The offset is maintained as being the exposure 
during the main phase since it is not possible to identify the amount of missing observation 
time.The degree of worsening, Δi, will gradually be increased to evaluate at which point the upper 
95% confidence limit of the prophylactic concizumab ABR is no longer below a threshold of 12.
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The results of the primary analysis will be considered robust if the tipping point is above what is 
considered clinical plausible.
17.5
Additional analyses
An additional evaluation of the primary endpoint will be made, including actual concizumab dose 
level as additional factor in the primary analysis model specified above. Point estimates and 95% 
confidence interval will be provided for the ABR at the different dose levels of concizumab (0.15, 
0.20 and 0.25 mg/kg). Furthermore, an analysis with individual steady state PK/PD assessments 
included as covariates in the negative binomial regression model as specified for the primary 
analysis will be performed in order to evaluate possible associations between PK/PD and ABR that 
potentially could guide dose-selection. The referred steady-state PK/PD assessments comprise the 
concizumab trough level, maximum plasma concentration (Cmax) of concizumab, TFPI value prior 
to the last s.c. dose administration, peak thrombin generation (nM), Endogenous thrombin potential  
(nM*min) and velocity index (nM/min).
17.6
Secondary endpoints
17.6.1
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during 76 weeks from treatment onset.
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment 
onset.
!
The number of spontaneous bleeding episodes during 76 weeks from treatment onset.
The supportive secondary endpoints will be estimated using the same negative binomial regression 
model as the primary endpoint.
17.6.2
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during 76 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during 76 weeks from treatment onset.
!
Change from baseline of fibrinogen during 24 weeks from treatment onset.
!
Change from baseline of fibrinogen during 76 weeks from treatment onset.
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!
Change from baseline of D-dimer during 24 weeks from treatment onset.
!
Change from baseline of D-dimer during 76 weeks from treatment onset
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset.
!
Change from baseline of F1 + 2 during 76 weeks from treatment onset.
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset.
!
Change from baseline of PT during 76 weeks from treatment onset.
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset.
!
Change from baseline of APTT during 76 weeks from treatment onset.
!
Change from baseline of antithrombin (AT) during 24 weeks from treatment onset.
!
Change from baseline of AT 76 weeks from treatment onset.
Adverse Events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has onset from the first 
exposure to treatment until the last visit in the trial. Treatment-emergent adverse event endpoints 
will be summarised by system organ class, preferred term, seriousness, severity and relation to trial 
product. All Adverse events will further be listed.
Frequency of binding anti-concizumab antibodies will by listed and summarised by time frame 
according to the two endpoint definitions.
All laboratory safety endpoints will be plotted by time, both as absolute values and change from 
baseline. Laboratory safety endpoints will further be summarised and listed.
17.6.3
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks.
!
Concentration of concizumab prior to the last dose administration at 76 weeks.
The pharmacokinetic endpoints will be summarised and listed.
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17.6.4
Supportive secondary pharmacodynamic endpoints
Free TFPI concentration:
!
Value prior to the last dose administration at 24 weeks.
!
Value prior to the last dose administration at 76 weeks.
Thrombin generation:
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks.
!
Peak thrombin generation (nM) prior to the last dose administration at 76 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 76 weeks.
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks.
!
Velocity index (nM/min) prior to the last dose administration at76 weeks.
The PD endpoints will be summarized and listed. 
17.7
Exploratory endpoints
17.7.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
Adverse events related to technical complaints will be listed and summarised.
17.7.2
Exploratory patient reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 24 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 76 weeks from treatment onset
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!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Change in PGI-C after 24 weeks from treatment onset
!
Change in PGI-C after 76 weeks from treatment onset
!
Change in H-DAT after 24 weeks from treatment onset
!
Change in H-DAT after 76 weeks from treatment onset
!
Patient reported outcomes (PROs) will be collected using questionnaires at visits 1, 2, 4, 5, 6, 7, 8,
9, 10 and 16. 
Patient reported outcome questionnaires to be analysed:
!
Haemophilia Treatment Experience Measure (Hemo-TEM) 
!
Validated Hemophilia Regimen Treatment Aderence Scale – Prophylaxis (VERITAS-Pro®)
or Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
!
36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
!
Patient Global Impression of Change (PGI-C)
!
Sheehan Disability Scale (SDS)16
!
Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
!
Haemophilia - Device Assessment Tool (H-DAT)
!
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
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VERITAS-Pro®orVERITAS-PRN®, SF-36v2, SDS, TSQM, H-DAT and SIAQ-ISRQ will be 
scored according to their respective scoring algorithms. Change from visit 2 to visit 9 and change 
from visit 2 to visit 16 will be described.
17.8
Interim analysis
The trial does not include a formal interim analysis. However, the split of the trial into a main and 
extension part offers the opportunity of reporting results before the end of the trial. Other reporting 
of the trial might be done during the extension part once the data collection and review of the main 
part data has been finalised and individual clinical study reports might in such case be issued. A 
final clinical study report describing results from the main and extension part will be written when 
the last patient has either completed or withdrawn from the trial.
All main conclusions regarding clinical proof of concept and dose guidance for phase 3 will be 
based on the reporting after the main part, see Figure 17–1.
Figure 17–1
Definition of main and extension part
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18 Ethics
18.1
Benefit-risk assessment of the trial
Benefits
Results from a multiple dose phase 1 trial where concizumab was dosed for approximately 6 weeks 
showed a trend towards efficacy in a limited number of patients who reached concizumab plasma 
concentrations above 100ng/mL., see section 3.1.2. Based on these results, it is expected that the 
majority of the patients treated with concizumab 0.15mg/kg daily dose will be protected from
bleeding episodes. Patients who experience excessive bleeding episodes on the lowest dose will 
have a possibility to be escalated to a higher dose where bleeding preventive efficacy of 
concizumab treatment is expected to improve. Also, concizumab is administered s.c. and might
reduce the burden of frequent i.v. injections associated with current treatment options in
haemophilia A patients without inhibitors as well as significantly reducing the risk of anti-FVIII 
inhibitor development.
Information gained from this trial will contribute to gaining regulatory approval for a product that is 
anticipated to offer clinical advantages over currently available products. 
Risks
No risks have been recognised as identified risks by review of safety data from the activities in the 
clinical development so far. However, the nonclinical toxicity studies have identified 
thromboembolic events as a potential risk when treating non-human primates with concizumab at 
high exposures. 
As observed for other pro-coagulant compounds, there is a potential safety risk of thrombosis and 
vascular ischemia with reaching very high concizumab plasma concentrations. In non-clinical 
toxicity studies with concizumab, thrombi were observed at high doses. However, a NOAEL for 
concizumab has been identified in non-haemophilic animals at plasma concentrations several fold 
higher than the currently anticipated effective plasma concentration (mean AUC and Cmax) based on 
PK modelling.
In clinical trials, except for one case of superficial thrombophlebitis in a healthy volunteer who
received a single dose of 1mg/kg, no other thromboembolic events were observed. A phase 1 
multiple dose trial was finalised in haemophilia A patients (0.8 mg/kg s.c. every 4 days for 6 
weeks). In this clinical trial, marked changes in coagulation parameters were observed including a 
decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range in patients with high plasma concentrations of concizumab. These changes were not 
judged as clinically significant by the investigators and were not followed by thromboembolic AEs 
or an increase in the number of bleeding episodes in the explorer™3 trial.
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A potential risk identified in non-clinical studies is vascular vessel wall changes due to immune 
complex deposition causing localized vascular vessel wall changes such as hypertrophy and 
inflammatory cell infiltration. Concizumab is a foreign protein to animals and it is generally 
recognized that animal studies are limited in their ability to predict human immune responses to a 
therapeutic protein product. The concentrations of concizumab in plasma in animals in the non-
clinical studies have reached levels far above the anticipated effective concentration. Humans are 
expected to have a very low immunogenic response towards a humanised mAb. The antibodies 
towards concizumab have not been observed so far in clinical trials. Furthermore, even if antibodies 
towards concizumab occur, the risk for the rate of immune complex formation exceeding the 
clearance capacity is considered low. Please refer to the Investigator’s Brochure for further 
information including subsequent replacement therapy.
If antibodies against concizumab develop, they might also inhibit the function of the administered 
drug. The consequence of this could be that the patient may not be able to benefit from this drug in 
the future. Antibody development against concizumab is not expected to reduce the effect of other 
treatment options.
Theoretical risks include bleeding due to consumption of coagulation factors and adverse reactions 
due to potentiation of inflammatory reactions or tissue damage due to impairment of tissue repair 
mechanisms 34 35 . TFPI is an important inhibitor of TF which, in addition to its role in haemostasis, 
is implicated in tissue repair processes and in a variety of physiological and pathophysiological 
states where repair mechanisms are activated. These include sepsis, DIC, inflammation, 
atherosclerosis, cancer and crush injuries 36 37, 38. There may be a risk of allergic reactions, including 
severe (anaphylactic) reactions, in connection with concizumab administration. Severe allergic 
reactions may potentially be life-threatening and thus, the trial products will be administered to the 
trial patients at the site under the surveillance of medically trained trial site staff in the beginning of 
the trial.
Overall the anticipated benefits from participating in the trial outweigh the potential risks.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the patient verbal and written 
information about the trial and the procedures involved in a form that the patient can read and 
understand. 
The patients 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.
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The investigator must ensure the patient ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the patient 
before any trial-related activity.  
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically trained staff in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the investigator must inform the patient in a timely manner, and a revised 
written patient information must be provided and a new informed consent must be obtained.
Only applicable for Japan: As a minor is unable to provide legally binding consent, informed 
consent must be sought from the parent(s)/LAR(s) on the child’s behalf prior to enrolling a child in 
the trial, according to local requirements. 
18.3
Data handling
If the patient withdraws from the trial or is lost to follow up, then the patient’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit will be retained by 
Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to patients during trial
All written information to patients must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the patients 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
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also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of patients who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the patients 
should be described.
19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The below process will be in place to prevent missing data in this trial.
The importance of patient retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The patients will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of patient retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
21 Critical documents
An Investigator Portal (Global Haemophilia Network [GHN]) will be used as primary media for 
exchange and handling of investigator trial master file documents between Novo Nordisk and the 
site and for electronic storage of these documents during trial conduct.
Before a trial site is allowed to start screening patients, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, patient information/informed consent form, 
any other written information to be provided to the patient and patient recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure
!
SmPC or similar labelling of rFVIII (turoctocog alfa)
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
Description of research facility obtained (applicable for non-US sites)
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Only applicable for US trial sites: 
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
For local laboratory parameters the following will be collected:
!
Laboratory normal ranges
!
Laboratory certification, quality assurance (QA) scheme or similar documentation
!
Laboratory assay methods (only non-standard assays) and/or analytical methods
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1,
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the patients.
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At least investigator must be trained in the current protocol version at a Novo Nordisk Investigator 
meeting or by the most recent version of the web training. It is recommended that all site staff  
completes the web protocol training.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the patient identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
patients to a specific qualified physician who will be readily available to patients during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
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researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications 39.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure how-we-disclose-trial-information8.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of the main part of the trial and other interim analyses, because the release of such 
information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors 39 (sometimes referred to as the Vancouver 
Criteria).
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23.1.2
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 a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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24 Retention of clinical trial documentation and humanbiosamples
24.1
Retention of clinical trial documentation
Patientsmedical records must be kept for the maximum period permitted by the hospital, institution 
or private practiceaccording to local regulation and practice.
The investigator must agree to archivethe documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other patientdata (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before accessis revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
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.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
Applicable only for Spain25 years retention according to the Spanish Royal Decree 1090/2015
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with localregulatory requirements. 
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24.2
Retention of human biosamples
This trial will involve collection of human biosamples at visit 1 (screening visit), and at visit 17
(end of trial) and these samples are to be stored maximum 15 years from end of trial. In addition,
samples which have been drawn as back up samples during the conduct of the trial and have not 
been analysed will be captured and stored under the same conditions. 
Storage of human biosamples is voluntarily and will not affect the patients’ participation in the trial. 
Therefore, patients will have the possibility to sign the informed consent for the trial and 
participate, while refusing permission for biological specimens to be stored for future exploratory 
analysis.
!
Human biosamples will be stored at the central laboratory.
!
1.2 mL citrated plasma, 1.0 mL serum and/or 2.0 ml whole blood (DNA for genotyping)
will be obtained.
!
The intended use of the stored human biosamples e.g.: As new biomarkers related to the 
disease and/or safety, efficacy, or mechanism of action of concizumab may evolve during 
the conduct of the trial, the analyses of the stored human biosamples may also include 
biomarkers that are unknown at present or have not been included in the scientific 
hypotheses at initiation of the trial 
!
Human biosamples may be transferred to third parties e.g. research consortias
!
The human biosamples will be transferred and stored after the end of trial at a designated 
central laboratory
!
Confidentiality and personal data protection will be ensured during storage after the end of 
trial
!
The human biosamples may be transferred to other countries (not applicable if local 
regulations prohibits export of human biosamples)
!
The human biosamples will be destroyed at the latest 15 years from end of trial
!
The patient may request the stored human biosamples to be destroyed by withdrawing 
consent. The results obtained from any already performed analyses of the samples will still 
be used
!
Novo Nordisk and laboratory will have access to the stored human biosamples 
!
Potential consequences for the patient and their relatives: In the event that the collected 
human biosamples (plasma, serum and/ or DNA for genotyping) will be used in the future, 
the investigator will become directly informed by Novo Nordisk about the results if the 
findings are deemed clinically relevant and analytically valid and quantifiable. In such case, 
a written summary of the findings, including listings of patient specific values, will be 
provided once a firm conclusion from the results has been drawn by Novo Nordisk. 
Potentially, observations of neoplastic diseases, serious hereditary diseases, other un-
treatable diseases, or any other abnormal findings could be part of the observations. Patients 
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Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
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can contact the investigator if they wish to be informed about results derived from stored 
human biosamples obtained from their own body. See also Section 5.1.
24.2.1
Antibody samples
Antibody samples will be retained until drug approval by U.S. Food and Drug Administration 
(FDA) and/or European Medicines Agency (EMA). 
The retained antibody samples may be used for later analysis for further characterisation of 
antibody responses towards drug if required by health authorities or for safety reasons. The samples 
will be stored at a central bio-repository after end of trial and until marketing authorisation approval 
or until the research project terminates, but no longer than 15 years from end of trial after which 
they will be destroyed.
The patients’ identity will remain confidential and the antibody samples will be identified only by 
patient number, visit number and trial identification number. No direct identification of the patient 
will be stored together with the samples.
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples.
Patients can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body.
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CONFIDENTIAL
Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: Updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the patients, new information that may affect adversely the safety of the patients or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the patients), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC (not 
applicable for Japan).
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the patients.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
Only applicable for France: The French Public Health Code article L 1121-10 (law no 2004-806 of 
9 August 2004 art. 88 I, IX, Journal Officiel of 11 August 2004. “The sponsor is responsible for 
identification of the harmful consequences of the biomedical the research for the person lending 
himself thereto and for indemnification of his beneficiaries, except in case of proof, incumbent on 
it, that the prejudice is not attributable to his fault or of the fault of any intervening party, without 
the sponsor’s being entitled to call on acts by a third party or the voluntary withdrawal of the person 
who had initially consented to cooperating in the research”.
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CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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27 References
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World Federation of Haemophilia. Report on the Annual Global Survey 2013.
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Date:
15 March 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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121 of 122
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Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. Validation of 
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Council Directive 93/42/EEC of 14 June 1993 concerning medical devices. Official Journal 
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Network Symposium. Annals of Emergency Medicine. 2006;47(4):373-80.
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Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third 
universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60(16):1581-98.
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Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, et al. Current diagnosis 
of venous thromboembolism in primary care: a clinical practice guideline from the 
American Academy of Family Physicians and the American College of Physicians. Ann 
Fam Med. 2007;5(1):57-62.
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Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated 
definition of stroke for the 21st century: a statement for healthcare professionals from the 
American Heart Association/American Stroke Association. Stroke. 2013;44(7):2064-89.
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Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition 
and evaluation of transient ischemic attack: a scientific statement for healthcare 
professionals from the American Heart Association/American Stroke Association Stroke 
Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular 
Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary 
Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the 
value of this statement as an educational tool for neurologists. Stroke. 2009;40(6):2276-93.
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Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, et al. 2011 
ACCF/AHA Focused Update of the Guideline for the Management of Patients With 
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of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J 
Am Coll Cardiol. 2011;58(19):2020-45.
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Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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29.
U.S. Food and Drug Administration. Code of Federal Regulations, 21 CFR Part 11, 
Electronic Records, Electronic Signatures. 2009 2009.
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Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 
study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 
2014;123(3):317-25.
31.
Valentino LA, Mamonov V, Hellmann A, Quon DV, Chybicka A, Schroth P, et al. A 
randomized comparison of two prophylaxis regimens and a paired comparison of on-
demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost. 
2012;10(3):359-67.
32.
Manco-Johnson MJ, Kempton CL, Reding MT, Lissitchkov T, Goranov S, Gercheva L, et 
al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand 
treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia 
A (SPINART). J Thromb Haemost. 2013;11(6):1119-27.
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Lentz SR, Misgav M, Ozelo M, Salek SZ, Veljkovic D, Recht M, et al. Results from a large 
multinational clinical trial (guardian1) using prophylactic treatment with turoctocog alfa in 
adolescent and adult patients with severe haemophilia A: safety and efficacy. Haemophilia. 
2013:10.
34.
Levi M, Keller TT, van GE, ten CH. Infection and inflammation and the coagulation system. 
Cardiovasc Res. 2003;60(1):26-39.
35.
Mast AE, Stadanlick JE, Lockett JM, Dietzen DJ, Hasty KA, Hall CL. Tissue factor 
pathway inhibitor binds to platelet thrombospondin-1. J Biol Chem. 2000;275(41):31715-
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Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. 
Arterioscler Thromb Vasc Biol. 2004;24(6):1015-22.
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Belting M, Ahamed J, Ruf W. Signaling of the tissue factor coagulation pathway in 
angiogenesis and cancer. Arterioscler Thromb Vasc Biol. 2005;25(8):1545-50.
38.
Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Vasc Biol. 
2005;25(1):47-56.
39.
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Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2016.
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Protocol
Trial ID: NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of Prophylactic 
Administration of Concizumab in Patients with Severe Haemophilia A 
without Inhibitors
Trial phase: 2
Protocol Version 1 (15 March 2017); Protocol Amendment no 1 (05 May 2017) for all participating 
countries.
Protocol originator
, 
Biopharm, Trial 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.
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
2 of 124
Table of Contents
Page
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................7
Table of Tables............................................................................................................................................7
List of abbreviations ...................................................................................................................................9
1
Summary............................................................................................................................................15
2
Flow chart ..........................................................................................................................................18
3
Background information and rationale for the trial.........................................................................21
3.1
Background information..........................................................................................................21
3.1.1
Haemophilia ..........................................................................................................21
3.1.2
Concizumab...........................................................................................................22
3.2
Rationale for the trial...............................................................................................................24
4
Objective(s) and endpoint(s)..............................................................................................................26
4.1
Objective(s) ............................................................................................................................26
4.1.1
Primary objective...................................................................................................26
4.1.2
Secondary objectives .............................................................................................26
4.2
Endpoint(s) .............................................................................................................................26
4.2.1
Primary endpoint ...................................................................................................26
4.2.2
Secondary endpoints ..............................................................................................26
4.2.2.1
Supportive secondary endpoints .......................................................26
4.2.3
Exploratory endpoints............................................................................................27
4.2.3.1
Exploratory safety endpoints ............................................................27
4.2.3.2
Exploratory patient-reported outcome endpoints...............................28
5
Trial design ........................................................................................................................................29
5.1
Type of trial ............................................................................................................................29
5.1.1
Surgery..................................................................................................................30
5.2
Rationale for trial design .........................................................................................................30
5.3
Treatment of patients...............................................................................................................33
5.3.1
Dose escalation......................................................................................................34
5.3.2
Treatment of bleeding episodes during the trial ......................................................35
5.3.3
Prohibited medication ............................................................................................35
5.4
Treatment after discontinuation of trial product .......................................................................36
5.5
Rationale for treatment............................................................................................................36
6
Trial population .................................................................................................................................37
6.1
Number of patients..................................................................................................................37
6.2
Inclusion criteria .....................................................................................................................37
6.3
Exclusion criteria ....................................................................................................................37
6.4
Criteria for premature discontinuation of trial product .............................................................38
6.5
Withdrawal from trial..............................................................................................................38
6.6
Patient replacement .................................................................................................................39
6.7
Rationale for trial population...................................................................................................39
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Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
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7
Milestones...........................................................................................................................................40
8
Methods and assessments ..................................................................................................................41
8.1
Visit procedures ......................................................................................................................41
8.1.1
Informed consent, long-term storage consent..........................................................42
8.1.2
Screening log, enrolment log, trial card and patient number....................................42
8.1.3
Screening failures and re-screening........................................................................42
8.1.4
Premature discontinuation of trial product..............................................................43
8.1.5
Withdrawal from trial.............................................................................................43
8.1.6
Review/evaluation of clinical outcome...................................................................43
8.1.7
Visit 1 (Screening part)..........................................................................................44
8.1.8
Training of patients visit 1 and visit 2.....................................................................45
8.1.9
Treatment period - Main part..................................................................................45
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site) ......................45
8.1.9.2
Treatment period at home.................................................................46
8.1.9.3
Visit 3 (Phone visit)..........................................................................46
8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits) .........................................47
8.1.9.5
Visit 9 (Assessment visits)................................................................47
8.1.10
Extension Part........................................................................................................48
8.1.10.1
Visit 10 (Assessment visits)..............................................................48
8.1.10.2
Visit 11, 12, 13, 14 and 15 (Assessment visits) .................................49
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) -
Extension part ..................................................................................50
8.1.11
Follow-up Part.......................................................................................................51
8.1.11.1
Visit 17 (End of trial) .......................................................................51
8.1.12
Unscheduled Visit..................................................................................................52
8.2
Patient related information/assessments...................................................................................52
8.2.1
Demography ..........................................................................................................52
8.2.2
Concomitant illness and medical history other than haemophilia ............................52
8.2.3
Concomitant medication ........................................................................................53
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History .......................53
8.3
Efficacy assessments...............................................................................................................54
8.3.1
Bleeding episodes ..................................................................................................54
8.4
Safety assessments ..................................................................................................................58
8.4.1
Physical examination .............................................................................................58
8.4.2
Body measurements...............................................................................................59
8.4.3
Vital signs..............................................................................................................59
8.4.4
Electrocardiogram..................................................................................................59
8.4.5
Adverse events.......................................................................................................60
8.4.5.1
Medication error...............................................................................60
8.4.5.2
Adverse events requiring additional data collection ..........................60
8.5
Laboratory assessments...........................................................................................................62
8.5.1
Laboratory assessments for efficacy.......................................................................63
8.5.1.1
Thrombin generation........................................................................63
8.5.1.2
Free TFPI.........................................................................................63
8.5.2
Laboratory assessments for safety ..........................................................................64
8.5.2.1
Urinalysis.........................................................................................64
8.5.2.2
Haematology....................................................................................64
8.5.2.3
Biochemistry....................................................................................65
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Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
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8.5.2.4
FVIII activity ...................................................................................65
8.5.2.5
Coagulation parameters....................................................................65
8.5.2.6
FVIII inhibitor test ...........................................................................66
8.5.2.7
Anti-concizumab antibodies .............................................................66
8.5.2.8
Concizumab ELISA .........................................................................68
8.5.2.9
Total TFPI........................................................................................68
8.5.3
Human biosamples.................................................................................................68
8.6
Other assessments ...................................................................................................................69
8.6.1
Patient reported outcomes ......................................................................................69
8.6.2
Training.................................................................................................................70
8.6.2.1
Concizumab and NovoPen® 4...........................................................70
8.6.2.2
Turoctocog alfa ................................................................................70
8.6.2.3
eDiary..............................................................................................71
8.6.3
Surgery..................................................................................................................71
8.7
Patient compliance..................................................................................................................71
8.8
Treatment compliance:............................................................................................................72
9
Trial supplies......................................................................................................................................73
9.1
Trial products..........................................................................................................................73
9.2
Labelling.................................................................................................................................73
9.3
Storage....................................................................................................................................74
9.4
Drug accountability and destruction ........................................................................................75
9.5
Auxiliary supplies ...................................................................................................................75
10
Interactive voice/web response system ..............................................................................................76
11
Randomisation procedure and breaking of blinded codes................................................................77
Randomisation.....................................................................................................................................77
12
Adverse events, and technical complaints .........................................................................................78
12.1
Definitions ..............................................................................................................................78
12.1.1
Adverse event ........................................................................................................78
12.1.2
Serious adverse event.............................................................................................79
12.1.3
Non-serious adverse event......................................................................................80
12.1.4
Medication errors...................................................................................................80
12.1.5
Adverse events requiring additional data collection................................................81
12.1.6
Adverse event of special interest ............................................................................82
12.1.7
Technical complaints .............................................................................................86
12.2
Reporting of adverse events.....................................................................................................86
12.3
Follow-up of adverse events....................................................................................................88
12.4
Technical complaints and technical complaint samples............................................................89
12.4.1
Reporting of technical complaints ..........................................................................89
12.4.2
Collection, storage and shipment of technical complaint samples ...........................90
12.5
Pregnancies.............................................................................................................................91
12.5.1
Pregnancies in female partners of male patients......................................................91
12.6
Precautions and/or overdose....................................................................................................92
12.7
Rules for putting enrolment on hold ........................................................................................92
12.8
Committees related to safety ...................................................................................................93
12.8.1
Novo Nordisk safety committee .............................................................................93
12.8.2
Data monitoring committee....................................................................................93
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Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
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13
Case report forms ..............................................................................................................................94
13.1
Corrections to case report forms..............................................................................................94
13.2
Case report form flow .............................................................................................................94
13.3
Electronic diary.......................................................................................................................95
13.3.1
Investigator review of eDiary data..........................................................................95
14
Monitoring procedures ......................................................................................................................95
15
Data management ..............................................................................................................................98
16
Computerised systems .......................................................................................................................98
17
Statistical considerations ...................................................................................................................99
17.1
Sample size calculation .........................................................................................................100
17.2
Definition of analysis sets......................................................................................................101
17.3
Primary endpoint...................................................................................................................101
17.4
Sensitivity analyses...............................................................................................................101
17.5
Additional analyses...............................................................................................................102
17.6
Secondary endpoints .............................................................................................................102
17.6.1
Supportive secondary efficacy endpoints..............................................................102
17.6.3
Supportive secondary pharmacokinetic endpoints.................................................103
17.6.4
Supportive secondary pharmacodynamic endpoints..............................................104
17.7
Exploratory endpoints ...........................................................................................................104
17.7.1
Exploratory safety endpoints................................................................................104
17.7.2
Exploratory patient reported outcome endpoints...................................................104
17.8
Interim analysis.....................................................................................................................106
18
Ethics................................................................................................................................................107
18.1
Benefit-risk assessment of the trial ........................................................................................107
18.2
Informed consent ..................................................................................................................108
18.3
Data handling........................................................................................................................109
18.4
Information to patients during trial ........................................................................................109
18.5
Premature termination of the trial and/or trial site..................................................................109
19
Protocol compliance.........................................................................................................................110
19.1
Protocol deviations................................................................................................................110
19.2
Prevention of missing data ....................................................................................................110
20
Audits and inspections .....................................................................................................................112
21
Critical documents...........................................................................................................................112
22
Responsibilities.................................................................................................................................113
23
Reports and publications .................................................................................................................114
23.1
Communication of results......................................................................................................115
23.1.1
Authorship...........................................................................................................115
23.1.2
Site-specific publication(s) by investigator(s).......................................................116
23.2
Investigator access to data and review of results ....................................................................116
24
Retention of clinical trial documentation and human biosamples..................................................117
24.1
Retention of clinical trial documentation ...............................................................................117
24.2
Retention of human biosamples.............................................................................................118
24.2.1
Antibody samples ................................................................................................119
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
6 of 124
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........120
26
Indemnity statement ........................................................................................................................121
27
References ........................................................................................................................................122
Appendix I Patient Reported Outcome
Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments, if applicable for the individual 
country
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
7 of 124
Table of Figures
Page
Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous 
(circles) and traumatic (triangles) bleeding episodes during the dosing period and 
follow-up period.................................................................................................................24
Figure 5–1
Schematic diagram of the trial design .................................................................................29
Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated 
patients in explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal 
lines indicate 100 ng/mL, and the shaded areas represent the full range (min-max) of the 
individual predicted profiles. ..............................................................................................31
Figure 5–3
Dose escalation of concizumab for one individual patient...................................................35
Figure 8–1
Overview of visit structure in explorer™5 ..........................................................................41
Figure 12–1
Reporting of AEs ...............................................................................................................88
Figure 17–1
Definition of main and extension part...............................................................................106
Table of Tables   
Page
Table 2–1
Flow chart..........................................................................................................................18
Table 2–2
Flow chart explanatory descriptions....................................................................................20
Table 5–1 
List of products provided by Novo Nordisk ........................................................................33
Table 8–1
Definition of stop of bleeding episode ................................................................................55
Table 8–2
Definitions of bleeding episodes (cause of bleed)................................................................55
Table 8–3
Definition of bleeding episode severity and treatment recommendation ..............................56
Table 8–4
Guide for dosing in bleeding episodes and surgery .............................................................57
Table 9–1
Trial products.....................................................................................................................73
Table 9–2
Storage conditions..............................................................................................................74
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion..........................100
Table 2–1
Flow chart..........................................................................................................................18
Table 2–2
Flow chart explanatory descriptions....................................................................................20
Table 5–1 
List of products provided by Novo Nordisk ........................................................................33
Table 8–1
Definition of stop of bleeding episode ................................................................................55
Table 8–2
Definitions of bleeding episodes (cause of bleed)................................................................55
Table 8–3
Definition of bleeding episode severity and treatment recommendation ..............................56
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
8 of 124
Table 8–4
Guide for dosing in bleeding episodes and surgery .............................................................57
Table 9–1
Trial products.....................................................................................................................73
Table 9–2
Storage conditions..............................................................................................................74
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion..........................100
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
9 of 124
List of abbreviations
ABI
ankle-brachial index
ABR
annualised bleeding rate 
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest 
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
antithrombin
BP
blood pressure
BU
Bethesda unit
CLAE
clinical laboratory adverse event
Cmax
maximum plasma concentration
CNS
central nervous system
concizumab B
the name concizumab is being used as an 
abbreviation for concizumab B. B is the 
formulation 
CPoC
clinical proof of concept
CRF
case report form
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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CRO
contract research organisation
CRP
c-reactive protein
CT
computerized tomography
cTn
cardiac troponin
CTR
clinical trial report
DFU
direction for use
DIC
disseminated intravascular coagulation
DMC
data monitoring committee
DUN
dispensing unit number
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EMA
European medicines agency
EOT
end of trial
ETP
endogenous thrombin potential 
FAS
full analysis set
FDA
U.S. Food and Drug Administration
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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FDAAA
U.S. Food and Drug Administration 
Amendment Act
FIX
coagulation factor IX
FPFV
first patient first visit
FVIII
coagulation factor VIII
FX
coagulation factor X
FXa
activated coagulation factor X
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GHN
global haemophilia network
HCP
host cell protein
IB
investigator’s brochure
IC
informed consent 
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal 
Editors
ID
identification
IEC
independent ethics committee
IgG4
immunoglobulin G4
IMP
investigational medicinal product
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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INN
International Non-Proprietary Names for 
Pharmaceutical Substances 
IRB
institutional review board
ISTH
International Society on Thrombosis and 
Haemostasis
i.v.
intravenous(-ly)
IWRS
interactive web response system
LBBB
left bundle branch block
LPFV
last patient first visit
LPLV
last patient last visit
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory 
Activities
MI
myocardial infarction
MRA
magnetic resonance angiogram
MRI
magnetic resonance imaging
NIMP
non investigational medicinal product
PCD
PD
primary completion date
pharmacodynamic
PEF
peak expiratory flow
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Protocol
CONFIDENTIAL
Date:
05 May 2017
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Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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PK
pharmacokinetic
PP
per protocol
PRO
patient reported outcome
PT
prothrombin time
QA
Q4D
quality assurance
every 4th day
rFVIII
the name ‘rFVIII’ will be used throughout 
the protocol and the product is identical to 
‘turoctocog alfa’
SAE
serious adverse event
SAS
safety analysis set
sBE
s.c.
spontaneous Bleeding Episode
subcutaneous(-ly)
SI
international system of units
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse 
reaction
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
TF
tissue factor
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
14 of 124
TFPI
tissue factor pathway inhibitor
TG
thrombin generation
TMM
trial materials manual
TPA
trial product administration
UTN
Universal Trial Number
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
15 of 124
1
Summary
The main objective for the phase 2 trial NN7415-4255, explorer™5, is to assess the efficacy of 
concizumab administered s.c. once daily to prevent bleeding episodes in patients with severe 
haemophilia A without inhibitors. Furthermore, this trial aims to assess the longer-term efficacy and 
safety of concizumab in severe haemophilia A patients without inhibitors. 
Objective(s) and endpoint(s):
Primary objective 
!
To assess the efficacy of concizumab administered  s.c. once daily in preventing bleeding 
episodes in patients with severe haemophilia A without inhibitors 
Secondary objectives 
!
To assess the longer-term efficacy of concizumab in patients with severe haemophilia A without 
inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without 
inhibitors
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset.
Key secondary endpoints
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of treatment emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset.
Time frames for evaluation of objectives/endpoints:
All endpoints referring to the time frame of at least 24 weeks will be evaluated in the main part of 
the trial, defined to end when the last patient has completed a minimum of 24 weeks of treatment 
with trial product (or have withdrawn). In addition, number of bleeding episodes during 76 weeks 
of treatment with prophylactic concizumab will be analysed. The extension part of the trial will 
provide additional safety and long-term efficacy data.
Trial design:
The trial is a multi-centre single arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation) administered daily s.c. in patients with 
severe haemophilia A without inhibitors. This is done by comparing the annual bleeding rate (ABR) 
to an ABR of 12.The selected dose regimen is based on relevant PK and TFPI data as well as 
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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pharmacokinetic/pharmacodynamic (PK/PD) modelling from the preceding explorer™ trials. Both 
on-demand and prophylaxis patients will be eligible for the trial.
The total trial duration for the individual patient will be approximately 86 weeks, consisting of a 2 
week screening period, a subsequent 76 week treatment period and an 8 week follow-up period. 
The 76 weeks treatment period is split into a main part which lasts at least 24 weeks and an 
extension part which lasts up to 52 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 30 patients have completed at least 24 weeks of concizumab 
dosing or have discontinued trial treatment. The analysis of the main part of the trial aims to 
substantiate clinical proof of concept (CPoC) that concizumab has the potential to prevent bleeding 
episodes in severe haemophilia A patients without inhibitors. 
rFVIII (turoctocog alfa) for treatment of breakthrough bleeding episodes will be provided by Novo 
Nordisk during the trial. The patient will not be provided with trial product or rFVIII (turoctocog 
alfa) after the end of the trial.
Trial population:
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product: 33
Number of patients expected to complete the trial: 30
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine the 
suitability for the trial
!
Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at screening
Key exclusion criteria
!
Known or suspected hypersensitivity to trial product(s) or related products
!
Known inherited or acquired bleeding disorder other than haemophilia A
!
Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at 
screening measured by the Nijmegen method 
Key Efficacy assessment
!
The number of bleeding episodes during at least 24 weeks.
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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Key Safety assessment
!
Number of TEAEs during at least 24 weeks.
Trial product(s):
The following products will be used in the trial:
!
Investigational Medicinal Product (IMP):
Concizumab B, 100 mg/mL to be administered s.c. with NovoPen®4 and needles 
!
Non Investigational Medical Product (NIMP):
Turoctocog alfa (rFVIII) 2000 IU/vial and isotonic sodium chloride (solvent). Turoctocog 
alfa (rFVIII) is for intravenous administration.
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CONFIDENTIAL


Protocol
UTN:U1111-1179-3872
Date:
05 May 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
2
Page:
18 of 124
2
Flow chart
Table 2–1
Flow chart
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
Timing of visit (d) d
14 to 21 days 
before Visit2
1
8
29
57
85
113
141
169
225
281
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 21 days 
before Visit 
2
0
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not applicable
-7
Treatment week (w)
---
0
1w
4w
8w
12w
16w
20w
24w
32w
40w
48w
56w
64w
72w
76w
---
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/Genotyping and Long-term storage consent
●
In/exclusion criteria
●
●e
Demography 
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial 
product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
EFFICACY ASSESSMENTS 
Bleeding episodes f, g
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Free TFPI (central lab)  
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
SAFETY ASSESSMENTS
Physical examination
●
●
●
●
●
●
●
Body measurements 
●
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
Vital signs
●
●j
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Biochemistry (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII activity (central lab)
●k
●l
Coagulation parameters (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII inhibitors (central lab)
●
●l
Anti-concizumab antibodies (ADA) (special lab)m
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Concizumab ELISA (special lab)
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Total TFPI (special lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
TRIAL MATERIALS
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Protocol
UTN:U1111-1179-3872
Date:
05 May 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
2
Page:
19 of 124
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
IWRS call
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab, turoctocog alfa) (IWRS)
●n
●
●
●
●
●
●
●
●
●
●
●
●
●
●n
●
Administration of trial product (concizumab) 
●o
Drug Accountability (concizumab, turoctocog alfa) 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product c, p
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires
●
●
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
Hand out ID Card 
●
Training (trial product, e-Diary and NovoPen® 4) q
●
●
●
Compliance (e-Diary)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
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Protocol
UTN:U1111-1179-3872
Date:
05 May 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
2
Page:
20 of 124
Table 2–2
Flow chart explanatory descriptions
Footer
Description
a
Concizumab administration is performed at home except for visit 2 where concizumab administration will take place at the trial site.
b
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 will be 
a phone call to the patient. 
c
For patients being dose escalated a phone call is recommended 1 week after first new dose of concizumab.
d
Daily dosing preferably at the same time in the morning.
e
Evaluation of laboratory results obtained from samples taken at screening.
f
Bleeding episodes occurring between visit 1 and visit 2 or at site should be registered in the eCRF. All bleeding episodes except for severe occurring after visit 
2 at home should be registered in the eDiary. Severe bleeding episodes must be registered in the eCRF.
g
Turoctocog alfa will be given to treat breakthrough bleeding episodes either in the clinic or at home.
h
At visit 9 and 16 all blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been performed.
i
Only body weight should be measured.
j
Vital signs should be evaluated before and after trial drug administration at visit 2. 
k
Sampling for FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours and medical records documenting the severity of 
haemophilia are not available.
l
FVIII activity and FVIII inhibitor tests should only be collected if reduced effect of turoctocog alfa or FVIII inhibitor development is suspected.
m
In case of clinical signs of e.g. hypersensitivity reactions or immune related events are seen, additional samples for ADAs may be taken. All antibody samples 
from the affected patient will be analysed on an ongoing basis. If antibodies are detected additional samples will be taken and stored for characterisation of the 
antibodies.
n
Only dispensing of turoctocog alfa and sodium chloride.
o
The trial patient must be in a non-bleeding state at the time of the first trial product administration (TPA), and should not have received any haemostatic drug
(e.g. FVIII) for prophylaxis or treatment of a bleeding episode within a period of 48 hours prior to first TPA.
p
Patient should be dose escalated at next scheduled visit if he experiences ≥3 spontaneous bleeding episodes within the preceding 12 weeks of treatment with 
concizumab. If investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose escalation.
q
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Home treatment training comprises handing out of Direction 
for Use (DFU), training in administration of concizumab with NovoPen®4, turoctocog alfa and data entry in eDiary. Further the patients will be trained in 
recognition of signs/symptoms of thrombosis.
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
21 of 124
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP)1 and applicable regulatory requirements, and in 
accordance with the Declaration of Helsinki2 and ISO 141553.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
The International Non-Proprietary Names for Pharmaceutical Substances (INN) name of the active 
pharmaceutical ingredient is concizumab (synonyms used during early development are NNC0172-
2021, anti-TFPI, NN7415 or mab2021). Throughout this document “concizumab” is used as the 
name of the trial drug.
3.1
Background information
3.1.1
Haemophilia
Haemophilia is an inherited bleeding disorder characterised by an increased bleeding tendency, 
typically in weight bearing joints. Haemophilia A is caused by a partial or complete deficiency of 
blood coagulation factor VIII (FVIII) and haemophilia B is caused by defect factor IX (FIX).  
Inheritance is chromosome X-linked and recessive; therefore the disease mainly affects males. The 
incidence of haemophilia A and B on average is estimated to be about 1 in 5000 live male births4. 
According to the World Federation of Haemophilia global survey of 2014, about 178,500 persons 
are diagnosed with haemophilia worldwide. Of these, about 80% have haemophilia A.
Haemophilia is classified as “severe”, “moderate” or “mild” according to the plasma activity of the 
affected coagulation factor5.With a deficiency of FVIII or FIX, the degree of activation of 
coagulation factor X (FX) becomes insufficient. Consequently, the thrombin burst is delayed and 
insufficient for normal haemostasis6.The haemostatic plug, if formed, in these patients is fragile and 
easily dissolved by normal fibrinolytic activity. This leads to impaired haemostasis and spontaneous 
prolonged bleeding episodes. In severe haemophilia, bleeding in joints occurs spontaneously and is 
the most frequent symptom of the disease. Recurrent bleeding episodes in the same location - most 
commonly a weight bearing joint - lead to chronic arthropathy, muscular atrophy and deformities. 
Treatment of bleeding episodes as they manifest (on-demand treatment) may delay arthropathy, but 
does not prevent it. The majority of children with severe haemophilia experience their first bleeding 
episode in a joint prior to the age of 4 years. Many children also bleed from other body sites, also 
before this age is reached7. For this reason, primary prophylaxis treatment with regular FVIII 
injections in the non-bleeding state is the recommended from early childhood.
The most common complication of replacement therapy is development of antibodies binding to 
FVIII. These binding antibodies might neutralise the exogenous of FVIII and are then called
inhibitors. In patients who have developed inhibitors towards FVIII, replacement therapy is 
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rendered ineffective. These patients may be treated with bypassing agents, activated FVII 
(NovoSeven®) and activated prothrombin complex concentrate (FEIBA®) given as intravenous 
(i.v.) injections.
Current treatment options in haemophilia A, includes replacement therapy or by-passing therapy are 
hampered by the fact that these products must be given as i.v. injections. Bypassing agents are 
characterized by relatively short half-lives, therefore prophylactic treatment is burdensome. A new 
therapeutic agent that can be administered subcutaneously will represent a major improvement in 
the treatment of these patients in a prophylaxis setting. 
3.1.2
Concizumab
The trial product, concizumab, is a humanised recombinant monoclonal antibody (mAb) of the 
immunoglobulin G4 (IgG4) isotype with a molecular weight of 149 kilo Daltons. Like other 
antibodies, concizumab is composed of two light chains and two heavy chains linked together by 
disulfide bridges. To prevent formation of half-antibodies, the serine at position 241 in the heavy 
chain has been replaced with a proline (S241P (Kabat annotation)) . The mechanism of action of 
concizumab is based on the concept of inhibiting the activity of a natural coagulation inhibitor, 
tissue factor pathway inhibitor (TFPI). TFPI is a potent inhibitor of the initiation phase of the 
coagulation process, i.e. the activation of FX to FXa by the tissue factor (TF)/factor VIIa (FVIIa) 
complex. TFPI first binds to and inhibits activated FXa and subsequently binds to and inhibits the 
TF/FVIIa complex, forming a TF/FVIIa/FXa/TFPI complex. Thus, concizumab prevents both 
inhibition of FXa and inhibition of FVIIa/TF by TFPI. In this manner, sufficient amounts of FXa to 
ensure effective haemostasis in the absence of a functional activated factor IX/activated factor VIII 
(FIXa/ FVIIIa) complex may be generated. This is a new concept that remains to be documented 
safe and efficacious in patients with haemophilia. More information about the physiological role of 
TFPI and the mode of action of concizumab is provided in the Investigator’s Brochure (IB). 
Key differentiator is thus a new mode of action (MoA), and the key benefit of concizumab in 
patients with severe haemophilia A is reduced treatment burden due to subcutaneous (s.c.) 
administration potentially leading to better adherence, more patients on prophylactic treatment and 
ultimately better outcome.
Four clinical trials with concizumab have been completed thus far: the first-human-dose trial 
(NN7415-3813, explorer™1), a single dose trial in Japanese healthy subjects (NN7415-3981), a 
multiple dose trial NN7415-3986 (explorer™2), and NN7415-4159 (explorer™3). When the first 
cohort with four healthy subjects in explorer™2 was completed, prior to the initiation of the 2nd 
cohort, the trial was halted due to findings related to thrombosis in an ongoing 26-week toxicity 
study in primates. In this study animal had plasma concentrations several hundred folds above 
clinically relevant concentrations. Follow up investigations confirmed that the animal’s condition 
was related to thrombosis in the lungs caused by exaggerated pharmacology at these high plasma 
concentrations. Before the initiation of the fourth phase 1 trial (, explorer™3) a new 52-week non-
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clinical toxicology study was conducted in primates to investigate the findings in the previous 
study. The conclusion from this new non-clinical study was that the results from non-clinical 
studies support further clinical development of concizumab. Explorer™3 was a multiple-dose 
clinical trial, which aimed to investigate the safety, pharmacokinetics and pharmacodynamics of 
concizumab at five different dose levels in adult severe haemophilia A patients without inhibitors. 
In this trial multiple doses of concizumab were administered s.c. over a period of six weeks. Doses 
of up to 0.8 mg/kg administered every four days did not raise safety concerns and a decision not to 
dose-escalate to a 1.1 mg/kg dose-cohort was taken. For further information, please refer to the 
Investigator’s Brochure.
The explorer™3 trial was finalised following the completion of cohort 3 (0.8 mg/kg sc every 4 days 
for 6 weeks). Blinded preliminary safety and PK/PD data from the cohort was reviewed by the 
concizumab safety committee. Marked changes in coagulation parameters were observed including 
a decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range. In addition, a substantial inter subject variation in pro-coagulant response to the drug 
was observed. Based on this, the Novo Nordisk safety committee (see section 12.8.1) decided not to 
proceed to cohort 4 (1.1 mg/kg sc every 4 days for 6 weeks). No clinical consequences or serious 
adverse were seen in the completed cohorts in explorer3.
The PK results from explorer™3 showed exposure-response in terms of fewer bleeding episodes 
recorded for patients who reached plasma concentrations of concizumab above 100 ng/mL. 
Individual predicted PK profiles merged with recorded spontaneous and traumatic bleeding 
episodes are shown in Figure 3–1.
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Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous (circles) and 
traumatic (triangles) bleeding episodes during the dosing period and follow-up period. 
All data originates from explorer™3 (N=24 patients). PK of concizumab is subdivided into three exposure levels of 
≤20 ng/mL, 20-100 ng/mL, and > 100 ng/mL together with the number of contributing patients. LLOQ: lower limit of 
quantification. a ‘Time in trial’ refers to the time that the patients spent on each concizumab exposure level, and the 
≤20 ng/mL level therefore also includes the screening period (not shown on this figure).
A large difference between the peak and trough plasma concentrations of concizumab were 
observed as well, especially in the highest dose group (0.80 mg/kg) of explorer™3. In patients who 
received 0.25, 0.5 and 0.8 mg/kg doses a significant overlap in plasma concentrations of 
concizumab was seen due to high between-patient variability in concizumab.
Single doses of concizumab up to 9 mg/kg have been administered to haemophilia patients in the 
first human dose trial with concizumab, explorer™1. These doses resulted in plasma concentrations 
of concizumab that were significantly higher than the ones that are modelled to be reached in the 
highest escalated daily dose (0.25 mg/kg) of explorer™5.
For an assessment of benefits and risks of the trial, see Section 18.1.
For further information, please refer to the Investigator’s Brochure.
3.2
Rationale for the trial
Four phase 1 clinical trials with concizumab have been finalised. Key safety and preliminary 
efficacy results from these phase 1 trials support further development of concizumab in haemophilia 
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patients. Therefore, the main objective in the phase 2 of concizumab development is to assess 
efficacy and safety and provide data that will guide for the confirmatory phase 3 concizumab trials. 
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4
Objective(s) and endpoint(s)
4.1
Objective(s)
4.1.1
Primary objective
!
To assess the efficacy of concizumab administered s.c. once daily in preventing bleeding 
episodes in patients with severe haemophilia A without inhibitors
4.1.2
Secondary objectives
!
To assess the long-termer efficacy of concizumab in patients with severe haemophilia A 
without inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without 
inhibitors
4.2
Endpoint(s)
4.2.1
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset
!
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary endpoints
!
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during 76 weeks from treatment onset
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of  spontaneous bleeding episodes during 76 weeks from treatment onset
!
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during 76 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during 76 weeks from treatment onset
!
!
Change from baseline of fibrinogen during 24 weeks from treatment onset
!
Change from baseline of fibrinogen during 76 weeks from treatment onset
!
Change from baseline of D-dimer during 24 weeks from treatment onset
!
Change from baseline of D-dimer during 76 weeks from treatment onset
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!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset
!
Change from baseline of F1 + 2 during 76 weeks from treatment onset
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset
!
Change from baseline of PT during 76 weeks from treatment onset
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset
!
Change from baseline of APTT during 76 weeks from treatment onset
!
Change from baseline of antithrombin (AT) during 24 weeks from treatment onset
!
Change from baseline of AT 76 weeks from treatment onset
!
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks
!
Concentration of concizumab prior to the last dose administration at 76 weeks
Supportive secondary pharmacodynamic endpoints
Plasma free TFPI concentration
!
Value prior to the last dose administration at 24 weeks 
!
Value prior to the last dose administration at 76 weeks 
Thrombin generation
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks 
!
Peak thrombin generation (nM) prior to the last dose administration at 76 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 76 weeks 
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks 
!
Velocity index (nM/min) prior to the last dose administration at 76 weeks 
4.2.3
Exploratory endpoints
4.2.3.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
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4.2.3.2
Exploratory patient-reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 24 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Change in PGI-C after 24 weeks from treatment onset
!
Change in PGI-C after 76 weeks from treatment onset
!
Change in H-DAT after 24 weeks from treatment onset
!
Change in H-DAT after 76 weeks from treatment onset
All endpoints referring to a time frame of either 24 weeks or of at least 24 weeks will be evaluated 
in the main part of the trial. 
All endpoints referring to a time frame of 76 weeks will be evaluated in the extension part of the 
trial.
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5
Trial design
5.1
Type of trial
The trial is a multicentre single-arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation to 0.20 and 0.25 mg/kg) administered daily 
s.c. in patients with severe haemophilia A without inhibitors. The selected dose regimen is based on
relevant PK and TFPI data as well as PK/PD modelling from the preceding explorer™ trials. Both
on-demand and prophylaxis patients will be eligible for the trial.
Figure 5–1
Schematic diagram of the trial design
The total trial duration for the individual patient will be approximately 86 weeks, including a 2-
week screening period, a subsequent 76-week treatment period and an 8-week follow-up period, see 
Figure 5–1.
The76 weeks treatment periodis further split into a main part which lasts at least 24 weeks for all 
patients in the trial and an extension part which lasts 52 weeks.After completion ofthe main part of 
the trial, patients will continue into the extension part. All available data up to the time point where 
the last patients ends 24 weeks of treatment (or have withdrawn) will be used in the analysis of the 
main part, see Section 17.7.
Breakthrough bleeding episodes occurring from visit 1 to end-of-trial visit will be treated by the 
patients at home with FVIII at the discretion of the investigator, who will also choose dose levels. 
Only turoctocog alfa/NovoEight®will be provided and paid by Novo Nordisk for this purpose.
The analysis of the main part (after 24 weeks) of the trial aims to substantiate CPoC that 
concizumab has the potential to prevent bleeding episodes in patients with severe haemophilia A 
without inhibitors. The extension part will provide additional safety data on 52 weeksdosing of 
concizumab.
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Human biosamples (plasma, serum, and/or DNA for genotyping) will be collected in this trial  for 
future exploratory analysis to pursue a deeper insight into the biology of TFPI, coagulation, and 
effect of concizumab on joint health that may include coagulation parameters and markers of joint 
status or damage. Acceptance of storage of human biological specimens is voluntary and will not 
affect the patients’ participation in the trial. Therefore, patients will have the possibility to sign the 
informed consent for the trial and participate, while refusing permission for biological specimens to 
be stored for future exploratory analysis. Please refer to Section 24.1 for further information.
An independent data monitoring committee (DMC) will be established for this trial. The DMC will 
review all safety data from all ongoing trials with concizumab exposure, see Section 12.8.2.
5.1.1
Surgery
Minor surgery is allowed in this trial. Major surgery conducted more than one month (30 days) 
prior to trial start is allowed, see exclusion criterion no 6.
Minor surgery is defined as an invasive operative procedure where only the skin, the mucous 
membranes or superficial connective tissue is manipulated. Examples of minor surgery include 
implanting of central venous access devices (ports, CVC, pumps and other CVADs) in 
subcutaneous tissue, skin biopsies or simple dental procedures.
5.2
Rationale for trial design
Explorer™5 is a phase 2, clinical proof of concept (CPoC) and safety trial. The trial aims to 
substantiate CPoC that concizumab has the potential to prevent bleeding episodes in haemophilia 
patients without inhibitors. A dose escalation design will allow cautious dose escalation in order to 
choose the efficacious and safe concizumab dose for the individual patient from the selected dose 
regimenConcizumab 0.15 mg/kg (with two potential dose-escalation steps, 0.20mg/kgand 0.25 
mg/kg) given s.c. once daily will be investigated.
The duration of 24 weeks for the main part of the trial is deemed necessary in order to obtain 
information on the annual bleeding rate (ABR)during concizumab prophylaxis. The duration of the 
extension part of the trial will be 52 weeks and will provide further information on long-term 
efficacy, i.e. ABR, and also provide additional safety data upon 76 weeks treatment with 
concizumab.
A total of 33 patientsare planned to receive concizumab s.c.once daily in this single arm trial,
please see Figure 5–1.
The concizumab dose regimentswill be startingwith0.15 mg/kg with the possibilityto escalate to 
0.20 mg/kg and 0.25 mg/kg, see section 5.3.1.
Daily dosing with 0.15 mg/kg aims to ensure steady-state levels of concizumab plasma 
concentrations above 100 ng/mL for the majority of the patients starting on this dose. The PK 
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results from explorer™3 showed exposure-response in terms of fewer bleeding episodes recorded 
for patients who reached plasma concentrations of concizumab above 100 ng/mLsee Figure 3–1. 
The minority of patients which are predicted to have steady-state plasma concentrations below this 
threshold are expected to experience bleeding episodes and therefore will have the opportunity to be 
dose-escalated to the dose of 0.2 mg/kg. A further dose escalation to 0.25 mg/kg per day is 
permitted, again based on the bleeding rate,see section 5.3.1.
Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated patients in 
explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal lines indicate 100 ng/mL, 
and the shaded areas represent the full range (min-max) of the individual predicted profiles1.
1 Plasma concentrations in the same range as those in explorer™3 are expected to be reached in this trial with daily dose 
administration. The starting dose for all patients will be 0.15 mg/kg daily. The plasma steady-state exposure for a typical subject at 
this dose level is predicted to fourfold lower compared to a typical subject on 0.8 mg/kg Q4D (cohort 3 of explorer3) in terms of both 
Cmax and AUC 0-24h. For 0.20 mg/kg daily and 0.25 mg/kg, the plasma steady-state exposure levels for a typical subject are 
predicted to be less than 40% and 70% respectively, compared to the typical subject exposure in the 3rd cohort of explorer™3 (AUC 
and Cmax). The maximum predicted plasma exposure levels (Cmax and AUC 0-24h) for the 0.15 mg/kg daily dose level is predicted 
to be more than 8 fold lower than for 0.80 mg/kg Q4D. For 0.20 mg/kg daily both Cmax and AUC 0-24h are predicted to be more 
than 3 times lower than for 0.80 mg/kg Q4D. For 0.25 mg/kg daily, the maximum Cmax and AUC 0-24h are predicted to be 35 % 
lower than for 0.80 mg/kg Q4D.
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Due to the high between-patient variability in concizumab concentration observed in explorer™3, a 
significant overlap in plasma concentrations of concizumab in patients who received 0.25, 0.5 and 
0.8 mg/kg doses was seen, see Figure 5–2. Therefore, choosing three doses that would lead to 
reasonably distinct mean plasma concentrations of concizumab, and thus different efficacy at each 
dose level was not deemed possible. For this reason, a traditional parallel arm design was not 
chosen for the phase 2 trials. In contrast, the titration trial design allows patients to start on a low 
dose, which is expected to ensure prophylaxis but not marked changes in coagulation parameters, 
for the majority of patients. Escalation to the next dose level will only occur in the case of lack of 
efficacy (≥3 spontaneous bleeding episodes within the preceding 12 weeks. In addition, the PK of 
concizumab is heavily influenced by target mediated drug disposition, which means that small 
differences in concizumab dose ultimately leads to large differences in plasma concentrations. 
Therefore, daily dosing is proposed for the phase 2 trial, explorer™5. Daily dosing will allow for 
the increase in trough levels and thus better efficacy may be expected with a lower dose. 
Embryonic exposure in pregnant female partners of men treated with concizumab is highly unlikely 
and there is no need for protocol requirements for use of contraception in phase 2 and 3 trials.
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5.3
Treatment of patients
Table 5–1
List of products provided by Novo Nordisk
Compound Name 
Strength
Dosage form 
Route of 
administration
Treatment period
Concizumab B2, 
100 mg/mL
3 mL solution in 
a 3 mL 
cartridge3. 
S.c.
administration
using NovoPen® 4
For prophylactic 
treatment for 76 
weeks. 
Turoctocog alfa 
(NovoEight®)4, 
Sodium chloride 
solution 4ml  
2000 
IU/vial
Powder for 
solution for 
injection
Solvent for 
solution for i.v. 
injection used 
for 
reconstitution of 
turoctocog alfa.
I.v. administration
For treatment of 
breakthrough 
bleeding episodes 
(or prophylaxis in 
the screening and 
follow-up phases), 
at the discretion of 
the treating 
physician (patients 
may choose to use 
other familiar pre-
trial FVIII drug).
For further 
information see 
section 5.3.2
Concizumab will be given s.c., once daily for a total dosing period of 76 weeks. 
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. It will be labelled in accordance with national legislation and a copy of the label can 
be found within the Trial Materials Manual, see Section 9.1.
The first dose of concizumab will be given at the trial site under medical supervision. After the 
initial dose the patient must be observed for potential emergence of AEs/safety signals for at least 2 
hours at the trial site. At the screening visit and the first scheduled treatment visit patients will be 
trained in s.c. administration of concizumab with NovoPen® 4 and in the use of eDiary.
Investigational medicinal product (IMP)
3 Not to be confused with the daily injected volume (~150 μL, depending on dose strength and body weight)
4 Non-investigational medicinal product (NIMP)
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In case safety concerns meet the criteria(See section12)for putting enrolment of additional 
patients on hold,further enrolment in the trial will be halted. Dosing of patients on treatment may 
continue while further evaluation is made by the safety committee. In case of other safety concerns 
all available data will be evaluated by the DMCsee Section 12.8.2.
5.3.1
Dose escalation
Bleeding episodes will be assessed during the trial both at scheduled visits and also between visits.
The first 2 weeks of the treatment with concizumab 0.15 mg/kg is considered as a run-in period. 
Hence the bleeding episodes occurring during the first 2 weeks should not influence a dose 
escalation decision.
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (first-dose visit) 
until visit 16 (end-of-treatment visit), i.e. a total of 74 weeks. Dose-escalation will be based on the 
number of spontaneous, treated bleeding episodes in patients within preceding 12 weeks. However, 
before dose-escalation can occur, to ensure the safety of the patients, the investigator must take into 
account the full clinical picture the patient is presenting with and all available laboratory results, 
including coagulation parameters.
Dose 0.15 mg/kg:
When a sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the preceding 
12 weeks since visit 2+2weeks (including the current sBE). If yes, and if investigator deems it safe, 
the patient will have to be dose escalated from 0.15 to 0.20 mg/kg at the next scheduled visit. If the 
investigator judges that this visit is scheduled too late, he/she should contact the patient for an 
unscheduled visit.
Dose 0.20 mg/kg:
When an sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the 
preceding 12 weeks (including the current sBE), counting only new sBEs from the beginning of the 
0.20 mg/kg treatment period. If yes, and if investigator deems it safe, the patient will have to be 
dose escalated from 0.20 to 0.25 mg/kg at the next scheduled visit. If the investigator judges that 
this visit is scheduled too late, he/she should contact the patient for an unscheduled visit.
Dose 0.25 mg/kg:
Patients are not dose escalated further regardless of the number of sBEs. When an sBE occurs, the 
investigator will determine if ≥ 3 sBEs have occurred within the preceding 12 weeks (including the 
current sBE), counting only the new sBEs from the beginning of the 0,25mg/kg treatment period. If 
yes, then the patient must be discontinued from treatment due to lack of efficacy, see Section 6.4.
Since the patient may have to wait up to 8 weeks for the next scheduled visit (in the extension part), 
the possibility of dose escalation at unscheduled visits is necessary for the dose-escalation eliciting 
bleeding episode to occur soon after previous scheduled visit.
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Figure 5–3
Dose escalation of concizumab for one individual patient
5.3.2
Treatment of bleeding episodes during the trial
Bleeding episodes (main part, extension part, and follow-up part):
Breakthrough bleeding episodes during the course of the trial will be treated at the discretion of the 
treating physician, with either turoctocog alfa/Novoeight® (rFVIII) (provided by Novo Nordisk) or 
other non-modified FVIII products (not provided by Novo Nordisk). Treatment dose is chosen at 
the discretion of the investigator. The patient can treat himself and then he must call the site. 
Bleeding episodes classified as severe must be recorded in the electronic case report form (eCRF)
as serious adverse events (SAEs) see Table 8–3. The bleeding episodes must be recorded in the 
eDiary.
FVIII prophylactic treatment (follow-up part):
During the follow-up part of the trial (i.e. from concizumab end-of-treatment visit to end-of-trial 
visit) patients will receive pre-trial FVIII medication at the discretion of the treating investigator, 
who will also choose dose levels. Only turoctocog alfa/NovoEight® will be provided by Novo 
Nordisk for this purpose.
5.3.3
Prohibited medication 
!
Treatment with anti-fibrinolytics (e.g. tranexamic acid, aminocaproic acid)
!
Heparin, except for sealing of central venous access ports according to local practice
!
Vitamin-K antagonists
!
Direct oral anti-coagulants (DOACs)
!
Modified FVIII products with extended half-life
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CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
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5.4
Treatment after discontinuation of trial product
When discontinuing trial products the patient should be switched to a suitable marketed product at 
the discretion of the investigator. The patient will not be provided with concizumab or FVIII 
(turoctocog alfa/NovoEight®) by Novo Nordisk after end of trial (visit 17). 
5.5
Rationale for treatment
Concizumab is a monoclonal antibody and as such offers the possibility of s.c. administration. S.c. 
administration of an effective prophylactic drug has potential to reduce treatment burden 
significantly compared to the currently approved prophylactic drugs which have to be administered 
i.v.
The treatment period of 24 weeks (the main part of the trial) is considered necessary for providing 
data that allow demonstration of CPoC and to support decision-making regarding a phase 3 
confirmatory trial. Dosing for an additional 52 weeks will provide valuable long-term efficacy and 
safety.
Breakthrough bleeding episodes may occur during prophylactic regimens with conventional FVIII 
replacement therapy. Therefore, it is expected that breakthrough bleeding episodes will also occur 
during prophylaxis with concizumab even if clinical proof of concept is demonstrated. 
Consequently turoctocog alfa (FVIII) will be provided by Novo Nordisk A/S in this trial for 
treatment of breakthrough bleeding episodes. 
Patients are not obliged to use turoctocog alfa (FVIII) and can use their previously used FVIII 
concentrate for treatment of breakthrough bleeding episode. Novo Nordisk A/S will not provide or 
reimburse these products.
Please refer to the Investigator’s Brochure for further information.
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CONFIDENTIAL
Date:
05 May 2017
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product(s): 33
Number of patients planned to complete the trial: 30
Discontinued patients will not be replaced.
6.2
Inclusion criteria
For an eligible patient, all inclusion criteria must be answered “yes”.
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at 
screening.
3. For patients being treated on-demand with FVIII replacement therapy, a minimum of six 
documented and treated bleeding episodes during the 24 weeks (or twelve bleeds during 52 
weeks) prior to screening.
6.3
Exclusion criteria
For an eligible patient, all exclusion criteria must be answered “no”.
1. Known or suspected hypersensitivity to trial product(s) or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within the last 30 days or 5 half-lives (whichever is longer) from the last drug 
administration before screening.
4. Any disorder, which in the investigator’s opinion might jeopardise patient’s safety or 
compliance with the protocol.
5. Known inherited or acquired bleeding disorder other than haemophilia A.
6. Major surgery conducted within one month prior to the initiation of trial activities or major 
surgery planned to occur during the trial.
7. Previous history of thromboembolic disease. Current clinical signs of thromboembolic 
disease, or patients who in the judgement of the investigator are considered at high risk of 
thromboembolic events.
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Trial ID:NN7415-4255
Version:
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Status:
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8. Mental incapacity, unwillingness to cooperate or language barrier precluding adequate
understanding and cooperation.
9. Patients who, at screening, have a significant infection or known systemic inflammatory
condition which require systemic treatment according to the investigator’s judgement.
10. Hepatic dysfunction defined as elevated liver transaminases (ALT) >3 times the upper limit
of normal laboratory reference ranges at screening.
11. Renal impairment defined as estimated glomerular filtration rate (eGFR) ≤60
mL/min/1.73m2 based on serum creatinine measured at screening or evidence of renal
damage.
12. Platelet count ≤ 100x109/L at screening.
13. Fibrinogen level < the lower limit of normal at screening
14. Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at
screening measured by the Nijmegen method.
15. History of inhibitors towards FVIII based on investigator’s knowledge or documentation in
available medical records.
6.4
Criteria for premature discontinuation of trial product
The patient may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
The patient must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria
2. Simultaneous participation in another clinical trial of an approved or non-approved
investigational medicinal product.
3. Incapacity or unwillingness to follow the trial procedures
4. Anaphylactic reaction
5. Thromboembolic event
6. Event of disseminated intravascular coagulation (DIC)
7. Development of inhibitors to Factor VIII (≥0.6 BU)
8. Lack of efficacy due to neutralising antibodies towards concizumab
9. Lack of efficacy defined as ≥3 treated sBEs within the previous 12 weeks in patients being
treated with the highest dose level (0.25 mg/kg) of concizumab.
See Section8.1.4 for procedures to be performed for patients discontinuing trial 
product prematurely.
6.5
Withdrawal from trial
The patientmay withdraw consent at will at any time.
See Section 8.1.5for procedures to be performed for patients withdrawing consent.
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Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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6.6
Patient replacement
Patients who discontinue trial product prematurely will not be replaced.
6.7
Rationale for trial population 
The most important reason for choosing the trial population, haemophilia A without inhibitors, is 
that there is a significant unmet medical need in this patient population for a treatment option which 
reduces the burden associated with the current care, including small volume s.c. administration 
instead of i.v. Finally, the trial population reflects the patient population that will be selected in a 
potential subsequent phase 3 trial in which the efficacy and safety of concizumab is to be 
confirmed.
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CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
Final
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7
Milestones
Planned duration of recruitment period first patient first visit – last patient first visit (FPFV-LPFV): 
4 months
Planned FPFV: 
16-Aug-2017
Planned FPFT: 
30-Aug-2017
Planned LPFV: 
16-Dec-2017
Planned LPLV: 
11-Sep-2019
The total duration of concizumab treatment in the trial is 76 weeks for an individual patient enrolled 
in the trial for concizumab treatment at visit 2.
End of trial is defined as last patient last visit (LPLV).
Recruitment:
The screening and enrolment rate will be followed closely via the interactive web response system 
(IWRS) in order to estimate when to stop screening. All investigators will be notified immediately 
when the recruitment period ends, after which no further patients may be screened and the IWRS 
will be closed for further screening. All patients screened during the recruitment period and found 
eligible for enrolment can be enrolled within the timelines specified in the flow chart (see Section 
2).
Trial registration:
Information about the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and clinical 
trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure, how-we-
disclose-trial-information8, it will also be disclosed according to other applicable requirements such 
as those of the International Committee of Medical Journal Editors (ICMJE) 9, the Food and Drug 
Administration Amendment Act (FDAAA)10 , European Commission Requirements 11, 12 and other 
relevant recommendations or regulations 13. If a patient requests to be included in the trial via the 
Novo Nordisk e-mail contact at these web sites, Novo Nordisk may disclose the investigator’s 
contact details to the patient. As a result of increasing requirements for transparency, some 
countries require public disclosure of investigator names and their affiliations.
Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
protocol Last Patient First Treatment LPFT (visit2) + 24 weeks ( i.e. last patient visit 9) If the last 
patient is withdrawn early the PCD is the date when the last patient would have completed visit 9. 
The PCD determines the deadline for results disclosure at ClinicalTrials.gov according to 
FDAAA.10
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CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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8
Methods and assessments
Assessments to be performed at the scheduled and at unscheduled visits in this trial are described in 
this section and in the trial flow chart (section 2).
Figure 8–1
Overview of visit structure in explorer™5
8.1
Visit procedures
For each patient the trial consists of the following scheduled parts and visits:
Screening Part:
Visit 1 (screening visit)
Main Part:
Visit 2 (1st treatment visit with concizumab at site)
Home treatment with concizumab daily
Visit 3 (phone visit with site)
Visit 4 (Assessment visit, patients treat themselves at home)
Visit 5 (Assessment visit, patients treat themselves at home)
Visit 6 (Assessment visit, patients treat themselves at home)
Visit 7 (Assessment visit, patients treat themselves at home)
Visit 8 (Assessment visit, patients treat themselves at home)
Visit 9 (Assessment visit, after the visit patients treat themselves at home)
Extension Part:
Visit 10 (Assessment visit, patients treat themselves at home)
Visit 11 (Assessment visit, patients treat themselves at home)
Visit 12 (Assessment visit, patients treat themselves at home)
Visit 13 (Assessment visit, patients treat themselves at home)
Visit 14 (Assessment visit, patients treat themselves at home)
Visit 15 (Assessment visit, patients treat themselves at home)
Visit 16 (Assessment visit and End of treatment)
Follow-up part
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Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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Visit 17 (Assessment visit and End of trial)
Unscheduled visits can occur e.g. for dispensing of trial products, when an assessment of bleeding 
episodes is necessary at site or at the discretion of the investigator.
The duration of the visits (V1-V17) will depend on the assessments and the patient’s individual 
training and/or discussion need on concizumab administration, NovoPen® 4, usage of e-Diary, 
completion of the patient reported outcome (PRO) etc.
8.1.1
Informed consent, long-term storage consent
Informed consent must be obtained before any trial related activity, see Section 18.2.
The trial includes a separate informed consent for long-term storage of human biosamples, see 
Section 24.2. 
Storage of human biosamples and genotyping is voluntary and will not affect the patients’ 
participation in the trial. Therefore, patients will have the possibility to sign the informed consent 
for the trial and participate, while refusing permission for biological specimens and /or genotyping 
to be stored for future exploratory analysis.
8.1.2
Screening log, enrolment log, trial card and patient number
The investigator must keep a patient screening log, a patient identification (ID) code list and a 
patient enrolment log. Only patients who have signed the informed consent form should be included 
on the logs. The patient screening log and patient enrolment log may be combined in one log.
At screening, patients will be provided with a card stating that they are participating in a trial and 
given contact address(es) and telephone number(s) of relevant trial clinic staff. Patients should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each patient will be assigned a unique 6-digit patient number which will remain the same 
throughout the trial.
8.1.3
Screening failures and re-screening
For screening failures the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial. Serious and non-serious adverse events 
from screening failures must be transcribed by the investigator into the eCRF. Follow-up on serious 
adverse events (SAEs) must be carried out according to Section 12.
A screening failure session must be made in the IWRS. The case book must be signed in the eCRF.
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Version:
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UTN:U1111-1179-3872
Status:
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Re-screening is NOT allowed if the patient has failed one of the inclusion or exclusion criteria; this 
includes re-sampling if the patient has failed one of the inclusion or exclusion criteria related to 
laboratory parameters.
8.1.4
Premature discontinuation of trial product
If a patient prematurely discontinues trial product, the investigator must undertake procedures 
similar to those for visit 9 (the last treatment in the main part) or visit 16 (the last treatment visit in 
the extension part) as soon as possible. The follow up visit (visit 17) must be performed 8 weeks 
(window minus 7 days) after last dose of trial drug.
The primary reason for premature discontinuation of trial product must be specified in the end of 
treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
Permanent premature discontinuation of treatment with trial product will lead to patient withdrawal 
from the trial.
8.1.5
Withdrawal from trial
If a patient withdraws consent, the investigator must aim to undertake procedures similar to those 
for visit 9 (the last visit in the main part) or visit 16 (the last visit in the extension part) as soon as 
possible depending on where the patient is in the trial schedule.
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the patient is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS and the case book must be signed in the eCRF.
Although a patient is not obliged to give his reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the patient’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.6
Review/evaluation of clinical outcome
Novo Nordisk has constituted an internal concizumab safety committee and established an external 
DMC to perform ongoing safety surveillance of safety data relevant for concizumab, see Section 
12.8.
Review of eDiary data and laboratory reports etc. must be documented either on the documents or 
in the patient’s medical record.
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Version:
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Status:
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If unclear entries or discrepancies in the eDiary or PRO are identified and a clarification is needed, 
the patient must be asked for clarification and a conclusion made in the patient’s medical record. 
Care must be taken not to bias the patient.
8.1.7
Visit 1 (Screening part)
Informed consent must be obtained before any trial related activity, see Section 18.2.
In cases where a patient's baseline FVIII level is not documented in medical records, sampling for 
FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours.
Screening can take place between 14 to 21 days prior to planned enrolment day (visit 2).
All assessments to be performed at screening are listed in Table 2–1, see Section 2.
Apart from informed consent patients will be asked to complete the ePRO questionnaires before any 
other trial related activities are performed according to Section 8.6;
!
Hemo-TEM,
!
VERITAS-Pro® orVERITAS-PRN®
Assessment results from physical examination, body measurements, as well as measurements of 
vital signs, urinalysis electrocardiogram (ECG) and details of any contemporary adverse events 
must be entered into the eCRF.
A screening confirmation call must be performed in the IWRS, at the day of the visit.
The investigator must review all information obtained from the screening procedures. If a patient
does not meet all inclusion criteria or meets one or more of the exclusion criteria for the trial the 
patient does not qualify to be enrolled.
Patients will be provided with turoctocog alfa (rFVIII) trial injection kits and directions for use 
(DFU) to cover the potential FVIII treatment in the screening part of the trial and investigator will 
ensure that the patients are capable of treating themselves with rFVIII (turoctocog alfa). Patients on 
any previous FVIII prophylaxis can continue with this treatment until 48 hours before visit 2.
Dispensing of rFVIII (turoctocog alfa) should be performed in the IWRS
For bleeding episodes that occur in the period from Screening visit (Visit1) to enrolment visit (Visit 
2) information about the bleeding episode is to be entered in the eCRF at visit 2. 
The patient should be instructed to call the site if any bleeding episodes, questions or issues arise 
after he has left the site.
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Date:
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Version:
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8.1.8
Training of patients visit 1 and visit 2
During the site visits 1 and 2 patients must be trained in self administration of concizumab in the 
home setting using NovoPen® 4. The dose of concizumab to be administered must be 
communicated to the patient at visit 2. Furthermore patients must be instructed and trained in the 
importance and reporting of all home treatment with concizumab, details of the bleeding episodes 
and the turoctocog alfa (FVIII) treatment associated with these bleeding episodes in the eDiary,(See 
section 8.6.2).
Patients should be trained on how to recognize and react to signs of thromboembolic events, so that 
the patient without any delay contacts the site.
8.1.9
Treatment period - Main part
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site)
Visit 2 should be scheduled 14 to 21 days after visit 1. The date of visit 2 will be considered as trial 
day 1.
Before any concizumab administration it is important to verify the in/exclusion criteria again and 
review central laboratory test results from screening. 
The patient must be in a non-bleeding state at the time of first administration with concizumab and 
should not have received any FVIII treatment for prophylaxis or for treatment of a bleeding episode 
within a period of 48 hours prior to dosing.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
Hemo-TEM,
o
SF-36v2, 
o
SDS, 
o
TSQM, 
o
SIAQ-ISRQ
All protocol assessments must be performed before 1st administration of concizumab. Vital signs 
must be assessed both before and after concizumab administration.
Assessment results from concomitant medication, vital signs, Body measurements (weight only)
and details of adverse events must be entered into the eCRF.
At this, the 1st treatment visit, the allocated dose of concizumab will be given. Concizumab will be 
administered at the trial site supervised by medically trained trial staff.
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Version:
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Status:
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The time point at which the completion of the first dose takes place corresponds to Time on 
treatment = 0 and must be recorded in the eCRF.
The patient must be observed at the trial site for at least 2 hours after the administration of the first 
dose of concizumab.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.
Investigator will communicate any the daily dose of concizumab to the patient and record the dose 
for the coming home treatment period in the eCRF. 
Prior to the first dose a dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits as well as an eDiary device to be able to conduct and report 
home treatment until the next scheduled visit.
The patient will be reminded to report bleeding episodes and home treatment in the eDiary device.
The patient will be asked to return all used, partly used and unused turoctocog alfa (FVIII) during 
the trial as instructed by the investigator. Drug accountability must be performed for turoctocog alfa
(rFVIII), including injection kits if applicable, according to section 9.4.
8.1.9.2
Treatment period at home
Home treatment is defined as self-administration of trial product, performed independently by the 
patient, preferablyin the morning.Home treatment starts after visit 2 or when the patient is 
comfortable self-administrating trial product subcutaneously (concizumab)  and intravenously 
(turoctocog alfa(FVIII) ) .
8.1.9.3
Visit 3 (Phone visit)
Visit 3 is to be scheduled as a phone contact (or similar) 7days after visit 2 (with a visit window of 
+1 day) .
All relevant protocol assessments listed in table 2-1 must be discussed. Assessment results from 
concomitant medication and details of adverse events must be entered into the eCRF.
Patients should be informed to treat themselves at home according to the dosing schedule regardless 
of when visits 4, 5, 6, 7 and 8 are scheduled. 
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CONFIDENTIAL
Date:
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Version:
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UTN:U1111-1179-3872
Status:
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8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits)
Visits 4, 5, 6, 7 and 8 are to be scheduled on trial day 29 (4 weeks), day 57 (8 weeks), day 85 (12 
weeks), day 113 (16 weeks) and day 141 (20 weeks) respectively with a visit window of ± 7days.
Patients should treat themselves at home according to the dosing schedule regardless of when visits 
4, 5, 6, 7 and 8 are scheduled
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6;
o
PGI-C
o
Hemo-TEM
Assessments are to be performed according to Table 2–1and the assessment results from 
concomitant medication, vital signs, Body measurements (weight only) and details of adverse 
events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewingcollected data from the eDiary.Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab dosesis needed 
according the escalationrules described in section 5.3.1. All decisionsto escalate the concizumab 
dosemust be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocogalfa) including injection kits, if 
applicable.
At visit 8 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 9.
8.1.9.5
Visit 9(Assessment visits)  
Visit 9is to be scheduled on trial day 169(24 weeks) with a visit window of ± 7days.
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Treatment with concizumab must take place after the blood sampling at this visit.
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
PGI-C
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
Assessments are to be performed according to Table 2–1and the assessment results from physical 
examination, concomitant medication, vital signs, Body measurements (weight only) and details of 
adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through the available access to collected data from the eDiary. Based on the assessment of any 
spontaneous bleeding episodes the investigator must evaluate if an escalation of the concizumab 
doses is needed according the escalation rules described in section 5.3.1. All decisions to escalate 
the concizumab dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
8.1.10
Extension Part
8.1.10.1
Visit 10 (Assessment visits) 
Visit 10 is to be scheduled on trial day 225 (32 weeks), with a visit window of ± 7days.
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Version:
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Assessments are to be performed according to the flowchart section 2 and the assessment results 
from concomitant medication, vital signs, Body measurements (weight only)and details of adverse 
events must be entered into the eCRF.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performedaccording tosection 8.6.1;
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
SIAQ-ISRQ
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable.
8.1.10.2
Visit 11, 12, 13, 14 and 15 (Assessment visits)
Visits 11 to 15 are to be scheduled on trial day 281 (40 weeks), day 337 (48 weeks), day 393 (56 
weeks), day 449 (64 weeks) and day 505 (week 72) respectively with a visit window of ± 7days.
Assessments are to be performed according to Table 2–1 and the assessment results from physical 
examination (applicable for V12), concomitant medication, vital signs, Body measurements (weight 
only) and details of adverse events must be entered into the eCRF.
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
At visit 15 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 16.
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) - Extension part
Visit 16 is to be scheduled on trial day 533 (76 weeks) with a visit window of ± 7days.
Visit 16 should be scheduled to be conducted at the last day of treatment with concizumab.
Treatment with concizumab must take place after the blood sampling at this visit.
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
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CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
2
UTN:U1111-1179-3872
Status:
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Assessments are to be performed according to Table 2–1 and the assessment results from 
concomitant medication, vital signs and details of adverse events (AE) must be entered into the 
eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. 
In the period from visit 16 to visit 17 the patient can be treated with turoctocog alfa (rFVIII) at the 
discretion of the investigator. Treatment can either be prophylactically and/or treatment of eventual 
bleeding episodes. Only turoctocog alfa will be provided by Novo Nordisk.
If necessary, a dispensing call must be performed in the IWRS. At the visit the patient will be 
provided with rFVIII (turoctocog alfa) and injection kits to be able to conduct home treatment until 
final visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. NovoPen 4 must be 
returned. Drug accountability must be performed at all visits for concizumab and rFVIII (turoctocog 
alfa) including injection kits, if applicable.
8.1.11
Follow-up Part
8.1.11.1
Visit 17 (End of trial)
Visit17is to be scheduled on trial day 589(84 weeks) with a visit window of minus 7days 
Assessments are to be performed according to Table 2–1and the assessment results from
concomitant medication,physical examination, body measurements(weight only), vital signsand 
details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Patients must be asked if their female partner has 
become pregnant during the trial (see Section 12.5.1).
The patient will be asked to return all used, partly used and unusedturoctocog alfa (rFVIII), eDiary
deviceand Trial card.Drug accountability must be performed for turoctocog alfa (rFVIII)including 
injection kits, if applicable.
End of trial information must be entered in the End of Trial form in the eCRF.
End of trial Call must be made in the IWRS.
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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8.1.12
Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Table 2–1.
The purpose of the unscheduled visit must be documented in the eCRF. During unscheduled visits 
assessments and blood sampling must be performed according to Table 2–1. Assessment results 
must be recorded in the eCRF. Assessments and blood sampling can be omitted if the only reason 
for the unscheduled visit is dispensing of trial product. 
If trial product administration or dispensing is required, dispensing of trial product must be 
performed via IWRS.
The following forms can be found in the unscheduled visit in the eCRF:
!
Bleeding episodes
!
Dosing with FVIII, concizumab including dose escalation section 5.3.1
!
Surgery
!
Local, special and central laboratory (re-) sampling/results
!
Body measurements
8.2
Patient related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Concomitant illness and medical history other than haemophilia
A concomitant illness is any illness, other than haemophilia A, that is present at the start of the trial 
(i.e. at the first visit) or found as a result of a screening procedure or other trial procedures 
performed before first exposure to trial product. All concomitant illnesses should be reported in the 
Concomitant illness forms in the eCRF except information on haemophilia A which is to be 
reported in the Haemophilia Medical history section of the eCRF.
Medical history is a medical event, other than haemophilia A, which the patient has experienced in 
the past. Only relevant medical history should be reported. The information collected for 
concomitant illness and medical history should include diagnosis, date of onset and date of 
resolution or continuation, as applicable. Any change to a concomitant illness should be recorded 
during the trial. A clinically significant worsening of a concomitant illness must be reported as an 
AE. 
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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It must be possible to verify the patient’s medical history in source documents such as patient’s
medical record:
If a patient is not from the investigators own practice; the investigator must make a reasonable 
effort to obtain a copy of the patient’s medical record from relevant party e.g. primary physician. 
See section 6.2 and 6.3 for full description of the selection criteria. The investigator must document 
any attempt to obtain external medical information by noting the date(s) when information was 
requested and who has been contacted.  
8.2.3
Concomitant medication
A concomitant medication is any medication, other than concizumab and turoctocog alfa (rFVIII)
(and connected 0.9% Isotonic Sodium Chloride) used for rescue treatment, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the patient’s eligibility to continue in the trial, the monitor must be informed.
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History
All available information on haemophilia, prior to screening should be recorded in the eCRF. 
!
Diagnosis of haemophilia (date)
!
Classification of haemophilia type (haemophilia A)
!
Severity of haemophilia (severe, moderate or mild)
!
Etiology of haemophilia (congenital or acquired)
!
Family history of haemophilia [yes or no in eCRF]
!
Family history of Prothrombotic disorders [yes or no in eCRF]
!
Family history of Thromboembolism [yes or no in eCRF]
!
Family history of inhibitors [yes or no in eCRF]
!
Deficiency factor level
The following information on bleeding episodes one year prior to screening should be recorded in 
the eCRF:
!
Type of treatment
o
Prophylaxis or on-demand
o
Start date
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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o
Stop date
!
Number of bleeding episodes
o
If possible specify number of spontaneous bleeding episodes.
!
Coagulation factor product(s)
o
Brand name, or if the brand is not known, the type of product, (plasma derived or
recombinant)
!
Dosage used for prophylaxis  (for prophylaxis patients only)
!
Dosing frequency during prophylaxis (only for prophylaxis patients)
!
Approximate dose to treat a bleeding episode
!
Approximate number of doses to treat a bleeding episode
!
Target joint listing (definition: a target joint is a joint in which 3 or more spontaneous
bleeding episodes have occurred within a consecutive 6-month period)
o
Location
o
Position (left/right)
o
Number of bleeding episodes
8.3
Efficacy assessments
8.3.1
Bleeding episodes
All bleeding episodes treated with FVIII and symptoms related to the underlying disease must be 
captured in the eDiary by the patient or in the eCRF by the investigator. The trial site should be 
informed of the details of all bleeding episodes, including those that are treated outside of the trial 
site. All information captured including severe bleeding episodes, during visits at the trial site will 
be collected in the eCRF.
When home treatment is initiated at visit 2 all bleeding episodes and injections with concizumab 
and turoctocog alfa (rFVIII) infusions occurring outside the trial site should be entered in the eDiary 
by the patient (Section 8.6.2.3). The completed eDiary is considered source data.
The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with rFVIII (turoctocog alfa):
!
Start date and time
!
Stop date and time (see Table 8–1 for definition)
!
Anatomical location(s)
o
Position (left/ right)
!
Cause (see Table 8–2 for definitions)
o
spontaneous
o
traumatic
o
post-surgical
!
Severity (see Table 8–3 for definitions)
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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o
mild/moderate, severe

classification and of severe bleeding episodes is the responsibility of the
investigator
!
Treatment, if any
o
rFVIII (turoctocog alfa) administration(s) or other product administrations

dose, date, time
o
other medicinal treatments related to the bleeding episode (e.g. pain relieving
medication, non-medical therapy etc.)

record as concomitant medication (see Section 8.2.3)
!
Symptoms during bleeding episodes
o
Pain
o
Blood in urine
o
Tingling sensation
o
Swelling
o
Mouth/Gum bleed
o
Warmth
o
Loss of movement
o
Bruises
o
Nose bleed
Only report the bleeding episode as an AE/SAE if fatal, life threatening or evaluated as related to 
trial product (see section 12.1)
Table 8–1
Definition of stop of bleeding episode
Stop time is:
When the patient experiences/observes signs of cessation of the active 
bleeding episode such as; pain relief, no increase in swelling/limitation of 
motion and improvement in other objective signs of the bleeding episode
Stop time is not:
When pain and objective signs of the bleeding episode are completely 
resolved
Table 8–2
Definitions of bleeding episodes (cause of bleed)
Category
Definition
Spontaneous
Not linked to a specific, known action or event
Traumatic
Caused by a specific, known action or event (e.g. injury or exercise)
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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Post-surgical
Bleeding episodes after surgery from the surgical wound. Bleeding 
episodes during surgery does not fall under this category 
Table 8–3
Definition of bleeding episode severity and treatment recommendation
Category
Definition
Treatment recommendation
Mild/Moderate
Examples: uncomplicated musculoskeletal 
bleeding episodes (joint, muscular bleeds 
without compartment syndrome), mucosal- or 
subcutaneous bleeding episodes
Mild/moderate bleeding episodes may occur in 
other anatomical locations
Mild/moderate bleeding 
episodes can be treated at home 
before contact to the 
investigator
Severe
Examples: intracranial, retroperitoneal, 
iliopsoas and internal neck bleeding episodes; 
muscle bleeding episodes with compartment 
syndrome; bleeding episodes associated with a 
significant decrease in the haemoglobin level 
(>3g/dl)
Severe bleeding episodes may occur in other 
anatomical locations 
Bleeding episodes that require hospitalisation
All life-threatening bleeding episodes 
Severe bleeding episodes must 
be treated immediately 
Instruction for 
patients
The patient must be instructed to contact the investigator immediately if in doubt 
regarding treatment of a bleeding episode and to discuss what other actions may 
need to be taken
Information about bleeding episodes prior to visit 2 will be recorded in eCRF.
The trial site should be informed of the details of all bleeding episodes, including those that are 
treated outside of the trial site. After visit 2 bleeding episodes must be recorded either in the eDiary 
(if treated at home) or in the eCRF (if treated at the trial site), see section 12.3.
Severity of bleeding episodes must be evaluated by the investigator according to Table 8–3and 
reported in the eDiary database.
Prophylactic treatment with concizumab should continue independent of bleeding episodes and 
their treatment, i.e. the original dosing schedule should be maintained unless investigator judges 
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CONFIDENTIAL
Date:
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Trial ID:NN7415-4255
Version:
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Status:
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otherwise. Decisions to alter dosing schedule, including the rationale for the alteration, should be 
documented. If applicable, investigator must instruct the patient to use rFVIII (turoctocog alfa) as 
rescue medication to treat bleeding episodes.
Treatment of bleeding episodes will be at the discretion of the investigator. In countries where 
turoctocog alfa is approved for the market it is recommended to follow the approved labelling for 
NovoEight®. For countries where turoctocog alfa is not approved it is recommended to follow the 
instructions in the EU-SMPC for turoctocog alfa (FVIII): “The calculation of the required dose of 
factor VIII is based on the empirical finding that 1 IU factor VIII per kg body weight raises the 
plasma factor VIII activity by 2 IU/dl. The required dose is determined using the following formula:
Required units (IU) = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5 (IU/kg per 
IU/dl).
The amount to be administered and frequency of administration should always be oriented to the 
clinical effectiveness in the individual case.
In case of the following haemorrhagic events, the factor VIII activity should not fall below the 
given plasma activity level (in % of normal or IU/dl) in the corresponding period. The following 
table can be used to guide dosing in bleeding episodes and surgery:”
Table 8–4
Guide for dosing in bleeding episodes and surgery
Degree of haemorrhage/ Type of
surgical procedure
FVIII level required (%)
(IU/dl)*
Frequency of doses (hours)/ 
Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding
or oral bleeding
More extensive haemarthrosis, muscle
bleeding or haematoma
Life threatening haemorrhages
20-40 
30-60 
60-100
Repeat every 12 to 24 hours, at least1 
day, until the bleeding episode as
indicated by pain is resolved or
healing achieved
Repeat infusion every 12-24 hours for 
3-4 days or more until pain and acute 
disability are resolved
Repeat infusion every 8 to 24 hours
until threat is resolved
Surgery
Minor surgery including tooth
extraction
Major surgery
30-60 
80-100 (pre- and postoperative)
Every 24 hours, at least 1 day, until
healing is achieved
Repeat infusion every 8-24 hours
until adequate wound healing, then
therapy for at least another 7 days to
maintain a factor VIII activity of 30%
to 60% (IU/dl)
*however in this trial any given single dose should not exceed 50 IU/kg 
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Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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Furthermore investigator must instruct the patient to contact the site when a bleeding episode occurs 
to discuss the bleed.
It is the responsibility of the investigator to instruct the patient when to contact the site according to
Table 8–3 .
In absence of apparent effect of turoctocog alfa (rFVIII) the site must be contacted for further 
advice and before any further dosing. In case of a bleeding episode that requires treatment occurring 
outside the trial site’s opening hours the patient must be treated according to local procedure. All 
contacts to the patient must be recorded in the patient’s medical chart. 
It is the responsibility of the investigator to instruct the patient about the timelines for timely 
completion of the eDiary. Furthermore the investigator must review the bleeding and treatment data 
collected by the eDiary according to section 13.3.
For in-between visit administrations of trial drug, patients will self-administer concizumab (and 
turoctocog alfa (rFVIII) as rescue medication)) and will record treatment in the hand-held, eDiary, 
which will be reviewed during periodic calls to/contact with the patient and at each visit by trial site
staff and the sponsor staff.
8.4
Safety assessments 
8.4.1
Physical examination
Performed as standard physical examination and include the following:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Genito-Urinary system, breasts
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
The investigator must evaluate the results of the examination and classify the outcome as either:
!
Normal or abnormal.
!
If abnormal the investigator must:
o
Specify the abnormality
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at Screening: record as Medical History (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
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Date:
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Version:
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Status:
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!
Measurements will be reported in the eCRF
8.4.2
Body measurements
Height (cm), at screening
Body Weight (kg), with 1 decimal.
The body weight assessed at each visit will be used for determination of the concizumab dose to be 
administered until next visit.
Measurements will be reported in the eCRF
8.4.3
Vital signs
Before measurement of vital signs the patient should preferably rest comfortably for at least five
minutes and all measurements should, if possible, be performed using the same method and sitting 
position throughout the trial. 
Measurements at visits must be performed prior to any trial product administration unless otherwise 
specified
!
Body temperature (°C)
!
Systolic and diastolic blood pressure, sitting (BP) (mmHg)
!
Pulse, sitting (beats/min)
!
Respiratory rate
Exception: At visit 2, the measurement is also performed after concizumab administration.
The investigator must evaluate the results and classify the outcome as either: 
!
Normal or abnormal
!
If abnormal the investigator must:
o
Specify the abnormality
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2.)
o
If observed after screening: report an AE/SAE (section 12)
Measurements will be reported in the eCRF.
8.4.4
Electrocardiogram 
The investigator must evaluate the ECG (standard 12 lead) at screening and classify the outcome as
either:
!
Normal or Abnormal.
!
If Abnormal the investigator must:
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Date:
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o
Specify the abnormality 
o
Record if the result is clinically significant? (Yes/No)
o
If observed before or at Screening: record as Medical History (Section 8.2.1)
o
If observed after screening: report an AE/SAE (Section 12)
The ECG results must be dated and signed by the investigator to verify that the data have been 
reviewed. Outcome will be reported in the eCRF.
8.4.5
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12.
8.4.5.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form: 
!
Trial product(s) involved 
!
Classification of medication error
!
Whether the patient experienced any adverse event(s) as a result of the medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4.
8.4.5.2
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section12.
Injection site reaction 
Investigation of injection site reactions will be performed locally at visit 2 based on patient 
feedback and by following visual inspections of injection sites for concizumab administration:
Symptoms e.g.
!
Pain 
!
Numbness 
!
Itching
!
Burning
Signs e.g.:
!
Redness (mm x mm)
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Version:
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!
Induration (mm x mm)
!
Swelling
!
Dimpling
!
Macula
!
Haematoma
!
Bleeding
!
Other (visual reactions) 
Any injection site reaction symptom (evaluated between visit 2-16) should be recorded in the AE 
form and the injection site reaction form, see section 12.1.5. 
A separate AE should be recorded for each injection site reaction symptom. The affected area 
should also be evaluated for redness and induration in mm using a ruler. To ensure all local 
injection site assessments are performed at the injection site, the area around the site will be marked 
with a pen prior to injection. 
In the event of a local reaction, additional visual assessments (as described above) will be 
performed until resolution as judged necessary by the investigator.
Assessment of injection site reactions can be performed at any time, if deemed necessary by the 
investigator.
Hypersensitivity reaction
If suspicion of a hypersensitivity reaction occurs the patients should be instructed to contact the site
staff as soon as possible for further guidance.
All events of hypersensitivity reactions must be reported and the following information must be 
obtained if available on the hypersensitivity reaction form: 
!
Signs and symptoms associated with the event
!
Time of appearance after administration of trial drug
!
Relevant immunological tests performed (See section 8.5.2.7)
!
Treatment given for the reaction
!
Previous history of similar reactions
!
Association with the trial product(s)
!
Relevant risk factors associated with the event
!
Storage condition of the trial product
!
Total number of doses, from first day on trial product, up to the time of this event
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Version:
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8.5
Laboratory assessments
An approximate total blood volume of 450 mL will be taken from each patient in the trial. Ports 
cannot be used for blood sampling.
A laboratory manual will be provided for detailed description of obtaining and processing blood 
samples.
All laboratory blood samples collected for this trial except for haematology samples are to be 
shipped for analysis at central laboratories or further distribution to special laboratories.
Haematology samples are to be analysed locally.
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in international system of units (SI) .
Laboratory reports listing results from centrally analysed samples will be made available for the 
investigator. Investigator must review and evaluate the results and report AEs for results which are 
clinical significant. Laboratory reports will where possible indicate normal ranges 
Categorisation of clinical significance for out of range results may not be required for the following 
laboratory parameters and the investigator is therefore not required to perform a categorisation even 
though these parameters are listed in the laboratory report: FVIII activity, FVIII inhibitor test, 
Thrombin generation, TFPI not bound to concizumab, concizumab concentration in plasma, Anti-
concizumab binding antibodies, and Total TFPI.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to section 8.2.2 and section 12.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory except for biomarkers and anti-drug antibodies (anti-concizumab IgE antibodies and 
anti-concizumab binding antibodies).
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report (CTR).
Antibody samples and human bio-samples, if applicable will be stored as described in section 24.2. 
The investigator may not be able to review the results of antibody measurements in relation to AEs 
as these are often analysed after LPLV.
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Date:
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Version:
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Status:
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8.5.1
Laboratory assessments for efficacy
8.5.1.1
Thrombin generation
The Thrombin Generation Assay (TGA) will be performed at all visits, except visit 3.
The TGA is included as an exploratory PD assessment.
The generation of thrombin is a fundamental part of the haemostatic system, and is a key 
measurable parameter of the formation of a clot under bleeding or thrombotic conditions. The 
thrombin burst is crucial for the formation of a stable fibrin clot. 
The Calibrated Automated Thrombogram (CAT) method (used by Thrombinoscope BV) will be 
used to measure thrombin generation (TG). This method uses a slow acting fluorogenic substrate 
that allows continuous measurement of thrombin generation in double centrifuged citrated plasma. 
In this assay set-up thrombin generation is initiated by low-dose tissue factor that is combined with 
phospholipid. The result is obtained by comparison to a constant known thrombin activity in a 
parallel non tissue factor initiated sample. The assay has been validated fit-for-purpose.
The thrombin generation endpoints are defined, but not limited to,
!
The Endogenous Thrombin Potential (ETP) – the area under the curve 
!
Peak thrombin generation
!
Velocity Index 
8.5.1.2
Free TFPI
Free TFPI measures TFPI not bound to concizumab. This enzyme-linked immunosorbent assay 
(ELISA) test will be will be sampled for at all assessment visits.
The free TFPI ELISA assay is an enzyme immunoassay measuring levels of TFPI not bound to 
concizumab from Diagnostica Stago (named and referred to Asserachrom TOTAL TFPI) and will 
be used for PD assessments. 
Free TFPI is included as a PD assessment.
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Version:
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8.5.2
Laboratory assessments for safety
8.5.2.1
Urinalysis
!
pH
!
Protein
!
Glucose
!
Bilirubin
This is a semi qualitative measurement which will be performed (locally) at the screening visit by 
the site by using the appropriate reagent strips for urinalysis. The results will be recorded in the 
eCRF.
Clinically significant findings must be recorded as: 
!
Normal or abnormal
o
if abnormal the investigator must:
o
record if the result is clinically significant? (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
8.5.2.2
Haematology
Haematology samples are to be sampled and analysed locally at all visits, except visit 3. 
!
Haemoglobin 
!
Erythrocytes (cell count) 
!
Thrombocytes (Platelet count)
!
Leucocytes (cell count) 
!
Differential leucocytes cell count 
o
Lymphocytes
o
Monocytes
o
Neutrophils
o
Eosinophils 
o
Basophils
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
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Version:
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Haematology results are to be entered into the eCRF.
8.5.2.3
Biochemistry
!
Creatinine 
!
Albumin 
!
Bilirubin; total, direct and indirect)
!
Aspartate aminotransferase (AST) 
!
Alanine aminotransferase (ALT)
!
Gamma glutamyltransferase (GGT) 
!
Alkaline phosphatase
!
C-reactive protein (CRP) 
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
8.5.2.4
FVIII activity
!
FVIII activity (IU/ml)
8.5.2.5
Coagulation parameters 
!
Fibrinogen
!
Prothrombin time  (PT) including INR
!
D-dimer 
!
Prothrombin fragment 1+2 
!
Activated partial thromboplastin time (APTT)
!
Antithrombin (AT)
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
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Date:
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Version:
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8.5.2.6
FVIII inhibitor test
The inhibitor level of the patient will be measured by the Nijmegen method at visit 1 (screening). 
!
FVIII inhibitor titre (BU)
8.5.2.7
Anti-concizumab antibodies
Sampling will be performed at all visits except at visit 3. Samples will be collected pre-dose at visit 
2, 9 and 16.
Assessment of binding antibodies against concizumab (anti-drug antibodies (ADA)) will be 
performed at specialised laboratories whereas assessment of neutralising antibodies will be 
performed at Novo Nordisk A/S.
Analysis for ADA will be done as listed in Table 2–1, with a bridging ECL assay (binding ADA 
assay), using labelled concizumab for antibody capture and detection. Confirmed positive samples 
will be characterised for binding to IgG backbone, CDR region or the S241P mutation. 
Furthermore, positive samples will be characterised for neutralising activity using a modified TFPI 
functionality assay (neutralising ADA assay). All antibody assays are validated according to 
international guidelines and recommendations.
The following analyses will be available:
!
Anti-concizumab antibody assay
!
Specificity assay (Anti-concizumab antibodies cross reacting with IgG4 backbone, CDR region
or S241P mutation) 
!
Anti-concizumab neutralising antibody assay
Samples will be drawn at all visits except at visit 3. The samples will be analysed in batches during 
the trial and results will be available to the data monitoring committee approximately every third 
month after the first patient has been dosed (Section 12). Neutralising antibodies will be analysed 
and reported at the end of trial. A detailed description of the assay methods will be included in the 
antibody analysis report at the end of the trial.
Investigators will be notified in case their patient is shown to have developed neutralising 
antibodies against concizumab.
Samples for the determination of anti-drug antibodies collected during the treatment period must be 
drawn prior to administering trial products.
In the event that a trial patient develops binding ADAs towards concizumab during the course of the 
trial and has measurable binding ADAs at his End of Trial visit, the patient may attend an ADA 
follow-up visit. The ADA positive patients will be called for additional visits, e.g. every 4 to 6 
weeks, for safety assessment and blood sampling for ADA and PD markers (free TFPI and 
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Thrombin generation). The ADA positive patients will be followed no longer than one year after 
End of Trial.
Hypersensitivity
If suspicion of a hypersensitivity reaction occurs, patients should be instructed to contact the site 
staff as soon as possible for further guidance, see Section 12.1.5.
In the event of a severe local and/or systemic hypersensitivity reaction possibly or probably related 
to trial product, blood sampling for assessment of anti-concizumab IgE antibodies as well as anti-
concizumab antibodies should be conducted in relation to the reaction and no later than 1-2 weeks 
after the event. Additional testing may be performed if deemed relevant (e.g. anti-Host Cell Proteins 
(HCP) antibodies). 
In the event of a severe systemic hypersensitivity reaction to trial product it is recommended also to 
test for tryptase (total and/or mature tryptase) within 3 hours of the reaction. Moreover, a baseline 
tryptase measurement is necessary 1-2 weeks after the immediate severe hypersensitivity reaction 
due to individual to individual variation in tryptase baseline concentration. 
A follow up visit should be conducted 3-4 weeks post the allergic reaction with repeated blood 
sampling for assessment of anti-concizumab IgE antibodies as well as anti-concizumab antibodies 
and if possible also at a visit 3 months post the hypersensitivity reaction for assessing the 
persistence of the IgE response. Tryptase measurements are not required at the follow up visits.
Additionally, basophil activation testing may be performed if deemed relevant. This can be 
performed using existing samples and/or by analysing the patient’s basophil cells from an additional 
blood sample taken 3-4 weeks and no later than 2 months after the event. Similarly, prick tests 
and/or intra-dermal tests may be performed if relevant using trial product or components of trial 
product. Complement may be measured in case of suspicion of immune complex mediated 
hypersensitivity reactions.
Results from the following additional tests will be reported to Novo Nordisk Safety Operations for 
inclusion in the ARGUS database and included in the narratives, if measured:
Test to be performed in case of severe hypersensitivity
!
Anti-concizumab IgE antibodies
!
Anti-concizumab antibodies (additional to scheduled time points)
Additional testing may be performed if deemed relevant e.g
!
Anti-Host Cell Proteins (HCP) antibodies
!
Anti-HCP IgE antibodies
!
Basophil activation results
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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!
Prick test/intra-dermal test
!
Complement test results
Furthermore, it is recommended locally to test for
!
Tryptase (total and/or mature tryptase)
8.5.2.8
Concizumab ELISA
Concizumab ELISA will be performed at all visits except at screening and at visit 3. Samples will 
be collected pre-dose at visit 2, 9 and 16.
Concizumab will be quantified using a validated ELISA assay. Recombinant human TFPI will be 
used to capture concizumab. A colorimetric detection signal is obtained by the enzymatic reaction 
of horseradish peroxidase labelled anti-human IgG4 specific antibodies with the chromogenic 
substrate TMB (3,3´,5,5´-tetramethylbenzidine). The amount of anti-TFPI present in the calibration, 
quality control and test samples correlates with the obtained signal strength.
Validation of the assay follows current guidelines for bioanalytical method validation. Bioanalytical 
data will be reported in a bioanalytical report.
8.5.2.9
Total TFPI
Total TFPI ELISA sampling will be performed at all visits except at visit 3. Samples will be 
collected pre-dose at visit 2, 9 and 16.
The Total TFPI ELISA is included as an exploratory PD assessment.
The total TFPI level (free and concizumab bound) will be included as an exploratory biomarker 
assessment. The assay is an ELISA, where TFPI is captured by polyclonal anti-TFPI antibody, 
distanced from the binding site of concizumab, meaning that both free TFPI and concizumab bound 
TFPI will be captured. Detection will be obtained with a monoclonal antibody against TFPI, which 
does not bind to the concizumab epitope. Data will be reported in ng/mL TFPI.
Total TFPI ELISA will be performed at all visits, except visit 3. Sample will be collected pre-dose 
at visit 2.
Data will be reported in mg/ml TFPI
8.5.3
Human biosamples
If patient permission is obtained, plasma, serum and/or DNA for genotyping samples are to be taken 
for long term retention. The blood samples can be stored up to 15 years, for future potential 
exploratory purposes please refer to section 24.2.
Antibody samples storage and retention see section 24.2.1. The investigator is not able to review the 
results of antibody measurements in relation to AEs as these are analysed after LPLV.
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Date:
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Version:
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Status:
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If applicable, samples will be collected at visit 1 and at visit 17.
8.6
Other assessments
8.6.1
Patient reported outcomes
In this trial a newly developed disease specific PRO -the Hemophilia Treatment Experience 
Measure (Hemo-TEM) -is being validated. In order to assess the psychometric properties of 
Hemo-TEM,  other questionnaires will be provided; see further appendix 1.
The following ePRO questionnaires are used:
- Haemophilia Treatment Experience Measure (Hemo-TEM)
- Validated Hemophilia Regimen Treatment Adherence Scale – Prophylaxis (VERITAS-
Pro®)/Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
- 36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
- Patient Global Impression of Change (PGI-C)
- Sheehan Disability Scale (SDS)16
- Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
- Haemophilia - Device Assessment Tool (H-DAT)
- Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
The PROs should be assessed at the scheduled visits following the order listed below:
!
visit 1 (Hemo-TEM, VERITAS-Pro® or VERITAS-PRN®)
!
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 4 (PGI-C, Hemo-TEM)a
!
visit 5 (PGI-C, Hemo-TEM)
!
visit 6 (PGI-C, Hemo-TEM)
!
visit 7 (PGI-C, Hemo-TEM)
!
visit 8 (PGI-C, Hemo-TEM)
!
visit 9 (PGI-C, Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
!
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 16 (Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
At visit 1 before any visit-related activities all patients should complete Hemo-TEM and 
VERITAS-Pro® (if the patient at baseline receives prophylactic treatment) / VERITAS-PRN® (if 
patient at baseline receives on demand treatment).   
At visit 2 before any visit-related activities all patients should complete Hemo-TEM, SF36v2, SDS, 
TSQM and SIAQ-ISRQ.
At visit 4-8: before any visit-related activities the patient should complete the PGI-C before the 
Hemo-TEM. These are the rules that apply:
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Date:
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Version:
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!
If the patient responds “1” to question 1 in the PGI-C, the patient should also complete the
Hemo-TEM. In this case the patient should not fill in the PGI-C any more in the trial and the
Hemo-TEM only again at visit 9.
!
If the patient responds “0” or “2” to question 1 in the PGI-C, the patient should not complete
any other questionnaires at this visit, but should repeat the procedure at next visit.
At visit 9 if the patient has responded “0”or “2”in the PGIC at all previous visits, the patient 
should complete PGI-C. All patients should complete Hemo-TEM, SF-36v2,SDS, TSQM, H-DAT
and SIAQ-ISRQ.
At visit 10 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and SIAQ-ISRQ.
At visit 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT and SIAQ-
ISRQ. The investigator mustcheck the ePROs for potential AEs and SAEs.
The completed ePROs should be transmitted to the ePRO database by the investigator at each visit.
All PROs can be found in Appendix I. 
8.6.2
Training 
The patients must be trained in how to handle bleeding episodes and how to recognize the signs and 
symptoms of thrombosis. The training must be recorded in the medical records. 
8.6.2.1
Concizumab and NovoPen® 4
A direction for use (DFU) will be available as hand out for patients at visit 2. Training in 
NovoPen®4 can start at screening (visit 1) and s.c. administration of concizumab using the 
NovoPen®4 can start at the first dose at the trial site (visit 2). Patients must be instructed that 
injections are to be performed subcutaneously, not intravenously. Concizumab and NovoPen®4 will 
be dispensed to patients at visit 2. Training must be performed at site until patients feel comfortable
using the device or performing the treatment. The training must be documented in the medical 
records.
Detailed instructions can be found in the DFU.
8.6.2.2
Turoctocog alfa
A direction for use (DFU) will be available as hand out for patients at visit 1. Training must be 
performed at site until patients feel comfortable performing the treatment. The training must be 
documented in the medical records. 
Detailed instructions can be found in the DFU.
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8.6.2.3
eDiary
Training on the use of the eDiary can start at visit 1. The eDiary will be provided to the patients at 
visit 2.
Training must be repeated at the site until patients feel comfortable using the device. The training 
must be documented in the medical records.
During the home treatment period the patient must ensure that all home treatments of concizumab, 
details of bleeding episodes and the turoctocog alfa (FVIII) treatment associated with these bleeding 
episodes are captured in the eDiary as instructed and trained by investigator or delegated staff.
It will be the responsibility of the investigator or delegated staff to assess the eDiary data 
throughout the conduct of the trial and to ensure data entry compliance (timely entry, no duplicates 
data, no missing data etc.) and retraining if necessary.
For patients completing the trial or in case of withdrawal, the eDiary will be collected at the end of 
trial.
8.6.3
Surgery
Minor surgery can be performed within this trial at the investigator’s discretion according to local 
guidelines. Definition of minor surgery, see section 5.1.1. Major surgery is not allowed, see 
exclusion criteria no 6.
For minor surgery the following should be recorded in the eCRF:
!
Date, stop time and dose of preventive treatment with turoctocog alfa before surgery, if this was 
deemed necessary by the investigator
!
Indication for surgery
!
Location of surgery
!
Date of surgery
!
Start and stop time of surgery
8.7
Patient compliance
Throughout the trial, the investigator will remind the patients to follow the trial procedures and 
requirements to ensure patient compliance. If a patient is found to be non-compliant, the 
investigator will remind the patient in the importance of following the instructions given including 
taking the trial products as prescribed.
Assessment of patient compliance with protocol procedures for determination of continuation of the 
trial will be done by the investigator on an ongoing basis.
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8.8
Treatment compliance:
Treatment compliance will be monitored and documented through timely review of eDiary data and 
drug accountability. 
Concizumab will be administered at the trial site at visit 2 supervised by medically trained trial staff
and administration at home can be initiated after visit 2 if the patient feels comfortable with the s.c. 
administration. Administration of turoctocog alfa (rFVIII) for bleeding episodes will be 
administered at the trial site by a medically trained trial staff or at home by the patient, see section 
8.3.1. 
The patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator. Drug accountability will be performed and will be used to assess 
patient compliance together with the patient’s adherence to trial procedures. 
Compliance check includes a cross check between records in EDC/eDiary (number of 
administrations and bleeding episodes) and the used/returned cartridges/vials. 
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Version:
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
The trial product, concizumab B, appears clear to slightly opalescent and colourless to slightly 
yellow. The trial product must not be used if it contains visible particles or discolouration.
The reconstituted turoctocog alfa (FVIII) solution appears as a clear or slightly opalescent solution. 
Do not use the reconstituted solution if it has visible particles or discoloration. 
Trial products must not be dispensed to any person not included in the trial.
9.1
Trial products
The following trial products will be provided by Novo Nordisk, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
concizumab B 
(IMP a)
100 mg/mL
Solution for injection
s.c. injection
3 ml cartridge
turoctocog alfa
(NIMP b)
2000 IU/vial
Powder for solution for 
injection
i.v. injection
Vial
0.9% Sodium Chloride 
Solution
(NIMP b)  
N/A
Solvent for solution for
injection 
i.v. injection
4 ml prefilled 
syringe
a Investigational Medicinal Product (IMP) 
b Non-Investigational Medical Product (NIMP) given as NIMP for bleeding episodes
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. NovoPen®4 will be labelled in accordance with the EMA directive on medical devices 
annex I 21 and similar national legislation. A description on how to use the device is given in the
DFU.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 22, local regulations and trial 
requirements.
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Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial products will be distributed to the trial sites according to enrolment 
and drug dispensing of distribution.
The investigator must document that direction for use is given to the patient orally and in writing at 
the first dispensing visit (see flow chart section 2). 
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time a
concizumab B 100 mg/mL
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
Store at room temperature 
(below 30°C)
Do not refrigerate
Protect from light
Use within 4 weeks 
(28 days)
turoctocog alfa
2000 IU/vial
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
May be stored at room 
temperature (9-30oC) for a 
single period not exceeding 9
months. Do not return the 
product to the refrigerator.
Write the start date for the 
storage at room temperature on 
the label
For single use
To be used immediately after 
reconstitution
Use within 4 hours after 
reconstitution when stored at 
room temperature
N/A
0.9% sodium chloride 
solution
Store at 2°-30°C
Do not freeze
Protect from light
For single use
N/A
a In-use time for concizumab starts when first dose is administrated from an individual cartridge and for turoctocog alfa 
when the product is reconstituted
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any patient before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
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Investigator must instruct the patient to use and store trial product according to the label.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator. The 
patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator except for the sodium chloride solution which should be discarded at 
home and not accounted for.
All cartridges (concizumab) and vials (FVIII) must be accounted for as used, partly used, or unused. 
The investigator will perform drug accountability using the IWRS Drug Accountability module.
Returned trial product (used/partly used and unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Destruction of concizumab can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
For Japan only: Responsibility for storage and drug accountability of the trial drug product at the 
trial site rests with the head of the trial site. The head of the trial site could assign some or all of the 
responsibilities for accountability of the trial drug product at the trial sites to a trial product storage 
manager (a pharmacist in principle). The trial product storage manager should control and take 
accountability of the trial drug product in accordance with procedures specified by Novo Nordisk. 
The head of the trial site or the trial product storage manager must ensure the availability of proper 
storage conditions, and record and evaluate the temperature.
9.5
Auxiliary supplies
Novo Nordisk will provide the auxiliaries for this trial: 
!
For concizumab administration: NovoPen®4, needles, and DFU
!
For turoctocog alfa reconstitution and administration: Trial Injection Kit and DFU
Only needles and trial injection kits provided by Novo Nordisk must be used for administration of 
trial product.  
For further guidance please see the TMM.
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for:
!
Screening
!
Screening failure
!
Medication arrival
!
Dispensing
!
Dispensing verification
!
Treatment discontinuation 
!
Completion
!
Drug accountability
!
Data change
An IWRS user manual will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
Randomisation 
Not applicable for this trial
Breaking of blinded codes
Not applicable for this trial.
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12 Adverse events, and technical complaints
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial 
procedures performed before exposure to trial product (pre-existing conditions should be 
reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the patient has signed the informed 
consent.
!
Bleeding episodes and other symptoms (e.g. pain, swelling, synovitis, arthralgia, injection 
site haematoma) in connection with bleeding episodes should not be reported as AEs/SAEs 
unless the event is fatal, life-threatening or evaluated by the investigator as related to trial 
product or trial procedure. All bleeding episodes and other findings related to underlying 
disease will be captured in the eCRF/eDiary
The following three definitions are used when assessing an AE:
!
Severity 
o
Mild – no or transient symptoms, no interference with the patient’s daily activities.
o
Moderate – marked symptoms, moderate interference with the patient’s daily activities.
o
Severe – considerable interference with the patient’s daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial product(s): 
o
Probable - Good reason and sufficient documentation to assume a causal relationship.
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o
Possible - A causal relationship is conceivable and cannot be dismissed.
o
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome 
o
Recovered/resolved - The patient has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the patient signed the informed consent.
o
Recovering/resolving - The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the trial 
or has died from another AE.
o
Recovered/resolved with sequelae - The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
o
Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known.
o
Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he 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.
o
Unknown - This term is only applicable if the patient is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
a. The term “life threatening” in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
b. The term “hospitalisation” is used when a patient: 
o
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
o
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c.A substantial disruption of a patient’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the patient has significant, persistent or permanent change, 
impairment, damage or disruption in his body function or structure, physical activity and/or quality 
of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
Suspicion of transmission of infectious agents via the trial product 
!
Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative 
aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error unless 
it results in administration of wrong drug.
!
Wrong route of administration, 
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. However, the 
administered dose must deviate from the intended dose to an extent where clinical 
consequences for the trial patient were likely to happen as judged by the investigator, 
although they did not necessarily occur
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1
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12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
In this trial the following AEs require the completion of specific event forms in the eCRF:
!
Injection site reaction (see section 8.4.5.2)
!
Hypersensitivity type reactions, incl. anaphylactic reactions, as defined below 
Injection site reactions:
Any injection site reaction symptom must be reported on the AE form and the injection site reaction 
form, See section 8.4.5.2.
Hypersensitivity type reactions:
In cases where clinical signs of a severe and immediate hypersensitivity reaction resembling a type
I hypersensitivity reaction are present, blood should be sampled for central laboratory assessment of 
anti-drug IgE antibodies and anti-drug binding antibodies. In the event of an immediate systemic 
hypersensitivity reaction to the trial product, it is recommended to also test for tryptase (total and/or 
mature tryptase) within 3 hours of the reaction. Moreover, a baseline tryptase measurement is 
necessary ~1 week after the immediate severe hypersensitivity reaction due to individual to 
individual variation in tryptase baseline concentration. Tryptase concentrations (if measured) must 
be interpreted and considered in the context of a complete workup of each patient.
Special attention should be given to clinical signs and symptoms of hypersensitivity reactions of 
type II and III. Common clinical signs and symptoms characteristic for these types of reactions may 
include but are not limited to: fever/malaise, cutaneous eruptions, arthralgia, lymphadenopathy, 
itching, headaches and myalgia. Related laboratory findings may include but are not limited to: mild 
proteinuria or haematuria, leukopenia or leucocytosis, decreased complement levels or increased 
complement split products and transient elevations of serum creatinine levels. In cases where there 
is a suspicion of hypersensitivity reaction that requires systemic treatment, additional sampling for 
the purpose of measuring ADA is to be performed.
Definition of anaphylaxis23
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
!
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (e.g. generalised hives, pruritus or flushing, swollen lips-tongue-uvula) and 
at least one of the following:
a) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)
b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.
hypotonia [collapse], syncope, incontinence)
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!
Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):
a) Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush, swollen 
lips-tongue-uvula)
b) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
!
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
Systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
BP.
If a patient fulfils any of the three criteria of anaphylaxis outlined above, the patient should receive 
epinephrine/adrenalin immediately. Dose regimen should be according to hospital operating 
procedure, and the patient should be transferred to an emergency department or intensive care unit, 
if clinically warranted.
Events not fulfilling the criteria for an anaphylactic reaction and other allergic reactions must be 
treated at the discretion of the investigator. If according to the investigators judgment, 
hypersensitivity type reactions that require systemic treatment are suspected, dosing with 
concizumab should be stopped immediately and treatment at the discretion of the treating physician 
initiated.
12.1.6
Adverse event of special interest
An adverse event of special interest (AESI) is an event, which in the evaluation of safety, has a 
special focus. In this trial, the following AEs fulfil the AESI criteria:
!
Thromboembolic events including but not limited to,
o
disseminated intravascular coagulation (DIC) (A), 
o
clinical signs or laboratory indications of arterial and venous thrombosis including 
myocardial infarction (B), 
o
pulmonary embolism (C), 
o
stroke (D), 
o
deep vein thrombosis (E), 
o
other clinically significant thromboembolic events (F) and peripheral artery 
occlusion (see below G), see definitions below.
The AESIs must be reported on an AE form and a safety information form.
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A) Definition of disseminated intravascular coagulation (DIC), as defined below:
The definition of DIC in this trial should be made according to the International Society on
Thrombosis and Haemostasis (ISTH) criteria. Thus, a DIC diagnosis may be based on 
clinical signs and symptoms of a bleeding tendency or thrombotic tendency, organ 
dysfunction and the laboratory parameters criteria as listed below:
o
Platelet count (>100 × 109/L = 0, <100 × 109/L = 1, <50 × 109/L = 2)
o
Elevated D-dimer (no increase = 0, moderate increase = 2, strong increase = 3)
o
Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
o
Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
o
Calculate score: ≥5 compatible with overt DIC
(B) Myocardial infarction is defined according to the “Third Universal Definition of
Myocardical Infarction” 24
Criteria for acute myocardial infarction - The term acute myocardial infarction (MI) should be used 
when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial 
ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI:
!
Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin
(cTn)] with at least one value above the 99th percentile upper reference limit (URL) and
with at least one of the following:
o
Symptoms of ischemia.
o
New or presumed new significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB).
o
Development of pathological Q waves in the ECG.
o
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality.
o
Identification of an intracoronary thrombus by angiography or autopsy.
Criteria for prior myocardial infarction- Any one of the following criteria meets the diagnosis for
prior MI:
!
Pathological Q waves with or without symptoms in the absence of non-ischemic causes.
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to
contract, in the absence of a non-ischemic cause.
!
Pathological findings of a prior MI.
Recurrent myocardial infarction - Incident MI’ is defined as the individual’s first MI. When features 
of MI occur in the first 28 days after an incident event, this is not counted as a new event for 
epidemiological purposes. If characteristics of MI occur after 28 days following an incident MI, it is
considered to be a recurrent MI.
C) Definition of pulmonary embolism:
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The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends diagnostic
imaging studies for patients with intermediate or high pre-test probability of pulmonary embolism25.
Accordingly, the definition of pulmonary embolism is the following: obstruction of a pulmonary 
artery or one of its branches, most frequently by detached fragments of thrombus from a leg or 
pelvic vein, diagnosed by at least one of the following:
!
Positive findings in ventilation/perfusion scan
!
Positive findings in a spiral (helical) computerised tomography (CT) or angiography
!
Positive findings in a magnetic resonance imaging (MRI)
!
Positive findings in a pulmonary angiography
D) Definition of stroke:
The definition of central nervous infarction is according to the American Heart
Association/American Stroke Association Expert Consensus Document:  “An Updated Definition of 
Stroke for the 21st Century”26.
Accordingly, the term “stroke” should be broadly used to include all of the following:
Definition of central nervous system (CNS) infarction: CNS infarction is brain, spinal
cord, or retinal cell death attributable to ischemia, based on:
o
1. pathological, imaging, or other objective evidence of cerebral, spinal cord, or
retinal focal ischemic injury in a defined vascular distribution; or
o
2. clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on
symptoms persisting 24 hours or until death, and other etiologies excluded.
Note: CNS infarction includes haemorrhagic infarctions, types I and II; see “Haemorrhagic
Infarction”.
Definition of ischemic stroke: An episode of neurological dysfunction caused by focal cerebral,
spinal, or retinal infarction. Note: Evidence of CNS infarction is defined above.
Definition of silent CNS infarction: Imaging or neuropathological evidence of CNS infarction,
without a history of acute neurological dysfunction attributable to the lesion.
Definition of intracerebral haemorrhage: A focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma. Note: Intracerebral haemorrhage includes
parenchymal haemorrhages after CNS infarction, types I and II - see “Haemorragic Infarction”.
Definition of stroke caused by intracerebral haemorrhage: Rapidly developing clinical signs of
neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma.
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Definition of silent cerebral haemorrhage: A focal collection of chronic blood products within the
brain parenchyma, subarachnoid space, or ventricular system on neuroimaging or neuropathological
examination that is not caused by trauma and without a history of acute neurological dysfunction
attributable to the lesion.
Definition of subarachnoid haemorrhage: Bleeding into the subarachnoid space (the space between
the arachnoid membrane and the pia mater of the brain or spinal cord).
Definition of stroke caused by subarachnoid haemorrhage: Rapidly developing signs of
neurological dysfunction and/or headache because of bleeding into the subarachnoid space (the
space between the arachnoid membrane and the pia mater of the brain or spinal cord), which is not
caused by trauma.
Definition of stroke caused by cerebral venous thrombosis: Infarction or haemorrhage in the brain,
spinal cord, or retina because of thrombosis of a cerebral venous structure. Symptoms or signs
caused by reversible edema without infarction or haemorrhage do not qualify as stroke.
Definition of stroke, not otherwise specified: An episode of acute neurological dysfunction 
presumed to be caused by ischemia or haemorrhage, persisting ≥24 hours or until death, but without
sufficient evidence to be classified as one of the above.
Definition of a Transient Ischemic Attack: The definition of Transient Ischemic Attack is according
to the American Heart Association/American Stroke Association. Accordingly: a Transient 
ischemic attack (TIA) is a transient episode of neurological dysfunction caused by focal brain, 
spinal cord, or retinal ischemia, without acute infarction 27.
E) Definition of deep vein thrombosis:
The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends
ultrasound scanning for patients with intermediate or high pre-test probability of deep vein 
thrombosis (DVT) in the lower extremities 25. Accordingly, venous thrombosis should be 
demonstrated by compression ultrasound,
duplex ultrasound, colour Doppler imaging or venography (phlebography).
F) Definition of other clinically significant thromboembolic events:
Signs or suspicion of a clinically significant thromboembolic event (e.g. visceral arterial 
embolus/thrombus, extremity arterial embolus/thrombus, or portal venous thrombosis).
Superficial thrombophlebitis is not considered a clinically significant thromboembolic event unless 
evaluated as such by the investigator.
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G) Definition of peripheral artery occlusion:
Clinical signs of acute arterial occlusion verified by ankle-brachial index (ABI) test, Doppler and
ultrasound (Duplex) imaging, computerised tomographic angiography, magnetic resonance 
angiogram (MRA), or conventional angiography. The 2011 American College of Cardiology 
Foundation/American Heart Association Focused Update of the Guideline for the Management of 
Patients With Peripheral Artery Disease could serve as a reference for the diagnosis of lower 
extremity peripheral artery disease 28
12.1.7
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between pen and needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the patient has signed the informed consent until the end of 
the post-treatment follow-up period (visit 17). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12–1
During each contact with the trial site staff, the patient must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?
All AEs, either observed by the investigator or patient, must be reported by the investigator and 
evaluated. All AEs must be recorded by the investigator on an AE form. The investigator should 
report the diagnosis, if available. If no diagnosis is available, the investigator should record each 
sign and symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
AESIs regardless of the seriousness, must be reported using the AE form and safety information 
form
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For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the case report form (CRF)/eCRF within the 
specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator’s first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in the 
eCRF. 
For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
!
Non-serious AEs fulfilling the AESI criteria: The AE form and safety information form 
within 14 calendar days of the investigator’s first knowledge of the event.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: Investigator’s Brochure; Current version and any updates thereto.
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP 1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the
International Review Boards/Independent Ethics Committees (IRBs/IECs) of trial product-related 
SUSARs in accordance with local requirement and ICH GCP 1, unless locally this is an obligation 
of the investigator.
Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
non-investigational medicinal product rFVIII (turoctocog alfa) or concomitant medication in the 
trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to report this 
adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. 
Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is 
“recovered/resolved”, “recovered/resolved with sequelae” or “fatal”, and until all queries 
have been resolved. Cases of chronic conditions, cancer or AEs ongoing at time of death 
(where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the 
outcome of “recovering/resolving” when the patient has completed the follow-up period 
and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
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information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or 
until the end of the follow-up period stated in the protocol, whichever comes first, and 
until all queries related to these AEs have been resolved. Cases of chronic conditions, 
cancer or AEs ongoing at time of death (where death is due to another AE) may be 
closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the patient has 
completed the follow-up period and is expected by the investigator to recover.
!
Non-serious AEs fulfilling the AESI criteria: Non-serious AE fulfilling the AESI 
criteria must be followed as specified for non-serious AE. Follow-up information on 
AESIs 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 AESI criteria.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a patient after the patient has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 
!
Concizumab B 100 mg/mL, solution for injection in a 3 ml cartridge
!
NovoPen®4
!
Novo Nordisk needles
!
Turoctocog alfa 2000 IU/vial, powder for solution for injection in a vial  
!
0.9 % sodium chloride 4.0 mL prefilled syringe
!
Novo Nordisk trial injection kit
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which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Centre, Novo Nordisk.
Contact details (fax, e-mail and address)  are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, AESIs and/or 
SAEs.
Technical complaints must be reported on a separate technical complaint form: 
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each batch, code or lot number
must be completed
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not patient related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Centre, Novo Nordisk (the address is provided in Attachment I)  and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. 
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12.5
Pregnancies 
12.5.1
Pregnancies in female partners of male patients
Male patients must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period (from visit 1 to dosing at visit 2). At the last 
scheduled visit, male patients must be asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male patient and assess, if the pregnancy 
outcome is normal or abnormal. 
When the pregnancy outcome is normal this information is recorded in the patient’s medical record 
only, no further information is collected and reported to Novo Nordisk. When the pregnancy 
outcome is abnormal (i.e. congenital anomalies, foetal death including spontaneous abortion and/or 
any anomalies of the foetus observed at gross examination or during autopsy), the following must 
be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
1. Reporting of pregnancy information
Information from the male patient has to be reported on the Paternal Form. Furthermore, 
information from the female partner (including information about the pregnancy outcome and 
health status of the infant until the age of one month) has to be reported on the Maternal Forms 
1A, 1B and 2, after an informed consent has been obtained from the female partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information. 
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
o
Non-serious AEs evaluated as possible/probably related to the father’s treatment 
with the trial product(s). 
o
SAEs in the foetus and newborn infant - whether or not related to the father’s 
treatment with the trial product(s). This includes an abnormal outcome - such as 
foetal death (including spontaneous abortion) and congenital anomalies (including 
those observed at gross examination or during autopsy of the foetus).
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
Paper AE forma within 14 calendar days of the investigator’s first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
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!
Paper AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
Paper safety information form within 5 calendar days of the investigator’s first knowledge 
of the SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information.
a It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
patient, foetus or new born infant. 
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Dose limiting toxicities of concizumab has not been investigated in clinical trials.
There have been no reports about overdosing of concizumab and therefore no experience with 
overdose and overdose reactions exists. In case of a concizumab overdose, symptomatic medical 
treatment according to the clinical condition should be applied. No antidote exists in case of 
concizumab overdose.
Any overdose should be reported as an AE, with or without clinical manifestations. Overdoses are 
considered medication errors.
Treatment should be as appropriate and in accordance with hospital practice and guidelines.
12.7
Rules for putting enrolment on hold
If one of below mentioned criteria is fulfilled, enrolment of additional patients in the clinical trial 
program will be placed on hold. An urgent safety committee meeting will be scheduled to decide 
further actions. Dosing of patients on treatment may continue while further evaluation is made by 
the safety committee. A substantial amendment with relevant data must be submitted to the 
regulatory authorities to support restart of the trial.
!
Significant thromboembolic event* 
!
Event of DIC 
!
Anaphylactic reaction related to trial drug administration 
!
Death of trial patient which may be related to the trial product
!
Two or more other trial product related SAEs similar in nature have been reported and/or 
detected by laboratory measurements
!
Trends in AEs, clinical observations or laboratory parameters which raise concerns about 
the safety of continued treatment
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* Superficial thrombophlebitis or venous thrombosis associated with indwelling catheters is not considered a significant 
thromboembolic event unless evaluated as such by the investigator
If two or more other trial product related SAEs similar in nature have been reported and/or detected 
by laboratory measurements, or if trends in AEs, clinical observations or laboratory parameters 
raise concerns about the safety of continued treatment, the safety committee (see section 12.8.1) 
will then decide whether further dosing of any patients in the clinical trial program should be 
continued, paused or discontinued.
12.8
Committees related to safety
12.8.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal concizumab safety committee to perform ongoing safety 
surveillance of safety data relevant to concizumab. The safety committee is a cross functional group 
within Novo Nordisk.
12.8.2
Data monitoring committee
The DMC is an independent, external committee composed of members whose expertise covers 
relevant specialties including statistics. The DMC is established to review and evaluate accumulated 
data from the trial at predefined time points as well as ad-hoc. This is in order to protect the safety 
of the patients and to evaluate the benefit-risk balance. The DMC will have access to the unblinded
data, and will provide recommendations on trial continuation, modification or termination.
In case there is any safety concern data will be compiled and the DMC will review these data. Their 
recommendation will go to the Novo Nordisk Safety committee for final decision of what next step 
is in this trial.
The DMC members will only have direct contact with the Novo Nordisk Global Safety department 
through the safety surveillance representatives, and will have no direct interaction with those in trial 
management. The DMC recommendations should be addressed directly to the Novo Nordisk Global 
Safety department and the internal Novo Nordisk safety committee for concizumab. It is the 
responsibility of the Novo Nordisk internal safety committee for concizumab to take action(s) for
patient safety based on the DMC recommendations.
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter.
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13 Case report forms 
For this trial a combination of electronic case report forms (eCRFs) and paper CRFs will be used.
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
Safety information forms
!
Technical complaint forms 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
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Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
13.3
Electronic diary
Novo Nordisk will provide the patient with an eDiary for electronic recording of details of their 
home treatment, bleeding episodes and treatment of bleeding episodes (i.e. use of FVIII). The 
eDiary and related support services will be supplied by a vendor working under the direction and 
supervision of Novo Nordisk. 
Patients will be instructed in the use of the eDiary by the investigator or delegated person before 
entering of any data. The eDiary will be dispensed to the patient at visit 2. After visit 2 and 
onwards, data will be entered by the patient in the eDiary device during home treatment.
The eDiary will be returned by the patient at the end of trial (EOT) visit.
All data entered will be transferred from the device to an electronic database, where it is kept as a 
certified copy of the source data by the eDiary vendor. Data entered in the device will upon 
confirmation of a successful back-up be deleted from the device. 
The eDiary will have built in edit checks and reminders, to ensure that all relevant questions are 
answered. 
eDiary data transferred to the electronic database will be viewable to relevant trial site staff and 
Novo Nordisk personnel on a secure, password protected web portal.
13.3.1
Investigator review of eDiary data
It is the responsibility of the Investigator or delegated staff to review the eDiary data reported by the 
patient. As a minimum it must be verified that the eDiary data is complete, consistent and according 
to the requirements defined in this protocol. This also includes that the number of doses reported in 
the eDiary is reviewed against the number of vials/cartridge accounted for as used by the patient.  
Upon review the Investigator must document that the review has taken place and any actions 
required e.g. retraining of the patient or decision to amend or correct the data reported by the 
patient. 
If the Investigator finds it necessary to amend or correct eDiary data, the patient must be consulted 
prior to requesting the actual data change. A Data Correction Request must be submitted to the 
eDiary vendor. An audit trail will be maintained.
14 Monitoring procedures 
Monitoring will be conducted using a risk based approach including risk assessment, monitoring 
plans, centralised monitoring and visits to trial sites. During the course of the trial, the monitor will 
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visit the trial site to ensure that the protocol is adhered to, that all issues have been recorded, to 
perform source data verification and to monitor drug accountability. The first monitoring visit will 
be performed as soon as possible after FPFV at the trial site and no later than 4 weeks after. The 
monitoring visit intervals will depend on the outcome of the centralised monitoring of the eCRFs 
(remote assessment of data by Novo Nordisk), the trial site's recruitment rate and the compliance of 
the trial site to the protocol and GCP, but will not exceed 12 weeks until LPLV at the trial site. This 
only applies to sites with scheduled, ongoing and/or discontinued patients.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone or text message).
All data must be verifiable in source documentation other than the eCRF. eDiary data is entered by 
the patient and will also be treated as source data. 
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
For historical data such as medical history, details of haemophilia and haemophilia treatment 
history, a reasonable effort must be made by the investigator, considering local requirements, to 
obtain this information from external sources, if not known by the patient. It is accepted that the 
earliest practically retainable record should be considered as the location of the source data and 
therefore the source document. This means that for laboratory results (e.g. biochemistry and 
haematology) a signed printout of the electronic results must be available.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The monitor will ensure that the eCRFs are completed and paper CRFs (if any) collected, that PROs 
and eDiaries are completed and reviewed by the investigator at the relevant scheduled visits and 
needed action has been taken and documented, if any.
The following data will be source data verified for screening failures:
!
Date for obtaining informed consent
!
Inclusion and exclusion criteria
!
Screen failure reason if possible
!
Date patient left the trial
!
Data relating to AEs if applicable
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!
Demography (See section 8.2.1)
!
Date of visit
Monitors will review the patient’s medical records and other source data (e.g. eDiaries and ePROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract reseach organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of patientdata, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The laboratory will provide all laboratory reports to the investigator for filing at the trial site. The 
laboratory report must be signed and dated by the investigator or delegated person and stored at the 
trial siteas source data.
The patientand any biological material obtained from the patientwill be identified by patient
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of patients in all presentations and publications as required by 
local, regional and national requirements
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk 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 use the Global Haemophilia Network (GHN) Investigator Portal to distribute 
and share trial-related documents and information with the participating sites.
After trial completion,Novo Nordisk will supply each trial site with long-life CDs or other relevant 
electronic archiving containing the electronic Investigator Trial Master File (eITMF) for each trial 
site. These CDs or other relevant electronic archiving will contain site-specific trial documentation 
as well as trial specific news and other relevant trial information, including audit trail on documents 
and site staff users. The GHN Portal software and hardware implementation are compliant with the 
requirements of U.S. Food andDrug Administration (FDA)21 CFR Part 11 and ICH E6 (EU 
directive for personal data protection)1,29.
Novo Nordisk will provide electronic tablets for reporting of all PROs questionnaires described in 
section8.6.1and in Appendix 1. In case the electronic tablet is revoked the questionnaires will be 
available in paper.
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The eDiary software and hardware implementation are compliant with the requirements of FDA 21
CFR Part 11 and ICH E6 (EU directive for personal data protection)1, 29.After trial completion, each 
trial site will be supplied with long-life CDs. These CDs will contain site-specific patient records 
including the patient’s eDiaries and ePROs as PROs are handled seperately from eDiary and audit 
trail including any data additions and corrections made on each form. The eDiary vendor will 
furthermore retain and securely store copies of all archived documents and data for 15 years or as 
required by local data retention laws for trial data
17 Statistical considerations
All endpoints referring to a time frame of at least 24 weeks will be evaluated in the main part of the 
trial, defined to end when the last patient have completed a minimum of 24 weeks of dosing or at 
LPFT (visit 2)+24 weeks if the last patient has withdrawn before visit 9. Please refer to Figure 17–1
for further information. All available data up to the time point where the last patient ends 24 weeks 
of treatment or has withdrawn will in such case be used in the analysis of the main part.
Endpoints comprising number of bleeding episodes will be evaluated based on treated bleeding 
episodes only. Multiple bleeding locations occurring from the same event (e.g., due to a bicycle 
accident) or at the same time point will be counted as one bleeding episode. Further, the endpoints 
will not include re-bleed.
A re-bleed is defined as a bleeding episode (worsening of bleeding site conditions e.g. swelling, 
pain) within 72 hours after stopping of a previous bleeding episode at the same (or subset of the 
same) anatomical location. If a bleeding episode occurs in the same location 72 hours after 
stopping, the treatment is defined as a new bleeding episode.
Clinical proof of concept
The statistical analysis of the collected data aims to establish CPoC that concizumab is efficacious 
in preventing bleeding episodes in haemophilia A patients without inhibitors. The objective will be 
assessed when the last of the 30 patients have completed 24 weeks of dosing (or have withdrawn). 
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the ABR of all patients with a threshold of 12, irrespective of individual dose 
titration. The primary CPoC criterion aims at evaluating the effect of concizumab at the last dose 
level reached for a patient. Hence, for this evaluation, only observations from the period where 
patients are on their end dose at time of analysis will contribute to the analysis. Furthermore, 
observations from the 2 week run-in period will be not be included. Since this evaluation disregards 
a subset of data collected the result should be viewed taking in to account the potential bias. The 
second CPoC criterion aims at evaluating the effect of concizumab when given as an escalation 
regimen. Hence, this will compare the ABR of haemophilia A patients treated with concizumab 
with the typical historical ABR of haemophilia A patients being treated on-demand using all data 
after enrolment. The second CPoC criterion will only be evaluated if the first one succeeds.
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The referred comparisons will be made using a negative binomial model with log of exposure time 
in main phase as offset. For each criterion, evidence of effect will be concluded if the 95% 
confidence interval of the estimated ABR is below 12. 
The value of 12 bleeds per year reflects conservatively a 50% reduction from the bleeding rate 
during on-demand treatment, which in previous trials typically has been reported to be above 30 
bleeds per year 30-32. A confidence limit lower than 12 will also to a certain extent substantiate that 
the prophylactic efficacy of concizumab may be similar to that of FVIII replacement therapy where 
an estimated mean of 6.5 bleeds per year was observed33.
Clinical arguments for the hierarchical test approach
Concizumab exhibits non-linear PK due to target mediated drug disposition and it is expected that 
the dose response curve of the ABR is rather steep. This implies that patients that are on a dose 
which is not efficacious are likely to bleed as patients that are not treated at all. The subset of data 
collected from the last dose clinically deemed as efficacious would reflect the efficacy of 
concizumab in the given patient.
17.1
Sample size calculation
The sample size calculation has been determined taking the small patient population into account, 
while also aiming for an acceptably narrow 95% confidence interval for the ABR. 
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be
accommodated by 30 patients. 
It is expected that the treatment duration of the main part allowing for escalation time for some 
patients is on average 6 months in the below calculations. 
When evaluating the power of the negative binomial analysis referred above, an annual bleeding 
rate of 4 is assumed for the end dose concizumab regimen, respectively in combination with an 
over-dispersion of 6. The power for concluding a bleeding rate lower than 12 then becomes 
approximately 95%. The power under varying values of true ABR and over-dispersion for the 
primary CPoC criterion are shown below in Table 17–1.
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion.
Power
Over-dispersion
ABR
5
6
7
4
99%
95%
92%
5
95%
90%
86%
6
87%
81%
72%
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For the secondary CPoC criterion that includes data prior to potential dose escalation, it is expected 
that the treatment duration of the main part is on average 8 months with an average ABR of 5.4 for 
the concizumab treated patients. This yields a marginal power of approximately 87% for the 
secondary CPoC criterion. 
In prior Novo Nordisk trials conducted in haemophilia patients, the typical 1-year over-dispersion 
for non-inhibitor patients on prophylaxis with FVIII or FIX has been in the range 4-8, implying 24 
weeks over-dispersion of 3-5 (e.g. in NN7008-3543, NN7088-3859 and NN7999-3747). On that 
background, an over-dispersion of 6 over the 24 weeks in the main part of the current trial is 
deemed realistic.
17.2
Definition of analysis sets
All dosed patients will be included in the Full Analysis Set (FAS) as well as in the Safety Analysis 
Set (SAS).
17.3
Primary endpoint
The primary endpoint is the number of bleeding episodes during at least 24 weeks from treatment 
onset.
The primary endpoint will be estimated using negative binomial regression with log of exposure 
time in main phase as offset, providing an actual estimate of the ABR as well as a corresponding 
95% confidence interval.
This analysis has the underlying assumption that the missing data mechanism is “missing at 
random”, i.e. MAR. Under this assumption, the statistical behaviour of the missing data (given the 
observed responses and the mean value structure) is assumed to be the same as for the observed 
data. The endpoint will be estimated based on the full analysis set (FAS) and only data collected 
prior to discontinuation of trial product or initiation of alternative treatment options will be used to 
draw inference.
17.4
Sensitivity analyses
To evaluate the robustness of the MAR assumption implied in the primary analysis, a modified 
tipping point analysis will be performed where patients having discontinued before finalization of 
the main part are assumed to have a worse outcome compared to what was observed during the 
main part of the trial. This will be done by adding a value Δi to the observed bleeding episodes in 
the main part of the trial before analysing the data. The offset is maintained as being the exposure 
during the main phase since it is not possible to identify the amount of missing observation 
time.The degree of worsening, Δi, will gradually be increased to evaluate at which point the upper 
95% confidence limit of the prophylactic concizumab ABR is no longer below a threshold of 12.
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The results of the primary analysis will be considered robust if the tipping point is above what is 
considered clinical plausible.
17.5
Additional analyses
An additional evaluation of the primary endpoint will be made, including actual concizumab dose 
level as additional factor in the primary analysis model specified above. Point estimates and 95% 
confidence interval will be provided for the ABR at the different dose levels of concizumab (0.15, 
0.20 and 0.25 mg/kg). Furthermore, an analysis with individual steady state PK/PD assessments 
included as covariates in the negative binomial regression model as specified for the primary 
analysis will be performed in order to evaluate possible associations between PK/PD and ABR that 
potentially could guide dose-selection. The referred steady-state PK/PD assessments comprise the 
concizumab trough level, maximum plasma concentration (Cmax) of concizumab, TFPI value prior 
to the last s.c. dose administration, peak thrombin generation (nM), Endogenous thrombin potential  
(nM*min) and velocity index (nM/min).
17.6
Secondary endpoints
17.6.1
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during 76 weeks from treatment onset.
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment 
onset.
!
The number of spontaneous bleeding episodes during 76 weeks from treatment onset.
The supportive secondary endpoints will be estimated using the same negative binomial regression 
model as the primary endpoint.
17.6.2
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during 76 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during 76 weeks from treatment onset.
!
Change from baseline of fibrinogen during 24 weeks from treatment onset.
!
Change from baseline of fibrinogen during 76 weeks from treatment onset.
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!
Change from baseline of D-dimer during 24 weeks from treatment onset.
!
Change from baseline of D-dimer during 76 weeks from treatment onset
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset.
!
Change from baseline of F1 + 2 during 76 weeks from treatment onset.
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset.
!
Change from baseline of PT during 76 weeks from treatment onset.
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset.
!
Change from baseline of APTT during 76 weeks from treatment onset.
!
Change from baseline of antithrombin (AT) during 24 weeks from treatment onset.
!
Change from baseline of AT 76 weeks from treatment onset.
Adverse Events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has onset from the first 
exposure to treatment until the last visit in the trial. Treatment-emergent adverse event endpoints 
will be summarised by system organ class, preferred term, seriousness, severity and relation to trial 
product. All Adverse events will further be listed.
Frequency of binding anti-concizumab antibodies will by listed and summarised by time frame 
according to the two endpoint definitions.
All laboratory safety endpoints will be plotted by time, both as absolute values and change from 
baseline. Laboratory safety endpoints will further be summarised and listed.
17.6.3
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks.
!
Concentration of concizumab prior to the last dose administration at 76 weeks.
The pharmacokinetic endpoints will be summarised and listed.
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17.6.4
Supportive secondary pharmacodynamic endpoints
Free TFPI concentration:
!
Value prior to the last dose administration at 24 weeks.
!
Value prior to the last dose administration at 76 weeks.
Thrombin generation:
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks.
!
Peak thrombin generation (nM) prior to the last dose administration at 76 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 76 weeks.
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks.
!
Velocity index (nM/min) prior to the last dose administration at76 weeks.
The PD endpoints will be summarized and listed. 
17.7
Exploratory endpoints
17.7.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
Adverse events related to technical complaints will be listed and summarised.
17.7.2
Exploratory patient reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 24 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 76 weeks from treatment onset
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!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Change in PGI-C after 24 weeks from treatment onset
!
Change in PGI-C after 76 weeks from treatment onset
!
Change in H-DAT after 24 weeks from treatment onset
!
Change in H-DAT after 76 weeks from treatment onset
!
Patient reported outcomes (PROs) will be collected using questionnaires at visits 1, 2, 4, 5, 6, 7, 8,
9, 10 and 16. 
Patient reported outcome questionnaires to be analysed:
!
Haemophilia Treatment Experience Measure (Hemo-TEM) 
!
Validated Hemophilia Regimen Treatment Aderence Scale – Prophylaxis (VERITAS-Pro®)
or Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
!
36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
!
Patient Global Impression of Change (PGI-C)
!
Sheehan Disability Scale (SDS)16
!
Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
!
Haemophilia - Device Assessment Tool (H-DAT)
!
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
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VERITAS-Pro®orVERITAS-PRN®, SF-36v2, SDS, TSQM, H-DAT and SIAQ-ISRQ will be 
scored according to their respective scoring algorithms. Change from visit 2 to visit 9 and change 
from visit 2 to visit 16 will be described.
17.8
Interim analysis
The trial does not include a formal interim analysis. However, the split of the trial into a main and 
extension part offers the opportunity of reporting results before the end of the trial. Other reporting 
of the trial might be done during the extension part once the data collection and review of the main 
part data has been finalised and individual clinical study reports might in such case be issued. A 
final clinical study report describing results from the main and extension part will be written when 
the last patient has either completed or withdrawn from the trial.
All main conclusions regarding clinical proof of concept and dose guidance for phase 3 will be 
based on the reporting after the main part, see Figure 17–1.
Figure 17–1
Definition of main and extension part
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18 Ethics
18.1
Benefit-risk assessment of the trial
Benefits
Results from a multiple dose phase 1 trial where concizumab was dosed for approximately 6 weeks 
showed a trend towards efficacy in a limited number of patients who reached concizumab plasma 
concentrations above 100ng/mL., see section 3.1.2. Based on these results, it is expected that the 
majority of the patients treated with concizumab 0.15mg/kg daily dose will be protected from
bleeding episodes. Patients who experience excessive bleeding episodes on the lowest dose will 
have a possibility to be escalated to a higher dose where bleeding preventive efficacy of 
concizumab treatment is expected to improve. Also, concizumab is administered s.c. and might
reduce the burden of frequent i.v. injections associated with current treatment options in
haemophilia A patients without inhibitors as well as significantly reducing the risk of anti-FVIII 
inhibitor development.
Information gained from this trial will contribute to gaining regulatory approval for a product that is 
anticipated to offer clinical advantages over currently available products. 
Risks
No risks have been recognised as identified risks by review of safety data from the activities in the 
clinical development so far. However, the nonclinical toxicity studies have identified 
thromboembolic events as a potential risk when treating non-human primates with concizumab at 
high exposures. 
As observed for other pro-coagulant compounds, there is a potential safety risk of thrombosis and 
vascular ischemia with reaching very high concizumab plasma concentrations. In non-clinical 
toxicity studies with concizumab, thrombi were observed at high doses. However, a NOAEL for
concizumab has been identified in non-haemophilic animals at plasma concentrations several fold 
higher than the currently anticipated effective plasma concentration (mean AUC and Cmax) based on 
PK modelling.
In clinical trials, except for one case of superficial thrombophlebitis in a healthy volunteer who
received a single dose of 1mg/kg, no other thromboembolic events were observed. A phase 1 
multiple dose trial was finalised in haemophilia A patients (0.8 mg/kg s.c. every 4 days for 6 
weeks). In this clinical trial, marked changes in coagulation parameters were observed including a 
decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range in patients with high plasma concentrations of concizumab. These changes were not 
judged as clinically significant by the investigators and were not followed by thromboembolic AEs 
or an increase in the number of bleeding episodes in the explorer™3 trial.
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A potential risk identified in non-clinical studies is vascular vessel wall changes due to immune 
complex deposition causing localized vascular vessel wall changes such as hypertrophy and 
inflammatory cell infiltration. Concizumab is a foreign protein to animals and it is generally 
recognized that animal studies are limited in their ability to predict human immune responses to a 
therapeutic protein product. The concentrations of concizumab in plasma in animals in the non-
clinical studies have reached levels far above the anticipated effective concentration. Humans are 
expected to have a very low immunogenic response towards a humanised mAb. The antibodies 
towards concizumab have not been observed so far in clinical trials. Furthermore, even if antibodies 
towards concizumab occur, the risk for the rate of immune complex formation exceeding the 
clearance capacity is considered low. Please refer to the Investigator’s Brochure for further 
information including subsequent replacement therapy.
If antibodies against concizumab develop, they might also inhibit the function of the administered 
drug. The consequence of this could be that the patient may not be able to benefit from this drug in 
the future. Antibody development against concizumab is not expected to reduce the effect of other 
treatment options.
Theoretical risks include bleeding due to consumption of coagulation factors and adverse reactions 
due to potentiation of inflammatory reactions or tissue damage due to impairment of tissue repair 
mechanisms 34 35 . TFPI is an important inhibitor of TF which, in addition to its role in haemostasis, 
is implicated in tissue repair processes and in a variety of physiological and pathophysiological 
states where repair mechanisms are activated. These include sepsis, DIC, inflammation, 
atherosclerosis, cancer and crush injuries 36 37, 38. There may be a risk of allergic reactions, including 
severe (anaphylactic) reactions, in connection with concizumab administration. Severe allergic 
reactions may potentially be life-threatening and thus, the trial products will be administered to the 
trial patients at the site under the surveillance of medically trained trial site staff in the beginning of 
the trial.
Overall the anticipated benefits from participating in the trial outweigh the potential risks.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the patient verbal and written 
information about the trial and the procedures involved in a form that the patient can read and 
understand. 
The patients 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.
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The investigator must ensure the patient ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the patient 
before any trial-related activity.  
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically trained staff in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the investigator must inform the patient in a timely manner, and a revised 
written patient information must be provided and a new informed consent must be obtained.
Only applicable for Japan: As a minor is unable to provide legally binding consent, informed 
consent must be sought from the parent(s)/LAR(s) on the child’s behalf prior to enrolling a child in 
the trial, according to local requirements. 
18.3
Data handling
If the patient withdraws from the trial or is lost to follow up, then the patient’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit will be retained by 
Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to patients during trial
All written information to patients must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the patients 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
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also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of patients who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the patients 
should be described.
19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided and protocol waivers are not acceptable under any 
circumstances.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed. The Sponsor will assess any protocol deviation and 
decide whether any of these non-compliances are likely to affect to a significant degree the safety 
and rights of a patient or the reliability and robustness of the data generated (potential serious 
breach) and if it should be reported to the Regulatory Authorities as a serious breach of GCP and/or
the protocol.
In addition, deviations must be documented and explained in a protocol deviation by stating the 
reason, date, and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The below process will be in place to prevent missing data in this trial.
The importance of patient retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The patients will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of patient retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
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The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
21 Critical documents
An Investigator Portal (Global Haemophilia Network [GHN]) will be used as primary media for 
exchange and handling of investigator trial master file documents between Novo Nordisk and the 
site and for electronic storage of these documents during trial conduct.
Before a trial site is allowed to start screening patients, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, patient information/informed consent form, 
any other written information to be provided to the patient and patient recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure
!
SmPC or similar labelling of rFVIII (turoctocog alfa)
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
Description of research facility obtained (applicable for non-US sites)
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Only applicable for US trial sites: 
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
For local laboratory parameters the following will be collected:
!
Laboratory normal ranges
!
Laboratory certification, quality assurance (QA) scheme or similar documentation
!
Laboratory assay methods (only non-standard assays) and/or analytical methods
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1,
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the patients.
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At least investigator must be trained in the current protocol version at a Novo Nordisk Investigator 
meeting or by the most recent version of the web training. It is recommended that all site staff  
completes the web protocol training.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the patient identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
patients to a specific qualified physician who will be readily available to patients during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
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researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications 39.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure how-we-disclose-trial-information8.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of the main part of the trial and other interim analyses, because the release of such 
information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors 39 (sometimes referred to as the Vancouver 
Criteria).
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23.1.2
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 a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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24 Retention of clinical trial documentation and human biosamples
24.1
Retention of clinical trial documentation
Patientsmedical records must be kept for the maximum period permitted bythe hospital, institution 
or private practiceaccording to local regulation and practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other patientdata (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
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.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
Applicable only for Spain25 years retention according to the Spanish Royal Decree 1090/2015
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. Thedeletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements. 
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24.2
Retention of human biosamples
This trial will involve collection of human biosamples at visit 1 (screening visit), and at visit 17
(end of trial) and these samples are to be stored maximum 15 years from end of trial. In addition, 
samples which have been drawn as back up samples during the conduct of the trial and have not 
been analysed will be captured and stored under the same conditions. 
Storage of human biosamples is voluntarily and will not affect the patients’ participation in the trial. 
Therefore, patients will have the possibility to sign the informed consent for the trial and 
participate, while refusing permission for biological specimens to be stored for future exploratory 
analysis.
!
Human biosamples will be stored at the central laboratory.
!
1.2 mL citrated plasma, 1.0 mL serum and/or 2.0 ml whole blood (DNA for genotyping)
will be obtained.
!
The intended use of the stored human biosamples e.g.: As new biomarkers related to the 
disease and/or safety, efficacy, or mechanism of action of concizumab may evolve during 
the conduct of the trial, the analyses of the stored human biosamples may also include 
biomarkers that are unknown at present or have not been included in the scientific 
hypotheses at initiation of the trial 
!
Human biosamples may be transferred to third parties e.g. research consortias
!
The human biosamples will be transferred and stored after the end of trial at a designated 
central laboratory
!
Confidentiality and personal data protection will be ensured during storage after the end of 
trial
!
The human biosamples may be transferred to other countries (not applicable if local 
regulations prohibits export of human biosamples)
!
The human biosamples will be destroyed at the latest 15 years from end of trial
!
The patient may request the stored human biosamples to be destroyed by withdrawing 
consent. The results obtained from any already performed analyses of the samples will still 
be used
!
Novo Nordisk and laboratory will have access to the stored human biosamples 
!
Potential consequences for the patient and their relatives: In the event that the collected 
human biosamples (plasma, serum and/ or DNA for genotyping) will be used in the future, 
the investigator will become directly informed by Novo Nordisk about the results if the 
findings are deemed clinically relevant and analytically valid and quantifiable. In such case, 
a written summary of the findings, including listings of patient specific values, will be 
provided once a firm conclusion from the results has been drawn by Novo Nordisk. 
Potentially, observations of neoplastic diseases, serious hereditary diseases, other un-
treatable diseases, or any other abnormal findings could be part of the observations. Patients 
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can contact the investigator if they wish to be informed about results derived from stored 
human biosamples obtained from their own body. See also Section 5.1.
24.2.1
Antibody samples
Antibody samples will be retained until drug approval by U.S. Food and Drug Administration 
(FDA) and/or European Medicines Agency (EMA). 
The retained antibody samples may be used for later analysis for further characterisation of 
antibody responses towards drug if required by health authorities or for safety reasons. The samples 
will be stored at a central bio-repository after end of trial and until marketing authorisation approval 
or until the research project terminates, but no longer than 15 years from end of trial after which 
they will be destroyed.
The patients’ identity will remain confidential and the antibody samples will be identified only by 
patient number, visit number and trial identification number. No direct identification of the patient 
will be stored together with the samples.
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples.
Patients can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body.
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: Updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the patients, new information that may affect adversely the safety of the patients or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the
planned follow-up of the patients), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC (not 
applicable for Japan).
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the patients.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
Only applicable for France: The French Public Health Code article L 1121-10 (law no 2004-806 of 
9 August 2004 art. 88 I, IX, Journal Officiel of 11 August 2004. “The sponsor is responsible for 
identification of the harmful consequences of the biomedical the research for the person lending 
himself thereto and for indemnification of his beneficiaries, except in case of proof, incumbent on 
it, that the prejudice is not attributable to his fault or of the fault of any intervening party, without 
the sponsor’s being entitled to call on acts by a third party or the voluntary withdrawal of the person 
who had initially consented to cooperating in the research”.
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al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand 
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Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2016.
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Protocol
Trial ID: NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of Prophylactic 
Administration of Concizumab in Patients with Severe Haemophilia A 
without Inhibitors
Trial phase: 2
Protocol Version 1 (15 March 2017); Protocol Amendment no 1 (05 May 2017) and Protocol 
Amendment no 2 (14 Dec2017) for all participating countries. 
Protocol originator
, 
Biopharm, Trial 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.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


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Table of Contents
Page
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................7
Table of Tables............................................................................................................................................7
List of abbreviations ...................................................................................................................................9
1
Summary............................................................................................................................................15
2
Flow chart ..........................................................................................................................................18
3
Background information and rationale for the trial.........................................................................21
3.1
Background information..........................................................................................................21
3.1.1
Haemophilia ..........................................................................................................21
3.1.2
Concizumab...........................................................................................................22
3.2
Rationale for the trial...............................................................................................................24
4
Objective(s) and endpoint(s)..............................................................................................................26
4.1
Objective(s) ............................................................................................................................26
4.1.1
Primary objective...................................................................................................26
4.1.2
Secondary objectives .............................................................................................26
4.2
Endpoint(s) .............................................................................................................................26
4.2.1
Primary endpoint ...................................................................................................26
4.2.2
Secondary endpoints ..............................................................................................26
4.2.2.1
Supportive secondary endpoints .......................................................26
4.2.3
Exploratory endpoints............................................................................................27
4.2.3.1
Exploratory safety endpoints ............................................................27
4.2.3.2
Exploratory patient-reported outcome endpoints...............................28
4.2.3.3
Exploratory pharmacokinetic and pharmacodynamic endpoints ........28
5
Trial design ........................................................................................................................................29
5.1
Type of trial ............................................................................................................................29
5.1.1
Surgery..................................................................................................................30
5.2
Rationale for trial design .........................................................................................................30
5.3
Treatment of patients...............................................................................................................33
5.3.1
Dose escalation......................................................................................................34
5.3.2
Treatment of bleeding episodes during the trial ......................................................35
5.3.3
Prohibited medication ............................................................................................35
5.4
Treatment after discontinuation of trial product .......................................................................36
5.5
Rationale for treatment............................................................................................................36
6
Trial population .................................................................................................................................37
6.1
Number of patients..................................................................................................................37
6.2
Inclusion criteria .....................................................................................................................37
6.3
Exclusion criteria ....................................................................................................................37
6.4
Criteria for premature discontinuation of trial product .............................................................38
6.5
Withdrawal from trial..............................................................................................................38
6.6
Patient replacement .................................................................................................................39
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6.7
Rationale for trial population...................................................................................................39
7
Milestones...........................................................................................................................................40
8
Methods and assessments ..................................................................................................................41
8.1
Visit procedures ......................................................................................................................41
8.1.1
Informed consent, long-term storage consent..........................................................42
8.1.2
Screening log, enrolment log, trial card and patient number....................................42
8.1.3
Screening failures and re-screening........................................................................42
8.1.4
Premature discontinuation of trial product..............................................................43
8.1.5
Withdrawal from trial.............................................................................................43
8.1.6
Review/evaluation of clinical outcome...................................................................43
8.1.7
Visit 1 (Screening part)..........................................................................................44
8.1.8
Training of patients visit 1 and visit 2.....................................................................45
8.1.9
Treatment period - Main part..................................................................................45
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site) ......................45
8.1.9.2
Treatment period at home.................................................................46
8.1.9.3
Visit 3 (Phone visit)..........................................................................46
8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits) .........................................47
8.1.9.5
Visit 9 (Assessment visits)................................................................48
8.1.10
Extension Part........................................................................................................49
8.1.10.1
Visit 10 (Assessment visits)..............................................................49
8.1.10.2
Visit 11, 12, 13, 14 and 15 (Assessment visits) .................................50
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) -
Extension part ..................................................................................50
8.1.11
Follow-up Part.......................................................................................................51
8.1.11.1
Visit 17 (End of trial) .......................................................................51
8.1.12
Unscheduled Visit..................................................................................................52
8.1.12.1
Unscheduled 24 hour PK-Visit .........................................................52
8.2
Patient related information/assessments...................................................................................53
8.2.1
Demography ..........................................................................................................53
8.2.2
Concomitant illness and medical history other than haemophilia ............................53
8.2.3
Concomitant medication ........................................................................................53
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History .......................54
8.3
Efficacy assessments...............................................................................................................55
8.3.1
Bleeding episodes ..................................................................................................55
8.4
Safety assessments ..................................................................................................................59
8.4.1
Physical examination .............................................................................................59
8.4.2
Body measurements...............................................................................................59
8.4.3
Vital signs..............................................................................................................59
8.4.4
Electrocardiogram..................................................................................................60
8.4.5
Adverse events.......................................................................................................60
8.4.5.1
Medication error...............................................................................60
8.4.5.2
Adverse events requiring additional data collection ..........................61
8.5
Laboratory assessments...........................................................................................................62
8.5.1
Laboratory assessments for efficacy.......................................................................63
8.5.1.1
Thrombin generation........................................................................63
8.5.1.2
Free TFPI.........................................................................................64
8.5.2
Laboratory assessments for safety ..........................................................................64
8.5.2.1
Urinalysis.........................................................................................64
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
4 of 124
8.5.2.2
Haematology....................................................................................64
8.5.2.3
Biochemistry....................................................................................65
8.5.2.4
FVIII activity ...................................................................................65
8.5.2.5
Coagulation parameters....................................................................65
8.5.2.6
FVIII inhibitor test ...........................................................................66
8.5.2.7
Anti-concizumab antibodies .............................................................66
8.5.2.8
Concizumab ELISA .........................................................................68
8.5.2.9
Total TFPI........................................................................................69
8.5.3
Human biosamples.................................................................................................69
8.6
Other assessments ...................................................................................................................69
8.6.1
Patient reported outcomes ......................................................................................69
8.6.2
Training.................................................................................................................71
8.6.2.1
Concizumab and NovoPen® 4...........................................................71
8.6.2.2
Turoctocog alfa ................................................................................71
8.6.2.3
eDiary..............................................................................................71
8.6.3
Surgery..................................................................................................................72
8.7
Patient compliance..................................................................................................................72
8.8
Treatment compliance:............................................................................................................72
9
Trial supplies......................................................................................................................................73
9.1
Trial products..........................................................................................................................73
9.2
Labelling.................................................................................................................................73
9.3
Storage....................................................................................................................................74
9.4
Drug accountability and destruction ........................................................................................75
9.5
Auxiliary supplies ...................................................................................................................75
10
Interactive voice/web response system ..............................................................................................76
11
Randomisation procedure and breaking of blinded codes................................................................77
Randomisation.....................................................................................................................................77
12
Adverse events, and technical complaints .........................................................................................78
12.1
Definitions ..............................................................................................................................78
12.1.1
Adverse event ........................................................................................................78
12.1.2
Serious adverse event.............................................................................................79
12.1.3
Non-serious adverse event......................................................................................80
12.1.4
Medication errors...................................................................................................80
12.1.5
Adverse events requiring additional data collection................................................81
12.1.6
Adverse event of special interest ............................................................................82
12.1.7
Technical complaints .............................................................................................86
12.2
Reporting of adverse events.....................................................................................................86
12.3
Follow-up of adverse events....................................................................................................88
12.4
Technical complaints and technical complaint samples............................................................89
12.4.1
Reporting of technical complaints ..........................................................................89
12.4.2
Collection, storage and shipment of technical complaint samples ...........................90
12.5
Pregnancies.............................................................................................................................91
12.5.1
Pregnancies in female partners of male patients......................................................91
12.6
Precautions and/or overdose....................................................................................................92
12.7
Rules for putting enrolment on hold ........................................................................................92
12.8
Committees related to safety ...................................................................................................93
12.8.1
Novo Nordisk safety committee .............................................................................93
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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12.8.2
Data monitoring committee....................................................................................93
13
Case report forms ..............................................................................................................................94
13.1
Corrections to case report forms..............................................................................................94
13.2
Case report form flow .............................................................................................................94
13.3
Electronic diary.......................................................................................................................95
13.3.1
Investigator review of eDiary data..........................................................................95
14
Monitoring procedures ......................................................................................................................95
15
Data management ..............................................................................................................................98
16
Computerised systems .......................................................................................................................98
17
Statistical considerations ...................................................................................................................99
17.1
Sample size calculation .........................................................................................................100
17.2
Definition of analysis sets......................................................................................................101
17.3
Primary endpoint...................................................................................................................101
17.4
Sensitivity analyses...............................................................................................................101
17.5
Additional analyses...............................................................................................................102
17.6
Secondary endpoints .............................................................................................................102
17.6.1
Supportive secondary efficacy endpoints..............................................................102
17.6.3
Supportive secondary pharmacokinetic endpoints.................................................103
17.6.4
Supportive secondary pharmacodynamic endpoints..............................................104
17.7
Exploratory endpoints ...........................................................................................................104
17.7.1
Exploratory safety endpoints................................................................................104
17.7.2
Exploratory patient reported outcome endpoints...................................................104
17.7.3
Exploratory pharmacokinetic and pharmacodynamic endpoints............................106
17.8
Interim analysis.....................................................................................................................106
18
Ethics................................................................................................................................................107
18.1
Benefit-risk assessment of the trial ........................................................................................107
18.2
Informed consent ..................................................................................................................108
18.3
Data handling........................................................................................................................109
18.4
Information to patients during trial ........................................................................................109
18.5
Premature termination of the trial and/or trial site..................................................................109
19
Protocol compliance.........................................................................................................................110
19.1
Protocol deviations................................................................................................................110
19.2
Prevention of missing data ....................................................................................................110
20
Audits and inspections .....................................................................................................................112
21
Critical documents...........................................................................................................................112
22
Responsibilities.................................................................................................................................113
23
Reports and publications .................................................................................................................114
23.1
Communication of results......................................................................................................115
23.1.1
Authorship...........................................................................................................115
23.1.2
Site-specific publication(s) by investigator(s).......................................................116
23.2
Investigator access to data and review of results ....................................................................116
24
Retention of clinical trial documentation and human biosamples..................................................117
24.1
Retention of clinical trial documentation ...............................................................................117
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
6 of 124
24.2
Retention of human biosamples.............................................................................................118
24.2.1
Antibody samples ................................................................................................119
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........120
26
Indemnity statement ........................................................................................................................121
27
References ........................................................................................................................................122
Appendix I Patient Reported Outcome
Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments, if applicable for the individual 
country
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
7 of 124
Table of Figures
Page
Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous 
(circles) and traumatic (triangles) bleeding episodes during the dosing period and 
follow-up period.................................................................................................................24
Figure 5–1
Schematic diagram of the trial design .................................................................................29
Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated 
patients in explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal 
lines indicate 100 ng/mL, and the shaded areas represent the full range (min-max) of the 
individual predicted profiles. ..............................................................................................31
Figure 5–3
Dose escalation of concizumab for one individual patient...................................................35
Figure 8–1
Overview of visit structure in explorer™5 ..........................................................................41
Figure 12–1
Reporting of AEs ...............................................................................................................88
Figure 17–1
Definition of main and extension part...............................................................................106
Table of Tables   
Page
Table 2–1
Flow chart..........................................................................................................................18
Table 2–2
Flow chart explanatory descriptions....................................................................................20
Table 5–1 
List of products provided by Novo Nordisk ........................................................................33
Table 8–1
Definition of stop of bleeding episode ................................................................................56
Table 8–2
Definitions of bleeding episodes (cause of bleed)................................................................56
Table 8–3
Definition of bleeding episode severity and treatment recommendation ..............................56
Table 8–4
Guide for dosing in bleeding episodes and surgery .............................................................58
Table 9–1
Trial products.....................................................................................................................73
Table 9–2
Storage conditions..............................................................................................................74
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion..........................100
Table 2–1
Flow chart..........................................................................................................................18
Table 2–2
Flow chart explanatory descriptions....................................................................................20
Table 5–1 
List of products provided by Novo Nordisk ........................................................................33
Table 8–1
Definition of stop of bleeding episode ................................................................................56
Table 8–2
Definitions of bleeding episodes (cause of bleed)................................................................56
Table 8–3
Definition of bleeding episode severity and treatment recommendation ..............................56
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
8 of 124
Table 8–4
Guide for dosing in bleeding episodes and surgery .............................................................58
Table 9–1
Trial products.....................................................................................................................73
Table 9–2
Storage conditions..............................................................................................................74
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion..........................100
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
9 of 124
List of abbreviations
ABI
ankle-brachial index
ABR
annualised bleeding rate 
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest 
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
antithrombin
AUC
area under curve
BP
blood pressure
BU
Bethesda unit
CLAE
clinical laboratory adverse event
Cmax
maximum plasma concentration
CNS
central nervous system
concizumab B
the name concizumab is being used as an 
abbreviation for concizumab B. B is the 
formulation 
CPoC
clinical proof of concept
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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CRF
case report form
CRO
contract research organisation
CRP
c-reactive protein
CT
computerized tomography
cTn
cardiac troponin
CTR
clinical trial report
DFU
direction for use
DIC
disseminated intravascular coagulation
DMC
data monitoring committee
DUN
dispensing unit number
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EMA
European medicines agency
EOT
end of trial
ETP
endogenous thrombin potential 
FAS
full analysis set
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Protocol
CONFIDENTIAL
Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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FDA
U.S. Food and Drug Administration
FDAAA
U.S. Food and Drug Administration 
Amendment Act
FIX
coagulation factor IX
FPFV
first patient first visit
FVIII
coagulation factor VIII
FX
coagulation factor X
FXa
activated coagulation factor X
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GHN
global haemophilia network
HCP
host cell protein
H-DAT
Haemophilia Device Assessment Tool
Hemo-TEM
Hemophilia Treatment Experience Measure
IB
investigator’s brochure
IC
informed consent 
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal 
Editors
ID
identification
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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IEC
independent ethics committee
IgG4
immunoglobulin G4
IMP
investigational medicinal product
INN
International Non-Proprietary Names for 
Pharmaceutical Substances 
IRB
institutional review board
ISTH
International Society on Thrombosis and 
Haemostasis
ISRQ-SIAQ
Injection Site Reaction Questionnaire-Self-
Injection Assessment Questionnaire
i.v.
intravenous(-ly)
IWRS
interactive web response system
LBBB
left bundle branch block
LPFV
last patient first visit
LPLV
last patient last visit
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory 
Activities
MI
myocardial infarction
MRA
magnetic resonance angiogram
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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MRI
magnetic resonance imaging
NIMP
non investigational medicinal product
PCD
PD
primary completion date
pharmacodynamic
PEF
peak expiratory flow
PK
pharmacokinetic
PGI-C
Patient’s Global Impression of Change
PP
per protocol
PRO
patient reported outcome
PT
prothrombin time
QA
Q4D
quality assurance
every 4th day
rFVIII
the name ‘rFVIII’ will be used throughout 
the protocol and the product is identical to 
‘turoctocog alfa’
SAE
serious adverse event
SAS
safety analysis set
sBE
s.c.
spontaneous Bleeding Episode
subcutaneous(-ly)
SDS
Sheehan Disability Scale
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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SF-36v2
36-Item Short Form Health Survey
SI
international system of units
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse 
reaction
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
TF
tissue factor
TFPI
tissue factor pathway inhibitor
TG
thrombin generation
TMM
trial materials manual
TPA
trial product administration
TSQM
Treatment Satisfaction Questionnaire for 
Medication
UTN
Universal Trial Number
VERITAS-Pro®
Validated Hemophilia Regimen Treatment 
Adherence Scale-Prophylaxis
VERITAS-PRN® 
Validated Hemophilia Regimen Treatment 
Adherence Scale-Pro Re Nata
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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1
Summary
The main objective for the phase 2 trial NN7415-4255, explorer™5, is to assess the efficacy of 
concizumab administered s.c. once daily to prevent bleeding episodes in patients with severe 
haemophilia A without inhibitors. Furthermore, this trial aims to assess the longer-term efficacy and 
safety of concizumab in severe haemophilia A patients without inhibitors. 
Objective(s) and endpoint(s):
Primary objective 
!
To assess the efficacy of concizumab administered  s.c. once daily in preventing bleeding 
episodes in patients with severe haemophilia A without inhibitors 
Secondary objectives 
!
To assess the longer-term efficacy of concizumab in patients with severe haemophilia A without 
inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without 
inhibitors
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset.
Key secondary endpoints
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of treatment emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset.
Time frames for evaluation of objectives/endpoints:
All endpoints referring to the time frame of at least 24 weeks will be evaluated in the main part of 
the trial, defined to end when the last patient has completed a minimum of 24 weeks of treatment 
with trial product (or have withdrawn). In addition, number of bleeding episodes during 76 weeks 
of treatment with prophylactic concizumab will be analysed. The extension part of the trial will 
provide additional safety and long-term efficacy data.
Trial design:
The trial is a multi-centre single arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation) administered daily s.c. in patients with 
severe haemophilia A without inhibitors. This is done by comparing the annual bleeding rate (ABR) 
to an ABR of 12.The selected dose regimen is based on relevant PK and TFPI data as well as 
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Protocol
CONFIDENTIAL
Date:
18 December 2017
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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pharmacokinetic/pharmacodynamic (PK/PD) modelling from the preceding explorer™ trials. Both 
on-demand and prophylaxis patients will be eligible for the trial.
The total trial duration for the individual patient will be approximately 86 weeks, consisting of a 2 
week screening period, a subsequent 76 week treatment period and an 8 week follow-up period. 
The 76 weeks treatment period is split into a main part which lasts at least 24 weeks and an 
extension part which lasts up to 52 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 30 patients have completed at least 24 weeks of concizumab 
dosing or have discontinued trial treatment. The analysis of the main part of the trial aims to 
substantiate clinical proof of concept (CPoC) that concizumab has the potential to prevent bleeding 
episodes in severe haemophilia A patients without inhibitors. 
rFVIII (turoctocog alfa) for treatment of breakthrough bleeding episodes will be provided by Novo 
Nordisk during the trial. The patient will not be provided with trial product or rFVIII (turoctocog 
alfa) after the end of the trial.
Trial population:
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product: 33
Number of patients expected to complete the trial: 30
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine the 
suitability for the trial
!
Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at screening
Key exclusion criteria
!
Known or suspected hypersensitivity to trial product(s) or related products
!
Known inherited or acquired bleeding disorder other than haemophilia A
!
Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at 
screening measured by the Nijmegen method 
Key Efficacy assessment
!
The number of bleeding episodes during at least 24 weeks.
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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Key Safety assessment
!
Number of TEAEs during at least 24 weeks.
Trial product(s):
The following products will be used in the trial:
!
Investigational Medicinal Product (IMP):
Concizumab B, 100 mg/mL to be administered s.c. with NovoPen®4 and needles 
!
Non Investigational Medical Product (NIMP):
Turoctocog alfa (rFVIII) 2000 IU/vial and isotonic sodium chloride (solvent). Turoctocog 
alfa (rFVIII) is for intravenous administration.
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Protocol
UTN:U1111-1179-3872
Date:
18 December 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
3
Page:
18 of 124
2
Flow chart
Table 2–1
Flow chart
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
Timing of visit (d) d
14 to 21 days 
before Visit2
1
8
29
57
85
113
141
169
225
281
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 21 days 
before Visit 
2
0
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not applicable
-7
Treatment week (w)
---
0
1w
4w
8w
12w
16w
20w
24w
32w
40w
48w
56w
64w
72w
76w
---
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/Genotyping and Long-term storage consent
●
In/exclusion criteria
●
●e
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial 
product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
EFFICACY ASSESSMENTS 
Bleeding episodes f, g
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab)
●
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
Free TFPI (central lab)  
●
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
SAFETY ASSESSMENTS
Physical examination
●
●
●
●
●
●
●
Body measurements 
●
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
Vital signs
●
●j
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Biochemistry (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII activity (central lab)
●k
●l
Coagulation parameters (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII inhibitors (central lab)
●
●l
Anti-concizumab antibodies (ADA) (special lab)m
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Concizumab ELISA (special lab)
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
Total TFPI (special lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
TRIAL MATERIALS
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Protocol
UTN:U1111-1179-3872
Date:
18 December 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
3
Page:
19 of 124
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
IWRS call
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab, turoctocog alfa) (IWRS)
●n
●
●
●
●
●
●
●
●
●
●
●
●
●
●n
●
Administration of trial product (concizumab) 
●o
Drug Accountability (concizumab, turoctocog alfa) 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product c, p
●
●
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●
●
●
●
●
●
●
●
●
●
PRO questionnaires
●
●
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
Hand out ID Card 
●
Training (trial product, e-Diary and NovoPen® 4) q
●
●
●
Compliance (e-Diary)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
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Protocol
UTN:U1111-1179-3872
Date:
18 December 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
3
Page:
20 of 124
Table 2–2
Flow chart explanatory descriptions
Footer
Description
a
Concizumab administration is performed at home except for visit 2 where concizumab administration will take place at the trial site.
b
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 will be 
a phone call to the patient. 
c
For patients being dose escalated a phone call is recommended 1 week after first new dose of concizumab.
d
Daily dosing preferably at the same time in the morning.
e
Evaluation of laboratory results obtained from samples taken at screening.
f
Bleeding episodes occurring between visit 1 and visit 2 or at site should be registered in the eCRF. All bleeding episodes except for severe occurring after visit 
2 at home should be registered in the eDiary. Severe bleeding episodes must be registered in the eCRF.
g
Turoctocog alfa will be given to treat breakthrough bleeding episodes either in the clinic or at home.
h
At visit 9 and 16 all blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been performed.
For unscheduled PK-session visit; patients must not treat themselves with concizumab until pre-dose sampling for thrombin generation, concizumab ELISA 
and Free TFPI has been collected.
i
Only body weight should be measured.
j
Vital signs should be evaluated before and after trial drug administration at visit 2. 
k
Sampling for FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours and medical records documenting the severity of 
haemophilia are not available.
l
FVIII activity and FVIII inhibitor tests should only be collected if reduced effect of turoctocog alfa or FVIII inhibitor development is suspected.
m
In case of clinical signs of e.g. hypersensitivity reactions or immune related events are seen, additional samples for ADAs may be taken. All antibody samples 
from the affected patient will be analysed on an ongoing basis. If antibodies are detected additional samples will be taken and stored for characterisation of the 
antibodies.
n
Only dispensing of turoctocog alfa and sodium chloride.
o
The trial patient must be in a non-bleeding state at the time of the first trial product administration (TPA), and should not have received any haemostatic drug
(e.g. FVIII) for prophylaxis or treatment of a bleeding episode within a period of 48 hours prior to first TPA.
p
Patient should be dose escalated at next scheduled visit if he experiences ≥3 spontaneous bleeding episodes within the preceding 12 weeks of treatment with 
concizumab. If investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose escalation.
q
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Home treatment training comprises handing out of Direction 
for Use (DFU), training in administration of concizumab with NovoPen®4, turoctocog alfa and data entry in eDiary. Further the patients will be trained in 
recognition of signs/symptoms of thrombosis.
r
In case patients are participating in the 24 hour PK-session the sampling time points for thrombin generation, concizumab ELISA and Free TFPI are: pre-dose 
(-1 hour), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (± 20 min) and 24h (± 20 min). All time points, except pre-dose, occur after 
concizumab administration
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
21 of 124
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP)1 and applicable regulatory requirements, and in 
accordance with the Declaration of Helsinki2 and ISO 141553.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
The International Non-Proprietary Names for Pharmaceutical Substances (INN) name of the active 
pharmaceutical ingredient is concizumab (synonyms used during early development are NNC0172-
2021, anti-TFPI, NN7415 or mab2021). Throughout this document “concizumab” is used as the 
name of the trial drug.
3.1
Background information
3.1.1
Haemophilia
Haemophilia is an inherited bleeding disorder characterised by an increased bleeding tendency, 
typically in weight bearing joints. Haemophilia A is caused by a partial or complete deficiency of 
blood coagulation factor VIII (FVIII) and haemophilia B is caused by defect factor IX (FIX).  
Inheritance is chromosome X-linked and recessive; therefore the disease mainly affects males. The 
incidence of haemophilia A and B on average is estimated to be about 1 in 5000 live male births4. 
According to the World Federation of Haemophilia global survey of 2014, about 178,500 persons 
are diagnosed with haemophilia worldwide. Of these, about 80% have haemophilia A.
Haemophilia is classified as “severe”, “moderate” or “mild” according to the plasma activity level 
of the affected coagulation factor5.With a deficiency of FVIII or FIX, the degree of activation of 
coagulation factor X (FX) becomes insufficient. Consequently, the thrombin burst is delayed and 
insufficient for normal haemostasis6.The haemostatic plug, if formed, in these patients is fragile and 
easily dissolved by normal fibrinolytic activity. This leads to impaired haemostasis and spontaneous 
prolonged bleeding episodes. In severe haemophilia, bleeding in joints occurs spontaneously and is 
the most frequent symptom of the disease. Recurrent bleeding episodes in the same location - most 
commonly a weight bearing joint - lead to chronic arthropathy, muscular atrophy and deformities. 
Treatment of bleeding episodes as they manifest (on-demand treatment) may delay arthropathy, but 
does not prevent it. The majority of children with severe haemophilia experience their first bleeding 
episode in a joint prior to the age of 4 years. Many children also bleed from other body sites, also 
before this age is reached7. For this reason, primary prophylaxis treatment with regular FVIII 
injections in the non-bleeding state is the recommended from early childhood.
The most common complication of replacement therapy is development of antibodies binding to 
FVIII. These binding antibodies might neutralise the exogenous of FVIII and are then called
inhibitors. In patients who have developed inhibitors towards FVIII, replacement therapy is 
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
22 of 124
rendered ineffective. These patients may be treated with bypassing agents, recombinant FVII 
(NovoSeven®) and activated prothrombin complex concentrate (FEIBA®) given as intravenous 
(i.v.) injections.
Current treatment options in haemophilia A, includes replacement therapy or by-passing therapy are 
hampered by the fact that these products must be given as i.v. injections. Bypassing agents are 
characterized by relatively short half-lives, therefore prophylactic treatment is burdensome. A new 
therapeutic agent that can be administered subcutaneously will represent a major improvement in 
the treatment of these patients in a prophylaxis setting. 
3.1.2
Concizumab
The trial product, concizumab, is a humanised recombinant monoclonal antibody (mAb) of the 
immunoglobulin G4 (IgG4) isotype with a molecular weight of 149 kilo Daltons. Like other 
antibodies, concizumab is composed of two light chains and two heavy chains linked together by 
disulfide bridges. To prevent formation of half-antibodies, the serine at position 241 in the heavy 
chain has been replaced with a proline (S241P (Kabat annotation)) . The mechanism of action of 
concizumab is based on the concept of inhibiting the activity of a natural coagulation inhibitor, 
tissue factor pathway inhibitor (TFPI). TFPI is a potent inhibitor of the initiation phase of the 
coagulation process, i.e. the activation of FX to FXa by the tissue factor (TF)/factor VIIa (FVIIa) 
complex. TFPI first binds to and inhibits activated FXa and subsequently binds to and inhibits the 
TF/FVIIa complex, forming a TF/FVIIa/FXa/TFPI complex. Thus, concizumab prevents both 
inhibition of FXa and inhibition of FVIIa/TF by TFPI. In this manner, sufficient amounts of FXa to 
ensure effective haemostasis in the absence of a functional activated factor IX/activated factor VIII 
(FIXa/ FVIIIa) complex may be generated. This is a new concept that remains to be documented 
safe and efficacious in patients with haemophilia. More information about the physiological role of 
TFPI and the mode of action of concizumab is provided in the Investigator’s Brochure (IB). 
Key differentiator is thus a new mode of action (MoA), and the key benefit of concizumab in 
patients with severe haemophilia A is reduced treatment burden due to subcutaneous (s.c.) 
administration potentially leading to better adherence, more patients on prophylactic treatment and 
ultimately better outcome.
Four clinical trials with concizumab have been completed thus far: the first-human-dose trial 
(NN7415-3813, explorer™1), a single dose trial in Japanese healthy subjects (NN7415-3981), a 
multiple dose trial NN7415-3986 (explorer™2), and NN7415-4159 (explorer™3). When the first 
cohort with four healthy subjects in explorer™2 was completed, prior to the initiation of the 2nd 
cohort, the trial was halted due to findings related to thrombosis in an ongoing 26-week toxicity 
study in primates. In this study animal had plasma concentrations several hundred folds above 
clinically relevant concentrations. Follow up investigations confirmed that the animal’s condition 
was related to thrombosis in the lungs caused by exaggerated pharmacology at these high plasma 
concentrations. Before the initiation of the fourth phase 1 trial (, explorer™3) a new 52-week non-
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
23 of 124
clinical toxicology study was conducted in primates to investigate the findings in the previous 
study. The conclusion from this new non-clinical study was that the results from non-clinical 
studies support further clinical development of concizumab. Explorer™3 was a multiple-dose 
clinical trial, which aimed to investigate the safety, pharmacokinetics and pharmacodynamics of 
concizumab at five different dose levels in adult severe haemophilia A patients without inhibitors. 
In this trial multiple doses of concizumab were administered s.c. over a period of six weeks. Doses 
of up to 0.8 mg/kg administered every four days did not raise safety concerns and a decision not to 
dose-escalate to a 1.1 mg/kg dose-cohort was taken. For further information, please refer to the 
Investigator’s Brochure.
The explorer™3 trial was finalised following the completion of cohort 3 (0.8 mg/kg sc every 4 days 
for 6 weeks). Blinded preliminary safety and PK/PD data from the cohort was reviewed by the 
concizumab safety committee. Marked changes in coagulation parameters were observed including 
a decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range. In addition, a substantial inter subject variation in pro-coagulant response to the drug 
was observed. Based on this, the Novo Nordisk safety committee (see section 12.8.1) decided not to
proceed to cohort 4 (1.1 mg/kg sc every 4 days for 6 weeks). No clinical consequences or serious 
adverse were seen in the completed cohorts in explorer3.
The PK results from explorer™3 showed exposure-response in terms of fewer bleeding episodes 
recorded for patients who reached plasma concentrations of concizumab above 100 ng/mL. 
Individual predicted PK profiles merged with recorded spontaneous and traumatic bleeding 
episodes are shown in Figure 3–1.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
24 of 124
Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous (circles) and 
traumatic (triangles) bleeding episodes during the dosing period and follow-up period. 
All data originates from explorer™3 (N=24 patients). PK of concizumab is subdivided into three exposure levels of 
≤20 ng/mL, 20-100 ng/mL, and > 100 ng/mL together with the number of contributing patients. LLOQ: lower limit of 
quantification. a ‘Time in trial’ refers to the time that the patients spent on each concizumab exposure level, and the 
≤20 ng/mL level therefore also includes the screening period (not shown on this figure).
A large difference between the peak and trough plasma concentrations of concizumab were 
observed as well, especially in the highest dose group (0.80 mg/kg) of explorer™3. In patients who 
received 0.25, 0.5 and 0.8 mg/kg doses a significant overlap in plasma concentrations of 
concizumab was seen due to high between-patient variability in concizumab.
Single doses of concizumab up to 9 mg/kg have been administered to haemophilia patients in the 
first human dose trial with concizumab, explorer™1. These doses resulted in plasma concentrations 
of concizumab that were significantly higher than the ones that are modelled to be reached in the 
highest escalated daily dose (0.25 mg/kg) of explorer™5.
For an assessment of benefits and risks of the trial, see Section 18.1.
For further information, please refer to the Investigator’s Brochure.
3.2
Rationale for the trial
Four phase 1 clinical trials with concizumab have been finalised. Key safety and preliminary 
efficacy results from these phase 1 trials support further development of concizumab in haemophilia 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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patients. Therefore, the main objective in the phase 2 of concizumab development is to assess 
efficacy and safety and provide data that will guide for the confirmatory phase 3 concizumab trials. 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
26 of 124
4
Objective(s) and endpoint(s)
4.1
Objective(s)
4.1.1
Primary objective
!
To assess the efficacy of concizumab administered s.c. once daily in preventing bleeding 
episodes in patients with severe haemophilia A without inhibitors
4.1.2
Secondary objectives
!
To assess the long-termer efficacy of concizumab in patients with severe haemophilia A 
without inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without 
inhibitors
4.2
Endpoint(s)
4.2.1
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset
!
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary endpoints
!
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during 76 weeks from treatment onset
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of  spontaneous bleeding episodes during 76 weeks from treatment onset
!
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during 76 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during 76 weeks from treatment onset
!
!
Change from baseline of fibrinogen during 24 weeks from treatment onset
!
Change from baseline of fibrinogen during 76 weeks from treatment onset
!
Change from baseline of D-dimer during 24 weeks from treatment onset
!
Change from baseline of D-dimer during 76 weeks from treatment onset
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
27 of 124
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset
!
Change from baseline of F1 + 2 during 76 weeks from treatment onset
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset
!
Change from baseline of PT during 76 weeks from treatment onset
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset
!
Change from baseline of APTT during 76 weeks from treatment onset
!
Change from baseline of antithrombin (AT) during 24 weeks from treatment onset
!
Change from baseline of AT 76 weeks from treatment onset
!
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks
!
Concentration of concizumab prior to the last dose administration at 76 weeks
Supportive secondary pharmacodynamic endpoints
Plasma free TFPI concentration
!
Value prior to the last dose administration at 24 weeks 
!
Value prior to the last dose administration at 76 weeks 
Thrombin generation
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks 
!
Peak thrombin generation (nM) prior to the last dose administration at 76 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 76 weeks 
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks 
!
Velocity index (nM/min) prior to the last dose administration at 76 weeks 
4.2.3
Exploratory endpoints
4.2.3.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
28 of 124
4.2.3.2
Exploratory patient-reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Status of PGI-C after 24 weeks from treatment onset
!
!
Change in H-DAT after 76 weeks from treatment onset
4.2.3.3
Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP  time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
All endpoints referring to a time frame of either 24 weeks or of at least 24 weeks will be evaluated 
in the main part of the trial. 
All endpoints referring to a time frame of 76 weeks will be evaluated in the extension part of the 
trial.
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Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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5
Trial design
5.1
Type of trial
The trial is a multicentre single-arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation to 0.20 and 0.25 mg/kg) administered daily 
s.c. in patients with severe haemophilia A without inhibitors. The selected dose regimen is based on
relevant PK and TFPI data as well as PK/PD modelling from the preceding explorer™ trials. Both
on-demand and prophylaxis patients will be eligible for the trial.
Figure 5–1
Schematic diagram of the trial design
The total trial duration for the individual patient will be approximately 86 weeks, including a 2-
week screening period, a subsequent 76-week treatment period and an 8-week follow-up period, see 
Figure 5–1.
The76 weeks treatment periodis further split into a main part which lasts at least 24 weeks for all 
patients in the trial and an extension part which lasts 52 weeks.After completion ofthe main part of 
the trial, patients will continue into the extension part. All available data up to the time point where 
the last patients ends 24 weeks of treatment (or have withdrawn) will be used in the analysis of the 
main part, see Section 17.7.
Breakthrough bleeding episodes occurring from visit 1 to end-of-trial visit will be treated by the 
patients at home with FVIII at the discretion of the investigator, who will also choose dose levels. 
Only turoctocog alfa/NovoEight®will be provided and paid by Novo Nordisk for this purpose.
The analysis of the main part (after 24 weeks) of the trial aims to substantiate CPoC that 
concizumab has the potential to prevent bleeding episodes in patients with severe haemophilia A 
without inhibitors. The extension part will provide additional safety data on 52 weeksdosing of 
concizumab.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Human biosamples (plasma, serum, and/or DNA for genotyping) will be collected in this trial  for 
future exploratory analysis to pursue a deeper insight into the biology of TFPI, coagulation, and 
effect of concizumab on joint health that may include coagulation parameters and markers of joint 
status or damage. Acceptance of storage of human biological specimens is voluntary and will not 
affect the patients’ participation in the trial. Therefore, patients will have the possibility to sign the 
informed consent for the trial and participate, while refusing permission for biological specimens to 
be stored for future exploratory analysis. Please refer to Section 24.1 for further information.
An independent data monitoring committee (DMC) will be established for this trial. The DMC will 
review all safety data from all ongoing trials with concizumab exposure, see Section 12.8.2.
All patients will be asked to perform a 24 hour PK-session after treatment with concizumab is 
initiated.
5.1.1
Surgery
Minor surgery is allowed in this trial. Major surgery conducted more than one month (30 days) 
prior to trial start is allowed, see exclusion criterion no 6.
Minor surgery is defined as an invasive operative procedure where only the skin, the mucous 
membranes or superficial connective tissue is manipulated. Examples of minor surgery include 
implanting of central venous access devices (ports, CVC, pumps and other CVADs) in 
subcutaneous tissue, skin biopsies or simple dental procedures.
5.2
Rationale for trial design
Explorer™5 is a phase 2, clinical proof of concept (CPoC) and safety trial. The trial aims to 
substantiate CPoC that concizumab has the potential to prevent bleeding episodes in haemophilia 
patients without inhibitors. A dose escalation design will allow cautious dose escalation in order to 
choose the efficacious and safe concizumab dose for the individual patient from the selected dose 
regimenConcizumab 0.15 mg/kg (with two potential dose-escalation steps, 0.20mg/kgand 0.25 
mg/kg) given s.c. once daily will be investigated.
The duration of 24 weeks for the main part of the trial is deemed necessary in order to obtain 
information on the annual bleeding rate (ABR)during concizumab prophylaxis. The duration of the 
extension part of the trial will be 52 weeks and will provide further information on long-term 
efficacy, i.e. ABR, and also provide additional safety data upon 76 weeks treatment with 
concizumab.
A total of 33 patientsare planned to receive concizumab s.c.once daily in this single arm trial,
please see Figure 5–1.
The concizumab dose regimentswill be startingwith0.15 mg/kg with the possibilityto escalate to 
0.20 mg/kg and 0.25 mg/kg, see section 5.3.1.
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Daily dosing with 0.15 mg/kg aims to ensure steady-state levels of concizumab plasma 
concentrations above 100 ng/mL for the majority of the patients starting on this dose. The PK 
results from explorer™3 showed exposure-response in terms of fewer bleeding episodes recorded 
for patients who reached plasma concentrations of concizumab above 100 ng/mLsee Figure 3–1. 
The minority of patients which are predicted to have steady-state plasma concentrations below this 
threshold are expected to experience bleeding episodes and therefore will have the opportunity to be 
dose-escalated to the dose of 0.2 mg/kg. A further dose escalation to 0.25 mg/kg per day is 
permitted, again based on the bleeding rate,see section 5.3.1.
Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated patients in 
explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal lines indicate 100 ng/mL, 
and the shaded areas represent the full range (min-max) of the individual predicted profiles1.
1 Plasma concentrations in the same range as those in explorer™3 are expected to be reached in this trial with daily dose 
administration. The starting dose for all patients will be 0.15 mg/kg daily. The plasma steady-state exposure for a typical subject at 
this dose level is predicted to fourfold lower compared to a typical subject on 0.8 mg/kg Q4D (cohort 3 of explorer3) in terms of both 
Cmax and AUC 0-24h. For 0.20 mg/kg daily and 0.25 mg/kg, the plasma steady-state exposure levels for a typical subject are 
predicted to be less than 40% and 70% respectively, compared to the typical subject exposure in the 3rd cohort of explorer™3 (AUC 
and Cmax). The maximum predicted plasma exposure levels (Cmax and AUC 0-24h) for the 0.15 mg/kg daily dose level is predicted 
to be more than 8 fold lower than for 0.80 mg/kg Q4D. For 0.20 mg/kg daily both Cmax and AUC 0-24h are predicted to be more 
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Due to the high between-patient variability in concizumab concentration observed in explorer™3, a 
significant overlap in plasma concentrations of concizumab in patients who received 0.25, 0.5 and 
0.8 mg/kg doses was seen, see Figure 5–2. Therefore, choosing three doses that would lead to 
reasonably distinct mean plasma concentrations of concizumab, and thus different efficacy at each 
dose level was not deemed possible. For this reason, a traditional parallel arm design was not 
chosen for the phase 2 trials. In contrast, the titration trial design allows patients to start on a low 
dose, which is expected to ensure prophylaxis but not marked changes in coagulation parameters, 
for the majority of patients. Escalation to the next dose level will only occur in the case of lack of 
efficacy (≥3 spontaneous bleeding episodes within the preceding 12 weeks. In addition, the PK of 
concizumab is heavily influenced by target mediated drug disposition, which means that small 
differences in concizumab dose ultimately leads to large differences in plasma concentrations. 
Therefore, daily dosing is proposed for the phase 2 trial, explorer™5. Daily dosing will allow for 
the increase in trough levels and thus better efficacy may be expected with a lower dose. 
Embryonic exposure in pregnant female partners of men treated with concizumab is highly unlikely 
and there is no need for protocol requirements for use of contraception in phase 2 and 3 trials.
                                                                                                                                                           
than 3 times lower than for 0.80 mg/kg Q4D. For 0.25 mg/kg daily, the maximum Cmax and AUC 0-24h are predicted to be 35 % 
lower than for 0.80 mg/kg Q4D.
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Date:
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Trial ID:NN7415-4255
Version:
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5.3
Treatment of patients
Table 5–1
List of products provided by Novo Nordisk
Compound Name 
Strength
Dosage form 
Route of 
administration
Treatment period
Concizumab B2, 
100 mg/mL
3 mL solution in 
a 3 mL 
cartridge3. 
S.c.
administration
using NovoPen® 4
For prophylactic 
treatment for 76 
weeks. 
Turoctocog alfa 
(NovoEight®)4, 
Sodium chloride 
solution 4ml  
2000 
IU/vial
Powder for 
solution for 
injection
Solvent for 
solution for i.v. 
injection used 
for 
reconstitution of 
turoctocog alfa.
I.v. administration
For treatment of 
breakthrough 
bleeding episodes 
(or prophylaxis in 
the screening and 
follow-up phases), 
atthe discretion of 
the treating 
physician (patients 
may choose to use 
other familiar pre-
trial FVIII drug).
For further 
information see 
section 5.3.2
Concizumab will be given s.c., once daily for a total dosing period of 76 weeks. 
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. It will be labelled in accordance with national legislation and a copy of the label can 
be found within the Trial Materials Manual, see Section 9.1.
The first dose of concizumab will be given at the trial site under medical supervision. After the 
initial dose the patient must be observed for potential emergence of AEs/safety signals for at least 2 
hours at the trial site. At the screening visit and the first scheduled treatment visit patients will be 
trained in s.c. administration of concizumab with NovoPen® 4 and in the use of eDiary.
Investigational medicinal product (IMP)
3 Not to be confused with the daily injected volume (~150 μL, depending on dose strength and body weight)
4 Non-investigational medicinal product (NIMP)
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In case safety concerns meet the criteria(See section12)for putting enrolment of additional 
patients on hold,further enrolment in the trial will be halted. Dosing of patients on treatment may 
continue while further evaluation is made by the safety committee. In case of other safety concerns 
all available data will be evaluated by the DMCsee Section 12.8.2.
5.3.1
Dose escalation
Bleeding episodes will be assessed during the trial both at scheduled visits and also between visits.
The first 2 weeks of the treatment with concizumab 0.15 mg/kg is considered as a run-in period. 
Hence the bleeding episodes occurring during the first 2 weeks should not influence a dose 
escalation decision.
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (first-dose visit) 
until visit 16 (end-of-treatment visit), i.e. a total of 74 weeks. Dose-escalation will be based on the 
number of spontaneous, treated bleeding episodes in patients within preceding 12 weeks. However, 
before dose-escalation can occur, to ensure the safety of the patients, the investigator must take into 
account the full clinical picture the patient is presenting with and all available laboratory results, 
including coagulation parameters.
Dose 0.15 mg/kg:
When a sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the preceding 
12 weeks since visit 2+2weeks (including the current sBE). If yes, and if investigator deems it safe, 
the patient will have to be dose escalated from 0.15 to 0.20 mg/kg at the next scheduled visit. If the 
investigator judges that this visit is scheduled too late, he/she should contact the patient for an 
unscheduled visit.
Dose 0.20 mg/kg:
When an sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the 
preceding 12 weeks (including the current sBE), counting only new sBEs from the beginning of the 
0.20 mg/kg treatment period. If yes, and if investigator deems it safe, the patient will have to be 
dose escalated from 0.20 to 0.25 mg/kg at the next scheduled visit. If the investigator judges that 
this visit is scheduled too late, he/she should contact the patient for an unscheduled visit.
Dose 0.25 mg/kg:
Patients are not dose escalated further regardless of the number of sBEs. When an sBE occurs, the 
investigator will determine if ≥ 3 sBEs have occurred within the preceding 12 weeks (including the 
current sBE), counting only the new sBEs from the beginning of the 0,25mg/kg treatment period. If 
yes, then the patient must be discontinued from treatment due to lack of efficacy, see Section 6.4.
Since the patient may have to wait up to 8 weeks for the next scheduled visit (in the extension part), 
the possibility of dose escalation at unscheduled visits is necessary for the dose-escalation eliciting 
bleeding episode to occur soon after previous scheduled visit.
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Version:
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Figure 5–3
Dose escalation of concizumab for one individual patient
5.3.2
Treatment of bleeding episodes during the trial
Bleeding episodes (main part, extension part, and follow-up part) :
Breakthrough bleeding episodes during the course of the trial will be treated at the discretion of the 
treating physician, with either turoctocog alfa/Novoeight®(rFVIII)  (provided by Novo Nordisk)  or 
other non-modified FVIII products(not provided by Novo Nordisk) .Treatment dose ischosen at 
the discretionof the investigator;however; in this trial any given single dose should not exceed 50 
IU/kg (Table 8-4) . The patient can treat himself and thenhe must call the site.  The bleeding 
episodes must be recorded in the eDiary.. Bleeding episodes must be recorded in the electronic case 
report form (eCRF) as an AE/SAE if fatal, life threatening or evaluated as related to trial product 
(see section 12.1)
FVIII prophylactic treatment (follow-up part) :
During the follow-up part of the trial (i.e. from concizumab end-of-treatment visit to end-of-trial 
visit) patients will receive pre -trial FVIII medication at the discretion of the treating investigator, 
whowill also choose dose levels. Only turoctocog alfa/NovoEight®will be provided by Novo 
Nordisk for this purpose.
5.3.3
Prohibited medication 
!
Treatment with anti-fibrinolytics (e.g. tranexamic acid, aminocaproic acid)*
!
Heparin, except for sealing of central venous access ports according to local practice
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!
Vitamin-K antagonists
!
Direct oral anti-coagulants (DOACs)
!
Modified FVIII products with extended half-life
*Local/topical use is allowed. Use of single systemic doses in severe bleeding episodes, after 
careful benefit-risk evaluation, is allowed.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products the patient should be switched to a suitable marketed product at 
the discretion of the investigator. The patient will not be provided with concizumab or FVIII 
(turoctocog alfa/NovoEight®) by Novo Nordisk after end of trial (visit 17). 
5.5
Rationale for treatment
Concizumab is a monoclonal antibody and as such offers the possibility of s.c. administration. S.c. 
administration of an effective prophylactic drug has potential to reduce treatment burden 
significantly compared to the currently approved prophylactic drugs which have to be administered 
i.v.
The treatment period of 24 weeks (the main part of the trial) is considered necessary for providing 
data that allow demonstration of CPoC and to support decision-making regarding a phase 3 
confirmatory trial. Dosing for an additional 52 weeks will provide valuable long-term efficacy and 
safety.
Breakthrough bleeding episodes may occur during prophylactic regimens with conventional FVIII 
replacement therapy. Therefore, it is expected that breakthrough bleeding episodes will also occur 
during prophylaxis with concizumab even if clinical proof of concept is demonstrated. 
Consequently turoctocog alfa (FVIII) will be provided by Novo Nordisk A/S in this trial for 
treatment of breakthrough bleeding episodes. 
Patients are not obliged to use turoctocog alfa (FVIII) and can use their previously used FVIII 
concentrate for treatment of breakthrough bleeding episode. Novo Nordisk A/S will not provide or 
reimburse these products.
Please refer to the Investigator’s Brochure for further information.
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Date:
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Version:
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product(s): 33
Number of patients planned to complete the trial: 30
Discontinued patients will not be replaced.
6.2
Inclusion criteria
For an eligible patient, all inclusion criteria must be answered “yes”.
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at 
screening.
3. For patients being treated on-demand with FVIII replacement therapy, a minimum of six 
documented and treated bleeding episodes during the 24 weeks (or twelve bleeds during 52 
weeks) prior to screening.
6.3
Exclusion criteria
For an eligible patient, all exclusion criteria must be answered “no”.
1. Known or suspected hypersensitivity to trial product(s) or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within the last 30 days or 5 half-lives (whichever is longer) from the last drug 
administration before screening.
4. Any disorder, which in the investigator’s opinion might jeopardise patient’s safety or 
compliance with the protocol.
5. Known inherited or acquired bleeding disorder other than haemophilia A.
6. Major surgery conducted within one month prior to the initiation of trial activities or major 
surgery planned to occur during the trial.
7. Previous history of thromboembolic disease. Current clinical signs of thromboembolic 
disease, or patients who in the judgement of the investigator are considered at high risk of 
thromboembolic events.
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8. Mental incapacity, unwillingness to cooperate or language barrier precluding adequate
understanding and cooperation.
9. Patients who, at screening, have a significant infection or known systemic inflammatory
condition which require systemic treatment according to the investigator’s judgement.
10. Hepatic dysfunction defined as elevated liver transaminases (ALT) >3 times the upper limit
of normal laboratory reference ranges at screening.
11. Renal impairment defined as estimated glomerular filtration rate (eGFR) ≤60
mL/min/1.73m2 based on serum creatinine measured at screening or evidence of renal
damage.
12. Platelet count ≤ 100x109/L at screening.
13. Fibrinogen level < the lower limit of normal at screening
14. Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at
screening measured by the Nijmegen method.
15. History of inhibitors towards FVIII based on investigator’s knowledge or documentation in
available medical records.
6.4
Criteria for premature discontinuation of trial product
The patient may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
The patient must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria
2. Simultaneous participation in another clinical trial of an approved or non-approved
investigational medicinal product.
3. Incapacity or unwillingness to follow the trial procedures
4. Anaphylactic reaction
5. Thromboembolic event
6. Event of disseminated intravascular coagulation (DIC)
7. Development of inhibitors to Factor VIII (≥0.6 BU)
8. Lack of efficacy due to neutralising antibodies towards concizumab
9. Lack of efficacy defined as ≥3 treated sBEs within the previous 12 weeks in patients being
treated with the highest dose level (0.25 mg/kg) of concizumab.
See Section8.1.4 for procedures to be performed for patients discontinuing trial 
product prematurely.
6.5
Withdrawal from trial
The patientmay withdraw consent at will at any time.
See Section 8.1.5for procedures to be performed for patients withdrawing 
consent.
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Version:
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6.6
Patient replacement
Patients who discontinue trial product prematurely will not be replaced.
6.7
Rationale for trial population 
The most important reason for choosing the trial population, haemophilia A without inhibitors, is 
that there is a significant unmet medical need in this patient population for a treatment option which 
reduces the burden associated with the current care, including small volume s.c. administration 
instead of i.v. Finally, the trial population reflects the patient population that will be selected in a 
potential subsequent phase 3 trial in which the efficacy and safety of concizumab is to be 
confirmed.
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CONFIDENTIAL
Date:
18 December 2017
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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7
Milestones
Planned duration of recruitment period first patient first visit – last patient first visit (FPFV-LPFV): 
4 months
Planned FPFV: 
16-Aug-2017
Planned FPFT: 
30-Aug-2017
Planned LPFV: 
16-Dec-2017
Planned LPLV: 
11-Sep-2019
The total duration of concizumab treatment in the trial is 76 weeks for an individual patient enrolled 
in the trial for concizumab treatment at visit 2.
End of trial is defined as last patient last visit (LPLV).
Recruitment:
The screening and enrolment rate will be followed closely via the interactive web response system 
(IWRS) in order to estimate when to stop screening. All investigators will be notified immediately 
when the recruitment period ends, after which no further patients may be screened and the IWRS 
will be closed for further screening. All patients screened during the recruitment period and found 
eligible for enrolment can be enrolled within the timelines specified in the flow chart (see Section 
2).
Trial registration:
Information about the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and clinical 
trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure, how-we-
disclose-trial-information8, it will also be disclosed according to other applicable requirements such 
as those of the International Committee of Medical Journal Editors (ICMJE) 9, the Food and Drug 
Administration Amendment Act (FDAAA)10 , European Commission Requirements 11, 12 and other 
relevant recommendations or regulations 13. If a patient requests to be included in the trial via the 
Novo Nordisk e-mail contact at these web sites, Novo Nordisk may disclose the investigator’s 
contact details to the patient. As a result of increasing requirements for transparency, some 
countries require public disclosure of investigator names and their affiliations.
Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
protocol Last Patient First Treatment LPFT (visit2) + 24 weeks ( i.e. last patient visit 9) If the last 
patient is withdrawn early the PCD is the date when the last patient would have completed visit 9. 
The PCD determines the deadline for results disclosure at ClinicalTrials.gov according to 
FDAAA.10
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Date:
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Trial ID:NN7415-4255
Version:
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8
Methods and assessments
Assessments to be performed at the scheduled and at unscheduled visits in this trial are described in 
this section and in the trial flow chart (section 2).
Figure 8–1
Overview of visit structure in explorer™5
8.1
Visit procedures
For each patient the trial consists of the following scheduled parts and visits:
Screening Part:
Visit 1 (screening visit)
Main Part:
Visit 2 (1st treatment visit with concizumab at site)
Home treatment with concizumab daily
Visit 3 (phone visit with site)
Visit 4 (Assessment visit, patients treat themselves at home)
Visit 5 (Assessment visit, patients treat themselves at home)
Visit 6 (Assessment visit, patients treat themselves at home)
Visit 7 (Assessment visit, patients treat themselves at home)
Visit 8 (Assessment visit, patients treat themselves at home)
Visit 9 (Assessment visit, after the visit patients treat themselves at home)
Extension Part:
Visit 10 (Assessment visit, patients treat themselves at home)
Visit 11 (Assessment visit, patients treat themselves at home)
Visit 12 (Assessment visit, patients treat themselves at home)
Visit 13 (Assessment visit, patients treat themselves at home)
Visit 14 (Assessment visit, patients treat themselves at home)
Visit 15 (Assessment visit, patients treat themselves at home)
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Visit 16 (Assessment visit and End of treatment)
Follow-up part
Visit 17 (Assessment visit and End of trial)
Unscheduled visits can occur e.g. for dispensing of trial products, when an assessment of bleeding 
episodes is necessary at site or at the discretion of the investigator.
The duration of the visits (V1-V17) will depend on the assessments and the patient’s individual 
training and/or discussion need on concizumab administration, NovoPen® 4, usage of e-Diary, 
completion of the patient reported outcome (PRO) etc.
8.1.1
Informed consent, long-term storage consent
Informed consent must be obtained before any trial related activity, see Section 18.2.
The trial includes a separate informed consent for long-term storage of human biosamples, see 
Section 24.2. 
Storage of human biosamples and genotyping is voluntary and will not affect the patients’ 
participation in the trial. Therefore, patients will have the possibility to sign the informed consent 
for the trial and participate, while refusing permission for biological specimens and /or genotyping 
to be stored for future exploratory analysis.
8.1.2
Screening log, enrolment log, trial card and patient number
The investigator must keep a patient screening log, a patient identification (ID) code list and a 
patient enrolment log. Only patients who have signed the informed consent form should be included 
on the logs. The patient screening log and patient enrolment log may be combined in one log.
At screening, patients will be provided with a card stating that they are participating in a trial and 
given contact address(es) and telephone number(s) of relevant trial clinic staff. Patients should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each patient will be assigned a unique 6-digit patient number which will remain the same 
throughout the trial.
8.1.3
Screening failures and re-screening
For screening failures the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial. Serious and non-serious adverse events 
from screening failures must be transcribed by the investigator into the eCRF. Follow-up on serious 
adverse events (SAEs) must be carried out according to Section 12.
A screening failure session must be made in the IWRS. The case book must be signed in the eCRF.
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Re-screening is NOT allowed if the patient has failed one of the inclusion or exclusion criteria; this 
includes re-sampling if the patient has failed one of the inclusion or exclusion criteria related to 
laboratory parameters.
8.1.4
Premature discontinuation of trial product
If a patient prematurely discontinues trial product, the investigator must undertake procedures 
similar to those for visit 9 (the last treatment in the main part) or visit 16 (the last treatment visit in 
the extension part) as soon as possible. The follow up visit (visit 17) must be performed 8 weeks 
(window minus 7 days) after last dose of trial drug.
The primary reason for premature discontinuation of trial product must be specified in the end of 
treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
Permanent premature discontinuation of treatment with trial product will lead to patient withdrawal 
from the trial.
8.1.5
Withdrawal from trial
If a patient withdraws consent, the investigator must aim to undertake procedures similar to those 
for visit 9 (the last visit in the main part) or visit 16 (the last visit in the extension part) as soon as 
possible depending on where the patient is in the trial schedule.
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the patient is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS and the case book must be signed in the eCRF.
Although a patient is not obliged to give his reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the patient’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.6
Review/evaluation of clinical outcome
Novo Nordisk has constituted an internal concizumab safety committee and established an external 
DMC to perform ongoing safety surveillance of safety data relevant for concizumab, see Section 
12.8.
Review of eDiary data and laboratory reports etc. must be documented either on the documents or 
in the patient’s medical record.
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If unclear entries or discrepancies in the eDiary or PRO are identified and a clarification is needed, 
the patient must be asked for clarification and a conclusion made in the patient’s medical record. 
Care must be taken not to bias the patient.
8.1.7
Visit 1 (Screening part)
Informed consent must be obtained before any trial related activity, see Section 18.2.
In cases where a patient's baseline FVIII level is not documented in medical records, sampling for 
FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours.
Screening can take place between 14 to 21 days prior to planned enrolment day (visit 2). For 
prophylactic treatment (prior to Screening) with extended half-life FVIII products, this period 
should be extended to a time-period equal to 8 half-lives of the used product
All assessments to be performed at screening are listed in Table 2–1, see Section 2.
Apart from informed consent patients will be asked to complete the ePRO questionnaires before any 
other trial related activities are performed according to Section 8.6;
!
Hemo-TEM,
!
VERITAS-Pro® orVERITAS-PRN®
Assessment results from physical examination, body measurements, as well as measurements of 
vital signs, urinalysis electrocardiogram (ECG) and details of any contemporary adverse events 
must be entered into the eCRF.
A screening confirmation call must be performed in the IWRS, at the day of the visit.
The investigator must review all information obtained from the screening procedures. If a patient
does not meet all inclusion criteria or meets one or more of the exclusion criteria for the trial the 
patient does not qualify to be enrolled.
Patients will be provided with turoctocog alfa (rFVIII) trial injection kits and directions for use 
(DFU) to cover the potential FVIII treatment in the screening part of the trial and investigator will 
ensure that the patients are capable of treating themselves with rFVIII (turoctocog alfa). Patients on 
any previous FVIII prophylaxis can continue with this treatment until 48 hours before visit 2.
Dispensing of rFVIII (turoctocog alfa) should be performed in the IWRS
For bleeding episodes that occur in the period from Screening visit (Visit1) to enrolment visit (Visit 
2) information about the bleeding episode is to be entered in the eCRF at visit 2. 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
45 of 124
The patient should be instructed to call the site if any bleeding episodes, questions or issues arise 
after he has left the site.
8.1.8
Training of patients visit 1 and visit 2
During the site visits 1 and 2 patients must be trained in self administration of concizumab in the 
home setting using NovoPen® 4. The dose of concizumab to be administered must be 
communicated to the patient at visit 2. Furthermore patients must be instructed and trained in the 
importance and reporting of all home treatment with concizumab, details of the bleeding episodes 
and the turoctocog alfa (FVIII) treatment associated with these bleeding episodes in the eDiary,(See 
section 8.6.2).
Patients should be trained on how to recognize and react to signs of thromboembolic events, so that 
the patient without any delay contacts the site.
8.1.9
Treatment period - Main part
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site)
Visit 2 should be scheduled 14 to 21 days after visit 1. The date of visit 2 will be considered as trial 
day 1.
Before any concizumab administration it is important to verify the in/exclusion criteria again and 
review central laboratory test results from screening. 
The patient must be in a non-bleeding state at the time of first administration with concizumab and 
should not have received any FVIII treatment for prophylaxis or for treatment of a bleeding episode 
within a period of 48 hours prior to dosing.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
Hemo-TEM,
o
SF-36v2, 
o
SDS, 
o
TSQM, 
o
SIAQ-ISRQ
All protocol assessments must be performed before 1st administration of concizumab. Vital signs 
must be assessed both before and after concizumab administration.
Assessment results from concomitant medication, vital signs, Body measurements (weight only)
and details of adverse events must be entered into the eCRF.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
46 of 124
At this, the 1st treatment visit, the allocated dose of concizumab will be given. Concizumab will be 
administered at the trial site supervised by medically trained trial staff.
The time point at which the completion of the first dose takes place corresponds to Time on 
treatment = 0 and must be recorded in the eCRF.
The patient must be observed at the trial site for at least 2 hours after the administration of the first 
dose of concizumab.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.
Investigator will communicate any the daily dose of concizumab to the patient and record the dose 
for the coming home treatment period in the eCRF. 
Prior to the first dose a dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits as well as an eDiary device to be able to conduct and report 
home treatment until the next scheduled visit.
The patient will be reminded to report bleeding episodes and home treatment in the eDiary device.
The patient will be asked to return all used, partly used and unused turoctocog alfa (FVIII) during 
the trial as instructed by the investigator. Drug accountability must be performed for turoctocog alfa
(rFVIII), including injection kits if applicable, according to section 9.4.. Unused sodium chloride 
syringes should be returned to site at every visit and new sodium chloride syringes should be 
dispensed to the patient.
8.1.9.2
Treatment period at home
Home treatment is defined as self-administration of trial product, performed independently by the 
patient, preferablyin the morning.Home treatment starts after visit 2 or when the patient is 
comfortable self-administrating trial product subcutaneously (concizumab)  and intravenously 
(turoctocog alfa(FVIII) ) .
8.1.9.3
Visit 3 (Phone visit)
Visit 3 is to be scheduled as a phone contact (or similar)  7days after visit 2 (with a visit window of 
+1 day) .
All relevant protocol assessments listed in table 2-1 must be discussed. Assessment results from 
concomitant medication and details of adverse events must be entered into the eCRF.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
47 of 124
Patients should be informed to treat themselves at home according to the dosing schedule regardless 
of when visits 4, 5, 6, 7 and 8 are scheduled. 
8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits)
Visits 4, 5, 6, 7 and 8 are to be scheduled on trial day 29 (4 weeks), day 57 (8 weeks), day 85 (12 
weeks), day 113 (16 weeks) and day 141 (20 weeks) respectively with a visit window of ± 7days.
Patients should treat themselves at home according to the dosing schedule regardless of when visits 
4, 5, 6, 7 and 8 are scheduled
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6;
o
PGI-C
o
Hemo-TEM
Assessments are to be performed according to Table 2–1and the assessment results from 
concomitant medication, vital signs, Body measurements (weight only) and details of adverse 
events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewingcollected data from the eDiary.Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab dosesis needed 
according the escalationrules described in section 5.3.1. All decisionsto escalate the concizumab 
dosemust be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable.Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
48 of 124
At visit 8 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 9.
8.1.9.5
Visit 9 (Assessment visits) 
Visit 9 is to be scheduled on trial day 169 (24 weeks) with a visit window of ± 7days.
Treatment with concizumab must take place after the blood sampling at this visit.
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
PGI-C
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
Assessments are to be performed according to Table 2–1and the assessment results from physical 
examination, concomitant medication, vital signs, Body measurements (weight only) and details of 
adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through the available access to collected data from the eDiary. Based on the assessment of any 
spontaneous bleeding episodes the investigator must evaluate if an escalation of the concizumab 
doses is needed according the escalation rules described in section 5.3.1. All decisions to escalate 
the concizumab dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
49 of 124
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
8.1.10
Extension Part
8.1.10.1
Visit 10 (Assessment visits) 
Visit 10is to be scheduled on trial day 225 (32 weeks), with a visit window of ± 7days.
Assessments are to be performed according to the flowchart section 2 and the assessment results 
from concomitant medication, vital signs, Body measurements (weight only)and details of adverse 
events must be entered into the eCRF.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performedaccording tosection 8.6.1;
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
SIAQ-ISRQ
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
50 of 124
8.1.10.2
Visit 11, 12, 13, 14 and 15 (Assessment visits)
Visits 11 to 15 are to be scheduled on trial day 281 (40 weeks), day 337 (48 weeks), day 393 (56 
weeks), day 449 (64 weeks) and day 505 (week 72) respectively with a visit window of ± 7days.
Assessments are to be performed according to Table 2–1 and the assessment results from physical 
examination (applicable for V12), concomitant medication, vital signs, Body measurements (weight 
only) and details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
At visit 15 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 16.
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) - Extension part
Visit 16 is to be scheduled on trial day 533 (76 weeks) with a visit window of ± 7days.
Visit 16 should be scheduled to be conducted at the last day of treatment with concizumab.
Treatment with concizumab must take place after the blood sampling at this visit.
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
51 of 124
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
Assessments are to be performed according to Table 2–1 and the assessment results from 
concomitant medication, vital signs and details of adverse events (AE) must be entered into the 
eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. 
In the period from visit 16 to visit 17 the patient can be treated with turoctocog alfa (rFVIII) at the 
discretion of the investigator. Treatment can either be prophylactically and/or treatment of eventual 
bleeding episodes. Only turoctocog alfa will be provided by Novo Nordisk.
If necessary, a dispensing call must be performed in the IWRS. At the visit the patient will be 
provided with rFVIII (turoctocog alfa) and injection kits to be able to conduct home treatment until 
final visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. NovoPen 4 must be 
returned. Drug accountability must be performed at all visits for concizumab and rFVIII (turoctocog 
alfa) including injection kits, if applicable. Unused sodium chloride syringes should be returned to 
site at every visit and new sodium chloride syringes should be dispensed to the patient.
8.1.11
Follow-up Part
8.1.11.1
Visit 17 (End of trial)
Visit17is to be scheduled on trial day 589(84 weeks) with a visit window of minus 7days 
Assessments are to be performed according to Table 2–1and the assessment results from
concomitant medication,physical examination, body measurements(weight only), vital signsand 
details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Patients must be asked iftheir female partner 
has become pregnant during the trial (see Section 12.5.1).
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
52 of 124
The patient will be asked to return all used, partly used and unused turoctocog alfa (rFVIII), eDiary
device and Trial card. Drug accountability must be performed for turoctocog alfa (rFVIII) including 
injection kits, if applicable. Unused sodium chloride syringes should be returned to site at every 
visit and new sodium chloride syringes should be dispensed to the patient.
End of trial information must be entered in the End of Trial form in the eCRF.
End of trial Call must be made in the IWRS.
8.1.12
Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Table 2–1.
The purpose of the unscheduled visit must be documented in the eCRF. During unscheduled visits 
assessments and blood sampling must be performed according to Table 2–1. Assessment results 
must be recorded in the eCRF. Assessments and blood sampling can be omitted if the only reason 
for the unscheduled visit is dispensing of trial product. 
If trial product administration or dispensing is required, dispensing of trial product must be 
performed via IWRS.or for an unscheduled 24 hour PK-visit.
The following forms can be found in the unscheduled visit in the eCRF:
!
Bleeding episodes
!
Dosing with FVIII, concizumab including dose escalation section 5.3.1
!
Surgery
!
Local, special and central laboratory (re-) sampling/results
!
Body measurements
8.1.12.1
Unscheduled 24 hour PK-Visit
All patients will be invited to participate in an optional unscheduled 24 hour PK-visit. The visit may 
take place after first dose of concizumab. Samples collected at the 24 hour PK-visit will be for 
analysis of concizumab-ELISA, Free TFPI and Thrombin Generation (TGA). Sampling will be at 
time points; 1 hour pre-dose (-1 hour), 1 (±10 min.), 3 (±10 min.), 6 (±10 min.), 9 (±10 min.), 12 
(±20 min.) and 24 hour(s) (±20 min.) post dose, related to the daily dosing of concizumab. 
Treatment dose of concizumab and the time of treatment will preferably be recorded in the eDiary 
by the patient or eCRF by site. Treatment will be at site.
This visit can be combined with a regular scheduled visit. Patients should be reminded not to 
administer the daily dose of concizumab until 1 hour after the pre-dose sampling has taken place
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
53 of 124
8.2
Patient related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Concomitant illness and medical history other than haemophilia
A concomitant illness is any illness, other than haemophilia A, that is present at the start of the trial 
(i.e. at the first visit) or found as a result of a screening procedure or other trial procedures 
performed before first exposure to trial product. All concomitant illnesses should be reported in the 
Concomitant illness forms in the eCRF except information on haemophilia A which is to be 
reported in the Haemophilia Medical history section of the eCRF.
Medical history is a medical event, other than haemophilia A, which the patient has experienced in 
the past. Only relevant medical history should be reported. The information collected for 
concomitant illness and medical history should include diagnosis, date of onset and date of 
resolution or continuation, as applicable. Any change to a concomitant illness should be recorded 
during the trial. A clinically significant worsening of a concomitant illness must be reported as an 
AE. 
It must be possible to verify the patient’s medical history in source documents such as patient’s
medical record:
If a patient is not from the investigators own practice; the investigator must make a reasonable 
effort to obtain a copy of the patient’s medical record from relevant party e.g. primary physician. 
See section 6.2 and 6.3 for full description of the selection criteria. The investigator must document 
any attempt to obtain external medical information by noting the date(s) when information was 
requested and who has been contacted.  
8.2.3
Concomitant medication
A concomitant medication is any medication, other than concizumab and turoctocog alfa (rFVIII)
(and connected 0.9% Isotonic Sodium Chloride) used for rescue treatment, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
54 of 124
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the patient’s eligibility to continue in the trial, the monitor must be informed.
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History
All available information on haemophilia, prior to screening should be recorded in the eCRF. 
!
Diagnosis of haemophilia (date)
!
Classification of haemophilia type (haemophilia A)
!
Severity of haemophilia (severe, moderate or mild)
!
Etiology of haemophilia (congenital or acquired)
!
Family history of haemophilia [yes or no in eCRF]
!
Family history of Prothrombotic disorders [yes or no in eCRF]
!
Family history of Thromboembolism [yes or no in eCRF]
!
Family history of inhibitors [yes or no in eCRF]
!
Deficiency factor level
The following information on bleeding episodes one year prior to screening should be recorded in 
the eCRF:
!
Type of treatment 
o
Prophylaxis or on-demand
o
Start date 
o
Stop date 
!
Number of bleeding episodes 
o
If possible specify number of spontaneous bleeding episodes.
!
Coagulation factor product(s) 
o
Brand name, or if the brand is not known, the type of product, (plasma derived or 
recombinant)
!
Dosage used for prophylaxis  (for prophylaxis patients only) 
!
Dosing frequency during prophylaxis (only for prophylaxis patients) 
!
Approximate dose to treat a bleeding episode 
!
Approximate number of doses to treat a bleeding episode
!
Target joint listing (definition: a target joint is a joint in which 3 or more spontaneous 
bleeding episodes have occurred within a consecutive 6-month period)
o
Location
o
Position (left/right)
o
Number of bleeding episodes
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
55 of 124
8.3
Efficacy assessments
8.3.1
Bleeding episodes
All bleeding episodes treated with FVIII and symptoms related to the underlying disease must be 
captured in the eDiary by the patient or in the eCRF by the investigator. The trial site should be 
informed of the details of all bleeding episodes, including those that are treated outside of the trial 
site. All information captured including severe bleeding episodes, during visits at the trial site will 
be collected in the eCRF.
When home treatment is initiated at visit 2 all bleeding episodes and injections with concizumab 
and turoctocog alfa (rFVIII) infusions occurring outside the trial site should be entered in the eDiary 
by the patient (Section 8.6.2.3). The completed eDiary is considered source data.
The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with rFVIII (turoctocog alfa):
!
Start date and time
!
Stop date and time (see Table 8–1 for definition) 
!
Anatomical location(s)
o
Position (left/ right)
!
Cause (see Table 8–2 for definitions)
o
spontaneous
o
traumatic
o
post-surgical
!
Severity (see Table 8–3 for definitions)
o
mild/moderate, severe

classification and of severe bleeding episodes is the responsibility of the 
investigator
!
Treatment, if any 
o
rFVIII (turoctocog alfa) administration(s) or other product administrations

dose, date, time 
o
other medicinal treatments related to the bleeding episode (e.g. pain relieving 
medication, non-medical therapy etc.)

record as concomitant medication (see Section 8.2.3)
!
Symptoms during bleeding episodes 
o
Pain 
o
Blood in urine
o
Tingling sensation
o
Swelling
o
Mouth/Gum bleed
o
Warmth
o
Loss of movement
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
56 of 124
o
Bruises
o
Nose bleed
Only report the bleeding episode as an AE/SAE if fatal, life threatening or evaluated as related to 
trial product (see section 12.1)
Table 8–1
Definition of stop of bleeding episode
Stop time is:
When the patient experiences/observes signs of cessation of the active 
bleeding episode such as; pain relief, no increase in swelling/limitation of 
motion and improvement in other objective signs of the bleeding episode
Stop time is not:
When pain and objective signs of the bleeding episode are completely 
resolved
Table 8–2
Definitions of bleeding episodes (cause of bleed)
Category
Definition
Spontaneous
Not linked to a specific, known action or event
Traumatic
Caused by a specific, known action or event (e.g. injury or exercise)
Post-surgical
Bleeding episodes after surgery from the surgical wound. Bleeding 
episodes during surgery does not fall under this category 
Table 8–3
Definition of bleeding episode severity and treatment recommendation
Category
Definition
Treatment recommendation
Mild/Moderate
Examples: uncomplicated musculoskeletal 
bleeding episodes (joint, muscular bleeds 
without compartment syndrome), mucosal- or 
subcutaneous bleeding episodes
Mild/moderate bleeding episodes may occur in 
other anatomical locations
Mild/moderate bleeding 
episodes can be treated at home 
before contact to the 
investigator
Severe
Examples: intracranial, retroperitoneal, 
iliopsoas and internal neck bleeding episodes; 
muscle bleeding episodes with compartment 
Severe bleeding episodes must 
be treated immediately 
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syndrome; bleeding episodes associated with a 
significant decrease in the haemoglobin level 
(>3g/dl)
Severe bleeding episodes may occur in other 
anatomical locations 
Bleeding episodes that require hospitalisation
All life-threatening bleeding episodes 
Instruction for 
patients
The patient must be instructed to contact the investigator immediately if in doubt 
regarding treatment of a bleeding episode and to discuss what other actions may 
need to be taken
Information about bleeding episodes prior to visit 2 will be recorded in eCRF.
The trial site should be informed of the details of all bleeding episodes, including those that are 
treated outside of the trial site. After visit 2 bleeding episodes must be recorded either in the eDiary 
(if treated at home) or in the eCRF (if treated at the trial site), see section 12.3.
Severity of bleeding episodes must be evaluated by the investigator according to Table 8–3and 
reported in the eDiary database.
Prophylactic treatment with concizumab should continue independent of bleeding episodes and 
their treatment, i.e. the original dosing schedule should be maintained unless investigator judges 
otherwise. Decisions to alter dosing schedule, including the rationale for the alteration, should be 
documented. If applicable, investigator must instruct the patient to use rFVIII (turoctocog alfa) as 
rescue medication to treat bleeding episodes.
Treatment of bleeding episodes will be at the discretion of the investigator. In countries where 
turoctocog alfa is approved for the market it is recommended to follow the approved labelling for 
NovoEight®. For countries where turoctocog alfa is not approved it is recommended to follow the 
instructions in the EU-SMPC for turoctocog alfa (FVIII): “The calculation of the required dose of 
factor VIII is based on the empirical finding that 1 IU factor VIII per kg body weight raises the 
plasma factor VIII activity by 2 IU/dl. The required dose is determined using the following formula:
Required units (IU) = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5 (IU/kg per 
IU/dl).
The amount to be administered and frequency of administration should always be oriented to the 
clinical effectiveness in the individual case.
In case of the following haemorrhagic events, the factor VIII activity should not fall below the 
given plasma activity level (in % of normal or IU/dl) in the corresponding period. The following 
table can be used to guide dosing in bleeding episodes and surgery:”
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Date:
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Table 8–4
Guide for dosing in bleeding episodes and surgery
Degree of haemorrhage/ Type of
surgical procedure
FVIII level required (%)
(IU/dl)*
Frequency of doses (hours)/ 
Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding
or oral bleeding
More extensive haemarthrosis, muscle
bleeding or haematoma
Life threatening haemorrhages
20-40 
30-60 
60-100
Repeat every 12 to 24 hours, at least1 
day, until the bleeding episode as
indicated by pain is resolved or
healing achieved
Repeat infusion every 12-24 hours for 
3-4 days or more until pain and acute 
disability are resolved
Repeat infusion every 8 to 24 hours
until threat is resolved
Surgery
Minor surgery including tooth
extraction
Major surgery
30-60 
80-100 (pre- and postoperative)
Every 24 hours, at least 1 day, until
healing is achieved
Repeat infusion every 8-24 hours
until adequate wound healing, then
therapy for at least another 7 days to
maintain a factor VIII activity of 30%
to 60% (IU/dl)
*however in this trial any given single dose should not exceed 50 IU/kg 
Furthermore investigator must instruct the patient to contact the site when a bleeding episode occurs 
to discuss the bleed.
It is the responsibility of the investigator to instruct the patient when to contact the site according to
Table 8–3 .
In absence of apparent effect of turoctocog alfa (rFVIII) the site must be contacted for further 
advice and before any further dosing. In case of a bleeding episode that requires treatment occurring 
outside the trial site’s opening hours the patient must be treated according to local procedure. All 
contacts to the patient must be recorded in the patient’s medical chart. 
It is the responsibility of the investigator to instruct the patient about the timelines for timely 
completion of the eDiary. Furthermore the investigator must review the bleeding and treatment data 
collected by the eDiary according to section 13.3.
For in-between visit administrations of trial drug, patients will self-administer concizumab (and 
turoctocog alfa (rFVIII) as rescue medication)) and will record treatment in the hand-held, eDiary, 
which will be reviewed during periodic calls to/contact with the patient and at each visit by trial site
staff and the sponsor staff.
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Date:
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Version:
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8.4
Safety assessments 
8.4.1
Physical examination
Performed as standard physical examination and include the following:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Genito-Urinary system, breasts 
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
The investigator must evaluate the results of the examination and classify the outcome as either:
!
Normal or abnormal.
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at Screening: record as Medical History (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
!
Measurements will be reported in the eCRF
8.4.2
Body measurements
Height (cm), at screening
Body Weight (kg), with 1 decimal.
The body weight assessed at each visit will be used for determination of the concizumab dose to be 
administered until next visit.
Measurements will be reported in the eCRF
8.4.3
Vital signs
Before measurement of vital signs the patient should preferably rest comfortably for at least five
minutes and all measurements should, if possible, be performed using the same method and sitting 
position throughout the trial. 
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Measurements at visits must be performed prior to any trial product administration unless otherwise 
specified
!
Body temperature (°C)
!
Systolic and diastolic blood pressure, sitting (BP) (mmHg)
!
Pulse, sitting (beats/min)
!
Respiratory rate
Exception: At visit 2, the measurement is also performed after concizumab administration.
The investigator must evaluate the results and classify the outcome as either: 
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2.)
o
If observed after screening: report an AE/SAE (section 12)
Measurements will be reported in the eCRF.
8.4.4
Electrocardiogram 
The investigator must evaluate the ECG (standard 12 lead) at screening and classify the outcome as
either:
!
Normal or Abnormal. 
!
If Abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant? (Yes/No)
o
If observed before or at Screening: record as Medical History (Section 8.2.1)
o
If observed after screening: report an AE/SAE (Section 12)
The ECG results must be dated and signed by the investigator to verify that the data have been 
reviewed. Outcome will be reported in the eCRF.
8.4.5
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12.
8.4.5.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form: 
!
Trial product(s) involved 
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Date:
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Version:
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!
Classification of medication error
!
Whether the patient experienced any adverse event(s) as a result of the medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4.
8.4.5.2
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section12.
Injection site reaction 
Investigation of injection site reactions will be performed locally at visit 2 based on patient 
feedback and by following visual inspections of injection sites for concizumab administration:
Symptoms e.g.
!
Pain 
!
Numbness 
!
Itching
!
Burning
Signs e.g.:
!
Redness (mm x mm)
!
Induration (mm x mm)
!
Swelling
!
Dimpling
!
Macula
!
Haematoma
!
Bleeding
!
Other (visual reactions) 
Any injection site reaction symptom (evaluated between visit 2-16) should be recorded in the AE 
form and the injection site reaction form, see section 12.1.5. 
A separate AE should be recorded for each injection site reaction symptom. The affected area 
should also be evaluated for redness and induration in mm using a ruler. To ensure all local 
injection site assessments are performed at the injection site, the area around the site will be marked 
with a pen prior to injection. 
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Date:
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In the event of a local reaction, additional visual assessments (as described above) will be 
performed until resolution as judged necessary by the investigator.
Assessment of injection site reactions can be performed at any time, if deemed necessary by the 
investigator.
Hypersensitivity reaction
If suspicion of a hypersensitivity reaction occurs the patients should be instructed to contact the site
staff as soon as possible for further guidance.
All events of hypersensitivity reactions must be reported and the following information must be 
obtained if available on the hypersensitivity reaction form: 
!
Signs and symptoms associated with the event
!
Time of appearance after administration of trial drug
!
Relevant immunological tests performed (See section 8.5.2.7)
!
Treatment given for the reaction
!
Previous history of similar reactions
!
Association with the trial product(s)
!
Relevant risk factors associated with the event
!
Storage condition of the trial product
!
Total number of doses, from first day on trial product, up to the time of this event
8.5
Laboratory assessments
An approximate total blood volume of 525 mL will be taken from each patient in the trial. Ports 
cannot be used for blood sampling.
A laboratory manual will be provided for detailed description of obtaining and processing blood 
samples.
All laboratory blood samples collected for this trial except for haematology samples are to be 
shipped for analysis at central laboratories or further distribution to special laboratories.
Haematology samples are to be analysed locally.
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in international system of units (SI) .
Laboratory reports listing results from centrally analysed samples will be made available for the 
investigator. Investigator must review and evaluate the results and report AEs for results which are 
clinical significant. Laboratory reports will where possible indicate normal ranges 
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Categorisation of clinical significance for out of range results may not be required for the following 
laboratory parameters and the investigator is therefore not required to perform a categorisation even 
though these parameters are listed in the laboratory report: FVIII activity, FVIII inhibitor test, 
Thrombin generation, TFPI not bound to concizumab, concizumab concentration in plasma, Anti-
concizumab binding antibodies, and Total TFPI.
The laboratory equipment may provide analyses not requested in the protocol but produced
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to section 8.2.2 and section 12.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory except for biomarkers and anti-drug antibodies (anti-concizumab IgE antibodies and 
anti-concizumab binding antibodies).
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report (CTR).
Antibody samples and human bio-samples, if applicable will be stored as described in section 24.2. 
The investigator may not be able to review the results of antibody measurements in relation to AEs 
as these are often analysed after LPLV.
8.5.1
Laboratory assessments for efficacy
8.5.1.1
Thrombin generation
The Thrombin Generation Assay (TGA) will be performed at all visits (including unscheduled 24 
hour PK visit), except visit 3.
The TGA is included as an exploratory PD assessment.
The generation of thrombin is a fundamental part of the haemostatic system, and is a key 
measurable parameter of the formation of a clot under bleeding or thrombotic conditions. The 
thrombin burst is crucial for the formation of a stable fibrin clot. 
The Calibrated Automated Thrombogram (CAT) method (used by Thrombinoscope BV) will be 
used to measure thrombin generation (TG). This method uses a slow acting fluorogenic substrate 
that allows continuous measurement of thrombin generation in double centrifuged citrated plasma. 
In this assay set-up thrombin generation is initiated by low-dose tissue factor that is combined with 
phospholipid. The result is obtained by comparison to a constant known thrombin activity in a 
parallel non tissue factor initiated sample. The assay has been validated fit-for-purpose.
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Date:
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Version:
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The thrombin generation endpoints are defined, but not limited to,
!
The Endogenous Thrombin Potential (ETP) – the area under the curve 
!
Peak thrombin generation
!
Velocity Index 
8.5.1.2
Free TFPI
Free TFPI measures TFPI not bound to concizumab. This enzyme-linked immunosorbent assay 
(ELISA) test will be will be sampled for at all assessment visits, including unscheduled 24 hour PK 
visit.
The free TFPI ELISA assay is an enzyme immunoassay measuring levels of TFPI not bound to 
concizumab from Diagnostica Stago (named and referred to Asserachrom TOTAL TFPI) and will 
be used for PD assessments. 
Free TFPI is included as a PD assessment.
8.5.2
Laboratory assessments for safety
8.5.2.1
Urinalysis
!
pH
!
Protein
!
Glucose
!
Bilirubin
This is a semi qualitative measurement which will be performed (locally) at the screening visit by 
the site by using the appropriate reagent strips for urinalysis. The results will be recorded in the 
eCRF.
Clinically significant findings must be recorded as: 
!
Normal or abnormal
o
if abnormal the investigator must:
o
record if the result is clinically significant? (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
8.5.2.2
Haematology
Haematology samples are to be sampled and analysed locally at all visits, except visit 3. 
!
Haemoglobin 
!
Erythrocytes (cell count) 
!
Thrombocytes (Platelet count)
!
Leucocytes (cell count) 
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!
Differential leucocytes cell count 
o
Lymphocytes
o
Monocytes
o
Neutrophils
o
Eosinophils 
o
Basophils
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
Haematology results are to be entered into the eCRF.
8.5.2.3
Biochemistry
!
Creatinine 
!
Albumin 
!
Bilirubin; total, direct and indirect)
!
Aspartate aminotransferase (AST) 
!
Alanine aminotransferase (ALT)
!
Gamma glutamyltransferase (GGT) 
!
Alkaline phosphatase
!
C-reactive protein (CRP) 
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
8.5.2.4
FVIII activity
!
FVIII activity (IU/ml)
8.5.2.5
Coagulation parameters 
!
Fibrinogen
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!
Prothrombin time  (PT) including INR
!
D-dimer 
!
Prothrombin fragment 1+2 
!
Activated partial thromboplastin time (APTT)
!
Antithrombin (AT)
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
8.5.2.6
FVIII inhibitor test
The inhibitor level of the patient will be measured by the Nijmegen method at visit 1 (screening). 
!
FVIII inhibitor titre (BU)
In order to minimise the risk of false negative results, circulating FVIII product levels should be 
less than 0.05 IU/ml, when sampling for the test. If the patient has received FVIII within 96 hours 
of screening the sampling of FVIII-Inhibitor should be postponed until a time period equal to 8 half-
lives of the used product has passed (counting from latest treatment).
8.5.2.7
Anti-concizumab antibodies
Sampling will be performed at all visits except at visit 3. Samples will be collected pre-dose at visit 
2, 9 and 16.
Assessment of binding antibodies against concizumab (anti-drug antibodies (ADA)) will be 
performed at specialised laboratories whereas assessment of neutralising antibodies will be 
performed at Novo Nordisk A/S.
Analysis for ADA will be done as listed in Table 2–1, with a bridging ECL assay (binding ADA 
assay), using labelled concizumab for antibody capture and detection.. If a sample is confirmed 
positive in the confirmatory assay, the sample is considered antibody positive. Confirmed positive 
samples will be characterised for binding to IgG backbone, CDR region or the S241P mutation. 
Furthermore, positive samples will be characterised for neutralising activity using a modified TFPI 
functionality assay (neutralising ADA assay). All antibody assays are validated according to 
international guidelines and recommendations.
The following analyses will be available:
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!
Anti-concizumab antibody assay
!
Specificity assay (Anti-concizumab antibodies cross reacting with IgG4 backbone, CDR region
or S241P mutation) 
!
Anti-concizumab neutralising antibody assay
Samples will be drawn at all visits except at visit 3. The samples will be analysed in batches during 
the trial and results will be available to the data monitoring committee approximately every third 
month after the first patient has been dosed (Section 12). Neutralising antibodies will be analysed 
and reported at the end of trial. A detailed description of the assay methods will be included in the 
antibody analysis report at the end of the trial.
Investigators will be notified in case their patient is shown to have developed neutralising 
antibodies against concizumab.
Samples for the determination of anti-drug antibodies collected during the treatment period must be 
drawn prior to administering trial products.
In the event that a trial patient develops binding ADAs towards concizumab during the course of the 
trial and has measurable binding ADAs at his End of Trial visit, the patient may attend an ADA 
follow-up visit. The ADA positive patients will be called for additional visits, e.g. every 4 to 6 
weeks, for safety assessment and blood sampling for ADA and PD markers (free TFPI and 
Thrombin generation). The ADA positive patients will be followed no longer than one year after 
End of Trial.
Hypersensitivity
If suspicion of a hypersensitivity reaction occurs, patients should be instructed to contact the site 
staff as soon as possible for further guidance, see Section 12.1.5.
In the event of a severe local and/or systemic hypersensitivity reaction possibly or probably related 
to trial product, blood sampling for assessment of anti-concizumab IgE antibodies as well as anti-
concizumab antibodies should be conducted in relation to the reaction and no later than 1-2 weeks 
after the event. Additional testing may be performed if deemed relevant (e.g. anti-Host Cell Proteins 
(HCP) antibodies). 
In the event of a severe systemic hypersensitivity reaction to trial product it is recommended also to 
test for tryptase (total and/or mature tryptase) within 3 hours of the reaction. Moreover, a baseline 
tryptase measurement is necessary 1-2 weeks after the immediate severe hypersensitivity reaction 
due to individual to individual variation in tryptase baseline concentration. 
A follow up visit should be conducted 3-4 weeks post the allergic reaction with repeated blood 
sampling for assessment of anti-concizumab IgE antibodies as well as anti-concizumab antibodies 
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and if possible also at a visit 3 months post the hypersensitivity reaction for assessing the 
persistence of the IgE response. Tryptase measurements are not required at the follow up visits.
Additionally, basophil activation testing may be performed if deemed relevant. This can be 
performed using existing samples and/or by analysing the patient’s basophil cells from an additional 
blood sample taken 3-4 weeks and no later than 2 months after the event. Similarly, prick tests 
and/or intra-dermal tests may be performed if relevant using trial product or components of trial 
product. Complement may be measured in case of suspicion of immune complex mediated 
hypersensitivity reactions.
Results from the following additional tests will be reported to Novo Nordisk Safety Operations for 
inclusion in the ARGUS database and included in the narratives, if measured:
Test to be performed in case of severe hypersensitivity
!
Anti-concizumab IgE antibodies
!
Anti-concizumab antibodies (additional to scheduled time points)
Additional testing may be performed if deemed relevant e.g
!
Anti-Host Cell Proteins (HCP) antibodies
!
Anti-HCP IgE antibodies
!
Basophil activation results
!
Prick test/intra-dermal test
!
Complement test results
Furthermore, it is recommended locally to test for
!
Tryptase (total and/or mature tryptase)
8.5.2.8
Concizumab ELISA
Concizumab ELISA will be performed at all visits except at screening and at visit 3. Samples will 
be collected pre-dose at visit 2, 9 and 16. For the unscheduled 24 hour PK visit, samples are 
collected; 1 hour pre-dose, (-1hour), 1(±10 min.), 3(±10 min.), 6(±10 min.), 9(±10 min.), 12(±20 
min.) and 24 hour(s) (±20 min.) post dose, related to the daily dosing of concizumab.
Concizumab will be quantified using a validated ELISA assay. Recombinant human TFPI will be 
used to capture concizumab. A colorimetric detection signal is obtained by the enzymatic reaction 
of horseradish peroxidase labelled anti-human IgG4 specific antibodies with the chromogenic 
substrate TMB (3,3´,5,5´-tetramethylbenzidine). The amount of anti-TFPI present in the calibration, 
quality control and test samples correlates with the obtained signal strength.
Validation of the assay follows current guidelines for bioanalytical method validation. Bioanalytical 
data will be reported in a bioanalytical report.
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8.5.2.9
Total TFPI
Total TFPI ELISA sampling will be performed at all visits except at visit 3. Samples will be 
collected pre-dose at visit 2, 9 and 16.
The Total TFPI ELISA is included as an exploratory PD assessment.
The total TFPI level (free and concizumab bound) will be included as an exploratory biomarker 
assessment. The assay is an ELISA, where TFPI is captured by polyclonal anti-TFPI antibody, 
distanced from the binding site of concizumab, meaning that both free TFPI and concizumab bound 
TFPI will be captured. Detection will be obtained with a monoclonal antibody against TFPI, which 
does not bind to the concizumab epitope. Data will be reported in ng/mL TFPI.
Total TFPI ELISA will be performed at all visits, except visit 3. Sample will be collected pre-dose 
at visit 2.
8.5.3
Human biosamples
If patient permission is obtained, plasma, serum and/or DNA for genotyping samples are to be taken 
for long term retention. The blood samples can be stored up to 15 years, for future potential 
exploratory purposes please refer to section 24.2.
Antibody samples storage and retention see section 24.2.1. The investigator is not able to review the 
results of antibody measurements in relation to AEs as these are analysed after LPLV.
If applicable, samples will be collected at visit 1 and at visit 17.
8.6
Other assessments
8.6.1
Patient reported outcomes
In this trial a newly developed disease specific PRO -the Hemophilia Treatment Experience 
Measure (Hemo-TEM) -is being validated. In order to assess the psychometric properties of 
Hemo-TEM,  other questionnaires will be provided; see further appendix 1.
The following ePRO questionnaires are used:
- Haemophilia Treatment Experience Measure (Hemo-TEM)
- Validated Hemophilia Regimen Treatment Adherence Scale – Prophylaxis (VERITAS-
Pro®)/Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
- 36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
- Patient Global Impression of Change (PGI-C)
- Sheehan Disability Scale (SDS)16
- Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
- Haemophilia - Device Assessment Tool (H-DAT)
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- Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
The PROs should be assessed at the scheduled visits following the order listed below:
!
visit 1 (Hemo-TEM, VERITAS-Pro® or VERITAS-PRN®)
!
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 4 (PGI-C, Hemo-TEM)a
!
visit 5 (PGI-C, Hemo-TEM)
!
visit 6 (PGI-C, Hemo-TEM)
!
visit 7 (PGI-C, Hemo-TEM)
!
visit 8 (PGI-C, Hemo-TEM)
!
visit 9 (PGI-C, Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
!
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 16 (Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
At visit 1 before any visit-related activities all patients should complete Hemo-TEM and 
VERITAS-Pro® (if the patient at baseline receives prophylactic treatment) / VERITAS-PRN® (if 
patient at baseline receives on demand treatment).   
At visit 2 before any visit-related activities all patients should complete Hemo-TEM, SF36v2, SDS, 
TSQM and SIAQ-ISRQ.
At visit 4-8: before any visit-related activities the patient should complete the PGI-C before the 
Hemo-TEM. These are the rules that apply:
!
If the patient responds “1” to question 1 in the PGI-C, the patient should also complete the
Hemo-TEM. In this case the patient should not fill in the PGI-C any more in the trial and the
Hemo-TEM only again at visit 9.
!
If the patient responds “0” or “2” to question 1 in the PGI-C, the patient should not complete
any other questionnaires at this visit, but should repeat the procedure at next visit.
At visit 9 if the patient has responded “0”or “2”in the PGIC at all previous visits, the patient 
should complete PGI-C. All patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT
and SIAQ-ISRQ.
At visit 10 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and SIAQ-ISRQ.
At visit 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT and SIAQ-
ISRQ. The investigator mustcheck the ePROs for potential AEs and SAEs.
The completed ePROs should be transmitted to the ePRO database by the investigator at each visit.
All PROs can be found in Appendix I. 
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8.6.2
Training 
The patients must be trained in how to handle bleeding episodes and how to recognize the signs and 
symptoms of thrombosis. The training must be recorded in the medical records. 
8.6.2.1
Concizumab and NovoPen® 4
A direction for use (DFU) will be available as hand out for patients at visit 2. Training in 
NovoPen®4 can start at screening (visit 1) and s.c. administration of concizumab using the 
NovoPen®4 can start at the first dose at the trial site (visit 2). Patients must be instructed that 
injections are to be performed subcutaneously, not intravenously. Concizumab and NovoPen®4 will 
be dispensed to patients at visit 2. Training must be performed at site until patients feel comfortable
using the device or performing the treatment. The training must be documented in the medical 
records.
Detailed instructions can be found in the DFU.
8.6.2.2
Turoctocog alfa
A direction for use (DFU) will be available as hand out for patients at visit 1. Training must be 
performed at site until patients feel comfortable performing the treatment. The training must be 
documented in the medical records. 
Detailed instructions can be found in the DFU.
8.6.2.3
eDiary
Training on the use of the eDiary can start at visit 1. The eDiary will be provided to the patients at 
visit 2.
Training must be repeated at the site until patients feel comfortable using the device. The training 
must be documented in the medical records.
During the home treatment period the patient must ensure that all home treatments of concizumab, 
details of bleeding episodes and the turoctocog alfa (FVIII) treatment associated with these bleeding 
episodes are captured in the eDiary as instructed and trained by investigator or delegated staff.
It will be the responsibility of the investigator or delegated staff to assess the eDiary data 
throughout the conduct of the trial and to ensure data entry compliance (timely entry, no duplicates 
data, no missing data etc.) and retraining if necessary.
For patients completing the trial or in case of withdrawal, the eDiary will be collected at the end of 
trial.
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8.6.3
Surgery
Minor surgery can be performed within this trial at the investigator’s discretion according to local 
guidelines. Definition of minor surgery, see section 5.1.1. Major surgery is not allowed, see 
exclusion criteria no 6.
For minor surgery the following should be recorded in the eCRF:
!
Date, stop time and dose of preventive treatment with turoctocog alfa before surgery, if this was 
deemed necessary by the investigator
!
Indication for surgery
!
Location of surgery
!
Date of surgery
!
Start and stop time of surgery
8.7
Patient compliance
Throughout the trial, the investigator will remind the patients to follow the trial procedures and 
requirements to ensure patient compliance. If a patient is found to be non-compliant, the 
investigator will remind the patient in the importance of following the instructions given including 
taking the trial products as prescribed.
Assessment of patient compliance with protocol procedures for determination of continuation of the 
trial will be done by the investigator on an ongoing basis.
8.8
Treatment compliance:
Treatment compliance will be monitored and documented through timely review of eDiary data and 
drug accountability. 
Concizumab will be administered at the trial site at visit 2 supervised by medically trained trial staff
and administration at home can be initiated after visit 2 if the patient feels comfortable with the s.c. 
administration. Administration of turoctocog alfa (rFVIII) for bleeding episodes will be 
administered at the trial site by a medically trained trial staff or at home by the patient, see section 
8.3.1. 
The patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator. Drug accountability will be performed and will be used to assess 
patient compliance together with the patient’s adherence to trial procedures. 
Compliance check includes a cross check between records in EDC/eDiary (number of 
administrations and bleeding episodes) and the used/returned cartridges/vials. 
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
The trial product, concizumab B, appears clear to slightly opalescent and colourless to slightly 
yellow. The trial product must not be used if it contains visible particles or discolouration.
The reconstituted turoctocog alfa (FVIII) solution appears as a clear or slightly opalescent solution. 
Do not use the reconstituted solution if it has visible particles or discoloration. 
Trial products must not be dispensed to any person not included in the trial.
9.1
Trial products
The following trial products will be provided by Novo Nordisk, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
concizumab B 
(IMP a)
100 mg/mL
Solution for injection
s.c. injection
3 ml cartridge
turoctocog alfa
(NIMP b)
2000 IU/vial
Powder for solution for 
injection
i.v. injection
Vial
0.9% Sodium Chloride 
Solution
(NIMP b)  
N/A
Solvent for solution for
injection 
i.v. injection
4 ml prefilled 
syringe
a Investigational Medicinal Product (IMP) 
b Non-Investigational Medical Product (NIMP) given as NIMP for bleeding episodes
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. NovoPen®4 will be labelled in accordance with the EMA directive on medical devices 
annex I 21 and similar national legislation. A description on how to use the device is given in the
DFU.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 22, local regulations and trial 
requirements.
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Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial products will be distributed to the trial sites according to enrolment 
and drug dispensing of distribution.
The investigator must document that direction for use is given to the patient orally and in writing at 
the first dispensing visit (see flow chart section 2). 
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time a
concizumab B 100 mg/mL
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
Store at room temperature 
(below 30°C)
Do not refrigerate
Protect from light
Use within 4 weeks 
(28 days)
turoctocog alfa
2000 IU/vial
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
May be stored at room 
temperature (9-30oC) for a 
single period not exceeding 9
months. Do not return the 
product to the refrigerator.
Write the start date for the 
storage at room temperature on 
the label
For single use
To be used immediately after 
reconstitution
Use within 4 hours after 
reconstitution when stored at 
room temperature
N/A
0.9% sodium chloride 
solution
Store at 2°-30°C
Do not freeze
Protect from light
For single use
N/A
a In-use time for concizumab starts when first dose is administrated from an individual cartridge and for turoctocog alfa 
when the product is reconstituted
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any patient before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
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Investigator must instruct the patient to use and store trial product according to the label.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator. The 
patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator except for the used sodium chloride solution which should be 
discarded at home and not accounted for. Unused sodium chloride syringes should be returned to 
site at every visit and new sodium chloride syringes should be dispensed to the patient.
All cartridges (concizumab) and vials (FVIII) must be accounted for as used, partly used, or unused. 
The investigator will perform drug accountability using the IWRS Drug Accountability module.
Returned trial product (used/partly used and unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Destruction of concizumab can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
For Japan only: Responsibility for storage and drug accountability of the trial drug product at the 
trial site rests with the head of the trial site. The head of the trial site could assign some or all of the 
responsibilities for accountability of the trial drug product at the trial sites to a trial product storage 
manager (a pharmacist in principle). The trial product storage manager should control and take 
accountability of the trial drug product in accordance with procedures specified by Novo Nordisk. 
The head of the trial site or the trial product storage manager must ensure the availability of proper 
storage conditions, and record and evaluate the temperature.
9.5
Auxiliary supplies
Novo Nordisk will provide the auxiliaries for this trial: 
!
For concizumab administration: NovoPen®4, needles, and DFU
!
For turoctocog alfa reconstitution and administration: Trial Injection Kit and DFU
Only needles and trial injection kits provided by Novo Nordisk must be used for administration of 
trial product.  
For further guidance please see the TMM.
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for:
!
Screening
!
Screening failure
!
Medication arrival
!
Dispensing
!
Dispensing verification
!
Treatment discontinuation 
!
Completion
!
Drug accountability
!
Data change
An IWRS user manual will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
Randomisation 
Not applicable for this trial
Breaking of blinded codes
Not applicable for this trial.
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12 Adverse events, and technical complaints 
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial 
procedures performed before exposure to trial product (pre-existing conditions should be 
reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the patient has signed the informed 
consent.
!
Bleeding episodes and other symptoms (e.g. pain, swelling, synovitis, arthralgia, injection 
site haematoma) in connection with bleeding episodes should not be reported as AEs/SAEs 
unless the event is fatal, life-threatening or evaluated by the investigator as related to trial 
product or trial procedure. All bleeding episodes and other findings related to underlying 
disease will be captured in the eCRF/eDiary
The following three definitions are used when assessing an AE:
!
Severity 
o
Mild – no or transient symptoms, no interference with the patient’s daily activities.
o
Moderate – marked symptoms, moderate interference with the patient’s daily activities.
o
Severe – considerable interference with the patient’s daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial product(s): 
o
Probable - Good reason and sufficient documentation to assume a causal relationship.
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o
Possible - A causal relationship is conceivable and cannot be dismissed.
o
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome 
o
Recovered/resolved - The patient has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the patient signed the informed consent.
o
Recovering/resolving - The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the trial 
or has died from another AE.
o
Recovered/resolved with sequelae - The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
o
Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known.
o
Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he 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.
o
Unknown - This term is only applicable if the patient is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
a. The term “life threatening” in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
b. The term “hospitalisation” is used when a patient: 
o
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
o
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c.A substantial disruption of a patient’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the patient has significant, persistent or permanent change, 
impairment, damage or disruption in his body function or structure, physical activity and/or quality 
of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
Suspicion of transmission of infectious agents via the trial product 
!
Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative 
aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error unless 
it results in administration of wrong drug.
!
Wrong route of administration, 
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. However, the 
administered dose must deviate from the intended dose to an extent where clinical 
consequences for the trial patient were likely to happen as judged by the investigator, 
although they did not necessarily occur
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1
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12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
In this trial the following AEs require the completion of specific event forms in the eCRF:
!
Injection site reaction (see section 8.4.5.2)
!
Hypersensitivity type reactions, incl. anaphylactic reactions, as defined below 
Injection site reactions:
Any injection site reaction symptom must be reported on the AE form and the injection site reaction 
form, See section 8.4.5.2.
Hypersensitivity type reactions:
In cases where clinical signs of a severe and immediate hypersensitivity reaction resembling a type
I hypersensitivity reaction are present, blood should be sampled for central laboratory assessment of 
anti-drug IgE antibodies and anti-drug binding antibodies. In the event of an immediate systemic 
hypersensitivity reaction to the trial product, it is recommended to also test for tryptase (total and/or 
mature tryptase) within 3 hours of the reaction. Moreover, a baseline tryptase measurement is 
necessary ~1 week after the immediate severe hypersensitivity reaction due to individual to 
individual variation in tryptase baseline concentration. Tryptase concentrations (if measured) must 
be interpreted and considered in the context of a complete workup of each patient.
Special attention should be given to clinical signs and symptoms of hypersensitivity reactions of 
type II and III. Common clinical signs and symptoms characteristic for these types of reactions may 
include but are not limited to: fever/malaise, cutaneous eruptions, arthralgia, lymphadenopathy, 
itching, headaches and myalgia. Related laboratory findings may include but are not limited to: mild 
proteinuria or haematuria, leukopenia or leucocytosis, decreased complement levels or increased 
complement split products and transient elevations of serum creatinine levels. In cases where there 
is a suspicion of hypersensitivity reaction that requires systemic treatment, additional sampling for 
the purpose of measuring ADA is to be performed.
Definition of anaphylaxis23
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
!
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (e.g. generalised hives, pruritus or flushing, swollen lips-tongue-uvula) and 
at least one of the following:
a) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)
b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.
hypotonia [collapse], syncope, incontinence)
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!
Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):
a) Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush, swollen 
lips-tongue-uvula)
b) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
!
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
Systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
BP.
If a patient fulfils any of the three criteria of anaphylaxis outlined above, the patient should receive 
epinephrine/adrenalin immediately. Dose regimen should be according to hospital operating 
procedure, and the patient should be transferred to an emergency department or intensive care unit, 
if clinically warranted.
Events not fulfilling the criteria for an anaphylactic reaction and other allergic reactions must be 
treated at the discretion of the investigator. If according to the investigators judgment, 
hypersensitivity type reactions that require systemic treatment are suspected, dosing with 
concizumab should be stopped immediately and treatment at the discretion of the treating physician 
initiated.
12.1.6
Adverse event of special interest
An adverse event of special interest (AESI) is an event, which in the evaluation of safety, has a 
special focus. In this trial, the following AEs fulfil the AESI criteria:
!
Thromboembolic events including but not limited to,
o
disseminated intravascular coagulation (DIC) (A), 
o
clinical signs or laboratory indications of arterial and venous thrombosis including 
myocardial infarction (B), 
o
pulmonary embolism (C), 
o
stroke (D), 
o
deep vein thrombosis (E), 
o
other clinically significant thromboembolic events (F) and peripheral artery 
occlusion (see below G), see definitions below.
The AESIs must be reported on an AE form and a safety information form.
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A) Definition of disseminated intravascular coagulation (DIC), as defined below:
The definition of DIC in this trial should be made according to the International Society on
Thrombosis and Haemostasis (ISTH) criteria. Thus, a DIC diagnosis may be based on 
clinical signs and symptoms of a bleeding tendency or thrombotic tendency, organ 
dysfunction and the laboratory parameters criteria as listed below:
o
Platelet count (>100 × 109/L = 0, <100 × 109/L = 1, <50 × 109/L = 2)
o
Elevated D-dimer (no increase = 0, moderate increase = 2, strong increase = 3)
o
Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
o
Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
o
Calculate score: ≥5 compatible with overt DIC
(B) Myocardial infarction is defined according to the “Third Universal Definition of
Myocardical Infarction” 24
Criteria for acute myocardial infarction - The term acute myocardial infarction (MI) should be used 
when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial 
ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI:
!
Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin
(cTn)] with at least one value above the 99th percentile upper reference limit (URL) and
with at least one of the following:
o
Symptoms of ischemia.
o
New or presumed new significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB).
o
Development of pathological Q waves in the ECG.
o
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality.
o
Identification of an intracoronary thrombus by angiography or autopsy.
Criteria for prior myocardial infarction- Any one of the following criteria meets the diagnosis for
prior MI:
!
Pathological Q waves with or without symptoms in the absence of non-ischemic causes.
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to
contract, in the absence of a non-ischemic cause.
!
Pathological findings of a prior MI.
Recurrent myocardial infarction - Incident MI’ is defined as the individual’s first MI. When features 
of MI occur in the first 28 days after an incident event, this is not counted as a new event for 
epidemiological purposes. If characteristics of MI occur after 28 days following an incident MI, it is
considered to be a recurrent MI.
C) Definition of pulmonary embolism:
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The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends diagnostic
imaging studies for patients with intermediate or high pre-test probability of pulmonary embolism25.
Accordingly, the definition of pulmonary embolism is the following: obstruction of a pulmonary 
artery or one of its branches, most frequently by detached fragments of thrombus from a leg or 
pelvic vein, diagnosed by at least one of the following:
!
Positive findings in ventilation/perfusion scan
!
Positive findings in a spiral (helical) computerised tomography (CT) or angiography
!
Positive findings in a magnetic resonance imaging (MRI)
!
Positive findings in a pulmonary angiography
D) Definition of stroke:
The definition of central nervous infarction is according to the American Heart
Association/American Stroke Association Expert Consensus Document:  “An Updated Definition of 
Stroke for the 21st Century”26.
Accordingly, the term “stroke” should be broadly used to include all of the following:
Definition of central nervous system (CNS) infarction: CNS infarction is brain, spinal
cord, or retinal cell death attributable to ischemia, based on:
o
1. pathological, imaging, or other objective evidence of cerebral, spinal cord, or
retinal focal ischemic injury in a defined vascular distribution; or
o
2. clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on
symptoms persisting 24 hours or until death, and other etiologies excluded.
Note: CNS infarction includes haemorrhagic infarctions, types I and II; see “Haemorrhagic
Infarction”.
Definition of ischemic stroke: An episode of neurological dysfunction caused by focal cerebral,
spinal, or retinal infarction. Note: Evidence of CNS infarction is defined above.
Definition of silent CNS infarction: Imaging or neuropathological evidence of CNS infarction,
without a history of acute neurological dysfunction attributable to the lesion.
Definition of intracerebral haemorrhage: A focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma. Note: Intracerebral haemorrhage includes
parenchymal haemorrhages after CNS infarction, types I and II - see “Haemorragic Infarction”.
Definition of stroke caused by intracerebral haemorrhage: Rapidly developing clinical signs of
neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma.
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Definition of silent cerebral haemorrhage: A focal collection of chronic blood products within the
brain parenchyma, subarachnoid space, or ventricular system on neuroimaging or neuropathological
examination that is not caused by trauma and without a history of acute neurological dysfunction
attributable to the lesion.
Definition of subarachnoid haemorrhage: Bleeding into the subarachnoid space (the space between
the arachnoid membrane and the pia mater of the brain or spinal cord).
Definition of stroke caused by subarachnoid haemorrhage: Rapidly developing signs of
neurological dysfunction and/or headache because of bleeding into the subarachnoid space (the
space between the arachnoid membrane and the pia mater of the brain or spinal cord), which is not
caused by trauma.
Definition of stroke caused by cerebral venous thrombosis: Infarction or haemorrhage in the brain,
spinal cord, or retina because of thrombosis of a cerebral venous structure. Symptoms or signs
caused by reversible edema without infarction or haemorrhage do not qualify as stroke.
Definition of stroke, not otherwise specified: An episode of acute neurological dysfunction 
presumed to be caused by ischemia or haemorrhage, persisting ≥24 hours or until death, but without
sufficient evidence to be classified as one of the above.
Definition of a Transient Ischemic Attack: The definition of Transient Ischemic Attack is according
to the American Heart Association/American Stroke Association. Accordingly: a Transient 
ischemic attack (TIA) is a transient episode of neurological dysfunction caused by focal brain, 
spinal cord, or retinal ischemia, without acute infarction 27.
E) Definition of deep vein thrombosis:
The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends
ultrasound scanning for patients with intermediate or high pre-test probability of deep vein 
thrombosis (DVT) in the lower extremities 25. Accordingly, venous thrombosis should be 
demonstrated by compression ultrasound,
duplex ultrasound, colour Doppler imaging or venography (phlebography).
F) Definition of other clinically significant thromboembolic events:
Signs or suspicion of a clinically significant thromboembolic event (e.g. visceral arterial 
embolus/thrombus, extremity arterial embolus/thrombus, or portal venous thrombosis).
Superficial thrombophlebitis is not considered a clinically significant thromboembolic event unless 
evaluated as such by the investigator.
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G) Definition of peripheral artery occlusion:
Clinical signs of acute arterial occlusion verified by ankle-brachial index (ABI) test, Doppler and
ultrasound (Duplex) imaging, computerised tomographic angiography, magnetic resonance 
angiogram (MRA), or conventional angiography. The 2011 American College of Cardiology 
Foundation/American Heart Association Focused Update of the Guideline for the Management of 
Patients With Peripheral Artery Disease could serve as a reference for the diagnosis of lower 
extremity peripheral artery disease 28
12.1.7
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between pen and needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the patient has signed the informed consent until the end of 
the post-treatment follow-up period (visit 17). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12–1
During each contact with the trial site staff, the patient must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?
All AEs, either observed by the investigator or patient, must be reported by the investigator and 
evaluated. All AEs must be recorded by the investigator on an AE form. The investigator should 
report the diagnosis, if available. If no diagnosis is available, the investigator should record each 
sign and symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
AESIs regardless of the seriousness, must be reported using the AE form and safety information 
form
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For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the case report form (CRF)/eCRF within the 
specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator’s first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in the 
eCRF. 
For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
!
Non-serious AEs fulfilling the AESI criteria: The AE form and safety information form 
within 14 calendar days of the investigator’s first knowledge of the event.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: Investigator’s Brochure; Current version and any updates thereto.
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP 1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the
International Review Boards/Independent Ethics Committees (IRBs/IECs) of trial product-related 
SUSARs in accordance with local requirement and ICH GCP 1, unless locally this is an obligation 
of the investigator.
Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
non-investigational medicinal product rFVIII (turoctocog alfa) or concomitant medication in the 
trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to report this 
adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. 
Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is 
“recovered/resolved”, “recovered/resolved with sequelae” or “fatal”, and until all queries 
have been resolved. Cases of chronic conditions, cancer or AEs ongoing at time of death 
(where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the 
outcome of “recovering/resolving” when the patient has completed the follow-up period 
and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
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information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or 
until the end of the follow-up period stated in the protocol, whichever comes first, and 
until all queries related to these AEs have been resolved. Cases of chronic conditions, 
cancer or AEs ongoing at time of death (where death is due to another AE) may be 
closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the patient has 
completed the follow-up period and is expected by the investigator to recover.
!
Non-serious AEs fulfilling the AESI criteria: Non-serious AE fulfilling the AESI 
criteria must be followed as specified for non-serious AE. Follow-up information on 
AESIs 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 AESI criteria.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a patient after the patient has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 
!
Concizumab B 100 mg/mL, solution for injection in a 3 ml cartridge
!
NovoPen®4
!
Novo Nordisk needles
!
Turoctocog alfa 2000 IU/vial, powder for solution for injection in a vial  
!
0.9 % sodium chloride 4.0 mL prefilled syringe
!
Novo Nordisk trial injection kit
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which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Centre, Novo Nordisk.
Contact details (fax, e-mail and address)  are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, AESIs and/or 
SAEs.
Technical complaints must be reported on a separate technical complaint form: 
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each batch, code or lot number
must be completed
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not patient related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Centre, Novo Nordisk (the address is provided in Attachment I)  and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. 
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12.5
Pregnancies 
12.5.1
Pregnancies in female partners of male patients
Male patients must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period (from visit 1 to dosing at visit 2). At the last 
scheduled visit, male patients must be asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male patient and assess, if the pregnancy 
outcome is normal or abnormal. 
When the pregnancy outcome is normal this information is recorded in the patient’s medical record 
only, no further information is collected and reported to Novo Nordisk. When the pregnancy 
outcome is abnormal (i.e. congenital anomalies, foetal death including spontaneous abortion and/or 
any anomalies of the foetus observed at gross examination or during autopsy), the following must 
be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
1. Reporting of pregnancy information
Information from the male patient has to be reported on the Paternal Form. Furthermore, 
information from the female partner (including information about the pregnancy outcome and 
health status of the infant until the age of one month) has to be reported on the Maternal Forms 
1A, 1B and 2, after an informed consent has been obtained from the female partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information. 
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
o
Non-serious AEs evaluated as possible/probably related to the father’s treatment 
with the trial product(s). 
o
SAEs in the foetus and newborn infant - whether or not related to the father’s 
treatment with the trial product(s). This includes an abnormal outcome - such as 
foetal death (including spontaneous abortion) and congenital anomalies (including 
those observed at gross examination or during autopsy of the foetus).
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
Paper AE forma within 14 calendar days of the investigator’s first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
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!
Paper AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
Paper safety information form within 5 calendar days of the investigator’s first knowledge 
of the SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information.
a It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
patient, foetus or new born infant. 
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Dose limiting toxicities of concizumab has not been investigated in clinical trials.
There have been no reports about overdosing of concizumab and therefore no experience with 
overdose and overdose reactions exists. In case of a concizumab overdose, symptomatic medical 
treatment according to the clinical condition should be applied. No antidote exists in case of 
concizumab overdose.
Any overdose should be reported as an AE, with or without clinical manifestations. Overdoses are 
considered medication errors.
Treatment should be as appropriate and in accordance with hospital practice and guidelines.
12.7
Rules for putting enrolment on hold
If one of below mentioned criteria is fulfilled, enrolment of additional patients in the clinical trial 
program will be placed on hold. An urgent safety committee meeting will be scheduled to decide 
further actions. Dosing of patients on treatment may continue while further evaluation is made by 
the safety committee. A substantial amendment with relevant data must be submitted to the 
regulatory authorities to support restart of the trial.
!
Significant thromboembolic event* 
!
Event of DIC 
!
Anaphylactic reaction related to trial drug administration 
!
Death of trial patient which may be related to the trial product
!
Two or more other trial product related SAEs similar in nature have been reported and/or 
detected by laboratory measurements
!
Trends in AEs, clinical observations or laboratory parameters which raise concerns about 
the safety of continued treatment
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* Superficial thrombophlebitis or venous thrombosis associated with indwelling catheters is not considered a significant 
thromboembolic event unless evaluated as such by the investigator
12.8
Committees related to safety
12.8.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal concizumab safety committee to perform ongoing safety 
surveillance of safety data relevant to concizumab. The safety committee is a cross functional group 
within Novo Nordisk.
12.8.2
Data monitoring committee
The DMC is an independent, external committee composed of members whose expertise covers 
relevant specialties including statistics. The DMC is established to review and evaluate accumulated 
data from the trial at predefined time points as well as ad-hoc. This is in order to protect the safety 
of the patients and to evaluate the benefit-risk balance. The DMC will have access to the unblinded
data, and will provide recommendations on trial continuation, modification or termination.
In case there is any safety concern data will be compiled and the DMC will review these data. Their 
recommendation will go to the Novo Nordisk Safety committee for final decision of what next step 
is in this trial.
The DMC members will only have direct contact with the Novo Nordisk Global Safety department 
through the safety surveillance representatives, and will have no direct interaction with those in trial 
management. The DMC recommendations should be addressed directly to the Novo Nordisk Global 
Safety department and the internal Novo Nordisk safety committee for concizumab. It is the 
responsibility of the Novo Nordisk internal safety committee for concizumab to take action(s) for
patient safety based on the DMC recommendations.
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter.
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13 Case report forms 
For this trial a combination of electronic case report forms (eCRFs) and paper CRFs will be used.
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
Safety information forms
!
Technical complaint forms 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
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Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
13.3
Electronic diary
Novo Nordisk will provide the patient with an eDiary for electronic recording of details of their 
home treatment, bleeding episodes and treatment of bleeding episodes (i.e. use of FVIII). The 
eDiary and related support services will be supplied by a vendor working under the direction and 
supervision of Novo Nordisk. 
Patients will be instructed in the use of the eDiary by the investigator or delegated person before 
entering of any data. The eDiary will be dispensed to the patient at visit 2. After visit 2 and 
onwards, data will be entered by the patient in the eDiary device during home treatment.
The eDiary will be returned by the patient at the end of trial (EOT) visit.
All data entered will be transferred from the device to an electronic database, where it is kept as a 
certified copy of the source data by the eDiary vendor. Data entered in the device will upon 
confirmation of a successful back-up be deleted from the device. 
The eDiary will have built in edit checks and reminders, to ensure that all relevant questions are 
answered. 
eDiary data transferred to the electronic database will be viewable to relevant trial site staff and 
Novo Nordisk personnel on a secure, password protected web portal.
13.3.1
Investigator review of eDiary data
It is the responsibility of the Investigator or delegated staff to review the eDiary data reported by the 
patient. As a minimum it must be verified that the eDiary data is complete, consistent and according 
to the requirements defined in this protocol. This also includes that the number of doses reported in 
the eDiary is reviewed against the number of vials/cartridge accounted for as used by the patient.  
Upon review the Investigator must document that the review has taken place and any actions 
required e.g. retraining of the patient or decision to amend or correct the data reported by the 
patient. 
If the Investigator finds it necessary to amend or correct eDiary data, the patient must be consulted 
prior to requesting the actual data change. A Data Correction Request must be submitted to the 
eDiary vendor. An audit trail will be maintained.
14 Monitoring procedures 
Monitoring will be conducted using a risk based approach including risk assessment, monitoring 
plans, centralised monitoring and visits to trial sites. During the course of the trial, the monitor will 
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visit the trial site to ensure that the protocol is adhered to, that all issues have been recorded, to 
perform source data verification and to monitor drug accountability. The first monitoring visit will 
be performed as soon as possible after FPFV at the trial site and no later than 4 weeks after. The 
monitoring visit intervals will depend on the outcome of the centralised monitoring of the eCRFs 
(remote assessment of data by Novo Nordisk), the trial site's recruitment rate and the compliance of 
the trial site to the protocol and GCP, but will not exceed 12 weeks until LPLV at the trial site. This 
only applies to sites with scheduled, ongoing and/or discontinued patients.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone or text message).
All data must be verifiable in source documentation other than the eCRF. eDiary data is entered by 
the patient and will also be treated as source data. 
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
For historical data such as medical history, details of haemophilia and haemophilia treatment 
history, a reasonable effort must be made by the investigator, considering local requirements, to 
obtain this information from external sources, if not known by the patient. It is accepted that the 
earliest practically retainable record should be considered as the location of the source data and 
therefore the source document. This means that for laboratory results (e.g. biochemistry and 
haematology) a signed printout of the electronic results must be available.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The monitor will ensure that the eCRFs are completed and paper CRFs (if any) collected, that PROs 
and eDiaries are completed and reviewed by the investigator at the relevant scheduled visits and 
needed action has been taken and documented, if any.
The following data will be source data verified for screening failures:
!
Date for obtaining informed consent
!
Inclusion and exclusion criteria
!
Screen failure reason if possible
!
Date patient left the trial
!
Data relating to AEs if applicable
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!
Demography (See section 8.2.1)
!
Date of visit
Monitors will review the patient’s medical records and other source data (e.g. eDiaries and ePROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract reseach organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of patientdata, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The laboratory will provide all laboratory reports to the investigator for filing at the trial site. The 
laboratory report must be signedand dated by the investigator or delegated person and stored at the 
trial siteas source data.
The patientand any biological material obtained from the patientwill be identified by patient
number and trial ID. Appropriate measures such as encryption orleaving out certain identifiers will 
be enforced to protect the identity of patients in all presentations and publications as required by 
local, regional and national requirements
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk 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 use the Global Haemophilia Network (GHN) Investigator Portal to distribute 
and share trial-related documents and information with the participating sites.
After trial completion, Novo Nordisk will supply each trial site with long-life CDs or other relevant 
electronic archiving containing the electronic Investigator Trial Master File (eITMF) for each trial 
site. These CDs or other relevant electronic archiving will contain site-specific trial documentation 
as well as trial specific news and other relevant trial information, including audit trail on documents 
and site staff users. The GHN Portal software and hardware implementation are compliant with the 
requirements of U.S. Food and Drug Administration (FDA)21 CFR Part 11 and ICH E6 (EU 
directive for personal data protection)1,29.
Novo Nordisk will provide electronic tablets for reporting of all PROs questionnaires described in 
section8.6.1and in Appendix 1. In case the electronic tablet is revoked the questionnaires will be 
available in paper.
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The eDiary software and hardware implementation are compliant with the requirements of FDA 21
CFR Part 11 and ICH E6 (EU directive for personal data protection)1, 29.After trial completion, each 
trial site will be supplied with long-life CDs. These CDs will contain site-specific patient records 
including the patient’s eDiaries and ePROs as PROs are handled seperately from eDiary and audit 
trail including any data additions and corrections made on each form. The eDiary vendor will 
furthermore retain and securely store copies of all archived documents and data for 15 years or as 
required by local data retention laws for trial data
17 Statistical considerations
All endpoints referring to a time frame of at least 24 weeks will be evaluated in the main part of the 
trial, defined to end when the last patient have completed a minimum of 24 weeks of dosing or at 
LPFT (visit 2)+24 weeks if the last patient has withdrawn before visit 9. Please refer to Figure 17–1
for further information. All available data up to the time point where the last patient ends 24 weeks 
of treatment or has withdrawn will in such case be used in the analysis of the main part.
Endpoints comprising number of bleeding episodes will be evaluated based on treated bleeding 
episodes only. Multiple bleeding locations occurring from the same event (e.g., due to a bicycle 
accident) or at the same time point will be counted as one bleeding episode. Further, the endpoints 
will not include re-bleed.
A re-bleed is defined as a bleeding episode (worsening of bleeding site conditions e.g. swelling, 
pain) within 72 hours after stopping treatment of a previous bleeding episode at the same (or subset 
of the same) anatomical location. If a bleeding episode occurs in the same location 72 hours after 
stopping treatment, the bleed is defined as a new bleeding episode.
Clinical proof of concept
The statistical analysis of the collected data aims to establish CPoC that concizumab is efficacious 
in preventing bleeding episodes in haemophilia A patients without inhibitors. The objective will be 
assessed when the last of the 30 patients have completed 24 weeks of dosing (or have withdrawn). 
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the ABR of all patients with a threshold of 12, irrespective of individual dose 
titration. The primary CPoC criterion aims at evaluating the effect of concizumab at the last dose 
level reached for a patient. Hence, for this evaluation, only observations from the period where 
patients are on their end dose at time of analysis will contribute to the analysis. Furthermore, 
observations from the 2 week run-in period will be not be included. Since this evaluation disregards 
a subset of data collected the result should be viewed taking in to account the potential bias. The 
second CPoC criterion aims at evaluating the effect of concizumab when given as an escalation 
regimen. Hence, this will compare the ABR of haemophilia A patients treated with concizumab 
with the typical historical ABR of haemophilia A patients being treated on-demand using all data 
after enrolment. The second CPoC criterion will only be evaluated if the first one succeeds.
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The referred comparisons will be made using a negative binomial model with log of exposure time 
in main phase as offset. For each criterion, evidence of effect will be concluded if the 95% 
confidence interval of the estimated ABR is below 12. 
The value of 12 bleeds per year reflects conservatively a 50% reduction from the bleeding rate 
during on-demand treatment, which in previous trials typically has been reported to be above 30 
bleeds per year 30-32. A confidence limit lower than 12 will also to a certain extent substantiate that 
the prophylactic efficacy of concizumab may be similar to that of FVIII replacement therapy where 
an estimated mean of 6.5 bleeds per year was observed33.
Clinical arguments for the hierarchical test approach
Concizumab exhibits non-linear PK due to target mediated drug disposition and it is expected that 
the dose response curve of the ABR is rather steep. This implies that patients that are on a dose 
which is not efficacious are likely to bleed as patients that are not treated at all. The subset of data 
collected from the last dose clinically deemed as efficacious would reflect the efficacy of 
concizumab in the given patient.
17.1
Sample size calculation
The sample size calculation has been determined taking the small patient population into account, 
while also aiming for an acceptably narrow 95% confidence interval for the ABR. 
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be
accommodated by 30 patients. 
It is expected that the treatment duration of the main part allowing for escalation time for some 
patients is on average 6 months in the below calculations. 
When evaluating the power of the negative binomial analysis referred above, an annual bleeding 
rate of 4 is assumed for the end dose concizumab regimen, respectively in combination with an 
over-dispersion of 6. The power for concluding a bleeding rate lower than 12 then becomes 
approximately 95%. The power under varying values of true ABR and over-dispersion for the 
primary CPoC criterion are shown below in Table 17–1.
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion.
Power
Over-dispersion
ABR
5
6
7
4
99%
95%
92%
5
95%
90%
86%
6
87%
81%
72%
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For the secondary CPoC criterion that includes data prior to potential dose escalation, it is expected 
that the treatment duration of the main part is on average 8 months with an average ABR of 5.4 for 
the concizumab treated patients. This yields a marginal power of approximately 87% for the 
secondary CPoC criterion. 
In prior Novo Nordisk trials conducted in haemophilia patients, the typical 1-year over-dispersion 
for non-inhibitor patients on prophylaxis with FVIII or FIX has been in the range 4-8, implying 24 
weeks over-dispersion of 3-5 (e.g. in NN7008-3543, NN7088-3859 and NN7999-3747). On that 
background, an over-dispersion of 6 over the 24 weeks in the main part of the current trial is 
deemed realistic.
17.2
Definition of analysis sets
All dosed patients will be included in the Full Analysis Set (FAS) as well as in the Safety Analysis 
Set (SAS).
17.3
Primary endpoint
The primary endpoint is the number of bleeding episodes during at least 24 weeks from treatment 
onset.
The primary endpoint will be estimated using negative binomial regression with log of exposure 
time in main phase as offset, providing an actual estimate of the ABR as well as a corresponding 
95% confidence interval.
This analysis has the underlying assumption that the missing data mechanism is “missing at 
random”, i.e. MAR. Under this assumption, the statistical behaviour of the missing data (given the 
observed responses and the mean value structure) is assumed to be the same as for the observed 
data. The endpoint will be estimated based on the full analysis set (FAS) and only data collected 
prior to discontinuation of trial product or initiation of alternative treatment options will be used to 
draw inference.
17.4
Sensitivity analyses
To evaluate the robustness of the MAR assumption implied in the primary analysis, a modified 
tipping point analysis will be performed where patients having discontinued before finalization of 
the main part are assumed to have a worse outcome compared to what was observed during the 
main part of the trial. This will be done by adding a value Δi to the observed bleeding episodes in 
the main part of the trial before analysing the data. The offset is maintained as being the exposure 
during the main phase since it is not possible to identify the amount of missing observation 
time.The degree of worsening, Δi, will gradually be increased to evaluate at which point the upper 
95% confidence limit of the prophylactic concizumab ABR is no longer below a threshold of 12.
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The results of the primary analysis will be considered robust if the tipping point is above what is 
considered clinical plausible.
17.5
Additional analyses
An additional evaluation of the primary endpoint will be made, including actual concizumab dose 
level as additional factor in the primary analysis model specified above. Point estimates and 95% 
confidence interval will be provided for the ABR at the different dose levels of concizumab (0.15, 
0.20 and 0.25 mg/kg). Furthermore, an analysis with individual steady state PK/PD assessments 
included as covariates in the negative binomial regression model as specified for the primary 
analysis will be performed in order to evaluate possible associations between PK/PD and ABR that 
potentially could guide dose-selection. The referred steady-state PK/PD assessments comprise the 
concizumab trough level, maximum plasma concentration (Cmax) of concizumab, TFPI value prior 
to the last s.c. dose administration, peak thrombin generation (nM), Endogenous thrombin potential  
(nM*min) and velocity index (nM/min).
17.6
Secondary endpoints
17.6.1
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during 76 weeks from treatment onset.
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment 
onset.
!
The number of spontaneous bleeding episodes during 76 weeks from treatment onset.
The supportive secondary endpoints will be estimated using the same negative binomial regression 
model as the primary endpoint.
17.6.2
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during 76 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during 76 weeks from treatment onset.
!
Change from baseline of fibrinogen during 24 weeks from treatment onset.
!
Change from baseline of fibrinogen during 76 weeks from treatment onset.
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!
Change from baseline of D-dimer during 24 weeks from treatment onset.
!
Change from baseline of D-dimer during 76 weeks from treatment onset
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset.
!
Change from baseline of F1 + 2 during 76 weeks from treatment onset.
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset.
!
Change from baseline of PT during 76 weeks from treatment onset.
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset.
!
Change from baseline of APTT during 76 weeks from treatment onset.
!
Change from baseline of antithrombin (AT) during 24 weeks from treatment onset.
!
Change from baseline of AT 76 weeks from treatment onset.
Adverse Events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has onset from the first 
exposure to treatment until the last visit in the trial. Treatment-emergent adverse event endpoints 
will be summarised by system organ class, preferred term, seriousness, severity and relation to trial 
product. All Adverse events will further be listed.
Frequency of binding anti-concizumab antibodies will by listed and summarised by time frame 
according to the two endpoint definitions.
All laboratory safety endpoints will be plotted by time, both as absolute values and change from 
baseline. Laboratory safety endpoints will further be summarised and listed.
17.6.3
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks.
!
Concentration of concizumab prior to the last dose administration at 76 weeks.
The pharmacokinetic endpoints will be summarised and listed.
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17.6.4
Supportive secondary pharmacodynamic endpoints
Free TFPI concentration:
!
Value prior to the last dose administration at 24 weeks.
!
Value prior to the last dose administration at 76 weeks.
Thrombin generation:
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks.
!
Peak thrombin generation (nM) prior to the last dose administration at 76 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 76 weeks.
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks.
!
Velocity index (nM/min) prior to the last dose administration at76 weeks.
The PD endpoints will be summarized and listed. 
17.7
Exploratory endpoints
17.7.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
Adverse events related to technical complaints will be listed and summarised.
17.7.2
Exploratory patient reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
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!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Status of PGI-C after 24 weeks from treatment onset
!
!
Change in H-DAT after 76 weeks from treatment onset
!
Patient reported outcomes (PROs) will be collected using questionnaires at visits 1, 2, 4, 5, 6, 7, 8,
9, 10 and 16. 
Patient reported outcome questionnaires to be analysed:
!
Haemophilia Treatment Experience Measure (Hemo-TEM) 
!
Validated Hemophilia Regimen Treatment Aderence Scale – Prophylaxis (VERITAS-Pro®)
or Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
!
36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
!
Patient Global Impression of Change (PGI-C)
!
Sheehan Disability Scale (SDS)16
!
Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
!
Haemophilia - Device Assessment Tool (H-DAT)
!
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
VERITAS-Pro®orVERITAS-PRN®, SF-36v2, SDS, TSQM, H-DAT and SIAQ-ISRQ will be 
scored according to their respective scoring algorithms. Change from visit 2 to visit 9 and change 
from visit 2 to visit 16 will be described.
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17.7.3
Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP  time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
17.8
Interim analysis
The trial does not include a formal interim analysis. However, the split of the trial into a main and 
extension part offers the opportunity of reporting results before the end of the trial. Other reporting 
of the trial might be done during the extension part once the data collection and review of the main 
part data has been finalised and individual clinical study reports might in such case be issued. A 
final clinical study report describing results from the main and extension part will be written when 
the last patient has either completed or withdrawn from the trial.
All main conclusions regarding clinical proof of concept and dose guidance for phase 3 will be 
based on the reporting after the main part, see Figure 17–1.
Figure 17–1
Definition of main and extension part
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18 Ethics
18.1
Benefit-risk assessment of the trial
Benefits
Results from a multiple dose phase 1 trial where concizumab was dosed for approximately 6 weeks 
showed a trend towards efficacy in a limited number of patients who reached concizumab plasma 
concentrations above 100ng/mL., see section 3.1.2. Based on these results, it is expected that the 
majority of the patients treated with concizumab 0.15mg/kg daily dose will be protected from
bleeding episodes. Patients who experience excessive bleeding episodes on the lowest dose will 
have a possibility to be escalated to a higher dose where bleeding preventive efficacy of 
concizumab treatment is expected to improve. Also, concizumab is administered s.c. and might
reduce the burden of frequent i.v. injections associated with current treatment options in
haemophilia A patients without inhibitors as well as significantly reducing the risk of anti-FVIII 
inhibitor development.
Information gained from this trial will contribute to gaining regulatory approval for a product that is 
anticipated to offer clinical advantages over currently available products. 
Risks
No risks have been recognised as identified risks by review of safety data from the activities in the 
clinical development so far. However, the nonclinical toxicity studies have identified 
thromboembolic events as a potential risk when treating non-human primates with concizumab at 
high exposures. 
As observed for other pro-coagulant compounds, there is a potential safety risk of thrombosis and 
vascular ischemia with reaching very high concizumab plasma concentrations. In non-clinical 
toxicity studies with concizumab, thrombi were observed at high doses. However, a no observed 
adverse effect level (NOAEL) for concizumab has been identified in non-haemophilic animals at 
plasma concentrations at least 24 fold higher than the currently anticipated effective plasma 
concentration (mean area under curve [AUC] and Cmax) based on PK modelling.
In clinical trials, except for one case of superficial thrombophlebitis in a healthy volunteer who
received a single dose of 1mg/kg, no other thromboembolic events were observed. A phase 1 
multiple dose trial was finalised in haemophilia A patients (0.8 mg/kg s.c. every 4 days for 6 
weeks). In this clinical trial, marked changes in coagulation parameters were observed including a 
decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range in patients with high plasma concentrations of concizumab. These changes were not 
judged as clinically significant by the investigators and were not followed by thromboembolic AEs 
or an increase in the number of bleeding episodes in the explorer™3 trial.
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Version:
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Status:
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A potential risk identified in non-clinical studies is vascular vessel wall changes due to immune 
complex deposition causing localized vascular vessel wall changes such as hypertrophy and 
inflammatory cell infiltration. Concizumab is a foreign protein to animals and it is generally 
recognized that animal studies are limited in their ability to predict human immune responses to a 
therapeutic protein product. The concentrations of concizumab in plasma in animals in the non-
clinical studies have reached levels far above the anticipated effective concentration. Humans are 
expected to have a very low immunogenic response towards a humanised mAb. The antibodies 
towards concizumab have not been observed so far in clinical trials. Furthermore, even if antibodies 
towards concizumab occur, the risk for the rate of immune complex formation exceeding the 
clearance capacity is considered low. Please refer to the Investigator’s Brochure for further 
information including subsequent replacement therapy.
If antibodies against concizumab develop, they might also inhibit the function of the administered 
drug. The consequence of this could be that the patient may not be able to benefit from this drug in 
the future. Antibody development against concizumab is not expected to reduce the effect of other 
treatment options.
Theoretical risks include bleeding due to consumption of coagulation factors and adverse reactions 
due to potentiation of inflammatory reactions or tissue damage due to impairment of tissue repair 
mechanisms 34 35 . TFPI is an important inhibitor of TF which, in addition to its role in haemostasis, 
is implicated in tissue repair processes and in a variety of physiological and pathophysiological 
states where repair mechanisms are activated. These include sepsis, DIC, inflammation, 
atherosclerosis, cancer and crush injuries 36 37, 38. There may be a risk of allergic reactions, including 
severe (anaphylactic) reactions, in connection with concizumab administration. Severe allergic 
reactions may potentially be life-threatening and thus, the trial products will be administered to the 
trial patients at the site under the surveillance of medically trained trial site staff in the beginning of 
the trial.
Overall the anticipated benefits from participating in the trial outweigh the potential risks.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the patient verbal and written 
information about the trial and the procedures involved in a form that the patient can read and 
understand. 
The patients 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.
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The investigator must ensure the patient ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the patient 
before any trial-related activity.  
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically trained staff in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the investigator must inform the patient in a timely manner, and a revised 
written patient information must be provided and a new informed consent must be obtained.
Only applicable for Japan: As a minor is unable to provide legally binding consent, informed 
consent must be sought from the parent(s)/LAR(s) on the child’s behalf prior to enrolling a child in 
the trial, according to local requirements. 
18.3
Data handling
If the patient withdraws from the trial or is lost to follow up, then the patient’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit will be retained by 
Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to patients during trial
All written information to patients must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the patients 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
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also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of patients who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the patients 
should be described.
19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided and protocol waivers are not acceptable under any 
circumstances.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed. The Sponsor will assess any protocol deviation and 
decide whether any of these non-compliances are likely to affect to a significant degree the safety 
and rights of a patient or the reliability and robustness of the data generated (potential serious 
breach) and if it should be reported to the Regulatory Authorities as a serious breach of GCP and/or
the protocol.
In addition, deviations must be documented and explained in a protocol deviation by stating the 
reason, date, and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The below process will be in place to prevent missing data in this trial.
The importance of patient retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The patients will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of patient retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
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The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
21 Critical documents
An Investigator Portal (Global Haemophilia Network [GHN]) will be used as primary media for 
exchange and handling of investigator trial master file documents between Novo Nordisk and the 
site and for electronic storage of these documents during trial conduct.
Before a trial site is allowed to start screening patients, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, patient information/informed consent form, 
any other written information to be provided to the patient and patient recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure
!
SmPC or similar labelling of rFVIII (turoctocog alfa)
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
Description of research facility obtained (applicable for non-US sites)
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Only applicable for US trial sites: 
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
For local laboratory parameters the following will be collected:
!
Laboratory normal ranges
!
Laboratory certification, quality assurance (QA) scheme or similar documentation
!
Laboratory assay methods (only non-standard assays) and/or analytical methods
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1,
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the patients.
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At least investigator must be trained in the current protocol version at a Novo Nordisk Investigator 
meeting or by the most recent version of the web training. It is recommended that all site staff  
completes the web protocol training.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the patient identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
patients to a specific qualified physician who will be readily available to patients during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
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researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications 39.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure how-we-disclose-trial-information8.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of the main part of the trial and other interim analyses, because the release of such 
information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors 39 (sometimes referred to as the Vancouver 
Criteria).
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23.1.2
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 a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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24 Retention of clinical trial documentation and humanbiosamples
24.1
Retention of clinical trial documentation
Patientsmedical records must be kept for the maximum period permitted by the hospital, institution 
or private practiceaccording to local regulation and practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other patientdata (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
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.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
Applicable only for Spain25 years retention according to the Spanish Royal Decree 1090/2015
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. Thedeletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements. 
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24.2
Retention of human biosamples
This trial will involve collection of human biosamples at visit 1 (screening visit), and at visit 17
(end of trial) and these samples are to be stored maximum 15 years from end of trial. In addition, 
samples which have been drawn as back up samples during the conduct of the trial and have not 
been analysed will be captured and stored under the same conditions. 
Storage of human biosamples is voluntarily and will not affect the patients’ participation in the trial. 
Therefore, patients will have the possibility to sign the informed consent for the trial and 
participate, while refusing permission for biological specimens to be stored for future exploratory 
analysis.
!
Human biosamples will be stored at the central laboratory.
!
1.2 mL citrated plasma, 1.0 mL serum and/or 2.0 ml whole blood (DNA for genotyping)
will be obtained.
!
The intended use of the stored human biosamples e.g.: As new biomarkers related to the 
disease and/or safety, efficacy, or mechanism of action of concizumab may evolve during 
the conduct of the trial, the analyses of the stored human biosamples may also include 
biomarkers that are unknown at present or have not been included in the scientific 
hypotheses at initiation of the trial 
!
Human biosamples may be transferred to third parties e.g. research consortias
!
The human biosamples will be transferred and stored after the end of trial at a designated 
central laboratory
!
Confidentiality and personal data protection will be ensured during storage after the end of 
trial
!
The human biosamples may be transferred to other countries (not applicable if local 
regulations prohibits export of human biosamples)
!
The human biosamples will be destroyed at the latest 15 years from end of trial
!
The patient may request the stored human biosamples to be destroyed by withdrawing 
consent. The results obtained from any already performed analyses of the samples will still 
be used
!
Novo Nordisk and laboratory will have access to the stored human biosamples 
!
Potential consequences for the patient and their relatives: In the event that the collected 
human biosamples (plasma, serum and/ or DNA for genotyping) will be used in the future, 
the investigator will become directly informed by Novo Nordisk about the results if the 
findings are deemed clinically relevant and analytically valid and quantifiable. In such case, 
a written summary of the findings, including listings of patient specific values, will be 
provided once a firm conclusion from the results has been drawn by Novo Nordisk. 
Potentially, observations of neoplastic diseases, serious hereditary diseases, other un-
treatable diseases, or any other abnormal findings could be part of the observations. Patients 
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can contact the investigator if they wish to be informed about results derived from stored 
human biosamples obtained from their own body. See also Section 5.1.
24.2.1
Antibody samples
Antibody samples will be retained until drug approval by U.S. Food and Drug Administration 
(FDA) and/or European Medicines Agency (EMA). 
The retained antibody samples may be used for later analysis for further characterisation of 
antibody responses towards drug if required by health authorities or for safety reasons. The samples 
will be stored at a central bio-repository after end of trial and until marketing authorisation approval 
or until the research project terminates, but no longer than 15 years from end of trial after which 
they will be destroyed.
The patients’ identity will remain confidential and the antibody samples will be identified only by 
patient number, visit number and trial identification number. No direct identification of the patient 
will be stored together with the samples.
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples.
Patients can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body.
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: Updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the patients, new information that may affect adversely the safety of the patients or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the patients), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC (not 
applicable for Japan).
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the patients.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
Only applicable for France: The French Public Health Code article L 1121-10 (law no 2004-806 of 
9 August 2004 art. 88 I, IX, Journal Officiel of 11 August 2004. “The sponsor is responsible for 
identification of the harmful consequences of the biomedical the research for the person lending 
himself thereto and for indemnification of his beneficiaries, except in case of proof, incumbent on 
it, that the prejudice is not attributable to his fault or of the fault of any intervening party, without 
the sponsor’s being entitled to call on acts by a third party or the voluntary withdrawal of the person 
who had initially consented to cooperating in the research”.
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27 References
1.
International Conference on Harmonisation. ICH Harmonised Tripatite Guideline. Guideline 
for Good Clinical Practise E6(R2), Step 4. 09 Nov 2016.
2.
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013.
3.
International Organization for Standardization. ISO 14155:2011, Clinical investigation of 
medical devices for human subjects - Good clinical practice. 01 Feb 2011.
4.
Soucie JM, Evatt B, Jackson D. Occurrence of hemophilia in the United States. The 
Hemophilia Surveillance System Project Investigators. Am J Hematol. 1998;59(4):288-94.
5.
White GC, 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J, et al. 
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.
6.
Hoffman M, Monroe III. A cell-based model of hemostasis. Thrombosis and haemostasis. 
2001;85(6):958-65.
7.
Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003;361(9371):1801-9.
8.
Novo Nordisk Code of Conduct for Clinical Trial Disclosure. Avaliable from: 
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QualityMetric Incorporated2013.
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Date:
18 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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123 of 124
16.
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treatment satisfaction questionnaire for medication (TSQM version II) among outpatient 
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an abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) among 
patients on antihypertensive medications. Health Qual Life Outcomes. 2009;7:36.
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Am Coll Cardiol. 2011;58(19):2020-45.
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Date:
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Trial ID:NN7415-4255
Version:
3
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 
study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 
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Valentino LA, Mamonov V, Hellmann A, Quon DV, Chybicka A, Schroth P, et al. A 
randomized comparison of two prophylaxis regimens and a paired comparison of on-
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Lentz SR, Misgav M, Ozelo M, Salek SZ, Veljkovic D, Recht M, et al. Results from a large 
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Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2016.
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Protocol
Trial ID: NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of Prophylactic 
Administration of Concizumab in Patients with Severe Haemophilia A 
without Inhibitors
Trial phase: 2
Protocol Version 1 (15 March 2017); Protocol Amendment no 1 (05 May 2017) and Protocol 
Amendment no 2 (14 Dec2017) for all participating countries. 
Protocol originator
, 
Biopharm, Trial 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.
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
2 of 124
Table of Contents
Page
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................7
Table of Tables............................................................................................................................................7
List of abbreviations ...................................................................................................................................9
1
Summary............................................................................................................................................15
2
Flow chart ..........................................................................................................................................18
3
Background information and rationale for the trial.........................................................................21
3.1
Background information..........................................................................................................21
3.1.1
Haemophilia ..........................................................................................................21
3.1.2
Concizumab...........................................................................................................22
3.2
Rationale for the trial...............................................................................................................24
4
Objective(s) and endpoint(s)..............................................................................................................26
4.1
Objective(s) ............................................................................................................................26
4.1.1
Primary objective...................................................................................................26
4.1.2
Secondary objectives .............................................................................................26
4.2
Endpoint(s) .............................................................................................................................26
4.2.1
Primary endpoint ...................................................................................................26
4.2.2
Secondary endpoints ..............................................................................................26
4.2.2.1
Supportive secondary endpoints .......................................................26
4.2.3
Exploratory endpoints............................................................................................27
4.2.3.1
Exploratory safety endpoints ............................................................27
4.2.3.2
Exploratory patient-reported outcome endpoints...............................28
4.2.3.3
Exploratory pharmacokinetic and pharmacodynamic endpoints ........28
5
Trial design ........................................................................................................................................29
5.1
Type of trial ............................................................................................................................29
5.1.1
Surgery..................................................................................................................30
5.2
Rationale for trial design .........................................................................................................30
5.3
Treatment of patients...............................................................................................................33
5.3.1
Dose escalation......................................................................................................34
5.3.2
Treatment of bleeding episodes during the trial ......................................................35
5.3.3
Prohibited medication ............................................................................................35
5.4
Treatment after discontinuation of trial product .......................................................................36
5.5
Rationale for treatment............................................................................................................36
6
Trial population .................................................................................................................................37
6.1
Number of patients..................................................................................................................37
6.2
Inclusion criteria .....................................................................................................................37
6.3
Exclusion criteria ....................................................................................................................37
6.4
Criteria for premature discontinuation of trial product .............................................................38
6.5
Withdrawal from trial..............................................................................................................38
6.6
Patient replacement .................................................................................................................39
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Protocol
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Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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6.7
Rationale for trial population...................................................................................................39
7
Milestones...........................................................................................................................................40
8
Methods and assessments ..................................................................................................................41
8.1
Visit procedures ......................................................................................................................41
8.1.1
Informed consent, long-term storage consent..........................................................42
8.1.2
Screening log, enrolment log, trial card and patient number....................................42
8.1.3
Screening failures and re-screening........................................................................42
8.1.4
Premature discontinuation of trial product..............................................................43
8.1.5
Withdrawal from trial.............................................................................................43
8.1.6
Review/evaluation of clinical outcome...................................................................43
8.1.7
Visit 1 (Screening part)..........................................................................................44
8.1.8
Training of patients visit 1 and visit 2.....................................................................45
8.1.9
Treatment period - Main part..................................................................................45
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site) ......................45
8.1.9.2
Treatment period at home.................................................................46
8.1.9.3
Visit 3 (Phone visit)..........................................................................46
8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits) .........................................47
8.1.9.5
Visit 9 (Assessment visits)................................................................48
8.1.10
Extension Part........................................................................................................49
8.1.10.1
Visit 10 (Assessment visits)..............................................................49
8.1.10.2
Visit 11, 12, 13, 14 and 15 (Assessment visits) .................................50
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) -
Extension part ..................................................................................50
8.1.11
Follow-up Part.......................................................................................................51
8.1.11.1
Visit 17 (End of trial) .......................................................................51
8.1.12
Unscheduled Visit..................................................................................................52
8.1.12.1
Unscheduled 24 hour PK-Visit .........................................................52
8.2
Patient related information/assessments...................................................................................53
8.2.1
Demography ..........................................................................................................53
8.2.2
Concomitant illness and medical history other than haemophilia ............................53
8.2.3
Concomitant medication ........................................................................................53
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History .......................54
8.3
Efficacy assessments...............................................................................................................55
8.3.1
Bleeding episodes ..................................................................................................55
8.4
Safety assessments ..................................................................................................................59
8.4.1
Physical examination .............................................................................................59
8.4.2
Body measurements...............................................................................................59
8.4.3
Vital signs..............................................................................................................59
8.4.4
Electrocardiogram..................................................................................................60
8.4.5
Adverse events.......................................................................................................60
8.4.5.1
Medication error...............................................................................60
8.4.5.2
Adverse events requiring additional data collection ..........................61
8.5
Laboratory assessments...........................................................................................................62
8.5.1
Laboratory assessments for efficacy.......................................................................63
8.5.1.1
Thrombin generation........................................................................63
8.5.1.2
Free TFPI.........................................................................................64
8.5.2
Laboratory assessments for safety ..........................................................................64
8.5.2.1
Urinalysis.........................................................................................64
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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8.5.2.2
Haematology....................................................................................64
8.5.2.3
Biochemistry....................................................................................65
8.5.2.4
FVIII activity ...................................................................................65
8.5.2.5
Coagulation parameters....................................................................65
8.5.2.6
FVIII inhibitor test ...........................................................................66
8.5.2.7
Anti-concizumab antibodies .............................................................66
8.5.2.8
Concizumab ELISA .........................................................................68
8.5.2.9
Total TFPI........................................................................................69
8.5.3
Human biosamples.................................................................................................69
8.6
Other assessments ...................................................................................................................69
8.6.1
Patient reported outcomes ......................................................................................69
8.6.2
Training.................................................................................................................71
8.6.2.1
Concizumab and NovoPen® 4...........................................................71
8.6.2.2
Turoctocog alfa ................................................................................71
8.6.2.3
eDiary..............................................................................................71
8.6.3
Surgery..................................................................................................................72
8.7
Patient compliance..................................................................................................................72
8.8
Treatment compliance:............................................................................................................72
9
Trial supplies......................................................................................................................................73
9.1
Trial products..........................................................................................................................73
9.2
Labelling.................................................................................................................................73
9.3
Storage....................................................................................................................................74
9.4
Drug accountability and destruction ........................................................................................75
9.5
Auxiliary supplies ...................................................................................................................75
10
Interactive voice/web response system ..............................................................................................76
11
Randomisation procedure and breaking of blinded codes................................................................77
Randomisation.....................................................................................................................................77
12
Adverse events, and technical complaints .........................................................................................78
12.1
Definitions ..............................................................................................................................78
12.1.1
Adverse event ........................................................................................................78
12.1.2
Serious adverse event.............................................................................................79
12.1.3
Non-serious adverse event......................................................................................80
12.1.4
Medication errors...................................................................................................80
12.1.5
Adverse events requiring additional data collection................................................81
12.1.6
Adverse event of special interest ............................................................................82
12.1.7
Technical complaints .............................................................................................86
12.2
Reporting of adverse events.....................................................................................................86
12.3
Follow-up of adverse events....................................................................................................88
12.4
Technical complaints and technical complaint samples............................................................89
12.4.1
Reporting of technical complaints ..........................................................................89
12.4.2
Collection, storage and shipment of technical complaint samples ...........................90
12.5
Pregnancies.............................................................................................................................91
12.5.1
Pregnancies in female partners of male patients......................................................91
12.6
Precautions and/or overdose....................................................................................................92
12.7
Rules for putting enrolment on hold ........................................................................................92
12.8
Committees related to safety ...................................................................................................93
12.8.1
Novo Nordisk safety committee .............................................................................93
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CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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12.8.2
Data monitoring committee....................................................................................93
13
Case report forms ..............................................................................................................................94
13.1
Corrections to case report forms..............................................................................................94
13.2
Case report form flow .............................................................................................................94
13.3
Electronic diary.......................................................................................................................95
13.3.1
Investigator review of eDiary data..........................................................................95
14
Monitoring procedures ......................................................................................................................95
15
Data management ..............................................................................................................................98
16
Computerised systems .......................................................................................................................98
17
Statistical considerations ...................................................................................................................99
17.1
Sample size calculation .........................................................................................................100
17.2
Definition of analysis sets......................................................................................................101
17.3
Primary endpoint...................................................................................................................101
17.4
Sensitivity analyses...............................................................................................................101
17.5
Additional analyses...............................................................................................................102
17.6
Secondary endpoints .............................................................................................................102
17.6.1
Supportive secondary efficacy endpoints..............................................................102
17.6.3
Supportive secondary pharmacokinetic endpoints.................................................103
17.6.4
Supportive secondary pharmacodynamic endpoints..............................................104
17.7
Exploratory endpoints ...........................................................................................................104
17.7.1
Exploratory safety endpoints................................................................................104
17.7.2
Exploratory patient reported outcome endpoints...................................................104
17.7.3
Exploratory pharmacokinetic and pharmacodynamic endpoints............................106
17.8
Interim analysis.....................................................................................................................106
18
Ethics................................................................................................................................................107
18.1
Benefit-risk assessment of the trial ........................................................................................107
18.2
Informed consent ..................................................................................................................108
18.3
Data handling........................................................................................................................109
18.4
Information to patients during trial ........................................................................................109
18.5
Premature termination of the trial and/or trial site..................................................................109
19
Protocol compliance.........................................................................................................................110
19.1
Protocol deviations................................................................................................................110
19.2
Prevention of missing data ....................................................................................................110
20
Audits and inspections .....................................................................................................................112
21
Critical documents...........................................................................................................................112
22
Responsibilities.................................................................................................................................113
23
Reports and publications .................................................................................................................114
23.1
Communication of results......................................................................................................115
23.1.1
Authorship...........................................................................................................115
23.1.2
Site-specific publication(s) by investigator(s).......................................................116
23.2
Investigator access to data and review of results ....................................................................116
24
Retention of clinical trial documentation and human biosamples..................................................117
24.1
Retention of clinical trial documentation ...............................................................................117
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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24.2
Retention of human biosamples.............................................................................................118
24.2.1
Antibody samples ................................................................................................119
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........120
26
Indemnity statement ........................................................................................................................121
27
References ........................................................................................................................................122
Appendix I Patient Reported Outcome
Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments, if applicable for the individual 
country
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
7 of 124
Table of Figures
Page
Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous 
(circles) and traumatic (triangles) bleeding episodes during the dosing period and 
follow-up period.................................................................................................................24
Figure 5–1
Schematic diagram of the trial design .................................................................................29
Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated 
patients in explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal 
lines indicate 100 ng/mL, and the shaded areas represent the full range (min-max) of the 
individual predicted profiles. ..............................................................................................31
Figure 5–3
Dose escalation of concizumab for one individual patient...................................................35
Figure 8–1
Overview of visit structure in explorer™5 ..........................................................................41
Figure 12–1
Reporting of AEs ...............................................................................................................88
Figure 17–1
Definition of main and extension part...............................................................................106
Table of Tables   
Page
Table 2–1
Flow chart..........................................................................................................................18
Table 2–2
Flow chart explanatory descriptions....................................................................................20
Table 5–1 
List of products provided by Novo Nordisk ........................................................................33
Table 8–1
Definition of stop of bleeding episode ................................................................................56
Table 8–2
Definitions of bleeding episodes (cause of bleed)................................................................56
Table 8–3
Definition of bleeding episode severity and treatment recommendation ..............................56
Table 8–4
Guide for dosing in bleeding episodes and surgery .............................................................58
Table 9–1
Trial products.....................................................................................................................73
Table 9–2
Storage conditions..............................................................................................................74
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion..........................100
Table 2–1
Flow chart..........................................................................................................................18
Table 2–2
Flow chart explanatory descriptions....................................................................................20
Table 5–1 
List of products provided by Novo Nordisk ........................................................................33
Table 8–1
Definition of stop of bleeding episode ................................................................................56
Table 8–2
Definitions of bleeding episodes (cause of bleed)................................................................56
Table 8–3
Definition of bleeding episode severity and treatment recommendation ..............................56
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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Table 8–4
Guide for dosing in bleeding episodes and surgery .............................................................58
Table 9–1
Trial products.....................................................................................................................73
Table 9–2
Storage conditions..............................................................................................................74
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion..........................100
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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List of abbreviations
ABI
ankle-brachial index
ABR
annualised bleeding rate 
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest 
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
antithrombin
AUC
area under curve
BP
blood pressure
BU
Bethesda unit
CLAE
clinical laboratory adverse event
Cmax
maximum plasma concentration
CNS
central nervous system
concizumab B
the name concizumab is being used as an 
abbreviation for concizumab B. B is the 
formulation 
CPoC
clinical proof of concept
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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CRF
case report form
CRO
contract research organisation
CRP
c-reactive protein
CT
computerized tomography
cTn
cardiac troponin
CTR
clinical trial report
DFU
direction for use
DIC
disseminated intravascular coagulation
DMC
data monitoring committee
DUN
dispensing unit number
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EMA
European medicines agency
EOT
end of trial
ETP
endogenous thrombin potential 
FAS
full analysis set
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
Page:
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FDA
U.S. Food and Drug Administration
FDAAA
U.S. Food and Drug Administration 
Amendment Act
FIX
coagulation factor IX
FPFV
first patient first visit
FVIII
coagulation factor VIII
FX
coagulation factor X
FXa
activated coagulation factor X
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GHN
global haemophilia network
HCP
host cell protein
H-DAT
Haemophilia Device Assessment Tool
Hemo-TEM
Hemophilia Treatment Experience Measure
IB
investigator’s brochure
IC
informed consent 
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal 
Editors
ID
identification
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
12 of 124
IEC
independent ethics committee
IgG4
immunoglobulin G4
IMP
investigational medicinal product
INN
International Non-Proprietary Names for 
Pharmaceutical Substances 
IRB
institutional review board
ISTH
International Society on Thrombosis and 
Haemostasis
ISRQ-SIAQ
Injection Site Reaction Questionnaire-Self-
Injection Assessment Questionnaire
i.v.
intravenous(-ly)
IWRS
interactive web response system
LBBB
left bundle branch block
LPFV
last patient first visit
LPLV
last patient last visit
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory 
Activities
MI
myocardial infarction
MRA
magnetic resonance angiogram
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
13 of 124
MRI
magnetic resonance imaging
NIMP
non investigational medicinal product
PCD
PD
primary completion date
pharmacodynamic
PEF
peak expiratory flow
PK
pharmacokinetic
PGI-C
Patient’s Global Impression of Change
PP
per protocol
PRO
patient reported outcome
PT
prothrombin time
QA
Q4D
quality assurance
every 4th day
rFVIII
the name ‘rFVIII’ will be used throughout 
the protocol and the product is identical to 
‘turoctocog alfa’
SAE
serious adverse event
SAS
safety analysis set
sBE
s.c.
spontaneous Bleeding Episode
subcutaneous(-ly)
SDS
Sheehan Disability Scale
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
14 of 124
SF-36v2
36-Item Short Form Health Survey
SI
international system of units
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse 
reaction
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
TF
tissue factor
TFPI
tissue factor pathway inhibitor
TG
thrombin generation
TMM
trial materials manual
TPA
trial product administration
TSQM
Treatment Satisfaction Questionnaire for 
Medication
UTN
Universal Trial Number
VERITAS-Pro®
Validated Hemophilia Regimen Treatment 
Adherence Scale-Prophylaxis
VERITAS-PRN® 
Validated Hemophilia Regimen Treatment 
Adherence Scale-Pro Re Nata
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
15 of 124
1
Summary
The main objective for the phase 2 trial NN7415-4255, explorer™5, is to assess the efficacy of 
concizumab administered s.c. once daily to prevent bleeding episodes in patients with severe 
haemophilia A without inhibitors. Furthermore, this trial aims to assess the longer-term efficacy and 
safety of concizumab in severe haemophilia A patients without inhibitors. 
Objective(s) and endpoint(s):
Primary objective 
!
To assess the efficacy of concizumab administered  s.c. once daily in preventing bleeding 
episodes in patients with severe haemophilia A without inhibitors 
Secondary objectives 
!
To assess the longer-term efficacy of concizumab in patients with severe haemophilia A without 
inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without 
inhibitors
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset.
Key secondary endpoints
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of treatment emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset.
Time frames for evaluation of objectives/endpoints:
All endpoints referring to the time frame of at least 24 weeks will be evaluated in the main part of 
the trial, defined to end when the last patient has completed a minimum of 24 weeks of treatment 
with trial product (or have withdrawn). In addition, number of bleeding episodes during 76 weeks 
of treatment with prophylactic concizumab will be analysed. The extension part of the trial will 
provide additional safety and long-term efficacy data.
Trial design:
The trial is a multi-centre single arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation) administered daily s.c. in patients with 
severe haemophilia A without inhibitors. This is done by comparing the annual bleeding rate (ABR) 
to an ABR of 12.The selected dose regimen is based on relevant PK and TFPI data as well as 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
16 of 124
pharmacokinetic/pharmacodynamic (PK/PD) modelling from the preceding explorer™ trials. Both 
on-demand and prophylaxis patients will be eligible for the trial.
The total trial duration for the individual patient will be approximately 86 weeks, consisting of a 2 
week screening period, a subsequent 76 week treatment period and an 8 week follow-up period. 
The 76 weeks treatment period is split into a main part which lasts at least 24 weeks and an 
extension part which lasts up to 52 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 30 patients have completed at least 24 weeks of concizumab 
dosing or have discontinued trial treatment. The analysis of the main part of the trial aims to 
substantiate clinical proof of concept (CPoC) that concizumab has the potential to prevent bleeding 
episodes in severe haemophilia A patients without inhibitors. 
rFVIII (turoctocog alfa) for treatment of breakthrough bleeding episodes will be provided by Novo 
Nordisk during the trial. The patient will not be provided with trial product or rFVIII (turoctocog 
alfa) after the end of the trial.
Trial population:
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product: 33
Number of patients expected to complete the trial: 30
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine the 
suitability for the trial
!
Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at screening
Key exclusion criteria
!
Known or suspected hypersensitivity to trial product(s) or related products
!
Known inherited or acquired bleeding disorder other than haemophilia A
!
Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at 
screening measured by the Nijmegen method 
Key Efficacy assessment
!
The number of bleeding episodes during at least 24 weeks.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
17 of 124
Key Safety assessment
!
Number of TEAEs during at least 24 weeks.
Trial product(s):
The following products will be used in the trial:
!
Investigational Medicinal Product (IMP):
Concizumab B, 100 mg/mL to be administered s.c. with NovoPen®4 and needles 
!
Non Investigational Medical Product (NIMP):
Turoctocog alfa (rFVIII) 2000 IU/vial and isotonic sodium chloride (solvent). Turoctocog 
alfa (rFVIII) is for intravenous administration.
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CONFIDENTIAL


Protocol
UTN:U1111-1179-3872
Date:
28 December 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
4.0
Page:
18 of 124
2
Flow chart
Table 2–1
Flow chart
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
Timing of visit (d) d
14 to 21 days 
before Visit2
1
8
29
57
85
113
141
169
225
281
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 21 days 
before Visit 
2
0
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not applicable
-7
Treatment week (w)
---
0
1w
4w
8w
12w
16w
20w
24w
32w
40w
48w
56w
64w
72w
76w
---
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/Genotyping and Long-term storage consent
●
In/exclusion criteria
●
●e
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial 
product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
EFFICACY ASSESSMENTS 
Bleeding episodes f, g
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab)
●
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
Free TFPI (central lab)  
●
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
SAFETY ASSESSMENTS
Physical examination
●
●
●
●
●
●
●
Body measurements 
●
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
Vital signs
●
●j
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Biochemistry (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII activity (central lab)
●k
●l
Coagulation parameters (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII inhibitors (central lab)
●
●l
Anti-concizumab antibodies (ADA) (special lab)m
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Concizumab ELISA (special lab)
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
Total TFPI (special lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
TRIAL MATERIALS
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Protocol
UTN:U1111-1179-3872
Date:
28 December 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
4.0
Page:
19 of 124
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
IWRS call
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab, turoctocog alfa) (IWRS)
●n
●
●
●
●
●
●
●
●
●
●
●
●
●
●n
●
Administration of trial product (concizumab) 
●o
Drug Accountability (concizumab, turoctocog alfa) 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product c, p
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires
●
●
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
Hand out ID Card 
●
Training (trial product, e-Diary and NovoPen® 4) q
●
●
●
Compliance (e-Diary)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
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Protocol
UTN:U1111-1179-3872
Date:
28 December 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
4.0
Page:
20 of 124
Table 2–2
Flow chart explanatory descriptions
Footer
Description
a
Concizumab administration is performed at home except for visit 2 where concizumab administration will take place at the trial site.
b
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 will be 
a phone call to the patient. 
c
For patients being dose escalated a phone call is recommended 1 week after first new dose of concizumab.
d
Daily dosing preferably at the same time in the morning.
e
Evaluation of laboratory results obtained from samples taken at screening.
f
Bleeding episodes occurring between visit 1 and visit 2 or at site should be registered in the eCRF. All bleeding episodes except for severe occurring after visit 
2 at home should be registered in the eDiary. Severe bleeding episodes must be registered in the eCRF.
g
Turoctocog alfa will be given to treat breakthrough bleeding episodes either in the clinic or at home.
h
At visit 9 and 16 all blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been performed.
For unscheduled PK-session visit; patients must not treat themselves with concizumab until pre-dose sampling for thrombin generation, concizumab ELISA 
and Free TFPI has been collected.
i
Only body weight should be measured.
j
Vital signs should be evaluated before and after trial drug administration at visit 2. 
k
Sampling for FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours and medical records documenting the severity of 
haemophilia are not available.
l
FVIII activity and FVIII inhibitor tests should only be collected if reduced effect of turoctocog alfa or FVIII inhibitor development is suspected.
m
In case of clinical signs of e.g. hypersensitivity reactions or immune related events are seen, additional samples for ADAs may be taken. All antibody samples 
from the affected patient will be analysed on an ongoing basis. If antibodies are detected additional samples will be taken and stored for characterisation of the 
antibodies.
n
Only dispensing of turoctocog alfa and sodium chloride.
o
The trial patient must be in a non-bleeding state at the time of the first trial product administration (TPA), and should not have received any haemostatic drug
(e.g. FVIII) for prophylaxis or treatment of a bleeding episode within a period of 48 hours prior to first TPA.
p
Patient should be dose escalated at next scheduled visit if he experiences ≥3 spontaneous bleeding episodes within the preceding 12 weeks of treatment with 
concizumab. If investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose escalation.
q
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Home treatment training comprises handing out of Direction 
for Use (DFU), training in administration of concizumab with NovoPen®4, turoctocog alfa and data entry in eDiary. Further the patients will be trained in 
recognition of signs/symptoms of thrombosis.
r
In case patients are participating in the 24 hour PK-session the sampling time points for thrombin generation, concizumab ELISA and Free TFPI are: pre-dose 
(-1 hour), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (± 20 min) and 24h (± 20 min). All time points, except pre-dose, occur after 
concizumab administration
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
21 of 124
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP)1 and applicable regulatory requirements, and in 
accordance with the Declaration of Helsinki2 and ISO 141553.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
The International Non-Proprietary Names for Pharmaceutical Substances (INN) name of the active 
pharmaceutical ingredient is concizumab (synonyms used during early development are NNC0172-
2021, anti-TFPI, NN7415 or mab2021). Throughout this document “concizumab” is used as the 
name of the trial drug.
3.1
Background information
3.1.1
Haemophilia
Haemophilia is an inherited bleeding disorder characterised by an increased bleeding tendency, 
typically in weight bearing joints. Haemophilia A is caused by a partial or complete deficiency of 
blood coagulation factor VIII (FVIII) and haemophilia B is caused by defect factor IX (FIX).  
Inheritance is chromosome X-linked and recessive; therefore the disease mainly affects males. The 
incidence of haemophilia A and B on average is estimated to be about 1 in 5000 live male births4. 
According to the World Federation of Haemophilia global survey of 2014, about 178,500 persons 
are diagnosed with haemophilia worldwide. Of these, about 80% have haemophilia A.
Haemophilia is classified as “severe”, “moderate” or “mild” according to the plasma activity level 
of the affected coagulation factor5.With a deficiency of FVIII or FIX, the degree of activation of 
coagulation factor X (FX) becomes insufficient. Consequently, the thrombin burst is delayed and 
insufficient for normal haemostasis6.The haemostatic plug, if formed, in these patients is fragile and 
easily dissolved by normal fibrinolytic activity. This leads to impaired haemostasis and spontaneous 
prolonged bleeding episodes. In severe haemophilia, bleeding in joints occurs spontaneously and is 
the most frequent symptom of the disease. Recurrent bleeding episodes in the same location - most 
commonly a weight bearing joint - lead to chronic arthropathy, muscular atrophy and deformities. 
Treatment of bleeding episodes as they manifest (on-demand treatment) may delay arthropathy, but 
does not prevent it. The majority of children with severe haemophilia experience their first bleeding 
episode in a joint prior to the age of 4 years. Many children also bleed from other body sites, also 
before this age is reached7. For this reason, primary prophylaxis treatment with regular FVIII 
injections in the non-bleeding state is the recommended from early childhood.
The most common complication of replacement therapy is development of antibodies binding to 
FVIII. These binding antibodies might neutralise the exogenous of FVIII and are then called
inhibitors. In patients who have developed inhibitors towards FVIII, replacement therapy is 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
22 of 124
rendered ineffective. These patients may be treated with bypassing agents, recombinant FVII 
(NovoSeven®) and activated prothrombin complex concentrate (FEIBA®) given as intravenous 
(i.v.) injections.
Current treatment options in haemophilia A, includes replacement therapy or by-passing therapy are 
hampered by the fact that these products must be given as i.v. injections. Bypassing agents are 
characterized by relatively short half-lives, therefore prophylactic treatment is burdensome. A new 
therapeutic agent that can be administered subcutaneously will represent a major improvement in 
the treatment of these patients in a prophylaxis setting. 
3.1.2
Concizumab
The trial product, concizumab, is a humanised recombinant monoclonal antibody (mAb) of the 
immunoglobulin G4 (IgG4) isotype with a molecular weight of 149 kilo Daltons. Like other 
antibodies, concizumab is composed of two light chains and two heavy chains linked together by 
disulfide bridges. To prevent formation of half-antibodies, the serine at position 241 in the heavy 
chain has been replaced with a proline (S241P (Kabat annotation)) . The mechanism of action of 
concizumab is based on the concept of inhibiting the activity of a natural coagulation inhibitor, 
tissue factor pathway inhibitor (TFPI). TFPI is a potent inhibitor of the initiation phase of the 
coagulation process, i.e. the activation of FX to FXa by the tissue factor (TF)/factor VIIa (FVIIa) 
complex. TFPI first binds to and inhibits activated FXa and subsequently binds to and inhibits the 
TF/FVIIa complex, forming a TF/FVIIa/FXa/TFPI complex. Thus, concizumab prevents both 
inhibition of FXa and inhibition of FVIIa/TF by TFPI. In this manner, sufficient amounts of FXa to 
ensure effective haemostasis in the absence of a functional activated factor IX/activated factor VIII 
(FIXa/ FVIIIa) complex may be generated. This is a new concept that remains to be documented 
safe and efficacious in patients with haemophilia. More information about the physiological role of 
TFPI and the mode of action of concizumab is provided in the Investigator’s Brochure (IB). 
Key differentiator is thus a new mode of action (MoA), and the key benefit of concizumab in 
patients with severe haemophilia A is reduced treatment burden due to subcutaneous (s.c.) 
administration potentially leading to better adherence, more patients on prophylactic treatment and 
ultimately better outcome.
Four clinical trials with concizumab have been completed thus far: the first-human-dose trial 
(NN7415-3813, explorer™1), a single dose trial in Japanese healthy subjects (NN7415-3981), a 
multiple dose trial NN7415-3986 (explorer™2), and NN7415-4159 (explorer™3). When the first 
cohort with four healthy subjects in explorer™2 was completed, prior to the initiation of the 2nd 
cohort, the trial was halted due to findings related to thrombosis in an ongoing 26-week toxicity 
study in primates. In this study animal had plasma concentrations several hundred folds above 
clinically relevant concentrations. Follow up investigations confirmed that the animal’s condition 
was related to thrombosis in the lungs caused by exaggerated pharmacology at these high plasma 
concentrations. Before the initiation of the fourth phase 1 trial (, explorer™3) a new 52-week non-
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
23 of 124
clinical toxicology study was conducted in primates to investigate the findings in the previous 
study. The conclusion from this new non-clinical study was that the results from non-clinical 
studies support further clinical development of concizumab. Explorer™3 was a multiple-dose 
clinical trial, which aimed to investigate the safety, pharmacokinetics and pharmacodynamics of 
concizumab at five different dose levels in adult severe haemophilia A patients without inhibitors. 
In this trial multiple doses of concizumab were administered s.c. over a period of six weeks. Doses 
of up to 0.8 mg/kg administered every four days did not raise safety concerns and a decision not to 
dose-escalate to a 1.1 mg/kg dose-cohort was taken. For further information, please refer to the 
Investigator’s Brochure.
The explorer™3 trial was finalised following the completion of cohort 3 (0.8 mg/kg sc every 4 days 
for 6 weeks). Blinded preliminary safety and PK/PD data from the cohort was reviewed by the 
concizumab safety committee. Marked changes in coagulation parameters were observed including 
a decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range. In addition, a substantial inter subject variation in pro-coagulant response to the drug 
was observed. Based on this, the Novo Nordisk safety committee (see section 12.8.1) decided not to 
proceed to cohort 4 (1.1 mg/kg sc every 4 days for 6 weeks). No clinical consequences or serious 
adverse were seen in the completed cohorts in explorer3.
The PK results from explorer™3 showed exposure-response in terms of fewer bleeding episodes 
recorded for patients who reached plasma concentrations of concizumab above 100 ng/mL. 
Individual predicted PK profiles merged with recorded spontaneous and traumatic bleeding 
episodes are shown in Figure 3–1.
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Date:
28 December 2017
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Trial ID:NN7415-4255
Version:
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Status:
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Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous (circles) and 
traumatic (triangles) bleeding episodes during the dosing period and follow-up period. 
All data originates from explorer™3 (N=24 patients). PK of concizumab is subdivided into three exposure levels of 
≤20 ng/mL, 20-100 ng/mL, and > 100 ng/mL together with the number of contributing patients. LLOQ: lower limit of 
quantification. a ‘Time in trial’ refers to the time that the patients spent on each concizumab exposure level, and the 
≤20 ng/mL level therefore also includes the screening period (not shown on this figure).
A large difference between the peak and trough plasma concentrations of concizumab were 
observed as well, especially in the highest dose group (0.80 mg/kg) of explorer™3. In patients who 
received 0.25, 0.5 and 0.8 mg/kg doses a significant overlap in plasma concentrations of 
concizumab was seen due to high between-patient variability in concizumab.
Single doses of concizumab up to 9 mg/kg have been administered to haemophilia patients in the 
first human dose trial with concizumab, explorer™1. These doses resulted in plasma concentrations 
of concizumab that were significantly higher than the ones that are modelled to be reached in the 
highest escalated daily dose (0.25 mg/kg) of explorer™5.
For an assessment of benefits and risks of the trial, see Section 18.1.
For further information, please refer to the Investigator’s Brochure.
3.2
Rationale for the trial
Four phase 1 clinical trials with concizumab have been finalised. Key safety and preliminary 
efficacy results from these phase 1 trials support further development of concizumab in haemophilia 
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patients. Therefore, the main objective in the phase 2 of concizumab development is to assess 
efficacy and safety and provide data that will guide for the confirmatory phase 3 concizumab trials. 
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Date:
28 December 2017
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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4
Objective(s) and endpoint(s)
4.1
Objective(s)
4.1.1
Primary objective
!
To assess the efficacy of concizumab administered s.c. once daily in preventing bleeding 
episodes in patients with severe haemophilia A without inhibitors
4.1.2
Secondary objectives
!
To assess the long-termer efficacy of concizumab in patients with severe haemophilia A 
without inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without 
inhibitors
4.2
Endpoint(s)
4.2.1
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset
!
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary endpoints
!
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during 76 weeks from treatment onset
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of  spontaneous bleeding episodes during 76 weeks from treatment onset
!
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during 76 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during 76 weeks from treatment onset
!
!
Change from baseline of fibrinogen during 24 weeks from treatment onset
!
Change from baseline of fibrinogen during 76 weeks from treatment onset
!
Change from baseline of D-dimer during 24 weeks from treatment onset
!
Change from baseline of D-dimer during 76 weeks from treatment onset
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Date:
28 December 2017
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Trial ID:NN7415-4255
Version:
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Status:
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!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset
!
Change from baseline of F1 + 2 during 76 weeks from treatment onset
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset
!
Change from baseline of PT during 76 weeks from treatment onset
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset
!
Change from baseline of APTT during 76 weeks from treatment onset
!
Change from baseline of antithrombin (AT) during 24 weeks from treatment onset
!
Change from baseline of AT 76 weeks from treatment onset
!
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks
!
Concentration of concizumab prior to the last dose administration at 76 weeks
Supportive secondary pharmacodynamic endpoints
Plasma free TFPI concentration
!
Value prior to the last dose administration at 24 weeks 
!
Value prior to the last dose administration at 76 weeks 
Thrombin generation
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks 
!
Peak thrombin generation (nM) prior to the last dose administration at 76 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 76 weeks 
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks 
!
Velocity index (nM/min) prior to the last dose administration at 76 weeks 
4.2.3
Exploratory endpoints
4.2.3.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
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Date:
28 December 2017
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Trial ID:NN7415-4255
Version:
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4.2.3.2
Exploratory patient-reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Status of PGI-C after 24 weeks from treatment onset
!
Change in H-DAT after 76 weeks from treatment onset
4.2.3.3
Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP  time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
All endpoints referring to a time frame of either 24 weeks or of at least 24 weeks will be evaluated 
in the main part of the trial. 
All endpoints referring to a time frame of 76 weeks will be evaluated in the extension part of the 
trial.
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Date:
28 December 2017
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Trial ID:NN7415-4255
Version:
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5
Trial design
5.1
Type of trial
The trial is a multicentre single-arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation to 0.20 and 0.25 mg/kg) administered daily 
s.c. in patients with severe haemophilia A without inhibitors. The selected dose regimen is based on
relevant PK and TFPI data as well as PK/PD modelling from the preceding explorer™ trials. Both
on-demand and prophylaxis patients will be eligible for the trial.
Figure 5–1
Schematic diagram of the trial design
The total trial duration for the individual patient will be approximately 86 weeks, including a 2-
week screening period, a subsequent 76-week treatment period and an 8-week follow-up period, see 
Figure 5–1.
The76 weeks treatment periodis further split into a main part which lasts at least 24 weeks for all 
patients in the trial and an extension part which lasts 52 weeks.After completion ofthe main part of 
the trial, patients will continue into the extension part. All available data up to the time point where 
the last patients ends 24 weeks of treatment (or have withdrawn) will be used in the analysis of the 
main part, see Section 17.7.
Breakthrough bleeding episodes occurring from visit 1 to end-of-trial visit will be treated by the 
patients at home with FVIII at the discretion of the investigator, who will also choose dose levels. 
Only turoctocog alfa/NovoEight®will be provided and paid by Novo Nordisk for this purpose.
The analysis of the main part (after 24 weeks) of the trial aims to substantiate CPoC that 
concizumab has the potential to prevent bleeding episodes in patients with severe haemophilia A 
without inhibitors. The extension part will provide additional safety data on 52 weeksdosing of 
concizumab.
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Date:
28 December 2017
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Version:
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Status:
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Human biosamples (plasma, serum, and/or DNA for genotyping) will be collected in this trial  for
future exploratory analysis to pursue a deeper insight into the biology of TFPI, coagulation, and 
effect of concizumab on joint health that may include coagulation parameters and markers of joint 
status or damage. Acceptance of storage of human biological specimens is voluntary and will not 
affect the patients’ participation in the trial. Therefore, patients will have the possibility to sign the 
informed consent for the trial and participate, while refusing permission for biological specimens to 
be stored for future exploratory analysis. Please refer to Section 24.1 for further information.
An independent data monitoring committee (DMC) will be established for this trial. The DMC will 
review all safety data from all ongoing trials with concizumab exposure, see Section 12.8.2.
All patients will be asked to perform a 24 hour PK-session after treatment with concizumab is 
initiated.
5.1.1
Surgery
Minor surgery is allowed in this trial. Major surgery conducted more than one month (30 days) 
prior to trial start is allowed, see exclusion criterion no 6.
Minor surgery is defined as an invasive operative procedure where only the skin, the mucous 
membranes or superficial connective tissue is manipulated. Examples of minor surgery include 
implanting of central venous access devices (ports, CVC, pumps and other CVADs) in 
subcutaneous tissue, skin biopsies or simple dental procedures.
5.2
Rationale for trial design
Explorer™5 is a phase 2, clinical proof of concept (CPoC) and safety trial. The trial aims to 
substantiate CPoC that concizumab has the potential to prevent bleeding episodes in haemophilia 
patients without inhibitors. A dose escalation design will allow cautious dose escalation in order to 
choose the efficacious and safe concizumab dose for the individual patient from the selected dose 
regimenConcizumab 0.15 mg/kg (with two potential dose-escalation steps, 0.20mg/kgand 0.25 
mg/kg) given s.c. once daily will be investigated.
The duration of 24 weeks for the main part of the trial is deemed necessary in order to obtain 
information on the annual bleeding rate (ABR)during concizumab prophylaxis. The duration of the 
extension part of the trial will be 52 weeks and will provide further information on long-term 
efficacy, i.e. ABR, and also provide additional safety data upon 76 weeks treatment with 
concizumab.
A total of 33 patientsare planned to receive concizumab s.c.once daily in this single arm trial,
please see Figure 5–1.
The concizumab dose regimentswill be startingwith0.15 mg/kg with the possibilityto escalate to 
0.20 mg/kg and 0.25 mg/kg, see section 5.3.1.
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Date:
28 December 2017
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Trial ID:NN7415-4255
Version:
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Status:
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Daily dosing with 0.15 mg/kg aims to ensure steady-state levels of concizumab plasma 
concentrations above 100 ng/mL for the majority of the patients starting on this dose. The PK 
results from explorer™3 showed exposure-response in terms of fewer bleeding episodes recorded 
for patients who reached plasma concentrations of concizumab above 100 ng/mLsee Figure 3–1. 
The minority of patients which are predicted to have steady-state plasma concentrations below this 
threshold are expected to experience bleeding episodes and therefore will have the opportunity to be 
dose-escalated to the dose of 0.2 mg/kg. A further dose escalation to 0.25 mg/kg per day is 
permitted, again based on the bleeding rate,see section 5.3.1.
Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated patients in 
explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal lines indicate 100 ng/mL, 
and the shaded areas represent the full range (min-max) of the individual predicted profiles1.
1 Plasma concentrations in the same range as those in explorer™3 are expected to be reached in this trial with daily dose 
administration. The starting dose for all patients will be 0.15 mg/kg daily. The plasma steady-state exposure for a typical subject at 
this dose level is predicted to fourfold lower compared to a typical subject on 0.8 mg/kg Q4D (cohort 3 of explorer3) in terms of both 
Cmax and AUC 0-24h. For 0.20 mg/kg daily and 0.25 mg/kg, the plasma steady-state exposure levels for a typical subject are 
predicted to be less than 40% and 70% respectively, compared to the typical subject exposure in the 3rd cohort of explorer™3 (AUC 
and Cmax). The maximum predicted plasma exposure levels (Cmax and AUC 0-24h) for the 0.15 mg/kg daily dose level is predicted 
to be more than 8 fold lower than for 0.80 mg/kg Q4D. For 0.20 mg/kg daily both Cmax and AUC 0-24h are predicted to be more 
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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Due to the high between-patient variability in concizumab concentration observed in explorer™3, a 
significant overlap in plasma concentrations of concizumab in patients who received 0.25, 0.5 and 
0.8 mg/kg doses was seen, see Figure 5–2. Therefore, choosing three doses that would lead to 
reasonably distinct mean plasma concentrations of concizumab, and thus different efficacy at each 
dose level was not deemed possible. For this reason, a traditional parallel arm design was not 
chosen for the phase 2 trials. In contrast, the titration trial design allows patients to start on a low 
dose, which is expected to ensure prophylaxis but not marked changes in coagulation parameters, 
for the majority of patients. Escalation to the next dose level will only occur in the case of lack of 
efficacy (≥3 spontaneous bleeding episodes within the preceding 12 weeks. In addition, the PK of 
concizumab is heavily influenced by target mediated drug disposition, which means that small 
differences in concizumab dose ultimately leads to large differences in plasma concentrations. 
Therefore, daily dosing is proposed for the phase 2 trial, explorer™5. Daily dosing will allow for 
the increase in trough levels and thus better efficacy may be expected with a lower dose. 
Embryonic exposure in pregnant female partners of men treated with concizumab is highly unlikely 
and there is no need for protocol requirements for use of contraception in phase 2 and 3 trials.
                                                                                                                                                           
than 3 times lower than for 0.80 mg/kg Q4D. For 0.25 mg/kg daily, the maximum Cmax and AUC 0-24h are predicted to be 35 % 
lower than for 0.80 mg/kg Q4D.
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Date:
28 December 2017
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Trial ID:NN7415-4255
Version:
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5.3
Treatment of patients
Table 5–1
List of products provided by Novo Nordisk
Compound Name 
Strength
Dosage form 
Route of 
administration
Treatment period
Concizumab B2, 
100 mg/mL
3 mL solution in 
a 3 mL 
cartridge3. 
S.c.
administration
using NovoPen® 4
For prophylactic 
treatment for 76 
weeks. 
Turoctocog alfa 
(NovoEight®)4, 
Sodium chloride 
solution 4ml  
2000 
IU/vial
Powder for 
solution for 
injection
Solvent for 
solution for i.v. 
injection used 
for 
reconstitution of 
turoctocog alfa.
I.v. administration
For treatment of 
breakthrough 
bleeding episodes 
(or prophylaxis in 
the screening and 
follow-up phases), 
at the discretion of 
the treating 
physician (patients 
may choose to use 
other familiar pre-
trial FVIII drug).
For further 
information see 
section 5.3.2
Concizumab will be given s.c., once daily for a total dosing period of 76 weeks. 
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. It will be labelled in accordance with national legislation and a copy of the label can 
be found within the Trial Materials Manual, see Section 9.1.
The first dose of concizumab will be given at the trial site under medical supervision. After the 
initial dose the patient must be observed for potential emergence of AEs/safety signals for at least 2 
hours at the trial site. At the screening visit and the first scheduled treatment visit patients will be 
trained in s.c. administration of concizumab with NovoPen® 4 and in the use of eDiary.
Investigational medicinal product (IMP)
3 Not to be confused with the daily injected volume (~150 μL, depending on dose strength and body weight)
4 Non-investigational medicinal product (NIMP)
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Version:
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In case safety concerns meet the criteria(See section12)for putting enrolment of additional 
patients on hold,further enrolment in the trial will be halted. Dosing of patients on treatment may 
continue while further evaluation is made by the safety committee. In case of other safety concerns 
all available datawill be evaluated by the DMCsee Section 12.8.2.
5.3.1
Dose escalation
Bleeding episodes will be assessed during the trial both at scheduled visits and also between visits.
The first 2 weeks of the treatment with concizumab 0.15 mg/kg is considered as a run-in period. 
Hence the bleeding episodes occurring during the first 2 weeks should not influence a dose 
escalation decision.
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (first-dose visit) 
until visit 16 (end-of-treatment visit), i.e. a total of 74 weeks. Dose-escalation will be based on the 
number of spontaneous, treated bleeding episodes in patients within preceding 12 weeks. However, 
before dose-escalation can occur, to ensure the safety of the patients, the investigator must take into 
account the full clinical picture the patient is presenting with and all available laboratory results, 
including coagulation parameters.
Dose 0.15 mg/kg:
When a sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the preceding 
12 weeks since visit 2+2weeks (including the current sBE). If yes, and if investigator deems it safe, 
the patient will have to be dose escalated from 0.15 to 0.20 mg/kg at the next scheduled visit. If the 
investigator judges that this visit is scheduled too late, he/she should contact the patient for an 
unscheduled visit.
Dose 0.20 mg/kg:
When an sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the 
preceding 12 weeks (including the current sBE), counting only new sBEs from the beginning of the 
0.20 mg/kg treatment period. If yes, and if investigator deems it safe, the patient will have to be 
dose escalated from 0.20 to 0.25 mg/kg at the next scheduled visit. If the investigator judges that 
this visit is scheduled too late, he/she should contact the patient for an unscheduled visit.
Dose 0.25 mg/kg:
Patients are not dose escalated further regardless of the number of sBEs. When an sBE occurs, the 
investigator will determine if ≥ 3 sBEs have occurred within the preceding 12 weeks (including the 
current sBE), counting only the new sBEs from the beginning of the 0,25mg/kg treatment period. If 
yes, then the patient must be discontinued from treatment due to lack of efficacy, see Section 6.4.
Since the patient may have to wait up to 8 weeks for the next scheduled visit (in the extension part), 
the possibility of dose escalation at unscheduled visits is necessary for the dose-escalation eliciting 
bleeding episode to occur soon after previous scheduled visit.
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Version:
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Figure 5–3
Dose escalation of concizumab for one individual patient
5.3.2
Treatment of bleeding episodes during the trial
Bleeding episodes (main part, extension part, and follow-up part) :
Breakthrough bleeding episodes during the course of the trial will be treated at the discretion of the 
treating physician, with either turoctocog alfa/Novoeight®(rFVIII)  (provided by Novo Nordisk)  or 
other non-modified FVIII products(not provided by Novo Nordisk) .Treatment dose ischosen at 
the discretionof the investigator;however; in this trial any given single dose should not exceed 50 
IU/kg (Table 8-4).  The patient can treat himself and then he must call the site.  The bleeding 
episodesmust be recorded in the eDiary. Bleeding episodes must be recorded in the electronic case 
report form (eCRF) as an AE/SAE if fatal, life threatening or evaluated as related to trial product 
(see section 12.1)
FVIII prophylactic treatment (follow-up part) :
During the follow-up part of the trial (i.e. from concizumab end-of-treatment visit to end-of-trial 
visit) patients will receive pre -trial FVIII medication at the discretion of the treating investigator, 
who will also choose dose levels. Only turoctocog alfa/NovoEight®will be provided by Novo 
Nordisk for this purpose.
5.3.3
Prohibited medication 
!
Treatment with anti-fibrinolytics (e.g. tranexamic acid, aminocaproic acid)*
!
Heparin, except for sealing of central venous access ports according to local practice
!
Vitamin-K antagonists
!
Direct oral anti-coagulants (DOACs)
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Version:
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!
Modified FVIII products with extended half-life
*Local/topical use is allowed. Use of single systemic doses in severe bleeding episodes, after 
careful benefit-risk evaluation, is allowed.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products the patient should be switched to a suitable marketed product at 
the discretion of the investigator. The patient will not be provided with concizumab or FVIII 
(turoctocog alfa/NovoEight®) by Novo Nordisk after end of trial (visit 17). 
5.5
Rationale for treatment
Concizumab is a monoclonal antibody and as such offers the possibility of s.c. administration. S.c. 
administration of an effective prophylactic drug has potential to reduce treatment burden 
significantly compared to the currently approved prophylactic drugs which have to be administered 
i.v.
The treatment period of 24 weeks (the main part of the trial) is considered necessary for providing 
data that allow demonstration of CPoC and to support decision-making regarding a phase 3 
confirmatory trial. Dosing for an additional 52 weeks will provide valuable long-term efficacy and 
safety.
Breakthrough bleeding episodes may occur during prophylactic regimens with conventional FVIII 
replacement therapy. Therefore, it is expected that breakthrough bleeding episodes will also occur 
during prophylaxis with concizumab even if clinical proof of concept is demonstrated. 
Consequently turoctocog alfa (FVIII) will be provided by Novo Nordisk A/S in this trial for 
treatment of breakthrough bleeding episodes. 
Patients are not obliged to use turoctocog alfa (FVIII) and can use their previously used FVIII 
concentrate for treatment of breakthrough bleeding episode. Novo Nordisk A/S will not provide or 
reimburse these products.
Please refer to the Investigator’s Brochure for further information.
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Date:
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Trial ID:NN7415-4255
Version:
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product(s): 33
Number of patients planned to complete the trial: 30
Discontinued patients will not be replaced.
6.2
Inclusion criteria
For an eligible patient, all inclusion criteria must be answered “yes”.
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at 
screening.
3. For patients being treated on-demand with FVIII replacement therapy, a minimum of six 
documented and treated bleeding episodes during the 24 weeks (or twelve bleeds during 52 
weeks) prior to screening.
6.3
Exclusion criteria
For an eligible patient, all exclusion criteria must be answered “no”.
1. Known or suspected hypersensitivity to trial product(s) or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within the last 30 days or 5 half-lives (whichever is longer) from the last drug 
administration before screening.
4. Any disorder, which in the investigator’s opinion might jeopardise patient’s safety or 
compliance with the protocol.
5. Known inherited or acquired bleeding disorder other than haemophilia A.
6. Major surgery conducted within one month prior to the initiation of trial activities or major 
surgery planned to occur during the trial.
7. Previous history of thromboembolic disease. Current clinical signs of thromboembolic 
disease, or patients who in the judgement of the investigator are considered at high risk of 
thromboembolic events.
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Date:
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Version:
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8. Mental incapacity, unwillingness to cooperate or language barrier precluding adequate
understanding and cooperation.
9. Patients who, at screening, have a significant infection or known systemic inflammatory
condition which require systemic treatment according to the investigator’s judgement.
10. Hepatic dysfunction defined as elevated liver transaminases (ALT) >3 times the upper limit
of normal laboratory reference ranges at screening.
11. Renal impairment defined as estimated glomerular filtration rate (eGFR) ≤60
mL/min/1.73m2 based on serum creatinine measured at screening or evidence of renal
damage.
12. Platelet count ≤ 100x109/L at screening.
13. Fibrinogen level < the lower limit of normal at screening
14. Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at
screening measured by the Nijmegen method.
15. History of inhibitors towards FVIII based on investigator’s knowledge or documentation in
available medical records.
6.4
Criteria for premature discontinuation of trial product
The patient may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
The patient must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria
2. Simultaneous participation in another clinical trial of an approved or non-approved
investigational medicinal product.
3. Incapacity or unwillingness to follow the trial procedures
4. Anaphylactic reaction
5. Thromboembolic event
6. Event of disseminated intravascular coagulation (DIC)
7. Development of inhibitors to Factor VIII (≥0.6 BU)
8. Lack of efficacy due to neutralising antibodies towards concizumab
9. Lack of efficacy defined as ≥3 treated sBEs within the previous 12 weeks in patients being
treated with the highest dose level (0.25 mg/kg) of concizumab.
See Section8.1.4 for procedures to be performed for patients discontinuing trial 
product prematurely.
6.5
Withdrawal from trial
The patientmay withdraw consent at will at any time.
See Section 8.1.5for procedures to be performed for patients withdrawing 
consent.
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Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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6.6
Patient replacement
Patients who discontinue trial product prematurely will not be replaced.
6.7
Rationale for trial population 
The most important reason for choosing the trial population, haemophilia A without inhibitors, is 
that there is a significant unmet medical need in this patient population for a treatment option which 
reduces the burden associated with the current care, including small volume s.c. administration 
instead of i.v. Finally, the trial population reflects the patient population that will be selected in a 
potential subsequent phase 3 trial in which the efficacy and safety of concizumab is to be 
confirmed.
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CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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7
Milestones
Planned duration of recruitment period first patient first visit – last patient first visit (FPFV-LPFV): 
4 months
Planned FPFV: 
16-Aug-2017
Planned FPFT: 
30-Aug-2017
Planned LPFV: 
16-Dec-2017
Planned LPLV: 
11-Sep-2019
The total duration of concizumab treatment in the trial is 76 weeks for an individual patient enrolled 
in the trial for concizumab treatment at visit 2.
End of trial is defined as last patient last visit (LPLV).
Recruitment:
The screening and enrolment rate will be followed closely via the interactive web response system 
(IWRS) in order to estimate when to stop screening. All investigators will be notified immediately 
when the recruitment period ends, after which no further patients may be screened and the IWRS 
will be closed for further screening. All patients screened during the recruitment period and found 
eligible for enrolment can be enrolled within the timelines specified in the flow chart (see Section 
2).
Trial registration:
Information about the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and clinical 
trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure, how-we-
disclose-trial-information8, it will also be disclosed according to other applicable requirements such 
as those of the International Committee of Medical Journal Editors (ICMJE) 9, the Food and Drug 
Administration Amendment Act (FDAAA)10 , European Commission Requirements 11, 12 and other 
relevant recommendations or regulations 13. If a patient requests to be included in the trial via the 
Novo Nordisk e-mail contact at these web sites, Novo Nordisk may disclose the investigator’s 
contact details to the patient. As a result of increasing requirements for transparency, some 
countries require public disclosure of investigator names and their affiliations.
Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
protocol Last Patient First Treatment LPFT (visit2) + 24 weeks ( i.e. last patient visit 9) If the last 
patient is withdrawn early the PCD is the date when the last patient would have completed visit 9. 
The PCD determines the deadline for results disclosure at ClinicalTrials.gov according to 
FDAAA.10
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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8
Methods and assessments
Assessments to be performed at the scheduled and at unscheduled visits in this trial are described in 
this sectionand in the trial flow chart (section 2) .
Figure 8–1
Overview of visit structure in explorer™5
8.1
Visit procedures
For each patient the trial consists of the following scheduled parts and visits:
Screening Part:
Visit 1 (screening visit)
Main Part:
Visit 2 (1st treatment visit with concizumab at site)
Home treatment with concizumab daily
Visit 3 (phone visit with site)
Visit 4 (Assessment visit, patients treat themselves at home)
Visit 5 (Assessment visit, patients treat themselves at home)
Visit 6 (Assessment visit, patients treat themselves at home)
Visit 7 (Assessment visit, patients treat themselves at home)
Visit 8 (Assessment visit, patients treat themselves at home)
Visit 9 (Assessment visit, after the visit patients treat themselves at home)
Extension Part:
Visit 10 (Assessment visit, patients treat themselves at home)
Visit 11 (Assessment visit, patients treat themselves at home)
Visit 12 (Assessment visit, patients treat themselves at home)
Visit 13 (Assessment visit, patients treat themselves at home)
Visit 14 (Assessment visit, patients treat themselves at home)
Visit 15 (Assessment visit, patients treat themselves at home)
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Date:
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Version:
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UTN:U1111-1179-3872
Status:
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Visit 16 (Assessment visit and End of treatment)
Follow-up part
Visit 17 (Assessment visit and End of trial)
Unscheduled visits can occur e.g. for dispensing of trial products, when an assessment of bleeding 
episodes is necessary at site or at the discretion of the investigator.
The duration of the visits (V1-V17) will depend on the assessments and the patient’s individual 
training and/or discussion need on concizumab administration, NovoPen® 4, usage of e-Diary, 
completion of the patient reported outcome (PRO) etc.
8.1.1
Informed consent, long-term storage consent
Informed consent must be obtained before any trial related activity, see Section 18.2.
The trial includes a separate informed consent for long-term storage of human biosamples, see 
Section 24.2. 
Storage of human biosamples and genotyping is voluntary and will not affect the patients’ 
participation in the trial. Therefore, patients will have the possibility to sign the informed consent 
for the trial and participate, while refusing permission for biological specimens and /or genotyping 
to be stored for future exploratory analysis.
8.1.2
Screening log, enrolment log, trial card and patient number
The investigator must keep a patient screening log, a patient identification (ID) code list and a 
patient enrolment log. Only patients who have signed the informed consent form should be included 
on the logs. The patient screening log and patient enrolment log may be combined in one log.
At screening, patients will be provided with a card stating that they are participating in a trial and 
given contact address(es) and telephone number(s) of relevant trial clinic staff. Patients should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each patient will be assigned a unique 6-digit patient number which will remain the same 
throughout the trial.
8.1.3
Screening failures and re-screening
For screening failures the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial. Serious and non-serious adverse events 
from screening failures must be transcribed by the investigator into the eCRF. Follow-up on serious 
adverse events (SAEs) must be carried out according to Section 12.
A screening failure session must be made in the IWRS. The case book must be signed in the eCRF.
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Trial ID:NN7415-4255
Version:
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Status:
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Re-screening is NOT allowed if the patient has failed one of the inclusion or exclusion criteria; this 
includes re-sampling if the patient has failed one of the inclusion or exclusion criteria related to 
laboratory parameters.
8.1.4
Premature discontinuation of trial product
If a patient prematurely discontinues trial product, the investigator must undertake procedures 
similar to those for visit 9 (the last treatment in the main part) or visit 16 (the last treatment visit in 
the extension part) as soon as possible. The follow up visit (visit 17) must be performed 8 weeks 
(window minus 7 days) after last dose of trial drug.
The primary reason for premature discontinuation of trial product must be specified in the end of 
treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
Permanent premature discontinuation of treatment with trial product will lead to patient withdrawal 
from the trial.
8.1.5
Withdrawal from trial
If a patient withdraws consent, the investigator must aim to undertake procedures similar to those 
for visit 9 (the last visit in the main part) or visit 16 (the last visit in the extension part) as soon as 
possible depending on where the patient is in the trial schedule.
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the patient is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS and the case book must be signed in the eCRF.
Although a patient is not obliged to give his reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the patient’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.6
Review/evaluation of clinical outcome
Novo Nordisk has constituted an internal concizumab safety committee and established an external 
DMC to perform ongoing safety surveillance of safety data relevant for concizumab, see Section 
12.8.
Review of eDiary data and laboratory reports etc. must be documented either on the documents or 
in the patient’s medical record.
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Date:
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Version:
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If unclear entries or discrepancies in the eDiary or PRO are identified and a clarification is needed, 
the patient must be asked for clarification and a conclusion made in the patient’s medical record. 
Care must be taken not to bias the patient.
8.1.7
Visit 1 (Screening part)
Informed consent must be obtained before any trial related activity, see Section 18.2.
In cases where a patient's baseline FVIII level is not documented in medical records, sampling for 
FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours.
Screening can take place between 14 to 21 days prior to planned enrolment day (visit 2). For 
prophylactic treatment (prior to Screening) with extended half-life FVIII products, this period 
should be extended to a time-period equal to 8 half-lives of the used product
All assessments to be performed at screening are listed in Table 2–1, see Section 2.
Apart from informed consent patients will be asked to complete the ePRO questionnaires before any 
other trial related activities are performed according to Section 8.6;
!
Hemo-TEM,
!
VERITAS-Pro® orVERITAS-PRN®
Assessment results from physical examination, body measurements, as well as measurements of 
vital signs, urinalysis electrocardiogram (ECG) and details of any contemporary adverse events 
must be entered into the eCRF.
A screening confirmation call must be performed in the IWRS, at the day of the visit.
The investigator must review all information obtained from the screening procedures. If a patient
does not meet all inclusion criteria or meets one or more of the exclusion criteria for the trial the 
patient does not qualify to be enrolled.
Patients will be provided with turoctocog alfa (rFVIII) trial injection kits and directions for use 
(DFU) to cover the potential FVIII treatment in the screening part of the trial and investigator will 
ensure that the patients are capable of treating themselves with rFVIII (turoctocog alfa). Patients on 
any previous FVIII prophylaxis can continue with this treatment until 48 hours before visit 2.
Dispensing of rFVIII (turoctocog alfa) should be performed in the IWRS
For bleeding episodes that occur in the period from Screening visit (Visit1) to enrolment visit (Visit 
2) information about the bleeding episode is to be entered in the eCRF at visit 2.
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Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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The patient should be instructed to call the site if any bleeding episodes, questions or issues arise 
after he has left the site.
8.1.8
Training of patients visit 1 and visit 2
During the site visits 1 and 2 patients must be trained in self administration of concizumab in the 
home setting using NovoPen® 4. The dose of concizumab to be administered must be 
communicated to the patient at visit 2. Furthermore patients must be instructed and trained in the 
importance and reporting of all home treatment with concizumab, details of the bleeding episodes 
and the turoctocog alfa (FVIII) treatment associated with these bleeding episodes in the eDiary,(See 
section 8.6.2).
Patients should be trained on how to recognize and react to signs of thromboembolic events, so that 
the patient without any delay contacts the site.
8.1.9
Treatment period - Main part
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site)
Visit 2 should be scheduled 14 to 21 days after visit 1. The date of visit 2 will be considered as trial 
day 1.
Before any concizumab administration it is important to verify the in/exclusion criteria again and 
review central laboratory test results from screening. 
The patient must be in a non-bleeding state at the time of first administration with concizumab and 
should not have received any FVIII treatment for prophylaxis or for treatment of a bleeding episode 
within a period of 48 hours prior to dosing.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
Hemo-TEM,
o
SF-36v2,
o
SDS,
o
TSQM,
o
SIAQ-ISRQ
All protocol assessments must be performed before 1st administration of concizumab. Vital signs 
must be assessed both before and after concizumab administration.
Assessment results from concomitant medication, vital signs, Body measurements (weight only)
and details of adverse events must be entered into the eCRF.
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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At this, the 1st treatment visit, the allocated dose of concizumab will be given. Concizumab will be 
administered at the trial site supervised by medically trained trial staff.
The time point at which the completion of the first dose takes place corresponds to Time on 
treatment = 0 and must be recorded in the eCRF.
The patient must be observed at the trial site for at least 2 hours after the administration of the first 
dose of concizumab.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.
Investigator will communicate any the daily dose of concizumab to the patient and record the dose 
for the coming home treatment period in the eCRF. 
Prior to the first dose a dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits as well as an eDiary device to be able to conduct and report 
home treatment until the next scheduled visit.
The patient will be reminded to report bleeding episodes and home treatment in the eDiary device.
The patient will be asked to return all used, partly used and unused turoctocog alfa (FVIII) during 
the trial as instructed by the investigator. Drug accountability must be performed for turoctocog alfa
(rFVIII), including injection kits if applicable, according to section 9.4. Unused sodium chloride 
syringes should be returned to site at every visit and new sodium chloride syringes should be 
dispensed to the patient.
8.1.9.2
Treatment period at home
Home treatment is defined as self-administration of trial product, performed independently by the 
patient, preferablyin the morning.Home treatment starts after visit 2 or when the patient is 
comfortable self-administrating trial product subcutaneously (concizumab)  and intravenously 
(turoctocog alfa(FVIII) ) .
8.1.9.3
Visit 3 (Phone visit)
Visit 3 is to be scheduled as a phone contact (or similar)  7days after visit 2 (with a visit window of 
+1 day) .
All relevant protocol assessments listed in table 2-1 must be discussed. Assessment results from 
concomitant medication and details of adverse events must be entered into the eCRF.
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CONFIDENTIAL
Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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Patients should be informed to treat themselves at home according to the dosing schedule regardless 
of when visits 4, 5, 6, 7 and 8 are scheduled. 
8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits)
Visits 4, 5, 6, 7 and 8 are to be scheduled on trial day 29 (4 weeks), day 57 (8 weeks), day 85 (12 
weeks), day 113 (16 weeks) and day 141 (20 weeks) respectively with a visit window of ± 7days.
Patients should treat themselves at home according to the dosing schedule regardless of when visits 
4, 5, 6, 7 and 8 are scheduled
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6;
o
PGI-C
o
Hemo-TEM
Assessments are to be performed according to Table 2–1and the assessment results from 
concomitant medication, vital signs, Body measurements (weight only) and details of adverse 
events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewingcollected data from the eDiary.Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab dosesis needed 
according the escalationrules described in section 5.3.1. All decisionsto escalate the concizumab 
dosemust be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable.Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
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CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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At visit 8 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 9.
8.1.9.5
Visit 9 (Assessment visits) 
Visit 9 is to be scheduled on trial day 169 (24 weeks) with a visit window of ± 7days.
Treatment with concizumab must take place after the blood sampling at this visit.
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
PGI-C
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
Assessments are to be performed according to Table 2–1and the assessment results from physical 
examination, concomitant medication, vital signs, Body measurements (weight only) and details of 
adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through the available access to collected data from the eDiary. Based on the assessment of any 
spontaneous bleeding episodes the investigator must evaluate if an escalation of the concizumab 
doses is needed according the escalation rules described in section 5.3.1. All decisions to escalate 
the concizumab dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
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At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
8.1.10
Extension Part
8.1.10.1
Visit 10 (Assessment visits) 
Visit 10is to be scheduled on trial day 225 (32 weeks), with a visit window of ± 7days.
Assessments are to be performed according to the flowchart section 2 and the assessment results 
from concomitant medication, vital signs, Body measurements (weight only)and details of adverse 
events must be entered into the eCRF.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performedaccording tosection 8.6.1;
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
SIAQ-ISRQ
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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8.1.10.2
Visit 11, 12, 13, 14 and 15 (Assessment visits)
Visits 11 to 15 are to be scheduled on trial day 281 (40 weeks), day 337 (48 weeks), day 393 (56 
weeks), day 449 (64 weeks) and day 505 (week 72) respectively with a visit window of ± 7days.
Assessments are to be performed according to Table 2–1 and the assessment results from physical 
examination (applicable for V12), concomitant medication, vital signs, Body measurements (weight 
only) and details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
At visit 15 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 16.
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) - Extension part
Visit 16 is to be scheduled on trial day 533 (76 weeks) with a visit window of ± 7days.
Visit 16 should be scheduled to be conducted at the last day of treatment with concizumab.
Treatment with concizumab must take place after the blood sampling at this visit.
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
Assessments are to be performed according to Table 2–1 and the assessment results from 
concomitant medication, vital signs and details of adverse events (AE) must be entered into the 
eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. 
In the period from visit 16 to visit 17 the patient can be treated with turoctocog alfa (rFVIII) at the 
discretion of the investigator. Treatment can either be prophylactically and/or treatment of eventual 
bleeding episodes. Only turoctocog alfa will be provided by Novo Nordisk.
If necessary, a dispensing call must be performed in the IWRS. At the visit the patient will be 
provided with rFVIII (turoctocog alfa) and injection kits to be able to conduct home treatment until 
final visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. NovoPen 4 must be 
returned. Drug accountability must be performed at all visits for concizumab and rFVIII (turoctocog 
alfa) including injection kits, if applicable. Unused sodium chloride syringes should be returned to 
site at every visit and new sodium chloride syringes should be dispensed to the patient.
8.1.11
Follow-up Part
8.1.11.1
Visit 17 (End of trial)
Visit17is to be scheduled on trial day 589(84 weeks) with a visit window of minus 7days 
Assessments are to be performed according to Table 2–1and the assessment results from
concomitant medication,physical examination, body measurements(weight only), vital signsand 
details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Patients must be asked if their female partner has 
become pregnant during the trial (see Section 12.5.1).
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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The patient will be asked to return all used, partly used and unused turoctocog alfa (rFVIII), eDiary
device and Trial card. Drug accountability must be performed for turoctocog alfa (rFVIII) including 
injection kits, if applicable. Unused sodium chloride syringes should be returned to site at every 
visit and new sodium chloride syringes should be dispensed to the patient.
End of trial information must be entered in the End of Trial form in the eCRF.
End of trial Call must be made in the IWRS.
8.1.12
Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Table 2–1.
The purpose of the unscheduled visit must be documented in the eCRF. During unscheduled visits 
assessments and blood sampling must be performed according to Table 2–1. Assessment results 
must be recorded in the eCRF. Assessments and blood sampling can be omitted if the only reason 
for the unscheduled visit is dispensing of trial product, or for an unscheduled 24 hour PK-visit. 
If trial product administration or dispensing is required, dispensing of trial product must be 
performed via IWRS.
The following forms can be found in the unscheduled visit in the eCRF:
!
Bleeding episodes
!
Dosing with FVIII, concizumab including dose escalation section 5.3.1
!
Surgery
!
Local, special and central laboratory (re-) sampling/results
!
Body measurements
8.1.12.1
Unscheduled 24 hour PK-Visit
All patients will be invited to participate in an optional unscheduled 24 hour PK-visit. The visit may 
take place after first dose of concizumab. Samples collected at the 24 hour PK-visit will be for 
analysis of concizumab-ELISA, Free TFPI and Thrombin Generation (TGA). Sampling will be at 
time points; 1 hour pre-dose (-1 hour), 1 (±10 min.), 3 (±10 min.), 6 (±10 min.), 9 (±10 min.), 12 
(±20 min.) and 24 hour(s) (±20 min.) post dose, related to the daily dosing of concizumab. 
Treatment dose of concizumab and the time of treatment will preferably be recorded in the eDiary 
by the patient or eCRF by site. Treatment will be at site.
This visit can be combined with a regular scheduled visit. Patients should be reminded not to 
administer the daily dose of concizumab until 1 hour after the pre-dose sampling has taken place
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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8.2
Patient related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Concomitant illness and medical history other than haemophilia
A concomitant illness is any illness, other than haemophilia A, that is present at the start of the trial 
(i.e. at the first visit) or found as a result of a screening procedure or other trial procedures 
performed before first exposure to trial product. All concomitant illnesses should be reported in the 
Concomitant illness forms in the eCRF except information on haemophilia A which is to be 
reported in the Haemophilia Medical history section of the eCRF.
Medical history is a medical event, other than haemophilia A, which the patient has experienced in 
the past. Only relevant medical history should be reported. The information collected for 
concomitant illness and medical history should include diagnosis, date of onset and date of 
resolution or continuation, as applicable. Any change to a concomitant illness should be recorded 
during the trial. A clinically significant worsening of a concomitant illness must be reported as an 
AE. 
It must be possible to verify the patient’s medical history in source documents such as patient’s
medical record:
If a patient is not from the investigators own practice; the investigator must make a reasonable 
effort to obtain a copy of the patient’s medical record from relevant party e.g. primary physician. 
See section 6.2 and 6.3 for full description of the selection criteria. The investigator must document 
any attempt to obtain external medical information by noting the date(s) when information was 
requested and who has been contacted.  
8.2.3
Concomitant medication
A concomitant medication is any medication, other than concizumab and turoctocog alfa (rFVIII)
(and connected 0.9% Isotonic Sodium Chloride) used for rescue treatment, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the patient’s eligibility to continue in the trial, the monitor must be informed.
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History
All available information on haemophilia, prior to screening should be recorded in the eCRF. 
!
Diagnosis of haemophilia (date)
!
Classification of haemophilia type (haemophilia A)
!
Severity of haemophilia (severe, moderate or mild)
!
Etiology of haemophilia (congenital or acquired)
!
Family history of haemophilia [yes or no in eCRF]
!
Family history of Prothrombotic disorders [yes or no in eCRF]
!
Family history of Thromboembolism [yes or no in eCRF]
!
Family history of inhibitors [yes or no in eCRF]
!
Deficiency factor level
The following information on bleeding episodes one year prior to screening should be recorded in 
the eCRF:
!
Type of treatment 
o
Prophylaxis or on-demand
o
Start date 
o
Stop date 
!
Number of bleeding episodes 
o
If possible specify number of spontaneous bleeding episodes.
!
Coagulation factor product(s) 
o
Brand name, or if the brand is not known, the type of product, (plasma derived or 
recombinant)
!
Dosage used for prophylaxis  (for prophylaxis patients only) 
!
Dosing frequency during prophylaxis (only for prophylaxis patients) 
!
Approximate dose to treat a bleeding episode 
!
Approximate number of doses to treat a bleeding episode
!
Target joint listing (definition: a target joint is a joint in which 3 or more spontaneous 
bleeding episodes have occurred within a consecutive 6-month period)
o
Location
o
Position (left/right)
o
Number of bleeding episodes
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
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8.3
Efficacy assessments
8.3.1
Bleeding episodes
All bleeding episodes treated with FVIII and symptoms related to the underlying disease must be 
captured in the eDiary by the patient or in the eCRF by the investigator. The trial site should be 
informed of the details of all bleeding episodes, including those that are treated outside of the trial 
site. All information captured including severe bleeding episodes, during visits at the trial site will 
be collected in the eCRF.
When home treatment is initiated at visit 2 all bleeding episodes and injections with concizumab 
and turoctocog alfa (rFVIII) infusions occurring outside the trial site should be entered in the eDiary 
by the patient (Section 8.6.2.3). The completed eDiary is considered source data.
The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with rFVIII (turoctocog alfa):
!
Start date and time
!
Stop date and time (see Table 8–1 for definition) 
!
Anatomical location(s)
o
Position (left/ right)
!
Cause (see Table 8–2 for definitions)
o
spontaneous
o
traumatic
o
post-surgical
!
Severity (see Table 8–3 for definitions)
o
mild/moderate, severe

classification and of severe bleeding episodes is the responsibility of the 
investigator
!
Treatment, if any 
o
rFVIII (turoctocog alfa) administration(s) or other product administrations

dose, date, time 
o
other medicinal treatments related to the bleeding episode (e.g. pain relieving 
medication, non-medical therapy etc.)

record as concomitant medication (see Section 8.2.3)
!
Symptoms during bleeding episodes 
o
Pain 
o
Blood in urine
o
Tingling sensation
o
Swelling
o
Mouth/Gum bleed
o
Warmth
o
Loss of movement
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
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o
Bruises
o
Nose bleed
Only report the bleeding episode as an AE/SAE if fatal, life threatening or evaluated as related to 
trial product (see section 12.1)
Table 8–1
Definition of stop of bleeding episode
Stop time is:
When the patient experiences/observes signs of cessation of the active 
bleeding episode such as; pain relief, no increase in swelling/limitation of 
motion and improvement in other objective signs of the bleeding episode
Stop time is not:
When pain and objective signs of the bleeding episode are completely 
resolved
Table 8–2
Definitions of bleeding episodes (cause of bleed)
Category
Definition
Spontaneous
Not linked to a specific, known action or event
Traumatic
Caused by a specific, known action or event (e.g. injury or exercise)
Post-surgical
Bleeding episodes after surgery from the surgical wound. Bleeding 
episodes during surgery does not fall under this category 
Table 8–3
Definition of bleeding episode severity and treatment recommendation
Category
Definition
Treatment recommendation
Mild/Moderate
Examples: uncomplicated musculoskeletal 
bleeding episodes (joint, muscular bleeds 
without compartment syndrome), mucosal- or 
subcutaneous bleeding episodes
Mild/moderate bleeding episodes may occur in 
other anatomical locations
Mild/moderate bleeding 
episodes can be treated at home 
before contact to the 
investigator
Severe
Examples: intracranial, retroperitoneal, 
iliopsoas and internal neck bleeding episodes; 
muscle bleeding episodes with compartment 
Severe bleeding episodes must 
be treated immediately 
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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syndrome; bleeding episodes associated with a 
significant decrease in the haemoglobin level 
(>3g/dl)
Severe bleeding episodes may occur in other 
anatomical locations 
Bleeding episodes that require hospitalisation
All life-threatening bleeding episodes 
Instruction for 
patients
The patient must be instructed to contact the investigator immediately if in doubt 
regarding treatment of a bleeding episode and to discuss what other actions may 
need to be taken
Information about bleeding episodes prior to visit 2 will be recorded in eCRF.
The trial site should be informed of the details of all bleeding episodes, including those that are 
treated outside of the trial site. After visit 2 bleeding episodes must be recorded either in the eDiary 
(if treated at home) or in the eCRF (if treated at the trial site), see section 12.3.
Severity of bleeding episodes must be evaluated by the investigator according to Table 8–3and 
reported in the eDiary database.
Prophylactic treatment with concizumab should continue independent of bleeding episodes and 
their treatment, i.e. the original dosing schedule should be maintained unless investigator judges 
otherwise. Decisions to alter dosing schedule, including the rationale for the alteration, should be 
documented. If applicable, investigator must instruct the patient to use rFVIII (turoctocog alfa) as 
rescue medication to treat bleeding episodes.
Treatment of bleeding episodes will be at the discretion of the investigator. In countries where 
turoctocog alfa is approved for the market it is recommended to follow the approved labelling for 
NovoEight®. For countries where turoctocog alfa is not approved it is recommended to follow the 
instructions in the EU-SMPC for turoctocog alfa (FVIII): “The calculation of the required dose of 
factor VIII is based on the empirical finding that 1 IU factor VIII per kg body weight raises the 
plasma factor VIII activity by 2 IU/dl. The required dose is determined using the following formula:
Required units (IU) = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5 (IU/kg per 
IU/dl).
The amount to be administered and frequency of administration should always be oriented to the 
clinical effectiveness in the individual case.
In case of the following haemorrhagic events, the factor VIII activity should not fall below the 
given plasma activity level (in % of normal or IU/dl) in the corresponding period. The following 
table can be used to guide dosing in bleeding episodes and surgery:”
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Table 8–4
Guide for dosing in bleeding episodes and surgery
Degree of haemorrhage/ Type of
surgical procedure
FVIII level required (%)
(IU/dl)*
Frequency of doses (hours)/ 
Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding
or oral bleeding
More extensive haemarthrosis, muscle
bleeding or haematoma
Life threatening haemorrhages
20-40 
30-60 
60-100
Repeat every 12 to 24 hours, at least1 
day, until the bleeding episode as
indicated by pain is resolved or
healing achieved
Repeat infusion every 12-24 hours for 
3-4 days or more until pain and acute 
disability are resolved
Repeat infusion every 8 to 24 hours
until threat is resolved
Surgery
Minor surgery including tooth
extraction
Major surgery
30-60 
80-100 (pre- and postoperative)
Every 24 hours, at least 1 day, until
healing is achieved
Repeat infusion every 8-24 hours
until adequate wound healing, then
therapy for at least another 7 days to
maintain a factor VIII activity of 30%
to 60% (IU/dl)
*however in this trial any given single dose should not exceed 50 IU/kg 
Furthermore investigator must instruct the patient to contact the site when a bleeding episode occurs 
to discuss the bleed.
It is the responsibility of the investigator to instruct the patient when to contact the site according to
Table 8–3 .
In absence of apparent effect of turoctocog alfa (rFVIII) the site must be contacted for further 
advice and before any further dosing. In case of a bleeding episode that requires treatment occurring 
outside the trial site’s opening hours the patient must be treated according to local procedure. All 
contacts to the patient must be recorded in the patient’s medical chart. 
It is the responsibility of the investigator to instruct the patient about the timelines for timely 
completion of the eDiary. Furthermore the investigator must review the bleeding and treatment data 
collected by the eDiary according to section 13.3.
For in-between visit administrations of trial drug, patients will self-administer concizumab (and 
turoctocog alfa (rFVIII) as rescue medication)) and will record treatment in the hand-held, eDiary, 
which will be reviewed during periodic calls to/contact with the patient and at each visit by trial site
staff and the sponsor staff.
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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8.4
Safety assessments 
8.4.1
Physical examination
Performed as standard physical examination and include the following:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Genito-Urinary system, breasts 
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
The investigator must evaluate the results of the examination and classify the outcome as either:
!
Normal or abnormal.
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at Screening: record as Medical History (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
!
Measurements will be reported in the eCRF
8.4.2
Body measurements
Height (cm), at screening
Body Weight (kg), with 1 decimal.
The body weight assessed at each visit will be used for determination of the concizumab dose to be 
administered until next visit.
Measurements will be reported in the eCRF
8.4.3
Vital signs
Before measurement of vital signs the patient should preferably rest comfortably for at least five
minutes and all measurements should, if possible, be performed using the same method and sitting 
position throughout the trial. 
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CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
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Measurements at visits must be performed prior to any trial product administration unless otherwise 
specified
!
Body temperature (°C)
!
Systolic and diastolic blood pressure, sitting (BP) (mmHg)
!
Pulse, sitting (beats/min)
!
Respiratory rate
Exception: At visit 2, the measurement is also performed after concizumab administration.
The investigator must evaluate the results and classify the outcome as either: 
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2.)
o
If observed after screening: report an AE/SAE (section 12)
Measurements will be reported in the eCRF.
8.4.4
Electrocardiogram 
The investigator must evaluate the ECG (standard 12 lead) at screening and classify the outcome as
either:
!
Normal or Abnormal. 
!
If Abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant? (Yes/No)
o
If observed before or at Screening: record as Medical History (Section 8.2.1)
o
If observed after screening: report an AE/SAE (Section 12)
The ECG results must be dated and signed by the investigator to verify that the data have been 
reviewed. Outcome will be reported in the eCRF.
8.4.5
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12.
8.4.5.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form: 
!
Trial product(s) involved 
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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!
Classification of medication error
!
Whether the patient experienced any adverse event(s) as a result of the medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4.
8.4.5.2
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section12.
Injection site reaction 
Investigation of injection site reactions will be performed locally at visit 2 based on patient 
feedback and by following visual inspections of injection sites for concizumab administration:
Symptoms e.g.
!
Pain 
!
Numbness 
!
Itching
!
Burning
Signs e.g.:
!
Redness (mm x mm)
!
Induration (mm x mm)
!
Swelling
!
Dimpling
!
Macula
!
Haematoma
!
Bleeding
!
Other (visual reactions) 
Any injection site reaction symptom (evaluated between visit 2-16) should be recorded in the AE 
form and the injection site reaction form, see section 12.1.5. 
A separate AE should be recorded for each injection site reaction symptom. The affected area 
should also be evaluated for redness and induration in mm using a ruler. To ensure all local 
injection site assessments are performed at the injection site, the area around the site will be marked 
with a pen prior to injection. 
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
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In the event of a local reaction, additional visual assessments (as described above) will be 
performed until resolution as judged necessary by the investigator.
Assessment of injection site reactions can be performed at any time, if deemed necessary by the 
investigator.
Hypersensitivity reaction
If suspicion of a hypersensitivity reaction occurs the patients should be instructed to contact the site
staff as soon as possible for further guidance.
All events of hypersensitivity reactions must be reported and the following information must be 
obtained if available on the hypersensitivity reaction form: 
!
Signs and symptoms associated with the event
!
Time of appearance after administration of trial drug
!
Relevant immunological tests performed (See section 8.5.2.7)
!
Treatment given for the reaction
!
Previous history of similar reactions
!
Association with the trial product(s)
!
Relevant risk factors associated with the event
!
Storage condition of the trial product
!
Total number of doses, from first day on trial product, up to the time of this event
8.5
Laboratory assessments
An approximate total blood volume of 525 mL will be taken from each patient in the trial. Ports 
cannot be used for blood sampling.
A laboratory manual will be provided for detailed description of obtaining and processing blood 
samples.
All laboratory blood samples collected for this trial except for haematology samples are to be 
shipped for analysis at central laboratories or further distribution to special laboratories.
Haematology samples are to be analysed locally.
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in international system of units (SI) .
Laboratory reports listing results from centrally analysed samples will be made available for the 
investigator. Investigator must review and evaluate the results and report AEs for results which are 
clinical significant. Laboratory reports will where possible indicate normal ranges 
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Protocol
CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
4.0
UTN:U1111-1179-3872
Status:
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Categorisation of clinical significance for out of range results may not be required for the following 
laboratory parameters and the investigator is therefore not required to perform a categorisation even 
though these parameters are listed in the laboratory report: FVIII activity, FVIII inhibitor test, 
Thrombin generation, TFPI not bound to concizumab, concizumab concentration in plasma, Anti-
concizumab binding antibodies, and Total TFPI.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to section 8.2.2 and section 12.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory except for biomarkers and anti-drug antibodies (anti-concizumab IgE antibodies and 
anti-concizumab binding antibodies).
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report (CTR).
Antibody samples and human bio-samples, if applicable will be stored as described in section 24.2. 
The investigator may not be able to review the results of antibody measurements in relation to AEs 
as these are often analysed after LPLV.
8.5.1
Laboratory assessments for efficacy
8.5.1.1
Thrombin generation
The Thrombin Generation Assay (TGA) will be performed at all visits (including unscheduled 24 
hour PK visit), except visit 3.
The TGA is included as an exploratory PD assessment.
The generation of thrombin is a fundamental part of the haemostatic system, and is a key 
measurable parameter of the formation of a clot under bleeding or thrombotic conditions. The 
thrombin burst is crucial for the formation of a stable fibrin clot. 
The Calibrated Automated Thrombogram (CAT) method (used by Thrombinoscope BV) will be 
used to measure thrombin generation (TG). This method uses a slow acting fluorogenic substrate 
that allows continuous measurement of thrombin generation in double centrifuged citrated plasma. 
In this assay set-up thrombin generation is initiated by low-dose tissue factor that is combined with 
phospholipid. The result is obtained by comparison to a constant known thrombin activity in a 
parallel non tissue factor initiated sample. The assay has been validated fit-for-purpose.
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The thrombin generation endpoints are defined, but not limited to,
!
The Endogenous Thrombin Potential (ETP) – the area under the curve 
!
Peak thrombin generation
!
Velocity Index 
8.5.1.2
Free TFPI
Free TFPI measures TFPI not bound to concizumab. This enzyme-linked immunosorbent assay 
(ELISA) test will be will be sampled for at all assessment visits, including unscheduled 24 hour PK 
visit.
The free TFPI ELISA assay is an enzyme immunoassay measuring levels of TFPI not bound to 
concizumab from Diagnostica Stago (named and referred to Asserachrom TOTAL TFPI) and will 
be used for PD assessments. 
Free TFPI is included as a PD assessment.
8.5.2
Laboratory assessments for safety
8.5.2.1
Urinalysis
!
pH
!
Protein
!
Glucose
!
Bilirubin
This is a semi qualitative measurement which will be performed (locally) at the screening visit by 
the site by using the appropriate reagent strips for urinalysis. The results will be recorded in the 
eCRF.
Clinically significant findings must be recorded as: 
!
Normal or abnormal
o
if abnormal the investigator must:
o
record if the result is clinically significant? (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
8.5.2.2
Haematology
Haematology samples are to be sampled and analysed locally at all visits, except visit 3. 
!
Haemoglobin 
!
Erythrocytes (cell count) 
!
Thrombocytes (Platelet count)
!
Leucocytes (cell count) 
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!
Differential leucocytes cell count 
o
Lymphocytes
o
Monocytes
o
Neutrophils
o
Eosinophils 
o
Basophils
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
Haematology results are to be entered into the eCRF.
8.5.2.3
Biochemistry
!
Creatinine 
!
Albumin 
!
Bilirubin; total, direct and indirect)
!
Aspartate aminotransferase (AST) 
!
Alanine aminotransferase (ALT)
!
Gamma glutamyltransferase (GGT) 
!
Alkaline phosphatase
!
C-reactive protein (CRP) 
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
8.5.2.4
FVIII activity
!
FVIII activity (IU/ml)
8.5.2.5
Coagulation parameters 
!
Fibrinogen
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!
Prothrombin time  (PT) including INR
!
D-dimer 
!
Prothrombin fragment 1+2 
!
Activated partial thromboplastin time (APTT)
!
Antithrombin (AT)
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
8.5.2.6
FVIII inhibitor test
The inhibitor level of the patient will be measured by the Nijmegen method at visit 1 (screening). 
!
FVIII inhibitor titre (BU)
In order to minimise the risk of false negative results, circulating FVIII product levels should be 
less than 0.05 IU/ml, when sampling for the test. If the patient has received FVIII within 96 hours 
of screening, the sampling of FVIII-Inhibitor should be postponed until a time period equal to 8 
half-lives of the used product has passed (counting from latest treatment).
8.5.2.7
Anti-concizumab antibodies
Sampling will be performed at all visits except at visit 3. Samples will be collected pre-dose at visit 
2, 9 and 16.
Assessment of binding antibodies against concizumab (anti-drug antibodies (ADA)) will be 
performed at specialised laboratories whereas assessment of neutralising antibodies will be 
performed at Novo Nordisk A/S.
Analysis for ADA will be done as listed in Table 2–1, with a bridging ECL assay (binding ADA 
assay), using labelled concizumab for antibody capture and detection. If a sample is confirmed 
positive in the confirmatory assay, the sample is considered antibody positive. Confirmed positive 
samples will be characterised for binding to IgG backbone, CDR region or the S241P mutation. 
Furthermore, positive samples will be characterised for neutralising activity using a modified TFPI 
functionality assay (neutralising ADA assay). All antibody assays are validated according to 
international guidelines and recommendations.
The following analyses will be available:
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Date:
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Version:
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!
Anti-concizumab antibody assay
!
Specificity assay (Anti-concizumab antibodies cross reacting with IgG4 backbone, CDR region
or S241P mutation) 
!
Anti-concizumab neutralising antibody assay
Samples will be drawn at all visits except at visit 3. The samples will be analysed in batches during 
the trial and results will be available to the data monitoring committee approximately every third 
month after the first patient has been dosed (Section 12). Neutralising antibodies will be analysed 
and reported at the end of trial. A detailed description of the assay methods will be included in the 
antibody analysis report at the end of the trial.
Investigators will be notified in case their patient is shown to have developed neutralising 
antibodies against concizumab.
Samples for the determination of anti-drug antibodies collected during the treatment period must be 
drawn prior to administering trial products.
In the event that a trial patient develops binding ADAs towards concizumab during the course of the 
trial and has measurable binding ADAs at his End of Trial visit, the patient may attend an ADA 
follow-up visit. The ADA positive patients will be called for additional visits, e.g. every 4 to 6 
weeks, for safety assessment and blood sampling for ADA and PD markers (free TFPI and 
Thrombin generation). The ADA positive patients will be followed no longer than one year after 
End of Trial.
Hypersensitivity
If suspicion of a hypersensitivity reaction occurs, patients should be instructed to contact the site 
staff as soon as possible for further guidance, see Section 12.1.5.
In the event of a severe local and/or systemic hypersensitivity reaction possibly or probably related 
to trial product, blood sampling for assessment of anti-concizumab IgE antibodies as well as anti-
concizumab antibodies should be conducted in relation to the reaction and no later than 1-2 weeks 
after the event. Additional testing may be performed if deemed relevant (e.g. anti-Host Cell Proteins 
(HCP) antibodies). 
In the event of a severe systemic hypersensitivity reaction to trial product it is recommended also to 
test for tryptase (total and/or mature tryptase) within 3 hours of the reaction. Moreover, a baseline 
tryptase measurement is necessary 1-2 weeks after the immediate severe hypersensitivity reaction 
due to individual to individual variation in tryptase baseline concentration. 
A follow up visit should be conducted 3-4 weeks post the allergic reaction with repeated blood 
sampling for assessment of anti-concizumab IgE antibodies as well as anti-concizumab antibodies 
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Date:
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Trial ID:NN7415-4255
Version:
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and if possible also at a visit 3 months post the hypersensitivity reaction for assessing the 
persistence of the IgE response. Tryptase measurements are not required at the follow up visits.
Additionally, basophil activation testing may be performed if deemed relevant. This can be 
performed using existing samples and/or by analysing the patient’s basophil cells from an additional 
blood sample taken 3-4 weeks and no later than 2 months after the event. Similarly, prick tests
and/or intra-dermal tests may be performed if relevant using trial product or components of trial 
product. Complement may be measured in case of suspicion of immune complex mediated 
hypersensitivity reactions.
Results from the following additional tests will be reported to Novo Nordisk Safety Operations for 
inclusion in the ARGUS database and included in the narratives, if measured:
Test to be performed in case of severe hypersensitivity
!
Anti-concizumab IgE antibodies
!
Anti-concizumab antibodies (additional to scheduled time points)
Additional testing may be performed if deemed relevant e.g
!
Anti-Host Cell Proteins (HCP) antibodies
!
Anti-HCP IgE antibodies
!
Basophil activation results
!
Prick test/intra-dermal test
!
Complement test results
Furthermore, it is recommended locally to test for
!
Tryptase (total and/or mature tryptase)
8.5.2.8
Concizumab ELISA
Concizumab ELISA will be performed at all visits except at screening and at visit 3. Samples will 
be collected pre-dose at visit 2, 9 and 16. For the unscheduled 24 hour PK visit, samples are 
collected; 1 hour pre-dose (-1hour), 1(±10 min.), 3(±10 min.), 6(±10 min.), 9(±10 min.), 12(±20 
min.) and 24 hour(s) (±20 min.) post dose, related to the daily dosing of concizumab.
Concizumab will be quantified using a validated ELISA assay. Recombinant human TFPI will be 
used to capture concizumab. A colorimetric detection signal is obtained by the enzymatic reaction 
of horseradish peroxidase labelled anti-human IgG4 specific antibodies with the chromogenic 
substrate TMB (3,3´,5,5´-tetramethylbenzidine). The amount of anti-TFPI present in the calibration, 
quality control and test samples correlates with the obtained signal strength.
Validation of the assay follows current guidelines for bioanalytical method validation. Bioanalytical 
data will be reported in a bioanalytical report.
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Version:
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8.5.2.9
Total TFPI
Total TFPI ELISA sampling will be performed at all visits except at visit 3. Samples will be 
collected pre-dose at visit 2, 9 and 16.
The Total TFPI ELISA is included as an exploratory PD assessment.
The total TFPI level (free and concizumab bound) will be included as an exploratory biomarker 
assessment. The assay is an ELISA, where TFPI is captured by polyclonal anti-TFPI antibody, 
distanced from the binding site of concizumab, meaning that both free TFPI and concizumab bound 
TFPI will be captured. Detection will be obtained with a monoclonal antibody against TFPI, which 
does not bind to the concizumab epitope. Data will be reported in ng/mL TFPI.
Total TFPI ELISA will be performed at all visits, except visit 3. Sample will be collected pre-dose 
at visit 2.
8.5.3
Human biosamples
If patient permission is obtained, plasma, serum and/or DNA for genotyping samples are to be taken 
for long term retention. The blood samples can be stored up to 15 years, for future potential 
exploratory purposes please refer to section 24.2.
Antibody samples storage and retention see section 24.2.1. The investigator is not able to review the 
results of antibody measurements in relation to AEs as these are analysed after LPLV.
If applicable, samples will be collected at visit 1 and at visit 17.
8.6
Other assessments
8.6.1
Patient reported outcomes
In this trial a newly developed disease specific PRO -the Hemophilia Treatment Experience 
Measure (Hemo-TEM) -is being validated.In order to assess the psychometric properties of 
Hemo-TEM,  other questionnaires will be provided; see further appendix 1.
The following ePRO questionnaires are used:
- Haemophilia Treatment Experience Measure (Hemo-TEM)
- Validated Hemophilia Regimen Treatment Adherence Scale – Prophylaxis (VERITAS-
Pro®)/Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
- 36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
- Patient Global Impression of Change (PGI-C)
- Sheehan Disability Scale (SDS)16
- Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
- Haemophilia - Device Assessment Tool (H-DAT)
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Date:
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Version:
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- Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
The PROs should be assessed at the scheduled visits following the order listed below:
!
visit 1 (Hemo-TEM, VERITAS-Pro® or VERITAS-PRN®)
!
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 4 (PGI-C, Hemo-TEM)a
!
visit 5 (PGI-C, Hemo-TEM)
!
visit 6 (PGI-C, Hemo-TEM)
!
visit 7 (PGI-C, Hemo-TEM)
!
visit 8 (PGI-C, Hemo-TEM)
!
visit 9 (PGI-C, Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
!
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 16 (Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
At visit 1 before any visit-related activities all patients should complete Hemo-TEM and 
VERITAS-Pro® (if the patient at baseline receives prophylactic treatment) / VERITAS-PRN® (if 
patient at baseline receives on demand treatment).   
At visit 2 before any visit-related activities all patients should complete Hemo-TEM, SF36v2, SDS, 
TSQM and SIAQ-ISRQ.
At visit 4-8: before any visit-related activities the patient should complete the PGI-C before the 
Hemo-TEM. These are the rules that apply:
!
If the patient responds “1” to question 1 in the PGI-C, the patient should also complete the
Hemo-TEM. In this case the patient should not fill in the PGI-C any more in the trial and the
Hemo-TEM only again at visit 9.
!
If the patient responds “0” or “2” to question 1 in the PGI-C, the patient should not complete
any other questionnaires at this visit, but should repeat the procedure at next visit.
At visit 9 if the patient has responded “0”or “2”in the PGIC at all previous visits, the patient 
should complete PGI-C. All patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT
and SIAQ-ISRQ.
At visit 10 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and SIAQ-ISRQ.
At visit 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT and SIAQ-
ISRQ. The investigator mustcheck the ePROs for potential AEs and SAEs.
The completed ePROs should be transmitted to the ePRO database by the investigator at each visit.
All PROs can be found in Appendix I. 
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8.6.2
Training 
The patients must be trained in how to handle bleeding episodes and how to recognize the signs and 
symptoms of thrombosis. The training must be recorded in the medical records. 
8.6.2.1
Concizumab and NovoPen® 4
A direction for use (DFU) will be available as hand out for patients at visit 2. Training in 
NovoPen®4 can start at screening (visit 1) and s.c. administration of concizumab using the 
NovoPen®4 can start at the first dose at the trial site (visit 2). Patients must be instructed that 
injections are to be performed subcutaneously, not intravenously. Concizumab and NovoPen®4 will 
be dispensed to patients at visit 2. Training must be performed at site until patients feel comfortable
using the device or performing the treatment. The training must be documented in the medical 
records.
Detailed instructions can be found in the DFU.
8.6.2.2
Turoctocog alfa
A direction for use (DFU) will be available as hand out for patients at visit 1. Training must be 
performed at site until patients feel comfortable performing the treatment. The training must be 
documented in the medical records. 
Detailed instructions can be found in the DFU.
8.6.2.3
eDiary
Training on the use of the eDiary can start at visit 1. The eDiary will be provided to the patients at 
visit 2.
Training must be repeated at the site until patients feel comfortable using the device. The training 
must be documented in the medical records.
During the home treatment period the patient must ensure that all home treatments of concizumab, 
details of bleeding episodes and the turoctocog alfa (FVIII) treatment associated with these bleeding 
episodes are captured in the eDiary as instructed and trained by investigator or delegated staff.
It will be the responsibility of the investigator or delegated staff to assess the eDiary data 
throughout the conduct of the trial and to ensure data entry compliance (timely entry, no duplicates 
data, no missing data etc.) and retraining if necessary.
For patients completing the trial or in case of withdrawal, the eDiary will be collected at the end of 
trial.
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8.6.3
Surgery
Minor surgery can be performed within this trial at the investigator’s discretion according to local 
guidelines. Definition of minor surgery, see section 5.1.1. Major surgery is not allowed, see 
exclusion criteria no 6.
For minor surgery the following should be recorded in the eCRF:
!
Date, stop time and dose of preventive treatment with turoctocog alfa before surgery, if this was 
deemed necessary by the investigator
!
Indication for surgery
!
Location of surgery
!
Date of surgery
!
Start and stop time of surgery
8.7
Patient compliance
Throughout the trial, the investigator will remind the patients to follow the trial procedures and 
requirements to ensure patient compliance. If a patient is found to be non-compliant, the 
investigator will remind the patient in the importance of following the instructions given including 
taking the trial products as prescribed.
Assessment of patient compliance with protocol procedures for determination of continuation of the 
trial will be done by the investigator on an ongoing basis.
8.8
Treatment compliance:
Treatment compliance will be monitored and documented through timely review of eDiary data and 
drug accountability. 
Concizumab will be administered at the trial site at visit 2 supervised by medically trained trial staff
and administration at home can be initiated after visit 2 if the patient feels comfortable with the s.c. 
administration. Administration of turoctocog alfa (rFVIII) for bleeding episodes will be 
administered at the trial site by a medically trained trial staff or at home by the patient, see section 
8.3.1. 
The patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator. Drug accountability will be performed and will be used to assess 
patient compliance together with the patient’s adherence to trial procedures. 
Compliance check includes a cross check between records in EDC/eDiary (number of 
administrations and bleeding episodes) and the used/returned cartridges/vials. 
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Version:
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
The trial product, concizumab B, appears clear to slightly opalescent and colourless to slightly 
yellow. The trial product must not be used if it contains visible particles or discolouration.
The reconstituted turoctocog alfa (FVIII) solution appears as a clear or slightly opalescent solution. 
Do not use the reconstituted solution if it has visible particles or discoloration. 
Trial products must not be dispensed to any person not included in the trial.
9.1
Trial products
The following trial products will be provided by Novo Nordisk, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
concizumab B 
(IMP a)
100 mg/mL
Solution for injection
s.c. injection
3 ml cartridge
turoctocog alfa
(NIMP b)
2000 IU/vial
Powder for solution for 
injection
i.v. injection
Vial
0.9% Sodium Chloride 
Solution
(NIMP b)  
N/A
Solvent for solution for
injection 
i.v. injection
4 ml prefilled 
syringe
a Investigational Medicinal Product (IMP) 
b Non-Investigational Medical Product (NIMP) given as NIMP for bleeding episodes
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. NovoPen®4 will be labelled in accordance with the EMA directive on medical devices 
annex I 21 and similar national legislation. A description on how to use the device is given in the
DFU.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 22, local regulations and trial 
requirements.
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Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial products will be distributed to the trial sites according to enrolment 
and drug dispensing of distribution.
The investigator must document that direction for use is given to the patient orally and in writing at 
the first dispensing visit (see flow chart section 2). 
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time a
concizumab B 100 mg/mL
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
Store at room temperature 
(below 30°C)
Do not refrigerate
Protect from light
Use within 4 weeks 
(28 days)
turoctocog alfa
2000 IU/vial
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
May be stored at room 
temperature (9-30oC) for a 
single period not exceeding 9
months. Do not return the 
product to the refrigerator.
Write the start date for the 
storage at room temperature on 
the label
For single use
To be used immediately after 
reconstitution
Use within 4 hours after 
reconstitution when stored at 
room temperature
N/A
0.9% sodium chloride 
solution
Store at 2°-30°C
Do not freeze
Protect from light
For single use
N/A
a In-use time for concizumab starts when first dose is administrated from an individual cartridge and for turoctocog alfa 
when the product is reconstituted
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any patient before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
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Investigator must instruct the patient to use and store trial product according to the label.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator. The 
patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator except for the used sodium chloride solution which should be 
discarded at home and not accounted for. Unused sodium chloride syringes should be returned to 
site at every visit and new sodium chloride syringes should be dispensed to the patient.
All cartridges (concizumab) and vials (FVIII) must be accounted for as used, partly used, or unused. 
The investigator will perform drug accountability using the IWRS Drug Accountability module.
Returned trial product (used/partly used and unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Destruction of concizumab can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
For Japan only: Responsibility for storage and drug accountability of the trial drug product at the 
trial site rests with the head of the trial site. The head of the trial site could assign some or all of the 
responsibilities for accountability of the trial drug product at the trial sites to a trial product storage 
manager (a pharmacist in principle). The trial product storage manager should control and take 
accountability of the trial drug product in accordance with procedures specified by Novo Nordisk. 
The head of the trial site or the trial product storage manager must ensure the availability of proper 
storage conditions, and record and evaluate the temperature.
9.5
Auxiliary supplies
Novo Nordisk will provide the auxiliaries for this trial: 
!
For concizumab administration: NovoPen®4, needles, and DFU
!
For turoctocog alfa reconstitution and administration: Trial Injection Kit and DFU
Only needles and trial injection kits provided by Novo Nordisk must be used for administration of 
trial product.  
For further guidance please see the TMM.
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for:
!
Screening
!
Screening failure
!
Medication arrival
!
Dispensing
!
Dispensing verification
!
Treatment discontinuation 
!
Completion
!
Drug accountability
!
Data change
An IWRS user manual will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
Randomisation 
Not applicable for this trial
Breaking of blinded codes
Not applicable for this trial.
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12 Adverse events, and technical complaints 
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is
of a severity that requires active management. Active management includes active treatment
or further investigations, for example change of medicine dose or more frequent follow-up
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial
procedures performed before exposure to trial product (pre-existing conditions should be
reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has
worsened from the first trial related activity after the patient has signed the informed
consent.
!
Bleeding episodes and other symptoms (e.g. pain, swelling, synovitis, arthralgia, injection
site haematoma) in connection with bleeding episodes should not be reported as AEs/SAEs
unless the event is fatal, life-threatening or evaluated by the investigator as related to trial
product or trial procedure. All bleeding episodes and other findings related to underlying
disease will be captured in the eCRF/eDiary
The following three definitions are used when assessing an AE:
!
Severity
o
Mild – no or transient symptoms, no interference with the patient’s daily activities.
o
Moderate – marked symptoms, moderate interference with the patient’s daily activities.
o
Severe – considerable interference with the patient’s daily activities; unacceptable.
!
Causality
Relationship between an AE and the relevant trial product(s):
o
Probable - Good reason and sufficient documentation to assume a causal relationship.
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o
Possible - A causal relationship is conceivable and cannot be dismissed.
o
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome 
o
Recovered/resolved - The patient has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the patient signed the informed consent.
o
Recovering/resolving - The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the trial 
or has died from another AE.
o
Recovered/resolved with sequelae - The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
o
Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known.
o
Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he 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.
o
Unknown - This term is only applicable if the patient is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
a. The term “life threatening” in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
b. The term “hospitalisation” is used when a patient: 
o
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
o
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c.A substantial disruption of a patient’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the patient has significant, persistent or permanent change, 
impairment, damage or disruption in his body function or structure, physical activity and/or quality 
of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
Suspicion of transmission of infectious agents via the trial product 
!
Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative 
aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error unless 
it results in administration of wrong drug.
!
Wrong route of administration, 
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. However, the 
administered dose must deviate from the intended dose to an extent where clinical 
consequences for the trial patient were likely to happen as judged by the investigator, 
although they did not necessarily occur
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1
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12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
In this trial the following AEs require the completion of specific event forms in the eCRF:
!
Injection site reaction (see section 8.4.5.2)
!
Hypersensitivity type reactions, incl. anaphylactic reactions, as defined below 
Injection site reactions:
Any injection site reaction symptom must be reported on the AE form and the injection site reaction 
form, See section 8.4.5.2.
Hypersensitivity type reactions:
In cases where clinical signs of a severe and immediate hypersensitivity reaction resembling a type
I hypersensitivity reaction are present, blood should be sampled for central laboratory assessment of 
anti-drug IgE antibodies and anti-drug binding antibodies. In the event of an immediate systemic 
hypersensitivity reaction to the trial product, it is recommended to also test for tryptase (total and/or 
mature tryptase) within 3 hours of the reaction. Moreover, a baseline tryptase measurement is 
necessary ~1 week after the immediate severe hypersensitivity reaction due to individual to 
individual variation in tryptase baseline concentration. Tryptase concentrations (if measured) must 
be interpreted and considered in the context of a complete workup of each patient.
Special attention should be given to clinical signs and symptoms of hypersensitivity reactions of 
type II and III. Common clinical signs and symptoms characteristic for these types of reactions may 
include but are not limited to: fever/malaise, cutaneous eruptions, arthralgia, lymphadenopathy, 
itching, headaches and myalgia. Related laboratory findings may include but are not limited to: mild 
proteinuria or haematuria, leukopenia or leucocytosis, decreased complement levels or increased 
complement split products and transient elevations of serum creatinine levels. In cases where there 
is a suspicion of hypersensitivity reaction that requires systemic treatment, additional sampling for 
the purpose of measuring ADA is to be performed.
Definition of anaphylaxis23
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
!
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (e.g. generalised hives, pruritus or flushing, swollen lips-tongue-uvula) and 
at least one of the following:
a) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)
b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.
hypotonia [collapse], syncope, incontinence)
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!
Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):
a) Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush, swollen 
lips-tongue-uvula)
b) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
!
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
Systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
BP.
If a patient fulfils any of the three criteria of anaphylaxis outlined above, the patient should receive 
epinephrine/adrenalin immediately. Dose regimen should be according to hospital operating 
procedure, and the patient should be transferred to an emergency department or intensive care unit, 
if clinically warranted.
Events not fulfilling the criteria for an anaphylactic reaction and other allergic reactions must be 
treated at the discretion of the investigator. If according to the investigators judgment, 
hypersensitivity type reactions that require systemic treatment are suspected, dosing with 
concizumab should be stopped immediately and treatment at the discretion of the treating physician 
initiated.
12.1.6
Adverse event of special interest
An adverse event of special interest (AESI) is an event, which in the evaluation of safety, has a 
special focus. In this trial, the following AEs fulfil the AESI criteria:
!
Thromboembolic events including but not limited to,
o
disseminated intravascular coagulation (DIC) (A), 
o
clinical signs or laboratory indications of arterial and venous thrombosis including 
myocardial infarction (B), 
o
pulmonary embolism (C), 
o
stroke (D), 
o
deep vein thrombosis (E), 
o
other clinically significant thromboembolic events (F) and peripheral artery 
occlusion (see below G), see definitions below.
The AESIs must be reported on an AE form and a safety information form.
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A) Definition of disseminated intravascular coagulation (DIC), as defined below:
The definition of DIC in this trial should be made according to the International Society on
Thrombosis and Haemostasis (ISTH) criteria. Thus, a DIC diagnosis may be based on 
clinical signs and symptoms of a bleeding tendency or thrombotic tendency, organ 
dysfunction and the laboratory parameters criteria as listed below:
o
Platelet count (>100 × 109/L = 0, <100 × 109/L = 1, <50 × 109/L = 2)
o
Elevated D-dimer (no increase = 0, moderate increase = 2, strong increase = 3)
o
Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
o
Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
o
Calculate score: ≥5 compatible with overt DIC
(B) Myocardial infarction is defined according to the “Third Universal Definition of
Myocardical Infarction” 24
Criteria for acute myocardial infarction - The term acute myocardial infarction (MI) should be used 
when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial 
ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI:
!
Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin
(cTn)] with at least one value above the 99th percentile upper reference limit (URL) and
with at least one of the following:
o
Symptoms of ischemia.
o
New or presumed new significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB).
o
Development of pathological Q waves in the ECG.
o
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality.
o
Identification of an intracoronary thrombus by angiography or autopsy.
Criteria for prior myocardial infarction- Any one of the following criteria meets the diagnosis for
prior MI:
!
Pathological Q waves with or without symptoms in the absence of non-ischemic causes.
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to
contract, in the absence of a non-ischemic cause.
!
Pathological findings of a prior MI.
Recurrent myocardial infarction - Incident MI’ is defined as the individual’s first MI. When features 
of MI occur in the first 28 days after an incident event, this is not counted as a new event for 
epidemiological purposes. If characteristics of MI occur after 28 days following an incident MI, it is
considered to be a recurrent MI.
C) Definition of pulmonary embolism:
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The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends diagnostic
imaging studies for patients with intermediate or high pre-test probability of pulmonary embolism25.
Accordingly, the definition of pulmonary embolism is the following: obstruction of a pulmonary 
artery or one of its branches, most frequently by detached fragments of thrombus from a leg or 
pelvic vein, diagnosed by at least one of the following:
!
Positive findings in ventilation/perfusion scan
!
Positive findings in a spiral (helical) computerised tomography (CT) or angiography
!
Positive findings in a magnetic resonance imaging (MRI)
!
Positive findings in a pulmonary angiography
D) Definition of stroke:
The definition of central nervous infarction is according to the American Heart
Association/American Stroke Association Expert Consensus Document:  “An Updated Definition of 
Stroke for the 21st Century”26.
Accordingly, the term “stroke” should be broadly used to include all of the following:
Definition of central nervous system (CNS) infarction: CNS infarction is brain, spinal
cord, or retinal cell death attributable to ischemia, based on:
o
1. pathological, imaging, or other objective evidence of cerebral, spinal cord, or
retinal focal ischemic injury in a defined vascular distribution; or
o
2. clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on
symptoms persisting 24 hours or until death, and other etiologies excluded.
Note: CNS infarction includes haemorrhagic infarctions, types I and II; see “Haemorrhagic
Infarction”.
Definition of ischemic stroke: An episode of neurological dysfunction caused by focal cerebral,
spinal, or retinal infarction. Note: Evidence of CNS infarction is defined above.
Definition of silent CNS infarction: Imaging or neuropathological evidence of CNS infarction,
without a history of acute neurological dysfunction attributable to the lesion.
Definition of intracerebral haemorrhage: A focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma. Note: Intracerebral haemorrhage includes
parenchymal haemorrhages after CNS infarction, types I and II - see “Haemorragic Infarction”.
Definition of stroke caused by intracerebral haemorrhage: Rapidly developing clinical signs of
neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma.
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Definition of silent cerebral haemorrhage: A focal collection of chronic blood products within the
brain parenchyma, subarachnoid space, or ventricular system on neuroimaging or neuropathological
examination that is not caused by trauma and without a history of acute neurological dysfunction
attributable to the lesion.
Definition of subarachnoid haemorrhage: Bleeding into the subarachnoid space (the space between
the arachnoid membrane and the pia mater of the brain or spinal cord).
Definition of stroke caused by subarachnoid haemorrhage: Rapidly developing signs of
neurological dysfunction and/or headache because of bleeding into the subarachnoid space (the
space between the arachnoid membrane and the pia mater of the brain or spinal cord), which is not
caused by trauma.
Definition of stroke caused by cerebral venous thrombosis: Infarction or haemorrhage in the brain,
spinal cord, or retina because of thrombosis of a cerebral venous structure. Symptoms or signs
caused by reversible edema without infarction or haemorrhage do not qualify as stroke.
Definition of stroke, not otherwise specified: An episode of acute neurological dysfunction 
presumed to be caused by ischemia or haemorrhage, persisting ≥24 hours or until death, but without
sufficient evidence to be classified as one of the above.
Definition of a Transient Ischemic Attack: The definition of Transient Ischemic Attack is according
to the American Heart Association/American Stroke Association. Accordingly: a Transient 
ischemic attack (TIA) is a transient episode of neurological dysfunction caused by focal brain, 
spinal cord, or retinal ischemia, without acute infarction 27.
E) Definition of deep vein thrombosis:
The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends
ultrasound scanning for patients with intermediate or high pre-test probability of deep vein 
thrombosis (DVT) in the lower extremities 25. Accordingly, venous thrombosis should be 
demonstrated by compression ultrasound,
duplex ultrasound, colour Doppler imaging or venography (phlebography).
F) Definition of other clinically significant thromboembolic events:
Signs or suspicion of a clinically significant thromboembolic event (e.g. visceral arterial 
embolus/thrombus, extremity arterial embolus/thrombus, or portal venous thrombosis).
Superficial thrombophlebitis is not considered a clinically significant thromboembolic event unless 
evaluated as such by the investigator.
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G) Definition of peripheral artery occlusion:
Clinical signs of acute arterial occlusion verified by ankle-brachial index (ABI) test, Doppler and
ultrasound (Duplex) imaging, computerised tomographic angiography, magnetic resonance 
angiogram (MRA), or conventional angiography. The 2011 American College of Cardiology 
Foundation/American Heart Association Focused Update of the Guideline for the Management of 
Patients With Peripheral Artery Disease could serve as a reference for the diagnosis of lower 
extremity peripheral artery disease 28
12.1.7
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between pen and needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the patient has signed the informed consent until the end of 
the post-treatment follow-up period (visit 17). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12–1
During each contact with the trial site staff, the patient must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?
All AEs, either observed by the investigator or patient, must be reported by the investigator and 
evaluated. All AEs must be recorded by the investigator on an AE form. The investigator should 
report the diagnosis, if available. If no diagnosis is available, the investigator should record each 
sign and symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
AESIs regardless of the seriousness, must be reported using the AE form and safety information 
form
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For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the case report form (CRF)/eCRF within the 
specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator’s first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in the 
eCRF. 
For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
!
Non-serious AEs fulfilling the AESI criteria: The AE form and safety information form 
within 14 calendar days of the investigator’s first knowledge of the event.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: Investigator’s Brochure; Current version and any updates thereto.
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP 1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the
International Review Boards/Independent Ethics Committees (IRBs/IECs) of trial product-related 
SUSARs in accordance with local requirement and ICH GCP 1, unless locally this is an obligation 
of the investigator.
Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
non-investigational medicinal product rFVIII (turoctocog alfa) or concomitant medication in the 
trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to report this 
adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. 
Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is 
“recovered/resolved”, “recovered/resolved with sequelae” or “fatal”, and until all queries 
have been resolved. Cases of chronic conditions, cancer or AEs ongoing at time of death 
(where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the 
outcome of “recovering/resolving” when the patient has completed the follow-up period 
and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
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information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or 
until the end of the follow-up period stated in the protocol, whichever comes first, and 
until all queries related to these AEs have been resolved. Cases of chronic conditions, 
cancer or AEs ongoing at time of death (where death is due to another AE) may be 
closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the patient has 
completed the follow-up period and is expected by the investigator to recover.
!
Non-serious AEs fulfilling the AESI criteria: Non-serious AE fulfilling the AESI 
criteria must be followed as specified for non-serious AE. Follow-up information on 
AESIs 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 AESI criteria.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a patient after the patient has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 
!
Concizumab B 100 mg/mL, solution for injection in a 3 ml cartridge
!
NovoPen®4
!
Novo Nordisk needles
!
Turoctocog alfa 2000 IU/vial, powder for solution for injection in a vial  
!
0.9 % sodium chloride 4.0 mL prefilled syringe
!
Novo Nordisk trial injection kit
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whichoccur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Centre, Novo Nordisk.
Contact details (fax, e-mail and address)  are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, AESIs and/or 
SAEs.
Technical complaints must be reported on a separate technical complaint form: 
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each batch, code or lot number
must be completed
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not patient related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Centre, Novo Nordisk (the address is provided in Attachment I)  and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. 
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12.5
Pregnancies 
12.5.1
Pregnancies in female partners of male patients
Male patients must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period (from visit 1 to dosing at visit 2). At the last 
scheduled visit, male patients must be asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male patient and assess, if the pregnancy 
outcome is normal or abnormal. 
When the pregnancy outcome is normal this information is recorded in the patient’s medical record 
only, no further information is collected and reported to Novo Nordisk. When the pregnancy 
outcome is abnormal (i.e. congenital anomalies, foetal death including spontaneous abortion and/or 
any anomalies of the foetus observed at gross examination or during autopsy), the following must 
be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
1. Reporting of pregnancy information
Information from the male patient has to be reported on the Paternal Form. Furthermore, 
information from the female partner (including information about the pregnancy outcome and 
health status of the infant until the age of one month) has to be reported on the Maternal Forms 
1A, 1B and 2, after an informed consent has been obtained from the female partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information. 
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
o
Non-serious AEs evaluated as possible/probably related to the father’s treatment 
with the trial product(s). 
o
SAEs in the foetus and newborn infant - whether or not related to the father’s 
treatment with the trial product(s). This includes an abnormal outcome - such as 
foetal death (including spontaneous abortion) and congenital anomalies (including 
those observed at gross examination or during autopsy of the foetus).
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
Paper AE forma within 14 calendar days of the investigator’s first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
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!
Paper AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
Paper safety information form within 5 calendar days of the investigator’s first knowledge 
of the SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information.
a It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
patient, foetus or new born infant. 
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Dose limiting toxicities of concizumab has not been investigated in clinical trials.
There have been no reports about overdosing of concizumab and therefore no experience with 
overdose and overdose reactions exists. In case of a concizumab overdose, symptomatic medical 
treatment according to the clinical condition should be applied. No antidote exists in case of 
concizumab overdose.
Any overdose should be reported as an AE, with or without clinical manifestations. Overdoses are 
considered medication errors.
Treatment should be as appropriate and in accordance with hospital practice and guidelines.
12.7
Rules for putting enrolment on hold
If one of below mentioned criteria is fulfilled, enrolment of additional patients in the clinical trial 
program will be placed on hold. An urgent safety committee meeting will be scheduled to decide 
further actions. Dosing of patients on treatment may continue while further evaluation is made by 
the safety committee. A substantial amendment with relevant data must be submitted to the 
regulatory authorities to support restart of the trial.
!
Significant thromboembolic event* 
!
Event of DIC 
!
Anaphylactic reaction related to trial drug administration 
!
Death of trial patient which may be related to the trial product
!
Two or more other trial product related SAEs similar in nature have been reported and/or 
detected by laboratory measurements
!
Trends in AEs, clinical observations or laboratory parameters which raise concerns about 
the safety of continued treatment
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* Superficial thrombophlebitis or venous thrombosis associated with indwelling catheters is not considered a significant 
thromboembolic event unless evaluated as such by the investigator
12.8
Committees related to safety
12.8.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal concizumab safety committee to perform ongoing safety 
surveillance of safety data relevant to concizumab. The safety committee is a cross functional group 
within Novo Nordisk.
12.8.2
Data monitoring committee
The DMC is an independent, external committee composed of members whose expertise covers 
relevant specialties including statistics. The DMC is established to review and evaluate accumulated 
data from the trial at predefined time points as well as ad-hoc. This is in order to protect the safety 
of the patients and to evaluate the benefit-risk balance. The DMC will have access to the unblinded
data, and will provide recommendations on trial continuation, modification or termination.
In case there is any safety concern data will be compiled and the DMC will review these data. Their 
recommendation will go to the Novo Nordisk Safety committee for final decision of what next step 
is in this trial.
The DMC members will only have direct contact with the Novo Nordisk Global Safety department 
through the safety surveillance representatives, and will have no direct interaction with those in trial 
management. The DMC recommendations should be addressed directly to the Novo Nordisk Global 
Safety department and the internal Novo Nordisk safety committee for concizumab. It is the 
responsibility of the Novo Nordisk internal safety committee for concizumab to take action(s) for
patient safety based on the DMC recommendations.
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter.
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13 Case report forms 
For this trial a combination of electronic case report forms (eCRFs) and paper CRFs will be used.
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
Safety information forms
!
Technical complaint forms 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
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Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
13.3
Electronic diary
Novo Nordisk will provide the patient with an eDiary for electronic recording of details of their 
home treatment, bleeding episodes and treatment of bleeding episodes (i.e. use of FVIII). The 
eDiary and related support services will be supplied by a vendor working under the direction and 
supervision of Novo Nordisk. 
Patients will be instructed in the use of the eDiary by the investigator or delegated person before 
entering of any data. The eDiary will be dispensed to the patient at visit 2. After visit 2 and 
onwards, data will be entered by the patient in the eDiary device during home treatment.
The eDiary will be returned by the patient at the end of trial (EOT) visit.
All data entered will be transferred from the device to an electronic database, where it is kept as a 
certified copy of the source data by the eDiary vendor. Data entered in the device will upon 
confirmation of a successful back-up be deleted from the device. 
The eDiary will have built in edit checks and reminders, to ensure that all relevant questions are 
answered. 
eDiary data transferred to the electronic database will be viewable to relevant trial site staff and 
Novo Nordisk personnel on a secure, password protected web portal.
13.3.1
Investigator review of eDiary data
It is the responsibility of the Investigator or delegated staff to review the eDiary data reported by the 
patient. As a minimum it must be verified that the eDiary data is complete, consistent and according 
to the requirements defined in this protocol. This also includes that the number of doses reported in 
the eDiary is reviewed against the number of vials/cartridge accounted for as used by the patient.  
Upon review the Investigator must document that the review has taken place and any actions 
required e.g. retraining of the patient or decision to amend or correct the data reported by the 
patient. 
If the Investigator finds it necessary to amend or correct eDiary data, the patient must be consulted 
prior to requesting the actual data change. A Data Correction Request must be submitted to the 
eDiary vendor. An audit trail will be maintained.
14 Monitoring procedures 
Monitoring will be conducted using a risk based approach including risk assessment, monitoring 
plans, centralised monitoring and visits to trial sites. During the course of the trial, the monitor will 
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visit the trial site to ensure that the protocol is adhered to, that all issues have been recorded, to 
perform source data verification and to monitor drug accountability. The first monitoring visit will 
be performed as soon as possible after FPFV at the trial site and no later than 4 weeks after. The 
monitoring visit intervals will depend on the outcome of the centralised monitoring of the eCRFs 
(remote assessment of data by Novo Nordisk), the trial site's recruitment rate and the compliance of 
the trial site to the protocol and GCP, but will not exceed 12 weeks until LPLV at the trial site. This 
only applies to sites with scheduled, ongoing and/or discontinued patients.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone or text message).
All data must be verifiable in source documentation other than the eCRF. eDiary data is entered by 
the patient and will also be treated as source data. 
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
For historical data such as medical history, details of haemophilia and haemophilia treatment 
history, a reasonable effort must be made by the investigator, considering local requirements, to 
obtain this information from external sources, if not known by the patient. It is accepted that the 
earliest practically retainable record should be considered as the location of the source data and 
therefore the source document. This means that for laboratory results (e.g. biochemistry and 
haematology) a signed printout of the electronic results must be available.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The monitor will ensure that the eCRFs are completed and paper CRFs (if any) collected, that PROs 
and eDiaries are completed and reviewed by the investigator at the relevant scheduled visits and 
needed action has been taken and documented, if any.
The following data will be source data verified for screening failures:
!
Date for obtaining informed consent
!
Inclusion and exclusion criteria
!
Screen failure reason if possible
!
Date patient left the trial
!
Data relating to AEs if applicable
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!
Demography (See section 8.2.1)
!
Date of visit
Monitors will review the patient’s medical records and other source data (e.g. eDiaries and ePROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract reseach organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of patientdata, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The laboratory will provide all laboratory reports to the investigator for filing at the trial site. The 
laboratory report must be signedand dated by the investigator or delegated person and stored at the 
trial siteas source data.
The patientand any biological material obtained from the patientwill be identified by patient
number and trial ID. Appropriate measures such as encryption orleaving out certain identifiers will 
be enforced to protect the identity of patients in all presentations and publications as required by 
local, regional and national requirements
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk 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 use the Global Haemophilia Network (GHN) Investigator Portal to distribute 
and share trial-related documents and information with the participating sites.
After trial completion, Novo Nordisk will supply each trial site with long-life CDs or other relevant 
electronic archiving containing the electronic Investigator Trial Master File (eITMF) for each trial 
site. These CDs or other relevant electronic archiving will contain site-specific trial documentation 
as well as trial specific news and other relevant trial information, including audit trail on documents 
and site staff users. The GHN Portal software and hardware implementation are compliant with the 
requirements of U.S. Food and Drug Administration (FDA)21 CFR Part 11 and ICH E6 (EU 
directive for personal data protection)1,29.
Novo Nordisk will provide electronic tablets for reporting of all PROs questionnaires described in 
section8.6.1and in Appendix 1. In case the electronic tablet is revoked the questionnaires will be 
available in paper.
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The eDiary software and hardware implementation are compliant with the requirements of FDA 21
CFR Part 11 and ICH E6 (EU directive for personal data protection)1, 29.After trial completion, each 
trial site will be supplied with long-life CDs. These CDs will contain site-specific patient records 
including the patient’s eDiaries and ePROs as PROs are handled seperately from eDiary and audit 
trail including any data additions and corrections made on each form. The eDiary vendor will 
furthermore retain and securely store copies of all archived documents and data for 15 years or as 
required by local data retention laws for trial data
17 Statistical considerations
All endpoints referring to a time frame of at least 24 weeks will be evaluated in the main part of the 
trial, defined to end when the last patient have completed a minimum of 24 weeks of dosing or at 
LPFT (visit 2)+24 weeks if the last patient has withdrawn before visit 9. Please refer to Figure 17–1
for further information. All available data up to the time point where the last patient ends 24 weeks 
of treatment or has withdrawn will in such case be used in the analysis of the main part.
Endpoints comprising number of bleeding episodes will be evaluated based on treated bleeding 
episodes only. Multiple bleeding locations occurring from the same event (e.g., due to a bicycle 
accident) or at the same time point will be counted as one bleeding episode. Further, the endpoints 
will not include re-bleed.
A re-bleed is defined as a bleeding episode (worsening of bleeding site conditions e.g. swelling, 
pain) within 72 hours after stopping treatment of a previous bleeding episode at the same (or subset 
of the same) anatomical location. If a bleeding episode occurs in the same location 72 hours after 
stopping treatment, the bleed is defined as a new bleeding episode.
Clinical proof of concept
The statistical analysis of the collected data aims to establish CPoC that concizumab is efficacious 
in preventing bleeding episodes in haemophilia A patients without inhibitors. The objective will be 
assessed when the last of the 30 patients have completed 24 weeks of dosing (or have withdrawn). 
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the ABR of all patients with a threshold of 12, irrespective of individual dose 
titration. The primary CPoC criterion aims at evaluating the effect of concizumab at the last dose 
level reached for a patient. Hence, for this evaluation, only observations from the period where 
patients are on their end dose at time of analysis will contribute to the analysis. Furthermore, 
observations from the 2 week run-in period will be not be included. Since this evaluation disregards 
a subset of data collected the result should be viewed taking in to account the potential bias. The 
second CPoC criterion aims at evaluating the effect of concizumab when given as an escalation 
regimen. Hence, this will compare the ABR of haemophilia A patients treated with concizumab 
with the typical historical ABR of haemophilia A patients being treated on-demand using all data 
after enrolment. The second CPoC criterion will only be evaluated if the first one succeeds.
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The referred comparisons will be made using a negative binomial model with log of exposure time 
in main phase as offset. For each criterion, evidence of effect will be concluded if the 95% 
confidence interval of the estimated ABR is below 12. 
The value of 12 bleeds per year reflects conservatively a 50% reduction from the bleeding rate 
during on-demand treatment, which in previous trials typically has been reported to be above 30 
bleeds per year 30-32. A confidence limit lower than 12 will also to a certain extent substantiate that 
the prophylactic efficacy of concizumab may be similar to that of FVIII replacement therapy where 
an estimated mean of 6.5 bleeds per year was observed33.
Clinical arguments for the hierarchical test approach
Concizumab exhibits non-linear PK due to target mediated drug disposition and it is expected that 
the dose response curve of the ABR is rather steep. This implies that patients that are on a dose 
which is not efficacious are likely to bleed as patients that are not treated at all. The subset of data 
collected from the last dose clinically deemed as efficacious would reflect the efficacy of 
concizumab in the given patient.
17.1
Sample size calculation
The sample size calculation has been determined taking the small patient population into account, 
while also aiming for an acceptably narrow 95% confidence interval for the ABR. 
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be
accommodated by 30 patients. 
It is expected that the treatment duration of the main part allowing for escalation time for some 
patients is on average 6 months in the below calculations. 
When evaluating the power of the negative binomial analysis referred above, an annual bleeding 
rate of 4 is assumed for the end dose concizumab regimen, respectively in combination with an 
over-dispersion of 6. The power for concluding a bleeding rate lower than 12 then becomes 
approximately 95%. The power under varying values of true ABR and over-dispersion for the 
primary CPoC criterion are shown below in Table 17–1.
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion.
Power
Over-dispersion
ABR
5
6
7
4
99%
95%
92%
5
95%
90%
86%
6
87%
81%
72%
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For the secondary CPoC criterion that includes data prior to potential dose escalation, it is expected 
that the treatment duration of the main part is on average 8 months with an average ABR of 5.4 for 
the concizumab treated patients. This yields a marginal power of approximately 87% for the 
secondary CPoC criterion. 
In prior Novo Nordisk trials conducted in haemophilia patients, the typical 1-year over-dispersion 
for non-inhibitor patients on prophylaxis with FVIII or FIX has been in the range 4-8, implying 24 
weeks over-dispersion of 3-5 (e.g. in NN7008-3543, NN7088-3859 and NN7999-3747). On that 
background, an over-dispersion of 6 over the 24 weeks in the main part of the current trial is 
deemed realistic.
17.2
Definition of analysis sets
All dosed patients will be included in the Full Analysis Set (FAS) as well as in the Safety Analysis 
Set (SAS).
17.3
Primary endpoint
The primary endpoint is the number of bleeding episodes during at least 24 weeks from treatment 
onset.
The primary endpoint will be estimated using negative binomial regression with log of exposure 
time in main phase as offset, providing an actual estimate of the ABR as well as a corresponding 
95% confidence interval.
This analysis has the underlying assumption that the missing data mechanism is “missing at 
random”, i.e. MAR. Under this assumption, the statistical behaviour of the missing data (given the 
observed responses and the mean value structure) is assumed to be the same as for the observed 
data. The endpoint will be estimated based on the full analysis set (FAS) and only data collected 
prior to discontinuation of trial product or initiation of alternative treatment options will be used to 
draw inference.
17.4
Sensitivity analyses
To evaluate the robustness of the MAR assumption implied in the primary analysis, a modified 
tipping point analysis will be performed where patients having discontinued before finalization of 
the main part are assumed to have a worse outcome compared to what was observed during the 
main part of the trial. This will be done by adding a value Δi to the observed bleeding episodes in 
the main part of the trial before analysing the data. The offset is maintained as being the exposure 
during the main phase since it is not possible to identify the amount of missing observation 
time.The degree of worsening, Δi, will gradually be increased to evaluate at which point the upper 
95% confidence limit of the prophylactic concizumab ABR is no longer below a threshold of 12.
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The results of the primary analysis will be considered robust if the tipping point is above what is 
considered clinical plausible.
17.5
Additional analyses
An additional evaluation of the primary endpoint will be made, including actual concizumab dose 
level as additional factor in the primary analysis model specified above. Point estimates and 95% 
confidence interval will be provided for the ABR at the different dose levels of concizumab (0.15, 
0.20 and 0.25 mg/kg). Furthermore, an analysis with individual steady state PK/PD assessments 
included as covariates in the negative binomial regression model as specified for the primary 
analysis will be performed in order to evaluate possible associations between PK/PD and ABR that 
potentially could guide dose-selection. The referred steady-state PK/PD assessments comprise the 
concizumab trough level, maximum plasma concentration (Cmax) of concizumab, TFPI value prior 
to the last s.c. dose administration, peak thrombin generation (nM), Endogenous thrombin potential  
(nM*min) and velocity index (nM/min).
17.6
Secondary endpoints
17.6.1
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during 76 weeks from treatment onset.
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment 
onset.
!
The number of spontaneous bleeding episodes during 76 weeks from treatment onset.
The supportive secondary endpoints will be estimated using the same negative binomial regression 
model as the primary endpoint.
17.6.2
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during 76 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during 76 weeks from treatment onset.
!
Change from baseline of fibrinogen during 24 weeks from treatment onset.
!
Change from baseline of fibrinogen during 76 weeks from treatment onset.
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!
Change from baseline of D-dimer during 24 weeks from treatment onset.
!
Change from baseline of D-dimer during 76 weeks from treatment onset
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset.
!
Change from baseline of F1 + 2 during 76 weeks from treatment onset.
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset.
!
Change from baseline of PT during 76 weeks from treatment onset.
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset.
!
Change from baseline of APTT during 76 weeks from treatment onset.
!
Change from baseline of antithrombin (AT) during 24 weeks from treatment onset.
!
Change from baseline of AT 76 weeks from treatment onset.
Adverse Events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has onset from the first 
exposure to treatment until the last visit in the trial. Treatment-emergent adverse event endpoints 
will be summarised by system organ class, preferred term, seriousness, severity and relation to trial 
product. All Adverse events will further be listed.
Frequency of binding anti-concizumab antibodies will by listed and summarised by time frame 
according to the two endpoint definitions.
All laboratory safety endpoints will be plotted by time, both as absolute values and change from 
baseline. Laboratory safety endpoints will further be summarised and listed.
17.6.3
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks.
!
Concentration of concizumab prior to the last dose administration at 76 weeks.
The pharmacokinetic endpoints will be summarised and listed.
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17.6.4
Supportive secondary pharmacodynamic endpoints
Free TFPI concentration:
!
Value prior to the last dose administration at 24 weeks.
!
Value prior to the last dose administration at 76 weeks.
Thrombin generation:
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks.
!
Peak thrombin generation (nM) prior to the last dose administration at 76 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 76 weeks.
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks.
!
Velocity index (nM/min) prior to the last dose administration at76 weeks.
The PD endpoints will be summarized and listed. 
17.7
Exploratory endpoints
17.7.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
Adverse events related to technical complaints will be listed and summarised.
17.7.2
Exploratory patient reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
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!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Status of PGI-C after 24 weeks from treatment onset
!
Change in H-DAT after 76 weeks from treatment onset
Patient reported outcomes (PROs) will be collected using questionnaires at visits 1, 2, 4, 5, 6, 7, 8,
9, 10 and 16. 
Patient reported outcome questionnaires to be analysed:
!
Haemophilia Treatment Experience Measure (Hemo-TEM) 
!
Validated Hemophilia Regimen Treatment Aderence Scale – Prophylaxis (VERITAS-Pro®)
or Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
!
36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
!
Patient Global Impression of Change (PGI-C)
!
Sheehan Disability Scale (SDS)16
!
Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
!
Haemophilia - Device Assessment Tool (H-DAT)
!
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
VERITAS-Pro®orVERITAS-PRN®, SF-36v2, SDS, TSQM, H-DAT and SIAQ-ISRQ will be 
scored according to their respective scoring algorithms. Change from visit 2 to visit 9 and change 
from visit 2 to visit 16 will be described.
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17.7.3
Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP  time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
Individual "concentration over time" curves will be presented in a plot. A mean plot including error
bars will also be presented. For thrombin generation the endpoints will be summarized and listed.
17.8
Interim analysis
The trial does not include a formal interim analysis. However, the split of the trial into a main and 
extension part offers the opportunity of reporting results before the end of the trial. Other reporting 
of the trial might be done during the extension part once the data collection and review of the main 
part data has been finalised and individual clinical study reports might in such case be issued. A 
final clinical study report describing results from the main and extension part will be written when 
the last patient has either completed or withdrawn from the trial.
All main conclusions regarding clinical proof of concept and dose guidance for phase 3 will be 
based on the reporting after the main part, see Figure 17–1.
Figure 17–1
Definition of main and extension part
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18 Ethics
18.1
Benefit-risk assessment of the trial
Benefits
Results from a multiple dose phase 1 trial where concizumab was dosed for approximately 6 weeks 
showed a trend towards efficacy in a limited number of patients who reached concizumab plasma 
concentrations above 100ng/mL., see section 3.1.2. Based on these results, it is expected that the 
majority of the patients treated with concizumab 0.15mg/kg daily dose will be protected from
bleeding episodes. Patients who experience excessive bleeding episodes on the lowest dose will 
have a possibility to be escalated to a higher dose where bleeding preventive efficacy of 
concizumab treatment is expected to improve. Also, concizumab is administered s.c. and might
reduce the burden of frequent i.v. injections associated with current treatment options in
haemophilia A patients without inhibitors as well as significantly reducing the risk of anti-FVIII 
inhibitor development.
Information gained from this trial will contribute to gaining regulatory approval for a product that is 
anticipated to offer clinical advantages over currently available products. 
Risks
No risks have been recognised as identified risks by review of safety data from the activities in the 
clinical development so far. However, the nonclinical toxicity studies have identified 
thromboembolic events as a potential risk when treating non-human primates with concizumab at 
high exposures. 
As observed for other pro-coagulant compounds, there is a potential safety risk of thrombosis and 
vascular ischemia with reaching very high concizumab plasma concentrations. In non-clinical 
toxicity studies with concizumab, thrombi were observed at high doses. However, a no observed 
adverse effect level (NOAEL) for concizumab has been identified in non-haemophilic animals at 
plasma concentrations at least 24 fold higher than the currently anticipated effective plasma 
concentration (mean area under curve [AUC] and Cmax) based on PK modelling.
In clinical trials, except for one case of superficial thrombophlebitis in a healthy volunteer who
received a single dose of 1mg/kg, no other thromboembolic events were observed. A phase 1 
multiple dose trial was finalised in haemophilia A patients (0.8 mg/kg s.c. every 4 days for 6 
weeks). In this clinical trial, marked changes in coagulation parameters were observed including a 
decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range in patients with high plasma concentrations of concizumab. These changes were not 
judged as clinically significant by the investigators and were not followed by thromboembolic AEs 
or an increase in the number of bleeding episodes in the explorer™3 trial.
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A potential risk identified in non-clinical studies is vascular vessel wall changes due to immune 
complex deposition causing localized vascular vessel wall changes such as hypertrophy and 
inflammatory cell infiltration. Concizumab is a foreign protein to animals and it is generally 
recognized that animal studies are limited in their ability to predict human immune responses to a 
therapeutic protein product. The concentrations of concizumab in plasma in animals in the non-
clinical studies have reached levels far above the anticipated effective concentration. Humans are 
expected to have a very low immunogenic response towards a humanised mAb. The antibodies 
towards concizumab have not been observed so far in clinical trials. Furthermore, even if antibodies 
towards concizumab occur, the risk for the rate of immune complex formation exceeding the 
clearance capacity is considered low. Please refer to the Investigator’s Brochure for further 
information including subsequent replacement therapy.
If antibodies against concizumab develop, they might also inhibit the function of the administered 
drug. The consequence of this could be that the patient may not be able to benefit from this drug in 
the future. Antibody development against concizumab is not expected to reduce the effect of other 
treatment options.
Theoretical risks include bleeding due to consumption of coagulation factors and adverse reactions 
due to potentiation of inflammatory reactions or tissue damage due to impairment of tissue repair 
mechanisms 34 35 . TFPI is an important inhibitor of TF which, in addition to its role in haemostasis, 
is implicated in tissue repair processes and in a variety of physiological and pathophysiological 
states where repair mechanisms are activated. These include sepsis, DIC, inflammation, 
atherosclerosis, cancer and crush injuries 36 37, 38. There may be a risk of allergic reactions, including 
severe (anaphylactic) reactions, in connection with concizumab administration. Severe allergic 
reactions may potentially be life-threatening and thus, the trial products will be administered to the 
trial patients at the site under the surveillance of medically trained trial site staff in the beginning of 
the trial.
Overall the anticipated benefits from participating in the trial outweigh the potential risks.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the patient verbal and written 
information about the trial and the procedures involved in a form that the patient can read and 
understand. 
The patients 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.
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The investigator must ensure the patient ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the patient 
before any trial-related activity.  
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically trained staff in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the investigator must inform the patient in a timely manner, and a revised 
written patient information must be provided and a new informed consent must be obtained.
Only applicable for Japan: As a minor is unable to provide legally binding consent, informed 
consent must be sought from the parent(s)/LAR(s) on the child’s behalf prior to enrolling a child in 
the trial, according to local requirements. 
18.3
Data handling
If the patient withdraws from the trial or is lost to follow up, then the patient’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit will be retained by 
Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to patients during trial
All written information to patients must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the patients 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
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also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of patients who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the patients 
should be described.
19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided and protocol waivers are not acceptable under any 
circumstances.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed. The Sponsor will assess any protocol deviation and 
decide whether any of these non-compliances are likely to affect to a significant degree the safety 
and rights of a patient or the reliability and robustness of the data generated (potential serious 
breach) and if it should be reported to the Regulatory Authorities as a serious breach of GCP and/or
the protocol.
In addition, deviations must be documented and explained in a protocol deviation by stating the 
reason, date, and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The below process will be in place to prevent missing data in this trial.
The importance of patient retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The patients will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of patient retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
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The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
21 Critical documents
An Investigator Portal (Global Haemophilia Network [GHN]) will be used as primary media for 
exchange and handling of investigator trial master file documents between Novo Nordisk and the 
site and for electronic storage of these documents during trial conduct.
Before a trial site is allowed to start screening patients, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, patient information/informed consent form, 
any other written information to be provided to the patient and patient recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure
!
SmPC or similar labelling of rFVIII (turoctocog alfa)
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
Description of research facility obtained (applicable for non-US sites)
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Only applicable for US trial sites: 
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
For local laboratory parameters the following will be collected:
!
Laboratory normal ranges
!
Laboratory certification, quality assurance (QA) scheme or similar documentation
!
Laboratory assay methods (only non-standard assays) and/or analytical methods
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1,
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the patients.
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At least investigator must be trained in the current protocol version at a Novo Nordisk Investigator 
meeting or by the most recent version of the web training. It is recommended that all site staff  
completes the web protocol training.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the patient identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
patients to a specific qualified physician who will be readily available to patients during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
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Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications 39.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure how-we-disclose-trial-information8.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of the main part of the trial and other interim analyses, because the release of such 
information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors 39 (sometimes referred to as the Vancouver 
Criteria).
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23.1.2
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 a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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Version:
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24 Retention of clinical trial documentation and humanbiosamples
24.1
Retention of clinical trial documentation
Patientsmedical records must be kept for the maximum period permitted by the hospital, institution 
or private practiceaccording to local regulation and practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other patientdata (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
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.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
Applicable only for Spain25 years retention according to the Spanish Royal Decree 1090/2015
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. Thedeletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements. 
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Date:
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Version:
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UTN:U1111-1179-3872
Status:
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24.2
Retention of human biosamples
This trial will involve collection of human biosamples at visit 1 (screening visit), and at visit 17
(end of trial) and these samples are to be stored maximum 15 years from end of trial. In addition, 
samples which have been drawn as back up samples during the conduct of the trial and have not 
been analysed will be captured and stored under the same conditions. 
Storage of human biosamples is voluntarily and will not affect the patients’ participation in the trial. 
Therefore, patients will have the possibility to sign the informed consent for the trial and 
participate, while refusing permission for biological specimens to be stored for future exploratory 
analysis.
!
Human biosamples will be stored at the central laboratory.
!
1.2 mL citrated plasma, 1.0 mL serum and/or 2.0 ml whole blood (DNA for genotyping)
will be obtained.
!
The intended use of the stored human biosamples e.g.: As new biomarkers related to the 
disease and/or safety, efficacy, or mechanism of action of concizumab may evolve during 
the conduct of the trial, the analyses of the stored human biosamples may also include 
biomarkers that are unknown at present or have not been included in the scientific 
hypotheses at initiation of the trial 
!
Human biosamples may be transferred to third parties e.g. research consortias
!
The human biosamples will be transferred and stored after the end of trial at a designated 
central laboratory
!
Confidentiality and personal data protection will be ensured during storage after the end of 
trial
!
The human biosamples may be transferred to other countries (not applicable if local 
regulations prohibits export of human biosamples)
!
The human biosamples will be destroyed at the latest 15 years from end of trial
!
The patient may request the stored human biosamples to be destroyed by withdrawing 
consent. The results obtained from any already performed analyses of the samples will still 
be used
!
Novo Nordisk and laboratory will have access to the stored human biosamples 
!
Potential consequences for the patient and their relatives: In the event that the collected 
human biosamples (plasma, serum and/ or DNA for genotyping) will be used in the future, 
the investigator will become directly informed by Novo Nordisk about the results if the 
findings are deemed clinically relevant and analytically valid and quantifiable. In such case, 
a written summary of the findings, including listings of patient specific values, will be 
provided once a firm conclusion from the results has been drawn by Novo Nordisk. 
Potentially, observations of neoplastic diseases, serious hereditary diseases, other un-
treatable diseases, or any other abnormal findings could be part of the observations. Patients 
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Version:
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can contact the investigator if they wish to be informed about results derived from stored 
human biosamples obtained from their own body. See also Section 5.1.
24.2.1
Antibody samples
Antibody samples will be retained until drug approval by U.S. Food and Drug Administration 
(FDA) and/or European Medicines Agency (EMA). 
The retained antibody samples may be used for later analysis for further characterisation of 
antibody responses towards drug if required by health authorities or for safety reasons. The samples 
will be stored at a central bio-repository after end of trial and until marketing authorisation approval 
or until the research project terminates, but no longer than 15 years from end of trial after which 
they will be destroyed.
The patients’ identity will remain confidential and the antibody samples will be identified only by 
patient number, visit number and trial identification number. No direct identification of the patient 
will be stored together with the samples.
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples.
Patients can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body.
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CONFIDENTIAL
Date:
28 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: Updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the patients, new information that may affect adversely the safety of the patients or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the patients), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC (not 
applicable for Japan).
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the patients.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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CONFIDENTIAL
Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
Only applicable for France: The French Public Health Code article L 1121-10 (law no 2004-806 of 
9 August 2004 art. 88 I, IX, Journal Officiel of 11 August 2004. “The sponsor is responsible for 
identification of the harmful consequences of the biomedical the research for the person lending 
himself thereto and for indemnification of his beneficiaries, except in case of proof, incumbent on 
it, that the prejudice is not attributable to his fault or of the fault of any intervening party, without 
the sponsor’s being entitled to call on acts by a third party or the voluntary withdrawal of the person 
who had initially consented to cooperating in the research”.
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Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition 
and evaluation of transient ischemic attack: a scientific statement for healthcare 
professionals from the American Heart Association/American Stroke Association Stroke 
Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular 
Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary 
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value of this statement as an educational tool for neurologists. Stroke. 2009;40(6):2276-93.
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Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, et al. 2011 
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Am Coll Cardiol. 2011;58(19):2020-45.
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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29.
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study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 
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randomized comparison of two prophylaxis regimens and a paired comparison of on-
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al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand 
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A (SPINART). J Thromb Haemost. 2013;11(6):1119-27.
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Lentz SR, Misgav M, Ozelo M, Salek SZ, Veljkovic D, Recht M, et al. Results from a large 
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Belting M, Ahamed J, Ruf W. Signaling of the tissue factor coagulation pathway in 
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Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2016.
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Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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Protocol
Trial ID: NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of Prophylactic 
Administration of Concizumab in Patients with Severe Haemophilia A 
without Inhibitors
Trial phase: 2
Protocol Version 1 (15 March 2017); Protocol Amendment no 1 (05 May 2017) ; Protocol 
Amendment no 2 (14 Dec2017) and Protocol Amendment no 3 (21 Aug 2018) for all participating 
countries. 
Protocol originator
, 
Biopharm, Trial 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.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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Table of Contents
Page
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................7
Table of Tables............................................................................................................................................7
List of abbreviations ...................................................................................................................................9
1
Summary............................................................................................................................................15
2
Flow chart ..........................................................................................................................................18
3
Background information and rationale for the trial.........................................................................21
3.1
Background information..........................................................................................................21
3.1.1
Haemophilia ..........................................................................................................21
3.1.2
Concizumab...........................................................................................................22
3.2
Rationale for the trial...............................................................................................................24
4
Objective(s) and endpoint(s)..............................................................................................................26
4.1
Objective(s) ............................................................................................................................26
4.1.1
Primary objective...................................................................................................26
4.1.2
Secondary objectives .............................................................................................26
4.2
Endpoint(s) .............................................................................................................................26
4.2.1
Primary endpoint ...................................................................................................26
4.2.2
Secondary endpoints ..............................................................................................26
4.2.2.1
Supportive secondary endpoints .......................................................26
4.2.3
Exploratory endpoints............................................................................................28
4.2.3.1
Exploratory safety endpoints ............................................................28
4.2.3.2
Exploratory patient-reported outcome endpoints...............................28
4.2.3.3
Exploratory pharmacokinetic and pharmacodynamic endpoints ........28
5
Trial design ........................................................................................................................................29
5.1
Type of trial ............................................................................................................................29
5.1.1
Surgery..................................................................................................................30
5.2
Rationale for trial design .........................................................................................................30
5.3
Treatment of patients...............................................................................................................33
5.3.1
Dose escalation......................................................................................................34
5.3.2
Treatment of bleeding episodes during the trial ......................................................35
5.3.3
Prohibited medication ............................................................................................35
5.4
Treatment after discontinuation of trial product .......................................................................36
5.5
Rationale for treatment............................................................................................................36
6
Trial population .................................................................................................................................37
6.1
Number of patients..................................................................................................................37
6.2
Inclusion criteria .....................................................................................................................37
6.3
Exclusion criteria ....................................................................................................................37
6.4
Criteria for premature discontinuation of trial product .............................................................38
6.5
Withdrawal from trial..............................................................................................................38
6.6
Patient replacement .................................................................................................................39
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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6.7
Rationale for trial population...................................................................................................39
7
Milestones...........................................................................................................................................40
8
Methods and assessments ..................................................................................................................41
8.1
Visit procedures ......................................................................................................................41
8.1.1
Informed consent, long-term storage consent..........................................................42
8.1.2
Screening log, enrolment log, trial card and patient number....................................42
8.1.3
Screening failures and re-screening........................................................................42
8.1.4
Premature discontinuation of trial product..............................................................43
8.1.5
Withdrawal from trial.............................................................................................43
8.1.6
Review/evaluation of clinical outcome...................................................................44
8.1.7
Visit 1 (Screening part)..........................................................................................44
8.1.8
Training of patients visit 1 and visit 2.....................................................................45
8.1.9
Treatment period - Main part..................................................................................45
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site) ......................45
8.1.9.2
Treatment period at home.................................................................46
8.1.9.3
Visit 3 (Phone visit)..........................................................................47
8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits) .........................................47
8.1.9.5
Visit 9 (Assessment visits)................................................................48
8.1.10
Extension Part........................................................................................................49
8.1.10.1
Visit 10 (Assessment visits)..............................................................49
8.1.10.2
Visit 11, 12, 13, 14 and 15, 15.1, 15.2, 15.n (Assessment visits) .......50
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) -
Extension part ..................................................................................51
8.1.11
Follow-up Part.......................................................................................................52
8.1.11.1
Visit 17 (End of trial) .......................................................................52
8.1.12
Unscheduled Visit..................................................................................................53
8.1.12.1
Unscheduled 24 hour PK-Visit .........................................................53
8.2
Patient related information/assessments...................................................................................54
8.2.1
Demography ..........................................................................................................54
8.2.2
Concomitant illness and medical history other than haemophilia ............................54
8.2.3
Concomitant medication ........................................................................................54
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History .......................55
8.3
Efficacy assessments...............................................................................................................56
8.3.1
Bleeding episodes ..................................................................................................56
8.4
Safety assessments ..................................................................................................................60
8.4.1
Physical examination .............................................................................................60
8.4.2
Body measurements...............................................................................................60
8.4.3
Vital signs..............................................................................................................61
8.4.4
Electrocardiogram..................................................................................................61
8.4.5
Adverse events.......................................................................................................61
8.4.5.1
Medication error...............................................................................62
8.4.5.2
Adverse events requiring additional data collection ..........................62
8.5
Laboratory assessments...........................................................................................................63
8.5.1
Laboratory assessments for efficacy.......................................................................64
8.5.1.1
Thrombin generation........................................................................64
8.5.1.2
Free TFPI.........................................................................................65
8.5.2
Laboratory assessments for safety ..........................................................................65
8.5.2.1
Urinalysis.........................................................................................65
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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8.5.2.2
Haematology....................................................................................65
8.5.2.3
Biochemistry....................................................................................66
8.5.2.4
FVIII activity ...................................................................................67
8.5.2.5
Coagulation parameters....................................................................67
8.5.2.6
FVIII inhibitor test ...........................................................................67
8.5.2.7
Anti-concizumab antibodies .............................................................67
8.5.2.8
Concizumab ELISA .........................................................................69
8.5.2.9
Total TFPI........................................................................................70
8.5.3
Human biosamples.................................................................................................70
8.6
Other assessments ...................................................................................................................70
8.6.1
Patient reported outcomes ......................................................................................70
8.6.2
Training.................................................................................................................72
8.6.2.1
Concizumab and NovoPen® 4...........................................................72
8.6.2.2
Turoctocog alfa ................................................................................72
8.6.2.3
eDiary..............................................................................................72
8.6.3
Surgery..................................................................................................................73
8.7
Patient compliance..................................................................................................................73
8.8
Treatment compliance:............................................................................................................73
9
Trial supplies......................................................................................................................................75
9.1
Trial products..........................................................................................................................75
9.2
Labelling.................................................................................................................................75
9.3
Storage....................................................................................................................................76
9.4
Drug accountability and destruction ........................................................................................77
9.5
Auxiliary supplies ...................................................................................................................77
10
Interactive voice/web response system ..............................................................................................78
11
Randomisation procedure and breaking of blinded codes................................................................79
Randomisation.....................................................................................................................................79
12
Adverse events, and technical complaints .........................................................................................80
12.1
Definitions ..............................................................................................................................80
12.1.1
Adverse event ........................................................................................................80
12.1.2
Serious adverse event.............................................................................................81
12.1.3
Non-serious adverse event......................................................................................82
12.1.4
Medication errors...................................................................................................82
12.1.5
Adverse events requiring additional data collection................................................83
12.1.6
Adverse event of special interest ............................................................................84
12.1.7
Technical complaints .............................................................................................88
12.2
Reporting of adverse events.....................................................................................................88
12.3
Follow-up of adverse events....................................................................................................91
12.4
Technical complaints and technical complaint samples............................................................92
12.4.1
Reporting of technical complaints ..........................................................................92
12.4.2
Collection, storage and shipment of technical complaint samples ...........................93
12.5
Pregnancies.............................................................................................................................94
12.5.1
Pregnancies in female partners of male patients......................................................94
12.6
Precautions and/or overdose....................................................................................................95
12.7
Rules for putting enrolment on hold ........................................................................................95
12.8
Committees related to safety ...................................................................................................96
12.8.1
Novo Nordisk safety committee .............................................................................96
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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12.8.2
Data monitoring committee....................................................................................96
13
Case report forms ..............................................................................................................................97
13.1
Corrections to case report forms..............................................................................................97
13.2
Case report form flow .............................................................................................................97
13.3
Electronic diary.......................................................................................................................98
13.3.1
Investigator review of eDiary data..........................................................................98
14
Monitoring procedures ......................................................................................................................98
15
Data management ............................................................................................................................101
16
Computerised systems .....................................................................................................................101
17
Statistical considerations .................................................................................................................102
17.1
Sample size calculation .........................................................................................................103
17.2
Definition of analysis sets......................................................................................................104
17.3
Primary endpoint...................................................................................................................104
17.4
Sensitivity analyses...............................................................................................................105
17.5
Additional analyses...............................................................................................................105
17.6
Secondary endpoints .............................................................................................................105
17.6.1
Supportive secondary efficacy endpoints..............................................................105
17.6.2
Supportive secondary safety endpoints.................................................................106
17.6.3
Supportive secondary pharmacokinetic endpoints.................................................106
17.6.4
Supportive secondary pharmacodynamic endpoints..............................................107
17.7
Exploratory endpoints ...........................................................................................................107
17.7.1
Exploratory safety endpoints................................................................................107
17.7.2
Exploratory patient reported outcome endpoints...................................................108
17.7.3
Exploratory pharmacokinetic and pharmacodynamic endpoints............................109
17.8
Interim analysis.....................................................................................................................109
18
Ethics................................................................................................................................................110
18.1
Benefit-risk assessment of the trial ........................................................................................110
18.2
Informed consent ..................................................................................................................111
18.3
Data handling........................................................................................................................112
18.4
Information to patients during trial ........................................................................................112
18.5
Premature termination of the trial and/or trial site..................................................................112
19
Protocol compliance.........................................................................................................................113
19.1
Protocol deviations................................................................................................................113
19.2
Prevention of missing data ....................................................................................................113
20
Audits and inspections .....................................................................................................................115
21
Critical documents...........................................................................................................................115
22
Responsibilities.................................................................................................................................116
23
Reports and publications .................................................................................................................117
23.1
Communication of results......................................................................................................118
23.1.1
Authorship...........................................................................................................118
23.1.2
Site-specific publication(s) by investigator(s).......................................................119
23.2
Investigator access to data and review of results ....................................................................119
24
Retention of clinical trial documentation and human biosamples..................................................120
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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24.1
Retention of clinical trial documentation ...............................................................................120
24.2
Retention of human biosamples.............................................................................................121
24.2.1
Antibody samples ................................................................................................122
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........123
26
Indemnity statement ........................................................................................................................124
27
References ........................................................................................................................................125
Appendix I Patient Reported Outcome
Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments, if applicable for the individual 
country
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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Table of Figures
Page
Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous 
(circles) and traumatic (triangles) bleeding episodes during the dosing period and 
follow-up period.................................................................................................................24
Figure 5–1
Schematic diagram of the trial design .................................................................................29
Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated 
patients in explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal 
lines indicate 100 ng/mL, and the shaded areas represent the full range (min-max) of the 
individual predicted profiles. ..............................................................................................32
Figure 5–3
Dose escalation of concizumab for one individual patient...................................................35
Figure 8–1
Overview of visit structure in explorer™5 ..........................................................................41
Figure 12–1
Reporting of AEs ...............................................................................................................90
Figure 17–1
Definition of main and extension part...............................................................................109
Table of Tables   
Page
Table 2–1
Flow chart..........................................................................................................................18
Table 2–2
Flow chart explanatory descriptions....................................................................................20
Table 5–1 
List of products provided by Novo Nordisk ........................................................................33
Table 8–1
Definition of stop of bleeding episode ................................................................................57
Table 8–2
Definitions of bleeding episodes (cause of bleed)................................................................57
Table 8–3
Definition of bleeding episode severity and treatment recommendation ..............................57
Table 8–4
Guide for dosing in bleeding episodes and surgery .............................................................59
Table 9–1
Trial products.....................................................................................................................75
Table 9–2
Storage conditions..............................................................................................................76
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion..........................104
Table 2–1
Flow chart..........................................................................................................................18
Table 2–2
Flow chart explanatory descriptions....................................................................................20
Table 5–1 
List of products provided by Novo Nordisk ........................................................................33
Table 8–1
Definition of stop of bleeding episode ................................................................................57
Table 8–2
Definitions of bleeding episodes (cause of bleed)................................................................57
Table 8–3
Definition of bleeding episode severity and treatment recommendation ..............................57
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
8 of 127
Table 8–4
Guide for dosing in bleeding episodes and surgery .............................................................59
Table 9–1
Trial products.....................................................................................................................75
Table 9–2
Storage conditions..............................................................................................................76
Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion..........................104
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
9 of 127
List of abbreviations
ABI
ankle-brachial index
ABR
annualised bleeding rate 
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest 
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
antithrombin
AUC
area under curve
BP
blood pressure
BU
Bethesda unit
CLAE
clinical laboratory adverse event
Cmax
maximum plasma concentration
CNS
central nervous system
concizumab B
the name concizumab is being used as an 
abbreviation for concizumab B. B is the 
formulation 
CPoC
clinical proof of concept
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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CRF
case report form
CRO
contract research organisation
CRP
c-reactive protein
CT
computerized tomography
cTn
cardiac troponin
CTR
clinical trial report
DFU
direction for use
DIC
disseminated intravascular coagulation
DMC
data monitoring committee
DUN
dispensing unit number
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EMA
European medicines agency
EOT
end of trial
ETP
endogenous thrombin potential 
FAS
full analysis set
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Protocol
CONFIDENTIAL
Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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FDA
U.S. Food and Drug Administration
FDAAA
U.S. Food and Drug Administration 
Amendment Act
FIX
coagulation factor IX
FPFV
first patient first visit
FVIII
coagulation factor VIII
FX
coagulation factor X
FXa
activated coagulation factor X
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GHN
global haemophilia network
HCP
host cell protein
H-DAT
Haemophilia Device Assessment Tool
Hemo-TEM
Hemophilia Treatment Experience Measure
IB
investigator’s brochure
IC
informed consent 
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal 
Editors
ID
identification
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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IEC
independent ethics committee
IgG4
immunoglobulin G4
IMP
investigational medicinal product
INN
International Non-Proprietary Names for 
Pharmaceutical Substances 
IRB
institutional review board
ISTH
International Society on Thrombosis and 
Haemostasis
ISRQ-SIAQ
Injection Site Reaction Questionnaire-Self-
Injection Assessment Questionnaire
i.v.
intravenous(-ly)
IWRS
interactive web response system
LBBB
left bundle branch block
LPFV
last patient first visit
LPLV
last patient last visit
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory 
Activities
MI
myocardial infarction
MRA
magnetic resonance angiogram
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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MRI
magnetic resonance imaging
NIMP
non investigational medicinal product
PCD
PD
primary completion date
pharmacodynamic
PEF
peak expiratory flow
PK
pharmacokinetic
PGI-C
Patient’s Global Impression of Change
PP
per protocol
PRO
patient reported outcome
PT
prothrombin time
QA
Q4D
quality assurance
every 4th day
rFVIII
the name ‘rFVIII’ will be used throughout 
the protocol and the product is identical to 
‘turoctocog alfa’
SAE
serious adverse event
SAS
safety analysis set
sBE
s.c.
spontaneous Bleeding Episode
subcutaneous(-ly)
SDS
Sheehan Disability Scale
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Protocol
CONFIDENTIAL
Date:
28 August 2018
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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SF-36v2
36-Item Short Form Health Survey
SI
international system of units
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse 
reaction
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
TF
tissue factor
TFPI
tissue factor pathway inhibitor
TG
thrombin generation
TMM
trial materials manual
TPA
trial product administration
TSQM
Treatment Satisfaction Questionnaire for 
Medication
UTN
Universal Trial Number
VERITAS-Pro®
Validated Hemophilia Regimen Treatment 
Adherence Scale-Prophylaxis
VERITAS-PRN® 
Validated Hemophilia Regimen Treatment 
Adherence Scale-Pro Re Nata
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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1
Summary
The main objective for the phase 2 trial NN7415-4255, explorer™5, is to assess the efficacy of 
concizumab administered s.c. once daily to prevent bleeding episodes in patients with severe 
haemophilia A without inhibitors. Furthermore, this trial aims to assess the longer-term efficacy and 
safety of concizumab in severe haemophilia A patients without inhibitors. 
Objective(s) and endpoint(s):
Primary objective 
!
To assess the efficacy of concizumab administered  s.c. once daily in preventing bleeding 
episodes in patients with severe haemophilia A without inhibitors
Secondary objectives 
!
To assess the longer-term efficacy of concizumab in patients with severe haemophilia A without 
inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without 
inhibitors
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset.
Key secondary endpoints
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of treatment emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset.
Time frames for evaluation of objectives/endpoints:
All endpoints referring to the time frame of at least 24 weeks will be evaluated in the main part of 
the trial, defined to end when the last patient has completed a minimum of 24 weeks of treatment 
with trial product (or have withdrawn). The extension part of the trial will provide additional safety 
and long-term efficacy data.
Trial design:
The trial is a multi-centre single arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation) administered daily s.c. in patients with 
severe haemophilia A without inhibitors. This is done by comparing the annual bleeding rate (ABR) 
to an ABR of 12.The selected dose regimen is based on relevant PK and TFPI data as well as 
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Protocol
CONFIDENTIAL
Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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pharmacokinetic/pharmacodynamic (PK/PD) modelling from the preceding explorer™ trials. Both 
on-demand and prophylaxis patients will be eligible for the trial.
The total trial duration for the individual patient will be approximately 86 - 138 weeks, consisting 
of a 2 week screening period, a subsequent 76 – 126 week treatment period and an 8 week follow-
up period. 
The 76 – 126 weeks treatment period is split into a main part which lasts at least 24 weeks and an 
extension part which lasts up to 102 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 30 patients have completed at least 24 weeks of concizumab 
dosing or have discontinued trial treatment. The analysis of the main part of the trial aims to 
substantiate clinical proof of concept (CPoC) that concizumab has the potential to prevent bleeding 
episodes in severe haemophilia A patients without inhibitors. 
rFVIII (turoctocog alfa) for treatment of breakthrough bleeding episodes will be provided by Novo 
Nordisk during the trial. The patient will not be provided with trial product or rFVIII (turoctocog 
alfa) after the end of the trial.
Trial population:
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product: 33
Number of patients expected to complete the trial: 30
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine the 
suitability for the trial
!
Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at screening
Key exclusion criteria
!
Known or suspected hypersensitivity to trial product(s) or related products
!
Known inherited or acquired bleeding disorder other than haemophilia A
!
Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at 
screening measured by the Nijmegen method 
Key Efficacy assessment
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Protocol
CONFIDENTIAL
Date:
28 August 2018
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
Page:
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!
The number of bleeding episodes during at least 24 weeks.
Key Safety assessment
!
Number of TEAEs during at least 24 weeks.
Trial product(s):
The following products will be used in the trial:
!
Investigational Medicinal Product (IMP):
Concizumab B, 100 mg/mL to be administered s.c. with NovoPen®4 and needles 
!
Non Investigational Medical Product (NIMP):
Turoctocog alfa (rFVIII) 2000 IU/vial and isotonic sodium chloride (solvent). Turoctocog 
alfa (rFVIII) is for intravenous administration.
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Protocol
UTN:U1111-1179-3872
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
5.0
Page:
18 of 127
2
Flow chart
Table 2–1
Flow chart
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up
Visit number b
1
2
3
4-8
9
10-11
12
13-14
15, 15.1, 
15.2, 15.ns
16
Unscheduled c
17t
Timing of visit (d) d
14 to 21 days 
before Visit2
1
8
29-141
169
225-281 337
393-449
505-841
Up to
883
When 
applicable
Up to
945
Visit window (d)
0
+1
±7
±7
±7
±7
±7
±7
±7
Not applicable
-7
Treatment week (w)
---
0
1w
Every 
4w
24w
Every 
8w
48w Every 8 w
Every 8w
Up to 
126w
---
Up to135w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/Genotyping and Long-term storage consent
●
In/exclusion criteria
●
●e
Demography 
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial 
product
●
●
●
●
●
●
●
●
●
●
●
EFFICACY ASSESSMENTS 
Bleeding episodes f, g
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab)
●
●
●r
●h,r
●r
●r
●r
●r
●h,r
●h,r
●
Free TFPI (central lab)  
●
●
●r
●h,r
●r
●r
●r
●r
●h,r
●h,r
●
SAFETY ASSESSMENTS
Physical examination
●
●
●
●
●
●
●
Body measurements 
●
●i
●i
●i
●i
●i
●i
●i
●i
●i
Vital signs
●
●j
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●
●h
●
●
●
●
●h
●
●
Biochemistry (central lab)
●
●
●
●h
●
●
●
●
●h
●
●
FVIII activity (central lab)
●k
●l
Coagulation parameters (central lab)
●
●
●
●h
●
●
●
●
●h
●
●
FVIII inhibitors (central lab)
●
●l
Anti-concizumab antibodies (ADA) (special lab)m
●
●
●
●h
●
●
●
●
●h
●
●
Concizumab ELISA (special lab)
●
●r
●h,r
●r
●r
●r
●r
●h,r
●h,r
●
Total TFPI (special lab)
●
●
●
●h
●
●
●
●
●h
●
●
TRIAL MATERIALS
IWRS call
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab, turoctocog alfa) (IWRS)
●n
●
●
●
●
●
●
●
●n
●
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Protocol
UTN:U1111-1179-3872
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
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explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up
Visit number b
1
2
3
4-8
9
10-11
12
13-14
15, 15.1, 
15.2, 15.ns
16
Unscheduled c
17t
Administration of trial product (concizumab) 
●o
Drug Accountability (concizumab, turoctocog alfa) 
●
●
●
●
●
●
●
●
●
●
New dose of trial product c, p
●
●
●
●
●
●
●
PRO questionnaires
●
●
●
●
●
●U
●V
REMINDERS
Human biological specimen for storage (central lab)
●
●
Hand out ID Card 
●
Training (trial product, e-Diary and NovoPen® 4) q
●
●
●
Compliance (e-Diary)
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
●
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Protocol
UTN:U1111-1179-3872
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no.:2016-000614-29
Version:
5.0
Page:
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Table 2–2
Flow chart explanatory descriptions
Footer
Description
a
Concizumab administration is performed at home except for visit 2 where concizumab administration will take place at the trial site.
b
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 will be 
a phone call to the patient. 
c
For patients being dose escalated a phone call is recommended 1 week after first new dose of concizumab.
d
Daily dosing preferably at the same time in the morning.
e
Evaluation of laboratory results obtained from samples taken at screening.
f
Bleeding episodes occurring between visit 1 and visit 2 or at site should be registered in the eCRF. All bleeding episodes except for severe occurring after visit 
2 at home should be registered in the eDiary. Severe bleeding episodes must be registered in the eCRF.
g
Turoctocog alfa will be given to treat breakthrough bleeding episodes either in the clinic or at home.
h
At visit 9 and 16 all blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been performed. For 
unscheduled PK-session visit all blood samples should be collected pre-dose except for post dose samples
i
Only body weight should be measured.
j
Vital signs should be evaluated before and after trial drug administration at visit 2. 
k
Sampling for FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours and medical records documenting the severity of 
haemophilia are not available.
l
FVIII activity and FVIII inhibitor tests should only be collected if reduced effect of turoctocog alfa or FVIII inhibitor development is suspected.
m
In case of clinical signs of e.g. hypersensitivity reactions or immune related events are seen, additional samples for ADAs may be taken. All antibody samples 
from the affected patient will be analysed on an ongoing basis. If antibodies are detected additional samples will be taken and stored for characterisation of the 
antibodies.
n
Only dispensing of turoctocog alfa and sodium chloride.
o
The trial patient must be in a non-bleeding state at the time of the first trial product administration (TPA), and should not have received any haemostatic drug 
(e.g. FVIII) for prophylaxis or treatment of a bleeding episode within a period of 48 hours prior to first TPA.
p
Patient should be dose escalated at next scheduled visit if he experiences ≥3 spontaneous bleeding episodes within the preceding 12 weeks of treatment with 
concizumab. If investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose escalation.
q
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Home treatment training comprises handing out of Direction 
for Use (DFU), training in administration of concizumab with NovoPen®4, turoctocog alfa and data entry in eDiary. Further the patients will be trained in 
recognition of signs/symptoms of thrombosis.
r
In case patients are participating in the 24 hour PK-session the sampling time points for thrombin generation, concizumab ELISA and Free TFPI are: pre-dose 
(-1 hour), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (± 20 min) and 24h (± 20 min). All time points, except pre-dose, occur after 
concizumab administration
s
Visit repeated every 8 week until patient either discontinues, completes extension or is enrolled into a subsequent trial with concizumab
t
For patients continuing a subsequent trial End of Trial must be completed at visit 16. For patients declining participation in a subsequent trial the End of Trial
must be completed at visit 17, 8 weeks after End of Treatment.
u
PRO questionnaires should only be completed at 15.1 for patients continuing in the prolongation of the trial.
v
PRO questionnaires should only be completed at visit 16 for patients not continuing in the prolongation of the trial
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP)1 and applicable regulatory requirements, and in 
accordance with the Declaration of Helsinki2 and ISO 141553.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
The International Non-Proprietary Names for Pharmaceutical Substances (INN) name of the active 
pharmaceutical ingredient is concizumab (synonyms used during early development are NNC0172-
2021, anti-TFPI, NN7415 or mab2021). Throughout this document “concizumab” is used as the 
name of the trial drug.
3.1
Background information
3.1.1
Haemophilia
Haemophilia is an inherited bleeding disorder characterised by an increased bleeding tendency, 
typically in weight bearing joints. Haemophilia A is caused by a partial or complete deficiency of 
blood coagulation factor VIII (FVIII) and haemophilia B is caused by defect factor IX (FIX).  
Inheritance is chromosome X-linked and recessive; therefore the disease mainly affects males. The 
incidence of haemophilia A and B on average is estimated to be about 1 in 5000 live male births4. 
According to the World Federation of Haemophilia global survey of 2014, about 178,500 persons 
are diagnosed with haemophilia worldwide. Of these, about 80% have haemophilia A.
Haemophilia is classified as “severe”, “moderate” or “mild” according to the plasma activity level 
of the affected coagulation factor5.With a deficiency of FVIII or FIX, the degree of activation of 
coagulation factor X (FX) becomes insufficient. Consequently, the thrombin burst is delayed and 
insufficient for normal haemostasis6.The haemostatic plug, if formed, in these patients is fragile and 
easily dissolved by normal fibrinolytic activity. This leads to impaired haemostasis and spontaneous 
prolonged bleeding episodes. In severe haemophilia, bleeding in joints occurs spontaneously and is 
the most frequent symptom of the disease. Recurrent bleeding episodes in the same location - most 
commonly a weight bearing joint - lead to chronic arthropathy, muscular atrophy and deformities. 
Treatment of bleeding episodes as they manifest (on-demand treatment) may delay arthropathy, but 
does not prevent it. The majority of children with severe haemophilia experience their first bleeding 
episode in a joint prior to the age of 4 years. Many children also bleed from other body sites, also 
before this age is reached7. For this reason, primary prophylaxis treatment with regular FVIII 
injections in the non-bleeding state is the recommended from early childhood.
The most common complication of replacement therapy is development of antibodies binding to 
FVIII. These binding antibodies might neutralise the exogenous of FVIII and are then called
inhibitors. In patients who have developed inhibitors towards FVIII, replacement therapy is 
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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rendered ineffective. These patients may be treated with bypassing agents, recombinant FVII 
(NovoSeven®) and activated prothrombin complex concentrate (FEIBA®) given as intravenous 
(i.v.) injections.
Current treatment options in haemophilia A, includes replacement therapy or by-passing therapy are 
hampered by the fact that these products must be given as i.v. injections. Bypassing agents are 
characterized by relatively short half-lives, therefore prophylactic treatment is burdensome. A new 
therapeutic agent that can be administered subcutaneously will represent a major improvement in 
the treatment of these patients in a prophylaxis setting. 
3.1.2
Concizumab
The trial product, concizumab, is a humanised recombinant monoclonal antibody (mAb) of the 
immunoglobulin G4 (IgG4) isotype with a molecular weight of 149 kilo Daltons. Like other 
antibodies, concizumab is composed of two light chains and two heavy chains linked together by 
disulfide bridges. To prevent formation of half-antibodies, the serine at position 241 in the heavy 
chain has been replaced with a proline (S241P (Kabat annotation)) . The mechanism of action of 
concizumab is based on the concept of inhibiting the activity of a natural coagulation inhibitor, 
tissue factor pathway inhibitor (TFPI). TFPI is a potent inhibitor of the initiation phase of the 
coagulation process, i.e. the activation of FX to FXa by the tissue factor (TF)/factor VIIa (FVIIa) 
complex. TFPI first binds to and inhibits activated FXa and subsequently binds to and inhibits the 
TF/FVIIa complex, forming a TF/FVIIa/FXa/TFPI complex. Thus, concizumab prevents both 
inhibition of FXa and inhibition of FVIIa/TF by TFPI. In this manner, sufficient amounts of FXa to 
ensure effective haemostasis in the absence of a functional activated factor IX/activated factor VIII 
(FIXa/ FVIIIa) complex may be generated. This is a new concept that remains to be documented 
safe and efficacious in patients with haemophilia. More information about the physiological role of 
TFPI and the mode of action of concizumab is provided in the Investigator’s Brochure (IB). 
Key differentiator is thus a new mode of action (MoA), and the key benefit of concizumab in 
patients with severe haemophilia A is reduced treatment burden due to subcutaneous (s.c.) 
administration potentially leading to better adherence, more patients on prophylactic treatment and 
ultimately better outcome.
Four clinical trials with concizumab have been completed thus far: the first-human-dose trial 
(NN7415-3813, explorer™1), a single dose trial in Japanese healthy subjects (NN7415-3981), a 
multiple dose trial NN7415-3986 (explorer™2), and NN7415-4159 (explorer™3). When the first 
cohort with four healthy subjects in explorer™2 was completed, prior to the initiation of the 2nd 
cohort, the trial was halted due to findings related to thrombosis in an ongoing 26-week toxicity 
study in primates. In this study animal had plasma concentrations several hundred folds above 
clinically relevant concentrations. Follow up investigations confirmed that the animal’s condition 
was related to thrombosis in the lungs caused by exaggerated pharmacology at these high plasma 
concentrations. Before the initiation of the fourth phase 1 trial (, explorer™3) a new 52-week non-
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CONFIDENTIAL
Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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clinical toxicology study was conducted in primates to investigate the findings in the previous 
study. The conclusion from this new non-clinical study was that the results from non-clinical 
studies support further clinical development of concizumab. Explorer™3 was a multiple-dose 
clinical trial, which aimed to investigate the safety, pharmacokinetics and pharmacodynamics of 
concizumab at five different dose levels in adult severe haemophilia A patients without inhibitors. 
In this trial multiple doses of concizumab were administered s.c. over a period of six weeks. Doses 
of up to 0.8 mg/kg administered every four days did not raise safety concerns and a decision not to 
dose-escalate to a 1.1 mg/kg dose-cohort was taken. For further information, please refer to the 
Investigator’s Brochure.
The explorer™3 trial was finalised following the completion of cohort 3 (0.8 mg/kg sc every 4 days 
for 6 weeks). Blinded preliminary safety and PK/PD data from the cohort was reviewed by the 
concizumab safety committee. Marked changes in coagulation parameters were observed including 
a decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range. In addition, a substantial inter subject variation in pro-coagulant response to the drug 
was observed. Based on this, the Novo Nordisk safety committee (see section 12.8.1) decided not to 
proceed to cohort 4 (1.1 mg/kg sc every 4 days for 6 weeks). No clinical consequences or serious 
adverse were seen in the completed cohorts in explorer3.
The PK results from explorer™3 showed exposure-response in terms of fewer bleeding episodes 
recorded for patients who reached plasma concentrations of concizumab above 100 ng/mL. 
Individual predicted PK profiles merged with recorded spontaneous and traumatic bleeding 
episodes are shown in Figure 3–1.
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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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Figure 3–1
Individual predicted PK profiles based on data merged with recorded spontaneous (circles) and 
traumatic (triangles) bleeding episodes during the dosing period and follow-up period. 
All data originates from explorer™3 (N=24 patients). PK of concizumab is subdivided into three exposure levels of 
≤20 ng/mL, 20-100 ng/mL, and > 100 ng/mL together with the number of contributing patients. LLOQ: lower limit of 
quantification. a ‘Time in trial’ refers to the time that the patients spent on each concizumab exposure level, and the 
≤20 ng/mL level therefore also includes the screening period (not shown on this figure).
A large difference between the peak and trough plasma concentrations of concizumab were 
observed as well, especially in the highest dose group (0.80 mg/kg) of explorer™3. In patients who 
received 0.25, 0.5 and 0.8 mg/kg doses a significant overlap in plasma concentrations of 
concizumab was seen due to high between-patient variability in concizumab.
Single doses of concizumab up to 9 mg/kg have been administered to haemophilia patients in the 
first human dose trial with concizumab, explorer™1. These doses resulted in plasma concentrations 
of concizumab that were significantly higher than the ones that are modelled to be reached in the 
highest escalated daily dose (0.25 mg/kg) of explorer™5.
For an assessment of benefits and risks of the trial, see Section 18.1.
For further information, please refer to the Investigator’s Brochure.
3.2
Rationale for the trial
Four phase 1 clinical trials with concizumab have been finalised. Key safety and preliminary 
efficacy results from these phase 1 trials support further development of concizumab in haemophilia 
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Protocol
CONFIDENTIAL
Date:
28 August 2018
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Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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patients. Therefore, the main objective in the phase 2 of concizumab development is to assess 
efficacy and safety and provide data that will guide for the confirmatory phase 3 concizumab trials. 
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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4
Objective(s) and endpoint(s)
4.1
Objective(s)
4.1.1
Primary objective
!
To assess the efficacy of concizumab administered s.c. once daily in preventing bleeding 
episodes in patients with severe haemophilia A without inhibitors
4.1.2
Secondary objectives
!
To assess the long-termer efficacy of concizumab in patients with severe haemophilia A 
without inhibitors
!
To assess the safety of concizumab in patients with severe haemophilia A without inhibitors
!
To assess the immunogenicity of concizumab in patients with severe haemophilia A without 
inhibitors
4.2
Endpoint(s)
4.2.1
Primary endpoint
!
The number of bleeding episodes during at least 24 weeks from treatment onset
!
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary endpoints
!
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during at least 76 weeks from treatment onset
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of  spontaneous bleeding episodes during at least 76 weeks from treatment 
onset
!
Supportive secondary safety endpoints
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Protocol
CONFIDENTIAL
Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during  at least 76 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 76 weeks from treatment onset
!
Change from baseline of fibrinogen during 24 weeks from treatment onset
!
Change from baseline of fibrinogen during at least 76 weeks from treatment onset
!
Change from baseline of D-dimer during 24 weeks from treatment onset
!
Change from baseline of D-dimer during at least 76 weeks from treatment onset
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset
!
Change from baseline of F1 + 2 during at least 76 weeks from treatment onset
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset
!
Change from baseline of PT during at least 76 weeks from treatment onset
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset
!
Change from baseline of APTT during at least 76 weeks from treatment onset
!
Change from baseline of anti-thrombin (AT) during 24 weeks from treatment onset
!
Change from baseline of AT after at least 76 weeks from treatment onset
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks
!
Concentration of concizumab prior to the last dose administration after at least 76 weeks
Supportive secondary pharmacodynamic endpoints
Plasma free TFPI concentration
!
Value prior to the last dose administration at 24 weeks 
!
Value prior to the last dose administration after at least 76 weeks 
Thrombin generation
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks 
!
Peak thrombin generation (nM) prior to the last dose administration after at least 76 weeks
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration after at least 
76 weeks 
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks 
!
Velocity index (nM/min) prior to the last dose administration after at least 76 weeks
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Protocol
CONFIDENTIAL
Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
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EudraCT no.:2016-000614-29
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4.2.3
Exploratory endpoints
4.2.3.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
4.2.3.2
Exploratory patient-reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after at least 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after at least 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after at least 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after at least 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after at least 76 weeks from treatment onset
!
Status of PGI-C after 24 weeks from treatment onset
!
H-DAT after at least 76 weeks from treatment onset
4.2.3.3
Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP  time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
All endpoints referring to a time frame of either 24 weeks or of at least 24 weeks will be evaluated 
in the main part of the trial. 
All endpoints referring to a time frame of at least 76 weeks will be evaluated in the extension part 
of the trial.
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CONFIDENTIAL
Date:
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Trial ID:NN7415-4255
Version:
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5
 Trial design
5.1
Type of trial
The trial is a multicentre single-arm trial, which aim to evaluate the efficacy and safety of 
concizumab 0.15 mg/kg (with potential dose escalation to 0.20 and 0.25 mg/kg) administered daily 
s.c. in patients with severe haemophilia A without inhibitors. The selected dose regimen is based on 
relevant PK and TFPI data as well as PK/PD modelling from the preceding explorer™ trials. Both 
on-demand and prophylaxis patients will be eligible for the trial. 
Figure 5–1
Schematic diagram of the trial design
The total trial duration for the individual patient will be 86 -138 weeks, including a 2-week 
screening period, a subsequent 76 -126 week treatment period and an 8-week follow-up period, see 
Figure 5–1.
The 76 -126 weeks treatment period is further split into a main part which lasts at least 24 weeks for 
all patients in the trial and an extension part which lasts up to 102 weeks. After completion of the 
main part of the trial, patients will continue into the extension part. All available data up to the time 
point where the last patients ends 24 weeks of treatment (or have withdrawn) will be used in the 
analysis of the main part, see Section 17.7.
Breakthrough bleeding episodes occurring from visit 1 to end-of-trial visit will be treated by the 
patients at home with FVIII at the discretion of the investigator, who will also choose dose levels. 
Only turoctocog alfa/NovoEight® will be provided and paid by Novo Nordisk for this purpose.
The analysis of the main part (after 24 weeks) of the trial aims to substantiate CPoC that 
concizumab has the potential to prevent bleeding episodes in patients with severe haemophilia A 
without inhibitors. The extension part will provide additional safety data on up to 102 weeks dosing 
of concizumab.
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CONFIDENTIAL
Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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Human biosamples (plasma, serum, and/or DNA for genotyping) will be collected in this trial  for 
future exploratory analysis to pursue a deeper insight into the biology of TFPI, coagulation, and 
effect of concizumab on joint health that may include coagulation parameters and markers of joint 
status or damage. Acceptance of storage of human biological specimens is voluntary and will not 
affect the patients’ participation in the trial. Therefore, patients will have the possibility to sign the 
informed consent for the trial and participate, while refusing permission for biological specimens to 
be stored for future exploratory analysis. Please refer to Section 24.1 for further information.
An independent data monitoring committee (DMC) will be established for this trial. The DMC will 
review all safety data from all ongoing trials with concizumab exposure, see Section 12.8.2.
All patients will be asked to perform a 24 hour PK-session after treatment with concizumab is 
initiated.
5.1.1
Surgery
Minor surgery is allowed in this trial. Major surgery conducted more than one month (30 days) 
prior to trial start is allowed, see exclusion criterion no 6.
Minor surgery is defined as an invasive operative procedure where only the skin, the mucous 
membranes or superficial connective tissue is manipulated. Examples of minor surgery include 
implanting of central venous access devices (ports, CVC, pumps and other CVADs) in 
subcutaneous tissue, skin biopsies or simple dental procedures.
5.2
Rationale for trial design
Explorer™5 is a phase 2, clinical proof of concept (CPoC) and safety trial. The trial aims to 
substantiate CPoC that concizumab has the potential to prevent bleeding episodes in haemophilia 
patients without inhibitors. A dose escalation design will allow cautious dose escalation in order to 
choose the efficacious and safe concizumab dose for the individual patient from the selected dose 
regimen Concizumab 0.15 mg/kg (with two potential dose-escalation steps, 0.20 mg/kg and 0.25 
mg/kg) given s.c. once daily will be investigated.
The duration of at least 24 weeks for the main part of the trial is deemed necessary in order to 
obtain information on the annual bleeding rate (ABR) during concizumab prophylaxis. The duration 
of the extension part of the trial will be up to 102 weeks and will provide further information on 
long-term efficacy, i.e. ABR, and also provide additional safety data upon 76 – 126 weeks treatment 
with concizumab.
Patients participating in NN7415-4255 will be offered screening for eligibility to participate in the 
subsequent clinical trials for concizumab, following their participation in NN7415-4255 and 
provided that either the site participates in the subsequent trial with concizumab or if possible the 
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CONFIDENTIAL
Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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patient can be transferred to a participating site. It is expected that the majority of the participating 
patients will join a subsequent trial and thus may continue prophylactic treatment with concizumab.
A total of 33 patientsare planned to receive concizumab s.c.once daily in this single arm trial,
please see Figure 5–1.
The concizumab dose regimentswill be startingwith0.15 mg/kg with the possibilityto escalate to 
0.20 mg/kg and 0.25 mg/kg, see section 5.3.1.
Daily dosing with 0.15 mg/kg aims to ensure steady-state levels of concizumab plasma 
concentrations above 100 ng/mL for the majority of the patients starting on this dose. The PK 
results from explorer™3 showed exposure-response in terms of fewer bleeding episodes recorded 
for patients who reached plasma concentrations of concizumab above 100 ng/mLsee Figure 3–1. 
The minority of patients which are predicted to have steady-state plasma concentrations below this 
threshold are expected to experience bleeding episodes and therefore will have the opportunity to be 
dose-escalated to the dose of 0.2 mg/kg. A further dose escalation to 0.25 mg/kg per day is 
permitted, again based on the bleeding rate,see section 5.3.1.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Figure 5–2
Individual predicted concizumab concentration profiles for all concizumab-treated patients in 
explorer™2 (n=4 patients) and explorer™3 (n=18 patients). The horizontal lines indicate 100 ng/mL, 
and the shaded areas represent the full range (min-max) of the individual predicted profiles1.
Due to the high between-patient variability in concizumab concentration observed in explorer™3, a 
significant overlap in plasma concentrations of concizumab in patients who received 0.25, 0.5 and 
0.8 mg/kg doses was seen, see Figure 5–2. Therefore, choosing three doses that would lead to 
reasonably distinct mean plasma concentrations of concizumab, and thus different efficacy at each 
dose level was not deemed possible. For this reason, a traditional parallel arm design was not 
chosen for the phase 2 trials. In contrast, the titration trial design allows patients to start on a low 
dose, which is expected to ensure prophylaxis but not marked changes in coagulation parameters, 
for the majority of patients. Escalation to the next dose level will only occur in the case of lack of 
efficacy (≥3 spontaneous bleeding episodes within the preceding 12 weeks. In addition, the PK of 
concizumab is heavily influenced by target mediated drug disposition, which means that small 
differences in concizumab dose ultimately leads to large differences in plasma concentrations. 
Therefore, daily dosing is proposed for the phase 2 trial, explorer™5. Daily dosing will allow for 
the increase in trough levels and thus better efficacy may be expected with a lower dose. 
Embryonic exposure in pregnant female partners of men treated with concizumab is highly unlikely 
and there is no need for protocol requirements for use of contraception in phase 2 and 3 trials.
                                               
1 Plasma concentrations in the same range as those in explorer™3 are expected to be reached in this trial with daily dose 
administration. The starting dose for all patients will be 0.15 mg/kg daily. The plasma steady-state exposure for a typical subject at 
this dose level is predicted to fourfold lower compared to a typical subject on 0.8 mg/kg Q4D (cohort 3 of explorer3) in terms of both 
Cmax and AUC 0-24h. For 0.20 mg/kg daily and 0.25 mg/kg, the plasma steady-state exposure levels for a typical subject are 
predicted to be less than 40% and 70% respectively, compared to the typical subject exposure in the 3rd cohort of explorer™3 (AUC 
and Cmax). The maximum predicted plasma exposure levels (Cmax and AUC 0-24h) for the 0.15 mg/kg daily dose level is predicted 
to be more than 8 fold lower than for 0.80 mg/kg Q4D. For 0.20 mg/kg daily both Cmax and AUC 0-24h are predicted to be more 
than 3 times lower than for 0.80 mg/kg Q4D. For 0.25 mg/kg daily, the maximum Cmax and AUC 0-24h are predicted to be 35 % 
lower than for 0.80 mg/kg Q4D.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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5.3
Treatment of patients
Table 5–1
List of products provided by Novo Nordisk
Compound Name 
Strength
Dosage form 
Route of 
administration
Treatment period
Concizumab B2, 
100 mg/mL
3 mL solution in 
a 3 mL 
cartridge3. 
S.c.
administration
using NovoPen® 4
For prophylactic 
treatment for at 
least 76 weeks. 
Turoctocog alfa 
(NovoEight®)4, 
Sodium chloride 
solution 4ml  
2000 
IU/vial
Powder for 
solution for 
injection
Solvent for 
solution for i.v. 
injection used 
for 
reconstitution of 
turoctocog alfa.
I.v. administration
For treatment of 
breakthrough 
bleeding episodes 
(or prophylaxis in 
the screening and 
follow-up phases) , 
at the discretion of 
the treating 
physician (patients 
may choose to use 
other familiar pre-
trial non-modified 
FVIII drug) .
For further 
information see 
section 5.3.2
Concizumab will be given s.c., once daily for a total dosing period of at least 76 weeks. 
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. It will be labelled in accordance with national legislation and a copy of the label can 
be found within the Trial Materials Manual, see Section 9.1.
The first dose of concizumab will be given at the trial site under medical supervision. After the 
initial dose the patient must be observed for potential emergence of AEs/safety signals for at least 2 
hours at the trial site. At the screening visit and the first scheduled treatment visit patients will be 
trained in s.c. administration of concizumab with NovoPen® 4 and in the use of eDiary.
Investigational medicinal product (IMP)
3 Not to be confused with the daily injected volume (~150 μL, depending on dose strength and body weight)
4 Non-investigational medicinal product (NIMP)
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
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In case safety concerns meet the criteria(See section12) for putting enrolment of additional 
patients on hold,further enrolment in the trial will be halted. Dosing of patients on treatment may 
continue while further evaluation is made by the safety committee. In case of other safety concerns 
all available data will be evaluated by the DMCsee Section 12.8.2.
5.3.1
Dose escalation
Bleeding episodes will be assessed during the trial both at scheduled visits and also between visits.
The first 2 weeks of the treatment with concizumab 0.15 mg/kg is considered as a run-in period. 
Hence the bleeding episodes occurring during the first 2 weeks should not influence a dose 
escalation decision.
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (first-dose visit) 
until visit 16 (end-of-treatment visit), i.e. a total of up to 124 weeks. Dose-escalation will be based 
on the number of spontaneous, treated bleeding episodes in patients within preceding 12 weeks. 
However, before dose-escalation can occur, to ensure the safety of the patients, the investigator 
must take into account the full clinical picture the patient is presenting with and all available 
laboratory results, including coagulation parameters.
Dose 0.15 mg/kg:
When a sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the preceding 
12 weeks since visit 2+2weeks (including the current sBE). If yes, and if investigator deems it safe, 
the patient will have to be dose escalated from 0.15 to 0.20 mg/kg at the next scheduled visit. If the 
investigator judges that this visit is scheduled too late, he/she should contact the patient for an 
unscheduled visit.
Dose 0.20 mg/kg:
When an sBE occurs, the investigator will determine if ≥ 3 sBEs have occurred within the 
preceding 12 weeks (including the current sBE), counting only new sBEs from the beginning of the 
0.20 mg/kg treatment period. If yes, and if investigator deems it safe, the patient will have to be 
dose escalated from 0.20 to 0.25 mg/kg at the next scheduled visit. If the investigator judges that 
this visit is scheduled too late, he/she should contact the patient for an unscheduled visit.
Dose 0.25 mg/kg:
Patients are not dose escalated further regardless of the number of sBEs. When an sBE occurs, the 
investigator will determine if ≥ 3 sBEs have occurred within the preceding 12 weeks (including the 
current sBE), counting only the new sBEs from the beginning of the 0,25mg/kg treatment period. If 
yes, then the patient must be discontinued from treatment due to lack of efficacy, see Section 6.4.
Since the patient may have to wait up to 8 weeks for the next scheduled visit (in the extension part), 
the possibility of dose escalation at unscheduled visits is necessary for the dose-escalation eliciting 
bleeding episode to occur soon after previous scheduled visit.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Figure 5–3
Dose escalation of concizumab for one individual patient
5.3.2
Treatment of bleeding episodes during the trial
Bleeding episodes (main part, extension part, and follow-up part) :
Breakthrough bleeding episodes during the course of the trial will be treated at the discretion of the 
treating physician, with either turoctocog alfa/Novoeight®(rFVIII)  (provided by Novo Nordisk)  or 
other non-modified FVIII products(not provided by Novo Nordisk) .Treatment dose ischosen at 
the discretionof the investigator;however; in this trial any given single dose should not exceed 50 
IU/kg (Table 8-4) . The patient can treat himself and then he must call the site.  The bleeding 
episodesmust be recorded in the eDiary. Bleeding episodes must be recorded in the electronic case 
report form (eCRF) as an AE/SAE if fatal, life threatening or evaluated as related to trial product 
(see section 12.1)
FVIII prophylactic treatment (follow-up part) :
During the follow-up part of the trial (i.e. from concizumab end-of-treatment visit to end-of-trial 
visit) patients will receive pre -trial FVIII medication at the discretion of the treating investigator, 
who will also choose dose levels. Only turoctocog alfa/NovoEight®will be provided by Novo 
Nordisk for this purpose.
5.3.3
Prohibited medication 
!
Treatment with anti-fibrinolytics (e.g. tranexamic acid, aminocaproic acid)*
!
Heparin, except for sealing of central venous access ports according to local practice
!
Vitamin-K antagonists
!
Direct oral anti-coagulants (DOACs)
!
Modified FVIII products with extended half-life
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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*Local/topical use is allowed. Use of single systemic doses in severe bleeding episodes, after 
careful benefit-risk evaluation, is allowed. Not applicable for France.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products the patient should be switched to a suitable marketed product at 
the discretion of the investigator. The patient will not be provided with concizumab or FVIII 
(turoctocog alfa/NovoEight®) by Novo Nordisk after end of trial (visit 17). 
5.5
Rationale for treatment
Concizumab is a monoclonal antibody and as such offers the possibility of s.c. administration. S.c. 
administration of an effective prophylactic drug has potential to reduce treatment burden 
significantly compared to the currently approved prophylactic drugs which have to be administered 
i.v.
The treatment period of at least 24 weeks (the main part of the trial) is considered necessary for 
providing data that allow demonstration of CPoC and to support decision-making regarding a phase 
3 confirmatory trial. Dosing for up to an additional 102 weeks will provide valuable long-term 
efficacy and safety.
Breakthrough bleeding episodes may occur during prophylactic regimens with conventional FVIII 
replacement therapy. Therefore, it is expected that breakthrough bleeding episodes will also occur 
during prophylaxis with concizumab even if clinical proof of concept is demonstrated. 
Consequently turoctocog alfa (FVIII) will be provided by Novo Nordisk A/S in this trial for 
treatment of breakthrough bleeding episodes. 
Patients are not obliged to use turoctocog alfa (FVIII) and can use their previously used FVIII 
concentrate for treatment of breakthrough bleeding episode. Novo Nordisk A/S will not provide or 
reimburse these products.
Please refer to the Investigator’s Brochure for further information.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 36
Number of patients planned to be started on trial product(s): 33
Number of patients planned to complete the trial: 30
Discontinued patients will not be replaced.
6.2
Inclusion criteria
For an eligible patient, all inclusion criteria must be answered “yes”.
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male patients aged ≥ 18 years at the time of signing informed consent, diagnosed with 
severe haemophilia A (FVIII activity <1%), based on medical records or results at 
screening.
3. For patients being treated on-demand with FVIII replacement therapy, a minimum of six 
documented and treated bleeding episodes during the 24 weeks (or twelve bleeds during 52 
weeks) prior to screening.
6.3
Exclusion criteria
For an eligible patient, all exclusion criteria must be answered “no”.
1. Known or suspected hypersensitivity to trial product(s) or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within the last 30 days or 5 half-lives (whichever is longer) from the last drug 
administration before screening.
4. Any disorder, which in the investigator’s opinion might jeopardise patient’s safety or 
compliance with the protocol.
5. Known inherited or acquired bleeding disorder other than haemophilia A.
6. Major surgery conducted within one month prior to the initiation of trial activities or major 
surgery planned to occur during the trial.
7. Previous history of thromboembolic disease. Current clinical signs of thromboembolic 
disease, or patients who in the judgement of the investigator are considered at high risk of 
thromboembolic events.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
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8. Mental incapacity, unwillingness to cooperate or language barrier precluding adequate
understanding and cooperation.
9. Patients who, at screening, have a significant infection or known systemic inflammatory
condition which require systemic treatment according to the investigator’s judgement.
10. Hepatic dysfunction defined as elevated liver transaminases (ALT) >3 times the upper limit
of normal laboratory reference ranges at screening.
11. Renal impairment defined as estimated glomerular filtration rate (eGFR) ≤60
mL/min/1.73m2 based on serum creatinine measured at screening or evidence of renal
damage.
12. Platelet count ≤ 100x109/L at screening.
13. Fibrinogen level < the lower limit of normal at screening
14. Presence of inhibitors (neutralising antibodies) to Factor VIII (≥0.6 Bethesda Units) at
screening measured by the Nijmegen method.
15. History of inhibitors towards FVIII based on investigator’s knowledge or documentation in
available medical records.
6.4
Criteria for premature discontinuation of trial product
The patient may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
The patient must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria
2. Simultaneous participation in another clinical trial of an approved or non-approved
investigational medicinal product.
3. Incapacity or unwillingness to follow the trial procedures
4. Anaphylactic reaction
5. Thromboembolic event
6. Event of disseminated intravascular coagulation (DIC)
7. Development of inhibitors to Factor VIII (≥0.6 BU)
8. Lack of efficacy due to neutralising antibodies towards concizumab
9. Lack of efficacy defined as ≥3 treated sBEs within the previous 12 weeks in patients being
treated with the highest dose level (0.25 mg/kg) of concizumab.
See Section8.1.4 for procedures to be performed for patients discontinuing trial 
product prematurely.
6.5
Withdrawal from trial
The patientmay withdraw consent at will at any time.
See Section 8.1.5for procedures to be performed for patients withdrawing consent.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
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6.6
Patient replacement
Patients who discontinue trial product prematurely will not be replaced.
6.7
Rationale for trial population 
The most important reason for choosing the trial population, haemophilia A without inhibitors, is 
that there is a significant unmet medical need in this patient population for a treatment option which 
reduces the burden associated with the current care, including small volume s.c. administration 
instead of i.v. Finally, the trial population reflects the patient population that will be selected in a 
potential subsequent phase 3 trial in which the efficacy and safety of concizumab is to be 
confirmed.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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7
Milestones
Planned duration of recruitment period first patient first visit – last patient first visit (FPFV-LPFV): 
4 months
FPFV: 
16-Aug-2017
FPFT: 
30-Aug-2017
LPFV: 
16-Dec-2017
Planned LPLV: 
31-Mar-2020
The total duration of concizumab treatment in the trial is at least 76 weeks for an individual patient 
enrolled in the trial for concizumab treatment at visit 2.
End of trial is defined as last patient last visit (LPLV).
Recruitment:
The screening and enrolment rate will be followed closely via the interactive web response system 
(IWRS) in order to estimate when to stop screening. All investigators will be notified immediately 
when the recruitment period ends, after which no further patients may be screened and the IWRS 
will be closed for further screening. All patients screened during the recruitment period and found 
eligible for enrolment can be enrolled within the timelines specified in the flow chart (see Section 
2).
Trial registration:
Information about the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and clinical 
trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure, how-we-
disclose-trial-information8, it will also be disclosed according to other applicable requirements such 
as those of the International Committee of Medical Journal Editors (ICMJE) 9, the Food and Drug 
Administration Amendment Act (FDAAA)10 , European Commission Requirements 11, 12 and other 
relevant recommendations or regulations 13. If a patient requests to be included in the trial via the 
Novo Nordisk e-mail contact at these web sites, Novo Nordisk may disclose the investigator’s 
contact details to the patient. As a result of increasing requirements for transparency, some 
countries require public disclosure of investigator names and their affiliations.
Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
protocol Last Patient First Treatment LPFT (visit2) + 24 weeks ( i.e. last patient visit 9) If the last 
patient is withdrawn early the PCD is the date when the last patient would have completed visit 9. 
The PCD determines the deadline for results disclosure at ClinicalTrials.gov according to 
FDAAA.10
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
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8
Methods and assessments
Assessments to be performed at the scheduled and at unscheduled visits in this trial are described in 
this section andin the trial flow chart (section 2) .
Figure 8–1
Overview of visit structure in explorer™5
8.1
Visit procedures
For each patient the trial consists of the following scheduled parts and visits:
Screening Part:
Visit 1 (screening visit)
Main Part:
Visit 2 (1st treatment visit with concizumab at site)
Home treatment with concizumab daily
Visit 3 (phone visit with site)
Visit 4 (Assessment visit, patients treat themselves at home)
Visit 5 (Assessment visit, patients treat themselves at home)
Visit 6 (Assessment visit, patients treat themselves at home)
Visit 7 (Assessment visit, patients treat themselves at home)
Visit 8 (Assessment visit, patients treat themselves at home)
Visit 9 (Assessment visit, after the visit patients treat themselves at home)
Extension Part:
Visit 10 (Assessment visit, patients treat themselves at home)
Visit 11 (Assessment visit, patients treat themselves at home)
Visit 12 (Assessment visit, patients treat themselves at home)
Visit 13 (Assessment visit, patients treat themselves at home)
Visit 14 (Assessment visit, patients treat themselves at home)
Visit 15-15.n (Assessment visit, patients treat themselves at home)
Visit 16 (Assessment visit and End of treatment)
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
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Follow-up part
Visit 17 (Assessment visit and End of trial)
Unscheduled visits can occur e.g. for dispensing of trial products, when an assessment of bleeding 
episodes is necessary at site or at the discretion of the investigator.
The duration of the visits (V1-V17) will depend on the assessments and the patient’s individual 
training and/or discussion need on concizumab administration, NovoPen® 4, usage of e-Diary, 
completion of the patient reported outcome (PRO) etc.
8.1.1
Informed consent, long-term storage consent
Informed consent must be obtained before any trial related activity, see Section 18.2.
The trial includes a separate informed consent for long-term storage of human biosamples, see 
Section 24.2. 
Storage of human biosamples and genotyping is voluntary and will not affect the patients’ 
participation in the trial. Therefore, patients will have the possibility to sign the informed consent 
for the trial and participate, while refusing permission for biological specimens and /or genotyping 
to be stored for future exploratory analysis.
8.1.2
Screening log, enrolment log, trial card and patient number
The investigator must keep a patient screening log, a patient identification (ID) code list and a 
patient enrolment log. Only patients who have signed the informed consent form should be included 
on the logs. The patient screening log and patient enrolment log may be combined in one log.
At screening, patients will be provided with a card stating that they are participating in a trial and 
given contact address(es) and telephone number(s) of relevant trial clinic staff. Patients should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each patient will be assigned a unique 6-digit patient number which will remain the same 
throughout the trial.
8.1.3
Screening failures and re-screening
For screening failures the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial. Serious and non-serious adverse events 
from screening failures must be transcribed by the investigator into the eCRF. Follow-up on serious 
adverse events (SAEs) must be carried out according to Section 12.
A screening failure session must be made in the IWRS. The case book must be signed in the eCRF.
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CONFIDENTIAL
Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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Re-screening is NOT allowed if the patient has failed one of the inclusion or exclusion criteria; this 
includes re-sampling if the patient has failed one of the inclusion or exclusion criteria related to 
laboratory parameters.
8.1.4
Premature discontinuation of trial product
If a patient prematurely discontinues trial product, the investigator must undertake procedures 
similar to those for visit 9 (the last treatment in the main part) or visit 16 (the last treatment visit in 
the extension part) as soon as possible. The follow up visit (visit 17) must be performed 8 weeks 
(window minus 7 days) after last dose of trial drug.
The primary reason for premature discontinuation of trial product must be specified in the end of 
treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
The patients who permanently prematurely discontinue trial product at Investigator’s discretion due 
to a safety concern after completion of the main part of the trial may have visit 17 scheduled 8 
weeks after visit 16. Furthermore additional unscheduled visits will be conducted at least every 8 
weeks for safety assessments (see Section 8.4 and 8.5.2), PK and PD markers. The patients who 
permanently prematurely discontinue trial product due to safety concerns may have the safety 
follow up period extended at Investigator’s discretion until the safety concern have been resolved, 
but no later than Last Patient Last Visit as defined in Milestones (Section 7 of the protocol).
Permanent premature discontinuation of treatment with trial product will lead to patient withdrawal 
from the trial.
8.1.5
Withdrawal from trial
If a patient withdraws consent, the investigator must aim to undertake procedures similar to those 
for visit 9 (the last visit in the main part) or visit 16 (the last visit in the extension part) as soon as 
possible depending on where the patient is in the trial schedule.
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the patient is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS and the case book must be signed in the eCRF.
Although a patient is not obliged to give his reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the patient’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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8.1.6
Review/evaluation of clinical outcome
Novo Nordisk has constituted an internal concizumab safety committee and established an external 
DMC to perform ongoing safety surveillance of safety data relevant for concizumab, see Section 
12.8.
Review of eDiary data and laboratory reports etc. must be documented either on the documents or 
in the patient’s medical record.
If unclear entries or discrepancies in the eDiary or PRO are identified and a clarification is needed, 
the patient must be asked for clarification and a conclusion made in the patient’s medical record. 
Care must be taken not to bias the patient.
8.1.7
Visit 1 (Screening part)
Informed consent must be obtained before any trial related activity, see Section 18.2.
In cases where a patient's baseline FVIII level is not documented in medical records, sampling for 
FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours.
Screening can take place between 14 to 21 days prior to planned enrolment day (visit 2). For 
prophylactic treatment (prior to Screening) with extended half-life FVIII products, this period 
should be extended to a time-period equal to 8 half-lives of the used product
All assessments to be performed at screening are listed in Table 2–1, see Section 2.
Apart from informed consent patients will be asked to complete the ePRO questionnaires before any 
other trial related activities are performed according to Section 8.6;
!
Hemo-TEM,
!
VERITAS-Pro® orVERITAS-PRN®
Assessment results from physical examination, body measurements, as well as measurements of 
vital signs, urinalysis electrocardiogram (ECG) and details of any contemporary adverse events 
must be entered into the eCRF.
A screening confirmation call must be performed in the IWRS, at the day of the visit.
The investigator must review all information obtained from the screening procedures. If a patient
does not meet all inclusion criteria or meets one or more of the exclusion criteria for the trial the 
patient does not qualify to be enrolled.
Patients will be provided with turoctocog alfa (rFVIII) trial injection kits and directions for use 
(DFU) to cover the potential FVIII treatment in the screening part of the trial and investigator will 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
45 of 127
ensure that the patients are capable of treating themselves with rFVIII (turoctocog alfa). Patients on 
any previous FVIII prophylaxis can continue with this treatment until 48 hours before visit 2.
Dispensing of rFVIII (turoctocog alfa) should be performed in the IWRS
For bleeding episodes that occur in the period from Screening visit (Visit1) to enrolment visit (Visit 
2) information about the bleeding episode is to be entered in the eCRF at visit 2. 
The patient should be instructed to call the site if any bleeding episodes, questions or issues arise 
after he has left the site.
8.1.8
Training of patients visit 1 and visit 2
During the site visits 1 and 2 patients must be trained in self administration of concizumab in the 
home setting using NovoPen® 4. The dose of concizumab to be administered must be 
communicated to the patient at visit 2. Furthermore patients must be instructed and trained in the 
importance and reporting of all home treatment with concizumab, details of the bleeding episodes 
and the turoctocog alfa (FVIII) treatment associated with these bleeding episodes in the eDiary,(See 
section 8.6.2).
Patients should be trained on how to recognize and react to signs of thromboembolic events, so that 
the patient without any delay contacts the site.
8.1.9
Treatment period - Main part
8.1.9.1
Visit 2 (Assessment, 1st concizumab treatment at site)
Visit 2 should be scheduled 14 to 21 days after visit 1. The date of visit 2 will be considered as trial 
day 1.
Before any concizumab administration it is important to verify the in/exclusion criteria again and 
review central laboratory test results from screening. 
The patient must be in a non-bleeding state at the time of first administration with concizumab and 
should not have received any FVIII treatment for prophylaxis or for treatment of a bleeding episode 
within a period of 48 hours prior to dosing.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
Hemo-TEM,
o
SF-36v2, 
o
SDS, 
o
TSQM, 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
46 of 127
o
SIAQ-ISRQ
All protocol assessments must be performed before 1st administration of concizumab. Vital signs 
must be assessed both before and after concizumab administration.
Assessment results from concomitant medication, vital signs, Body measurements (weight only)
and details of adverse events must be entered into the eCRF.
At this, the 1st treatment visit, the allocated dose of concizumab will be given. Concizumab will be 
administered at the trial site supervised by medically trained trial staff.
The time point at which the completion of the first dose takes place corresponds to Time on 
treatment = 0 and must be recorded in the eCRF.
The patient must be observed at the trial site for at least 2 hours after the administration of the first 
dose of concizumab.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.
Investigator will communicate any the daily dose of concizumab to the patient and record the dose 
for the coming home treatment period in the eCRF. 
Prior to the first dose a dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits as well as an eDiary device to be able to conduct and report 
home treatment until the next scheduled visit.
The patient will be reminded to report bleeding episodes and home treatment in the eDiary device.
The patient will be asked to return all used, partly used and unused turoctocog alfa (FVIII) during 
the trial as instructed by the investigator. Drug accountability must be performed for turoctocog alfa
(rFVIII), including injection kits if applicable, according to section 9.4. Unused sodium chloride 
syringes should be returned to site at every visit and new sodium chloride syringes should be 
dispensed to the patient.
8.1.9.2
Treatment period at home
Home treatment is defined as self-administration of trial product, performed independently by the 
patient, preferably in the morning. Home treatment starts after visit 2 or when the patient is 
comfortable self-administrating trial product subcutaneously (concizumab) and intravenously 
(turoctocog alfa (FVIII)).
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
47 of 127
8.1.9.3
Visit 3 (Phone visit)
Visit 3 is to be scheduled as a phone contact (or similar)  7days after visit 2 (with a visit window of 
+1 day) .
All relevant protocol assessments listed in table 2-1 must be discussed. Assessment results from 
concomitant medication and details of adverse events must be entered into the eCRF.
Patients should be informed to treat themselves at home according to the dosing schedule regardless 
of when visits 4, 5, 6, 7 and 8 are scheduled. 
8.1.9.4
Visits 4, 5, 6, 7 and 8 (Assessment visits)
Visits 4, 5, 6, 7 and 8 are to be scheduled on trial day 29 (4 weeks), day 57 (8 weeks), day 85 (12 
weeks), day 113 (16 weeks) and day 141 (20 weeks) respectively with a visit window of ± 7days.
Patients should treat themselves at home according to the dosing schedule regardless of when visits 
4, 5, 6, 7 and 8 are scheduled
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6;
o
PGI-C
o
Hemo-TEM
Assessments are to be performed according to Table 2–1and the assessment results from 
concomitant medication, vital signs, Body measurements (weight only)  and details of adverse 
events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewingcollected data from the eDiary.Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab dosesis needed 
according the escalationrules described in section 5.3.1. All decisionsto escalate the concizumab 
dosemust be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight.Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa) )  and injection kits to be able to conduct home treatment until next scheduled visit.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
48 of 127
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
At visit 8 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 9.
8.1.9.5
Visit 9 (Assessment visits) 
Visit 9 is to be scheduled on trial day 169 (24 weeks) with a visit window of ± 7days.
Treatment with concizumab must take place after the blood sampling at this visit.
Patients will be asked to complete the PRO questionnaires before any other trial related activities 
are performed according to section 8.6.1;
o
PGI-C
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
Assessments are to be performed according to Table 2–1and the assessment results from physical 
examination, concomitant medication, vital signs, Body measurements (weight only) and details of 
adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through the available access to collected data from the eDiary. Based on the assessment of any 
spontaneous bleeding episodes the investigator must evaluate if an escalation of the concizumab 
doses is needed according the escalation rules described in section 5.3.1. All decisions to escalate 
the concizumab dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
49 of 127
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
8.1.10
Extension Part
8.1.10.1
Visit 10 (Assessment visits) 
Visit 10is to be scheduled on trial day 225 (32 weeks) , with a visit window of ± 7days.
Assessments are to be performed according to the flowchart section 2 and the assessment results 
from concomitant medication, vital signs, Body measurements (weight only) and details of adverse 
events must be entered into the eCRF.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performedaccording tosection 8.6.1;
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
SIAQ-ISRQ
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
50 of 127
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
8.1.10.2
Visit 11, 12, 13, 14 and 15, 15.1, 15.2, 15.n (Assessment visits)
Visits 11 to 15.n are to be scheduled with an interval of 8 weeks with a visit window of ± 7days 
until the patient either discontinues treatment or completes visit 16. 
If the patient declines participation in the prolongation of the extension, visit 16 should be 
conducted 4 weeks after visit 15 (see Section 8.1.10.3)
Assessments are to be performed according to Table Table 2–1and the assessment results from 
physical examination (applicable for V12), concomitant medication, vital signs, Body 
measurements (weight only) and details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
At visit 15.1 only patients continuing in the prolongation will be asked to complete the PRO 
questionnaires before any other trial related activities are performed according to section 8.6.1;
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
51 of 127
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
At the last visit (visit 15 or 15.n) before visit 16 (End of treatment) patients should be reminded that 
treatment with concizumab must take place after the blood sampling at visit 16.
8.1.10.3
Visit 16 (Assessment visit end of treatment with Concizumab) - Extension part
Visit 16 is to be scheduled:
!
on trial day 533 (for patients declining participation in the prolongation of the trial) 
!
or later (for patients continuing in the extension or enrolled in a subsequent trial) 
with a visit window of ± 7days.
Visit 16 should be scheduled to be conducted at the last day of treatment with concizumab.
Treatment with concizumab must take place after the blood sampling at this visit.
Patients not continuing in the prolongation will be asked to complete the PRO questionnaires before 
any other trial related activities are performed according to section 8.6.1;
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
Assessments are to be performed according to Table 2–1 and the assessment results from 
concomitant medication, vital signs and details of adverse events (AE) must be entered into the 
eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. 
For patients not continuing in the prolongation of the trial a completion session must be made at 
Visit 16 in the IWRS. In the period from visit 16 to visit 17 the patient can be treated with 
turoctocog alfa at the discretion of the investigator. Turoctocog alfa may be requested via IWRS. 
Treatment can either be prophylactically and/or treatment of any bleeding episodes. Only 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
52 of 127
turoctocog alfa will be provided by Novo Nordisk. If necessary, a dispensing call must be 
performed in the IWRS. At the visit the patient will be provided with rFVIII (turoctocog alfa) and 
injection kits to be able to conduct home treatment until final visit. 
For patients continuing in the prolongation of the trial and are enrolled in a subsequent trial as 
completion session must be made at visit 16 in the IWRS, but no additional trial product 
(turoctocog alfa) will be provided to the patient.
For patients continuing in the prolongation of the trial but not enrolled in a subsequent trial a 
completion session must be made at Visit 16 in the IWRS. In the period from visit 16 to visit 17 the 
patient can be treated with turoctocog alfa at the discretion of the investigator.  Turoctocog alfa may 
be requested via IWRS. Treatment can either be prophylactically and/or treatment of any bleeding 
episodes. Only turoctocog alfa will be provided by Novo Nordisk. If necessary, a dispensing call 
must be performed in the IWRS. At the visit the patient will be provided with rFVIII (turoctocog 
alfa) and injection kits to be able to conduct home treatment until final visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. NovoPen®4 must be 
returned. Drug accountability must be performed at all visits for concizumab and rFVIII (turoctocog 
alfa) including injection kits, if applicable. Unused sodium chloride syringes should be returned to 
site at every visit and new sodium chloride syringes should be dispensed to the patient.
End of trial information must be entered in the End of Trial form in the eCRF at visit 16 for all 
patients enrolled in a subsequent trial with concizumab.
8.1.11
Follow-up Part
8.1.11.1
Visit 17 (End of trial)
For patients not enrolled into a subsequent trial with concizumab visit 17 is to be scheduled 8 weeks 
after visit 16 with a visit window of minus 7 days.
Assessments are to be performed according to Table 2–1 and the assessment results from 
concomitant medication, physical examination, body measurements (weight only), vital signs and 
details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Patients must be asked if their female partner has 
become pregnant during the trial (see Section 12.5.1).
The patient will be asked to return all used, partly used and unused turoctocog alfa (rFVIII), eDiary 
device and Trial card. Drug accountability must be performed for turoctocog alfa (rFVIII) including 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
53 of 127
injection kits, if applicable. Unused sodium chloride syringes should be returned to site at every 
visit and new sodium chloride syringes should be dispensed to the patient.
End of trial information must be entered in the End of Trial form in the eCRF at visit 17 for all 
patients not enrolled in a subsequent trial with concizumab.
If turoctocog alfa was requested at visit 16 drug accountability should be performed in IWRS, see 
Section 10.
8.1.12
Unscheduled Visit
Unscheduled visits can be performed at any time during the trialas listed in Table 2–1.
Unscheduled visits may be performed after visit 17 at the discretion of the investigator for patients 
who has permanently prematurely discontinue trial product due to a safety concern (see Section 
8.1.4) .
The purpose of the unscheduled visit must be documentedin the eCRF. During unscheduled visits 
assessments and blood sampling must be performed according to Table 2–1. Assessment results 
must be recorded in the eCRF. Assessments and bloodsampling can be omittedif the only reason 
for the unscheduled visit is dispensing of trial product,replacement of eDiary or NovoPen®4 or for 
an unscheduled 24 hour PK-visit. 
If trial product administration or dispensingis required, dispensing of trial product must be 
performed via IWRS.
The following forms can be found in the unscheduled visit in the eCRF:
!
Bleeding episodes
!
Dosing with FVIII, concizumab including dose escalation section 5.3.1
!
Surgery
!
Local, special and central laboratory (re-) sampling/results
!
Body measurements
8.1.12.1
Unscheduled 24 hour PK-Visit
All patients will be invited to participate in an optional unscheduled 24 hour PK-visit. The visit may 
take place after first dose of concizumab. Samples collected at the 24 hour PK-visit will be for 
analysis of concizumab-ELISA, Free TFPI and Thrombin Generation (TGA). Sampling will be at 
time points; 1 hour pre-dose (-1 hour), 1 (±10 min.), 3 (±10 min.), 6 (±10 min.), 9 (±10 min.), 12 
(±20 min.) and 24 hour(s) (±20 min.) post dose, related to the daily dosing of concizumab. 
Treatment dose of concizumab and the time of treatment will preferably be recorded in the eDiary 
by the patient or eCRF by site. Treatment will be at site.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
54 of 127
This visit can be combined with a regular scheduled visit. Patients should be reminded not to 
administer the daily dose of concizumab until 1 hour after the pre-dose sampling has taken place
8.2
Patient related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Concomitant illness and medical history other than haemophilia
A concomitant illness is any illness, other than haemophilia A, that is present at the start of the trial 
(i.e. at the first visit) or found as a result of a screening procedure or other trial procedures 
performed before first exposure to trial product. All concomitant illnesses should be reported in the 
Concomitant illness forms in the eCRF except information on haemophilia A which is to be 
reported in the Haemophilia Medical history section of the eCRF.
Medical history is a medical event, other than haemophilia A, which the patient has experienced in 
the past. Only relevant medical history should be reported. The information collected for 
concomitant illness and medical history should include diagnosis, date of onset and date of 
resolution or continuation, as applicable. Any change to a concomitant illness should be recorded 
during the trial. A clinically significant worsening of a concomitant illness must be reported as an 
AE. 
It must be possible to verify the patient’s medical history in source documents such as patient’s
medical record:
If a patient is not from the investigators own practice; the investigator must make a reasonable 
effort to obtain a copy of the patient’s medical record from relevant party e.g. primary physician. 
See section 6.2 and 6.3 for full description of the selection criteria. The investigator must document 
any attempt to obtain external medical information by noting the date(s) when information was 
requested and who has been contacted.  
8.2.3
Concomitant medication
A concomitant medication is any medication, other than concizumab and turoctocog alfa (rFVIII)
(and connected 0.9% Isotonic Sodium Chloride) used for rescue treatment, which is taken during 
the trial, including the screening and follow-up periods.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
55 of 127
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the patient’s eligibility to continue in the trial, the monitor must be informed.
8.2.4
Details of Haemophilia, Haemophilia Treatment and Bleed History
All available information on haemophilia, prior to screening should be recorded in the eCRF. 
!
Diagnosis of haemophilia (date)
!
Classification of haemophilia type (haemophilia A)
!
Severity of haemophilia (severe, moderate or mild)
!
Etiology of haemophilia (congenital or acquired)
!
Family history of haemophilia [yes or no in eCRF]
!
Family history of Prothrombotic disorders [yes or no in eCRF]
!
Family history of Thromboembolism [yes or no in eCRF]
!
Family history of inhibitors [yes or no in eCRF]
!
Deficiency factor level
The following information on bleeding episodes one year prior to screening should be recorded in 
the eCRF:
!
Type of treatment 
o
Prophylaxis or on-demand
o
Start date 
o
Stop date 
!
Number of bleeding episodes 
o
If possible specify number of spontaneous bleeding episodes.
!
Coagulation factor product(s) 
o
Brand name, or if the brand is not known, the type of product, (plasma derived or 
recombinant)
!
Dosage used for prophylaxis  (for prophylaxis patients only) 
!
Dosing frequency during prophylaxis (only for prophylaxis patients) 
!
Approximate dose to treat a bleeding episode 
!
Approximate number of doses to treat a bleeding episode
!
Target joint listing (definition: a target joint is a joint in which 3 or more spontaneous 
bleeding episodes have occurred within a consecutive 6-month period)
o
Location
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
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o
Position (left/right)
o
Number of bleeding episodes
8.3
Efficacy assessments
8.3.1
Bleeding episodes
All bleeding episodes treated with FVIII and symptoms related to the underlying disease must be 
captured in the eDiary by the patient or in the eCRF by the investigator. The trial site should be 
informed of the details of all bleeding episodes, including those that are treated outside of the trial 
site. All information captured including severe bleeding episodes, during visits at the trial site will 
be collected in the eCRF.
When home treatment is initiated at visit 2 all bleeding episodes and injections with concizumab 
and turoctocog alfa (rFVIII) infusions occurring outside the trial site should be entered in the eDiary 
by the patient (Section 8.6.2.3). The completed eDiary is considered source data.
The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with rFVIII (turoctocog alfa):
!
Start date and time
!
Stop date and time (see Table 8–1 for definition) 
!
Anatomical location(s)
o
Position (left/ right)
!
Cause (see Table 8–2 for definitions)
o
spontaneous
o
traumatic
o
post-surgical
!
Severity (see Table 8–3 for definitions)
o
mild/moderate, severe

classification and of severe bleeding episodes is the responsibility of the 
investigator
!
Treatment, if any 
o
rFVIII (turoctocog alfa) administration(s) or other product administrations

dose, date, time 
o
other medicinal treatments related to the bleeding episode (e.g. pain relieving 
medication, non-medical therapy etc.)

record as concomitant medication (see Section 8.2.3)
!
Symptoms during bleeding episodes 
o
Pain 
o
Blood in urine
o
Tingling sensation
o
Swelling
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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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Status:
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o
Mouth/Gum bleed
o
Warmth
o
Loss of movement
o
Bruises
o
Nose bleed
Only report the bleeding episode as an AE/SAE if fatal, life threatening or evaluated as related to 
trial product (see section 12.1)
Table 8–1
Definition of stop of bleeding episode
Stop time is:
When the patient experiences/observes signs of cessation of the active 
bleeding episode such as; pain relief, no increase in swelling/limitation of 
motion and improvement in other objective signs of the bleeding episode
Stop time is not:
When pain and objective signs of the bleeding episode are completely 
resolved
Table 8–2
Definitions of bleeding episodes (cause of bleed)
Category
Definition
Spontaneous
Not linked to a specific, known action or event
Traumatic
Caused by a specific, known action or event (e.g. injury or exercise)
Post-surgical
Bleeding episodes after surgery from the surgical wound. Bleeding 
episodes during surgery does not fall under this category 
Table 8–3
Definition of bleeding episode severity and treatment recommendation
Category
Definition
Treatment recommendation
Mild/Moderate
Examples: uncomplicated musculoskeletal 
bleeding episodes (joint, muscular bleeds 
without compartment syndrome), mucosal- or 
subcutaneous bleeding episodes
Mild/moderate bleeding episodes may occur in 
other anatomical locations
Mild/moderate bleeding 
episodes can be treated at home 
before contact to the 
investigator
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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
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Severe
Examples: intracranial, retroperitoneal, 
iliopsoas and internal neck bleeding episodes; 
muscle bleeding episodes with compartment 
syndrome; bleeding episodes associated with a 
significant decrease in the haemoglobin level 
(>3g/dl)
Severe bleeding episodes may occur in other 
anatomical locations 
Bleeding episodes that require hospitalisation
All life-threatening bleeding episodes 
Severe bleeding episodes must 
be treated immediately 
Instruction for 
patients
The patient must be instructed to contact the investigator immediately if in doubt 
regarding treatment of a bleeding episode and to discuss what other actions may 
need to be taken
Information about bleeding episodes prior to visit 2 will be recorded in eCRF.
The trial site should be informed of the details of all bleeding episodes, including those that are 
treated outside of the trial site. After visit 2 bleeding episodes must be recorded either in the eDiary 
(if treated at home) or in the eCRF (if treated at the trial site), see section 12.3.
Severity of bleeding episodes must be evaluated by the investigator according to Table 8–3and 
reported in the eDiary database.
Prophylactic treatment with concizumab should continue independent of bleeding episodes and 
their treatment, i.e. the original dosing schedule should be maintained unless investigator judges 
otherwise. Decisions to alter dosing schedule, including the rationale for the alteration, should be 
documented. If applicable, investigator must instruct the patient to use rFVIII (turoctocog alfa) as 
rescue medication to treat bleeding episodes.
Treatment of bleeding episodes will be at the discretion of the investigator. In countries where 
turoctocog alfa is approved for the market it is recommended to follow the approved labelling for 
NovoEight®. For countries where turoctocog alfa is not approved it is recommended to follow the 
instructions in the EU-SMPC for turoctocog alfa (FVIII): “The calculation of the required dose of 
factor VIII is based on the empirical finding that 1 IU factor VIII per kg body weight raises the 
plasma factor VIII activity by 2 IU/dl. The required dose is determined using the following formula:
Required units (IU) = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5 (IU/kg per 
IU/dl).
The amount to be administered and frequency of administration should always be oriented to the 
clinical effectiveness in the individual case.
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Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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In case of the following haemorrhagic events, the factor VIII activity should not fall below the 
given plasma activity level (in % of normal or IU/dl) in the corresponding period. The following 
table can be used to guide dosing in bleeding episodes and surgery:”
Table 8–4
Guide for dosing in bleeding episodes and surgery
Degree of haemorrhage/ Type of
surgical procedure
FVIII level required (%)
(IU/dl)*
Frequency of doses (hours)/ 
Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding
or oral bleeding
More extensive haemarthrosis, muscle
bleeding or haematoma
Life threatening haemorrhages
20-40 
30-60 
60-100
Repeat every 12 to 24 hours, at least1 
day, until the bleeding episode as
indicated by pain is resolved or
healing achieved
Repeat infusion every 12-24 hours for 
3-4 days or more until pain and acute 
disability are resolved
Repeat infusion every 8 to 24 hours
until threat is resolved
Surgery
Minor surgery including tooth
extraction
Major surgery
30-60 
80-100 (pre- and postoperative)
Every 24 hours, at least 1 day, until
healing is achieved
Repeat infusion every 8-24 hours
until adequate wound healing, then
therapy for at least another 7 days to
maintain a factor VIII activity of 30%
to 60% (IU/dl)
*however in this trial any given single dose should not exceed 50 IU/kg 
Furthermore investigator must instruct the patient to contact the site when a bleeding episode occurs 
to discuss the bleed.
It is the responsibility of the investigator to instruct the patient when to contact the site according to
Table 8–3 .
In absence of apparent effect of turoctocog alfa (rFVIII) the site must be contacted for further 
advice and before any further dosing. In case of a bleeding episode that requires treatment occurring 
outside the trial site’s opening hours the patient must be treated according to local procedure. All 
contacts to the patient must be recorded in the patient’s medical chart. 
It is the responsibility of the investigator to instruct the patient about the timelines for timely 
completion of the eDiary. Furthermore the investigator must review the bleeding and treatment data 
collected by the eDiary according to section 13.3.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
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For in-between visit administrations of trial drug, patients will self-administer concizumab (and 
turoctocog alfa (rFVIII) as rescue medication)) and will record treatment in the hand-held, eDiary, 
which will be reviewed during periodic calls to/contact with the patient and at each visit by trial site
staff and the sponsor staff.
8.4
Safety assessments 
8.4.1
Physical examination
Performed as standard physical examination and include the following:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Genito-Urinary system, breasts 
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
The investigator must evaluate the results of the examination and classify the outcome as either:
!
Normal or abnormal.
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at Screening: record as Medical History (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
!
Measurements will be reported in the eCRF
8.4.2
Body measurements
Height (cm), at screening
Body Weight (kg), with 1 decimal.
The body weight assessed at each visit will be used for determination of the concizumab dose to be 
administered until next visit.
Measurements will be reported in the eCRF
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Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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8.4.3
Vital signs
Before measurement of vital signs the patient should preferably rest comfortably for at least five
minutes and all measurements should, if possible, be performed using the same method and sitting 
position throughout the trial. 
Measurements at visits must be performed prior to any trial product administration unless otherwise 
specified
!
Body temperature (°C)
!
Systolic and diastolic blood pressure, sitting (BP) (mmHg)
!
Pulse, sitting (beats/min)
!
Respiratory rate
Exception: At visit 2, the measurement is also performed after concizumab administration.
The investigator must evaluate the results and classify the outcome as either: 
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2.)
o
If observed after screening: report an AE/SAE (section 12)
Measurements will be reported in the eCRF.
8.4.4
Electrocardiogram 
The investigator must evaluate the ECG (standard 12 lead) at screening and classify the outcome as
either:
!
Normal or Abnormal. 
!
If Abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant? (Yes/No)
o
If observed before or at Screening: record as Medical History (Section 8.2.1)
o
If observed after screening: report an AE/SAE (Section 12)
The ECG results must be dated and signed by the investigator to verify that the data have been 
reviewed. Outcome will be reported in the eCRF.
8.4.5
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12.
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Date:
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Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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8.4.5.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form: 
!
Trial product(s) involved 
!
Classification of medication error
!
Whether the patient experienced any adverse event(s) as a result of the medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4.
8.4.5.2
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section12.
Injection site reaction 
Investigation of injection site reactions will be performed locally at visit 2 based on patient 
feedback and by following visual inspections of injection sites for concizumab administration:
Symptoms e.g.
!
Pain 
!
Numbness 
!
Itching
!
Burning
Signs e.g.:
!
Redness (mm x mm)
!
Induration (mm x mm)
!
Swelling
!
Dimpling
!
Macula
!
Haematoma
!
Bleeding
!
Other (visual reactions) 
Any injection site reaction symptom (evaluated between visit 2-16) should be recorded in the AE 
form and the injection site reaction form, see section 12.1.5. 
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Date:
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1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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A separate AE should be recorded for each injection site reaction symptom. The affected area 
should also be evaluated for redness and induration in mm using a ruler. To ensure all local 
injection site assessments are performed at the injection site, the area around the site will be marked 
with a pen prior to injection. 
In the event of a local reaction, additional visual assessments (as described above) will be 
performed until resolution as judged necessary by the investigator.
Assessment of injection site reactions can be performed at any time, if deemed necessary by the 
investigator.
Hypersensitivity reaction
If suspicion of a hypersensitivity reaction occurs the patients should be instructed to contact the site
staff as soon as possible for further guidance.
All events of hypersensitivity reactions must be reported and the following information must be 
obtained if available on the hypersensitivity reaction form: 
!
Signs and symptoms associated with the event
!
Time of appearance after administration of trial drug
!
Relevant immunological tests performed (See section 8.5.2.7)
!
Treatment given for the reaction
!
Previous history of similar reactions
!
Association with the trial product(s)
!
Relevant risk factors associated with the event
!
Storage condition of the trial product
!
Total number of doses, from first day on trial product, up to the time of this event
8.5
Laboratory assessments
An approximate total blood volume of 686 mL will be taken from each patient in the trial. Ports 
cannot be used for blood sampling.
A laboratory manual will be provided for detailed description of obtaining and processing blood 
samples.
All laboratory blood samples collected for this trial except for haematology samples are to be 
shipped for analysis at central laboratories or further distribution to special laboratories.
Haematology samples are to be analysed locally.
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in international system of units (SI) .
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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Laboratory reports listing results from centrally analysed samples will be made available for the 
investigator. Investigator must review and evaluate the results and report AEs for results which are 
clinical significant. Laboratory reports will where possible indicate normal ranges 
Categorisation of clinical significance for out of range results may not be required for the following 
laboratory parameters and the investigator is therefore not required to perform a categorisation even 
though these parameters are listed in the laboratory report: FVIII activity, FVIII inhibitor test, 
Thrombin generation, TFPI not bound to concizumab, concizumab concentration in plasma, Anti-
concizumab binding antibodies, and Total TFPI.
The laboratory equipment may provide analyses not requested in the protocol but produced
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to section 8.2.2 and section 12.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory except for biomarkers and anti-drug antibodies (anti-concizumab IgE antibodies and 
anti-concizumab binding antibodies).
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report (CTR).
Antibody samples and human bio-samples, if applicable will be stored as described in section 24.2. 
The investigator may not be able to review the results of antibody measurements in relation to AEs 
as these are often analysed after LPLV.
8.5.1
Laboratory assessments for efficacy
8.5.1.1
Thrombin generation
The Thrombin Generation Assay (TGA) will be performed at all visits (including unscheduled 24 
hour PK visit), except visit 3.
The TGA is included as an exploratory PD assessment.
The generation of thrombin is a fundamental part of the haemostatic system, and is a key 
measurable parameter of the formation of a clot under bleeding or thrombotic conditions. The 
thrombin burst is crucial for the formation of a stable fibrin clot. 
The Calibrated Automated Thrombogram (CAT) method (used by Thrombinoscope BV) will be 
used to measure thrombin generation (TG). This method uses a slow acting fluorogenic substrate 
that allows continuous measurement of thrombin generation in double centrifuged citrated plasma. 
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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
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In this assay set-up thrombin generation is initiated by low-dose tissue factor that is combined with 
phospholipid. The result is obtained by comparison to a constant known thrombin activity in a 
parallel non tissue factor initiated sample. The assay has been validated fit-for-purpose.
The thrombin generation endpoints are defined, but not limited to,
!
The Endogenous Thrombin Potential (ETP) – the area under the curve 
!
Peak thrombin generation
!
Velocity Index 
8.5.1.2
Free TFPI
Free TFPI measures TFPI not bound to concizumab. This enzyme-linked immunosorbent assay 
(ELISA) test will be will be sampled for at all assessment visits, including unscheduled 24 hour PK 
visit.
The free TFPI ELISA assay is an enzyme immunoassay measuring levels of TFPI not bound to 
concizumab from Diagnostica Stago (named and referred to Asserachrom TOTAL TFPI) and will 
be used for PD assessments. 
Free TFPI is included as a PD assessment.
8.5.2
Laboratory assessments for safety
8.5.2.1
Urinalysis
!
pH
!
Protein
!
Glucose
!
Bilirubin
This is a semi qualitative measurement which will be performed (locally) at the screening visit by 
the site by using the appropriate reagent strips for urinalysis. The results will be recorded in the 
eCRF.
Clinically significant findings must be recorded as: 
!
Normal or abnormal
o
if abnormal the investigator must:
o
record if the result is clinically significant? (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
8.5.2.2
Haematology
Haematology samples are to be sampled and analysed locally at all visits, except visit 3. 
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Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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!
Haemoglobin 
!
Erythrocytes (cell count) 
!
Thrombocytes (Platelet count)
!
Leucocytes (cell count) 
!
Differential leucocytes cell count 
o
Lymphocytes
o
Monocytes
o
Neutrophils
o
Eosinophils 
o
Basophils
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
Haematology results are to be entered into the eCRF.
8.5.2.3
Biochemistry
!
Creatinine 
!
Albumin 
!
Bilirubin; total, direct and indirect)
!
Aspartate aminotransferase (AST) 
!
Alanine aminotransferase (ALT)
!
Gamma glutamyltransferase (GGT) 
!
Alkaline phosphatase
!
C-reactive protein (CRP) 
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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8.5.2.4
FVIII activity
!
FVIII activity (IU/ml)
8.5.2.5
Coagulation parameters 
!
Fibrinogen
!
Prothrombin time  (PT) including INR
!
D-dimer 
!
Prothrombin fragment 1+2 
!
Activated partial thromboplastin time (APTT)
!
Antithrombin (AT)
The investigator must evaluate the results and record the outcome as:
!
Normal or abnormal
!
If abnormal the investigator must: 
o
Specify the abnormality 
o
Record if the result is clinically significant (Yes/No)
o
If observed before or at screening: record as concomitant illness (section 8.2.2)
o
If observed after screening: report an AE/SAE (section 12)
8.5.2.6
FVIII inhibitor test
The inhibitor level of the patient will be measured by the Nijmegen method at visit 1 (screening). 
!
FVIII inhibitor titre (BU)
In order to minimise the risk of false negative results, circulating FVIII product levels should be 
less than 0.05 IU/ml, when sampling for the test. If the patient has received FVIII within 96 hours 
of screening, the sampling of FVIII-Inhibitor should be postponed until a time period equal to 8 
half-lives of the used product has passed (counting from latest treatment).
8.5.2.7
Anti-concizumab antibodies
Sampling will be performed at all visits except at visit 3. Samples will be collected pre-dose at visit 
2, 9 and 16.
Assessment of binding antibodies against concizumab (anti-drug antibodies (ADA)) will be 
performed at specialised laboratories whereas assessment of neutralising antibodies will be 
performed at Novo Nordisk A/S.
Analysis for ADA will be done as listed in Table 2–1, with a bridging ECL assay (binding ADA 
assay), using labelled concizumab for antibody capture and detection. If a sample is confirmed 
positive in the confirmatory assay, the sample is considered antibody positive. Confirmed positive 
samples will be characterised for binding to IgG backbone, CDR region or the S241P mutation. 
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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Furthermore, positive samples will be characterised for neutralising activity using a modified TFPI 
functionality assay (neutralising ADA assay). All antibody assays are validated according to 
international guidelines and recommendations.
The following analyses will be available:
!
Anti-concizumab antibody assay
!
Specificity assay (Anti-concizumab antibodies cross reacting with IgG4 backbone, CDR region
or S241P mutation) 
!
Anti-concizumab neutralising antibody assay
Samples will be drawn at all visits except at visit 3. The binding ADA samples will be analysed in 
batches during the trial and results will be available to the data monitoring committee 
approximately every third month after the first patient has been dosed (Section 12). Neutralising 
antibodies will be analysed and reported at the end of trial. A detailed description of the assay 
methods will be included in the antibody analysis report at the end of the trial.
Investigators will be notified in case their patient is shown to have developed binding and/or
neutralising antibodies against concizumab.
Samples for the determination of anti-drug antibodies collected during the treatment period must be 
drawn prior to administering trial products.
In the event that a trial patient develops binding ADAs towards concizumab during the course of the 
trial and has measurable binding ADAs at his End of Trial visit, the patient may attend an ADA 
follow-up visit. The ADA positive patients will be called for additional visits, e.g. every 4 to 6 
weeks, for safety assessment and blood sampling for binding ADA and PD markers (free TFPI and 
Thrombin generation). The ADA positive patients will be followed no longer than one year after 
End of Trial.
Hypersensitivity
If suspicion of a hypersensitivity reaction occurs, patients should be instructed to contact the site 
staff as soon as possible for further guidance, see Section 12.1.5.
In the event of a severe local and/or systemic hypersensitivity reaction possibly or probably related 
to trial product, blood sampling for assessment of anti-concizumab IgE antibodies as well as anti-
concizumab antibodies should be conducted in relation to the reaction and no later than 1-2 weeks 
after the event. Additional testing may be performed if deemed relevant (e.g. anti-Host Cell Proteins 
(HCP) antibodies). 
In the event of a severe systemic hypersensitivity reaction to trial product it is recommended also to 
test for tryptase (total and/or mature tryptase) within 3 hours of the reaction. Moreover, a baseline 
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Date:
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Trial ID:NN7415-4255
Version:
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Status:
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tryptase measurement is necessary 1-2 weeks after the immediate severe hypersensitivity reaction 
due to individual to individual variation in tryptase baseline concentration. 
A follow up visit should be conducted 3-4 weeks post the allergic reaction with repeated blood 
sampling for assessment of anti-concizumab IgE antibodies as well as anti-concizumab antibodies 
and if possible also at a visit 3 months post the hypersensitivity reaction for assessing the 
persistence of the IgE response. Tryptase measurements are not required at the follow up visits.
Additionally, basophil activation testing may be performed if deemed relevant. This can be 
performed using existing samples and/or by analysing the patient’s basophil cells from an additional 
blood sample taken 3-4 weeks and no later than 2 months after the event. Similarly, prick tests 
and/or intra-dermal tests may be performed if relevant using trial product or components of trial 
product. Complement may be measured in case of suspicion of immune complex mediated 
hypersensitivity reactions.
Results from the following additional tests will be reported to Novo Nordisk Safety Operations for 
inclusion in the ARGUS database and included in the narratives, if measured:
Test to be performed in case of severe hypersensitivity
!
Anti-concizumab IgE antibodies
!
Anti-concizumab antibodies (additional to scheduled time points)
Additional testing may be performed if deemed relevant e.g
!
Anti-Host Cell Proteins (HCP) antibodies
!
Anti-HCP IgE antibodies
!
Basophil activation results
!
Prick test/intra-dermal test
!
Complement test results
Furthermore, it is recommended locally to test for
!
Tryptase (total and/or mature tryptase)
8.5.2.8
Concizumab ELISA
Concizumab ELISA will be performed at all visits except at screening and at visit 3. Samples will 
be collected pre-dose at visit 2, 9 and 16. For the unscheduled 24 hour PK visit, samples are 
collected; 1 hour pre-dose (-1hour), 1(±10 min.), 3(±10 min.), 6(±10 min.), 9(±10 min.), 12(±20 
min.) and 24 hour(s) (±20 min.) post dose, related to the daily dosing of concizumab.
Concizumab will be quantified using a validated ELISA assay. Recombinant human TFPI will be 
used to capture concizumab. A colorimetric detection signal is obtained by the enzymatic reaction 
of horseradish peroxidase labelled anti-human IgG4 specific antibodies with the chromogenic 
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substrate TMB (3,3´,5,5´-tetramethylbenzidine). The amount of anti-TFPI present in the calibration, 
quality control and test samples correlates with the obtained signal strength.
Validation of the assay follows current guidelines for bioanalytical method validation. Bioanalytical 
data will be reported in a bioanalytical report.
8.5.2.9
Total TFPI
Total TFPI ELISA sampling will be performed at all visits except at visit 3. Samples will be 
collected pre-dose at visit 2, 9 and 16.
The Total TFPI ELISA is included as an exploratory PD assessment.
The total TFPI level (free and concizumab bound) will be included as an exploratory biomarker 
assessment. The assay is an ELISA, where TFPI is captured by polyclonal anti-TFPI antibody, 
distanced from the binding site of concizumab, meaning that both free TFPI and concizumab bound 
TFPI will be captured. Detection will be obtained with a monoclonal antibody against TFPI, which 
does not bind to the concizumab epitope. Data will be reported in ng/mL TFPI.
Total TFPI ELISA will be performed at all visits, except visit 3. Sample will be collected pre-dose 
at visit 2.
8.5.3
Human biosamples
If patient permission is obtained, plasma, serum and/or DNA for genotyping samples are to be taken 
for long term retention. The blood samples can be stored up to 15 years, for future potential 
exploratory purposes please refer to section 24.2.
Antibody samples storage and retention see section 24.2.1. The investigator is not able to review the 
results of antibody measurements in relation to AEs as these are analysed after LPLV.
If applicable, samples will be collected at visit 1 and at visit 17.
8.6
Other assessments
8.6.1
Patient reported outcomes
In this trial a newly developed disease specific PRO -the Hemophilia Treatment Experience 
Measure (Hemo-TEM) -is being validated. In order to assess the psychometric properties of 
Hemo-TEM, other questionnaires will be provided; see further appendix 1.
The following ePRO questionnairesare used:
-Haemophilia Treatment Experience Measure (Hemo-TEM)
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- Validated Hemophilia Regimen Treatment Adherence Scale – Prophylaxis (VERITAS-
Pro®)/Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
- 36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
- Patient Global Impression of Change (PGI-C)
- Sheehan Disability Scale (SDS)16
- Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
- Haemophilia - Device Assessment Tool (H-DAT)
- Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
The PROs should be assessed at the scheduled visits following the order listed below:
!
visit 1 (Hemo-TEM, VERITAS-Pro® or VERITAS-PRN®)
!
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 4 (PGI-C, Hemo-TEM)a
!
visit 5 (PGI-C, Hemo-TEM)
!
visit 6 (PGI-C, Hemo-TEM)
!
visit 7 (PGI-C, Hemo-TEM)
!
visit 8 (PGI-C, Hemo-TEM)
!
visit 9 (PGI-C, Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
!
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 15.1 or 16 (Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
At visit 1 before any visit-related activities all patients should complete Hemo-TEM and 
VERITAS-Pro® (if the patient at baseline receives prophylactic treatment) / VERITAS-PRN® (if 
patient at baseline receives on demand treatment).
At visit 2 before any visit-related activities all patients should complete Hemo-TEM, SF36v2, SDS, 
TSQM and SIAQ-ISRQ.
At visit 4-8: before any visit-related activities the patient should complete the PGI-C before the 
Hemo-TEM. These are the rules that apply:
!
If the patient responds “1” to question 1 in the PGI-C, the patient should also complete the 
Hemo-TEM. In this case the patient should not fill in the PGI-C any more in the trial and the 
Hemo-TEM only again at visit 9.
!
If the patient responds “0” or “2” to question 1 in the PGI-C, the patient should not complete 
any other questionnaires at this visit, but should repeat the procedure at next visit. 
At visit 9 if the patient has responded “0” or “2” in the PGIC at all previous visits, the patient 
should complete PGI-C. All patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT
and SIAQ-ISRQ.
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At visit 10 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and SIAQ-ISRQ.
At visit15.1 or16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT and 
SIAQ-ISRQ. The investigator mustcheck the ePROs forcompleteness.
The completed ePROs should be transmitted to the ePRO database by the investigator at each visit.
All PROs can be found in Appendix I. 
8.6.2
Training 
The patients must be trained in how to handle bleeding episodes and how to recognize the signs and 
symptoms of thrombosis. The training must be recorded in the medical records. 
8.6.2.1
Concizumab and NovoPen® 4
A direction for use (DFU) will be available as hand out for patients at visit 2. Training in 
NovoPen®4 can start at screening (visit 1) and s.c. administration of concizumab using the 
NovoPen®4 can start at the first dose at the trial site (visit 2). Patients must be instructed that 
injections are to be performed subcutaneously, not intravenously. Concizumab and NovoPen®4 will 
be dispensed to patients at visit 2. Training must be performed at site until patients feel comfortable
using the device or performing the treatment. The training must be documented in the medical 
records.
Detailed instructions can be found in the DFU.
8.6.2.2
Turoctocog alfa
A direction for use (DFU) will be available as hand out for patients at visit 1. Training must be 
performed at site until patients feel comfortable performing the treatment. The training must be 
documented in the medical records. 
Detailed instructions can be found in the DFU.
8.6.2.3
eDiary
Training on the use of the eDiary can start at visit 1. The eDiary will be provided to the patients at 
visit 2.
Training must be repeated at the site until patients feel comfortable using the device. The training 
must be documented in the medical records.
During the home treatment period the patient must ensure that all home treatments of concizumab, 
details of bleeding episodes and the turoctocog alfa (FVIII) treatment associated with these bleeding 
episodes are captured in the eDiary as instructed and trained by investigator or delegated staff.
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It will be the responsibility of the investigator or delegated staff to assess the eDiary data 
throughout the conduct of the trial and to ensure data entry compliance (timely entry, no duplicates 
data, no missing data etc.) and retraining if necessary.
For patients completing the trial or in case of withdrawal, the eDiary will be collected at the end of 
trial.
8.6.3
Surgery
Minor surgery can be performed within this trial at the investigator’s discretion according to local 
guidelines. Definition of minor surgery, see section 5.1.1. Major surgery is not allowed, see 
exclusion criteria no 6.
For minor surgery the following should be recorded in the eCRF:
!
Date, stop time and dose of preventive treatment with turoctocog alfa before surgery, if this was 
deemed necessary by the investigator
!
Indication for surgery
!
Location of surgery
!
Date of surgery
!
Start and stop time of surgery
8.7
Patient compliance
Throughout the trial, the investigator will remind the patients to follow the trial procedures and 
requirements to ensure patient compliance. If a patient is found to be non-compliant, the 
investigator will remind the patient in the importance of following the instructions given including 
taking the trial products as prescribed.
Assessment of patient compliance with protocol procedures for determination of continuation of the 
trial will be done by the investigator on an ongoing basis.
8.8
Treatment compliance:
Treatment compliance will be monitored and documented through timely review of eDiary data and 
drug accountability. 
Concizumab will be administered at the trial site at visit 2 supervised by medically trained trial staff
and administration at home can be initiated after visit 2 if the patient feels comfortable with the s.c. 
administration. Administration of turoctocog alfa (rFVIII) for bleeding episodes will be 
administered at the trial site by a medically trained trial staff or at home by the patient, see section 
8.3.1. 
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The patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator. Drug accountability will be performed and will be used to assess 
patient compliance together with the patient’s adherence to trial procedures. 
Compliance check includes a cross check between records in EDC/eDiary (number of 
administrations and bleeding episodes) and the used/returned cartridges/vials. 
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
The trial product, concizumab B, appears clear to slightly opalescent and colourless to slightly 
yellow. The trial product must not be used if it contains visible particles or discolouration.
The reconstituted turoctocog alfa (FVIII) solution appears as a clear or slightly opalescent solution. 
Do not use the reconstituted solution if it has visible particles or discoloration. 
Trial products must not be dispensed to any person not included in the trial.
9.1
Trial products
The following trial products will be provided by Novo Nordisk, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
concizumab B 
(IMP a)
100 mg/mL
Solution for injection
s.c. injection
3 ml cartridge
turoctocog alfa
(NIMP b)
2000 IU/vial
Powder for solution for 
injection
i.v. injection
Vial
0.9% Sodium Chloride 
Solution
(NIMP b)  
N/A
Solvent for solution for
injection 
i.v. injection
4 ml prefilled 
syringe
a Investigational Medicinal Product (IMP) 
b Non-Investigational Medical Product (NIMP) given as NIMP for bleeding episodes
The NovoPen®4 injector will be supplied by Novo Nordisk and used for the s.c. administration of 
concizumab. NovoPen®4 will be labelled in accordance with the EMA directive on medical devices 
annex I 21 and similar national legislation. A description on how to use the device is given in the
DFU.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 22, local regulations and trial 
requirements.
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Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial products will be distributed to the trial sites according to enrolment 
and drug dispensing of distribution.
The investigator must document that direction for use is given to the patient orally and in writing at 
the first dispensing visit (see flow chart section 2). 
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time a
concizumab B 100 mg/mL
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
Store at room temperature 
(below 30°C)
Do not refrigerate
Protect from light
Use within 4 weeks 
(28 days)
turoctocog alfa
2000 IU/vial
Store in refrigerator (2o-8oC)
Do not freeze
Protect from light
May be stored at room 
temperature (9-30oC) for a 
single period not exceeding 9
months. Do not return the 
product to the refrigerator.
Write the start date for the 
storage at room temperature on 
the label
For single use
To be used immediately after 
reconstitution
Use within 4 hours after 
reconstitution when stored at 
room temperature
N/A
0.9% sodium chloride 
solution
Store at 2°-30°C
Do not freeze
Protect from light
For single use
N/A
a In-use time for concizumab starts when first dose is administrated from an individual cartridge and for turoctocog alfa 
when the product is reconstituted
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any patient before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
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Investigator must instruct the patient to use and store trial product according to the label.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator. The 
patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator except for the used sodium chloride solution which should be 
discarded at home and not accounted for. Unused sodium chloride syringes should be returned to 
site at every visit and new sodium chloride syringes should be dispensed to the patient.
All cartridges (concizumab) and vials (FVIII) must be accounted for as used, partly used, or unused. 
The investigator will perform drug accountability using the IWRS Drug Accountability module.
Returned trial product (used/partly used and unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Destruction of concizumab can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
For Japan only: Responsibility for storage and drug accountability of the trial drug product at the 
trial site rests with the head of the trial site. The head of the trial site could assign some or all of the 
responsibilities for accountability of the trial drug product at the trial sites to a trial product storage 
manager (a pharmacist in principle). The trial product storage manager should control and take 
accountability of the trial drug product in accordance with procedures specified by Novo Nordisk. 
The head of the trial site or the trial product storage manager must ensure the availability of proper 
storage conditions, and record and evaluate the temperature.
9.5
Auxiliary supplies
Novo Nordisk will provide the auxiliaries for this trial: 
!
For concizumab administration: NovoPen®4, needles, and DFU
!
For turoctocog alfa reconstitution and administration: Trial Injection Kit and DFU
Only needles and trial injection kits provided by Novo Nordisk must be used for administration of 
trial product.  
For further guidance please see the TMM.
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for:
!
Screening
!
Screening failure
!
Medication arrival
!
Dispensing
!
Dispensing verification
!
Treatment discontinuation 
!
Completion
!
Drug accountability
!
Data change
An IWRS user manual will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
Randomisation 
Not applicable for this trial
Breaking of blinded codes
Not applicable for this trial.
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12 Adverse events, and technical complaints 
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial 
procedures performed before exposure to trial product (pre-existing conditions should be 
reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the patient has signed the informed 
consent.
!
Bleeding episodes and other symptoms (e.g. pain, swelling, synovitis, arthralgia) in 
connection with bleeding episodes should not be reported as AEs/SAEs unless the event is 
fatal, life-threatening or evaluated by the investigator as related to trial product or trial 
procedure. All bleeding episodes and other findings related to underlying disease will be 
captured in the eCRF/eDiary
The following three definitions are used when assessing an AE:
!
Severity 
o
Mild – no or transient symptoms, no interference with the patient’s daily activities.
o
Moderate – marked symptoms, moderate interference with the patient’s daily activities.
o
Severe – considerable interference with the patient’s daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial product(s): 
o
Probable - Good reason and sufficient documentation to assume a causal relationship.
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o
Possible - A causal relationship is conceivable and cannot be dismissed.
o
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome 
o
Recovered/resolved - The patient has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the patient signed the informed consent.
o
Recovering/resolving - The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the trial 
or has died from another AE.
o
Recovered/resolved with sequelae - The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
o
Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known.
o
Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he 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.
o
Unknown - This term is only applicable if the patient is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
a. The term “life threatening” in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
b. The term “hospitalisation” is used when a patient: 
o
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
o
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c.A substantial disruption of a patient’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the patient has significant, persistent or permanent change, 
impairment, damage or disruption in his body function or structure, physical activity and/or quality 
of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
Suspicion of transmission of infectious agents via the trial product 
!
Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative 
aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error unless 
it results in administration of wrong drug.
!
Wrong route of administration, 
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. However, the 
administered dose must deviate from the intended dose to an extent where clinical 
consequences for the trial patient were likely to happen as judged by the investigator, 
although they did not necessarily occur
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1
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12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
In this trial the following AEs require the completion of specific event forms in the eCRF:
!
Injection site reaction (see section 8.4.5.2)
!
Hypersensitivity type reactions, incl. anaphylactic reactions, as defined below 
Injection site reactions:
Any injection site reaction symptom must be reported on the AE form and the injection site reaction 
form, See section 8.4.5.2.
Hypersensitivity type reactions:
In cases where clinical signs of a severe and immediate hypersensitivity reaction resembling a type
I hypersensitivity reaction are present, blood should be sampled for central laboratory assessment of 
anti-drug IgE antibodies and anti-drug binding antibodies. In the event of an immediate systemic 
hypersensitivity reaction to the trial product, it is recommended to also test for tryptase (total and/or 
mature tryptase) within 3 hours of the reaction. Moreover, a baseline tryptase measurement is 
necessary ~1 week after the immediate severe hypersensitivity reaction due to individual to 
individual variation in tryptase baseline concentration. Tryptase concentrations (if measured) must 
be interpreted and considered in the context of a complete workup of each patient.
Special attention should be given to clinical signs and symptoms of hypersensitivity reactions of 
type II and III. Common clinical signs and symptoms characteristic for these types of reactions may 
include but are not limited to: fever/malaise, cutaneous eruptions, arthralgia, lymphadenopathy, 
itching, headaches and myalgia. Related laboratory findings may include but are not limited to: mild 
proteinuria or haematuria, leukopenia or leucocytosis, decreased complement levels or increased 
complement split products and transient elevations of serum creatinine levels. In cases where there 
is a suspicion of hypersensitivity reaction that requires systemic treatment, additional sampling for 
the purpose of measuring ADA is to be performed.
Definition of anaphylaxis23
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
!
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (e.g. generalised hives, pruritus or flushing, swollen lips-tongue-uvula) and 
at least one of the following:
a) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)
b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.
hypotonia [collapse], syncope, incontinence)
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!
Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):
a) Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush, swollen 
lips-tongue-uvula)
b) Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
!
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
Systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
BP.
If a patient fulfils any of the three criteria of anaphylaxis outlined above, the patient should receive 
epinephrine/adrenalin immediately. Dose regimen should be according to hospital operating 
procedure, and the patient should be transferred to an emergency department or intensive care unit, 
if clinically warranted.
Events not fulfilling the criteria for an anaphylactic reaction and other allergic reactions must be 
treated at the discretion of the investigator. If according to the investigators judgment, 
hypersensitivity type reactions that require systemic treatment are suspected, dosing with 
concizumab should be stopped immediately and treatment at the discretion of the treating physician 
initiated.
12.1.6
Adverse event of special interest
An adverse event of special interest (AESI) is an event, which in the evaluation of safety, has a 
special focus. In this trial, the following AEs fulfil the AESI criteria:
!
Thromboembolic events including but not limited to,
o
disseminated intravascular coagulation (DIC) (A), 
o
clinical signs or laboratory indications of arterial and venous thrombosis including 
myocardial infarction (B), 
o
pulmonary embolism (C), 
o
stroke (D), 
o
deep vein thrombosis (E), 
o
other clinically significant thromboembolic events (F) and peripheral artery 
occlusion (see below G), see definitions below.
The AESIs must be reported on an AE form and a safety information form.
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A) Definition of disseminated intravascular coagulation (DIC), as defined below:
The definition of DIC in this trial should be made according to the International Society on
Thrombosis and Haemostasis (ISTH) criteria. Thus, a DIC diagnosis may be based on 
clinical signs and symptoms of a bleeding tendency or thrombotic tendency, organ 
dysfunction and the laboratory parameters criteria as listed below:
o
Platelet count (>100 × 109/L = 0, <100 × 109/L = 1, <50 × 109/L = 2)
o
Elevated D-dimer (no increase = 0, moderate increase = 2, strong increase = 3)
o
Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
o
Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
o
Calculate score: ≥5 compatible with overt DIC
(B) Myocardial infarction is defined according to the “Third Universal Definition of
Myocardical Infarction” 24
Criteria for acute myocardial infarction - The term acute myocardial infarction (MI) should be used 
when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial 
ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI:
!
Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin
(cTn)] with at least one value above the 99th percentile upper reference limit (URL) and
with at least one of the following:
o
Symptoms of ischemia.
o
New or presumed new significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB).
o
Development of pathological Q waves in the ECG.
o
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality.
o
Identification of an intracoronary thrombus by angiography or autopsy.
Criteria for prior myocardial infarction- Any one of the following criteria meets the diagnosis for
prior MI:
!
Pathological Q waves with or without symptoms in the absence of non-ischemic causes.
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to
contract, in the absence of a non-ischemic cause.
!
Pathological findings of a prior MI.
Recurrent myocardial infarction - Incident MI’ is defined as the individual’s first MI. When features 
of MI occur in the first 28 days after an incident event, this is not counted as a new event for 
epidemiological purposes. If characteristics of MI occur after 28 days following an incident MI, it is
considered to be a recurrent MI.
C) Definition of pulmonary embolism:
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The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends diagnostic
imaging studies for patients with intermediate or high pre-test probability of pulmonary embolism25.
Accordingly, the definition of pulmonary embolism is the following: obstruction of a pulmonary 
artery or one of its branches, most frequently by detached fragments of thrombus from a leg or 
pelvic vein, diagnosed by at least one of the following:
!
Positive findings in ventilation/perfusion scan
!
Positive findings in a spiral (helical) computerised tomography (CT) or angiography
!
Positive findings in a magnetic resonance imaging (MRI)
!
Positive findings in a pulmonary angiography
D) Definition of stroke:
The definition of central nervous infarction is according to the American Heart
Association/American Stroke Association Expert Consensus Document:  “An Updated Definition of 
Stroke for the 21st Century”26.
Accordingly, the term “stroke” should be broadly used to include all of the following:
Definition of central nervous system (CNS) infarction: CNS infarction is brain, spinal
cord, or retinal cell death attributable to ischemia, based on:
o
1. pathological, imaging, or other objective evidence of cerebral, spinal cord, or
retinal focal ischemic injury in a defined vascular distribution; or
o
2. clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on
symptoms persisting 24 hours or until death, and other etiologies excluded.
Note: CNS infarction includes haemorrhagic infarctions, types I and II; see “Haemorrhagic
Infarction”.
Definition of ischemic stroke: An episode of neurological dysfunction caused by focal cerebral,
spinal, or retinal infarction. Note: Evidence of CNS infarction is defined above.
Definition of silent CNS infarction: Imaging or neuropathological evidence of CNS infarction,
without a history of acute neurological dysfunction attributable to the lesion.
Definition of intracerebral haemorrhage: A focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma. Note: Intracerebral haemorrhage includes
parenchymal haemorrhages after CNS infarction, types I and II - see “Haemorragic Infarction”.
Definition of stroke caused by intracerebral haemorrhage: Rapidly developing clinical signs of
neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or
ventricular system that is not caused by trauma.
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Definition of silent cerebral haemorrhage: A focal collection of chronic blood products within the
brain parenchyma, subarachnoid space, or ventricular system on neuroimaging or neuropathological
examination that is not caused by trauma and without a history of acute neurological dysfunction
attributable to the lesion.
Definition of subarachnoid haemorrhage: Bleeding into the subarachnoid space (the space between
the arachnoid membrane and the pia mater of the brain or spinal cord).
Definition of stroke caused by subarachnoid haemorrhage: Rapidly developing signs of
neurological dysfunction and/or headache because of bleeding into the subarachnoid space (the
space between the arachnoid membrane and the pia mater of the brain or spinal cord), which is not
caused by trauma.
Definition of stroke caused by cerebral venous thrombosis: Infarction or haemorrhage in the brain,
spinal cord, or retina because of thrombosis of a cerebral venous structure. Symptoms or signs
caused by reversible edema without infarction or haemorrhage do not qualify as stroke.
Definition of stroke, not otherwise specified: An episode of acute neurological dysfunction 
presumed to be caused by ischemia or haemorrhage, persisting ≥24 hours or until death, but without
sufficient evidence to be classified as one of the above.
Definition of a Transient Ischemic Attack: The definition of Transient Ischemic Attack is according
to the American Heart Association/American Stroke Association. Accordingly: a Transient 
ischemic attack (TIA) is a transient episode of neurological dysfunction caused by focal brain, 
spinal cord, or retinal ischemia, without acute infarction 27.
E) Definition of deep vein thrombosis:
The “Clinical Practice Guideline from the American Academy of Family Physicians and the
American College of Physicians” on diagnosis of venous thromboembolism recommends
ultrasound scanning for patients with intermediate or high pre-test probability of deep vein 
thrombosis (DVT) in the lower extremities 25. Accordingly, venous thrombosis should be 
demonstrated by compression ultrasound,
duplex ultrasound, colour Doppler imaging or venography (phlebography).
F) Definition of other clinically significant thromboembolic events:
Signs or suspicion of a clinically significant thromboembolic event (e.g. visceral arterial 
embolus/thrombus, extremity arterial embolus/thrombus, or portal venous thrombosis).
Superficial thrombophlebitis is not considered a clinically significant thromboembolic event unless 
evaluated as such by the investigator.
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G) Definition of peripheral artery occlusion:
Clinical signs of acute arterial occlusion verified by ankle-brachial index (ABI) test, Doppler and
ultrasound (Duplex) imaging, computerised tomographic angiography, magnetic resonance 
angiogram (MRA), or conventional angiography. The 2011 American College of Cardiology 
Foundation/American Heart Association Focused Update of the Guideline for the Management of 
Patients With Peripheral Artery Disease could serve as a reference for the diagnosis of lower 
extremity peripheral artery disease 28
12.1.7
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between pen and needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the patient has signed the informed consent until visit 16 
(end of treatment) for patients enrolling into a subsequent trial with concizumab and at the end of 
the post-treatment follow-up period (visit 17) for patients not enrolling in to a new trial. The events 
must be recorded in the applicable eCRF forms in a timely manner; see timelines below in Figure 
12–1
During each contact with the trial site staff, the patient must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?
All AEs, either observed by the investigator or patient, must be reported by the investigator and 
evaluated. All AEs must be recorded by the investigator on an AE form. The investigator should 
report the diagnosis, if available. If no diagnosis is available, the investigator should record each 
sign and symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
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AESIs regardless of the seriousness, must be reported using the AE form and safety information 
form
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the case report form (CRF)/eCRF within the 
specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator’s first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in the 
eCRF. 
For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
!
Non-serious AEs fulfilling the AESI criteria: The AE form and safety information form 
within 14 calendar days of the investigator’s first knowledge of the event.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
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Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: Investigator’s Brochure; Current version and any updates thereto.
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP 1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the
International Review Boards/Independent Ethics Committees (IRBs/IECs) of trial product-related 
SUSARs in accordance with local requirement and ICH GCP 1, unless locally this is an obligation 
of the investigator.
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Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
non-investigational medicinal product rFVIII (turoctocog alfa) or concomitant medication in the 
trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to report this 
adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. 
Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is 
“recovered/resolved”, “recovered/resolved with sequelae” or “fatal”, and until all queries 
have been resolved. Cases of chronic conditions, cancer or AEs ongoing at time of death 
(where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the 
outcome of “recovering/resolving” when the patient has completed the follow-up period 
and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
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!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or 
until the end of the follow-up period stated in the protocol, whichever comes first, and 
until all queries related to these AEs have been resolved. Cases of chronic conditions, 
cancer or AEs ongoing at time of death (where death is due to another AE) may be 
closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the patient has 
completed the follow-up period and is expected by the investigator to recover.
!
Non-serious AEs fulfilling the AESI criteria: Non-serious AE fulfilling the AESI 
criteria must be followed as specified for non-serious AE. Follow-up information on 
AESIs 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 AESI criteria.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a patient after the patient has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 
!
Concizumab B 100 mg/mL, solution for injection in a 3 ml cartridge
!
NovoPen®4
!
Novo Nordisk needles
!
Turoctocog alfa 2000 IU/vial, powder for solution for injection in a vial  
!
0.9 % sodium chloride 4.0 mL prefilled syringe
!
Novo Nordisk trial injection kit
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Centre, Novo Nordisk.
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Contact details (fax, e-mail and address)  are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, AESIs and/or 
SAEs.
Technical complaints must be reported on a separate technical complaint form: 
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each batch, code or lot number
must be completed
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not patient related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. Themonitor must coordinate the shipment to 
Customer Complaint Centre, Novo Nordisk (the address is provided in Attachment I)  and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. 
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12.5
Pregnancies 
12.5.1
Pregnancies in female partners of male patients
Male patients must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period (from visit 1 to dosing at visit 2). At the last 
scheduled visit, male patients must be asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male patient and assess, if the pregnancy 
outcome is normal or abnormal. 
When the pregnancy outcome is normal this information is recorded in the patient’s medical record 
only, no further information is collected and reported to Novo Nordisk. When the pregnancy 
outcome is abnormal (i.e. congenital anomalies, foetal death including spontaneous abortion and/or 
any anomalies of the foetus observed at gross examination or during autopsy), the following must 
be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
1. Reporting of pregnancy information
Information from the male patient has to be reported on the Paternal Form. Furthermore, 
information from the female partner (including information about the pregnancy outcome and 
health status of the infant until the age of one month) has to be reported on the Maternal Forms 
1A, 1B and 2, after an informed consent has been obtained from the female partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information. 
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
o
Non-serious AEs evaluated as possible/probably related to the father’s treatment 
with the trial product(s). 
o
SAEs in the foetus and newborn infant - whether or not related to the father’s 
treatment with the trial product(s). This includes an abnormal outcome - such as 
foetal death (including spontaneous abortion) and congenital anomalies (including 
those observed at gross examination or during autopsy of the foetus).
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
Paper AE forma within 14 calendar days of the investigator’s first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
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!
Paper AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
Paper safety information form within 5 calendar days of the investigator’s first knowledge 
of the SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information.
a It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
patient, foetus or new born infant. 
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Dose limiting toxicities of concizumab has not been investigated in clinical trials.
There have been no reports about overdosing of concizumab and therefore no experience with 
overdose and overdose reactions exists. In case of a concizumab overdose, symptomatic medical 
treatment according to the clinical condition should be applied. No antidote exists in case of 
concizumab overdose.
Any overdose should be reported as an AE, with or without clinical manifestations. Overdoses are 
considered medication errors.
Treatment should be as appropriate and in accordance with hospital practice and guidelines.
12.7
Rules for putting enrolment on hold
If one of below mentioned criteria is fulfilled, enrolment of additional patients in the clinical trial 
program will be placed on hold. An urgent safety committee meeting will be scheduled to decide 
further actions. Dosing of patients on treatment may continue while further evaluation is made by 
the safety committee. A substantial amendment with relevant data must be submitted to the 
regulatory authorities to support restart of the trial.
!
Significant thromboembolic event
!
Event of DIC 
!
Anaphylactic reaction related to trial drug administration 
!
Death of trial patient which may be related to the trial product
!
Two or more other trial product related SAEs similar in nature have been reported and/or 
detected by laboratory measurements
!
Trends in AEs, clinical observations or laboratory parameters which raise concerns about 
the safety of continued treatment
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12.8
Committees related to safety
12.8.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal concizumab safety committee to perform ongoing safety 
surveillance of safety data relevant to concizumab. The safety committee is a cross functional group 
within Novo Nordisk.
12.8.2
Data monitoring committee
The DMC is an independent, external committee composed of members whose expertise covers 
relevant specialties including statistics. The DMC is established to review and evaluate accumulated 
data from the trial at predefined time points as well as ad-hoc. This is in order to protect the safety 
of the patients and to evaluate the benefit-risk balance. The DMC will have access to the unblinded
data, and will provide recommendations on trial continuation, modification or termination.
In case there is any safety concern data will be compiled and the DMC will review these data. Their 
recommendation will go to the Novo Nordisk Safety committee for final decision of what next step 
is in this trial.
The DMC members will only have direct contact with the Novo Nordisk Global Safety department 
through the safety surveillance representatives, and will have no direct interaction with those in trial 
management. The DMC recommendations should be addressed directly to the Novo Nordisk Global 
Safety department and the internal Novo Nordisk safety committee for concizumab. It is the 
responsibility of the Novo Nordisk internal safety committee for concizumab to take action(s) for
patient safety based on the DMC recommendations.
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter.
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13 Case report forms 
For this trial a combination of electronic case report forms (eCRFs) and paper CRFs will be used.
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
Safety information forms
!
Technical complaint forms 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
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Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
13.3
Electronic diary
Novo Nordisk will provide the patient with an eDiary for electronic recording of details of their 
home treatment, bleeding episodes and treatment of bleeding episodes (i.e. use of FVIII). The 
eDiary and related support services will be supplied by a vendor working under the direction and 
supervision of Novo Nordisk. 
Patients will be instructed in the use of the eDiary by the investigator or delegated person before 
entering of any data. The eDiary will be dispensed to the patient at visit 2. After visit 2 and 
onwards, data will be entered by the patient in the eDiary device during home treatment.
The eDiary will be returned by the patient at the end of trial (EOT) visit.
All data entered will be transferred from the device to an electronic database, where it is kept as a 
certified copy of the source data by the eDiary vendor. Data entered in the device will upon 
confirmation of a successful back-up be deleted from the device. 
The eDiary will have built in edit checks and reminders, to ensure that all relevant questions are 
answered. 
eDiary data transferred to the electronic database will be viewable to relevant trial site staff and 
Novo Nordisk personnel on a secure, password protected web portal.
13.3.1
Investigator review of eDiary data
It is the responsibility of the Investigator or delegated staff to review the eDiary data reported by the 
patient. As a minimum it must be verified that the eDiary data is complete, consistent and according 
to the requirements defined in this protocol. This also includes that the number of doses reported in 
the eDiary is reviewed against the number of vials/cartridge accounted for as used by the patient.  
Upon review the Investigator must document that the review has taken place and any actions 
required e.g. retraining of the patient or decision to amend or correct the data reported by the 
patient. 
If the Investigator finds it necessary to amend or correct eDiary data, the patient must be consulted 
prior to requesting the actual data change. A Data Correction Request must be submitted to the 
eDiary vendor. An audit trail will be maintained.
14 Monitoring procedures 
Monitoring will be conducted using a risk based approach including risk assessment, monitoring 
plans, centralised monitoring and visits to trial sites. During the course of the trial, the monitor will 
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visit the trial site to ensure that the protocol is adhered to, that all issues have been recorded, to 
perform source data verification and to monitor drug accountability. The first monitoring visit will 
be performed as soon as possible after FPFV at the trial site and no later than 4 weeks after. The 
monitoring visit intervals will depend on the outcome of the centralised monitoring of the eCRFs 
(remote assessment of data by Novo Nordisk), the trial site's recruitment rate and the compliance of 
the trial site to the protocol and GCP, but will not exceed 12 weeks until LPLV at the trial site. This 
only applies to sites with scheduled, ongoing and/or discontinued patients.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone or text message).
All data must be verifiable in source documentation other than the eCRF. eDiary data is entered by 
the patient and will also be treated as source data. 
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
For historical data such as medical history, details of haemophilia and haemophilia treatment 
history, a reasonable effort must be made by the investigator, considering local requirements, to 
obtain this information from external sources, if not known by the patient. It is accepted that the 
earliest practically retainable record should be considered as the location of the source data and 
therefore the source document. This means that for laboratory results (e.g. biochemistry and 
haematology) a signed printout of the electronic results must be available.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The monitor will ensure that the eCRFs are completed and paper CRFs (if any) collected, that PROs 
and eDiaries are completed and reviewed by the investigator at the relevant scheduled visits and 
needed action has been taken and documented, if any.
The following data will be source data verified for screening failures:
!
Date for obtaining informed consent
!
Inclusion and exclusion criteria
!
Screen failure reason if possible
!
Date patient left the trial
!
Data relating to AEs if applicable
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!
Demography (See section 8.2.1)
!
Date of visit
Monitors will review the patient’s medical records and other source data (e.g. eDiaries and ePROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract reseach organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data,will be 
used to ensure confidentiality of patientdata, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The laboratory will provide all laboratory reports to the investigator for filing at the trial site. The 
laboratory report must be signed and dated by the investigator or delegated person and stored at the 
trial siteas source data.
The patientand any biological material obtained from the patientwill be identified by patient
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of patients in all presentations and publications as required by 
local, regional and national requirements
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk 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 use the Global Haemophilia Network (GHN) InvestigatorPortal to distribute 
and share trial-related documents and information with the participating sites.
After trial completion, Novo Nordisk will supply each trial site with long-life CDs or other relevant 
electronic archiving containing the electronic Investigator Trial Master File (eITMF) for each trial 
site. These CDs or other relevant electronic archiving will contain site-specific trial documentation 
as well as trial specific news and other relevant trial information, including audit trail on documents 
and site staff users. The GHN Portal software and hardware implementation are compliant with the 
requirements of U.S. Food and Drug Administration (FDA)21 CFR Part 11 and ICH E6 (EU 
directive for personal data protection)1,29.
Novo Nordisk will provide electronic tablets for reporting of all PROs questionnaires described in 
section8.6.1and in Appendix 1. In case the electronic tablet is revoked the questionnaires will be 
available in paper.
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The eDiary software and hardware implementation are compliant with the requirements of FDA 21
CFR Part 11 and ICH E6 (EU directive for personal data protection)1, 29.After trial completion, each 
trial site will be supplied with long-life CDs. These CDs will contain site-specific patient records 
including the patient’s eDiaries and ePROs as PROs are handled seperately from eDiary and audit 
trail including any data additions and corrections made on each form. The eDiary vendor will 
furthermore retain and securely store copies of all archived documents and data for 15 years or as 
required by local data retention laws for trial data
17 Statistical considerations
All endpoints referring to a time frame of at least 24 weeks will be evaluated in the main part of the 
trial, defined to end when the last patient have completed a minimum of 24 weeks of dosing or at 
LPFT (visit 2)+24 weeks if the last patient has withdrawn before visit 9. Please refer to Figure 17–1
for further information. All available data up to the time point where the last patient ends 24 weeks 
of treatment or has withdrawn will in such case be used in the analysis of the main part.
Endpoints comprising number of bleeding episodes will be evaluated based on treated bleeding 
episodes only. Multiple bleeding locations occurring from the same event (e.g., due to a bicycle 
accident) or at the same time point will be counted as one bleeding episode. Further, the endpoints 
will not include re-bleed.
A re-bleed is defined as a bleeding episode (worsening of bleeding site conditions e.g. swelling, 
pain) within 72 hours after stopping treatment of a previous bleeding episode at the same (or subset 
of the same) anatomical location. If a bleeding episode occurs in the same location 72 hours after 
stopping treatment, the bleed is defined as a new bleeding episode.
Data collected among permanently prematurely discontinued from trial products due to a safety 
concern patients after visit 17, in the possible extended safety follow-up period (ref section 8.1.4) 
will be listed only. 
Clinical proof of concept
The statistical analysis of the collected data aims to establish CPoC that concizumab is efficacious 
in preventing bleeding episodes in haemophilia A patients without inhibitors. The objective will be 
assessed when the last of the 30 patients have completed 24 weeks of dosing (or have withdrawn). 
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the ABR of all patients with a threshold of 12, irrespective of individual dose 
titration. The primary CPoC criterion aims at evaluating the effect of concizumab at the last dose 
level reached for a patient. Hence, for this evaluation, only observations from the period where 
patients are on their end dose at time of analysis will contribute to the analysis. Furthermore, 
observations from the 2 week run-in period will be not be included. Since this evaluation disregards 
a subset of data collected the result should be viewed taking in to account the potential bias. The 
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second CPoC criterion aims at evaluating the effect of concizumab when given as an escalation 
regimen. Hence, this will compare the ABR of haemophilia A patients treated with concizumab 
with the typical historical ABR of haemophilia A patients being treated on-demand using all data 
after enrolment. The second CPoC criterion will only be evaluated if the first one succeeds.
The referred comparisons will be made using a negative binomial model with log of exposure time 
in main phase as offset. For each criterion, evidence of effect will be concluded if the 95% 
confidence interval of the estimated ABR is below 12. 
The value of 12 bleeds per year reflects conservatively a 50% reduction from the bleeding rate 
during on-demand treatment, which in previous trials typically has been reported to be above 30 
bleeds per year 30-32. A confidence limit lower than 12 will also to a certain extent substantiate that 
the prophylactic efficacy of concizumab may be similar to that of FVIII replacement therapy where 
an estimated mean of 6.5 bleeds per year was observed33.
Clinical arguments for the hierarchical test approach
Concizumab exhibits non-linear PK due to target mediated drug disposition and it is expected that 
the dose response curve of the ABR is rather steep. This implies that patients that are on a dose 
which is not efficacious are likely to bleed as patients that are not treated at all. The subset of data 
collected from the last dose clinically deemed as efficacious would reflect the efficacy of 
concizumab in the given patient.
17.1
Sample size calculation
The sample size calculation has been determined taking the small patient population into account, 
while also aiming for an acceptably narrow 95% confidence interval for the ABR. 
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be
accommodated by 30 patients. 
It is expected that the treatment duration of the main part allowing for escalation time for some 
patients is on average 6 months in the below calculations. 
When evaluating the power of the negative binomial analysis referred above, an annual bleeding 
rate of 4 is assumed for the end dose concizumab regimen, respectively in combination with an 
over-dispersion of 6. The power for concluding a bleeding rate lower than 12 then becomes 
approximately 95%. The power under varying values of true ABR and over-dispersion for the 
primary CPoC criterion are shown below in Table 17–1.
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Table 17–1
Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion.
Power
Over-dispersion
ABR
5
6
7
4
99%
95%
92%
5
95%
90%
86%
6
87%
81%
72%
For the secondary CPoC criterion that includes data prior to potential dose escalation, it is expected 
that the treatment duration of the main part is on average 8 months with an average ABR of 5.4 for 
the concizumab treated patients. This yields a marginal power of approximately 87% for the 
secondary CPoC criterion. 
In prior Novo Nordisk trials conducted in haemophilia patients, the typical 1-year over-dispersion 
for non-inhibitor patients on prophylaxis with FVIII or FIX has been in the range 4-8, implying 24 
weeks over-dispersion of 3-5 (e.g. in NN7008-3543, NN7088-3859 and NN7999-3747). On that 
background, an over-dispersion of 6 over the 24 weeks in the main part of the current trial is 
deemed realistic.
17.2
Definition of analysis sets
All dosed patients will be included in the Full Analysis Set (FAS) as well as in the Safety Analysis 
Set (SAS).
17.3
Primary endpoint
The primary endpoint is the number of bleeding episodes during at least 24 weeks from treatment 
onset. All treated bleeding episodes will be considered for this endpoint, including bleeding 
episodes recorded as post-surgical or caused by surgery or other medical for dental procedures.
The primary endpoint will be estimated using negative binomial regression with log of exposure 
time (the included observational period of the main part) as offset, providing an actual estimate of 
the ABR as well as a corresponding 95% confidence interval. The offset for first CPoC criterion is 
the log of the individual exposure time at the last dose level reached at the time of analysis 
excluding the 2 weeks run-in period for subjects on 0.15 mg/kg. The offset for the second criterion 
is the log of the individual exposure time in the main part.
This analysis has the underlying assumption that the missing data mechanism is “missing at 
random”, i.e. MAR. Under this assumption, the statistical behaviour of the missing data (given the 
observed responses and the mean value structure) is assumed to be the same as for the observed 
data. The endpoint will be estimated based on the full analysis set (FAS) and only data collected 
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prior to discontinuation of trial product or initiation of alternative treatment options will be used to 
draw inference.
17.4
Sensitivity analyses
To evaluate the robustness of the MAR assumption implied in the primary analysis, a modified 
tipping point analysis will be performed where patients having discontinued before finalization of 
the main part are assumed to have a worse outcome compared to what was observed during the 
main part of the trial. This will be done by adding a value Δi to the observed bleeding episodes in 
the main part of the trial before analysing the data. The offset is maintained as being the exposure 
during the main phase since it is not possible to identify the amount of missing observation 
time.The degree of worsening, Δi, will gradually be increased to evaluate at which point the upper 
95% confidence limit of the prophylactic concizumab ABR is no longer below a threshold of 12.
The results of the primary analysis will be considered robust if the tipping point is above what is 
considered clinical plausible.
17.5
Additional analyses
An additional evaluation of the primary endpoint will be made, including actual concizumab dose 
level (interpreted as the patient’s last dose level) as additional factor in the primary analysis model 
specified above. Point estimates and 95% confidence interval will be provided for the ABR at the 
different dose levels of concizumab (0.15, 0.20 and 0.25 mg/kg). Furthermore, a series of analyses 
with individual steady state PK/PD assessments included as covariates in the negative binomial 
regression model as specified for the primary analysis will be performed in order to evaluate 
possible associations between PK/PD and ABR that potentially could guide dose-selection. The 
referred steady-state PK/PD assessments comprise the concizumab trough level, maximum plasma 
concentration (Cmax) of concizumab, TFPI value prior to the last s.c. dose administration, peak 
thrombin generation (nM), Endogenous thrombin potential (nM*min) and velocity index (nM/min).
17.6
Secondary endpoints
17.6.1
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during at least76 weeks from treatment onset.
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment 
onset.
!
The number of spontaneous bleeding episodes during at least 76 weeks from treatment 
onset.
The supportive secondary endpoints will be estimated using the same negative binomial regression 
model as the primary endpoint and performing the same two analyses as for the primary endpoint; 
one only including observations from the period on the last dose level and one including the entire 
escalation pattern.
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17.6.2
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during  at least 76 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during  at least 76 weeks from treatment onset
!
Change from baseline of fibrinogen during 24 weeks from treatment onset
!
Change from baseline of fibrinogen during at least 76 weeks from treatment onset
!
Change from baseline of D-dimer during 24 weeks from treatment onset
!
Change from baseline of D-dimer during at least 76 weeks from treatment onset
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset
!
Change from baseline of F1 + 2 during at least 76 weeks from treatment onset
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset
!
Change from baseline of PT during at least 76 weeks from treatment onset
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset
!
Change from baseline of APTT during at least 76 weeks from treatment onset
!
Change from baseline of anti-thrombin (AT) during 24 weeks from treatment onset
!
Change from baseline of AT after at least 76 weeks from treatment onset
Adverse Events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has onset from the first 
exposure to treatment until the last visit in the trial. Adverse events collected among permanently 
prematurely discontinued from trial product due to a safety concern patients after visit 17 in the 
possible extended follow-up (ref section 8.1.4) are not considered treatment emergent. Treatment-
emergent adverse event endpoints will be summarised by system organ class, preferred term, 
seriousness, severity and relation to trial product. All Adverse events will further be listed.
Frequency of binding anti-concizumab antibodies will by listed and summarised by time frame 
according to the two endpoint definitions.
All laboratory safety endpoints will be plotted by time, both as absolute values and change from 
baseline. Laboratory safety endpoints will further be summarised and listed.
17.6.3
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks.
!
Concentration of concizumab prior to the last dose administration after at least 76 weeks.
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The pharmacokinetic endpoints will be summarised and listed.
17.6.4
Supportive secondary pharmacodynamic endpoints
Free TFPI concentration:
!
Value prior to the last dose administration at 24 weeks.
!
Value prior to the last dose administration after at least 76 weeks.
Thrombin generation:
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks.
!
Peak thrombin generation (nM) prior to the last dose administration after at least 76 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks.
!
Endogenous thrombin potential (nM*min) prior to the last dose administration after at least
76 weeks.
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks.
!
Velocity index (nM/min) prior to the last dose administration after at least 76 weeks.
The PD endpoints will be summarized and listed. 
17.7
Exploratory endpoints
17.7.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset 
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
Adverse events related to technical complaints will be listed and summarised.
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17.7.2
Exploratory patient reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after at least 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after at least 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after at least 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after at least 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after at least 76 weeks from treatment onset
!
Status of PGI-C after 24 weeks from treatment onset
!
H-DAT after at least 76 weeks from treatment onset
Patient reported outcomes (PROs) will be collected using questionnaires at visits 1, 2, 4, 5, 6, 7, 8, 
9, 10 and at either visit 15.1 or 16.
Patient reported outcome questionnaires to be analysed:
!
Haemophilia Treatment Experience Measure (Hemo-TEM) 
!
Validated Hemophilia Regimen Treatment Aderence Scale – Prophylaxis (VERITAS-Pro®)
or Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)14
!
36-Item Short Form Health Survey (SF-36v2) (4 week recall)15
!
Patient Global Impression of Change (PGI-C)
!
Sheehan Disability Scale (SDS)16
!
Treatment Satisfaction Questionnaire for Medication (TSQM, version II)17-19
!
Haemophilia - Device Assessment Tool (H-DAT)
!
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)20
VERITAS-Pro®orVERITAS-PRN®, SF-36v2, SDS, TSQM, will be scored according to their 
respective scoring algorithms. Change from visit 2 to visit 9 and change from visit 2 to visit 15.1 or 
16 for SF-36v2, SDS, TSQM and SIAQ-ISRQ will be described.
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17.7.3
Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP  time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
All endpoints referring to a time frame of either 24 weeks or of at least 24 weeks will be evaluated 
in the main part of the trial. 
All endpoints referring to a time frame of 76 or more weeks will be evaluated in the extension part 
of the trial.
Individual "concentration over time" curves will be presented in a plot. A mean plot including error
bars will also be presented. For thrombin generation the endpoints will be summarized and listed.
17.8
Interim analysis
The trial does not include a formal interim analysis. However, the split of the trial into a main and 
extension part offers the opportunity of reporting results before the end of the trial. Other reporting 
of the trial might be done during the extension part once the data collection and review of the main 
part data has been finalised and individual clinical study reports might in such case be issued. A 
final clinical study report describing results from the main and extension part will be written when 
the last patient has either completed or withdrawn from the trial.
All main conclusions regarding clinical proof of concept and dose guidance for phase 3 will be 
based on the reporting after the main part, see Figure 17–1.
Figure 17–1
Definition of main and extension part
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18 Ethics
18.1
Benefit-risk assessment of the trial
Benefits
Results from a multiple dose phase 1 trial where concizumab was dosed for approximately 6 weeks 
showed a trend towards efficacy in a limited number of patients who reached concizumab plasma 
concentrations above 100ng/mL., see section 3.1.2. Based on these results, it is expected that the 
majority of the patients treated with concizumab 0.15mg/kg daily dose will be protected from
bleeding episodes. Patients who experience excessive bleeding episodes on the lowest dose will 
have a possibility to be escalated to a higher dose where bleeding preventive efficacy of 
concizumab treatment is expected to improve. Also, concizumab is administered s.c. and might
reduce the burden of frequent i.v. injections associated with current treatment options in
haemophilia A patients without inhibitors as well as significantly reducing the risk of anti-FVIII 
inhibitor development.
Information gained from this trial will contribute to gaining regulatory approval for a product that is 
anticipated to offer clinical advantages over currently available products. 
Risks
No risks have been recognised as identified risks by review of safety data from the activities in the 
clinical development so far. However, the nonclinical toxicity studies have identified 
thromboembolic events as a potential risk when treating non-human primates with concizumab at 
high exposures. 
As observed for other pro-coagulant compounds, there is a potential safety risk of thrombosis and 
vascular ischemia with reaching very high concizumab plasma concentrations. In non-clinical 
toxicity studies with concizumab, thrombi were observed at high doses. However, a no observed 
adverse effect level (NOAEL) for concizumab has been identified in non-haemophilic animals at 
plasma concentrations at least 24 fold higher than the currently anticipated effective plasma 
concentration (mean area under curve [AUC] and Cmax) based on PK modelling.
In clinical trials, except for one case of superficial thrombophlebitis in a healthy volunteer who
received a single dose of 1mg/kg, no other thromboembolic events were observed. A phase 1 
multiple dose trial was finalised in haemophilia A patients (0.8 mg/kg s.c. every 4 days for 6 
weeks). In this clinical trial, marked changes in coagulation parameters were observed including a 
decrease from baseline in fibrinogen and a pronounced increase in D-dimer and F1+2 outside of 
normal range in patients with high plasma concentrations of concizumab. These changes were not 
judged as clinically significant by the investigators and were not followed by thromboembolic AEs 
or an increase in the number of bleeding episodes in the explorer™3 trial.
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A potential risk identified in non-clinical studies is vascular vessel wall changes due to immune 
complex deposition causing localized vascular vessel wall changes such as hypertrophy and 
inflammatory cell infiltration. Concizumab is a foreign protein to animals and it is generally 
recognized that animal studies are limited in their ability to predict human immune responses to a 
therapeutic protein product. The concentrations of concizumab in plasma in animals in the non-
clinical studies have reached levels far above the anticipated effective concentration. Humans are 
expected to have a very low immunogenic response towards a humanised mAb. The antibodies 
towards concizumab have not been observed so far in clinical trials. Furthermore, even if antibodies 
towards concizumab occur, the risk for the rate of immune complex formation exceeding the 
clearance capacity is considered low. Please refer to the Investigator’s Brochure for further 
information including subsequent replacement therapy.
If antibodies against concizumab develop, they might also inhibit the function of the administered 
drug. The consequence of this could be that the patient may not be able to benefit from this drug in 
the future. Antibody development against concizumab is not expected to reduce the effect of other 
treatment options.
Theoretical risks include bleeding due to consumption of coagulation factors and adverse reactions 
due to potentiation of inflammatory reactions or tissue damage due to impairment of tissue repair 
mechanisms 34 35 . TFPI is an important inhibitor of TF which, in addition to its role in haemostasis, 
is implicated in tissue repair processes and in a variety of physiological and pathophysiological 
states where repair mechanisms are activated. These include sepsis, DIC, inflammation, 
atherosclerosis, cancer and crush injuries 36 37, 38. There may be a risk of allergic reactions, including 
severe (anaphylactic) reactions, in connection with concizumab administration. Severe allergic 
reactions may potentially be life-threatening and thus, the trial products will be administered to the 
trial patients at the site under the surveillance of medically trained trial site staff in the beginning of 
the trial.
Overall the anticipated benefits from participating in the trial outweigh the potential risks.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the patient verbal and written 
information about the trial and the procedures involved in a form that the patient can read and 
understand. 
The patients 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.
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The investigator must ensure the patient ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the patient 
before any trial-related activity.  
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically trained staff in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the investigator must inform the patient in a timely manner, and a revised 
written patient information must be provided and a new informed consent must be obtained.
Only applicable for Japan: As a minor is unable to provide legally binding consent, informed 
consent must be sought from the parent(s)/LAR(s) on the child’s behalf prior to enrolling a child in 
the trial, according to local requirements. 
18.3
Data handling
If the patient withdraws from the trial or is lost to follow up, then the patient’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit will be retained by 
Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to patients during trial
All written information to patients must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the patients 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
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also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of patients who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the patients 
should be described.
19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided and protocol waivers are not acceptable under any 
circumstances.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed. The Sponsor will assess any protocol deviation and 
decide whether any of these non-compliances are likely to affect to a significant degree the safety 
and rights of a patient or the reliability and robustness of the data generated (potential serious 
breach) and if it should be reported to the Regulatory Authorities as a serious breach of GCP and/or
the protocol.
In addition, deviations must be documented and explained in a protocol deviation by stating the 
reason, date, and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The below process will be in place to prevent missing data in this trial.
The importance of patient retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The patients will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of patient retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
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The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
21 Critical documents
An Investigator Portal (Global Haemophilia Network [GHN]) will be used as primary media for 
exchange and handling of investigator trial master file documents between Novo Nordisk and the 
site and for electronic storage of these documents during trial conduct.
Before a trial site is allowed to start screening patients, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, patient information/informed consent form, 
any other written information to be provided to the patient and patient recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure
!
SmPC or similar labelling of rFVIII (turoctocog alfa)
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
Description of research facility obtained (applicable for non-US sites)
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Only applicable for US trial sites: 
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
For local laboratory parameters the following will be collected:
!
Laboratory normal ranges
!
Laboratory certification, quality assurance (QA) scheme or similar documentation
!
Laboratory assay methods (only non-standard assays) and/or analytical methods
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1,
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the patients.
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At least investigator must be trained in the current protocol version at a Novo Nordisk Investigator 
meeting or by the most recent version of the web training. It is recommended that all site staff  
completes the web protocol training.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the patient identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
patients to a specific qualified physician who will be readily available to patients during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
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researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications 39.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure how-we-disclose-trial-information8.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of the main part of the trial and other interim analyses, because the release of such 
information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors 39 (sometimes referred to as the Vancouver 
Criteria).
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23.1.2
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 a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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24 Retention of clinical trial documentation and human biosamples
24.1
Retention of clinical trial documentation
Patientsmedical records must be kept for the maximum period permitted by the hospital, institution 
or private practiceaccording to local regulation and practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records)  pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other patientdata (in an electronic readable format or as paper 
copies or prints) will be provided to the invest igator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
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.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
Applicable only for Spain25 years retention according to the SpanishRoyal Decree 1090/2015
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements. 
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24.2
Retention of human biosamples
This trial will involve collection of human biosamples at visit 1 (screening visit), and at visit 17
(end of trial) and these samples are to be stored maximum 15 years from end of trial. In addition, 
samples which have been drawn as back up samples during the conduct of the trial and have not 
been analysed will be captured and stored under the same conditions. 
Storage of human biosamples is voluntarily and will not affect the patients’ participation in the trial. 
Therefore, patients will have the possibility to sign the informed consent for the trial and 
participate, while refusing permission for biological specimens to be stored for future exploratory 
analysis.
!
Human biosamples will be stored at the central laboratory.
!
1.2 mL citrated plasma, 1.0 mL serum and/or 2.0 ml whole blood (DNA for genotyping)
will be obtained.
!
The intended use of the stored human biosamples e.g.: As new biomarkers related to the 
disease and/or safety, efficacy, or mechanism of action of concizumab may evolve during 
the conduct of the trial, the analyses of the stored human biosamples may also include 
biomarkers that are unknown at present or have not been included in the scientific 
hypotheses at initiation of the trial 
!
Human biosamples may be transferred to third parties e.g. research consortias
!
The human biosamples will be transferred and stored after the end of trial at a designated 
central laboratory
!
Confidentiality and personal data protection will be ensured during storage after the end of 
trial
!
The human biosamples may be transferred to other countries (not applicable if local 
regulations prohibits export of human biosamples)
!
The human biosamples will be destroyed at the latest 15 years from end of trial
!
The patient may request the stored human biosamples to be destroyed by withdrawing 
consent. The results obtained from any already performed analyses of the samples will still 
be used
!
Novo Nordisk and laboratory will have access to the stored human biosamples 
!
Potential consequences for the patient and their relatives: In the event that the collected 
human biosamples (plasma, serum and/ or DNA for genotyping) will be used in the future, 
the investigator will become directly informed by Novo Nordisk about the results if the 
findings are deemed clinically relevant and analytically valid and quantifiable. In such case, 
a written summary of the findings, including listings of patient specific values, will be 
provided once a firm conclusion from the results has been drawn by Novo Nordisk. 
Potentially, observations of neoplastic diseases, serious hereditary diseases, other un-
treatable diseases, or any other abnormal findings could be part of the observations. Patients 
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can contact the investigator if they wish to be informed about results derived from stored 
human biosamples obtained from their own body. See also Section 5.1.
24.2.1
Antibody samples
Antibody samples will be retained until drug approval by U.S. Food and Drug Administration 
(FDA) and/or European Medicines Agency (EMA). 
The retained antibody samples may be used for later analysis for further characterisation of 
antibody responses towards drug if required by health authorities or for safety reasons. The samples 
will be stored at a central bio-repository after end of trial and until marketing authorisation approval 
or until the research project terminates, but no longer than 15 years from end of trial after which 
they will be destroyed.
The patients’ identity will remain confidential and the antibody samples will be identified only by 
patient number, visit number and trial identification number. No direct identification of the patient 
will be stored together with the samples.
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples.
Patients can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body.
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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
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UTN:U1111-1179-3872
Status:
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: Updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the patients, new information that may affect adversely the safety of the patients or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the patients), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC (not 
applicable for Japan).
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the patients.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
Only applicable for France: The French Public Health Code article L 1121-10 (law no 2004-806 of 
9 August 2004 art. 88 I, IX, Journal Officiel of 11 August 2004. “The sponsor is responsible for 
identification of the harmful consequences of the biomedical the research for the person lending 
himself thereto and for indemnification of his beneficiaries, except in case of proof, incumbent on 
it, that the prejudice is not attributable to his fault or of the fault of any intervening party, without 
the sponsor’s being entitled to call on acts by a third party or the voluntary withdrawal of the person 
who had initially consented to cooperating in the research”.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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27 References
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
Page:
126 of 127
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treatment satisfaction questionnaire for medication (TSQM version II) among outpatient 
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Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. Validation of 
an abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) among 
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Keininger D, Coteur G. Assessment of self-injection experience in patients with rheumatoid 
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Network Symposium. Annals of Emergency Medicine. 2006;47(4):373-80.
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Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third 
universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60(16):1581-98.
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Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, et al. Current diagnosis 
of venous thromboembolism in primary care: a clinical practice guideline from the 
American Academy of Family Physicians and the American College of Physicians. Ann 
Fam Med. 2007;5(1):57-62.
26.
Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated 
definition of stroke for the 21st century: a statement for healthcare professionals from the 
American Heart Association/American Stroke Association. Stroke. 2013;44(7):2064-89.
27.
Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition 
and evaluation of transient ischemic attack: a scientific statement for healthcare 
professionals from the American Heart Association/American Stroke Association Stroke 
Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular 
Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary 
Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the 
value of this statement as an educational tool for neurologists. Stroke. 2009;40(6):2276-93.
28.
Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, et al. 2011 
ACCF/AHA Focused Update of the Guideline for the Management of Patients With 
Peripheral Artery Disease (updating the 2005 guideline): a report of the American College 
of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J 
Am Coll Cardiol. 2011;58(19):2020-45.
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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
5.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no.:2016-000614-29
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U.S. Food and Drug Administration. Code of Federal Regulations, 21 CFR Part 11, 
Electronic Records, Electronic Signatures. 2009 2009.
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Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 
study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 
2014;123(3):317-25.
31.
Valentino LA, Mamonov V, Hellmann A, Quon DV, Chybicka A, Schroth P, et al. A 
randomized comparison of two prophylaxis regimens and a paired comparison of on-
demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost. 
2012;10(3):359-67.
32.
Manco-Johnson MJ, Kempton CL, Reding MT, Lissitchkov T, Goranov S, Gercheva L, et 
al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand 
treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia 
A (SPINART). J Thromb Haemost. 2013;11(6):1119-27.
33.
Lentz SR, Misgav M, Ozelo M, Salek SZ, Veljkovic D, Recht M, et al. Results from a large 
multinational clinical trial (guardian1) using prophylactic treatment with turoctocog alfa in 
adolescent and adult patients with severe haemophilia A: safety and efficacy. Haemophilia. 
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34.
Levi M, Keller TT, van GE, ten CH. Infection and inflammation and the coagulation system. 
Cardiovasc Res. 2003;60(1):26-39.
35.
Mast AE, Stadanlick JE, Lockett JM, Dietzen DJ, Hasty KA, Hall CL. Tissue factor 
pathway inhibitor binds to platelet thrombospondin-1. J Biol Chem. 2000;275(41):31715-
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Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. 
Arterioscler Thromb Vasc Biol. 2004;24(6):1015-22.
37.
Belting M, Ahamed J, Ruf W. Signaling of the tissue factor coagulation pathway in 
angiogenesis and cancer. Arterioscler Thromb Vasc Biol. 2005;25(8):1545-50.
38.
Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Vasc Biol. 
2005;25(1):47-56.
39.
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Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2016.
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CONFIDENTIAL


Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
1 of 18
Appendix 1
NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of 
Prophylactic Administration of Concizumab in Patients with 
Severe Haemophilia A without Inhibitors
Trial phase: 2
his confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
2 of 18
Table of Contents
The PROs in the explorer™5 trial is to validate the Hemo-TEM questionnaire (with Veritas-
PRO/Veritas-PRN, SDS, TSQM II, ISRQ-SIAQ) and collect quality of life data with SF-36v2.
Page
Table of Contents..............................................................................................................................................2
1
Hemophilia Treatment Experience Measure (Hemo-TEM) .................................................................4
!
The Hemo-TEM questionnaire measures the haemophilia treatment experience and is
currently being validated (through a ‘construct validity’ process) in this trials by using other
validated questionnaires: Veritas-PRO/Veritas-PRN, SDS, TSQM II, ISRQ-SIAQ. These
questionnaires are intended to check for the validity of measurements (by looking at the
consistency of the results) in the 5 domains of the Hemo-TEM questionnaire: adherence,
physical burden, ease of use, interference with daily life, emotional burden.
2
Veritas ........................................................................................................................................................7
2.1
Validated Hemophilia Regimen Treatment Adherence Scale - Prophylaxis (VERITAS-
Pro®)...............................................................................................................................................7
2.2
Validated Hemophilia Regimen Treatment Adherence Scale - PRN (VERITAS-PRN®).............9
!
The Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS-
PRO/VERITAS-PRN) measures adherence for prophylactic and on-demand participants
respectively.
3
36-Item Short Form Health Survey (SF-36v2)(standard) ...................................................................11
!
The SF-36v2 questionnaire measures physical and mental health status. It consists of 36
items and can be scored into 8 domains (physical functioning, role-physical, bodily pain,
general health, mental health, role-emotional, social functioning and vitality) and 2
summary components (physical component summary and mental component summary).
The data are scored on a 0-100 scale. Higher scores are associated with better outcomes.
4
Patient’s Global Impression of Change (PGI-C)..................................................................................12
!
PGIC (Patient’s Global Impression of Change) is used to capture clinically meaningful
change that makes a difference to the patient.
5
Sheehan Disability Scale (SDS)..............................................................................................................13
!
The Sheenan Disability Scale (SDS) assesses the extent to which the patient is impaired by
his symptoms in 3 inter-related domains – work/school, social and family life – on a 10-
point visual analog scale.
6
Treatment Satisfaction Questionnaire for Medication (TSQM, version II) ......................................14
!
The Treatment Satisfaction Questionnaire for Medication (TSQM-II) measures patient’s
treatment satisfaction
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
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7
Hemophilia – Device Assessment Tool (H-DAT)..................................................................................17
!
H-DAT (Haemophilia – Device Assessment Tool) is used to assess the patient’s experience
in using the device to take his haemophilia treatment (delivery method) in terms of
easiness.
8
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)................................18
!
The ISRQ questionnaire measures pain and skin reactions during or after the injection.
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
4 of 18
1
Hemophilia Treatment Experience Measure (Hemo-TEM)
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
5 of 18
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
6 of 18
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
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2
Veritas
2.1
Validated Hemophilia Regimen Treatment Adherence Scale - Prophylaxis 
(VERITAS-Pro®)
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
8 of 18
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
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2.2
Validated Hemophilia Regimen Treatment Adherence Scale - PRN (VERITAS-PRN®)
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
10 of 18
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
11 of 18
3
36-Item Short Form Health Survey (SF-36v2)(standard)
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
12 of 18
4
Patient’s Global Impression of Change (PGI-C)
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
13 of 18
5
Sheehan Disability Scale (SDS)
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
14 of 18
6
Treatment Satisfaction Questionnaire for Medication (TSQM, 
version II)
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
15 of 18
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
16 of 18
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
17 of 18
7
Hemophilia – Device Assessment Tool (H-DAT)
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Concizumab
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000614-29
Page:
18 of 18
8
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ 
(SIAQ-ISRQ)
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CONFIDENTIAL


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CONFIDENTIAL


Protocol Amendment no. 1
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
1 of 4
Protocol Amendment
no 1
to Protocol, version 1
dated 15 March 2017
Trial ID: NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of Prophylactic 
Administration of Concizumab in Patients with Severe Haemophilia A
without Inhibitors
Trial phase: 2
Applicable to all countries
Amendment originator:
–
Biopharm Trial Ops 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.
3URWRFRO$PHQGPHQWJORE_
_
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 no. 1
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
2 of 4
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
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CONFIDENTIAL


Protocol Amendment no. 1
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
This protocol amendment has been prepared to address VHP1080 requirements to clarify individual 
discontinuation criteria, holding rules for the trial and protocol deviations in order to improve safety 
and rights of the patients.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
Individual discontinuation criteria:
Section 5.3.1 Dose escalation
Dose 0.25 mg/kg:
Patients are not dose escalated further regardless of the number of sBEs. When an sBE occurs, the 
investigator will determine if ≥ 3 sBEs have occurred within the preceding 12 weeks (including the 
current sBE), counting only new sBEs from the beginning of the 0.25 mg/kg treatment period. If yes,
then the patient must be discontinued from treatment due to lack of efficacy, see Section 6.4.
Section 6.4 Criteria for premature discontinuation of trial product 
The patient may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
The patient must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria 
2. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
3. Incapacity or unwillingness to follow the trial procedures
4. Anaphylactic reaction
5. Thromboembolic event 
6. Event of disseminated intravascular coagulation (DIC)
7. Development of inhibitors to Factor VIII (≥ 0.6 BU)
8. Loss Lack of efficacy due to neutralising antibodies towards concizumab
9. Lack off efficacy defined as ≥ 3 treated sBEs within the previous 12 weeks in patients being 
treated with the highest dose level (0.25 mg/kg) of concizumab.
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no. 1
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
4 of 4
Holding rules for the trial:
Section 12.7 Rules for putting enrolment on hold. 
If one of below mentioned criteria is fulfilled, enrolment of additional patients in the clinical trial 
program will be placed on hold. An urgent safety committee meeting will be scheduled to decide 
further actions. Dosing of patients on treatment may continue while further evaluation is made by 
the safety committee. A substantial amendment with relevant data must be submitted to the 
regulatory authorities to support restart of the trial. 
• Significant thromboembolic event*
• Event of DIC
• Anaphylactic reaction related to trial drug administration
• Death of trial patient which may be related to the trial product
• Two or more other trial product related SAEs similar in nature have been reported and/or 
detected by laboratory measurements
• Trends in AEs, clinical observations or laboratory parameters which raise concerns about the 
safety of continued treatment. 
Protocol deviations:
Section 19.1 Protocol deviations
Deviations from the protocol should be avoided and protocol waivers are not acceptable under any 
circumstances.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed. The Sponsor will assess any protocol deviation and 
decide whether any of these non-compliances are likely to affect to a significant degree the safety 
and rights of a patient or the reliability and robustness of the data generated (potential serious 
breach) and if it should be reported to the Regulatory Authorities as a serious breach of GCP 
and/or the protocol.
In addition, dDeviations must be documented ...
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_
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
1 of 15
Protocol Amendment
no 2
to Protocol, version 2
dated 05 May 2017
and to Informed consent Form, version 1
dated 15 March 2017
Trial ID:NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of Prophylactic Administration of 
Concizumab in Patients with Severe Haemophilia A without Inhibitors
Trial phase: 2
Applicable to all countries
Protocol Amendment originator
-
Biopharm Trial Ops 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.
3URWRFRO$PHQGPHQWJORE_
_
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 no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
2 of 15
Table of Contents
1
Introduction including rationale for the protocol amendment and informed consent. .....................3
2
Changes ................................................................................................................................................4
2.1
Protocol ....................................................................................................................................4
2.2
Informed Consent....................................................................................................................14
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_
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
3 of 15
1
Introduction including rationale for the protocol amendment and 
informed consent.
Sections 2; 4.2.3.3; 5.1; 8.1.12; 8.1.12.1; 8.5; 8.5.1.1; 8.5.1.2; 8.5.2.8; 17.7.3 and informed consent
are updated due to a regulatory request to introduce a 24 hour concizumab PK-session to the 
explorer™5 trial. The 24 hour concizumab PK-session with sampling for concizumab-ELISA, Free 
TFPI and Thrombin Generation has been added to the trial as an unscheduled visit.This is done in 
order to obtain PK-profile of daily dosing with concizumab after initiation of multiple dosing in 
patients with haemophilia A without inhibitors.
Sections 4.2.3.2 and 17.7.2 Exploratory patient reported-outcome endpoints, are updated as the 
questionnaires VERITAS-Pro®/VERITAS-PRN® are not assessed at visit 9 and at visit 16, the
questionnaire PGI-C is not assessed at visit 1 and visit 16. Furthermore, the questionnaire H-DAT is 
not assessed before visit 9 (24 weeks).
Section 5.3.2 is updated to clarify the requirements for treatment and aligned with the instructions 
given in section 8.3.1 (Table 8.4) for treatment of turoctocog alfa and also with section 12.1.1 for 
reporting of adverse events.
Section 5.3.3 ‘Prohibited medication’ is updated because the use of anti-fibrinolytics is commonly 
local/topical used in dental procedures or dental surgery and thus not seen as compromising patient 
safety or trial conclusions. A single systemic dose may be needed: Anti-fibrinolytics (e.g.
tranexamic acid) has been used to reduce bleedings during orthopaedic surgery and trauma bleed 
without causing additional major thrombotic risks. It is also used in haemophilia patients during 
severe bleeding episodes. It is therefore considered adequate to allow a single dose after careful 
benefit risk evaluation by the investigator.
Section 8.5.2.7, Anti-concizumab antibodies, is updated to provide clarity on when a patient is 
considered to be positive for binding antibodies as this was perceived difficult to interpret with 
current text in version 2.0 of the protocol if the reader is not in possession of thorough knowledge 
of the different tests described.
Section 9.4, Drug accountability and destruction, is updated to ensure the solvent does not reach 
expiry when in patient’s custody. This includes clarifications in relevant visits described in section 
8:8.1.9.1; 8.1.9.4; 8.1.9.5; 8.1.10.1; 8.1.10.2 and 8.1.10.3.
Section 17, Statistical Considerations, re-bleed definition is updated to ensure optimal guidance in 
the dose escalation process.
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_
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
4 of 15
Section 18.1, Benefit-risk assessment of the trial, is updated to specify the minimum difference in 
plasma concentration between the NOAEL in non-haemophilic animals and highest anticipated 
plasma concentration in phase 2.
Sections 8.1.7 and 8.5.2.6 are updated to provide information about patients using FVIII-products 
with extended half-life before screening.
Clarifications, corrections and alignments which are seen as being minor are to be found in:
List of abbreviations; Figure 8-1 (3 weeks instead of 4 weeks between visit 3 and visit4) and in 
sections 3.1.1; 8.5.2.9 and 12.7
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Protocol
List of abbreviations
AUC
area under curve
Hemo-TEM 
Hemophilia Treatment Experience Measure
ISRQ-SIAQ
Injection Site Reaction Questionnaire-Self-Injection Assessment 
Questionnaire
PGI-C
Patient’s Global Impression of Change
SDS
Sheehan Disability Scale
SF-36v2
36-Item Short Form Health Survey
TSQM
Treatment Satisfaction Questionnaire for Medication 
VERITAS-Pro®
Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis
VERITAS-PRN®
Validated Hemophilia Regimen Treatment Adherence Scale-Pro Re Nata
H-DAT
Haemophilia Device Assessment Tool
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CONFIDENTIAL


Protocol Amendment no 2
UTN:U1111-1179-3872
Date:
14 December 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no: 2016-000614-29
Version:
1.0
Page:
5 of 15
Section 2 Flow Chart
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-
up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
Timing of visit (d) d
14 to 21 days 
before Visit2
1
8
29
57
85
113
141
169
225
281
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 21 days 
before Visit 2 
0
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not applicable
-7
Treatment week (w)
---
0
1w
4w
8w
12w
16w
20w
24w
32w 40w 48w 56w
64w
72w
76w
---
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/Genotyping and Long-term storage consent
●
In/exclusion criteria
●
●e
Demography 
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial 
product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
EFFICACY ASSESSMENTS 
Bleeding episodes f, g
●
●
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●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab)
●
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
Free TFPI (central lab)  
●
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
SAFETY ASSESSMENTS
Physical examination
●
●
●
●
●
●
●
Body measurements 
●
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
Vital signs
●
●j
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Biochemistry (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII activity (central lab)
●k
●l
Coagulation parameters (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII inhibitors (central lab)
●
●l
Anti-concizumab antibodies (ADA) (special lab)m
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Concizumab ELISA (special lab)
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
Total TFPI (special lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
TRIAL MATERIALS
IWRS call
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab, turoctocog alfa) (IWRS)
●n
●
●
●
●
●
●
●
●
●
●
●
●
●
●n
●
Administration of trial product (concizumab) 
●o
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_


Protocol Amendment no 2
UTN:U1111-1179-3872
Date:
14 December 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no: 2016-000614-29
Version:
1.0
Page:
6 of 15
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-
up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
Drug Accountability (concizumab, turoctocog alfa) 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product c, p
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires
●
●
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
Hand out ID Card 
●
Training (trial product, e-Diary and NovoPen® 4) q
●
●
●
Compliance (e-Diary)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
Footer
Description
a
Concizumab administration is performed at home except for visit 2 where concizumab administration will take place at the trial site.
b
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 will be 
a phone call to the patient. 
c
For patients being dose escalated a phone call is recommended 1 week after first new dose of concizumab.
d
Daily dosing preferably at the same time in the morning.
e
Evaluation of laboratory results obtained from samples taken at screening.
f
Bleeding episodes occurring between visit 1 and visit 2 or at site should be registered in the eCRF. All bleeding episodes except for severe occurring after visit 
2 at home should be registered in the eDiary. Severe bleeding episodes must be registered in the eCRF.
g
Turoctocog alfa will be given to treat breakthrough bleeding episodes either in the clinic or at home.
h
At visit 9 and 16 all blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been performed.
For unscheduled PK-session visit; patients must not treat themselves with concizumab until pre-dose sampling for thrombin generation, concizumab ELISA and 
Free TFPI has been collected.
i
Only body weight should be measured.
j
Vital signs should be evaluated before and after trial drug administration at visit 2. 
k
Sampling for FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours and medical records documenting the severity of 
haemophilia are not available.
l
FVIII activity and FVIII inhibitor tests should only be collected if reduced effect of turoctocog alfa or FVIII inhibitor development is suspected.
m
In case of clinical signs of e.g. hypersensitivity reactions or immune related events are seen, additional samples for ADAs may be taken. All antibody samples 
from the affected patient will be analysed on an ongoing basis. If antibodies are detected additional samples will be taken and stored for characterisation of the 
antibodies.
n
Only dispensing of turoctocog alfa and sodium chloride.
o
The trial patient must be in a non-bleeding state at the time of the first trial product administration (TPA), and should not have received any haemostatic drug 
(e.g. FVIII) for prophylaxis or treatment of a bleeding episode within a period of 48 hours prior to first TPA.
3URWRFRO$PHQGPHQWJORE_
_


Protocol Amendment no 2
UTN:U1111-1179-3872
Date:
14 December 2017
Status:
Final
1RYR1RUGLVN
Trial ID:NN7415-4255
EudraCT no: 2016-000614-29
Version:
1.0
Page:
7 of 15
p
Patient should be dose escalated at next scheduled visit if he experiences ≥3 spontaneous bleeding episodes within the preceding 12 weeks of treatment with 
concizumab. If investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose escalation.
q
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Home treatment training comprises handing out of Direction 
for Use (DFU), training in administration of concizumab with NovoPen®4, turoctocog alfa and data entry in eDiary. Further the patients will be trained in 
recognition of signs/symptoms of thrombosis.
r
In case patients are participating in the 24 hour PK-session the sampling time points for thrombin generation, concizumab ELISA and Free TFPI are: pre-dose 
(-1 hour), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (± 20 min) and 24h (± 20 min). All time points, except pre-dose, occur after 
concizumab administration
3URWRFRO$PHQGPHQWJORE_
_


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
8 of 15
Section 3.1.1 Haemophilia (page 21 paragraph 5)
Haemophilia is classified as “severe”, “moderate” or “mild” according to the plasma activity level
of the affected coagulation factor.
Section 3.1.1 Haemophilia (page 22 paragraph 1)
These patients may be treated with bypassing agents, recombinant activated FVII (NovoSeven®) 
and activated prothrombin complex concentrate (FEIBA®) given as intravenous (i.v.) injections.
Section 4.2.3.2 Exploratory patient-reported outcome endpoints (page 28 paragraph1)
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 24 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Change in Status of PGI-C after 24 weeks from treatment onset
!
Change in PGI-C after 76 weeks from treatment onset
!
Change in H-DAT after 24 weeks from treatment onset
!
Change in H-DAT after 76 weeks from treatment onset
Section 4.2.3.3 Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP  time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
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_
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
9 of 15
Section 5.1 (page 30 after section paragraph)
All patients will be asked to perform a 24 hour PK-session after treatment with concizumab is 
initiated.
Section 5.3.2 (page 35 first section last paragraph)
Treatment dose is chosen at the discretion of the investigator; however; in this trial any given single 
dose should not exceed 50 IU/kg (Table 8-4)”. The patient can treat himself and then he must call 
the site. Bleeding episodes classified as severe must be recorded in the electronic case report form 
(eCRF) as serious adverse events (SAEs) see Table 8–3. The bleeding episodes must be recorded in 
the eDiary. Bleeding episodes must be recorded in the electronic case report form (eCRF) as an 
AE/SAE if fatal, life threatening or evaluated as related to trial product (see section 12.1)
Section 5.3.3 Prohibited medication (page 35 last paragraph bullet 1)
!
Treatment with anti-fibrinolytics (e.g. tranexamic acid, aminocaproic acid)*
*Local/topical use is allowed. Use of single systemic doses in severe bleeding episodes, after 
careful benefit-risk evaluation, is allowed.
Section 8 Methods and assessments, Figure 8-1 overview of visit structure in explorer™5 
(page 41 paragraph 1)
Section 8.1.7 Visit 1 (Screening part) (page 44 end of paragraph 3)
For prophylactic treatment (prior to Screening) with extended half-life FVIII products, this period
should be extended to a time-period equal to 8 half-lives of the used product.
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
10 of 15
Section 8.1.9.1 Visit 2 (Assessment, 1st concizumab treatment at site) (page 46 paragraph 8)
The patient will be asked to return all used, partly used and unused turoctocog alfa (FVIII) during 
the trial as instructed by the investigator. Drug accountability must be performed for turoctocog alfa 
(rFVIII), including injection kits if applicable, according to section 9.4. Unused sodium chloride
syringes should be returned to site at every visit and new sodium chloride syringes should be 
dispensed to the patient.
Section 8.1.9.4 Visits 4, 5, 6, 7 and 8 (assessment visits) (page 47 paragraph 8)
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
Section 8.1.9.5 Visit 9 (Assessment visit) (page 48 paragraph 5)
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
Section 8.1.10.1 Visit 10 (Assessment visit) (page 49 paragraph 7)
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
Section 8.1.10.2 Visit 11, 12, 13, 14 and 15 (Assessment visits) (page 50 paragraph 2)
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
11 of 15
Section 8.1.10.3 Visit 16 (Assessment visit end of treatment with Concizumab) –Extension part 
(page 51 paragraph 5)
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
Section 8.1.12 Unscheduled Visit (page 52 paragraph 2)
The purpose of the unscheduled visit must be documented in the eCRF. During unscheduled visits 
assessments and blood sampling must be performed according to Table 2–1. Assessment results 
must be recorded in the eCRF. Assessments and blood sampling can be omitted if the only reason 
for the unscheduled visit is dispensing of trial product or for an unscheduled 24 hour PK-visit.
Section 8.1.12.1 Unscheduled 24 hour PK-Visit
All patients will be invited to participate in an optional unscheduled 24 hour PK-visit. The visit may 
take place after first dose of concizumab. Samples collected at the 24 hour PK-visit will be for 
analysis of concizumab-ELISA, Free TFPI and Thrombin Generation (TGA). Sampling will be at
time points; 1 hour pre-dose (-1 hour), 1 (±10 min.), 3 (±10 min.), 6 (±10 min.), 9 (±10 min.), 12
(±20 min.) and 24 hour(s) (±20 min.) post dose, related to the daily dosing of concizumab. 
Treatment dose of concizumab and the time of treatment will preferably be recorded in the eDiary 
by the patient or eCRF by site. Treatment will be at site.
This visit can be combined with a regular scheduled visit. Patients should be reminded not to 
administer the daily dose of concizumab until 1 hour after the pre-dose sampling has taken place.
Section 8.5 Laboratory assessments (page 62 paragraph 1)
An approximate total blood volume of 450 525 mL will be taken from each patient in the trial.
Section 8.5.1.1 Thrombin Generation
The Thrombin Generation Assay (TGA) will be performed at all visits (including unscheduled 24 
hour PK visit), except visit 3.
Section 8.5.1.2 Free TFPI (page 63 paragraph 7)
Free TFPI measures TFPI not bound to concizumab. This enzyme-linked immunosorbent assay 
(ELISA) test will be sampled for at all visits, including unscheduled 24 hour PK visit.
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
12 of 15
Section 8.5.2.6 FVIII inhibitor test (page 66 paragraph 1) 
In order to minimise the risk of false negative results, circulating FVIII product levels should be 
less than 0.05 IU/ml, when sampling for the test. If the patient has received FVIII within 96 hours of 
screening, the sampling of FVIII-Inhibitor should be postponed until a time period equal to 8 half-
lives of the used product has passed (counting from latest treatment).
Section 8.5.2.7 Anti-concizumab antibodies (page 66 paragraph 4)
Analysis for ADA will be done with a bridging ECL assay (binding ADA assay), using labelled 
concizumab for antibody capture and detection. If a sample is confirmed positive in the 
confirmatory assay, the sample is considered antibody positive. Confirmed positive samples will be 
characterised in a specificity assay for binding to IgG backbone, CDR region or the S241P 
mutation. Furthermore, positive samples will be characterised for neutralising activity using a 
modified TFPI functionality assay (neutralising ADA assay). All antibody assays are validated 
according to international guidelines and recommendations.
Section 8.5.2.8 Concizumab ELISA
Concizumab ELISA will be performed at all visits except at screening and at visit 3. Samples will 
be collected pre-dose at visit 2, 9 and 16. For the unscheduled 24 hour PK visit, samples are 
collected; 1 hour pre-dose, (-1hour), 1(±10 min.), 3(±10 min.), 6(±10 min.), 9(±10 min.), 12(±20 
min.) and 24 hour(s) (±20 min.) post dose, related to the daily dosing of concizumab.
Section 8.5.2.9 Total TFPI (page 68 Paragraph 7)
The total TFPI level (free and concizumab bound) will be included as an exploratory biomarker 
assessment. The assay is an ELISA, where TFPI is captured by polyclonal anti-TFPI antibody, 
distanced from the binding site of concizumab, meaning that both free TFPI and concizumab bound 
TFPI will be captured. Detection will be obtained with a monoclonal antibody against TFPI, which 
does not bind to the concizumab epitope. Data will be reported in ng/mL TFPI.
Total TFPI ELISA will be performed at all visits, except visit 3. Sample will be collected pre-dose 
at visit 2. 
Data will be reported in mg/ml TFPI
Section 9.4 Drug accountability and destruction (page 75 first paragraph)
Drug accountability of all trial products received at site is the responsibility of the investigator. The 
patient will be asked to return all used, partly used and unused trial product during the trial as 
instructed by the investigator except for the used sodium chloride solution which should be 
discarded at home and not accounted for. Unused sodium chloride syringes should be returned to 
site at every visit and new sodium chloride syringes should be dispended to the patient.
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
13 of 15
Section 12.7 Rules for putting enrolment on hold (page 93 paragraph 1)
If one of below mentioned criteria is fulfilled, enrolment of additional patients in the clinical trial 
programme will be placed on hold. An urgent safety committee meeting will be scheduled to decide 
further actions. Dosing of patients on treatment may continue while further evaluation is made by 
the safety committee. A substantial amendment with relevant data must be submitted to the 
regulatory authorities to support restart of the trial.
!
Significant thromboembolic event*
!
Event of DIC
!
Anaphylactic reaction related to trial drug administration
!
Death of trial patient which may be related to the trial product
!
Two or more other trial product related SAEs similar in nature have been reported and/or 
detected by laboratory measurements
!
Trends in AEs, clinical observations or laboratory parameters which raise concerns about 
the safety of continued treatment. 
*Superficial thrombophlebitis or venous thrombosis associated with indwelling catheters is not considered a significant 
thromboembolic event unless evaluated as such by the investigator
If two or more other trial product related SAEs similar in nature have been reported and/or detected 
by laboratory measurements, or if trends in AEs, clinical observations or laboratory parameters 
raise concerns about the safety of continued treatment, the safety committee (see Section 12.8.1) 
will decide if further dosing of any patients in the clinical trial programme should be continued, 
paused or discontinued.
Section 17 Statistical considerations (page 99 paragraph 4)
A re-bleed is defined as a bleeding episode (worsening of bleeding site conditions e.g. swelling, 
pain) within 72 hours after stopping treatment of a previous bleeding episode at the same (or subset 
of the same) anatomical location. If a bleeding episode occurs in the same location 72 hours after 
stopping treatment, the bleedtreatment is defined as a new bleeding episode.
Section 17.7.2 Exploratory patient reported outcome endpoints (page 104 paragraph 4)
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 24 weeks from treatment onset
!
Change in VERITAS-Pro®/VERITAS-PRN® after 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
14 of 15
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Change in Status of PGI-C after 24 weeks from treatment onset
!
Change in PGI-C after 76 weeks from treatment onset
!
Change in H-DAT after 24 weeks from treatment onset
!
Change in H-DAT after 76 weeks from treatment onset
Section 17.7.3 Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP  time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
Individual "concentration over time" curves will be presented in a plot. A mean plot including error 
bars will also be presented. For thrombin generation the endpoints will be summarized and listed.
Section 18.1 Benefit-risk assessment of the trial (page 107 paragraph 4)
However, a no observed adverse effect level (NOAEL) for concizumab has been identified in non-
haemophilic animals at plasma concentrations at least 24-several folds higher than the currently 
anticipated effective plasma concentration (mean area under curve [AUC] and Cmax), based on PK 
modelling. 
2.2
Informed Consent
What will happen at the different visits in the trial? (page 3 last paragraph )
You must read and sign this subject information and the informed consent form before any trial 
related activities can be performed. If you decide to take part in the trial, the trial doctor will 
interview and examine you in order to find out if you meet the criteria for participation. 
If you meet all criteria, your involvement in the trial will last approximately 87 weeks. During this 
time you will have 16 planned visits to your trial site and one phone contact. You will also be asked 
to participate in a 24 hour visit where you will have blood samples taken at 7 different time points. 
The blood samples from this visit will help in understanding how concizumab affects and moves 
around in the body. This specific visit is voluntary and it will not affect your participation in the 
trial if you do not participate. The duration of othereach visits at the site may vary depending upon 
3URWRFRO$PHQGPHQWJORE_
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 December 2017
1RYR1RUGLVN
Trial ID:NN7415-4255
Version:
1.0
UTN:U1111-1179-3872
Status:
Final
EudraCT no: 2016-000614-29
Page:
15 of 15
the different assessments to be performed and the routines at the site. Please feel free to ask the trial 
doctor how much time you should expect to spend on each specific visit. 
Treatment at Home (Visits 3 to 16):(page 5 first paragraph)
After visit 2, you will self-administer daily injections of concizumab at home except at visits 9, and
16 and at the unscheduled 24 hour visit if you agree to participate. At these visits you where you
will self-administer concizumab at your trial site
Unscheduled visit: (page 5 last paragraph)
You may be asked to visit the trial site outside of the scheduled visits, if judged necessary by your 
trial doctor, for example to provide an extra blood sample or if the trial doctor considers changing 
the dose of your trial drug in between planned visits. An unscheduled visit may also be necessary if 
you require additional trial product, or if you agree to participate in the 24 hour visit. The 24 hour 
visit may also be performed at an extended scheduled visit. During the 24 hour visit you will be 
asked to take your daily dose of concizumab at the site.
Between Visits: (page 6 paragraph 4)
You will self-administer concizumab daily in the period between visits. If you experience a 
bleeding episode in this period you should treat yourself with turoctocog alfa and contact your trial 
doctor. You may be asked to come to the trial site for follow up. 
During the trial blood samples will be taken for different tests. The total amount of blood drawn in 
the course of the trial is approximately 450 525 mL. For comparison purposes the blood taken at a 
blood donation is approximately 500 mL.
Signature page(page 16 first paragraph )
ALL INFORMATION IN THIS BOX MUST BE COMPLETED BY THE PATIENT 
Patient who has been informed and would like to continue participatione in the trial:
 YES                                                NO
Furthermore I agree to participate in the voluntary 24 hour visit
 YES                                                NO
Date:
Signature:
Name (print):
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_
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
1 of 29
Protocol Amendment
no 3
to Protocol, final version 4
dated 28 December 2017
Trial ID: NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of Prophylactic Administration of 
Concizumab in Patients with Severe Haemophilia A without Inhibitors
Trial phase: 2
Applicable to all countries
Amendment originator:
, 
Biopharm Trial Ops 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.
3URWRFRO$PHQGPHQWJORE_
_
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 no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
2 of 29
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................6
2.1
Protocol ....................................................................................................................................6
2.2
Informed Consent....................................................................................................................25
2.2.1
Master Informed Consent.......................................................................................25
2.2.2
Genotyping and Long-term Storage of Human Samples Informed Consent 
(page 4 last paragraph)...........................................................................................28
2.2.3
Female partner of a Male Subject in Case of an Abnormal Pregnancy Informed 
Consent (page 3 last paragraph) .............................................................................29
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
3 of 29
1
Introduction including rationale for the protocol amendment
The intention of this amendment is to provide patients current in an ongoing trial the option their 
participation in the trial being prolonged. During the prolongations the patients will be offered to be 
screened for eligibility for a subsequent clinical trial with concizumab. Furthermore additional 
clarification is made to the section of permanently premature discontinuation to ensure that patients 
with a safety concern are being followed until resolution or planned LPLV. Finally there is a change 
in the reporting to investigators about Anti-drug antibodies (ADA) towards concizumab to ensure 
that investigators are informed at an earlier time point than originally described. 
Sections affected
Sections 1, 2, 5.1, 5.1 (figure 5-1), 5.3 (figure 5-3), 5.3.1, 5.5, 5.5, 7, 17, 17.3, 17.5, 17.6.1, 17.6.2, 
17.6.3, 17.6.4, 17.7.3 and 17.8 (figure 17-1) are updated to reflect the prolongation of the extension 
part to offer patients the possibility of being screened for eligibility to participate in a subsequent 
clinical trial with concizumab provided that either the study site participates in the trial or the 
patient can be transferred to a participating site of the trial. 
Sections 4.2.2.1, 4.2.3.2, 4.2.3.3, 17.6.1, 17.6.2, 17.6.3, 17.6.4, 17.7.2 and 17.7.3 are updated to 
include the additional treatment weeks in the prolongation of the extension part. Currently the trial 
only accounts for 76 weeks of treatment therefore the endpoints have been updated to capture that 
patients are being treated at least of 76 weeks in total. 
Section 5.2, ‘Rationale of the trial design’ has been updated with and option for patients being 
screened for eligibility for a subsequent clinical trial based on site availability or if transferred to a 
participating site in the new trial. 
Section 5.3 ‘Treatment of patients’, Table 5-1 has been updated to reflect the extended use of 
concizumab based on the prolongation of the trial. 
Section 5.3.3 ‘Prohibited medication’ the ‘*’ has been updated with the explaining that the 
comment is not included in the French approval of protocol version 4. 
Section 8 (Figure 8-1), 8.1, 8.1.10.2, 8.1.10.3, 8.1.11.1 and 8.5 are updated to include the additional 
visits that have been added to the trial. Between visit 15 and visit 16(End of Treatment), additional 
visits have been added with 8 week intervals. Visit numbering is as following: 15, 15.1, 15.2, 15.n 
up to a maximum of 6 additional visits or until a subsequent clinical trial with concizumab is open 
for recruitment. When the patient can be enrolled in the trial, the patient is scheduled for visit 16 
and can from here be enrolled in the new trial. 
Section 8.1.4 and 8.1.12 ‘Premature discontinuation of trial product’ has been updated as well as 
‘Unscheduled Visit’ to provide the option of following patients who has permanently prematurely 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
4 of 29
discontinue trial product due to a safety concern after visit 17 (End of trial). The purpose of the 
visits is to collect additional safety information, if applicable. The additional follow up period may 
not be continued after the planned LPLV in Section 7, Milestones as described in section 8.1.4.
Section 8.1.10.2 and 8.6.1 have been updated as a result to the additional visits between visit 15 and 
visit 16. The ePROs have been added to visit 15.1 for patients participating in the prolongation of 
the extension. Whereas patients declining participation will continue to complete their last ePRO 
questionnaires at visit 16. 
Section 8.5.2.7 ‘anti-concizumab antibodies’ is updated to ensure that investigators are informed 
about any positive results of binding antibodies against concizumab and not only of neutralising 
antibodies towards concizumab as binding ADAs can affect PK of concizumab and thus efficacy 
and safety as well. 
Section 8.6.1 ‘Patient reported outcome’ the requirement of the investigator to review the ePROs 
for AEs and SAEs after completion has been removed as it is not possible for the patient to add own 
text to the ePROs.
Section 12.1.1 ‘Adverse event’ has been updated due to a leftover in the standard text from former 
trials where i.v. administration was the treatment being investigated. As current trial is investigating 
a new route of administration, subcutaneous, injection site reactions including haematomas are AEs 
requiring additional data collection. 
12.2 ‘Reporting of adverse events’ has been updated to specify the AE reporting requirements if the 
patients will be enrolled in a subsequent trial with concizumab or not. For patients enrolling into a 
new trial with concizumab any AEs reported after visit 16 will be reported in the new trial. 
Section 12.7 ‘Rules for putting enrolment on hold’ has per request from the Safety Committee been 
updated by removing the footnote. The footnote was not clear enough in regards to if 
thromboembolic events are considered significant or not. 
Section 17, 17.3, 17.5 and 17.6.1 ‘Statistical considerations’ has been updated due to technical 
details related to selection of bleeds and estimation of offset has been added.
Section 17.7.2,’Exploratory patient reported-outcome endpoints’, are updated as the questionnaire 
VERITAS-PRN is only assessed at visit 1 and therefore no change in outcome can be analysed. 
Main Informed consent is updated for give the patient the option of continuing in the trial after 76 
weeks of treatment has passed. By consenting the patient may stay in the trial for up to 126 weeks 
of treatment and be given the possibility to participate in a subsequent trial with concizumab if he is 
eligible and site continues in the trial or he can be transferred to a participating site. Furthermore 
has the GDPR standard text been added as required.
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
5 of 29
In this protocol amendment:
!
Any new text is written in italics.
!
Any text del eted from the protocol is written using strike through.
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
6 of 29
2
Changes
2.1
Protocol
Section 1 Summary
Time frames for evaluation of objectives/endpoints:
All endpoints referring to the time frame of at least 24 weeks will be evaluated in the main part of 
the trial, defined to end when the last patient has completed a minimum of 24 weeks of treatment 
with trial product (or have withdrawn). In addition, number of bleeding episodes during at least 76 
weeks of treatment with prophylactic concizumab will be analysed. The extension part of the trial 
will provide additional safety and long-term efficacy data.
Section 1 Summary 
Trial design
The total trial duration for the individual patient will be approximately 86-138 weeks, consisting of 
a 2 week screening period, a subsequent 76-126 week treatment period and an 8 week follow-up 
period. 
The 76-126 weeks treatment period is split into a main part which lasts at least 24 weeks and an 
extension part which lasts up to 102 52 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 30 patients have completed at least 24 weeks of concizumab 
dosing or have discontinued trial treatment. The analysis of the main part of the trial aims to 
substantiate clinical proof of concept (CPoC) that concizumab has the potential to prevent bleeding 
episodes in severe haemophilia A patients without inhibitors.
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CONFIDENTIAL


Protocol Amendment no 3
UTN: U1111-1179-3872
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4255
EudraCT No.: 2016-000614-29
Version:
1.0
Page:
7 of 29
Section 2 Flow chart with deletions (strike through)
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-
up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
Timing of visit (d) d
14 to 21 days 
before Visit2
1
8
29
57
85
113
141
169
225
281
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 21 days 
before Visit 2 
0
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not applicable
-7
Treatment week (w)
---
0
1w
4w
8w
12w
16w
20w
24w
32w 40w 48w 56w
64w
72w
76w
---
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/Genotyping and Long-term storage consent
●
In/exclusion criteria
●
●e
Demography 
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial 
product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
EFFICACY ASSESSMENTS 
Bleeding episodes f, g
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab)
●
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
Free TFPI (central lab)  
●
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
SAFETY ASSESSMENTS
Physical examination
●
●
●
●
●
●
●
Body measurements 
●
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
●i
Vital signs
●
●j
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Biochemistry (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII activity (central lab)
●k
●l
Coagulation parameters (central lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
FVIII inhibitors (central lab)
●
●l
Anti-concizumab antibodies (ADA) (special lab)m
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
Concizumab ELISA (special lab)
●
●r
●r
●r
●r
●r
●h,r
●r
●r
●r
●r
●r
●r
●h,r
●h,r
●
Total TFPI (special lab)
●
●
●
●
●
●
●
●h
●
●
●
●
●
●
●h
●
●
TRIAL MATERIALS
IWRS call
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab, turoctocog alfa) (IWRS)
●n
●
●
●
●
●
●
●
●
●
●
●
●
●
●n
●
Administration of trial product (concizumab) 
●o
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Protocol Amendment no 3
UTN: U1111-1179-3872
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4255
EudraCT No.: 2016-000614-29
Version:
1.0
Page:
8 of 29
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-
up  
Visit number b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Unscheduled c
17
Drug Accountability (concizumab, turoctocog alfa) 
●
●
●
●
●
●
●
●
●
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●
●
●
●
●
●
New dose of trial product c, p
●
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●
●
●
●
●
PRO questionnaires
●
●
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
Hand out ID Card 
●
Training (trial product, e-Diary and NovoPen® 4) q
●
●
●
Compliance (e-Diary)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
Section 2 Flow chart with updates (italics)
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up
Visit number b
1
2
3
4-8
9
10-11
12
13-14
15, 15.1, 
15.2, 15.ns
16
Unscheduled c
17t
Timing of visit (d) d
14 to 21 days 
before Visit2
1
8
29-141
169
225-281
337
393-449
505-841
Up to
883
When applicable
Up to
945
Visit window (d)
0
+1
±7
±7
±7
±7
±7
±7
±7
Not applicable
-7
Treatment week (w)
---
0
1w
Every 
4w
24w
Every 
8w
48w
Every 8w
Every 8w
Up to 
126w
---
Up to 135w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/Genotyping and Long-term storage consent
●
In/exclusion criteria
●
●e
Demography 
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial 
product
●
●
●
●
●
●
●
●
●
●
●
EFFICACY ASSESSMENTS 
Bleeding episodes f, g
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab)
●
●
●r
●h,r
●r
●r
●r
●r
●h,r
●h,r
●
Free TFPI (central lab)  
●
●
●r
●h,r
●r
●r
●r
●r
●h,r
●h,r
●
SAFETY ASSESSMENTS
Physical examination
●
●
●
●
●
●
●
Body measurements 
●
●i
●i
●i
●i
●i
●i
●i
●i
●i
Vital signs
●
●j
●
●
●
●
●
●
●
●
●
ECG
●
3URWRFRO$PHQGPHQWJORE_
_


Protocol Amendment no 3
UTN: U1111-1179-3872
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4255
EudraCT No.: 2016-000614-29
Version:
1.0
Page:
9 of 29
explorer™5 trial periods
Screening
Treatment maina
Treatment extension a
Follow-up
Visit number b
1
2
3
4-8
9
10-11
12
13-14
15, 15.1, 
15.2, 15.ns
16
Unscheduled c
17t
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●
●h
●
●
●
●
●h
●
●
Biochemistry (central lab)
●
●
●
●h
●
●
●
●
●h
●
●
FVIII activity (central lab)
●k
●l
Coagulation parameters (central lab)
●
●
●
●h
●
●
●
●
●h
●
●
FVIII inhibitors (central lab)
●
●l
Anti-concizumab antibodies (ADA) (special lab)m
●
●
●
●h
●
●
●
●
●h
●
●
Concizumab ELISA (special lab)
●
●r
●h,r
●r
●r
●r
●r
●h,r
●h,r
●
Total TFPI (special lab)
●
●
●
●h
●
●
●
●
●h
●
●
TRIAL MATERIALS
IWRS call
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab, turoctocog alfa) (IWRS)
●n
●
●
●
●
●
●
●
●n
●
Administration of trial product (concizumab) 
●o
Drug Accountability (concizumab, turoctocog alfa) 
●
●
●
●
●
●
●
●
●
●
New dose of trial product c, p
●
●
●
●
●
●
●
PRO questionnaires
●
●
●
●
●
●u
●v
REMINDERS
Human biological specimen for storage (central lab)
●
●
Hand out ID Card 
●
Training (trial product, e-Diary and NovoPen® 4) q
●
●
●
Compliance (e-Diary)
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●t
●t
Footer
Description
a
Concizumab administration is performed at home except for visit 2 where concizumab administration will take place at the trial site.
b
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 will be 
a phone call to the patient. 
c
For patients being dose escalated a phone call is recommended 1 week after first new dose of concizumab.
d
Daily dosing preferably at the same time in the morning.
e
Evaluation of laboratory results obtained from samples taken at screening.
f
Bleeding episodes occurring between visit 1 and visit 2 or at site should be registered in the eCRF. All bleeding episodes except for severe occurring after visit 
2 at home should be registered in the eDiary. Severe bleeding episodes must be registered in the eCRF.
g
Turoctocog alfa will be given to treat breakthrough bleeding episodes either in the clinic or at home.
3URWRFRO$PHQGPHQWJORE_
_


Protocol Amendment no 3
UTN: U1111-1179-3872
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4255
EudraCT No.: 2016-000614-29
Version:
1.0
Page:
10 of 29
h
At visit 9 and 16 all blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been performed. For 
unscheduled PK-session visit all blood samples should be collected pre-dose except for post dose samples
i
Only body weight should be measured.
j
Vital signs should be evaluated before and after trial drug administration at visit 2. 
k
Sampling for FVIII activity at screening should be postponed if the patient has received FVIII within 96 hours and medical records documenting the severity of 
haemophilia are not available.
l
FVIII activity and FVIII inhibitor tests should only be collected if reduced effect of turoctocog alfa or FVIII inhibitor development is suspected.
m
In case of clinical signs of e.g. hypersensitivity reactions or immune related events are seen, additional samples for ADAs may be taken. All antibody samples 
from the affected patient will be analysed on an ongoing basis. If antibodies are detected additional samples will be taken and stored for characterisation of the 
antibodies.
n
Only dispensing of turoctocog alfa and sodium chloride.
o
The trial patient must be in a non-bleeding state at the time of the first trial product administration (TPA), and should not have received any haemostatic drug 
(e.g. FVIII) for prophylaxis or treatment of a bleeding episode within a period of 48 hours prior to first TPA.
p
Patient should be dose escalated at next scheduled visit if he experiences ≥3 spontaneous bleeding episodes within the preceding 12 weeks of treatment with 
concizumab. If investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose escalation.
q
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Home treatment training comprises handing out of Direction 
for Use (DFU), training in administration of concizumab with NovoPen®4, turoctocog alfa and data entry in eDiary. Further the patients will be trained in 
recognition of signs/symptoms of thrombosis.
r
In case patients are participating in the 24 hour PK-session the sampling time points for thrombin generation, concizumab ELISA and Free TFPI are: pre-dose 
(-1 hour), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (± 20 min) and 24h (± 20 min). All time points, except pre-dose, occur after 
concizumab administration.
s
Visit repeated every 8 week until patient either discontinues, completes extension or is enrolled into a subsequent trial with concizumab
t
For patients continuing a subsequent trial End of Trial must be completed at visit 16. For patients declining participation in a subsequent trial the End of Trial 
must be completed at visit 17, 8 weeks after End of Treatment. 
u
PRO questionnaires should only be completed at 15.1 for patients continuing in the prolongation of the trial.
v
PRO questionnaires should only be completed at visit 16 for patients not continuing in the prolongation of the trial
3URWRFRO$PHQGPHQWJORE_
_


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
11 of 29
Section 4.2.2.1 Supportive secondary endpoints
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during at least 76 weeks from treatment onset
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of  spontaneous bleeding episodes during at least 76 weeks from treatment 
onset
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during at least 76 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 76 weeks from treatment onset
!
Change from baseline of fibrinogen during 24 weeks from treatment onset
!
Change from baseline of fibrinogen during at least 76 weeks from treatment onset
!
Change from baseline of D-dimer during 24 weeks from treatment onset
!
Change from baseline of D-dimer during at least 76 weeks from treatment onset
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from 
treatment onset
!
Change from baseline of F1 + 2 during at least 76 weeks from treatment onset
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset
!
Change from baseline of PT during at least 76 weeks from treatment onset
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks 
from treatment onset
!
Change from baseline of APTT during at least 76 weeks from treatment onset
!
Change from baseline of anti-thrombin (AT) during 24 weeks from treatment onset
!
Change from baseline of AT after at least 76 weeks from treatment onset
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks
!
Concentration of concizumab prior to the last dose administration after at least at 76 weeks
Supportive secondary pharmacodynamic endpoints
Plasma free TFPI concentration
!
Value prior to the last dose administration at 24 weeks 
!
Value prior to the last dose administration after at least 76 weeks 
Thrombin generation
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks 
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
12 of 29
!
Peak thrombin generation (nM) prior to the last dose administration after at least 76 weeks
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks 
!
Endogenous thrombin potential (nM*min) prior to the last dose administration after at least 
76 weeks
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks 
!
Velocity index (nM/min) prior to the last dose administration after at least 76 weeks
Section 4.2.3.2 Exploratory patient-reported outcome endpoints (page 28 1st paragraph)
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after at least 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after at least 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after at least 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after at least 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after at least 76 weeks from treatment onset
!
Status of PGI-C after 24 weeks from treatment onset
!
Change in H-DAT after at least 76 weeks from treatment onset
Section 4.2.3.3 Exploratory pharmacokinetic and pharmacodynamic endpoints
All endpoints referring to a time frame of at least 76 weeks will be evaluated in the extension part 
of the trial.
Section 5.1 Type of trial (Figure 5-1 Schematic diagram of the trial design)
Section 5.1 Type of trial
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
13 of 29
The total trial duration for the individual patient will be approximately 86 -138 weeks, including a 
2-week screening period, a subsequent 76 -126 week treatment period and an 8-week follow-up 
period,.
The 76 -126 weeks treatment period is further split into a main part which lasts at least 24 weeks for 
all patients in the trial and an extension part which lasts up to 102 52 weeks. After completion of the 
main part of the trial, patients will continue into the extension part. All available data up to the time 
point where the last patients ends 24 weeks of treatment (or have withdrawn) will be used in the 
analysis of the main part, see Section 17.7. 
Section 5.1 Type of trial 
The analysis of the main part (after 24 weeks) of the trial aims to substantiate CPoC that 
concizumab has the potential to prevent bleeding episodes in patients with severe haemophilia A 
without inhibitors. The extension part will provide additional safety data on up to 102 52 weeks 
dosing of concizumab.
Section 5.2 Rationale for trial design 
The duration of at least 24 weeks for the main part of the trial is deemed necessary in order to 
obtain information on the annual bleeding rate (ABR) during concizumab prophylaxis. The duration 
of the extension part of the trial will be up to 102 52 weeks and will provide further information on 
long-term efficacy, i.e. ABR, and also provide additional safety data upon 76 – 126 weeks treatment 
with concizumab.
Patients participating in NN7415-4255 will be offered screening for eligibility to participate in the 
subsequent clinical trials for concizumab, following their participation in NN7415-4255 and 
provided that either the site participates in the subsequent trial with concizumab or if possible the 
patient can be transferred to a participating site. It is expected that the majority of the participating 
patients will join a subsequent trial and thus may continue prophylactic treatment with concizumab.
Section 5.3 Treatment of patients (Table 5-1)
Compound Name 
Strength
Dosage form 
Route of 
administration
Treatment period
Concizumab B, 
100 mg/mL
3 mL solution in 
a 3 mL 
cartridge. 
S.c. 
administration 
using NovoPen® 4
For prophylactic 
treatment for at 
least 76 weeks. 
Turoctocog alfa 
(NovoEight®), 
Sodium chloride 
2000 
IU/vial
Powder for 
solution for 
injection
I.v. administration
For treatment of 
breakthrough 
bleeding episodes 
(or prophylaxis in 
the screening and 
follow-up phases), 
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
14 of 29
solution 4ml  
Solvent for 
solution for i.v. 
injection used 
for 
reconstitution of 
turoctocog alfa.
at the discretion of 
the treating 
physician (patients 
may choose to use 
other familiar pre-
trial non-modified
FVIII drug).
For further 
information see 
section 5.3.2
Concizumab will be given s.c., once daily for a total dosing period of at least 76 weeks. 
Section 5.3.1 Dose escalation 
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (first-dose visit) 
until visit 16 (end-of-treatment visit), i.e. a total of 74 up to 124 weeks. Dose-escalation will be 
based on the number of spontaneous, treated bleeding episodes in patients within preceding 12 
weeks. However, before dose-escalation can occur, to ensure the safety of the patients, the 
investigator must take into account the full clinical picture the patient is presenting with and all 
available laboratory results, including coagulation parameters.
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
15 of 29
Section 5.3.1 Dose escalation (Figure 5-3)
Section 5.3.3 Prohibited medication
*Local/topical use is allowed. Use of single systemic doses in severe bleeding episodes, after 
careful benefit-risk evaluation, is allowed. Not applicable for France. 
Section 5.5 Rationale for treatment 
The treatment period of at least 24 weeks (the main part of the trial) is considered necessary for 
providing data that allow demonstration of CPoC and to support decision-making regarding a phase 
3 confirmatory trial. Dosing for up to an additional 52 102 weeks will provide valuable long-term 
efficacy and safety.
Section 7 Milestones
Planned FPFV: 
16-Aug-2017
Planned FPFT: 
30-Aug-2017
Planned LPFV: 
16-Dec-2017
Planned LPLV: 
11-Sep-2019 -31-Mar-2020
The total duration of concizumab treatment in the trial is at least 76 weeks for an individual patient 
enrolled in the trial for concizumab treatment at visit 2.
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
16 of 29
Section 8 Methods and assessments in explorer™5 (Figure 8-1)
Section 8.1 Visit procedures
Extension Part:
!
Visit 10 (Assessment visit, patients treat themselves at home)
!
Visit 11 (Assessment visit, patients treat themselves at home)
!
Visit 12 (Assessment visit, patients treat themselves at home)
!
Visit 13 (Assessment visit, patients treat themselves at home)
!
Visit 14 (Assessment visit, patients treat themselves at home)
!
Visit 15-15.n (Assessment visit, patients treat themselves at home)
!
Visit 16 (Assessment visit and End of treatment)
Follow-up part
!
Visit 17 (Assessment visit and End of trial)
Section 8.1.4 Premature discontinuation of trial product
The patients who permanently prematurely discontinue trial product at Investigator’s discretion 
due to a safety concern after completion of the main part of the trial may have visit 17 scheduled 8 
weeks after visit 16. Furthermore additional unscheduled visits will be conducted at least every 8 
weeks for safety assessments (see Section 8.4 and 8.5.2), PK and PD markers. The patients who 
permanently prematurely discontinue trial product due to safety concerns may have the safety 
follow up period extended at Investigator’s discretion until the safety concern have been resolved, 
but no later than Last Patient Last Visit as defined in Milestones (Section 7 of the protocol).
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
17 of 29
Section 8.1.10.2 Visit 11, 12, 13, 14 and 15, 15.1, 15.2, 15.n (Assessment visits) 
Visits 11 to 15.n are to be scheduled with an interval of 8 weeks on trial day 281 (40 weeks), day 
337 (48 weeks), day 393 (56 weeks), day 449 (64 weeks) and day 505 (week 72) respectively with a 
visit window of ± 7days until the patient either discontinues treatment or completes visit 16. 
If the patient declines participation in the prolongation of the extension, visit 16 should be 
conducted 4 weeks after visit 15 (see Section 8.1.10.3)
Assessments are to be performed according to Table 2-1and the assessment results from physical 
examination (applicable for V12), concomitant medication, vital signs, Body measurements (weight 
only) and details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must evaluate if an escalation of the concizumab doses is needed 
according the escalation rules described in section 5.3.1. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. Drug accountability must 
be performed at all visits for concizumab and rFVIII (turoctocog alfa) including injection kits, if 
applicable. Unused sodium chloride syringes should be returned to site at every visit and new 
sodium chloride syringes should be dispensed to the patient.
In order to determine the correct amount of the patient’s daily dose of concizumab, until next 
scheduled visit, investigator will consult the dosing-table in the TMM on basis of the patient’s 
current body weight. Investigator will communicate any corrections in the daily dose of concizumab 
to the patient and record the dose for the coming home treatment period in the eCRF. 
A dispensing call must be performed in the IWRS.
At the visit the patient will be provided with trial product (concizumab and if necessary rFVIII 
(turoctocog alfa)) and injection kits to be able to conduct home treatment until next scheduled visit.
At visit 15.1 only patients continuing in the prolongation will be asked to complete the PRO 
questionnaires before any other trial related activities are performed according to section 8.6.1
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
18 of 29
At the last visit (visit 15 or 15.n) before visit 16 (End of treatment) (visit 15) patients should be 
reminded that treatment with concizumab must take place after the blood sampling at visit 16.
Section 8.1.10.3 Visit 16 (Assessment visit end of treatment with concizumab) – Extension part
Visit 16 is to be scheduled:
!
on trial day 533 (for patients declining participation in the prolongation of the trial)
!
or later (for patients continuing in the extension or enrolled in a subsequent trial) (76 
weeks)
with a visit window of ± 7days
Visit 16 should be scheduled to be conducted at the last day of treatment with concizumab.
Treatment with concizumab must take place after the blood sampling at this visit.
Patients not continuing in the prolongation will be asked to complete the PRO questionnaires 
before any other trial related activities are performed according to section 8.6.1;
o
Hemo-TEM
o
SF-36v2
o
SDS
o
TSQM
o
H-DAT
o
SIAQ-ISRQ
Assessments are to be performed according to Table 2–1 and the assessment results from 
concomitant medication, vital signs and details of adverse events (AE) must be entered into the 
eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. 
For patients not continuing in the prolongation of the trial a completion session must be made at 
Visit 16 in the IWRS. In the period from visit 16 to visit 17 the patient can be treated with 
turoctocog alfa at the discretion of the investigator. Turoctocog alfa may be requested via IWRS.
Treatment can either be prophylactically and/or treatment of eventual any bleeding episodes. Only 
turoctocog alfa will be provided by Novo Nordisk. If necessary, a dispensing call must be 
performed in the IWRS. At the visit the patient will be provided with rFVIII (turoctocog alfa) and 
injection kits to be able to conduct home treatment until final visit.
For patients continuing in the prolongation of the trial and are enrolled in a subsequent trial as 
completion session must be made at visit 16 in the IWRS, but no additional trial product 
(turoctocog alfa) will be provided to the patient.
3URWRFRO$PHQGPHQWJORE_
_
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
19 of 29
For patients continuing in the prolongation of the trial but not enrolled in a subsequent trial a 
completion session must be made at Visit 16 in the IWRS. In the period from visit 16 to visit 17 the 
patient can be treated with turoctocog alfa at the discretion of the investigator.  Turoctocog alfa 
may be requested via IWRS. Treatment can either be prophylactically and/or treatment of any 
bleeding episodes. Only turoctocog alfa will be provided by Novo Nordisk. If necessary, a 
dispensing call must be performed in the IWRS. At the visit the patient will be provided with rFVIII 
(turoctocog alfa) and injection kits to be able to conduct home treatment until final visit.
In the period from visit 16 to visit 17 the patient can be treated with turoctocog alfa (rFVIII) at the 
discretion of the investigator in the period from visit 16 to visit 17. Treatment can either be 
prophylactically and/or treatment of any bleeding episodes. Only turoctocog alfa will be provided 
by Novo Nordisk. 
If necessary,  a dispensing call must be performed in the IWRS. At the visit the patient will be 
provided with rFVIII (turoctocog alfa) and injection kits to be able to conduct home treatment until 
final visit.    
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
turoctocog alfa (FVIII) during the trial as instructed by the investigator. NovoPen®4 must be 
returned. Drug accountability must be performed at all visits for concizumab and rFVIII (turoctocog 
alfa) including injection kits, if applicable. Unused sodium chloride syringes should be returned to 
site at every visit and new sodium chloride syringes should be dispensed to the patient.
End of trial information must be entered in the End of Trial form in the eCRF at visit 16 for all 
patients enrolled in a subsequent trial with concizumab.
Section 8.1.11.1 Visit 17 (End of trial) 
For patients not enrolled into a subsequent trial with concizumab visit Visit 17 is to be scheduled 8 
weeks after visit 16 on trial day 589 (84 weeks) with a visit window of minus 7 days.
Assessments are to be performed according to Table 2–1 and the assessment results from 
concomitant medication, physical examination, body measurements (weight only), vital signs and 
details of adverse events must be entered into the eCRF.
Investigator is to perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the eDiary. Patients must be asked if their female partner has 
become pregnant during the trial (see Section 12.5.1).
The patient will be asked to return all used, partly used and unused turoctocog alfa (rFVIII), eDiary 
device and Trial card. Drug accountability must be performed for turoctocog alfa (rFVIII) including 
injection kits, if applicable. Unused sodium chloride syringes should be returned to site at every 
visit and new sodium chloride syringes should be dispensed to the patient.
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
20 of 29
End of trial information must be entered in the End of Trial form in the eCRF at visit 17 for all 
patients not enrolled in a subsequent trial with concizumab.
End of trial Call must be made in the IWRS. If turoctocog alfa was requested at visit 16 drug 
accountability should be performed in IWRS, see Section 10.
Section 8.1.12 Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Table 2–1.
Unscheduled visits may be performed after visit 17 at the discretion of the investigator for patients 
who has permanently prematurely discontinue trial product due to a safety concern (see Section 
8.1.4).
The purpose of the unscheduled visit must be documented in the eCRF. During unscheduled visits 
assessments and blood sampling must be performed according to Table 2–1. Assessment results 
must be recorded in the eCRF. Assessments and blood sampling can be omitted if the only reason 
for the unscheduled visit is dispensing of trial product, replacement of eDiary or NovoPen®4 or for 
an unscheduled 24 hour PK-visit.
Section 8.5 Laboratory assessments
An approximate total blood volume of 525 686 mL will be taken from each patient in the trial. Ports 
cannot be used for blood sampling. 
Section 8.5.2.7 Anti-concizumab antibodies 
Samples will be drawn at all visits except at visit 3. The binding ADA samples will be analysed in 
batches during the trial and results will be available to the data monitoring committee 
approximately every third month after the first patient has been dosed (Section 12). Neutralising 
antibodies will be analysed and reported at the end of trial. A detailed description of the assay 
methods will be included in the antibody analysis report at the end of the trial.
Investigators will be notified in case their patient is shown to have developed binding and/or
neutralising antibodies against concizumab.
In the event that a trial patient develops binding ADAs towards concizumab during the course of the 
trial and has measurable binding ADAs at his End of Trial visit, the patient may attend an ADA 
follow-up visit. The ADA positive patients will be called for additional visits, e.g. every 4 to 6 
weeks, for safety assessment and blood sampling for binding ADAs and PD markers (free TFPI and 
Thrombin generation). The ADA positive patients will be followed no longer than one year after 
End of Trial. 
Section 8.6.1 Patient reported outcome
The PROs should be assessed at the scheduled visits following the order listed below:
!
visit 1 (Hemo-TEM, VERITAS-Pro® or VERITAS-PRN®)
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
21 of 29
!
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 4 (PGI-C, Hemo-TEM)a
!
visit 5 (PGI-C, Hemo-TEM)
!
visit 6 (PGI-C, Hemo-TEM)
!
visit 7 (PGI-C, Hemo-TEM)
!
visit 8 (PGI-C, Hemo-TEM)
!
visit 9 (PGI-C, Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
!
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 16 15.1 or 16 (Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT, SIAQ-ISRQ)
Section 8.6.1 Patient reported outcome
At visit 16 15.1 or 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM, H-DAT and 
SIAQ-ISRQ. The investigator must check the ePROs for completeness potential AEs and SAEs.
Section 12.1.1 Adverse event 
Bleeding episodes and other symptoms (e.g. pain, swelling, synovitis, arthralgia, injection site 
haematoma) in connection with bleeding episodes should not be reported as AEs/SAEs unless the 
event is fatal, life-threatening or evaluated by the investigator as related to trial product or trial 
procedure. All bleeding episodes and other findings related to underlying disease will be captured in 
the eCRF/eDiary
Section 12.2 Reporting of adverse events 
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the patient has signed the informed consent until visit 16 
(end of treatment) for patients enrolling into a subsequent trial with concizumab and at the end of 
the post-treatment follow-up period (visit 17) for patient not enrolling in to a new trial. The events 
must be recorded in the applicable eCRF forms in a timely manner; see timelines below and in 
Figure 12-1
Section 12.7 Rules for putting enrolment on hold 
*Superficial thrombophlebitis or venous thrombosis associated with indwelling catheters is not 
considered a significant thromboembolic event unless evaluated as such by the investigator
Section 17 Statistical considerations
Data collected among permanently prematurely discontinued from trial products due to a safety 
concern patients after visit 17, in the possible extended safety follow-up period (ref section 8.1.4) 
will be listed only. 
Section 17.3 Primary endpoint 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
22 of 29
The primary endpoint is the number of bleeding episodes during at least 24 weeks from treatment 
onset. All treated bleeding episodes will be considered for this endpoint, including bleeding 
episodes recorded as post-surgical or caused by surgery or other medical for dental procedures.
The primary endpoint will be estimated using negative binomial regression with log of exposure 
time in (the included observational period of the main part) phase as offset, providing an actual 
estimate of the ABR as well as a corresponding 95% confidence interval. The offset for first CPoC 
criterion is the log of the individual exposure time at the last dose level reached at the time of 
analysis excluding the 2 weeks run-in period for subjects on 0.15 mg/kg. The offset for the second 
criterion is the log of the individual exposure time in the main part.
Section 17.5 Additional analyses 
An additional evaluation of the primary endpoint will be made, including actual concizumab dose 
level (interpreted as the patient’s last dose level) as additional factor in the primary analysis model 
specified above. Point estimates and 95% confidence interval will be provided for the ABR at the 
different dose levels of concizumab (0.15, 0.20 and 0.25 mg/kg). Furthermore, a series of analyses
an analysis with individual steady state PK/PD assessments included as covariates in the negative 
binomial regression model as specified for the primary analysis will be performed in order to 
evaluate possible associations between PK/PD and ABR that potentially could guide dose-selection. 
The referred steady-state PK/PD assessments comprise the concizumab trough level, maximum 
plasma concentration (Cmax) of concizumab, TFPI value prior to the last s.c. dose administration, 
peak thrombin generation (nM), Endogenous thrombin potential  (nM*min) and velocity index 
(nM/min).
Section 17.6.1 Supportive secondary efficacy endpoints
!
The number of bleeding episodes during at least 76 weeks from treatment onset
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of  spontaneous bleeding episodes during at least 76 weeks from treatment 
onset
The supportive secondary endpoints will be estimated using the same negative binomial regression 
model as the primary endpoint and performing the same two analyses as for the primary endpoint; 
one only including observations from the period on the last dose level and one including the entire 
escalation pattern.
Section 17.6.2 Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during at least 76 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
!
Occurrence of anti-concizumab antibodies during at least 76 weeks from treatment onset
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
23 of 29
!
Change from baseline of fibrinogen during 24 weeks from treatment onset
!
Change from baseline of fibrinogen during at least 76 weeks from treatment onset
!
Change from baseline of D-dimer during 24 weeks from treatment onset
!
Change from baseline of D-dimer during at least 76 weeks from treatment onset
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from
treatment onset
!
Change from baseline of F1 + 2 during at least 76 weeks from treatment onset
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset
!
Change from baseline of PT during at least 76 weeks from treatment onset
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks
from treatment onset
!
Change from baseline of APTT during at least 76 weeks from treatment onset
!
Change from baseline of anti-thrombin (AT) during 24 weeks from treatment onset
!
Change from baseline of AT after at least 76 weeks from treatment onset
Adverse Events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has onset from the first 
exposure to treatment until the last visit in the trial. Adverse events collected among permanently 
prematurely discontinued from trial product due to a safety concern patients after visit 17 in the 
possible extended follow-up (ref section 8.1.4) are not considered treatment emergent. Treatment-
emergent adverse event endpoints will be summarised by system organ class, preferred term, 
seriousness, severity and relation to trial product. All Adverse events will further be listed.
Section 17.6.3 Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks
!
Concentration of concizumab prior to the last dose administration after at least 76 weeks
Section 17.6.4 Supportive secondary pharmacodynamic endpoints
Plasma free TFPI concentration
!
Value prior to the last dose administration at 24 weeks
!
Value prior to the last dose administration after at least76 weeks
Thrombin generation
!
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks
!
Peak thrombin generation (nM) prior to the last dose administration after at least 76 weeks
!
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 weeks
!
Endogenous thrombin potential (nM*min) prior to the last dose administration after at least
76 weeks
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
24 of 29
!
Velocity index (nM/min) prior to the last dose administration at 24 weeks
!
Velocity index (nM/min) prior to the last dose administration after at least 76 weeks
Section 17.7.2 Exploratory patient-reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after at least 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after at least 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after at least 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after at least 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after at least 76 weeks from treatment onset
!
Status of PGI-C after 24 weeks from treatment onset
!
Change in H-DAT after at least 76 weeks from treatment onset
Patient reported outcomes (PROs) will be collected using questionnaires at visits 1, 2, 4, 5, 6, 7, 8, 
9, 10 and at either visit 15.1 or 16.
Section 17.7.2 Exploratory patient-reported outcome endpoints 
VERITAS-Pro®orVERITAS-PRN®, SF-36v2, SDS, TSQM, H-DAT and SIAQ-ISRQ will be 
scored according to their respective scoring algorithms. Change from visit 2 to visit 9 and change 
from visit 2 to visit 15.1 or 16 for SF-36v2, SDS, TSQM and SIAQ-ISRQ will be described.
Section 17.7.3 Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP  time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
All endpoints referring to a time frame of either 24 weeks or of at least 24 weeks will be evaluated 
in the main part of the trial. 
All endpoints referring to a time frame of 76 or more weeks will be evaluated in the extension part 
of the trial.
Section 17.8 Interim analysis (Figure 17-1)
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
25 of 29
2.2
Informed Consent
2.2.1
Master Informed Consent
What kind of trial products will you receive? 
If you agree to participate in the trial you will inject one dose of concizumab daily for up to 76 126
weeks. If you experience a bleeding episode you will treat this with turoctocog alfa. If you 
experience 3 or more bleeding episodes within a 12 week period of concizumab treatment, your trial 
doctor will discuss with you the possibility of increasing your concizumab dose. Bleeding episodes 
that occur within the first 2 weeks of concizumab treatment will not be included in the total number 
of bleeding episodes required for dose escalation. You will start treatment with the lowest dose of 
concizumab, 0.15 mg/kg. It will be possible to increase your dose twice during the trial: from 0.15 
to 0.20 mg/kg and from 0.20 to 0.25 mg/kg if the bleeding episodes occur within a second 12 week 
period after dose escalation has taken place. 
Once you have treated yourself daily with concizumab for up to 126 weeks you and your doctor will 
decide if you can continue being treated with concizumab in a new trial as long as your site 
participates in the trial or if you can be transferred to a site nearby. If you choose to say yes your 
last visit will be visit 16 and you will continue in the new trial. If you choose to say no you will 
discontinue treatment with concizumab at visit 16 and be followed for an additional 8 weeks before 
completing the trial. During this period you will still be provided turoctocog alfa for treatment of 
bleeding episodes.
What will happen at the different visits in the trial?
If you meet all criteria, your involvement in the trial will last from approximately 88 103 up to 138
weeks depending on when you started in the trial. During this time you will have 16 between 18-22
planned visits to your trial site and one phone contact. You will also be asked to participate in a 24 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
26 of 29
hour visit where you will have blood samples taken at 7 different time points. During this visit you 
are not required to stay overnight at the site.
Treatment at Home (Visits 3 to 16):
Visit 4 occurs approximately 3 weeks after visit 3. Visits 5 to 9 are scheduled approximately 4 
weeks apart and visits 10 to 16 are scheduled approximately 8 weeks apart. If you choose to 
continue in the trial the extra visits will be placed between visit 15 and visit 16 with following 
numbers 15.1, 15.2 and so on. The number of planned extra visits will be up to 6 depending on 
when you started in the trial. You will receive concizumab to take home at each visit and 
turoctocog alfa when needed.
At each visit your trial doctor will ask you if you have had any change in your health or medications 
since the last visit and evaluate if the trial is suitable for you to continue. Blood will be drawn for 
analysis, vital signs measured, and weight recorded. Your trial doctor or nurse will review your 
electronic diary and any information that you entered about bleeding episodes that may have 
occurred between visits. You will be asked to complete up to 7 questionnaires related to your 
quality of life, well-being and treatment at visits 4 to 10 and 5 questionnaires at visit 16 15.1. 
Follow-up visit (Visit 17): 
This visit will only happen if you do not continue in a new trial.
Between Visits: 
During the trial blood samples will be taken for different tests. The total amount of blood drawn in 
the course of the trial is approximately 525 up to 686 mL depending on how many planned visits 
you will have before completing the trial. For comparison purposes the blood taken at a blood 
donation is approximately 500 mL.
Turoctocog alfa (rFVIII)
What are the possible side effects or harms of taking part risks if you participate in this trial?
The use of rFVIII (turoctocog alfa, NovoEight®) to treat bleeding episodes at home may expose 
you to side effects. Your trial doctor will monitor you closely regarding possible side effects. If you 
experience side effects, you should report them to your trial doctor.
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 (side effects). The 
most frequently reported adverse reactions were elevated liver enzymes and injection site reactions. 
Less frequent adverse reactions included having trouble sleeping (insomnia), headache, dizziness, 
high blood pressure, rash, stiffness and pain in the muscles, pain in legs or arms, bruising, joint 
disease, swelling of legs and feet, tiredness, feeling hot and fever.
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
27 of 29
Your study doctor will watch closely for possible health problems that happen while you are taking 
part in the study. As with all medicines, side effects may happen. If side effects happen, they will be 
treated if needed.
Tell your study doctor or the study nurses about any side effects you have while taking part. Tell the 
doctor or nurses even if you do not think that they were caused by a study medicine.
These are side effects we know about from other studies with turoctocog alfa:
Common side effects: (may affect up to 1 in 10 people): 
!
Skin problems where the injection is given
!
Increased liver enzymes
Uncommon side effects (may affect up to 1 in 100 people): 
!
Having trouble sleeping
!
headache
!
feeling dizzy
!
fast heartbeat
!
heart attack
!
increased blood pressure
!
lymphoedema (localised fluid retention and tissue swelling)
!
feeling hot
!
rash with redness
!
lichenoid keratosis (raised plaque or papule on the skin)
!
skin burning sensation
!
joint related problems
!
muscle stiffness
!
pain in extremity
!
musculoskeletal pain
!
feeling tired
!
fever
!
contusion
Turoctocog alfa has no known effect on the ability to drive or use machines.
Inhibitor development
There is a risk of development of antibodies against FVIII that could decrease the effectiveness of 
the treatment with rFVIII (turoctocog alfa, NovoEight®) and future treatments with products 
containing FVIII. In patients not previously treated with any FVIII product, the risk of development 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
28 of 29
of antibodies is approximately 30% while the risk is approximately 2% in patients previously 
treated with a FVIII product (that is, treated more than 150 days).
There is a risk of development of antibodies against FVIII (inhibitors) that could decrease the 
effectiveness of the treatment with rFVIII (turoctocog alfa, NovoEight®) and future treatments with 
products containing FVIII. 
Factor VIII inhibitor development was not observed in > 250 previously treated patients (that is, 
treated more than 150 days) in completed clinical trials with turoctocog alfa.
Who can you contact during and after the trial? 
<EU countries only: If you have any questions, concerns or complaints as to how Novo Nordisk is 
using your personal information, you can contact your study doctor. Your study doctor will then 
contact Novo Nordisk’s Data Protection Officer. The [Country] Data Protection Authority is 
responsible for making sure that laws about personal information are followed in [Country]. For 
more information about your rights, or if you wish to make a complaint, you can contact [Data 
Protection Authorities contact information].>
Signature page
ALL INFORMATION IN THIS BOX MUST BE COMPLETED BY THE PATIENT 
Patient who has been informed and would like to continue participation in the trial:
 YES
 NO
Furthermore I  agree to participate in the voluntary 24 hour visit
 YES
 NO
2.2.2
Genotyping and Long-term Storage of Human Samples Informed Consent (page 4 
last paragraph)
<EU countries only: If you have any questions, concerns or complaints as to how Novo Nordisk is 
using your personal information, you can contact your study doctor. Your study doctor will then 
contact Novo Nordisk’s Data Protection Officer. The [Country] Data Protection Authority is 
responsible for making sure that laws about personal information are followed in [Country]. For 
more information about your rights, or if you wish to make a complaint, you can contact [Data 
Protection Authorities contact information].>
3URWRFRO$PHQGPHQWJORE_
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
29 of 29
2.2.3
Female partner of a Male Subject in Case of an Abnormal Pregnancy Informed 
Consent (page 3 last paragraph)
<EU countries only: If you have any questions, concerns or complaints as to how Novo Nordisk is 
using your personal information, you can contact your study doctor. Your study doctor will then 
contact Novo Nordisk’s Data Protection Officer. The [Country] Data Protection Authority is 
responsible for making sure that laws about personal information are followed in [Country]. For 
more information about your rights, or if you wish to make a complaint, you can contact [Data 
Protection Authorities contact information].>
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CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03196297 
Sponsor trial ID: 
NN7415-4255 
Official title of study: 
A Multi-Centre Trial Evaluating Efficacy and Safety of 
Prophylactic Administration of Concizumab in Patients with 
Severe Haemophilia A without Inhibitors 
Document date: 
13 July 2018 
 


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CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
1 of 14
Statistical Analysis Plan
Trial ID: NN7415-4255
A Multi-Centre Trial Evaluating Efficacy and Safety of 
Prophylactic Administration of Concizumab in Patients with 
Severe Haemophilia A without Inhibitors
Author:
Biostatistics LCM Haem, GH & Concizumab
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.
6$3Y_
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
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parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
2 of 14
Table of contents   Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.2
Scope of the statistical analysis plan..........................................................................................5
2
Statistical considerations .....................................................................................................................5
2.1
Sample size calculation .............................................................................................................6
2.2
Definition of analysis sets..........................................................................................................7
2.3
Primary endpoint.......................................................................................................................7
2.3.1
Sensitivity analysis ..................................................................................................8
2.3.2
Additional analysis ..................................................................................................8
2.4
Supportive secondary endpoints ................................................................................................9
2.4.1
Supportive secondary efficacy endpoints..................................................................9
2.4.2
Supportive secondary safety endpoints.....................................................................9
2.4.3
Supportive secondary pharmacokinetic endpoints...................................................10
2.4.4
Supportive secondary pharmacodynamic endpoints................................................10
2.4.5
Exploratory endpoints............................................................................................11
2.4.5.1
Exploratory safety endpoints ............................................................11
2.4.5.2
Exploratory patient reported outcome endpoints ...............................11
2.4.5.3
Exploratory pharmacokinetic and pharmacodynamic endpoints ........12
2.5
Interim analysis.......................................................................................................................12
3
Changes to the statistical analyses planned in the protocol..............................................................13
3.1
Clarification of bleeding episodes for primary endpoint...........................................................13
3.2
Offset definition for negative binomial regression for primary endpoint...................................13
3.3
Additional sensitivity analysis for second CPoC......................................................................13
3.4
Additional sensitivity analysis for primary endpoint ................................................................13
3.5
Clarification of additional analyses..........................................................................................14
3.6
Clarification of analyses for supportive secondary endpoints ...................................................14
3.7
Omission of endpoint including H-DAT..................................................................................14
3.8
Causal relation between turoctocog alfa/NovoEight® and AE ..................................................14
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
3 of 14
List of abbreviations
ABR
annualised bleeding rate 
AE
adverse event
aPTT
activated partial thromboplastin time
AT
antithrombin
Cmax
maximum plasma concentration
CPoC
clinical proof of concept
ETP
endogenous thrombin potential
FAS
full analysis set
FIX
coagulation factor IX
FVIII
coagulation factor VIII
H-DAT
Haemophilia Device Assessment Tool
Hemo-TEM 
Haemophilia Treatment Experience Measure
LPFT
last patient first treatment
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PGI-C
Patient’s Global Impression of Change
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
4 of 14
PK
pharmacokinetics
PRO
patient reported outcome
PT
prothrombin time
SAP
statistical analysis plan
SAS
safety analysis set
s.c.
subcutaneous(-ly)
SDS
Sheehan Disability Scale
SF-36v2
36-Item Short Form Health Survey
SIAQ-ISRQ
Self-Injection Assessment Questionnaire - Injection Site 
Reaction Questionnaire
TEAE
treatment emergent adverse events
TFPI
tissue factor pathway inhibitor
TSQM
Treatment Satisfaction Questionnaire for Medication 
VERITAS-PRN® 
Validated Hemophilia Regimen Treatment Adherence 
Scale
VERITAS-Pro®
Validated Hemophilia Regimen Treatment Adherence 
Scale – Prophylaxis
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
5 of 14
1
Introduction
1.1
Trial information
NN7415-4255, explorerTM5, multi-centre single arm trial, which aim to evaluate the efficacy and 
safety of concizumab 0.15 mg/kg (with potential dose escalation) administered daily s.c. in patients 
with severe haemophilia A without inhibitors. For further information about the trial please refer to 
the protocol.
1.2
Scope of the statistical analysis plan
This Statistical Analysis Plan (SAP) is based on the protocol A Multi-Centre Trial Evaluating
Efficacy and Safety of Prophylactic Administration of Concizumab in Patients with Severe 
Haemophilia A without Inhibitors, version 4, and amendments 1 and 2.
The scope of this SAP is to specify some further technical details on matters which have not been 
adequately described in the protocol. No changes have been made to the analyses specified in the 
protocol.
2
Statistical considerations
All endpoints referring to the time frame of at least 24 weeks will be evaluated in the main part of 
the trial, defined to end when the last patient has completed a minimum of 24 weeks of treatment or 
at LPFT (visit 2) + 24 weeks if the last patient has withdrawn before visit 9. Please refer to Figure 
2–1 for further information. 
Endpoints comprising number of bleeding episodes will be evaluated based on treated bleeding 
episodes only. Multiple bleeding locations occurring from the same event (e.g., due to a bicycle 
accident) or at the same time point will be counted as one bleeding episode. Further, the endpoints 
will not include re-bleed. 
A re-bleed is defined as a bleeding episode (worsening of bleeding site conditions e.g. swelling, 
pain) within 72 hours after stopping treatment of a previous bleeding episode at the same (or subset 
of the same) anatomical location. If a bleeding episode occurs in the same location 72 hours after 
stopping treatment, the bleed is defined as a new bleeding episode.
Clinical proof of concept
The statistical analysis of the collected data aims to establish CPoC that concizumab is efficacious 
in preventing bleeding episodes in haemophilia A patients without inhibitors. Since 36 patients were 
actually enrolled in the study compared to the planned number of 33 patients, the objective will be 
assessed when the last of the 36 patients has completed 24 weeks of dosing (or has withdrawn 
before that).
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
6 of 14
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a
comparison of the ABR of all patients with a threshold of 12, irrespective of individual dose 
titration. The primary CPoC criterion aims at evaluating the effect of concizumab at the last dose 
level reached for a patient. Hence, for this evaluation, only observations from the period where 
patients are on their end dose at time of analysis will contribute to the analysis. Furthermore, 
observations from the 2 week run-in period will be not be included. Since this evaluation disregards 
a subset of data collected the result should be viewed taking in to account the potential bias. The 
second CPoC criterion aims at evaluating the effect of concizumab when given as an escalation 
regimen. Hence, this will compare the ABR of haemophilia A patients treated with concizumab 
with the typical historical ABR of haemophilia A patients being treated on-demand using all data 
after enrolment. The second CPoC criterion will only be evaluated if the first one succeeds.
The referred comparisons will be made using a negative binomial model with log of exposure time 
in main part as offset. For each criterion, evidence of effect will be concluded if the 95% confidence 
interval of the estimated ABR is below 12.
Clinical arguments for the hierarchical test approach
Concizumab exhibits non-linear PK due to target mediated drug disposition and it is expected that 
the dose response curve of the ABR is rather steep. This implies that patients that are on a dose 
which is not efficacious are likely to bleed as patients that are not treated at all. Subset of data 
collected from the last dose clinically deemed as efficacious would reflect the efficacy of 
concizumab in the given patient.
2.1
Sample size calculation
The sample size calculation has been determined taking the small patient population into account, 
while also aiming for an acceptably narrow 95% confidence interval for the ABR. 
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be 
accommodated by 30 patients. 
It is expected that the treatment duration of the main part allowing for escalation time for some 
patients is on average 6 months in the below calculations.
When evaluating the power of the negative binomial analysis referred above, an annual bleeding 
rate of 4 is assumed for the end dose concizumab regimen, respectively in combination with an 
over-dispersion of 6. The power for concluding a bleeding rate lower than 12 then becomes 
approximately 95%. The power under varying values of true ABR and over-dispersion for the 
primary CPoC criterion are shown below in Table 2–1.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
7 of 14
Table 2–1 Power in comparison between concizumab prophylaxis treatment and an ABR 
threshold of 12 under different assumptions of ABR and over-dispersion.
Power
Over-dispersion
ABR
5
6
7
4
99%
95%
92%
5
95%
90%
86%
6
87%
81%
72%
For the secondary CPoC criterion that includes data prior to potential dose escalation, it is expected 
that the treatment duration of the main part is on average 8 months with an average ABR of 5.4 for 
the concizumab treated patients. This yields a marginal power of approximately 87% for the 
secondary CPoC criterion.
In prior Novo Nordisk trials conducted in haemophilia patients, the typical 1-year over-dispersion  
for non-inhibitor patients on prophylaxis with FVIII or FIX has been in the range 4-8, implying 24 
weeks over-dispersion of 3-5 (e.g. in NN7008-3543, NN7088-3859 and NN7999-3747). On that 
background, an over-dispersion of 6 over the 24 weeks in the main part of the current trial is 
deemed realistic.
2.2
Definition of analysis sets
All dosed patients will be included in the Full Analysis Set (FAS) as well as in Safety Analysis Set 
(SAS).
2.3
Primary endpoint
The primary endpoint is the number of bleeding episodes during at least 24 weeks from treatment 
onset. All treated bleeding episodes will be considered for this endpoint, including bleeding 
episodes recorded as post-surgical or caused by surgery or other medical or dental procedures.    
The primary endpoint will be estimated using negative binomial regression with log of exposure 
time in the included observational period of the main phase as offset, providing an actual estimate 
of the ABR as well as a corresponding 95% confidence interval. The offset for first CPoC criterion 
is the log of the individual exposure time at the last dose level reached at the time of analysis 
excluding the 2 weeks run-in period for subjects on 0.15 mg/kg. The offset for the second criterion 
is the log of the individual exposure time in the main part.
This analysis has the underlying assumption that the missing data mechanism is “missing at 
random”, i.e. MAR. Under this assumption, the statistical behaviour of the missing data (given the 
observed responses and the mean value structure) is assumed to be the same as for the observed 
data. The endpoint will be estimated based on the full analysis set (FAS) and only data collected 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
8 of 14
prior to discontinuation of trial product or initiation of alternative treatment options will be used to 
draw inference.
2.3.1
Sensitivity analysis
To evaluate the robustness of the MAR assumption implied in the primary analysis, a modified 
tipping point analysis will be performed where patients having discontinued before finalization of 
the main part are assumed to have a worse outcome compared to what was observed during the 
main part of the trial. This will be done by adding a value Δi to the observed bleeding episodes in 
the main part of the trial before analysing the data. The offset is maintained as being the exposure 
during the main phase since it is not possible to identify the amount of missing observation time.
The degree of worsening, Δi, will gradually be increased to evaluate at which point the upper 95% 
confidence limit of the prophylactic concizumab ABR is no longer below a threshold of 12. The 
results of the primary analysis will be considered robust if the tipping point is above what is 
considered clinical plausible.
The second CPoC criterion evaluating the effect of concizumab when given as an escalation 
regimen includes observations from the 2 week run-in period. In the 2 week run-in period some 
patients have been allowed to continue on pre-trial prophylaxis treatment and so including this 
period in the analysis may result in some patients having fewer bleeds in the run-in period. Since 
this can affect the ABR, an additional sensitivity analysis will be performed where the second CPoC 
criterion will be evaluated as described for the primary endpoint but without including observations 
from the 2 week run-in period.
The primary endpoint is assessed using all treated bleeding episodes including those recorded as 
post-surgery or caused by surgical or other medical or dental procedures. Since the inclusion of
bleeding episodes recorded as post-surgery or caused by surgical or other medical or dental 
procedures can affect the ABR, an additional sensitivity analysis will be performed excluding these
bleeding episodes from the primary and secondary CPoC criteria.
2.3.2
Additional analysis
An additional evaluation of the primary endpoint will be made, including actual concizumab dose 
level (interpreted as the patient’s last dose level) as additional factor in the primary analysis model 
specified above. Point estimates and 95% confidence interval will be provided for the ABR at the 
different dose levels of concizumab (0.15, 0.20 and 0.25 mg/kg). Furthermore, a series of analyses
with individual steady state PK/PD assessments included as log-transformed covariates in the 
negative binomial regression model as specified for the primary analysis will be performed in order 
to evaluate possible associations between PK/PD and ABR that potentially could guide dose-
selection. The referred steady-state PK/PD assessments comprise the concizumab trough level,
maximum plasma concentration (Cmax) of concizumab, TFPI value prior to the last s.c. dose 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
9 of 14
administration, peak thrombin generation (nM), Endogenous thrombin potential (nM*min) and 
velocity index (nM/min) prior to the last dose administration at 24 weeks.
2.4
Supportive secondary endpoints
2.4.1
Supportive secondary efficacy endpoints
!
The number of bleeding episodes during 76 weeks from treatment onset
!
The number of spontaneous bleeding episodes during at least 24 weeks from treatment onset
!
The number of spontaneous bleeding episodes during 76 weeks from treatment onset
The supportive secondary endpoints will be analysed using the same two analyses as for the 
primary endpoint; one only including observations from the period on the last dose level and one 
including the entire escalation regimen.
2.4.2
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from
!
treatment onset
!
Number of TEAEs during 76 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset.
!
Occurrence of anti-concizumab antibodies during 76 weeks from treatment onset.
!
Change from baseline of fibrinogen during 24 weeks from treatment onset.
!
Change from baseline of fibrinogen during 76 weeks from treatment onset.
!
Change from baseline of D-dimer during 24 weeks from treatment onset.
!
Change from baseline of D-dimer during 76 weeks from treatment onset
!
Change from baseline of prothrombin fragment 1 + 2 (F1 + 2) during 24 weeks from
treatment onset.
!
Change from baseline of F1 + 2 during 76 weeks from treatment onset.
!
Change from baseline of prothrombin time (PT) during 24 weeks from treatment onset.
!
Change from baseline of PT during 76 weeks from treatment onset.
!
Change from baseline of activated partial thromboplastin time (APTT) during 24 weeks
from treatment onset.
!
Change from baseline of APTT during 76 weeks from treatment onset.
!
Change from baseline of antithrombin (AT) during 24 weeks from treatment onset.
!
Change from baseline of AT 76 weeks from treatment onset.
Adverse Events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
10 of 14
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has onset from the first 
exposure to treatment until the last visit in the trial. Treatment-emergent adverse event endpoints 
will be summarised by system organ class, preferred term, seriousness, severity and relation to trial 
product. All Adverse events will further be listed. Relations to Novo Nordisk products used by 
patients in the trial, such as turoctocog alfa/NovoEight®, is reported as described in section 12.2 of 
the protocol and will be transferred to the Argus safety system and not reported in the report of the 
trial.
Frequency of binding anti-concizumab antibodies will by listed and summarised by time frame 
according to the two endpoint definitions.
All laboratory safety endpoints will be plotted by time, both as absolute values and change from 
baseline. Laboratory safety endpoints will further be summarised and listed.
2.4.3
Supportive secondary pharmacokinetic endpoints
!
Concentration of concizumab prior to the last dose administration at 24 weeks
!
Concentration of concizumab prior to the last dose administration at 76 weeks
The pharmacokinetic endpoints will be summarised and listed.
2.4.4
Supportive secondary pharmacodynamic endpoints
!
Free TFPI concentration
o
Value prior to the last dose administration at 24 weeks
o
Value prior to the last dose administration at 76 weeks
!
Thrombin generation
o
Peak thrombin generation (nM) prior to the last dose administration at 24 weeks
o
Peak thrombin generation (nM) prior to the last dose administration at 76 weeks
o
Endogenous thrombin potential (nM*min) prior to the last dose administration at 24 
weeks
o
Endogenous thrombin potential (nM*min) prior to the last dose administration at 76
weeks
o
Velocity index (nM/min) prior to the last dose administration at 24 weeks
o
Velocity index (nM/min) prior to the last dose administration at 76 weeks
The PD endpoints will be summarized and listed.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
11 of 14
2.4.5
Exploratory endpoints
2.4.5.1
Exploratory safety endpoints
!
Number of adverse events related to technical complaints during at least 24 weeks from 
treatment onset
!
Number of adverse events related to technical complaints during at least 76 weeks from 
treatment onset
Adverse events related to technical complaints will be listed and summarised
2.4.5.2
Exploratory patient reported outcome endpoints
!
Change in Hemo-TEM after 24 weeks from treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in SF-36v2 after 24 weeks from treatment onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in SDS after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in TSQM after 24 weeks from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in SIAQ-ISRQ after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Status of PGI-C after 24 weeks from treatment onset
Patient reported outcomes (PROs) will be collected using questionnaires at visits 1, 2, 4, 5, 6, 7, 8, 
9, 10 and 16.
Patient reported outcome questionnaires to be analysed:
!
Haemophilia Treatment Experience Measure (Hemo-TEM)
!
Validated Hemophilia Regimen Treatment Adherence Scale – Prophylaxis (VERITAS-
Pro®) or Validated Hemophilia Regimen Treatment Scale (/ VERITAS-PRN®)
!
36-Item Short Form Health Survey (SF-36v2) (4 week recall)
!
Patient Global Impression of Change (PGI-C)
!
Sheehan Disability Scale (SDS)
!
Treatment Satisfaction Questionnaire for Medication (TSQM, version II)
!
Haemophilia - Device Assessment Tool (H-DAT)
!
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)
VERITAS-Pro® or VERITAS-PRN®, SF-36v2, SDS, TSQM, H-DAT and SIAQ-ISRQ will be 
scored according to their respective scoring algorithms. Change after 24 weeks from treatment onset 
and after 76 weeks from treatment onset will be described.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
12 of 14
2.4.5.3
Exploratory pharmacokinetic and pharmacodynamic endpoints
!
Concentration of concizumab over time during 24 hours PK assessment
!
Concentration of free TFPI over time during 24 hours PD assessment
!
Thrombin generation over time during 24 hours PD assessment
o
Peak of thrombin generation time during 24 hours PD assessment
o
ETP time during 24 hours PD assessment
o
Velocity index time during 24 hours PD assessment
Individual "concentration over time" curves will be presented in a plot. A mean plot including error 
bars will also be presented. For thrombin generation the endpoints will be summarized and listed.
2.5
Interim analysis
The trial does not include a formal interim analysis. However, the split of the trial into a main and 
extension part offers the opportunity of reporting results before the end of the trial. Other reporting
of the trial might be done during the extension part once the data collection and review of the main
part data has been finalised and individual clinical study reports might in such case be issued. A 
final clinical study report describing results from the main and extension part will be written when 
the last patient has either completed or withdrawn from the trial.
All main conclusions regarding clinical proof of concept and dose guidance for phase 3 will be 
based on the reporting after the main part, see Figure 2–1.
Figure 2–1Definition of main and extension part
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
13 of 14
3
Changes to the statistical analyses planned in the protocol
As described in section 1.2 of this document, the scope of this SAP is to specify some further 
technical details on matters which have not been adequately described in the protocol. No changes 
have been made to the analyses specified in the protocol.
3.1
Clarification of bleeding episodes for primary endpoint
Section 17.3 of the protocol defines the primary endpoint as the number of bleeding episodes during 
at least 24 weeks from treatment onset. As specified in section 2.3 of this document, the bleeding 
episodes considered for the primary endpoint also includes bleeding episodes recorded as post-
surgical or caused by surgery or other medical or dental procedures.
3.2
Offset definition for negative binomial regression for primary endpoint
Section 17.3 of the protocol defines the offset of the negative binomial regression as log of 
exposure time in the main period. This definition only accounts for the second CPoC criterion. The 
offset should reflect the observation period which differs for the first CPoC which has been further 
clarified in section 2.3 of this document. This clarification is in line with the beginning of section 17 
as described below.
Section 17 of the protocol describes that the CPoC will be evaluated in a hierarchical fashion using 
two criteria to evaluate the effect of concizumab. The first CPoC criterion is evaluated using only a 
subset of observations where concizumab patients are at the last dose level reached at the time of 
analysis and excluding observations from the 2 weeks run-in period with 0.15 mg/kg. The second 
CPoC criterion is evaluated using all observations in the main part. 
The offset for first CPoC criterion is the log of the individual exposure time at the last dose level 
reached at the time of analysis excluding the 2 weeks run-in period for subjects on 0.15 mg/kg. The 
offset for the second criterion is the log of the individual exposure time in the main part.
3.3
Additional sensitivity analysis for second CPoC
Section 17 of the protocol describes how the second CPoC criteria uses all data after enrolment. 
Section 2.3.1 of this document describes how this may affect the ABR and how an additional 
sensitivity analysis will be performed.
3.4
Additional sensitivity analysis for primary endpoint
Section 2.3 of this document specifies how the bleeding episodes considered for the primary 
endpoint includes bleeding episodes recorded as post-surgical or caused by surgery or other medical 
or dental procedures. Since the inclusion of bleeding episodes recorded as post-surgical or caused 
by surgery or other medical or dental procedure may affect the ABR, an additional sensitivity 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
13 July 2018
1RYR1RUGLVN
Trial ID: NN7415-4255
Version:
1.0
UTN: U1111-1179-3872
Status:
Final
EudraCT No.: 2016-000614-29
Page:
14 of 14
analysis excluding these bleeding episodes will be performed as described in section 2.3.1 of this 
document.
3.5
Clarification of additional analyses
Section 17.5 of the protocol describes the additional analyses of the primary endpoint. Section 2.3.2 
of this document clarifies how the additional analysis including actual concizumab dose level as 
factor in the primary analysis model should be interpreted as including the patient’s last dose level 
as factor in the primary analysis.
Further, section 2.3.2 of this document clarifies that a series of additional analyses will be 
performed with each of the PK/PD variables taken prior to last dose at 24 weeks. Each of these 
PK/PD variables will be included as log-transformed covariates in the negative binomial regression 
model.
3.6
Clarification of analyses for supportive secondary endpoints
In section 17.6.1 of the protocol the analyses for the supportive secondary efficacy endpoints are 
defined. In section 2.4.1 of this document it is further clarified that the analyses are performed using 
observations from patients at the last dose level as well as throughout the escalation regimen.
3.7
Omission of endpoint including H-DAT
In section 17.7.2 of the protocol the last exploratory patient reported outcome endpoint to be 
summarised is the change in H-DAT after 76 weeks from treatment onset. However, it will not be 
possible to determine this change since the patients are not asked to complete the ePRO 
questionnaire H-DAT at treatment onset. In section 2.4.5 of this document the exploratory patient 
reported outcome endpoint related to change in H-DAT since treatment onset is not included. 
3.8
Causal relation between turoctocog alfa/NovoEight® and AE 
On the AE case report form for the trial it is not possible to fill in causality to turoctocog 
alfa/NovoEight®. As mentioned in section 12.2 in the protocol, an AE that is considered to have a 
causal relationship with a Novo Nordisk marketed product can be reported in the alternative 
aetiology section on the safety information form and will not be part of the report for this trial as 
described in section 2.4.2 of this document.
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CONFIDENTIAL