Clinical trial NCT03196284
Conditions: Congenital Bleeding Disorder Haemophilia A With Inhibitors Haemophilia B With Inhibitors
Sponsor: Novo Nordisk A/S
Start date: 2017-08-10; Completion date: 2020-01-31
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted in Africa, Asia, Europe and North America. 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 haemophilia A and B patients with inhibitors.

Detailed description:

Arms: arm 1: Concizumab administered in both the main phase and extension phase, with eptacog alfa administered on-demand during bleeding episodes arm 2: Eptacog alfa administered on-demand during bleeding episodes as the only intervention during the main phase. Concizumab given in the extension phase
Interventions: intervention 1: Concizumab intervention 2: Eptacog alfa
Intervention descriptions: intervention 1: A loading dose of 0.5 mg/kg will be given as the first dose, followed by 0.15 mg/kg (with potential stepwise dose escalation to 0.25 mg/kg) administered daily s.c. (subcutaneously, under the skin). Treatment duration is 24 weeks in the main trial, and up to 52 weeks in the extension phase intervention 2: A single dose of 90 μg/kg eptacog alfa one week after dosing with concizumab. On-demand treatment during bleeding episodes in both treatment arms

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03196284 
Sponsor trial ID: 
NN7415-4310 
Official title of study: 
A Multi-Centre, Randomised, Open-Label, Controlled Trial 
Evaluating the Efficacy and Safety of Prophylactic 
Administration of Concizumab in Haemophilia A and B 
Patients with Inhibitors 
Document date: 
24 June 2020 
 


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


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
1 of 137
Protocol
NN7415-4310
A Multi-Centre, Randomised, Open-Label, Controlled Trial 
Evaluating the Efficacy and Safety of Prophylactic 
Administration of Concizumab in Haemophilia A and B 
Patients with Inhibitors
Trial phase: 2
Protocol originator
Senior International Trial Manager 
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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: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
2 of 137
Table of Contents Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................7
Table of Tables..................................................................................................................................................8
List of abbreviations.........................................................................................................................................9
1
Summary..................................................................................................................................................15
2
Flow chart ................................................................................................................................................18
2.1
Visits and assessments.................................................................................................................18
2.2
Explanatory descriptions..............................................................................................................21
3
Background information and rationale for the trial............................................................................23
3.1
Background information..............................................................................................................23
3.1.1
Haemophilia...............................................................................................................23
3.1.2
Concizumab ...............................................................................................................24
3.2
Rationale for the trial...................................................................................................................27
4
Objective(s) and endpoint(s) ..................................................................................................................28
4.1
Objective(s)..................................................................................................................................28
4.1.1
Primary objective.......................................................................................................28
4.1.2
Secondary objectives .................................................................................................28
4.2
Endpoint(s)...................................................................................................................................28
4.2.1
Primary endpoint........................................................................................................28
4.2.2
Secondary endpoints..................................................................................................28
4.2.2.1
Supportive secondary endpoints..........................................................28
4.2.3
Exploratory endpoints................................................................................................29
4.2.3.1
Exploratory safety endpoints...............................................................29
4.2.3.2
Exploratory patient reported outcome endpoints ................................29
5
Trial design ..............................................................................................................................................31
5.1
Type of trial .................................................................................................................................31
5.1.1
Surgery.......................................................................................................................32
5.2
Rationale for trial design..............................................................................................................32
5.3
Treatment of patients ...................................................................................................................35
5.3.1
Concizumab arm........................................................................................................36
5.3.1.1
Concizumab prophylactic treatment (main and extension part)..........36
5.3.2
Comparator arm (eptacog alfa (rFVIIa))....................................................................37
5.3.2.1
On-demand treatment (main part).......................................................37
5.3.2.2
Concizumab prophylactic treatment (extension part)..........................37
5.3.3
Dose escalation ..........................................................................................................37
5.3.4
Co-administration of eptacog alfa (rFVIIa) ...............................................................39
5.3.5
Treatment of bleeding episodes during the trial.........................................................40
5.3.6
Prohibited medication................................................................................................41
5.4
Treatment after discontinuation of trial product ..........................................................................41
5.5
Rationale for treatment ................................................................................................................41
6
Trial population.......................................................................................................................................42
6.1
Number of patients.......................................................................................................................42
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
3 of 137
6.2
Inclusion criteria ..........................................................................................................................42
6.3
Exclusion criteria.........................................................................................................................42
6.4
Criteria for premature discontinuation of trial product................................................................43
6.5
Withdrawal from trial ..................................................................................................................43
6.6
Patient replacement......................................................................................................................44
6.7
Rationale for trial population.......................................................................................................44
7
Milestones.................................................................................................................................................45
8
Methods and assessments .......................................................................................................................46
8.1
Visit procedures...........................................................................................................................46
8.1.1
Informed consent, genotyping and long-term storage consent ..................................48
8.1.2
Screening log, enrolment log, trial card and patient number.....................................48
8.1.3
Screening failures and re-screening...........................................................................48
8.1.4
Premature discontinuation of trial product ................................................................50
8.1.5
Withdrawal from trial ................................................................................................50
8.1.6
Review/ evaluation of clinical outcome.....................................................................50
8.1.7
Visit 1 (Screening part)..............................................................................................51
8.1.8
Training of patients at visit 1, visit 2 and visit 9........................................................51
8.1.9
Treatment period at home..........................................................................................52
8.1.10
Staggered recruitment................................................................................................52
8.1.11
Treatment period – Main part ....................................................................................52
8.1.11.1
Visit 2 (Randomisation) ......................................................................52
8.1.11.2
Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and 
PK visit for concizumab arm) .............................................................54
8.1.11.3
Visit 4, 5, 6, 7 and 8 ............................................................................55
8.1.11.4
Visit 9..................................................................................................56
8.1.12
Treatment period – Extension part.............................................................................57
8.1.12.1
Visit 9.1 (PK visit and ONLY patients previously on the eptacog 
alfa (rFVIIa) on-demand arm).............................................................57
8.1.12.2
Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) 
on-demand arm) ..................................................................................58
8.1.12.3
Visit 10................................................................................................59
8.1.12.4
Visit 10.1 (ONLY patients previously on the eptacog alfa 
(rFVIIa) on-demand arm)....................................................................60
8.1.12.5
Visit 11................................................................................................61
8.1.12.6
Visit 11.1 (ONLY patients previously on the rFVIIa on-demand 
arm) .....................................................................................................61
8.1.12.7
Visit 12, 13, 14 and 15 ........................................................................62
8.1.12.8
Visit 16................................................................................................63
8.1.13
Visit 17 (End of trial) - Follow-up part......................................................................64
8.1.14
Unscheduled Visit......................................................................................................64
8.2
Patient related information/assessments ......................................................................................65
8.2.1
Demography...............................................................................................................65
8.2.2
Concomitant illness and medical history other than haemophilia .............................65
8.2.3
Concomitant medication............................................................................................65
8.2.4
Details of Haemophilia, Haemophilia treatment and bleed history...........................66
8.3
Efficacy assessments....................................................................................................................67
8.3.1
Bleeding episodes ......................................................................................................67
8.4
Safety assessments.......................................................................................................................70
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
4 of 137
8.4.1
Physical examination.................................................................................................70
8.4.2
Body measurements...................................................................................................71
8.4.3
Vital Signs..................................................................................................................71
8.4.4
Electrocardiogram......................................................................................................72
8.4.5
Adverse events...........................................................................................................72
8.4.5.1
Medication error..................................................................................72
8.4.5.2
Adverse events requiring additional data collection ...........................72
8.5
Laboratory assessments ...............................................................................................................74
8.5.1
Laboratory assessments for efficacy..........................................................................75
8.5.1.1
Thrombin generation...........................................................................75
8.5.1.2
Free TFPI.............................................................................................76
8.5.2
Laboratory assessments for safety .............................................................................76
8.5.2.1
Urinalysis ............................................................................................76
8.5.2.2
Haematology .......................................................................................76
8.5.2.3
Biochemistry .......................................................................................77
8.5.2.4
FVIII/FIX activity ...............................................................................77
8.5.2.5
Coagulation parameters.......................................................................78
8.5.2.6
FVIII/FIX inhibitors............................................................................78
8.5.2.7
Anti-concizumab antibodies................................................................78
8.5.2.8
Concizumab ELISA ............................................................................80
8.5.2.9
FVII ELISA.........................................................................................81
8.5.2.10
Total TFPI ...........................................................................................81
8.5.3
Human Biosamples....................................................................................................81
8.6
Other assessments........................................................................................................................82
8.6.1
Patient reported outcomes..........................................................................................82
8.6.2
Training......................................................................................................................83
8.6.2.1
Concizumab and NovoPen®4 ..............................................................83
8.6.2.2
eptacog alfa (rFVIIa)...........................................................................83
8.6.2.3
eDiary..................................................................................................84
8.6.3
Surgery.......................................................................................................................84
8.7
Patient compliance.......................................................................................................................84
8.8
Treatment compliance..................................................................................................................85
9
Trial supplies ...........................................................................................................................................86
9.1
Trial products...............................................................................................................................86
9.2
Labelling......................................................................................................................................86
9.3
Storage .........................................................................................................................................87
9.4
Drug accountability and destruction............................................................................................87
9.5
Auxiliary supplies........................................................................................................................88
10 Interactive voice/web response system ..................................................................................................89
11 Randomisation procedure and breaking of blinded codes..................................................................89
11.1
Randomisation .............................................................................................................................89
11.2
Breaking of blinded codes ...........................................................................................................89
12 Adverse events, and technical complaints.............................................................................................90
12.1
Definitions ...................................................................................................................................90
12.1.1
Adverse event ............................................................................................................90
12.1.2
Serious adverse event.................................................................................................91
12.1.3
Non-serious adverse event.........................................................................................92
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
5 of 137
12.1.4
Medication errors.......................................................................................................92
12.1.5
Adverse events requiring additional data collection..................................................93
12.1.6
Adverse Events of special interest.............................................................................94
12.1.7
Technical complaints.................................................................................................98
12.2
Reporting of adverse events.........................................................................................................98
12.3
Follow-up of adverse events......................................................................................................101
12.4
Technical complaints and technical complaint samples ............................................................102
12.4.1
Reporting of technical complaints ...........................................................................102
12.4.2
Collection, storage and shipment of technical complaint samples ..........................103
12.5
Pregnancies................................................................................................................................103
12.5.1
Pregnancies in female partners of male patients......................................................103
12.6
Precautions and/or overdose ......................................................................................................104
12.7
Rules for putting enrolment on hold..........................................................................................105
12.8
Committees related to safety......................................................................................................105
12.8.1
Novo Nordisk safety committee ..............................................................................105
12.8.2
Data monitoring committee .....................................................................................105
13 Case report forms..................................................................................................................................106
13.1
Corrections to case report forms................................................................................................107
13.2
Case report form flow................................................................................................................107
13.3
Electronic diary..........................................................................................................................107
14 Monitoring procedures .........................................................................................................................109
15 Data management..................................................................................................................................110
16 Computerised systems...........................................................................................................................111
17 Statistical considerations ......................................................................................................................112
17.1
Sample size calculation..............................................................................................................113
17.2
Definition of analysis sets..........................................................................................................114
17.3
Primary endpoint........................................................................................................................114
17.3.1
Estimand and primary statistical analysis................................................................114
17.3.2
Sensitivity analysis ..................................................................................................115
17.3.3
Additional analysis ..................................................................................................115
17.4
Supportive secondary endpoints ................................................................................................116
17.4.1
Supportive secondary efficacy endpoints ................................................................116
17.4.2
Supportive secondary safety endpoints....................................................................116
17.4.3
Supportive secondary pharmacokinetic endpoints...................................................117
17.4.4
Supportive secondary pharmacodynamic endpoints................................................117
17.4.5
Exploratory endpoints..............................................................................................118
17.4.5.1
Exploratory safety endpoints.............................................................118
17.4.5.2
Exploratory patient reported-outcome endpoints..............................118
17.5
Interim analysis..........................................................................................................................118
18 Ethics......................................................................................................................................................120
18.1
Benefit-risk assessment of the trial............................................................................................120
18.2
Informed consent .......................................................................................................................122
18.3
Data handling.............................................................................................................................122
18.4
Information to patients during trial............................................................................................123
18.5
Premature termination of the trial and/or trial site.....................................................................123
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
6 of 137
19 Protocol compliance..............................................................................................................................124
19.1
Protocol deviations ....................................................................................................................124
19.2
Prevention of missing data.........................................................................................................124
20 Audits and inspections ..........................................................................................................................125
21 Critical documents ................................................................................................................................125
22 Responsibilities......................................................................................................................................127
23 Reports and publications......................................................................................................................128
23.1
Communication of results..........................................................................................................128
23.1.1
Authorship ...............................................................................................................129
23.1.2
Site-specific publication(s) by investigator(s) .........................................................129
23.2
Investigator access to data and review of results.......................................................................129
24 Retention of clinical trial documentation and human biosamples....................................................130
24.1
Retention of clinical trial documentation...................................................................................130
24.2
Retention of human biosamples.................................................................................................130
24.2.1
Antibody samples ....................................................................................................131
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............133
26 Indemnity statement .............................................................................................................................134
27 References..............................................................................................................................................135
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. 
Appendix 1
Patient Reported Outcomes
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
7 of 137
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. 
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. ......................................26
Figure 5–1 Schematic diagram of the trial design..........................................................................................31
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. .......................................................................................................34
Figure 5–3 Dose escalation for one individual patient in the concizumab arm .............................................38
Figure 5–4 Dose escalation for one individual patient in the comparator arm...............................................39
Figure 8–1 Visit schedule – concizumab arm. ...............................................................................................46
Figure 8–2 Visit schedule – eptacog alfa (rFVIIa) arm later switching to concizumab.................................46
Figure 12–1 Reporting of AEs .......................................................................................................................100
Figure 17–1 Definition of main and extension part .......................................................................................119
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
8 of 137
Table of Tables
Page
Table 5–1
List of products provided by Novo Nordisk ................................................................................35
Table 8–1
Definition of stop of bleeding episode.........................................................................................68
Table 8–2
Definitions of bleeding episodes (cause of bleed) .......................................................................68
Table 8–3
Definition of bleeding episode severity and treatment recommendation.....................................69
Table 9–1
Trial products...............................................................................................................................86
Table 9–2
Storage conditions........................................................................................................................87
Table 17–1 Power in superiority comparison between concizumab prophylaxis and on-demand 
treatment under different assumptions of ABR for concizumab and over-dispersion 
(assuming on-demand ABR=24). ..............................................................................................114
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
9 of 137
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
CCDS
company core data sheet 
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 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
10 of 137
CPoC
clinical proof of concept
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
DRC
data request correction 
DUN
dispensing unit number
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
eITMF
electronic investigator trial master file
ELISA
enzyme-linked immunosorbent assay
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
11 of 137
EMA
european medicines agency
EOT
end of trial
ePRO
electronic patient reported outcome
eptacog alfa 
the name ‘eptacog alfa (rFVIIa)’ will be used throughout 
the protocol and the product is identical to 
rFVIIa,‘NovoSeven®, and ‘NiaStaseRT®’
ETP
endogenous thrombin potential 
FAS
full analysis set
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
FVIIa
activated coagulation factor VII
FVIII
coagulation factor VIII
FVIII:C
plasma activity of factor VIII
FX
coagulation factor X
FXa
activated coagulation factor X
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GHN
global haemophilia network
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
12 of 137
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
INN
International Non-Proprietary Names for Pharmaceutical 
Substances 
IRB
institutional review board
ISTH
International Society on Thrombosis and Haemostasis
IT
information technology
i.v.
intravenous(-ly)
IWRS
interactive web response system
LBBB
left bundle branch block
LPFV
last patient first visit
LPLV
last patient last visit
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
13 of 137
mAb
monoclonal antibody
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRA
magnetic resonance angiogram
MRI
magnetic resonance imaging
NOAEL
no observed adverse effect level 
NIMP
non investigational medicinal product
PCD
primary completion date 
PD
pharmacodynamics
PEF
peak expiratory flow
PK
pharmacokinetics
PP
per protocol
PRO
patient reported outcome
PT
prothrombin time
Q
Inter compartmental clearance
QA
quality assurance
Q4D
every 4th day
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
14 of 137
eptacog alfa (rFVIIa)
the name ‘eptacog alfa (rFVIIa)’ will be used throughout 
the protocol and the product is identical to ‘NovoSeven®’
sABR
spontaneous annualised bleeding rate
SAE
serious adverse event
SAS
safety analysis set
sBE
spontaneous bleeding episodes
s.c.
subcutaneous(-ly)
SI
international system of units
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse reaction
TAT
thrombin-antithrombin complex
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
TF
tissue factor
TFPI
tissue factor pathway inhibitor
TG
thrombin generation
TMM
trial materials manual
TVP
trial validation plan
UTN
Universal Trial Number
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
15 of 137
1
Summary
The main objective for the phase 2 trial NN7415-4310, explorer™4, is to assess the efficacy of 
concizumab administered s.c. once daily to prevent bleeding episodes in haemophilia A and B
patients with inhibitors. Furthermore, this trial aims to assess the longer-term efficacy and safety of 
concizumab in haemophilia A and B patients with inhibitors and to establish the safety of treating 
breakthrough bleeding episodes with recombinant factor VIIa (rFVIIa) in these patients.
Objective(s) and endpoint(s)
Primary objective
∀
To assess the efficacy of concizumab administered s.c. once daily in preventing bleeding 
episodes in haemophilia A and B patients with inhibitors.
Secondary objectives
∀
To assess the longer-term efficacy of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of administering recombinant factor VIIa (rFVIIa) to haemophilia 
patients with inhibitors that are exposed to concizumab 
∀
To assess the immunogenicity of concizumab in haemophilia patients with 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
∀
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 dosing
treatment with trial product (or has 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.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
16 of 137
Trial design
The trial is a multi-centre, randomised (2:1), open-label, controlled trial, aiming to evaluate the 
efficacy and safety of concizumab 0.15 mg/kg (with potential dose escalation) administered daily 
s.c. in haemophilia patients with inhibitors. We expect 16 patients to complete treatment in 
concizumab arm (concizumab prophylaxis) and 8 patients in comparator arm (rFVIIa on demand). 
The dose regimen is selected based on relevant PK and TFPI data as well as PK/PD modelling of 
the results from the preceding explorer™ trials. Both on-demand and prophylaxis patients will be 
eligible for the trial. 
For all patients treated with concizumab (concizumab arm and comparator arm extention part) a 
loading dose of 0,5 mg/kg concizumab will be given as the first dose, followed by one week of 
concizumab dosing 0,15 mg/kg. All patients in treatment with concizumab will in a non-bleeding 
state receive a single dose of 90 μg/kg eptacog alfa (rFVIIa) one week after dosing with 
concizumab. Hereafter, patients will be closely clinically observed at the site for potential safety 
issues for at least 12h and evaluated again at the site after 24h. 
The total trial duration for the individual patient will be approximately 86-88 weeks, consisting of a 
2-4 week screening period, a subsequent 76-week treatment period and an 8-week follow-up period.
eptacog alfa (rFVIIa) for treatment of bleeding episodes during the trial will be provided by Novo 
Nordisk. The patient will not be provided with trial product or eptacog alfa (rFVIIa) after end of 
trial.
The trial is split into a main part which lasts 24 weeks for all patients in the trial and an extension 
part which lasts 52 weeks. In the main part, the primary and selected secondary endpoints will be 
analysed when 16 patients have completed a minimum of 24 weeks of concizumab prophylaxis and 
8 patients have completed a minimum of 24 weeks of eptacog alfa (rFVIIa) on-demand or have 
withdrawn. The analysis of the main part of the trial aims to substantiate the clinical proof of 
concept (CPoC) that concizumab has the potential to prevent bleeding episodes in patients with 
haemophilia and inhibitors. The extension part of the trial will provide additional safety and long-
term efficacy data. 
Trial population
Number of patients planned to be screened: 28
Number of patients planned to be started on trial product: 26
Number of patients expected to complete the trial: 24
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
17 of 137
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 haemophilia A or B patients with inhibitors aged ≥ 18 years at the time of signing 
informed consent
∀
Patients currently in need of treatment with bypassing agents
Key exclusion criteria
∀
Known or suspected hypersensitivity to trial product(s) or related products
∀
Known inherited or acquired bleeding disorder other than haemophilia
∀
Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX
Key Efficacy assessment
∀
Number of bleeding episodes during at least 24 weeks of treatment onset
Key Safety assessment
∀
Number of treatment emergent adverse events during at least 24 weeks of treatment onset
Trial products
The following products will be used in the trial:
∀
Investigational Medicinal Products:
o
concizumab B, 100mg/mL to be administered s.c. with NovoPen®4 and needles
o
eptacog alfa (rFVIIa), 5mg /vial and histidine (solvent). Reconstituted eptacog alfa 
(rFVIIa) is for intravenous administration and used in the trial at visit 3 and 9.1 for all 
patients with the purpose of investigating the safety of administering eptacog alfa 
(rFVIIa) to haemophilia patients
∀
Non Investigational Medicinal Product:
o
eptacog alfa (rFVIIa) 5 mg /vial and histidine (solvent). Reconstituted eptacog alfa is for 
intravenous administration and used in this trial for treatment of bleeding episodes
3URWRFROY
CONFIDENTIAL


Protocol
UTN: U1111-1179-2925
Date:
15 March 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
1.0
Page:
18 of 137
2
Flow chart
2.1
Visits and assessments
explorerTM4 trial periods
Screening
Treatment main a,b
Treatment extension b
Follow-
up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-
scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
197
225
253
281
309
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w
72w
76w
-
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/ Genotyping and Long-term 
storage consent
●
In/exclusion criteria
●
●g
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and 
bleed history
●
Withdrawal criteria/ Criteria for premature 
discontinuation of trial product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Randomisation (IWRS)
●
EFFICACY
Bleeding episodes h, i
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab) 
●
●
●j, k
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Free TFPI (central lab)  
●
●
●k
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
SAFETY
Physical examination
●
●
●k
●
●
●
●
●
●
Body measurements 
●
●m
●k, m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
Vital signs 
●
●n
●k, n
●
●
●
●
●
●n
●n
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
3URWRFROY_


Protocol
UTN: U1111-1179-2925
Date:
15 March 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
1.0
Page:
19 of 137
explorerTM4 trial periods
Screening
Treatment main a,b
Treatment extension b
Follow-
up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-
scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
197
225
253
281
309
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w
72w
76w
-
84w
Injection site reaction  
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●j, k
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Biochemistry (central lab)
●
●
●k
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
FVIII/ FIX activity (central lab)
●
●l
●l
Coagulation parameters (central lab)
●
●
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●l
●
●
Coagulation parameters (PT, APTT and Fibrinogen 
(local lab))
●j, k
●j
FVIII/FIX  inhibitors (central lab)
●
●l
●l
Anti-concizumab antibodies (ADA) (special lab) o
●
●
●k, p
●p
●p
●p
●p
●p
●l, p
●
●
●
●
●
●
●
●
●
●
●l
●
●
Concizumab  ELISA (special lab)
●
●k, p
●p
●p
●p
●p
●p
●l, p
●
●
●
●
●
●
●
●
●
●
●l
●
●
FVII ELISA (special lab)
●j,k
●j
Total TFPI (special lab)
●
●
●k
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
TRIAL MATERIAL
IWRS call 
●
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab)r
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (eptacog alfa, histidine)q
●
●k
●
●
●
●
●
●
●
●
●
●
●
Administration of trial product (concizumab)r
●k, s
●k
●d, s 
●
●
Administration of trial product (eptacog alfa)
●k, t
●t
Drug accountability (concizumab)
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Drug accountability (eptacog alfa) 
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product e, u
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires 
●
●
●k
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
15 March 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
1.0
Page:
20 of 137
explorerTM4 trial periods
Screening
Treatment main a,b
Treatment extension b
Follow-
up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-
scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
197
225
253
281
309
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w
72w
76w
-
84w
Handout ID card 
●
Training v
●
●
●
●
●
Compliance: eDiary
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
The cells marked in ‘red’ are only for the patients randomised to eptacog alfa (rFVIIa) arm.
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
15 March 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
1.0
Page:
21 of 137
2.2
Explanatory descriptions
Footer
Description
a
There is staggered recruitment for the 4 first patients in the trial on the concizumab arm. 
b
Concizumab administration is performed at home except for visit 2 and visit 3 for patients randomised to concizumab and visit 9 and 9.1 for patients 
randomised to eptacog alfa. Sampling for Free TFPI, Anti-concizumab antibodies, Concizumab ELISA and Total TFPI are done prior to concizumab 
administration.
c
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 and 
visit 9.1 have a PK session of 24 hours and a safety follow up visit the following day. 
d
Visit and procedures only performed for patients randomised to eptacog alfa and switching to concizumab treatment.
e
For patients being dose escalated on concizumab a phone call is recommended 1 week after first dose of concizumab.
f
Daily dosing preferably at the same time in the morning.
g
Evaluation of the laboratory results obtained from samples taken at screening.
h
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.
i
Eptacog alfa will be given to treat breakthrough bleeding episodes. 
j
Sampling time schedule for thrombin generation, haematology,  coagulation parameters and FVII ELISA: pre-dose (-1 hour), post-dose: 10 min (±2 min), 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 eptacog alfa 
administration.
k
ONLY for patients randomised to concizumab arm.
l
At visit 9 and 16 blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been performed.
m
Only body weight should be measured. 
n
Vital signs should be evaluated before and after trial drug administration at visit 2 and visit 3 for concizumab arm and at visit 9 and visit 9.1 for patients in 
eptacog alfa arm switching to concizumab treatment.
o
In case 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 blood samples will be taken and stored for characterisation 
of the antibodies.
p
Blood sampling for anti-concizumab antibodies and concizumab ELISA testing should only be collected for patients on concizumab.
q
If needed dispensing of eptacog alfa, histidine, trial injection kits and Direction For Use (DFU). 
r
First treatment dose of concizumab is a loading dose and will be administered at visit 2 for the concizumab arm and visit 9 for the eptacog arm. 
s
The patient must be in a non-bleeding state at the time of the first concizumab administration and should not have received any bypassing agent drugs,(e.g., 
eptacog alfa, FEIBA®) for prophylaxis or treatment of a bleeding episode within a period of 24h (for eptacog alfa) or 48h (for FEIBA®) prior to first 
concizumab. Only eptacog alfa is allowed after visit 2.
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
15 March 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
1.0
Page:
22 of 137
t
Eptacog alfa administered in a non-bleeding state at site at visit 3 for the concizumab arm and at visit 9.1 for the eptacog alfa arm.
u
Patient treated with concizumab 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 the investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose 
escalation. 
v
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Patients randomised to eptacog alfa will be re-trained in 
NovoPen®4 and s.c. administration at visit 9 and 9.1. If necessary training can be performed as needed at other visits. The eDiary will be provided to the 
patients at visit 2 if the patient feels capable in s.c. administration and using the eDiary. Further the patients will be trained in recognition of signs/symptoms of 
thrombosis.
3URWRFROY


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
23 of 137
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP 1, applicable regulatory 
requirements,  in accordance with the Declaration of Helsinki 2 and ISO 14155 3.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
The 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). In haemophilia B, it is factor IX (FIX) that is deficient. 
Inheritance is chromosome X-linked; 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 births 4. According to 
the World Federation of Haemophilia global survey of 20145, 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 factor 6. With a deficiency of FVIII or FIX, the degree of activation of 
coagulation FX becomes insufficient. Consequently, the thrombin burst is delayed and insufficient 
for normal haemostasis 7. 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 symptoms 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 into a joint prior to age 4 year. Many children also bleed from other body sites before this 
age is reached 8. For this reason, primary prophylaxis with regular FVIII or FIX injections in the 
non-bleeding state is the recommended treatment from early childhood.
In patients who have developed inhibitors towards FVIII or FIX, replacement therapy is rendered 
ineffective. Though prevalence studies and registry data indicate that the prevalence of inhibitors in 
the haemophiliac population overall has been reported to be between 5% and 7% 9, the prevalence 
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amongst patients with severe haemophilia (FVIII:C < 1%) is higher and has been reported to be up 
to 30% 9, 10. These patients may be treated with bypassing agents, activated FVII (NovoSeven®) and 
activated prothrombin complex concentrate (FEIBA®) given as i.v. injections. 
Current treatment options in haemophilia, replacement therapy or bypassing therapy, are hampered 
by the fact that these products must be given as i.v. injections. Furthermore, bypassing agents are
characterized by relatively short half-lives, therefore prophylactic treatment is burdensome. It is
also generally acknowledged that the efficacy profile of bypassing agents is inferior to replacement 
therapy. Consequently, delayed or sub-optimal treatment occurs in a significant number of patients
with inhibitors. 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 Dalton’s.  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)) 10. 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. 
Key differentiators of this new mode of action (MoA) and the key benefit of concizumab in patients 
with severe haemophilia A and B with inhibitors is reduced treatment burden due to subcutaneous 
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, explorerTM1) 11, a single dose trial in Japanese healthy subjects (NN7415-3981), 
two multiple dose trials (NN7415-3986, explorerTM2) and (NN7415-4159, explorer™3). When the 
first cohort with 4 (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 trial animal had concizumab plasma concentrations several hundred fold 
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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 (NN7415-4159), explorer™3,
a new 52 week non-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.
The explorer™3 trial was finalised following the completion of cohort 3 (0.8 mg/kg s.c. 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 s.c. every 4 days for 6 weeks). No clinical consequences or 
serious adverse events were seen in the completed cohorts in explorer™3.
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 3–1Individual 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™4. 
In a drug–drug interaction study in monkeys (NN215431), three doses of up to 1 mg/kg of
NovoSeven® were administered at 2h intervals, alone or in the presence of a steady state 
concentration of concizumab. No notable clinical observations were made, no treatment-related 
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adverse findings were seen, i.e. no thrombi or other signs of excessive coagulation. Increased 
concentrations of thrombin–anti-thrombin (TAT) and D-dimer were seen, which tended to be 
additive when both concizumab and eptacog alfa (rFVIIa) were present in circulation.
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 studies with concizumab have been finalised. Key safety and preliminary 
efficacy results from these phase 1 studies support further development of concizumab in 
haemophilia 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 haemophilia A and B patients with inhibitors
4.1.2
Secondary objectives
∀
To assess the longer-term efficacy of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of administering recombinant factor VIIa (rFVIIa) to haemophilia 
patients with inhibitors that are exposed to concizumab 
∀
To assess the immunogenicity of concizumab in haemophilia patients with 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
∀
Number of TEAEs within 24 hours of rFVIIa administration
∀
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
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∀
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 anti-thrombin (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
∀
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 (nMxmin) prior to the last dose administration at 24 
weeks 
o
Endogenous thrombin potential (nMxmin) 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 
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
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∀
Change in Hemo-TEM after 76 weeks from treatment onset
∀
Change in VERITAS-Pro® or VERITAS-PRN® after 24 weeks from treatment onset
∀
Change in VERITAS-Pro® or 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
All endpoints referring to a time frame of either 24 weeks or of at least 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 multi-centre, randomised (2:1), open-label, controlled trial, aiming to evaluate the 
efficacy and safety of concizumab 0.15 mg/kg (with potential dose escalation) administered daily 
s.c. in haemophilia patients with inhibitors. The selected dose regimen is based on relevant PK and 
TFPI data as well as PK/PD modelling of the results from the preceding explorer™ trials. Both on-
demand and prophylaxis patients will be eligible for the trial. 
Figure 5–1Schematic diagram of the trial design
The total trial duration for the individual patient will be approximately 86-88 weeks, including a 2-4 
week screening period, a 76 week treatment period, and a follow-up period of 8 weeks, see Figure 
5–1
The trial is split into a main part which lasts 24 weeks for all patients in the trial and an extension 
part which lasts up to 52 weeks. In the main part, the primary and selected secondary endpoints will 
be analysed when 16 patients have completed a minimum of 24 weeks of concizumab prophylaxis
and 8 patients have completed a minimum of 24 weeks of eptacog alfa (rFVIIa) on-demand or have 
withdrawn.
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In the concizumab arm bleeding episodes occurring during the trial will be treated with eptacog alfa 
(rFVIIa). In all patients treated with concizumab a single 90 μg/kg dose of eptacog alfa (rFVIIa)
will be administered in a non-bleeding state one week after dosing with concizumab has been 
initiated. The investigator will evaluate if there are any safety concerns 24 hours post eptacog alfa 
(rFVIIa) administration. Furthermore, the scheduled administration of eptacog alfa (rFVIIa) for the 
first 4 patients entering the trial with concizumab will be staggered.
In the comparator arm, in the main part, patients will receive eptacog alfa (rFVIIa) on-demand 
treatment. After completion of the main part, the patients will continue the trial in the extension part 
being treated with prophylactic concizumab 0.15 mg/kg (with potential dose escalation) s.c. daily 
administration.
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 and damage. Acceptance of storage of human biosamples 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 human biosamples to be stored 
for future exploratory analysis, see Section 8.1.1.
An independent data monitoring committee (DMC) will be established for this trial. The DMC will 
review all safety data from the ongoing trial with concizumab exposure, see Section 12.8.2.
5.1.1
Surgery
Minor surgery is allowed in this trial. Major surgery conducted earlier than one month (30 days) 
prior to trial start is allowed, see exclusion criteria 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™4 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 with inhibitors. A dose escalation design will allow cautious dose escalation in order to 
identify an efficacious and safe concizumab dose for the individual patient. A comparator arm is 
included to assess if concizumab is superior to on-demand treatment. Furthermore, the trial will 
give a possibility to assess safety of co-administration of eptacog alfa (rFVIIa) to the patients 
exposed to the concizumab treatment. 
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The duration of 24 weeks for the main part of the trial is deemed necessary in order to obtain 
information on the annualised bleeding rate on concizumab prophylaxis. The duration of the 
extension part of the trial will be 52 weeks and provide further information on efficacy, i.e.
annualised bleeding rate, and also provide additional safety data upon 76 weeks treatment with 
concizumab.
A total of 26 patients previously on prophylaxis (PPX) or on-demand (OD) treatment will be 
randomised into one of the two arms, with 16 patients in the concizumab arm and 8 patients in the 
comparator arm see Figure 5–1. Concizumab will be administered s.c. daily for patients randomised 
to the concizumab arm in the main and the extension part of the trial. For patients in the comparator 
arm in the extension part treatment will be changed from on-demand with rFVIIa to prophylaxis 
with concizumab. 
The concizumab dose regimens will be starting with 0.15 mg/kg with the possibility to escalate to
0.20 mg/kg and 0.25 mg/kg based on bleeding frequency, see Section 5.3.3.
Daily dosing with concizumab 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 5.3.3
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Figure 5–2Individual 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.1
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 
                                                
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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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™4. Daily dosing will allow for 
the increase in trough levels and thus better efficacy may be expected with a lower dose.
A loading dose of 0.5 mg/kg concizumab will be given as the first dose, followed by one week of 
concizumab dosing 0.15 mg/kg in order to ensure steady-state levels at the time of eptacog alfa 
(rFVIIa) administration. eptacog alfa (rFVIIa) will be administered one week after initiation of 
dosing with concizumab in a non-bleeding state to assess safety of treatment with eptacog alfa 
(rFVIIa) in patients exposed to concizumab treatment.
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.
5.3
Treatment of patients
The following products will be administered in the trial.
Table 5–1 List of products provided by Novo Nordisk
Compound Name 
Strength
Dosage form
Route of administration
Treatment period
concizumab B a
100 mg/mL
solution for s.c. 
injection in a 3 mL 
cartridge b
Subcutaneous 
administration using
NovoPen®4
For prophylactic 
treatment in 76 weeks 
(for concizumab arm in 
the main part and 
extension part).
For prophylactic 
treatment in 52 weeks 
(for comparator arm in 
the extension part).
eptacog alfa (rFVIIa) a, c
5 mg/vial
Powder for solution 
for i.v. injection
Intravenous 
administration
For treatment of 
breakthrough bleeding 
episodes at the 
discretion of the 
investigator (screening, 
main, extension and 
follow up part). c
Administration of 
doses higher than 
histidine solvent (5 mL)
Prefilled syringes for 
solution for i.v. 
injection 
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90μg/kg to patients 
exposed to concizumab 
is not allowed.
For on-demand 
treatment at the 
discretion of the 
investigator in 24 
weeks for comparator 
arm in the main part. 
In the concizumab arm 
and comparator arm 
after switching to 
concizumab in the 
extension part of the 
study a single 90μg/kg 
dose for initial safety 
assessments in a non-
bleeding state. a
Will be provided for as 
long as patients 
participate in the trial 
(screening, main, 
extension and follow 
up part)
a Investigational medicinal product (IMP)
b Not to be confused with the daily injected volume (~150 μL, depending on dose strength and body weight)
c Non-investigational medicinal product (NIMP)
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 in the Trial Materials Manual, see Section 9.
5.3.1
Concizumab arm
5.3.1.1
Concizumab prophylactic treatment (main and extension part)
Concizumab will be given s.c. once daily 0.15 mg/kg (with potential dose escalation to 0.20 and 
0.25 mg/kg). The dose escalation criteria are described, see Section 5.3.3. The first dose of 
concizumab will be given at the trial site under medical supervision. 
A loading dose of 0.5 mg/kg will be given as the first concizumab dose at visit 2 in order to ensure 
steady state levels at the time of the administration of eptacog alfa (rFVIIa) in a non-bleeding state 
at visit 3, see Section 5.3.4. 
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The patients will be trained in s.c. administration of concizumab with NovoPen®4 at the screening 
visit and at the first scheduled treatment visit. 
5.3.2
Comparator arm (eptacog alfa (rFVIIa))
5.3.2.1
On-demand treatment (main part)
During the main part of the trial, patients will receive eptacog alfa (rFVIIa) for treatment of 
bleeding episodes, with a dose regimen at the discretion of the investigator.
5.3.2.2
Concizumab prophylactic treatment (extension part)
After completion of the main part, the patients will continue the trial in the extension part and will 
switch to prophylactic treatment with s.c. daily administration of concizumab 0.15 mg/kg (with 
potential dose escalation to 0.20 and 0.25 mg/kg) s.c. daily administration. 
The same dose escalation criteria as described below (for the initial concizumab arm) will apply.
A loading dose of 0.5 mg/kg will be given as the first concizumab dose at visit 9 in order to ensure 
steady state levels at the time of the administration of rFVIIa in a non-bleeding state at visit 9.1.
5.3.3
Dose escalation
The dose escalation criteria as described below will apply to all treatment arms.
Bleeding episodes will be assessed during the trial both at scheduled visit 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, bleeding episodes occurring during first 2 weeks should not influence a dose escalation 
decision. 
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (or visit 9 when
switching from eptacog alfa (rFVIIa) to concizumab) (first treatment 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. 
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Dose 0.15 mg/kg: 
When sBE occurs, the investigator will determine if ≥3 sBEs have occurred within the preceding 12
weeks (including the current sBE). If yes, and if investigator deems it safe, the patient will 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 sooner.
Dose 0.20 mg/kg: 
When 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 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 sooner.
Dose 0.25 mg/kg: 
Patients are not dose escalated further regardless of the number of sBEs.
The possibility of dose escalation at unscheduled visits is necessary in order to avoid  bleeding
episodes at inadequate dose level: e.g. if the dose escalation eliciting bleeding episode occurs soon 
after a scheduled visit, the patient will avoid to wait8 weeks for the next scheduled visit (in the 
extension part).
Figure 5–3Dose escalation for one individual patient in the concizumab arm
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Figure 5–4Dose escalation for one individual patient in the comparator arm
5.3.4
Co-administration of eptacog alfa (rFVIIa)
eptacog alfa (rFVIIa) will be used for treating breakthrough bleeding episodes in this trial; one 
week after initiation of dosing with concizumab, a single 90 μg/kg dose of eptacog alfa (rFVIIa)
will be administered in a non-bleeding state at the trial site under medical supervision to assess 
safety of treatment with eptacog alfa (rFVIIa) in patients exposed to concizumab treatment. 
Hereafter, patients will be closely clinically observed at the site for potential safety issues for at 
least 12h and evaluated again at site after 24h. Between 12h and 24h, the patient must either stay at 
the site or at a hotel or at home if he lives nearby to be able to continue visit 3 or 9.1 the day after.
Dosing of eptacog alfa (rFVIIa) in the first 4 patients randomised to concizumab arm will be 
staggered so that the period between eptacog alfa (rFVIIa) administrations from one patient to 
another is at least 48 hours. If no safety concerns are observed (for example signs and symptoms of 
thromboembolism, such as swelling, pain and redness of the leg, shortness of breath, and chest 
pain) by the investigator in the period between the administration of eptacog alfa (rFVIIa) and when 
the next daily concizumab dose is to be given, the investigator allows the individual patient to 
administer concizumab prophylactically at home and if needed, treat breakthrough bleeding 
episodes at home with eptacog alfa (rFVIIa). The patients will receive prophylactic doses of 
concizumab 0.15 mg/kg daily throughout the main part (24 weeks) and the extension part (52 
weeks), unless dose escalation criteria are fulfilled, see Section 5.3.3. 
In case safety concerns are raised by an investigator after eptacog alfa (rFVIIa) administration and 
these concerns meet the described criteria for putting enrolment of additional patients on hold, 
dosing in the individual patients will be halted and further recruitment in the trial will be halted, see 
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Section 12.7.  In case safety concerns that do not meet the criteria for putting enrolment of 
additional patients on hold are observed by the investigator, dosing in that individual patient will be 
halted until further evaluation. In such cases, all available data will be assessed by the Data 
Monitoring Committee (DMC), see Section 12.8.2.
5.3.5
Treatment of bleeding episodes during the trial
Breakthrough bleeding episodes between visit 1 and visit 2 can be treated with any bypassing agent 
(e.g., eptacog alfa (rFVIIa), FEIBA®) up to a period of 24 hours (for eptacog alfa (rFVIIa)) or 48 
hours (for FEIBA®) prior to first concizumab administration at visit 2. Novo Nordisk will provide 
eptacog alfa (rFVIIa) throughout the trial. The patient can treat himself and then he must call the 
site. The bleeding episode must be recorded in the eCRF. 
Breakthrough bleeding episodes between visit 2-3 in the concizumab arm and visit 9-9.1 in the 
comparator arm must be treated with eptacog alfa (rFVIIa). Upon breakthrough bleeding episodes 
in this period the patient must first call the site. The investigator should instruct the patient about 
whether he should go to the site to receive treatment or if he can administer a single dose of eptacog 
alfa (rFVIIa) which is not higher than 90μg/kg without delay to treat the breakthrough bleeding
episode. If the patient is instructed to administer the eptacog alfa (rFVIIa) dose at home, following 
the administration, the patient should immediately go to the site for further clinical evaluation. The 
bleeding episode must be recorded in the electronic Diary (eDiary).
Breakthrough bleeding episodes between visit 3 and visit 16 in the concizumab arm must be treated 
with eptacog alfa (rFVIIa). The patient can treat himself without delay but must inform the site that 
a bleeding episode has occurred. Doses of eptacog alfa (rFVIIa) that are lower than 90μg/kg may be 
used to treat breakthrough bleeding episodes at the discretion of the investigator. Administration of 
doses higher than 90μg/kg to patients exposed to concizumab is not allowed. If a single dose of 
eptacog alfa (rFVIIa) is not sufficient to stop a bleeding episode, the patient should inform the site 
and in agreement with the investigator may administer a second dose of eptacog alfa (rFVIIa) not 
higher than 90μg/kg 2-3h after the first dose has been administered. The same procedure should be 
repeated in case the second dose of eptacog alfa (rFVIIa) is not sufficient to stop the bleeding 
episode. If more than three 90μg/kg doses of eptacog alfa (rFVIIa) are needed to stop a bleeding 
episode, the patient should go to the site without delay. The definition and diagnostic criteria of 
DIC, acute myocardial infraction, stroke, deep vein thrombosis, pulmonary embolism and 
peripheral artery occlusion is provided in section 12.1.6. The bleeding episodes must be recorded in 
the eDiary.
Breakthrough bleeding episodes between visit 16 and visit 17 (follow-up part) may be treated with 
eptacog alfa (rFVIIa) or other products at the discretion of the investigator. The patient can treat 
himself with eptacog alfa (rFVIIa) at home without delay. Only eptacog alfa (rFVIIa) will be 
provided by Novo Nordisk. The bleeding episodes must be recorded in the eDiary.
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See Table 5–1 and Table 8–3.
5.3.6
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 anticoagulants (DOACs)
∀
Home treatment (between visit 2 and visit 16) with activated prothrombin complex 
concentrates (FEIBA®)
5.4
Treatment after discontinuation of trial product
When discontinuing trial products (visit 16 or earlier), the patient should be switched to a suitable 
marketed product at the discretion of the investigator. Only eptacog alfa (rFVIIa) will be provided 
by Novo Nordisk. The patient will not be provided with concizumab or eptacog alfa (rFVIIa) after 
end of trial (EOT) (visit 17) by Novo Nordisk.
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 the treatment burden 
compared to the currently approved prophylactic drugs which have to be administered i.v.
Furthermore, the current treatment options for prophylaxis in inhibitor patients do not reduce the 
frequency of breakthrough bleeding episodes to the same extent as prophylaxis with replacement 
therapy in non-inhibitor patients. Concizumab may therefore show a better efficacy profile 
compared to current treatment options in haemophilia A and B patients with inhibitors. 
The treatment period during at least 24 weeks (the main part of the trial) is considered necessary for 
providing robust data that allow demonstration of clinical proof of concept and to support decision 
making regarding a phase 3 confirmatory trial. Dosing for additional 52 weeks will provide 
valuable long term efficacy and safety data.
Breakthrough bleeding episodes occur in prophylactic regimens with both bypassing agents and 
replacement therapy. Therefore, it is expected that breakthrough bleeding episodes will occur 
during prophylaxis with concizumab even if clinical proof of concept is demonstrated. 
Consequently, eptacog alfa (rFVIIa) will be provided by Novo Nordisk in this trial for treatment of 
breakthrough bleeding episodes. In order to minimize the likelihood of any unforeseen adverse 
events associated with administration of eptacog alfa (rFVIIa) in these circumstances,
administration of eptacog alfa (rFVIIa) in a controlled setting will be performed at visit 3 or 9.1. 
Please refer to the Investigator’s Brochure for further information.
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 28
Number of patients planned to start on trial product: 26
Number of patients expected to complete the trial: 24
∀
Preferably 21 haemophilia A patients
∀
Preferably 3 haemophilia B patients
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 the suitability 
for the trial
2. Male haemophilia A or B patients with inhibitors aged ≥ 18 years at the time of signing 
informed consent
3. For patients treated on-demand, a minimum of six bleeding episodes during the 24 weeks (or 
twelve bleeds during 52 weeks) prior to screening
4. Documented history of high-titer inhibitors towards FVIII or FIX, defined as ≥5 Bethesda Units
5. Patients currently in need of treatment with bypassing agents
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
6. Major surgery conducted within one month prior to the initiation of trial activities or major 
surgery planned to occur during the trial
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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
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 requires 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 measured as estimated Glomerular Filtration Rate (eGFR) ≤ 60 ml/min/1.73 
m2 for serum creatinine measured at screening for patients without evidence of renal damage
12. Platelet count ≤ 100x109/L at screening
13. Fibrinogen level < the lower limit of normal
14. Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX
15. Antithrombin levels below the normal reference range at screening
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 and/or randomised in 
violation of the randomisation 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
7. Loss of efficacy due to neutralizing antibodies
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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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 with inhibitors, is that 
there is a significant unmet medical need in this patient population for
1. A more effective treatment and 
2. A treatment which reduces treatment burden. 
In addition to this, since most of these patients are likely to have been treated and therefore familiar 
with eptacog alfa (rFVIIa) on-demand treatment, this trial population is considered the most suitable 
for assessing the safety of administering eptacog alfa (rFVIIa) to patients in whom plasma TFPI 
levels are inhibited. 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 are to be 
confirmed.  
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Date:
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Version:
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7
Milestones
Planned duration of recruitment period (FPFV-LPFV): 28 weeks
Planned FPFV: 
16-Aug-2017
Planned FPFT: 
30-Aug-2017
Planned LPFV: 
28-Feb-2018
Planned LPLV: 
23-Oct-2019
The total duration of concizumab treatment in this trial is 76 weeks for an individual patient
randomised to concizumab prophylaxis treatment at visit 2.
The total duration of concizumab treatment in the trial is 52 weeks for an individual patient 
randomised to eptacog alfa (rFVIIa) on-demand treatment at visit 2.
EOT is defined as last patient last visit (LPLV).
Recruitment
The screening and randomisation 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 randomisation can be randomised in a 2:1 allocation to either the concizumab 
or the comparator arm within the timelines specified in the flow chart (see Section 2).
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and 
clinicaltrials.jp. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure,
how-we-disclose-trial-information, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors (ICMJE), 12
the Food and Drug Administration Amendment Act (FDAAA), 13 European Commission 
Requirements, 14 15 and other relevant recommendations or regulations. If a patient requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the patient. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
protocol LPFT (visit 2) + 24 weeks corresponding to 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.13
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8
Methods and assessments
Assessments to be performed at the scheduled and at the unscheduled visits in the trial are described 
in this section, Figure 8–1, Figure 8–2 and in Section 2.  
Figure 8–1Visit schedule – concizumab arm.
Figure 8–2Visit schedule – eptacog alfa (rFVIIa) arm later switching to concizumab.
8.1
Visit procedures
For each patient the trial can consist of the following scheduled parts and visits depending upon
which arm the patient is randomised to:
Screening Part:
∀
Visit 1 (screening visit)
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Main Part:
∀
Visit 2 (Randomisation and 1st treatment visit with concizumab at site for patients 
randomised to the concizumab-arm)
∀
Home treatment with concizumab daily
∀
Visit 3 (treatment and PK-visit with concizumab and eptacog alfa (rFVIIa) at site only for 
patients randomised to the concizumab-arm - phone visit for patients randomised to the 
eptacog alfa (rFVIIa) on-demand arm)
∀
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 – 1st treatment 
visit with concizumab at site for patients randomised to the eptacog alfa (rFVIIa) arm)
Extension Part:
∀
Visit 9.1 (treatment and PK-visit with concizumab and eptacog alfa (rFVIIa) at site ONLY
for patients randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 9.2 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 10 (Assessment visit, patients treat themselves at home)
∀
Visit 10.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 11 (Assessment visit, patients treat themselves at home)
∀
Visit 11.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on demand-arm)
∀
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, no treatment at home before the visit and End of Treatment)
Follow-up Part:
∀
Visit 17 (Assessment visit and End of Trial)
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Unscheduled Part: 
∀
Unscheduled visits can occur e.g. for dispensing of trial product, dose escalation or 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 and eptacog alfa (rFVIIa) administration, 
NovoPen®4, usage of eDiary, completion of the PRO etc.
8.1.1
Informed consent, genotyping and long-term storage consent
Informed consent must be obtained before any trial related activity at visit 1, 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/or 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 patients screening log, a patients identification code list and a patients 
enrolment log. Only patients who have signed the informed consent form should be included on the 
logs. The patients screening log and patients 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. 
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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 to 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 ePRO 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.
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Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
51 of 137
8.1.7
Visit 1 (Screening part)
Informed consent must be obtained before any trial related activity, see Section 18.2
All assessments to be performed at screening are listed in Section 2.
After informed consent is given, patients will be asked to complete the ePRO questionnaires before 
any other trial related activities are performed according to Section 8.6.1:
∀
Hemo-TEM,
∀
VERITAS-Pro® or VERITAS-PRN®
Assessment results from physical examination and body measurements, as well as measurements of 
vital signs, urinalysis and 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.
For bleeding episodes that occur in the period from Screening visit (Visit1) to randomisation visit 
(Visit 2), information about the bleeding episode is to be entered in the eCRF at visit 2. 
Patients will be provided with eptacog alfa (rFVIIa), trial injection kits and direction for use (DFU) 
to cover the potential eptacog alfa (rFVIIa) treatment after the screening part of the trial and 
investigator will ensure that the patients are capable of treating themselves with eptacog alfa 
(rFVIIa).
Dispensing of eptacog alfa (rFVIIa) should be performed in IWRS.
The patient must 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 at visit 1, visit 2 and visit 9
During visit 1 and visit 2 and visit 9 (comparator arm) 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 (if they are randomised to concizumab) 
or at visit 9 (if they are randomised to eptacog alfa (rFVIIa) and switching to concizumab at visit 9). 
Furthermore, patients must be instructed and trained in the importance of reporting all the home 
treatments with concizumab, details of the bleeding episodes and the eptacog alfa (rFVIIa) 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
52 of 137
treatments associated with these bleeding episodes in the eDiary. The patient should call the site if 
bleeding episodes occur between visit 1 and 2 for the site to register in the eCRF.
Patients should be trained on how to recognize signs of thromboembolic events, so that the patient
contacts the site without delay.
The site and patient can arrange for additional training whenever needed during the remaining time 
of the trial. 
8.1.9
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 (concizumab arm) or when the 
patient is comfortable self-administrating trial product subcutaneously (concizumab) and 
intravenously (eptacog alfa (rFVIIa)).
8.1.10
Staggered recruitment
Dosing of eptacog alfa (rFVIIa) in the first 4 patients randomised to the concizumab arm will be 
staggered until the 4th patient randomised to the concizumab arm has completed visit 3 without any 
safety concerns raised by the investigator. Until this time point, enrolled patients will not be 
randomised until the previous patient randomised to concizumab has completed visit 3 without any 
safety concerns raised by the investigator. Novo Nordisk will as sponsor control and communicate 
the staggered recruitment process. 
8.1.11
Treatment period – Main part
8.1.11.1
Visit 2 (Randomisation)
Visit 2 should be scheduled 14 to 28 days after visit 1. The date of visit 2 will be considered as trial 
day 1.
It is important to verify the in/exclusion criteria again and review central laboratory tests from 
screening. 
The patients must be in a non-bleeding state and should not have received any bypassing agent 
(e.g., eptacog alfa (rFVIIa), FEIBA®) for treatment of bleeding episodes within a period of 24 hours 
(for eptacog alfa (rFVIIa)) or 48 hours (for FEIBA®) prior to the potential first concizumab 
administration (depending on the treatment arm). After visit 2 only treatment with eptacog alfa 
(rFVIIa) for bleeding episodes is allowed.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
53 of 137
∀
Hemo-TEM
∀
SF-36v2 
∀
SDS
∀
TSQM 
∀
SIAQ-ISRQ
All assessments listed in 2, must be performed before potential administration of concizumab
(depending on the treatment arm). Vital signs must be assessed both before (within 1 hour) and after 
concizumab administration. Pre-dose blood sampling must take place no more than 1 hour before 
concizumab administration. 
Assessment results from concomitant medication, vital signs, body measurement (weight only) and 
details of adverse events must be entered into the eCRF.
A randomisation and dispensing call must be performed in the IWRS. 
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 Trial Materials Manual (TMM) on 
basis of the patient’s current body weight. Investigator will communicate the daily dose of 
concizumab to the patient and record the dose for the coming home treatment period in the eCRF.
For patients randomised to the concizumab arm, the first treatment with the loading dose of 
concizumab will be given. 
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.
At the visit the patient will be provided with trial product concizumab and/or eptacog alfa (rFVIIa)
and trial injection kits and an eDiary device to be able to conduct and report home treatment and 
bleeding episodes until next scheduled visit.
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa) during the 
trial as instructed by the investigator. Drug accountability must be performed for eptacog alfa 
(rFVIIa), if applicable according to section 9.4.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site. If the patient on concizumab needs to treat a 
bleeding episode with eptacog alfa (rFVIIa) at home, then he must visit the site immediately after. 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
54 of 137
8.1.11.2
Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and PK visit for 
concizumab arm)
eptacog alfa (rFVIIa) on-demand arm:
Visit 3 for eptacog alfa (rFVIIa) on-demand arm is a phone call scheduled 7 days after visit 2 (with 
a visit window of +1 day).
All relevant assessments listed in Section 2, must be discussed.
Assessment results from concomitant medication and details of adverse events must be entered into 
the eCRF.
concizumab arm:
Visit 3 is to be scheduled 7 days after visit 2 (with a visit window of +1 day) and the visit takes two 
days. 
All assessments are listed in Section 2, and must be performed accordingly and recorded in 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:
∀
PGI-C
∀
Hemo-TEM
Pre-dose blood sampling must take place no more than 1 hour before eptacog alfa (rFVIIa)
administration. Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa) dosing.
eptacog alfa (rFVIIa) should be administered to the trial patients at the site under the surveillance of 
medically trained trial site staff. Patient should continue his daily concizumab injections regardless 
of eptacog alfa (rFVIIa) administration. 
Samples for thrombin generation, haematology, coagulation parameters and FVII ELISA are taken 
pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 10 min (±2 min), 1h 
(± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (±20 min) and 24h (±20 min). 
The investigator must ensure all assessments are performed as described in Section 2, Investigator 
is requested to conclude after 24 hours if it is safe for the patient to continue in the trial and record 
the conclusion in the eCRF before next dose with concizumab is given the day after. 
Recruitment of the first four patients will be staggered according to section 8.1.9.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
55 of 137
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visits the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until the next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site. 
8.1.11.3
Visit 4, 5, 6, 7 and 8
Patients should treat themselves at home according to their individual dosing schedule regardless of 
when visits 4, 5, 6, 7 and 8 are scheduled. 
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 will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
PGI-C
∀
Hemo-TEM
All assessments are to be performed according to Section 2, and the assessment results from 
concomitant medication, vital signs, body measurement (weight only) and details of adverse events 
must be entered into the eCRF.
Investigator must perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the e-Diary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must, for patients randomised to concizumab arm at visit 2, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF. 
A dispensing call must be performed in the IWRS.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
56 of 137
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visits the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until the next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
At visit 8 patients should be reminded that treatment with concizumab (concizumab arm) must take 
place after the blood sampling at visit 9.
8.1.11.4
Visit 9
Visit 9 is to be scheduled on trial day 169 (24 weeks) with a visit window of ±7days.
Patients randomised to eptacog alfa (rFVIIa) on-demand treatment at visit 2 will now be switched to 
concizumab treatment. At this visit the first treatment (loading dose) with concizumab will take 
place. 
Treatment with concizumab must take place after the blood sampling for both the patients on the 
concizumab arm as well as patients on the eptacog alfa (rFVIIa on-demand) arm.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
PGI-C
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments are to be performed according to Section 2, and the assessment results from 
physical examination, concomitant medication, vital signs, body measurement (weight only) and 
details of adverse events must be entered into the eCRF.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
57 of 137
Investigator must perform compliance check of treatment and reporting of bleeding episodes 
through the available access to collected data from the e-Diary. Based on the assessment of any 
spontaneous bleeding episodes the investigator must, for patients randomised to concizumab arm at 
visit 2, evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in Section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 and eptacog alfa 
(rFVIIa) during the trial as instructed by the investigator. Drug accountability must be performed 
for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12
Treatment period – Extension part
8.1.12.1
Visit 9.1 (PK visit and ONLY patients previously on the eptacog alfa (rFVIIa)
on-demand arm)
Visit 9.1 is to be scheduled on trial day 176 (25 weeks) with a visit window of +1 day and the visit 
takes two days. 
All assessments are listed in Section 2, and must be performed accordingly and recorded in the 
eCRF.
Pre-dose blood sampling must take place no more than 1 hour before eptacog alfa (rFVIIa)
administration. Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa) dosing.
eptacog alfa (rFVIIa) should be administered at the site under the surveillance of medically trained 
trial site staff. Patient should continue his daily concizumab injections regardless of eptacog alfa 
(rFVIIa) administration. 
A dispensing call must be performed in the IWRS.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
58 of 137
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until next scheduled visit.
Samples for thrombin generation, haematology, coagulation parameters and FVII ELISA are taken 
pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 10 min (±2 min), 1h 
(± 10 min), 3h (± 10 min), 6h (± 10 min), 9 h (± 10 min) and 12h (±20 min) and 24h (±20 min). 
Investigator is requested to conclude after 24 hours if it is safe for the patient to continue in the trial 
and record the conclusion in the eCRF before the next dose of concizumab is given the day after. 
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.2
Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
Visit 9.2 is to be scheduled on trial day 197 (28 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
59 of 137
current body weight. Investigator will communicate the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.3
Visit 10
Visits 10 is to be scheduled on trial day 225 (32 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (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.
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
60 of 137
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.4
Visit 10.1 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
Visit 10.1 is to be scheduled on trial day 253 (36 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
61 of 137
8.1.12.5
Visit 11
Visit 11 is to be scheduled on trial day 281 (40 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site. 
8.1.12.6
Visit 11.1 (ONLY patients previously on the rFVIIa on-demand arm) 
Visit 11.1 is to be scheduled on trial day 309 (44 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
62 of 137
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.7
Visit 12, 13, 14 and 15
Visits 12, 13, 14 and 15 are to be scheduled on trial day 337 (48 weeks), 393(56 weeks), day 449 
(64 weeks) and day 505 (72 weeks) respectively with a visit window of ±7 days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
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At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site. 
At visit 15 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 16.
8.1.12.8
Visit 16
Visit 16 is to be scheduled on trial day 533 (76 weeks) with a visit window of ±7days. Further visit 
16 should be scheduled to be conducted at the last day of treatment with concizumab.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs and details of adverse events must be entered into the eCRF.
Investigator must 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 patients can be treated with eptacog alfa (rFVIIa) or other 
products at the discretion of the investigator to treat eventual bleeding episodes. Only eptacog alfa 
(rFVIIa) will be provided by Novo Nordisk during this period.  
If necessary, a dispensing call must be performed in the IWRS. At the visit the patient will be 
provided with eptacog alfa (rFVIIa) and trial injection kits to be able to conduct home treatment 
until next scheduled visit. 
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. NovoPen®4 must be returned.
Drug accountability must be performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes) arise 
after he has left the site. 
8.1.13
Visit 17 (End of trial) - Follow-up part
Visit 17 is to be scheduled on trial day 589 (84 weeks) with a visit window of minus 7 days.
All assessments are listed in Section 2, 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 must perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data. Patients should be asked if their female partner has become 
pregnant, see Section 12.5.1.
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa), eDiary 
device and Trial card. Drug accountability must be performed for eptacog alfa (rFVIIa).
End-of-Trial information must be entered in the End-of-Trial form in the eCRF.
Completion or treatment discontinuation (if the trial is not completed) session should be performed 
in IWRS, see Section 10.
8.1.14
Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Section 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 Section 
2. 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 eptacog alfa (rFVIIa), concizumab including dose escalation, see Section 5.3.3.
∀
Surgery
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
Status:
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EudraCT no.: 2016-000510-30
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∀
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, 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 with inhibitors which is 
to be reported in the haemophilia medical history section of the eCRF.
Medical history is a medical event, other than haemophilia, 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, see Section 6.2 and 6.3.
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.  
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 the concizumab and eptacog alfa 
(rFVIIa), which is taken during the trial, including the screening and follow-up period.
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CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
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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)
o
Classification of haemophilia type (haemophilia A/B) 
o
Severity of haemophilia (severe, moderate or mild)
o
Aetiology of haemophilia (congenital or acquired)
∀
Family history of
o
Haemophilia (Y/N)
o
Inhibitors (Y/N)
o
Prothrombotic disorders (Y/N)
o
Thromboembolism (Y/N)
∀
Inhibitor tests taken (Y/N)
o
Date (dd-mmm-yyyy) 
o
Result (BU)
∀
Cut-off for positive inhibitor result
∀
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
∀
Dosing frequency during prophylaxis 
∀
Approximate dose to treat a bleeding episode 
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Protocol
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Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
Status:
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∀
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 eptacog alfa (rFVIIa) 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 during visits to 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 eptacog alfa (rFVIIa) injection occurring outside the trial site should be entered in the eDiary by 
the patient, Section 13.3.
The completed eDiary is considered source data.
For reporting of bleeding episodes as AEs/SAEs, please refer to Section 12. In case of life-
threatening bleeding episode, it should always be reported as an SAE, see Section 12.1.2.
The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with eptacog alfa (rFVIIa):
∀
Start date and time
∀
Stop date and time (see Table 8–1)
∀
Anatomical location
o
Position (left/right)
∀
Cause (see Table 8–2)
o
spontaneous
o
traumatic
o
post-surgical
∀
Severity (see Table 8–3)
o
mild/moderate, severe
o
classification and recording of severe bleeding episodes is the responsibility 
of the investigator
∀
Treatment, if any 
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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o
eptacog alfa (rFVIIa) administration or other product administration 
o
dose, date, stop time 
o
other medicinal treatments related to the bleeding episode (pain relieving 
medication, non-medical therapy etc.)
o
record as concomitant medication  (section 8.2.3)
∀
Symptoms during bleeding episode(s)
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 12.1.1 and 12.1.2.
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 do not fall under this category
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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Table 8–3 Definition of bleeding episode severity and treatment recommendation
Category
Definition
Treatment recommendation
Mild/Moderate Examples: uncomplicated musculoskeletal 
bleeding episodes (joint, muscular bleeding 
episodes without compartment syndrome), 
mucosal- or subcutaneous bleeding episodes
Mild/moderate bleeding episodes may occur 
in other anatomical locations  
Mild/moderate bleeding episodes: 
∀
patient must call the site between 
visit 1-2 and visit 3-16 (see 2-3 
and 9-9.1 below)
∀
patient must call the site between 
visit 2-3 or visit 9-9.1 (eptacog 
alfa arm) and if treated at home, 
go to the site immediately after
∀
patient can treat themselves at 
home between visit 16 and visit 
17
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 site immediately if in doubt regarding 
treatment of a bleeding episode and to discuss what other actions may need to be 
taken
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. 
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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Dosing for bleeding episodes with eptacog alfa (rFVIIa) should be documented in the eCRF (visit 1 
to visit 2) and eDiary (visit 2 to visit 17). 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 13.3.
Investigator must instruct the patient not to perform preventive treatment with eptacog alfa (rFVIIa)
after bleeding stop as defined in Table 8–1. 
Investigator must instruct the patient to use eptacog alfa (rFVIIa) as rescue medication to treat 
bleeding episode between visit 2 and visit 16, see Section 5.3.5.
Furthermore investigator must instruct the patient to contact the site when a bleeding episode 
occurs. 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 
eptacog alfa (rFVIIa) as rescue medication) and will record treatment in the 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, breast(s)
∀
Musculoskeletal system
∀
Central and peripheral nervous system
∀
Skin
∀
Lymph node palpation
The investigator must evaluate the results of the examination and classify them as either:
∀
Normal or abnormal
∀
If abnormal the investigator must: 
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Date:
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1RYR1RUGLVN
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Version:
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UTN: U1111-1179-2925
Status:
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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 8.2.2)
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 one decimal)
The body weight assessed at each visit will be used for calculation 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 in a 
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 visits 2 and visit 3 (for patients randomised to concizumab) and at visit 9 and visit 9.1
(for patients initiating concizumab treatment at visit 9), the measurements are also performed after 
concizumab administration.
The investigator must evaluate the vital signs 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
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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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 8.2.2
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 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 some 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 Section 12.
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:
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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
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Injection site reaction 
Investigation of injection site reactions will be performed locally at all visits after visit 2 until visit 
16 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 at 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.
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Date:
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1RYR1RUGLVN
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Version:
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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 725 mL will be taken from each patient on the concizumab 
arm and 625 mL from each patient on the eptacog alfa (rFVIIa) arm.
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 at all visits and 
coagulation parameters at visits 3 and 9.1 are to be shipped for analysis at central laboratories or 
further distribution to special laboratories. Haematology samples (all visits) and coagulation 
parameters (visit 3 and 9.1) are to be analysed locally. Ports cannot be used for blood sampling.
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 SI units.
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 
clinically 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/FIX activity, FVIII/FIX inhibitor 
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Date:
15 March 2017
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Trial ID: NN7415-4310
Version:
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Status:
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test, Thrombin generation, Free TFPI (TFPI not bound to concizumab), concizumab concentration 
in plasma, anti-concizumab antibodies, Total TFPI and FVII antigen concentration.
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 8.2.3 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 antibodies).
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report (CTR).
Antibody samples and human biosamples, 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 collected at all visits. 
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa): 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9 h (± 
10 min), 12h (± 20 min) and 24h (± 20 min).
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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Protocol
CONFIDENTIAL
Date:
15 March 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
Status:
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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 (TFPI not bound to concizumab) will be collected at all visits, pre-dose at visit 2 and 3 
(concizumab arm) and visit 9 and 9.1 (eptacog alfa (rFVIIa) arm). 
The free TFPI assay is an enzyme immunoassay measuring levels of free TFPI from
 
 (named and referred to 
 TOTAL TFPI) and will be used for PD assessments. 
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.
The investigator must evaluate the results and record the outcome as:
∀
Normal or abnormal
∀
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. 
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa), 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9 h (± 
10 min), 12h (± 20 min) and 24h (± 20 min).
∀
Haemoglobin 
∀
Erythrocytes (cell count)
∀
Thrombocytes (platelet count)
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∀
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
Biochemistry samples are to be sampled and analysed centrally at all visits.
∀
Creatinine 
∀
Albumin 
∀
Bilirubin; total, direct, indirect
∀
Aspartate aminotransferase (AST) 
∀
Alanine aminotransferase (ALT)
∀
Gamma glutamyltransferase (GGT) 
∀
Alkaline phosphatase
∀
C-reactive protein (CRP)
The investigator must evaluate the results of the examination 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/FIX activity
FVIII/FIX activity is to be sampled and analysed centrally at visit 1, visit 9 and visit 16. 
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∀
FVIII activity level (IU/mL) or
∀
FIX activity level (IU/mL)
8.5.2.5
Coagulation parameters
Coagulation parameters will be performed centrally at all visits with the exception of visit 3 and 
visit 9.1 where the PT, APTT, and Fibrinogen will be performed locally.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa) at 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9h 
(±10 min) and 12h (±20 min) and 24h (± 20 min) locally.
∀
Fibrinogen – centrally and locally
∀
Prothrombin time (incl. INR) (PT) centrally and locally
∀
D-dimer – only centrally
∀
Prothrombin fragment 1+2 – only centrally
∀
Activated partial thromboplastin time (APTT) – centrally and locally
∀
Antithrombin (AT) activity – only centrally
The investigator must evaluate the results of the examination 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)
Coagulation parameters analysed locally are to be entered into the eCRF.
8.5.2.6
FVIII/FIX inhibitors
FVIII/FIX inhibitor level will be measured by the Nijmegen method at visit 1, visit 9 and visit 16. 
∀
FVIII inhibitors (BU) or
∀
FIX inhibitors (BU)
8.5.2.7
Anti-concizumab antibodies
Samples for the determination of anti-drug antibodies collected during the treatment period must be 
drawn at all visits and prior to administering concizumab at visit 2 and 3 (concizumab arm) and 
visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
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Date:
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Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
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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.
Analysis for ADA will be done 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 antibodies assay
∀
Specificity assay (Anti-concizumab antibodies cross reacting with IgG4 backbone, CDR 
region or S241P mutation) 
∀
Anti-concizumab neutralising antibodies assay
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. 
Neutralising antibodies will be analysed and reported at the EOT. A detailed description of the 
assay methods will be included in the antibody analysis report at the end of the trial.
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 
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Version:
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tryptase measurement is necessary 1-2 weeks after the immediate severe hypersensitivity reaction 
due 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 collected at all visits except at screening only for the concizumab arm. 
Samples will be collected pre-dose at visit 2 and 3 for concizumab arm and visit 9 and 9.1 for 
eptacog alfa (rFVIIa) arm) and visit 16 for both arms. 
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 
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Date:
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Version:
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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
FVII ELISA
FVII ELISA will be collected at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) pre-
dose eptacog alfa (rFVIIa) and post-dose at 10 min (±2 min), 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 eptacog alfa (rFVIIa) administration.
FVII in plasma will be quantified using a validated enzyme-linked immunosorbent assay (ELISA).
The FVII ELISA will detect the total sum of FVII in a sample, including endogenous FVII, eptacog 
alfa (rFVIIa) and FVII in complex with other molecules e.g. antithrombin. The ELISA has been 
validated for measuring FVII in human citrated plasma samples. Validation follows current 
guidelines for bioanalytical method validation. Bioanalytical data will be reported in a bioanalytical 
report.
8.5.2.10
Total TFPI
Total TFPI ELISA will be collected at all visits. Samples will be collected pre-dose at visit 2 and 3 
(concizumab arm) and visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
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 a 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.
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, see Section 2. 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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Date:
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Version:
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UTN: U1111-1179-2925
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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. Plasma 
and serum is taken at visit 1 and 17. DNA for genotyping is only taken at visit 1.
8.6
Other assessments
8.6.1
Patient reported outcomes 
A newly developed disease-specific electronic PRO (ePRO) the Hemophilia Treatment Experience 
Measure (Hemo-TEM) - is being validated in this trial. In order to assess the psychometric 
properties of Hemo-TEM, other questionnaires will be provided; see further appendix 1.
The following ePRO questionnaires will be used in the trial:
∀
Hemophilia Treatment Experience Measure (Hemo-TEM)
∀
Validated Hemophilia Regimen Treatment Adherence Scale - Prophylaxis (VERITAS-Pro®)
or Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS-PRN®) 16
∀
36-Item Short Form Health Survey (SF-36v2) (4 week recall) 17
∀
Patient’s Global Impression of Change (PGI-C)
∀
Sheehan Disability Scale (SDS) 18
∀
Treatment Satisfaction Questionnaire for Medication (TSQM, version II) 19 20 21
∀
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)22
The ePROs 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 3 (PGI-C, Hemo-TEM)
∀
visit 4 (PGI-C, Hemo-TEM)
∀
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, SIAQ-ISRQ)
∀
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ) 
∀
visit 16 (Hemo-TEM, SF-36v2, SDS, TSQM, 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) or VERITAS-PRN® (if 
the patient at baseline receives on-demand treatment).
At visit 2: before any visit-related activities all patients should complete Hemo-TEM, SF-36v2, 
SDS, TSQM and SIAQ-ISRQ.
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Date:
15 March 2017
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Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
Status:
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At visit 3-8: 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 visits 9, 10 and 16. 
∀
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. 
Exception: Patients randomised to eptacog alfa (rFVIIa) on-demand should not complete the 
ePRO at visit 3 as this is a phone visit.
At visit 9 if the patient has responded “0” or “2” in the PGI-C at all previous visits, the patient 
should complete PGI-C. All patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and 
SIAQ-ISRQ.  
At visit 10 and 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and SIAQ-
ISRQ.
The investigator must check the ePROs for potential AEs and SAEs. The completed ePROs should 
be transmitted at each visit to the PRO database by the Investigator.
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 documented in the medical record.
8.6.2.1
Concizumab and NovoPen®4
Direction for use (DFUs) will be available as a 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 the 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 DFUs .
8.6.2.2
eptacog alfa (rFVIIa)
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. 
The following should be emphasised for eptacog alfa (rFVIIa):
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∀
eptacog alfa (rFVIIa) should be slowly injected intravenously over 2 to 5 minutes
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 eptacog alfa (rFVIIa) treatments 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 duplicate 
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 EOT.
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 eptacog alfa (rFVIIa) 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 of the importance of following the instructions given including 
taking the trial products as prescribed.
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Version:
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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 for the concizumab arm 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 eptacog alfa (rFVIIa) 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. 
Drug accountability will be performed and will be used to assess patient compliance together with 
the patients’ 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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Date:
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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 TMM. 
The trial product, concizumab B, appears as clear to slightly opalescent and colourless to slightly 
yellow. The trial product must not be used if it contains visible particles or discoloration.
The reconstituted eptacog alfa (rFVIIa) solution appears clear and colourless. Do not use the 
reconstituted solution if it contains visible particles or if it is discoloured.
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)
100 mg/mL
Solution for injection
s.c. injection
3 mL cartridge
eptacog alfa
(IMP a and NIMP b)
5 mg/vial
Powder for solution
for injection
i.v. injection
Vial
histidine 5 mL
N/A
Solvent for solution 
for injection
i.v. injection
prefilled syringe
a Investigational Medicinal Product (IMP) given as IMP for a single dose at visit 3 and 9.1.
b Non-Investigational Medicinal 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. It will be labelled in accordance with the EMA directive on medical devices annex I 23
and similar national legislation. A description of how to use the device is given in the DFU.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 24, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation. 
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Version:
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The investigator must document that DFUs are given to the patient orally and in writing at the first 
dispensing visit (see 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 (2oC-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)
eptacog alfa
5mg
Store between 2oC-25oC  
Do not freeze
Protect from light
For single use
Do not freeze
Protect from light
To be used immediately 
after reconstitution
If not used 
immediately, store in 
refrigerator (2oC-8oC)
for up to 3 hours
histidine 5 mL
Store between 2oC-25oC 
Do not freeze
Protect from light
For single use
N/A
a In-use time for concizumab starts when first dose is administered from an individual cartridge and for eptacog alfa
(rFVIIa) 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.
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 (concizumab and eptacog alfa (rFVIIa) 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 histidine which 
should be discarded at home and not accounted for.
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Date:
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Version:
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All cartridges (concizumab) and vials (eptacog alfa (rFVIIa)) 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/or 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 product including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Destruction of concizumab and eptacog alfa (rFVIIa) 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 DFUs
∀
For eptacog alfa (rFVIIa) reconstitution and administration: Trial Injection Kit and DFU
Only needles and trial injection kit 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
∀
Randomisation
∀
Medication arrival
∀
Dispensing
∀
Dispensing verification
∀
Treatment discontinuation 
∀
Completion
∀
Drug accountability
∀
Data change
IWRS user manuals will be provided to each trial site.
11 Randomisation procedure and breaking of blinded codes
11.1
Randomisation 
Randomisation will be handed by the IWRS. 
All patients included in the screening period and eligible for the trial will enter the trial and be 
randomised at visit 2 in a 2:1 allocation to either concizumab prophylaxis arm or eptacog alfa 
(rFVIIa) on-demand arm.
11.2
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 
∀
Mild – no or transient symptoms, no interference with the patient’s daily activities
∀
Moderate – marked symptoms, moderate interference with the patient’s daily activities
∀
Severe – considerable interference with the patient’s daily activities; unacceptable
∀
Causality 
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Relationship between an AE and the relevant trial product(s): 
∀
Probable - Good reason and sufficient documentation to assume a causal relationship
∀
Possible - A causal relationship is conceivable and cannot be dismissed
∀
Unlikely - The event is most likely related to aetiology other than the trial product
∀
Final outcome 
∀
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
∀
Recovering/resolving - The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the trial 
or has died from another AE
∀
Recovered/resolved with sequelae - The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE
∀
Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged or the outcome is not known
∀
Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported 
as an SAE
∀
Unknown - This term is only applicable if the patient is lost to follow-up
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-threatening a experience
∀
In-patient hospitalisation b or prolongation of existing hospitalisation
∀
A persistent or significant disability or incapacity c
∀
A congenital anomaly or birth defect
∀
Important medical events that may not result in death, be life threatening a or require 
hospitalisation b 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 SAE d
a. The term “life threatening” in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
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b. The term “hospitalisation” is used when a patient: 
∀
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay or 
∀
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a patient’s ability to conduct normal life functions (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 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 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
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Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1
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, see Section 8.4.5.2
Injection site reactions: 
Any injection site reaction symptom must be recorded on the AE form and the injection site 
reaction form.
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 type 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 will be performed. 
Definition of anaphylaxis (25)
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. dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow [PEF], hypoxemia)
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b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.
hypotonia [collapse], syncope, incontinence)
∀
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. dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
∀
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 treating physician. If according to the investigators judgement, 
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 Events 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:
∀
Platelet count (>100 × 109/L = 0, <100 × 109/L = 1, <50 × 109/L = 2)
∀
Elevated D-dimer (no increase = 0, moderate increase = 2, strong increase = 3)
∀
Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
∀
Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
∀
Calculate score: ≥5 compatible with overt DIC
B) Myocardial infarction is defined according to the “Third Universal Definition of
Myocardical Infarction” (26)
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:
∀
Symptoms of ischemia
∀
New or presumed new significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB)
∀
Development of pathological Q waves in the ECG
∀
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality
∀
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.
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C) Definition of pulmonary embolism:
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 embolism
(27).
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” (28).
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 “Haemorrhagic Infarction”).
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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.
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. A Transient ischemic attack 
(TIA) is a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal 
ischemia, without acute infarction (29).
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 DVT in the lower
extremities27. 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, 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 (30).
12.1.7
Technical complaints
A technical complaint is any written, electronic or oral communication that alledges 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 the pen and the 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 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.
When eptacog alfa (rFVIIa), NovoSeven® is used as IMP, expectedness should be performed 
according to the Company Core Data Sheet (CCDS).
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
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 (eptacog alfa (rFVIIa)) 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. 
∀
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 AEs. 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.
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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
∀
Eptacog alfa (rFVIIa) 5 mg/vial, powder for solution for injection in a vial 
∀
Histidine 5 mL, solvent for solution for injection in a 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.
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, AESI 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
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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 
Centre, 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.
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 with concizumab at visit 2 or 
visit 9 depending on the arm). At the last scheduled visit (visit 17), 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.
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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: 
∀
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 newborn 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 have not been investigated in clinical trials.
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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 
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. 
∀
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)
will decide if further dosing of any patients in the clinical trial programme 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 
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of the patients and to evaluate the benefit-risk balance. The DMC will have access to the 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.
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:
∀
Pregnancy forms
∀
Technical complaint forms  
∀
AE forms 
∀
Safety information forms
The paper version of the technical complaint form, AE form, and safety information form must only 
be used to ensure timely reporting when/if the electronic CRF is unavailable.
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) 
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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.
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 eptacog alfa 
(rFVIIa)). 
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 EOT visit.
All data entered will be transferred from the device to an electronic database, where it is kept as a 
certified copy of the source data. Data entered in the device will upon confirmation of a successful 
back-up be deleted from the device.
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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.
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 Request Correction (DRC) must be submitted to 
the eDiary vendor. An audit trail will be maintained.
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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 
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. 
Monitoring visits should be scheduled as frequently as needed to support the first 6 patients 
recruited in the trial. 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 
ePROs and eDiaries are completed and reviewed by the investigator at the relevant scheduled visits 
and needed action has been taken and documented, if any.
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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
∀
Demography, see section 8.2.1
∀
Date of visit
Monitors will review the patient’s medical records and other source data (e.g. the 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.
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 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.
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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 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 archiving containing the 
electronic Investigator Trial Master File (eITMF) for each trial site. These CDs or other relevant 
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 FDA 21 CFR Part 11 
and ICH E6 (EU directive for personal data protection).1 31
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.
The eDiary and ePRO 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 31After trial completion, each
trial site will be supplied with long-life CDs. These CDs will contain site-specific patient records
including the patient’s eDiaries and audit trail including any data additions and corrections made on
each form. The eDiary vendor will furthermore retain and securely store copies of all archived
documents and data for 15 years or as required by local data retention laws for trial data.
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17 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 
17–1 for further information. 
Data from when the on-demand treated patients are transferred to concizumab s.c. prophylaxis will 
not be included in this evaluation. Observations from the extension part in the on-demand arm will 
be summarised separately as well as combined with observations from the main part when reporting 
the extension part data.
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 patients with inhibitors. The objective will be 
assessed when the last of the 24 patients has completed 24 weeks of dosing (or has withdrawn 
before that).
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the ABR of all patients in the concizumab group, irrespective of individual dose 
titration, with the ABR of the patients in the on-demand arm using different sets of observations. 
The primary CPoC criterion aims at evaluating the effect of concizumab when given at the last dose 
level reached for the 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 not be included. Since this evaluation disregards a 
subset of data collected post randomisation, the result should be viewed taking into 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 patients in the concizumab arm with 
the ABR of the patients in the on-demand arm using all data collected after randomisation. 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 part as offset and regimen as factor (concizumab vs. on-demand). For each criterion, 
evidence of effect will be concluded if the 95% confidence interval of the treatment ratio is below 1.
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.
17.1
Sample size calculation
The estimand will be defined as the “if all patients had adhered” estimand.
The treatment ratio between prophylactic s.c. concizumab and on-demand i.v. eptacog alfa (rFVIIa)
during at least 24 weeks for all randomised patients if all patients adhered to trial drug and did not 
initiate alternative treatment options.
This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand i.v. eptacog alfa 
(rFVIIa) under similar conditions as observed in this trial.
The sample size calculation has been determined based on this estimand and the CPoC criteria 
taking the small patient population into account, while also aiming for an acceptably narrow 95% 
confidence interval for the rate ratio. 
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be 
accommodated by 16 patients in the concizumab arm and 8 in the comparator arm. 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, annual bleeding rates 
of 24 and 6 are assumed for the on-demand patients and the end dose concizumab regimen, 
respectively. Assuming further over-dispersion of 7, the power for concluding superiority of the 
concizumab regimen becomes approximately 80%. 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 17–1Power in superiority comparison between concizumab prophylaxis and on-demand 
treatment under different assumptions of ABR for concizumab and over-
dispersion (assuming on-demand ABR=24).
Power
Over-dispersion (over 6 months)
ABR (concizumab)
6
7
8
6
89%
82%
75%
7
84%
75%
70%
8
77%
69%
66%
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 7.6 for 
the concizumab regimen. This yields a marginal power of approximately 70% 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). In the 
NN7128-1907 trial in inhibitor patients, larger 1-year over-dispersion values of approximately 21 
and 18, respectively, were observed during an initial 3-month on-demand period and a subsequent 
3-month prophylaxis period. It is expected that the variation in the current trial will be smaller, 
partly due to the longer duration of the trial and partly due to an expected more homogenous patient 
population. Another published trial including inhibitor patients, comparing prophylaxis using 
FEIBA® with on-demand treatment, showed 6-month over-dispersion of 4-5 32. On that background, 
an over-dispersion of 7 over the 24 weeks in 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 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 endpoint will be analysed when the main part of trial has been completed.
17.3.1
Estimand and primary statistical analysis
The estimand for the primary endpoint is the “if all patients had adhered” estimand.
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The treatment ratio between prophylaxis s.c. concizumab and on-demand i.v. eptacog alfa (rFVIIa)
during at least 24 weeks for all randomised patients if all patients adhered to trial drug and did not 
initiate alternative treatment options.
This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand  i.v. eptacog 
alfa (rFVIIa) under similar conditions as observed in this trial.
The estimand for the primary endpoint will be estimated using negative binomial regression with 
log of exposure time in main part as offset and regimen as factor, providing an estimate of the ABR 
ratio between regimens (concizumab prophylactic and on-demand eptacog alfa (rFVIIa)) with 
corresponding 95% confidence interval and also actual estimate of the ABR with corresponding 
95% confidence interval for each regimen. 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 estimand will be estimated based on the FAS
and only data collected prior to discontinuation of trial product or initiation of alternative treatment 
options will be used to draw inference. 
17.3.2
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 Δ 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 part 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 concizumab 
prophylaxis no longer is superior to on-demand eptacog alfa (rFVIIa). The results of the primary 
analysis will be considered robust if the tipping point is above what is considered clinically
plausible.
17.3.3
Additional analysis
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 of number of bleeding episodes 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, TFPI value prior to the last s.c. dose 
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administration, peak thrombin generation (nM) , Endogenous thrombin potential  (nMxmin)  and 
velocity index (nM/min).
17.4
Supportive secondary endpoints
17.4.1
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 number of spontaneous bleeding episodes during at least 24 weeks from treatment onset will be 
addressed in terms of the same estimand as for the primary endpoint. The estimand will be 
estimated using the same negative binomial regression model as for the primary endpoint.   
Furthermore, an additional evaluation will be made, where actual concizumab dose is included as 
factors in the model.
The remaining supportive secondary efficacy endpoints will be summarised descriptively by 
treatment regimen. In addition, number of bleeding episodes during 76 weeks of treatment with 
prophylactic concizumab will be analysed using a negative binomial model with log of trial 
duration as offset, providing estimates of the ABR with confidence interval for that particular 
regimen.
17.4.2
Supportive secondary safety endpoints
∀
Number of TEAEs during at least 24 weeks from treatment onset
∀
Number of TEAEs during 76 weeks from treatment onset
∀
Number of TEAEs within 24 hours of rFVIIa administration 
∀
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
∀
Occurrence rate 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
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∀
Change from baseline of APTT during 76 weeks from treatment onset
∀
Change from baseline of anti-thrombin (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.
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.
17.4.3
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.
17.4.4
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 (nMxmin) prior to the last dose administration at 24 
weeks 
o
Endogenous thrombin potential (nMxmin) prior to the last dose administration at 76 
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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17.4.5
Exploratory endpoints
17.4.5.1
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
17.4.5.2
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 VERITAS-Pro® or VERITAS-PRN® after 24 weeks from treatment onset
∀
Change in VERITAS-Pro® or 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
VERITAS-Pro® or VERITAS-PRN®, SF-36v2, SDS and TSQM will be scored according to their 
respective scoring algorithms. Change from visit 2 to visit 9 will be analysed with an ANCOVA 
model including regimen as a factor and baseline score as covariate.
The PRO endpoints will be summarised using descriptive statistics and the remaining 
questionnaires (Hemo-TEM, PGI-C, SIAQ-ISRQ) will be summarised and listed using descriptive 
statistics.
17.5
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. Main part is 
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. 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 CTRs might in such case be issued. A CTR describing results 
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from the main and the 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 100 ng/mL, see Section 3.1.2. Based on these results, it is expected that the 
majority of the patients randomised to the concizumab treatment with 0.15 mg/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. For haemophilia patients with inhibitors 
and who are treated on-demand, expected improved efficacy is considered to be a major benefit in 
participating in this trial. Also, concizumab is administered s.c. and might reduce the burden of 
frequent i.v. injections associated with current treatment options in haemophilia patients with 
inhibitors.
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 several folds higher than the currently anticipated effective plasma 
concentration (mean area under curve [AUC] and Cmax) based on PK modelling.
In a drug–drug interaction study in monkeys, three doses of up to 1 mg/kg of NovoSeven® were 
administered at 2-h intervals, alone or in the presence of a steady state concentration of 
concizumab. Increased concentrations of thrombin–anti-thrombin (TAT) and D-dimer were seen, 
which tended to be additive when both concizumab and eptacog alfa (rFVIIa) were present in 
circulation. No notable clinical observations were made. 
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
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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.
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.
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 the 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 33 34 . 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 35 36, 37.
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.
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18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP 1 and the requirements in the Declaration of 
Helsinki 2.
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.
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 qualified person, 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 CTR. 
∀
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.
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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 
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.
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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 eptacog alfa (rFVIIa)
∀
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 sites outside the US)
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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, 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 GCP 1
applicable regulatory requirements and the Declaration of Helsinki 2. 
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.
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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.
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).
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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 
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 CTR for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the CTR (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 38. 
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-information.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the CTR is available. This includes the right not to release the results of interim 
analyses, because the release of such information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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Version:
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UTN: U1111-1179-2925
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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 38(sometimes referred to as the Vancouver 
Criteria).
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.
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.
Only applicable 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 EOT 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.  
24.2
Retention of human biosamples
This trial will involve collection of human biosamples at visit 1 (screening visit) and at visit 17
(EOT) and these samples are to be stored maximum 15 years from EOT. 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 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 
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participate, while refusing permission for biological specimens to be stored for future exploratory 
analysis.
∀
Human biosamples will be stored at the central laboratory 
∀
1.0 mL citrated plasma, 1.2 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 consortia
∀
The human biosamples will be transferred and stored after the EOT at a designated central 
laboratory
∀
Confidentiality and personal data protection will be ensured during storage after the EOT
∀
The human biosamples may be transferred to other countries (not applicable if local 
regulations prohibit export of human biosamples)
∀
The human biosamples will be destroyed at the latest 15 years from EOT
∀
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
can contact the investigator if they wish to be informed about results derived from stored 
human biosamples obtained from their own body, see 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. Remaining 
blood from the samples already collected may be used for further development of Anti-Drug 
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antibody assays, and will not be reported in this trial. The samples will be stored at a central bio-
repository after EOT and until marketing authorisation approval or until the research project 
terminates, but no longer than 15 years from EOT 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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Version:
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UTN: U1111-1179-2925
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 CTR 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 CTR according to national requirements.
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Date:
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Version:
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UTN: U1111-1179-2925
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 Austria: Arzneimittelgesetz (BGBI. Nr. 185/1983) last amended with  BGBl. 
II Nr. 105/2015
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 research for the person lending 
himself thereto and for indemnification of his beneficiaries, except in case of proof, incumbent on 
it, that the prejudice is not attributable to his fault or the fault of any intervening party, without the 
sponsor’s being entitled to call on acts by a third party or the voluntary withdrawal of the person 
who had initially consented to cooperating in the research”
Only applicable for Poland: Novo Nordisk carries liability for the Trial exclusively in the scope 
defined by the applicable laws and in particular by the Civil Code and the Pharmaceutical Law 
dated 6 September 2001 (uniform version Journal pf Laws of 2008 No. 45 item 271 with 
amendments). In order to support potential claims for liability attributable to the Trial, Novo 
Nordisk and Investigators are covered by the Insurance Policy issued according to applicable Polish 
law.
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Version:
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UTN: U1111-1179-2925
Status:
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27 References
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1RYR1RUGLVN
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Version:
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UTN: U1111-1179-2925
Status:
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human and veterinary use and establishing a European Medicines Agency, article 57. 
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Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et 
al. Second symposium on the definition and management of anaphylaxis: summary report--
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Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7.
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Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third 
universal definition of myocardial infarction. Circulation. 2012;126(16):2020-35.
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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 
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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 
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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 
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Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular 
Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary 
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Version:
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UTN: U1111-1179-2925
Status:
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value of this statement as an educational tool for neurologists. Stroke. 2009;40(6):2276-93.
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of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J 
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inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 
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Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Vasc Biol. 
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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: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
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Protocol
NN7415-4310
A Multi-Centre, Randomised, Open-Label, Controlled Trial 
Evaluating the Efficacy and Safety of Prophylactic 
Administration of Concizumab in Haemophilia A and B 
Patients with Inhibitors
Trial phase: 2
Includes: Protocol Version 1 (15 March 2017); Protocol Amendment no 1 (05 May 2017) for all 
participating countries.
Protocol originator
, Senior International Trial Manager 
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.
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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:
05 May 2017
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Trial ID: NN7415-4310
Version:
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Status:
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Table of Contents Page
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................7
Table of Tables............................................................................................................................................8
List of abbreviations ...................................................................................................................................9
1
Summary............................................................................................................................................15
2
Flow chart ..........................................................................................................................................18
2.1
Visits and assessments ............................................................................................................18
2.2
Explanatory descriptions .........................................................................................................21
3
Background information and rationale for the trial.........................................................................23
3.1
Background information..........................................................................................................23
3.1.1
Haemophilia ..........................................................................................................23
3.1.2
Concizumab...........................................................................................................24
3.2
Rationale for the trial...............................................................................................................27
4
Objective(s) and endpoint(s)..............................................................................................................28
4.1
Objective(s) ............................................................................................................................28
4.1.1
Primary objective...................................................................................................28
4.1.2
Secondary objectives .............................................................................................28
4.2
Endpoint(s) .............................................................................................................................28
4.2.1
Primary endpoint ...................................................................................................28
4.2.2
Secondary endpoints ..............................................................................................28
4.2.2.1
Supportive secondary endpoints .......................................................28
4.2.3
Exploratory endpoints............................................................................................29
4.2.3.1
Exploratory safety endpoints ............................................................29
4.2.3.2
Exploratory patient reported outcome endpoints ...............................29
5
Trial design ........................................................................................................................................31
5.1
Type of trial ............................................................................................................................31
5.1.1
Surgery..................................................................................................................32
5.2
Rationale for trial design .........................................................................................................32
5.3
Treatment of patients...............................................................................................................35
5.3.1
Concizumab arm....................................................................................................36
5.3.1.1
Concizumab prophylactic treatment (main and extension part)..........36
5.3.2
Comparator arm (eptacog alfa (rFVIIa)).................................................................37
5.3.2.1
On-demand treatment (main part).....................................................37
5.3.2.2
Concizumab prophylactic treatment (extension part).........................37
5.3.3
Dose escalation......................................................................................................37
5.3.4
Co-administration of eptacog alfa (rFVIIa).............................................................39
5.3.5
Treatment of bleeding episodes during the trial ......................................................40
5.3.6
Prohibited medication ............................................................................................41
5.4
Treatment after discontinuation of trial product .......................................................................41
5.5
Rationale for treatment............................................................................................................41
6
Trial population .................................................................................................................................42
6.1
Number of patients..................................................................................................................42
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Version:
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6.2
Inclusion criteria .....................................................................................................................42
6.3
Exclusion criteria ....................................................................................................................42
6.4
Criteria for premature discontinuation of trial product .............................................................43
6.5
Withdrawal from trial..............................................................................................................43
6.6
Patient replacement .................................................................................................................44
6.7
Rationale for trial population...................................................................................................44
7
Milestones...........................................................................................................................................45
8
Methods and assessments ..................................................................................................................46
8.1
Visit procedures ......................................................................................................................46
8.1.1
Informed consent, genotyping and long-term storage consent .................................48
8.1.2
Screening log, enrolment log, trial card and patient number....................................48
8.1.3
Screening failures and re-screening........................................................................48
8.1.4
Premature discontinuation of trial product..............................................................49
8.1.5
Withdrawal from trial.............................................................................................49
8.1.6
Review/ evaluation of clinical outcome..................................................................49
8.1.7
Visit 1 (Screening part)..........................................................................................50
8.1.8
Training of patients at visit 1, visit 2 and visit 9......................................................50
8.1.9
Treatment period at home ......................................................................................51
8.1.10
Staggered recruitment ............................................................................................51
8.1.11
Treatment period – Main part.................................................................................51
8.1.11.1
Visit 2 (Randomisation) ...................................................................51
8.1.11.2
Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and 
PK visit for concizumab arm)...........................................................53
8.1.11.3
Visit 4, 5, 6, 7 and 8 .........................................................................54
8.1.11.4
Visit 9 ..............................................................................................55
8.1.12
Treatment period – Extension part..........................................................................56
8.1.12.1
Visit 9.1 (PK visit and ONLY patients previously on the eptacog 
alfa (rFVIIa) on-demand arm) ..........................................................56
8.1.12.2
Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) 
on-demand arm)...............................................................................57
8.1.12.3
Visit 10 ............................................................................................58
8.1.12.4
Visit 10.1 (ONLY patients previously on the eptacog alfa 
(rFVIIa) on-demand arm) .................................................................59
8.1.12.5
Visit 11 ............................................................................................60
8.1.12.6
Visit 11.1 (ONLY patients previously on the rFVIIa on-demand 
arm) .................................................................................................60
8.1.12.7
Visit 12, 13, 14 and 15 .....................................................................61
8.1.12.8
Visit 16 ............................................................................................62
8.1.13
Visit 17 (End of trial) - Follow-up part...................................................................63
8.1.14
Unscheduled Visit..................................................................................................63
8.2
Patient related information/assessments...................................................................................64
8.2.1
Demography ..........................................................................................................64
8.2.2
Concomitant illness and medical history other than haemophilia ............................64
8.2.3
Concomitant medication ........................................................................................65
8.2.4
Details of Haemophilia, Haemophilia treatment and bleed history..........................65
8.3
Efficacy assessments...............................................................................................................66
8.3.1
Bleeding episodes ..................................................................................................66
8.4
Safety assessments ..................................................................................................................69
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
4 of 136
8.4.1
Physical examination .............................................................................................69
8.4.2
Body measurements...............................................................................................70
8.4.3
Vital Signs.............................................................................................................70
8.4.4
Electrocardiogram..................................................................................................71
8.4.5
Adverse events.......................................................................................................71
8.4.5.1
Medication error...............................................................................71
8.4.5.2
Adverse events requiring additional data collection ..........................71
8.5
Laboratory assessments...........................................................................................................73
8.5.1
Laboratory assessments for efficacy.......................................................................74
8.5.1.1
Thrombin generation........................................................................74
8.5.1.2
Free TFPI.........................................................................................75
8.5.2
Laboratory assessments for safety ..........................................................................75
8.5.2.1
Urinalysis.........................................................................................75
8.5.2.2
Haematology....................................................................................75
8.5.2.3
Biochemistry....................................................................................76
8.5.2.4
FVIII/FIX activity............................................................................76
8.5.2.5
Coagulation parameters....................................................................77
8.5.2.6
FVIII/FIX inhibitors.........................................................................77
8.5.2.7
Anti-concizumab antibodies .............................................................77
8.5.2.8
Concizumab ELISA .........................................................................79
8.5.2.9
FVII ELISA .....................................................................................80
8.5.2.10
Total TFPI........................................................................................80
8.5.3
Human Biosamples ................................................................................................80
8.6
Other assessments ...................................................................................................................81
8.6.1
Patient reported outcomes ......................................................................................81
8.6.2
Training.................................................................................................................82
8.6.2.1
Concizumab and NovoPen®4............................................................82
8.6.2.2
eptacog alfa (rFVIIa)........................................................................82
8.6.2.3
eDiary..............................................................................................83
8.6.3
Surgery..................................................................................................................83
8.7
Patient compliance..................................................................................................................83
8.8
Treatment compliance.............................................................................................................84
9
Trial supplies......................................................................................................................................85
9.1
Trial products..........................................................................................................................85
9.2
Labelling.................................................................................................................................85
9.3
Storage....................................................................................................................................86
9.4
Drug accountability and destruction ........................................................................................86
9.5
Auxiliary supplies ...................................................................................................................87
10
Interactive voice/web response system ..............................................................................................88
11
Randomisation procedure and breaking of blinded codes................................................................88
11.1
Randomisation ........................................................................................................................88
11.2
Breaking of blinded codes .......................................................................................................88
12
Adverse events, and technical complaints .........................................................................................89
12.1
Definitions ..............................................................................................................................89
12.1.1
Adverse event ........................................................................................................89
12.1.2
Serious adverse event.............................................................................................90
12.1.3
Non-serious adverse event......................................................................................91
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
5 of 136
12.1.4
Medication errors...................................................................................................91
12.1.5
Adverse events requiring additional data collection................................................92
12.1.6
Adverse Events of special interest ..........................................................................93
12.1.7
Technical complaints .............................................................................................97
12.2
Reporting of adverse events.....................................................................................................97
12.3
Follow-up of adverse events..................................................................................................100
12.4
Technical complaints and technical complaint samples..........................................................101
12.4.1
Reporting of technical complaints ........................................................................101
12.4.2
Collection, storage and shipment of technical complaint samples .........................102
12.5
Pregnancies...........................................................................................................................102
12.5.1
Pregnancies in female partners of male patients....................................................102
12.6
Precautions and/or overdose..................................................................................................103
12.7
Rules for putting enrolment on hold ......................................................................................104
12.8
Committees related to safety .................................................................................................104
12.8.1
Novo Nordisk safety committee ...........................................................................104
12.8.2
Data monitoring committee..................................................................................105
13
Case report forms ............................................................................................................................105
13.1
Corrections to case report forms............................................................................................106
13.2
Case report form flow ...........................................................................................................106
13.3
Electronic diary.....................................................................................................................106
14
Monitoring procedures ....................................................................................................................108
15
Data management ............................................................................................................................109
16
Computerised systems .....................................................................................................................110
17
Statistical considerations .................................................................................................................111
17.1
Sample size calculation .........................................................................................................112
17.2
Definition of analysis sets......................................................................................................113
17.3
Primary endpoint...................................................................................................................113
17.3.1
Estimand and primary statistical analysis .............................................................113
17.3.2
Sensitivity analysis ..............................................................................................114
17.3.3
Additional analysis ..............................................................................................114
17.4
Supportive secondary endpoints ............................................................................................115
17.4.1
Supportive secondary efficacy endpoints..............................................................115
17.4.2
Supportive secondary safety endpoints.................................................................115
17.4.3
Supportive secondary pharmacokinetic endpoints.................................................116
17.4.4
Supportive secondary pharmacodynamic endpoints..............................................116
17.4.5
Exploratory endpoints..........................................................................................117
17.4.5.1
Exploratory safety endpoints ..........................................................117
17.4.5.2
Exploratory patient reported-outcome endpoints.............................117
17.5
Interim analysis.....................................................................................................................117
18
Ethics................................................................................................................................................119
18.1
Benefit-risk assessment of the trial ........................................................................................119
18.2
Informed consent ..................................................................................................................121
18.3
Data handling........................................................................................................................121
18.4
Information to patients during trial ........................................................................................122
18.5
Premature termination of the trial and/or trial site..................................................................122
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
6 of 136
19
Protocol compliance.........................................................................................................................123
19.1
Protocol deviations................................................................................................................123
19.2
Prevention of missing data ....................................................................................................123
20
Audits and inspections .....................................................................................................................124
21
Critical documents...........................................................................................................................124
22
Responsibilities.................................................................................................................................126
23
Reports and publications .................................................................................................................127
23.1
Communication of results......................................................................................................127
23.1.1
Authorship...........................................................................................................128
23.1.2
Site-specific publication(s) by investigator(s).......................................................128
23.2
Investigator access to data and review of results ....................................................................128
24
Retention of clinical trial documentation and human biosamples..................................................129
24.1
Retention of clinical trial documentation ...............................................................................129
24.2
Retention of human biosamples.............................................................................................129
24.2.1
Antibody samples ................................................................................................130
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........132
26
Indemnity statement ........................................................................................................................133
27
References ........................................................................................................................................134
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. 
Appendix 1
Patient Reported Outcomes
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
7 of 136
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. 
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......................................26
Figure 5–1 Schematic diagram of the trial design......................................................................................31
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. ...................................................................................................34
Figure 5–3 Dose escalation for one individual patient in the concizumab arm............................................38
Figure 5–4 Dose escalation for one individual patient in the comparator arm.............................................39
Figure 8–1 Visit schedule – concizumab arm. ...........................................................................................46
Figure 8–2 Visit schedule – eptacog alfa (rFVIIa) arm later switching to concizumab................................46
Figure 12–1 Reporting of AEs ....................................................................................................................99
Figure 17–1 Definition of main and extension part....................................................................................118
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
8 of 136
Table of Tables
Page
Table 5–1
List of products provided by Novo Nordisk .............................................................................35
Table 8–1
Definition of stop of bleeding episode .....................................................................................67
Table 8–2
Definitions of bleeding episodes (cause of bleed) ....................................................................67
Table 8–3
Definition of bleeding episode severity and treatment recommendation ...................................68
Table 9–1
Trial products..........................................................................................................................85
Table 9–2
Storage conditions...................................................................................................................86
Table 17–1 Power in superiority comparison between concizumab prophylaxis and on-demand 
treatment under different assumptions of ABR for concizumab and over-dispersion 
(assuming on-demand ABR=24). ..........................................................................................113
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
9 of 136
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
CCDS
company core data sheet 
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 
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
10 of 136
CPoC
clinical proof of concept
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
DRC
data request correction 
DUN
dispensing unit number
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
eITMF
electronic investigator trial master file
ELISA
enzyme-linked immunosorbent assay
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
11 of 136
EMA
european medicines agency
EOT
end of trial
ePRO
electronic patient reported outcome
eptacog alfa 
the name ‘eptacog alfa (rFVIIa)’ will be used throughout 
the protocol and the product is identical to 
rFVIIa,‘NovoSeven®, and ‘NiaStaseRT®’
ETP
endogenous thrombin potential 
FAS
full analysis set
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
FVIIa
activated coagulation factor VII
FVIII
coagulation factor VIII
FVIII:C
plasma activity of factor VIII
FX
coagulation factor X
FXa
activated coagulation factor X
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GHN
global haemophilia network
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
12 of 136
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
INN
International Non-Proprietary Names for Pharmaceutical 
Substances 
IRB
institutional review board
ISTH
International Society on Thrombosis and Haemostasis
IT
information technology
i.v.
intravenous(-ly)
IWRS
interactive web response system
LBBB
left bundle branch block
LPFV
last patient first visit
LPLV
last patient last visit
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
13 of 136
mAb
monoclonal antibody
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRA
magnetic resonance angiogram
MRI
magnetic resonance imaging
NOAEL
no observed adverse effect level 
NIMP
non investigational medicinal product
PCD
primary completion date 
PD
pharmacodynamics
PEF
peak expiratory flow
PK
pharmacokinetics
PP
per protocol
PRO
patient reported outcome
PT
prothrombin time
Q
Inter compartmental clearance
QA
quality assurance
Q4D
every 4th day
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
14 of 136
eptacog alfa (rFVIIa)
the name ‘eptacog alfa (rFVIIa)’ will be used throughout 
the protocol and the product is identical to ‘NovoSeven®’
sABR
spontaneous annualised bleeding rate
SAE
serious adverse event
SAS
safety analysis set
sBE
spontaneous bleeding episodes
s.c.
subcutaneous(-ly)
SI
international system of units
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse reaction
TAT
thrombin-antithrombin complex
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
TF
tissue factor
TFPI
tissue factor pathway inhibitor
TG
thrombin generation
TMM
trial materials manual
TVP
trial validation plan
UTN
Universal Trial Number
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
15 of 136
1
Summary
The main objective for the phase 2 trial NN7415-4310, explorer™4, is to assess the efficacy of 
concizumab administered s.c. once daily to prevent bleeding episodes in haemophilia A and B 
patients with inhibitors. Furthermore, this trial aims to assess the longer-term efficacy and safety of 
concizumab in haemophilia A and B patients with inhibitors and to establish the safety of treating 
breakthrough bleeding episodes with recombinant factor VIIa (rFVIIa) in these patients.
Objective(s) and endpoint(s)
Primary objective
∀
To assess the efficacy of concizumab administered s.c. once daily in preventing bleeding 
episodes in haemophilia A and B patients with inhibitors.
Secondary objectives
∀
To assess the longer-term efficacy of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of administering recombinant factor VIIa (rFVIIa) to haemophilia 
patients with inhibitors that are exposed to concizumab
∀
To assess the immunogenicity of concizumab in haemophilia patients with 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
∀
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 dosing
treatment with trial product (or has 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.
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
16 of 136
Trial design
The trial is a multi-centre, randomised (2:1), open-label, controlled trial, aiming to evaluate the 
efficacy and safety of concizumab 0.15 mg/kg (with potential dose escalation) administered daily 
s.c. in haemophilia patients with inhibitors. We expect 16 patients to complete treatment in 
concizumab arm (concizumab prophylaxis) and 8 patients in comparator arm (rFVIIa on demand). 
The dose regimen is selected based on relevant PK and TFPI data as well as PK/PD modelling of 
the results from the preceding explorer™ trials. Only on-demand patients will be eligible for the 
trial.
For all patients treated with concizumab (concizumab arm and comparator arm extention part) a 
loading dose of 0,5 mg/kg concizumab will be given as the first dose, followed by one week of 
concizumab dosing 0,15 mg/kg. All patients in treatment with concizumab will in a non-bleeding 
state receive a single dose of 90 μg/kg eptacog alfa (rFVIIa) one week after dosing with 
concizumab. Hereafter, patients will be closely clinically observed at the site for potential safety 
issues for at least 12h and evaluated again at the site after 24h.
The total trial duration for the individual patient will be approximately 86-88 weeks, consisting of a 
2-4 week screening period, a subsequent 76-week treatment period and an 8-week follow-up period.
eptacog alfa (rFVIIa) for treatment of bleeding episodes during the trial will be provided by Novo 
Nordisk. The patient will not be provided with trial product or eptacog alfa (rFVIIa) after end of 
trial.
The trial is split into a main part which lasts 24 weeks for all patients in the trial and an extension 
part which lasts 52 weeks. In the main part, the primary and selected secondary endpoints will be 
analysed when 16 patients have completed a minimum of 24 weeks of concizumab prophylaxis and 
8 patients have completed a minimum of 24 weeks of eptacog alfa (rFVIIa) on-demand or have 
withdrawn. The analysis of the main part of the trial aims to substantiate the clinical proof of 
concept (CPoC) that concizumab has the potential to prevent bleeding episodes in patients with 
haemophilia and inhibitors. The extension part of the trial will provide additional safety and long-
term efficacy data.
Trial population
Number of patients planned to be screened: 28
Number of patients planned to be started on trial product: 26
Number of patients expected to complete the trial: 24
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR 1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
17 of 136
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 haemophilia A or B patients with inhibitors aged ≥ 18 years at the time of signing 
informed consent
∀
Patients currently in need of treatment with bypassing agents
Key exclusion criteria
∀
Known or suspected hypersensitivity to trial product(s) or related products
∀
Known inherited or acquired bleeding disorder other than haemophilia
∀
Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX
Key Efficacy assessment
∀
Number of bleeding episodes during at least 24 weeks of treatment onset
Key Safety assessment
∀
Number of treatment emergent adverse events during at least 24 weeks of treatment onset
Trial products
The following products will be used in the trial:
∀
Investigational Medicinal Products:
o
concizumab B, 100mg/mL to be administered s.c. with NovoPen®4 and needles
o
eptacog alfa (rFVIIa), 5mg /vial and histidine (solvent). Reconstituted eptacog alfa 
(rFVIIa) is for intravenous administration and used in the trial at visit 3 and 9.1 for all 
patients with the purpose of investigating the safety of administering eptacog alfa 
(rFVIIa) to haemophilia patients
∀
Non Investigational Medicinal Product:
o
eptacog alfa (rFVIIa) 5 mg /vial and histidine (solvent). Reconstituted eptacog alfa is for 
intravenous administration and used in this trial for treatment of bleeding episodes
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CONFIDENTIAL


Protocol
UTN: U1111-1179-2925
Date:
05 May 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
2
Page:
18 of 136
2
Flow chart
2.1
Visits and assessments
explorerTM4 trial periods
Screening
Treatment main a,b
Treatment extension b
Follow-
up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-
scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
197
225
253
281
309
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w 72w 76w
-
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/ Genotyping and Long-term 
storage consent
●
In/exclusion criteria
●
●g
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and 
bleed history
●
Withdrawal criteria/ Criteria for premature 
discontinuation of trial product
●
●
●
●
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●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Randomisation (IWRS)
●
EFFICACY
Bleeding episodes h, i
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab) 
●
●
●j, k
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Free TFPI (central lab)  
●
●
●k
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
SAFETY
Physical examination
●
●
●k
●
●
●
●
●
●
Body measurements 
●
●m
●k, m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
Vital signs 
●
●n
●k, n
●
●
●
●
●
●n
●n
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
05 May 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
2
Page:
19 of 136
explorerTM4 trial periods
Screening
Treatment main a,b
Treatment extension b
Follow-
up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-
scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
197
225
253
281
309
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w 72w 76w
-
84w
Injection site reaction  
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●
●j, k
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Biochemistry (central lab)
●
●
●k
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
FVIII/ FIX activity (central lab)
●
●l
●l
Coagulation parameters (central lab)
●
●
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●l
●
●
Coagulation parameters (PT, APTT and Fibrinogen 
(local lab))
●j, k
●j
FVIII/FIX  inhibitors (central lab)
●
●l
●l
Anti-concizumab antibodies (ADA) (special lab) o
●
●
●k, p
●p
●p
●p
●p
●p
●l, p
●
●
●
●
●
●
●
●
●
●
●l
●
●
Concizumab  ELISA (special lab)
●
●k, p
●p
●p
●p
●p
●p
●l, p
●
●
●
●
●
●
●
●
●
●
●l
●
●
FVII ELISA (special lab)
●j,k
●j
Total TFPI (special lab)
●
●
●k
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
TRIAL MATERIAL
IWRS call 
●
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab)r
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (eptacog alfa, histidine)q
●
●w
●k
●
●
●
●
●
●
●
●
●
●
●
Administration of trial product (concizumab)r
●k, s
●k
●d, s 
●
●
Administration of trial product (eptacog alfa)
●k, t
●t
Drug accountability (concizumab)
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Drug accountability (eptacog alfa) 
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product e, u
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires 
●
●
●k
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
05 May 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
2
Page:
20 of 136
explorerTM4 trial periods
Screening
Treatment main a,b
Treatment extension b
Follow-
up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-
scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
197
225
253
281
309
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w 72w 76w
-
84w
Handout ID card 
●
Training v
●
●
●
●
●
Compliance: eDiary
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
The cells marked in ‘red’ are only for the patients randomised to eptacog alfa (rFVIIa) arm.
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
05 May 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
2
Page:
21 of 136
2.2
Explanatory descriptions
Footer
Description
a
There is staggered recruitment for the 4 first patients in the trial on the concizumab arm. 
b
Concizumab administration is performed at home except for visit 2 and visit 3 for patients randomised to concizumab and visit 9 and 9.1 for patients 
randomised to eptacog alfa. Sampling for Free TFPI, Anti-concizumab antibodies, Concizumab ELISA and Total TFPI are done prior to concizumab 
administration.
c
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 and 
visit 9.1 have a PK session of 24 hours and a safety follow up visit the following day. 
d
Visit and procedures only performed for patients randomised to eptacog alfa and switching to concizumab treatment.
e
For patients being dose escalated on concizumab a phone call is recommended 1 week after first dose of concizumab.
f
Daily dosing preferably at the same time in the morning.
g
Evaluation of the laboratory results obtained from samples taken at screening.
h
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.
i
Eptacog alfa will be given to treat breakthrough bleeding episodes. 
j
Sampling time schedule for thrombin generation, haematology,  coagulation parameters and FVII ELISA: pre-dose (-1 hour), post-dose: 10 min (±2 min), 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 eptacog alfa 
administration.
k
ONLY for patients randomised to concizumab arm.
l
At visit 9 and 16 blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been performed.
m
Only body weight should be measured. 
n
Vital signs should be evaluated before and after trial drug administration at visit 2 and visit 3 for concizumab arm and at visit 9 and visit 9.1 for patients in 
eptacog alfa arm switching to concizumab treatment.
o
In case 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 blood samples will be taken and stored for characterisation 
of the antibodies.
p
Blood sampling for anti-concizumab antibodies and concizumab ELISA testing should only be collected for patients on concizumab.
q
If needed dispensing of eptacog alfa, histidine, trial injection kits and Direction For Use (DFU). 
r
First treatment dose of concizumab is a loading dose and will be administered at visit 2 for the concizumab arm and visit 9 for the eptacog arm. 
s
The patient must be in a non-bleeding state at the time of the first concizumab administration and should not have received any bypassing agent drugs,(e.g., 
eptacog alfa, FEIBA®) for treatment of a bleeding episode within a period of 24h (for eptacog alfa) or 48h (for FEIBA®) prior to first concizumab. Only 
eptacog alfa is allowed after visit 2.
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
05 May 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
2
Page:
22 of 136
t
Eptacog alfa administered in a non-bleeding state at site at visit 3 for the concizumab arm and at visit 9.1 for the eptacog alfa arm.
u
Patient treated with concizumab 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 the investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose 
escalation. 
v
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Patients randomised to eptacog alfa will be re-trained in 
NovoPen®4 and s.c. administration at visit 9 and 9.1. If necessary training can be performed as needed at other visits. The eDiary will be provided to the 
patients at visit 2 if the patient feels capable in s.c. administration and using the eDiary. Further the patients will be trained in recognition of signs/symptoms of 
thrombosis.
w
Only for patients randomised to on-demand arm.
3URWRFROY


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
23 of 136
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP 1, applicable regulatory 
requirements,  in accordance with the Declaration of Helsinki 2 and ISO 14155 3.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
The 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). In haemophilia B, it is factor IX (FIX) that is deficient. 
Inheritance is chromosome X-linked; 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 births 4. According to 
the World Federation of Haemophilia global survey of 20145, 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 factor 6. With a deficiency of FVIII or FIX, the degree of activation of 
coagulation FX becomes insufficient. Consequently, the thrombin burst is delayed and insufficient 
for normal haemostasis 7. 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 symptoms 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 into a joint prior to age 4 year. Many children also bleed from other body sites before this 
age is reached 8. For this reason, primary prophylaxis with regular FVIII or FIX injections in the 
non-bleeding state is the recommended treatment from early childhood.
In patients who have developed inhibitors towards FVIII or FIX, replacement therapy is rendered 
ineffective. Though prevalence studies and registry data indicate that the prevalence of inhibitors in 
the haemophiliac population overall has been reported to be between 5% and 7% 9, the prevalence 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
24 of 136
amongst patients with severe haemophilia (FVIII:C < 1%) is higher and has been reported to be up 
to 30% 9, 10. These patients may be treated with bypassing agents, activated FVII (NovoSeven®) and 
activated prothrombin complex concentrate (FEIBA®) given as i.v. injections.
Current treatment options in haemophilia, replacement therapy or bypassing therapy, are hampered 
by the fact that these products must be given as i.v. injections. Furthermore, bypassing agents are
characterized by relatively short half-lives, therefore prophylactic treatment is burdensome. It is 
also generally acknowledged that the efficacy profile of bypassing agents is inferior to replacement 
therapy. Consequently, delayed or sub-optimal treatment occurs in a significant number of patients
with inhibitors. 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 Dalton’s.  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)) 10. 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.
Key differentiators of this new mode of action (MoA) and the key benefit of concizumab in patients 
with severe haemophilia A and B with inhibitors is reduced treatment burden due to subcutaneous 
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, explorerTM1) 11, a single dose trial in Japanese healthy subjects (NN7415-3981), 
two multiple dose trials (NN7415-3986, explorerTM2) and (NN7415-4159, explorer™3). When the 
first cohort with 4 (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 trial animal had concizumab plasma concentrations several hundred fold 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
25 of 136
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 (NN7415-4159), explorer™3,
a new 52 week non-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.
The explorer™3 trial was finalised following the completion of cohort 3 (0.8 mg/kg s.c. 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 s.c. every 4 days for 6 weeks). No clinical consequences or 
serious adverse events were seen in the completed cohorts in explorer™3.
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.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
26 of 136
Figure 3–1Individual 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™4.
In a drug–drug interaction study in monkeys (NN215431), three doses of up to 1 mg/kg of 
NovoSeven® were administered at 2h intervals, alone or in the presence of a steady state 
concentration of concizumab. No notable clinical observations were made, no treatment-related 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
27 of 136
adverse findings were seen, i.e. no thrombi or other signs of excessive coagulation. Increased 
concentrations of thrombin–anti-thrombin (TAT) and D-dimer were seen, which tended to be 
additive when both concizumab and eptacog alfa (rFVIIa) were present in circulation.
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 studies with concizumab have been finalised. Key safety and preliminary 
efficacy results from these phase 1 studies support further development of concizumab in 
haemophilia 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.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
28 of 136
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 haemophilia A and B patients with inhibitors
4.1.2
Secondary objectives
∀
To assess the longer-term efficacy of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of administering recombinant factor VIIa (rFVIIa) to haemophilia 
patients with inhibitors that are exposed to concizumab
∀
To assess the immunogenicity of concizumab in haemophilia patients with 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
∀
Number of TEAEs within 24 hours of rFVIIa administration
∀
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
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
29 of 136
∀
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 anti-thrombin (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
∀
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 (nMxmin) prior to the last dose administration at 24 
weeks 
o
Endogenous thrombin potential (nMxmin) 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
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
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∀
Change in Hemo-TEM after 76 weeks from treatment onset
∀
Change in VERITAS-PRN® after 24 weeks from treatment onset
∀
Change in 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
All endpoints referring to a time frame of either 24 weeks or of at least 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 multi-centre, randomised (2:1), open-label, controlled trial, aiming to evaluate the 
efficacy and safety of concizumab 0.15 mg/kg (with potential dose escalation) administered daily 
s.c. in haemophilia patients with inhibitors. The selected dose regimen is based on relevant PK and 
TFPI data as well as PK/PD modelling of the results from the preceding explorer™ trials. Only   
on-demand patients will be eligible for the trial.
Figure 5–1Schematic diagram of the trial design
The total trial duration for the individual patient will be approximately 86-88 weeks, including a 2-4 
week screening period, a 76 week treatment period, and a follow-up period of 8 weeks, see Figure 
5–1
The trial is split into a main part which lasts 24 weeks for all patients in the trial and an extension 
part which lasts up to 52 weeks. In the main part, the primary and selected secondary endpoints will 
be analysed when 16 patients have completed a minimum of 24 weeks of concizumab prophylaxis
and 8 patients have completed a minimum of 24 weeks of eptacog alfa (rFVIIa) on-demand or have 
withdrawn.
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In the concizumab arm bleeding episodes occurring during the trial will be treated with eptacog alfa 
(rFVIIa). In all patients treated with concizumab a single 90 μg/kg dose of eptacog alfa (rFVIIa)
will be administered in a non-bleeding state one week after dosing with concizumab has been 
initiated. The investigator will evaluate if there are any safety concerns 24 hours post eptacog alfa 
(rFVIIa) administration. Furthermore, the scheduled administration of eptacog alfa (rFVIIa) for the 
first 4 patients entering the trial with concizumab will be staggered.
In the comparator arm, in the main part, patients will receive eptacog alfa (rFVIIa) on-demand 
treatment. After completion of the main part, the patients will continue the trial in the extension part 
being treated with prophylactic concizumab 0.15 mg/kg (with potential dose escalation) s.c. daily 
administration.
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 and damage. Acceptance of storage of human biosamples 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 human biosamples to be stored 
for future exploratory analysis, see Section 8.1.1.
An independent data monitoring committee (DMC) will be established for this trial. The DMC will 
review all safety data from the ongoing trial with concizumab exposure, see Section 12.8.2.
5.1.1
Surgery
Minor surgery is allowed in this trial. Major surgery conducted earlier than one month (30 days) 
prior to trial start is allowed, see exclusion criteria 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™4 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 with inhibitors. A dose escalation design will allow cautious dose escalation in order to 
identify an efficacious and safe concizumab dose for the individual patient. A comparator arm is 
included to assess if concizumab is superior to on-demand treatment. Furthermore, the trial will 
give a possibility to assess safety of co-administration of eptacog alfa (rFVIIa) to the patients 
exposed to the concizumab treatment.
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The duration of 24 weeks for the main part of the trial is deemed necessary in order to obtain 
information on the annualised bleeding rate on concizumab prophylaxis. The duration of the 
extension part of the trial will be 52 weeks and provide further information on efficacy, i.e.
annualised bleeding rate, and also provide additional safety data upon 76 weeks treatment with 
concizumab.
A total of 26 patients previously on-demand (OD) treatment will be randomised into one of the two 
arms, with 16 patients in the concizumab arm and 8 patients in the comparator arm see Figure 5–1. 
Concizumab will be administered s.c. daily for patients randomised to the concizumab arm in the 
main and the extension part of the trial. For patients in the comparator arm in the extension part
treatment will be changed from on-demand with rFVIIa to prophylaxis with concizumab.
The concizumab dose regimens will be starting with 0.15 mg/kg with the possibility to escalate to
0.20 mg/kg and 0.25 mg/kg based on bleeding frequency, see Section 5.3.3.
Daily dosing with concizumab 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 5.3.3.
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Figure 5–2Individual 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.1
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 
                                               
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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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™4. Daily dosing will allow for 
the increase in trough levels and thus better efficacy may be expected with a lower dose.
A loading dose of 0.5 mg/kg concizumab will be given as the first dose, followed by one week of 
concizumab dosing 0.15 mg/kg in order to ensure steady-state levels at the time of eptacog alfa 
(rFVIIa) administration. eptacog alfa (rFVIIa) will be administered one week after initiation of 
dosing with concizumab in a non-bleeding state to assess safety of treatment with eptacog alfa 
(rFVIIa) in patients exposed to concizumab treatment.
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.
5.3
Treatment of patients
The following products will be administered in the trial.
Table 5–1 List of products provided by Novo Nordisk
Compound Name 
Strength
Dosage form
Route of administration
Treatment period
concizumab B a
100 mg/mL
solution for s.c. 
injection in a 3 mL 
cartridge b
Subcutaneous 
administration using
NovoPen®4
For prophylactic 
treatment in 76 weeks 
(for concizumab arm in 
the main part and 
extension part).
For prophylactic 
treatment in 52 weeks 
(for comparator arm in 
the extension part).
eptacog alfa (rFVIIa) a, c
5 mg/vial
Powder for solution 
for i.v. injection
Intravenous 
administration
For treatment of 
breakthrough bleeding 
episodes at the 
discretion of the 
investigator (screening, 
main, extension and 
follow up part). c
Administration of 
doses higher than 
histidine solvent (5 mL)
Prefilled syringes for 
solution for i.v. 
injection 
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90μg/kg to patients 
exposed to concizumab 
is not allowed.
For on-demand 
treatment at the 
discretion of the 
investigator in 24 
weeks for comparator 
arm in the main part. 
In the concizumab arm 
and comparator arm 
after switching to 
concizumab in the 
extension part of the 
study a single 90μg/kg 
dose for initial safety 
assessments in a non-
bleeding state. a
Will be provided for as 
long as patients 
participate in the trial 
(screening, main, 
extension and follow 
up part)
a Investigational medicinal product (IMP)
b Not to be confused with the daily injected volume (~150 μL, depending on dose strength and body weight)
c Non-investigational medicinal product (NIMP)
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 in the Trial Materials Manual, see Section 9.
5.3.1
Concizumab arm
5.3.1.1
Concizumab prophylactic treatment (main and extension part)
Concizumab will be given s.c. once daily 0.15 mg/kg (with potential dose escalation to 0.20 and 
0.25 mg/kg). The dose escalation criteria are described, see Section 5.3.3. The first dose of 
concizumab will be given at the trial site under medical supervision.
A loading dose of 0.5 mg/kg will be given as the first concizumab dose at visit 2 in order to ensure 
steady state levels at the time of the administration of eptacog alfa (rFVIIa) in a non-bleeding state 
at visit 3, see Section 5.3.4.
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The patients will be trained in s.c. administration of concizumab with NovoPen®4 at the screening 
visit and at the first scheduled treatment visit. 
5.3.2
Comparator arm (eptacog alfa (rFVIIa))
5.3.2.1
On-demand treatment (main part)
During the main part of the trial, patients will receive eptacog alfa (rFVIIa) for treatment of 
bleeding episodes, with a dose regimen at the discretion of the investigator.
5.3.2.2
Concizumab prophylactic treatment (extension part)
After completion of the main part, the patients will continue the trial in the extension part and will 
switch to prophylactic treatment with s.c. daily administration of concizumab 0.15 mg/kg (with 
potential dose escalation to 0.20 and 0.25 mg/kg) s.c. daily administration.
The same dose escalation criteria as described below (for the initial concizumab arm) will apply.
A loading dose of 0.5 mg/kg will be given as the first concizumab dose at visit 9 in order to ensure 
steady state levels at the time of the administration of rFVIIa in a non-bleeding state at visit 9.1.
5.3.3
Dose escalation
The dose escalation criteria as described below will apply to all treatment arms.
Bleeding episodes will be assessed during the trial both at scheduled visit 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, bleeding episodes occurring during first 2 weeks should not influence a dose escalation 
decision.
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (or visit 9 when
switching from eptacog alfa (rFVIIa) to concizumab) (first treatment 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.
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Dose 0.15 mg/kg: 
When sBE occurs, the investigator will determine if ≥3 sBEs have occurred within the preceding 12
weeks (including the current sBE). If yes, and if investigator deems it safe, the patient will 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 sooner.
Dose 0.20 mg/kg: 
When 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 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 sooner.
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 due to lack of efficacy, see Section 6.4.
The possibility of dose escalation at unscheduled visits is necessary in order to avoid  bleeding
episodes at inadequate dose level: e.g. if the dose escalation eliciting bleeding episode occurs soon 
after a scheduled visit, the patient will avoid to wait8 weeks for the next scheduled visit (in the 
extension part).
Figure 5–3Dose escalation for one individual patient in the concizumab arm
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Figure 5–4Dose escalation for one individual patient in the comparator arm
5.3.4
Co-administration of eptacog alfa (rFVIIa)
eptacog alfa (rFVIIa) will be used for treating breakthrough bleeding episodes in this trial; one 
week after initiation of dosing with concizumab, a single 90 μg/kg dose of eptacog alfa (rFVIIa)
will be administered in a non-bleeding state at the trial site under medical supervision to assess 
safety of treatment with eptacog alfa (rFVIIa) in patients exposed to concizumab treatment. 
Hereafter, patients will be closely clinically observed at the site for potential safety issues for at 
least 12h and evaluated again at site after 24h. Between 12h and 24h, the patient must either stay at 
the site or at a hotel or at home if he lives nearby to be able to continue visit 3 or 9.1 the day after.
Dosing of eptacog alfa (rFVIIa) in the first 4 patients randomised to concizumab arm will be 
staggered so that the period between eptacog alfa (rFVIIa) administrations from one patient to 
another is at least 48 hours. If no safety concerns are observed (for example signs and symptoms of 
thromboembolism, such as swelling, pain and redness of the leg, shortness of breath, and chest 
pain) by the investigator in the period between the administration of eptacog alfa (rFVIIa) and when 
the next daily concizumab dose is to be given, the investigator allows the individual patient to 
administer concizumab prophylactically at home and if needed, treat breakthrough bleeding 
episodes at home with eptacog alfa (rFVIIa). The patients will receive prophylactic doses of 
concizumab 0.15 mg/kg daily throughout the main part (24 weeks) and the extension part (52 
weeks), unless dose escalation criteria are fulfilled, see Section 5.3.3.
In case safety concerns are raised by an investigator after eptacog alfa (rFVIIa) administration and 
these concerns meet the described criteria for putting enrolment of additional patients on hold, 
dosing in the individual patients will be halted and further recruitment in the trial will be halted, see 
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Section 12.7. In case safety concerns that do not meet the criteria for putting enrolment of additional 
patients on hold are observed by the investigator, dosing in that individual patient will be halted 
until further evaluation. In such cases, all available data will be assessed by the Data Monitoring 
Committee (DMC), see Section 12.8.2.
5.3.5
Treatment of bleeding episodes during the trial
Breakthrough bleeding episodes between visit 1 and visit 2 can be treated with any bypassing agent 
(e.g., eptacog alfa (rFVIIa), FEIBA®) up to a period of 24 hours (for eptacog alfa (rFVIIa)) or 48 
hours (for FEIBA®) prior to first concizumab administration at visit 2. Novo Nordisk will provide 
eptacog alfa (rFVIIa) throughout the trial. The patient can treat himself and then he must call the 
site. The bleeding episode must be recorded in the eCRF.
Breakthrough bleeding episodes between visit 2-3 in the concizumab arm and visit 9-9.1 in the 
comparator arm must be treated with eptacog alfa (rFVIIa). Upon breakthrough bleeding episodes 
in this period the patient must first call the site. The investigator should instruct the patient about 
whether he should go to the site to receive treatment or if he can administer a single dose of eptacog 
alfa (rFVIIa) which is not higher than 90μg/kg without delay to treat the breakthrough bleeding
episode. If the patient is instructed to administer the eptacog alfa (rFVIIa) dose at home, following 
the administration, the patient should immediately go to the site for further clinical evaluation. The 
bleeding episode must be recorded in the electronic Diary (eDiary).
Breakthrough bleeding episodes between visit 3 and visit 16 in the concizumab arm must be treated 
with eptacog alfa (rFVIIa). The patient can treat himself without delay but must inform the site that 
a bleeding episode has occurred. Doses of eptacog alfa (rFVIIa) those are lower than 90μg/kg may 
be used to treat breakthrough bleeding episodes at the discretion of the investigator. Administration 
of doses higher than 90μg/kg to patients exposed to concizumab is not allowed. If a single dose of 
eptacog alfa (rFVIIa) is not sufficient to stop a bleeding episode, the patient should inform the site 
and in agreement with the investigator may administer a second dose of eptacog alfa (rFVIIa) not 
higher than 90μg/kg 2-3h after the first dose has been administered. The same procedure should be 
repeated in case the second dose of eptacog alfa (rFVIIa) is not sufficient to stop the bleeding 
episode. If more than three 90μg/kg doses of eptacog alfa (rFVIIa) are needed to stop a bleeding 
episode, the patient should go to the site without delay. The definition and diagnostic criteria of 
DIC, acute myocardial infraction, stroke, deep vein thrombosis, pulmonary embolism and 
peripheral artery occlusion is provided in section 12.1.6. The bleeding episodes must be recorded in 
the eDiary.
Breakthrough bleeding episodes between visit 16 and visit 17 (follow-up part) may be treated with 
eptacog alfa (rFVIIa) or other products at the discretion of the investigator. The patient can treat 
himself with eptacog alfa (rFVIIa) at home without delay. Only eptacog alfa (rFVIIa) will be 
provided by Novo Nordisk. The bleeding episodes must be recorded in the eDiary.
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See Table 5–1 and Table 8–3.
5.3.6
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 anticoagulants (DOACs)
∀
Home treatment (between visit 2 and visit 16) with activated prothrombin complex 
concentrates (FEIBA®)
5.4
Treatment after discontinuation of trial product
When discontinuing trial products (visit 16 or earlier), the patient should be switched to a suitable 
marketed product at the discretion of the investigator. Only eptacog alfa (rFVIIa) will be provided 
by Novo Nordisk. The patient will not be provided with concizumab or eptacog alfa (rFVIIa) after 
end of trial (EOT) (visit 17) by Novo Nordisk.
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 the treatment burden 
compared to the currently approved prophylactic drugs which have to be administered i.v.
Furthermore, the current treatment options for prophylaxis in inhibitor patients do not reduce the 
frequency of breakthrough bleeding episodes to the same extent as prophylaxis with replacement 
therapy in non-inhibitor patients. Concizumab may therefore show a better efficacy profile 
compared to current treatment options in haemophilia A and B patients with inhibitors.
The treatment period during at least 24 weeks (the main part of the trial) is considered necessary for 
providing robust data that allow demonstration of clinical proof of concept and to support decision 
making regarding a phase 3 confirmatory trial. Dosing for additional 52 weeks will provide 
valuable long term efficacy and safety data.
Breakthrough bleeding episodes occur in prophylactic regimens with both bypassing agents and 
replacement therapy. Therefore, it is expected that breakthrough bleeding episodes will occur 
during prophylaxis with concizumab even if clinical proof of concept is demonstrated. 
Consequently, eptacog alfa (rFVIIa) will be provided by Novo Nordisk in this trial for treatment of 
breakthrough bleeding episodes. In order to minimize the likelihood of any unforeseen adverse 
events associated with administration of eptacog alfa (rFVIIa) in these circumstances,
administration of eptacog alfa (rFVIIa) in a controlled setting will be performed at visit 3 or 9.1.
Please refer to the Investigator’s Brochure for further information.
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 28
Number of patients planned to start on trial product: 26
Number of patients expected to complete the trial: 24
∀
Preferably 21 haemophilia A patients
∀
Preferably 3 haemophilia B patients
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 the suitability 
for the trial
2. Male haemophilia A or B patients with inhibitors aged ≥ 18 years at the time of signing 
informed consent
3. Patients currently treated on-demand with a minimum of six bleeding episodes during the 24 
weeks (or twelve bleeds during 52 weeks) prior to screening
4. Documented history of high-titer inhibitors towards FVIII or FIX, defined as ≥5 Bethesda Units
5. Patients currently in need of treatment with bypassing agents
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
6. Major surgery conducted within one month prior to the initiation of trial activities or major 
surgery planned to occur during the trial
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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
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 requires 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 measured as estimated Glomerular Filtration Rate (eGFR) ≤ 60 ml/min/1.73 
m2 for serum creatinine measured at screening for patients without evidence of renal damage
12. Platelet count ≤ 100x109/L at screening
13. Fibrinogen level < the lower limit of normal
14. Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX
15. Antithrombin levels below the normal reference range at screening
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 and/or randomised in 
violation of the randomisation 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
7. Lack of efficacy due to neutralizing antibodies
8. 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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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 with inhibitors, is that 
there is a significant unmet medical need in this patient population for
1. A more effective treatment and
2. A treatment which reduces treatment burden.
In addition to this, since most of these patients are likely to have been treated and therefore familiar 
with eptacog alfa (rFVIIa) on-demand treatment, this trial population is considered the most suitable 
for assessing the safety of administering eptacog alfa (rFVIIa) to patients in whom plasma TFPI 
levels are inhibited. 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 are to be 
confirmed.
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Date:
05 May 2017
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Version:
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UTN: U1111-1179-2925
Status:
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7
Milestones
Planned duration of recruitment period (FPFV-LPFV): 28 weeks
Planned FPFV: 
16-Aug-2017
Planned FPFT: 
30-Aug-2017
Planned LPFV: 
28-Feb-2018
Planned LPLV: 
23-Oct-2019
The total duration of concizumab treatment in this trial is 76 weeks for an individual patient
randomised to concizumab prophylaxis treatment at visit 2.
The total duration of concizumab treatment in the trial is 52 weeks for an individual patient 
randomised to eptacog alfa (rFVIIa) on-demand treatment at visit 2.
EOT is defined as last patient last visit (LPLV).
Recruitment
The screening and randomisation 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 randomisation can be randomised in a 2:1 allocation to either the concizumab 
or the comparator arm within the timelines specified in the flow chart (see Section 2).
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and 
clinicaltrials.jp. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure,
how-we-disclose-trial-information, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors (ICMJE), 12
the Food and Drug Administration Amendment Act (FDAAA), 13 European Commission 
Requirements, 14 15 and other relevant recommendations or regulations. If a patient requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the patient. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
protocol LPFT (visit 2) + 24 weeks corresponding to 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.13
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8
Methods and assessments
Assessments to be performed at the scheduled and at the unscheduled visits in the trial are described 
in this section, Figure 8–1, Figure 8–2 and in Section 2.
Figure 8–1Visit schedule – concizumab arm.
Figure 8–2Visit schedule – eptacog alfa (rFVIIa) arm later switching to concizumab.
8.1
Visit procedures
For each patient the trial can consist of the following scheduled parts and visits depending upon
which arm the patient is randomised to:
Screening Part:
∀
Visit 1 (screening visit)
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Main Part:
∀
Visit 2 (Randomisation and 1st treatment visit with concizumab at site for patients 
randomised to the concizumab-arm)
∀
Home treatment with concizumab daily
∀
Visit 3 (treatment and PK-visit with concizumab and eptacog alfa (rFVIIa) at site only for 
patients randomised to the concizumab-arm - phone visit for patients randomised to the 
eptacog alfa (rFVIIa) on-demand arm)
∀
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 – 1st treatment 
visit with concizumab at site for patients randomised to the eptacog alfa (rFVIIa) arm)
Extension Part:
∀
Visit 9.1 (treatment and PK-visit with concizumab and eptacog alfa (rFVIIa) at site ONLY
for patients randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 9.2 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 10 (Assessment visit, patients treat themselves at home)
∀
Visit 10.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 11 (Assessment visit, patients treat themselves at home)
∀
Visit 11.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on demand-arm)
∀
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, no treatment at home before the visit and End of Treatment)
Follow-up Part:
∀
Visit 17 (Assessment visit and End of Trial)
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Unscheduled Part:
∀
Unscheduled visits can occur e.g. for dispensing of trial product, dose escalation or 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 and eptacog alfa (rFVIIa) administration, 
NovoPen®4, usage of eDiary, completion of the PRO etc.
8.1.1
Informed consent, genotyping and long-term storage consent
Informed consent must be obtained before any trial related activity at visit 1, 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/or 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 patients screening log, a patients identification code list and a patients 
enrolment log. Only patients who have signed the informed consent form should be included on the 
logs. The patients screening log and patients 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 to 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 ePRO 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
All assessments to be performed at screening are listed in Section 2.
After informed consent is given, patients will be asked to complete the ePRO questionnaires before 
any other trial related activities are performed according to Section 8.6.1:
∀
Hemo-TEM,
∀
VERITAS-PRN®
Assessment results from physical examination and body measurements, as well as measurements of 
vital signs, urinalysis and 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.
For bleeding episodes that occur in the period from Screening visit (Visit1) to randomisation visit 
(Visit 2), information about the bleeding episode is to be entered in the eCRF at visit 2.
Patients will be provided with eptacog alfa (rFVIIa), trial injection kits and direction for use (DFU) 
to cover the potential eptacog alfa (rFVIIa) treatment after the screening part of the trial and 
investigator will ensure that the patients are capable of treating themselves with eptacog alfa 
(rFVIIa).
Dispensing of eptacog alfa (rFVIIa) should be performed in IWRS.
The patient must 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 at visit 1, visit 2 and visit 9
During visit 1 and visit 2 and visit 9 (comparator arm) 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 (if they are randomised to concizumab) 
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or at visit 9 (if they are randomised to eptacog alfa (rFVIIa) and switching to concizumab at visit 9). 
Furthermore, patients must be instructed and trained in the importance of reporting all the home 
treatments with concizumab, details of the bleeding episodes and the eptacog alfa (rFVIIa) 
treatments associated with these bleeding episodes in the eDiary. The patient should call the site if 
bleeding episodes occur between visit 1 and 2 for the site to register in the eCRF.
Patients should be trained on how to recognize signs of thromboembolic events, so that the patient
contacts the site without delay.
The site and patient can arrange for additional training whenever needed during the remaining time 
of the trial.
8.1.9
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 (concizumab arm) or when the 
patient is comfortable self-administrating trial product subcutaneously (concizumab) and 
intravenously (eptacog alfa (rFVIIa)).
8.1.10
Staggered recruitment
Dosing of eptacog alfa (rFVIIa) in the first 4 patients randomised to the concizumab arm will be 
staggered until the 4th patient randomised to the concizumab arm has completed visit 3 without any 
safety concerns raised by the investigator. Until this time point, enrolled patients will not be 
randomised until the previous patient randomised to concizumab has completed visit 3 without any 
safety concerns raised by the investigator. Novo Nordisk will as sponsor control and communicate 
the staggered recruitment process.
8.1.11
Treatment period – Main part
8.1.11.1
Visit 2 (Randomisation)
Visit 2 should be scheduled 14 to 28 days after visit 1. The date of visit 2 will be considered as trial 
day 1.
It is important to verify the in/exclusion criteria again and review central laboratory tests from 
screening.
The patients must be in a non-bleeding state and should not have received any bypassing agent 
(e.g., eptacog alfa (rFVIIa), FEIBA®) for treatment of bleeding episodes within a period of 24 hours 
(for eptacog alfa (rFVIIa)) or 48 hours (for FEIBA®) prior to the potential first concizumab 
administration (depending on the treatment arm). After visit 2 only treatment with eptacog alfa 
(rFVIIa) for bleeding episodes is allowed.
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Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments listed in 2, must be performed before potential administration of concizumab
(depending on the treatment arm). Vital signs must be assessed both before (within 1 hour) and after 
concizumab administration. Pre-dose blood sampling must take place no more than 1 hour before 
concizumab administration.
Assessment results from concomitant medication, vital signs, body measurement (weight only) and 
details of adverse events must be entered into the eCRF.
A randomisation and dispensing call must be performed in the IWRS.
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 Trial Materials Manual (TMM) on 
basis of the patient’s current body weight. Investigator will communicate the daily dose of 
concizumab to the patient and record the dose for the coming home treatment period in the eCRF.
For patients randomised to the concizumab arm, the first treatment with the loading dose of 
concizumab will be given.
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.
At the visit the patient will be provided with trial product concizumab and/or eptacog alfa (rFVIIa)
and trial injection kits and an eDiary device to be able to conduct and report home treatment and 
bleeding episodes until next scheduled visit.
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa) during the 
trial as instructed by the investigator. Drug accountability must be performed for eptacog alfa 
(rFVIIa), if applicable according to section 9.4.
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The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site. If the patient on concizumab needs to treat a 
bleeding episode with eptacog alfa (rFVIIa) at home, then he must visit the site immediately after.
8.1.11.2
Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and PK visit for 
concizumab arm)
eptacog alfa (rFVIIa) on-demand arm:
Visit 3 for eptacog alfa (rFVIIa) on-demand arm is a phone call scheduled 7 days after visit 2 (with 
a visit window of +1 day).
All relevant assessments listed in Section 2, must be discussed.
Assessment results from concomitant medication and details of adverse events must be entered into 
the eCRF.
concizumab arm:
Visit 3 is to be scheduled 7 days after visit 2 (with a visit window of +1 day) and the visit takes two 
days.
All assessments are listed in Section 2, and must be performed accordingly and recorded in 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:
∀
PGI-C
∀
Hemo-TEM
Pre-dose blood sampling must take place no more than 1 hour before eptacog alfa (rFVIIa)
administration. Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa) dosing.
eptacog alfa (rFVIIa) should be administered to the trial patients at the site under the surveillance of 
medically trained trial site staff. Patient should continue his daily concizumab injections regardless 
of eptacog alfa (rFVIIa) administration.
Samples for thrombin generation, haematology, coagulation parameters and FVII ELISA are taken 
pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 10 min (±2 min), 1h 
(± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (±20 min) and 24h (±20 min).
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The investigator must ensure all assessments are performed as described in Section 2, Investigator 
is requested to conclude after 24 hours if it is safe for the patient to continue in the trial and record 
the conclusion in the eCRF before next dose with concizumab is given the day after.
Recruitment of the first four patients will be staggered according to section 8.1.9.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visits the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until the next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.11.3
Visit 4, 5, 6, 7 and 8
Patients should treat themselves at home according to their individual dosing schedule regardless of 
when visits 4, 5, 6, 7 and 8 are scheduled.
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 will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
PGI-C
∀
Hemo-TEM
All assessments are to be performed according to Section 2, and the assessment results from 
concomitant medication, vital signs, body measurement (weight only) and details of adverse events 
must be entered into the eCRF.
Investigator must perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the e-Diary. Based on the assessment of any spontaneous 
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bleeding episodes the investigator must, for patients randomised to concizumab arm at visit 2, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visits the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until the next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
At visit 8 patients should be reminded that treatment with concizumab (concizumab arm) must take 
place after the blood sampling at visit 9.
8.1.11.4
Visit 9
Visit 9 is to be scheduled on trial day 169 (24 weeks) with a visit window of ±7days.
Patients randomised to eptacog alfa (rFVIIa) on-demand treatment at visit 2 will now be switched to 
concizumab treatment. At this visit the first treatment (loading dose) with concizumab will take 
place.
Treatment with concizumab must take place after the blood sampling for both the patients on the 
concizumab arm as well as patients on the eptacog alfa (rFVIIa on-demand) arm.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
PGI-C
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
56 of 136
∀
TSQM
∀
SIAQ-ISRQ
All assessments are to be performed according to Section 2, and the assessment results from 
physical examination, concomitant medication, vital signs, body measurement (weight only) and 
details of adverse events must be entered into the eCRF.
Investigator must perform compliance check of treatment and reporting of bleeding episodes 
through the available access to collected data from the e-Diary. Based on the assessment of any 
spontaneous bleeding episodes the investigator must, for patients randomised to concizumab arm at 
visit 2, evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in Section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 and eptacog alfa 
(rFVIIa) during the trial as instructed by the investigator. Drug accountability must be performed 
for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12
Treatment period – Extension part
8.1.12.1
Visit 9.1 (PK visit and ONLY patients previously on the eptacog alfa (rFVIIa)
on-demand arm)
Visit 9.1 is to be scheduled on trial day 176 (25 weeks) with a visit window of +1 day and the visit 
takes two days.
All assessments are listed in Section 2, and must be performed accordingly and recorded in the 
eCRF.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
57 of 136
Pre-dose blood sampling must take place no more than 1 hour before eptacog alfa (rFVIIa)
administration. Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa) dosing.
eptacog alfa (rFVIIa) should be administered at the site under the surveillance of medically trained 
trial site staff. Patient should continue his daily concizumab injections regardless of eptacog alfa 
(rFVIIa) administration.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until next scheduled visit.
Samples for thrombin generation, haematology, coagulation parameters and FVII ELISA are taken 
pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 10 min (±2 min), 1h 
(± 10 min), 3h (± 10 min), 6h (± 10 min), 9 h (± 10 min) and 12h (±20 min) and 24h (±20 min).
Investigator is requested to conclude after 24 hours if it is safe for the patient to continue in the trial 
and record the conclusion in the eCRF before the next dose of concizumab is given the day after.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.2
Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
Visit 9.2 is to be scheduled on trial day 197 (28 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
58 of 136
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.3
Visit 10
Visits 10 is to be scheduled on trial day 225 (32 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (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.
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
59 of 136
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.4
Visit 10.1 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
Visit 10.1 is to be scheduled on trial day 253 (36 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until next scheduled visit.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
60 of 136
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.5
Visit 11
Visit 11 is to be scheduled on trial day 281 (40 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.6
Visit 11.1 (ONLY patients previously on the rFVIIa on-demand arm) 
Visit 11.1 is to be scheduled on trial day 309 (44 weeks) with a visit window of ±7days.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
61 of 136
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.7
Visit 12, 13, 14 and 15
Visits 12, 13, 14 and 15 are to be scheduled on trial day 337 (48 weeks), 393(56 weeks), day 449 
(64 weeks) and day 505 (72 weeks) respectively with a visit window of ±7 days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
62 of 136
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
At visit 15 patients should be reminded that treatment with concizumab must take place after the
blood sampling at visit 16.
8.1.12.8
Visit 16
Visit 16 is to be scheduled on trial day 533 (76 weeks) with a visit window of ±7days. Further visit 
16 should be scheduled to be conducted at the last day of treatment with concizumab.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs and details of adverse events must be entered into the eCRF.
Investigator must 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 patients can be treated with eptacog alfa (rFVIIa) or other 
products at the discretion of the investigator to treat eventual bleeding episodes. Only eptacog alfa 
(rFVIIa) will be provided by Novo Nordisk during this period.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
63 of 136
If necessary, a dispensing call must be performed in the IWRS. At the visit the patient will be 
provided with eptacog alfa (rFVIIa) and trial 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. NovoPen®4 must be returned.
Drug accountability must be performed for concizumab and eptacog alfa (rFVIIa).
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes) arise 
after he has left the site. 
8.1.13
Visit 17 (End of trial) - Follow-up part
Visit 17 is to be scheduled on trial day 589 (84 weeks) with a visit window of minus 7 days.
All assessments are listed in Section 2, 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 must perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data. Patients should be asked if their female partner has become 
pregnant, see Section 12.5.1.
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa), eDiary 
device and Trial card. Drug accountability must be performed for eptacog alfa (rFVIIa).
End-of-Trial information must be entered in the End-of-Trial form in the eCRF.
Completion or treatment discontinuation (if the trial is not completed) session should be performed 
in IWRS, see Section 10.
8.1.14
Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Section 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 Section 
2. 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.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
64 of 136
The following forms can be found in the unscheduled visit in the eCRF:
∀
Bleeding episodes
∀
Dosing with eptacog alfa (rFVIIa), concizumab including dose escalation, see Section 5.3.3.
∀
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, 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 with inhibitors which is 
to be reported in the haemophilia medical history section of the eCRF.
Medical history is a medical event, other than haemophilia, 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, see Section 6.2 and 6.3.
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. 
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.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
65 of 136
8.2.3
Concomitant medication
A concomitant medication is any medication, other than the concizumab and eptacog alfa 
(rFVIIa), which is taken during the trial, including the screening and follow-up period.
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)
o
Classification of haemophilia type (haemophilia A/B)
o
Severity of haemophilia (severe, moderate or mild)
o
Aetiology of haemophilia (congenital or acquired)
∀
Family history of
o
Haemophilia (Y/N)
o
Inhibitors (Y/N)
o
Prothrombotic disorders (Y/N)
o
Thromboembolism (Y/N)
∀
Inhibitor tests taken (Y/N)
o
Date (dd-mmm-yyyy) 
o
Result (BU)
∀
Cut-off for positive inhibitor result
∀
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)
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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o
Brand name, or if the brand is not known, the type of product, (plasma derived or 
recombinant)
∀
Dosage used for prophylaxis
∀
Dosing frequency during prophylaxis 
∀
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 eptacog alfa (rFVIIa) 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 during visits to 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 eptacog alfa (rFVIIa) injection occurring outside the trial site should be entered in the eDiary by 
the patient, Section 13.3.
The completed eDiary is considered source data.
For reporting of bleeding episodes as AEs/SAEs, please refer to Section 12. In case of life-
threatening bleeding episode, it should always be reported as an SAE, see Section 12.1.2.
The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with eptacog alfa (rFVIIa):
∀
Start date and time
∀
Stop date and time (see Table 8–1)
∀
Anatomical location
o
Position (left/right)
∀
Cause (see Table 8–2)
o
spontaneous
o
traumatic
o
post-surgical
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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∀
Severity (see Table 8–3)
o
mild/moderate, severe
o
classification and recording of severe bleeding episodes is the responsibility 
of the investigator
∀
Treatment, if any 
o
eptacog alfa (rFVIIa) administration or other product administration
o
dose, date, stop time
o
other medicinal treatments related to the bleeding episode (pain relieving 
medication, non-medical therapy etc.)
o
record as concomitant medication (section 8.2.3)
∀
Symptoms during bleeding episode(s)
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 12.1.1 and 12.1.2.
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 
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Category
Definition
during surgery do 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 bleeding 
episodes without compartment syndrome), 
mucosal- or subcutaneous bleeding episodes
Mild/moderate bleeding episodes may occur 
in other anatomical locations  
Mild/moderate bleeding episodes: 
∀
patient must call the site between 
visit 1-2 and visit 3-16 (see 2-3 
and 9-9.1 below)
∀
patient must call the site between 
visit 2-3 or visit 9-9.1 (eptacog 
alfa arm) and if treated at home, 
go to the site immediately after
∀
patient can treat themselves at 
home between visit 16 and visit 
17
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 site immediately if in doubt regarding 
treatment of a bleeding episode and to discuss what other actions may need to be 
taken
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Trial ID: NN7415-4310
Version:
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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.
Dosing for bleeding episodes with eptacog alfa (rFVIIa) should be documented in the eCRF (visit 1 
to visit 2) and eDiary (visit 2 to visit 17). 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 13.3.
Investigator must instruct the patient not to perform preventive treatment with eptacog alfa (rFVIIa)
after bleeding stop as defined in Table 8–1.
Investigator must instruct the patient to use eptacog alfa (rFVIIa) as rescue medication to treat 
bleeding episode between visit 2 and visit 16, see Section 5.3.5.
Furthermore investigator must instruct the patient to contact the site when a bleeding episode 
occurs. 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 
eptacog alfa (rFVIIa) as rescue medication) and will record treatment in the 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, breast(s)
∀
Musculoskeletal system
∀
Central and peripheral nervous system
∀
Skin
∀
Lymph node palpation
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Trial ID: NN7415-4310
Version:
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Status:
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The investigator must evaluate the results of the examination and classify them 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 one decimal)
The body weight assessed at each visit will be used for calculation 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 in a 
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 visits 2 and visit 3 (for patients randomised to concizumab) and at visit 9 and visit 9.1
(for patients initiating concizumab treatment at visit 9), the measurements are also performed after 
concizumab administration.
The investigator must evaluate the vital signs and classify the outcome as either:
∀
Normal or abnormal
∀
If abnormal the investigator must:
o
Specify the abnormality 
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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 8.2.2
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 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 some 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 Section 12.
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Version:
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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:
Injection site reaction 
Investigation of injection site reactions will be performed locally at all visits after visit 2 until visit 
16 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 at 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.
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Version:
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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 725 mL will be taken from each patient on the concizumab 
arm and 625 mL from each patient on the eptacog alfa (rFVIIa) arm.
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 at all visits and 
coagulation parameters at visits 3 and 9.1 are to be shipped for analysis at central laboratories or 
further distribution to special laboratories. Haematology samples (all visits) and coagulation 
parameters (visit 3 and 9.1) are to be analysed locally. Ports cannot be used for blood sampling.
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 SI units.
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 
clinically 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/FIX activity, FVIII/FIX inhibitor 
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Date:
05 May 2017
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Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
Status:
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test, Thrombin generation, Free TFPI (TFPI not bound to concizumab), concizumab concentration 
in plasma, anti-concizumab antibodies, Total TFPI and FVII antigen concentration.
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 8.2.3 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 antibodies).
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report (CTR).
Antibody samples and human biosamples, 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 collected at all visits.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa): 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9 h (± 
10 min), 12h (± 20 min) and 24h (± 20 min).
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:
05 May 2017
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Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
Status:
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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 (TFPI not bound to concizumab) will be collected at all visits, pre-dose at visit 2 and 3 
(concizumab arm) and visit 9 and 9.1 (eptacog alfa (rFVIIa) arm).
The free TFPI assay is an enzyme immunoassay measuring levels of free TFPI from 
 
 (named and referred to 
 TOTAL TFPI) and will be used for PD assessments.
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.
The investigator must evaluate the results and record the outcome as:
∀
Normal or abnormal
∀
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.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa), 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9 h (± 
10 min), 12h (± 20 min) and 24h (± 20 min).
∀
Haemoglobin
∀
Erythrocytes (cell count)
∀
Thrombocytes (platelet count)
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∀
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
Biochemistry samples are to be sampled and analysed centrally at all visits.
∀
Creatinine
∀
Albumin
∀
Bilirubin; total, direct, indirect
∀
Aspartate aminotransferase (AST)
∀
Alanine aminotransferase (ALT)
∀
Gamma glutamyltransferase (GGT) 
∀
Alkaline phosphatase
∀
C-reactive protein (CRP)
The investigator must evaluate the results of the examination 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/FIX activity
FVIII/FIX activity is to be sampled and analysed centrally at visit 1, visit 9 and visit 16.
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∀
FVIII activity level (IU/mL) or
∀
FIX activity level (IU/mL)
8.5.2.5
Coagulation parameters
Coagulation parameters will be performed centrally at all visits with the exception of visit 3 and 
visit 9.1 where the PT, APTT, and Fibrinogen will be performed locally.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa) at 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9h 
(±10 min) and 12h (±20 min) and 24h (± 20 min) locally.
∀
Fibrinogen – centrally and locally
∀
Prothrombin time (incl. INR) (PT) centrally and locally
∀
D-dimer – only centrally
∀
Prothrombin fragment 1+2 – only centrally
∀
Activated partial thromboplastin time (APTT) – centrally and locally
∀
Antithrombin (AT) activity – only centrally
The investigator must evaluate the results of the examination 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)
Coagulation parameters analysed locally are to be entered into the eCRF.
8.5.2.6
FVIII/FIX inhibitors
FVIII/FIX inhibitor level will be measured by the Nijmegen method at visit 1, visit 9 and visit 16. 
∀
FVIII inhibitors (BU) or
∀
FIX inhibitors (BU)
8.5.2.7
Anti-concizumab antibodies
Samples for the determination of anti-drug antibodies collected during the treatment period must be 
drawn at all visits and prior to administering concizumab at visit 2 and 3 (concizumab arm) and 
visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
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Date:
05 May 2017
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Version:
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Status:
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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.
Analysis for ADA will be done 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 antibodies assay
∀
Specificity assay (Anti-concizumab antibodies cross reacting with IgG4 backbone, CDR 
region or S241P mutation)
∀
Anti-concizumab neutralising antibodies assay
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. 
Neutralising antibodies will be analysed and reported at the EOT. A detailed description of the 
assay methods will be included in the antibody analysis report at the end of the trial.
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 
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tryptase measurement is necessary 1-2 weeks after the immediate severe hypersensitivity reaction 
due 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 collected at all visits except at screening only for the concizumab arm.
Samples will be collected pre-dose at visit 2 and 3 for concizumab arm and visit 9 and 9.1 for 
eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
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 
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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
FVII ELISA
FVII ELISA will be collected at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) pre-
dose eptacog alfa (rFVIIa) and post-dose at 10 min (±2 min), 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 eptacog alfa (rFVIIa) administration.
FVII in plasma will be quantified using a validated enzyme-linked immunosorbent assay (ELISA).
The FVII ELISA will detect the total sum of FVII in a sample, including endogenous FVII, eptacog 
alfa (rFVIIa) and FVII in complex with other molecules e.g. antithrombin. The ELISA has been 
validated for measuring FVII in human citrated plasma samples. Validation follows current 
guidelines for bioanalytical method validation. Bioanalytical data will be reported in a bioanalytical 
report.
8.5.2.10
Total TFPI
Total TFPI ELISA will be collected at all visits. Samples will be collected pre-dose at visit 2 and 3 
(concizumab arm) and visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
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 a 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.
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, see Section 2. 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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CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
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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. Plasma 
and serum is taken at visit 1 and 17. DNA for genotyping is only taken at visit 1.
8.6
Other assessments
8.6.1
Patient reported outcomes
A newly developed disease-specific electronic PRO (ePRO) the Hemophilia Treatment Experience 
Measure (Hemo-TEM) - is being validated in this trial. In order to assess the psychometric 
properties of Hemo-TEM, other questionnaires will be provided; see further appendix 1.
The following ePRO questionnaires will be used in the trial:
∀
Hemophilia Treatment Experience Measure (Hemo-TEM)
∀
Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS-PRN®) 16
∀
36-Item Short Form Health Survey (SF-36v2) (4 week recall)17
∀
Patient’s Global Impression of Change (PGI-C)
∀
Sheehan Disability Scale (SDS) 18
∀
Treatment Satisfaction Questionnaire for Medication (TSQM, version II) 19 20 21
∀
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)22
The ePROs should be assessed at the scheduled visits following the order listed below:
∀
visit 1 (Hemo-TEM, VERITAS-PRN®)
∀
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
∀
visit 3 (PGI-C, Hemo-TEM)
∀
visit 4 (PGI-C, Hemo-TEM)
∀
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, SIAQ-ISRQ)
∀
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
∀
visit 16 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
At visit 1: before any visit-related activities all patients should complete Hemo-TEM and 
VERITAS-PRN®.
At visit 2: before any visit-related activities all patients should complete Hemo-TEM, SF-36v2, 
SDS, TSQM and SIAQ-ISRQ.
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At visit 3-8: 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 visits 9, 10 and 16. 
∀
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. 
Exception: Patients randomised to eptacog alfa (rFVIIa) on-demand should not complete the 
ePRO at visit 3 as this is a phone visit.
At visit 9 if the patient has responded “0” or “2” in the PGI-C at all previous visits, the patient 
should complete PGI-C. All patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and 
SIAQ-ISRQ.
At visit 10 and 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and SIAQ-
ISRQ.
The investigator must check the ePROs for potential AEs and SAEs. The completed ePROs should 
be transmitted at each visit to the PRO database by the Investigator.
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 documented in the medical record.
8.6.2.1
Concizumab and NovoPen®4
Direction for use (DFUs) will be available as a 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 the 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 DFUs.
8.6.2.2
eptacog alfa (rFVIIa)
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.
The following should be emphasised for eptacog alfa (rFVIIa):
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∀
eptacog alfa (rFVIIa) should be slowly injected intravenously over 2 to 5 minutes
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 eptacog alfa (rFVIIa) treatments 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 duplicate 
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 EOT.
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 eptacog alfa (rFVIIa) 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 of the importance of following the instructions given including 
taking the trial products as prescribed.
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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 for the concizumab arm 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 eptacog alfa (rFVIIa) 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. 
Drug accountability will be performed and will be used to assess patient compliance together with 
the patients’ 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 TMM.
The trial product, concizumab B, appears as clear to slightly opalescent and colourless to slightly 
yellow. The trial product must not be used if it contains visible particles or discoloration.
The reconstituted eptacog alfa (rFVIIa) solution appears clear and colourless. Do not use the 
reconstituted solution if it contains visible particles or if it is discoloured.
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)
100 mg/mL
Solution for injection
s.c. injection
3 mL cartridge
eptacog alfa
(IMP a and NIMP b)
5 mg/vial
Powder for solution
for injection
i.v. injection
Vial
histidine 5 mL
N/A
Solvent for solution 
for injection
i.v. injection
prefilled syringe
a Investigational Medicinal Product (IMP) given as IMP for a single dose at visit 3 and 9.1.
b Non-Investigational Medicinal 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. It will be labelled in accordance with the EMA directive on medical devices annex I 23
and similar national legislation. A description of how to use the device is given in the DFU.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 24, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation.
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The investigator must document that DFUs are given to the patient orally and in writing at the first 
dispensing visit (see 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 (2oC-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)
eptacog alfa
5mg
Store between 2oC-25oC
Do not freeze
Protect from light
For single use
Do not freeze
Protect from light
To be used immediately 
after reconstitution
If not used 
immediately, store in 
refrigerator (2oC-8oC)
for up to 3 hours
histidine 5 mL
Store between 2oC-25oC 
Do not freeze
Protect from light
For single use
N/A
a In-use time for concizumab starts when first dose is administered from an individual cartridge and for eptacog alfa
(rFVIIa) 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.
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 (concizumab and eptacog alfa (rFVIIa) 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 histidine which 
should be discarded at home and not accounted for.
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All cartridges (concizumab) and vials (eptacog alfa (rFVIIa)) 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/or 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 product including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Destruction of concizumab and eptacog alfa (rFVIIa) 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 DFUs
∀
For eptacog alfa (rFVIIa) reconstitution and administration: Trial Injection Kit and DFU
Only needles and trial injection kit 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
∀
Randomisation
∀
Medication arrival
∀
Dispensing
∀
Dispensing verification
∀
Treatment discontinuation 
∀
Completion
∀
Drug accountability
∀
Data change
IWRS user manuals will be provided to each trial site.
11 Randomisation procedure and breaking of blinded codes
11.1
Randomisation 
Randomisation will be handed by the IWRS.
All patients included in the screening period and eligible for the trial will enter the trial and be 
randomised at visit 2 in a 2:1 allocation to either concizumab prophylaxis arm or eptacog alfa 
(rFVIIa) on-demand arm.
11.2
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 
∀
Mild – no or transient symptoms, no interference with the patient’s daily activities
∀
Moderate – marked symptoms, moderate interference with the patient’s daily activities
∀
Severe – considerable interference with the patient’s daily activities; unacceptable
∀
Causality 
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Relationship between an AE and the relevant trial product(s): 
∀
Probable - Good reason and sufficient documentation to assume a causal relationship
∀
Possible - A causal relationship is conceivable and cannot be dismissed
∀
Unlikely - The event is most likely related to aetiology other than the trial product
∀
Final outcome 
∀
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
∀
Recovering/resolving - The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the trial 
or has died from another AE
∀
Recovered/resolved with sequelae - The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE
∀
Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged or the outcome is not known
∀
Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported 
as an SAE
∀
Unknown - This term is only applicable if the patient is lost to follow-up
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-threatening a experience
∀
In-patient hospitalisation b or prolongation of existing hospitalisation
∀
A persistent or significant disability or incapacity c
∀
A congenital anomaly or birth defect
∀
Important medical events that may not result in death, be life threatening a or require 
hospitalisation b 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 SAE d
a. The term “life threatening” in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
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b. The term “hospitalisation” is used when a patient:
∀
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay or
∀
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a patient’s ability to conduct normal life functions (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 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 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
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Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1
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, see Section 8.4.5.2
Injection site reactions: 
Any injection site reaction symptom must be recorded on the AE form and the injection site 
reaction form.
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 type 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 will be performed. 
Definition of anaphylaxis (25)
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. dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow [PEF], hypoxemia)
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b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.
hypotonia [collapse], syncope, incontinence)
∀
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. dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
∀
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 treating physician. If according to the investigators judgement, 
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 Events 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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Trial ID: NN7415-4310
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Status:
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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:
∀
Platelet count (>100 × 109/L = 0, <100 × 109/L = 1, <50 × 109/L = 2)
∀
Elevated D-dimer (no increase = 0, moderate increase = 2, strong increase = 3)
∀
Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
∀
Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
∀
Calculate score: ≥5 compatible with overt DIC
B) Myocardial infarction is defined according to the “Third Universal Definition of
Myocardical Infarction” (26)
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:
∀
Symptoms of ischemia
∀
New or presumed new significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB)
∀
Development of pathological Q waves in the ECG
∀
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality
∀
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.
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C) Definition of pulmonary embolism:
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 embolism
(27).
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” (28).
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 “Haemorrhagic Infarction”).
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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.
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. A Transient ischemic attack 
(TIA) is a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal 
ischemia, without acute infarction (29).
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 DVT in the lower
extremities27. 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, 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 (30).
12.1.7
Technical complaints
A technical complaint is any written, electronic or oral communication that alledges 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 the pen and the 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 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.
When eptacog alfa (rFVIIa), NovoSeven® is used as IMP, expectedness should be performed 
according to the Company Core Data Sheet (CCDS).
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
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 (eptacog alfa (rFVIIa)) 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.
∀
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 AEs. 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.
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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
∀
Eptacog alfa (rFVIIa) 5 mg/vial, powder for solution for injection in a vial
∀
Histidine 5 mL, solvent for solution for injection in a 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.
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, AESI 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
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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 
Centre, 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.
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 with concizumab at visit 2 or 
visit 9 depending on the arm). At the last scheduled visit (visit 17), 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.
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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: 
∀
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 newborn 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 have not been investigated in clinical trials.
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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 
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.
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.
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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 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.
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:
∀
Pregnancy forms
∀
Technical complaint forms
∀
AE forms
∀
Safety information forms
The paper version of the technical complaint form, AE form, and safety information form must only 
be used to ensure timely reporting when/if the electronic CRF is unavailable.
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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.
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 eptacog alfa 
(rFVIIa)).
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 EOT visit.
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All data entered will be transferred from the device to an electronic database, where it is kept as a
certified copy of the source data. Data entered in the device will upon confirmation of a successful 
back-up be deleted from the device.
The eDiary will have built in edit checks and reminders to ensure that all relevant questions are 
answered. 
eDiary data transferred to the electronic database will be viewable to relevant trial site staff and 
Novo Nordisk personnel on a secure, password protected web portal.
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 Request Correction (DRC) must be submitted to 
the eDiary vendor. An audit trail will be maintained.
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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 
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. 
Monitoring visits should be scheduled as frequently as needed to support the first 6 patients 
recruited in the trial. 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 
ePROs and eDiaries are completed and reviewed by the investigator at the relevant scheduled visits 
and needed action has been taken and documented, if any.
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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
∀
Demography, see section 8.2.1
∀
Date of visit
Monitors will review the patient’s medical records and other source data (e.g. the 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.
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 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.
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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 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 archiving containing the 
electronic Investigator Trial Master File (eITMF) for each trial site. These CDs or other relevant 
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 FDA 21 CFR Part 11 
and ICH E6 (EU directive for personal data protection).1, 31
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.
The eDiary and ePRO 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, 31After trial 
completion, each trial site will be supplied with long-life CDs. These CDs will contain site-specific 
patient records including the patient’s eDiaries and audit trail including any data additions and 
corrections made on each form. The eDiary vendor will furthermore retain and securely store copies 
of all archived documents and data for 15 years or as required by local data retention laws for trial 
data.
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17 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 
17–1 for further information. 
Data from when the on-demand treated patients are transferred to concizumab s.c. prophylaxis will 
not be included in this evaluation. Observations from the extension part in the on-demand arm will 
be summarised separately as well as combined with observations from the main part when reporting 
the extension part data.
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 patients with inhibitors. The objective will be 
assessed when the last of the 24 patients has completed 24 weeks of dosing (or has withdrawn 
before that).
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the ABR of all patients in the concizumab group, irrespective of individual dose 
titration, with the ABR of the patients in the on-demand arm using different sets of observations. 
The primary CPoC criterion aims at evaluating the effect of concizumab when given at the last dose 
level reached for the 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 not be included. Since this evaluation disregards a 
subset of data collected post randomisation, the result should be viewed taking into 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 patients in the concizumab arm with 
the ABR of the patients in the on-demand arm using all data collected after randomisation. 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 part as offset and regimen as factor (concizumab vs. on-demand). For each criterion, 
evidence of effect will be concluded if the 95% confidence interval of the treatment ratio is below 1.
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.
17.1
Sample size calculation
The estimand will be defined as the “if all patients had adhered” estimand.
The treatment ratio between prophylactic s.c. concizumab and on-demand i.v. eptacog alfa (rFVIIa)
during at least 24 weeks for all randomised patients if all patients adhered to trial drug and did not 
initiate alternative treatment options.
This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand i.v. eptacog alfa 
(rFVIIa) under similar conditions as observed in this trial.
The sample size calculation has been determined based on this estimand and the CPoC criteria 
taking the small patient population into account, while also aiming for an acceptably narrow 95% 
confidence interval for the rate ratio.
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be 
accommodated by 16 patients in the concizumab arm and 8 in the comparator arm. 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, annual bleeding rates 
of 24 and 6 are assumed for the on-demand patients and the end dose concizumab regimen, 
respectively. Assuming further over-dispersion of 7, the power for concluding superiority of the 
concizumab regimen becomes approximately 80%. 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 17–1Power in superiority comparison between concizumab prophylaxis and on-demand 
treatment under different assumptions of ABR for concizumab and over-
dispersion (assuming on-demand ABR=24).
Power
Over-dispersion (over 6 months)
ABR (concizumab)
6
7
8
6
89%
82%
75%
7
84%
75%
70%
8
77%
69%
66%
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 7.6 for 
the concizumab regimen. This yields a marginal power of approximately 70% 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). In the 
NN7128-1907 trial in inhibitor patients, larger 1-year over-dispersion values of approximately 21 
and 18, respectively, were observed during an initial 3-month on-demand period and a subsequent 
3-month prophylaxis period. It is expected that the variation in the current trial will be smaller, 
partly due to the longer duration of the trial and partly due to an expected more homogenous patient 
population. Another published trial including inhibitor patients, comparing prophylaxis using 
FEIBA® with on-demand treatment, showed 6-month over-dispersion of 4-5 32. On that background, 
an over-dispersion of 7 over the 24 weeks in 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 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 endpoint will be analysed when the main part of trial has been completed.
17.3.1
Estimand and primary statistical analysis
The estimand for the primary endpoint is the “if all patients had adhered” estimand.
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The treatment ratio between prophylaxis s.c. concizumab and on-demand i.v. eptacog alfa (rFVIIa)
during at least 24 weeks for all randomised patients if all patients adhered to trial drug and did not 
initiate alternative treatment options.
This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand i.v. eptacog alfa 
(rFVIIa) under similar conditions as observed in this trial.
The estimand for the primary endpoint will be estimated using negative binomial regression with 
log of exposure time in main part as offset and regimen as factor, providing an estimate of the ABR 
ratio between regimens (concizumab prophylactic and on-demand eptacog alfa (rFVIIa)) with 
corresponding 95% confidence interval and also actual estimate of the ABR with corresponding 
95% confidence interval for each regimen. 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 estimand will be estimated based on the FAS
and only data collected prior to discontinuation of trial product or initiation of alternative treatment 
options will be used to draw inference.
17.3.2
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 Δ 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 part 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 concizumab 
prophylaxis no longer is superior to on-demand eptacog alfa (rFVIIa). The results of the primary 
analysis will be considered robust if the tipping point is above what is considered clinically
plausible.
17.3.3
Additional analysis
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 of number of bleeding episodes 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, TFPI value prior to the last s.c. dose 
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administration, peak thrombin generation (nM), Endogenous thrombin potential (nMxmin) and 
velocity index (nM/min).
17.4
Supportive secondary endpoints
17.4.1
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 number of spontaneous bleeding episodes during at least 24 weeks from treatment onset will be 
addressed in terms of the same estimand as for the primary endpoint. The estimand will be 
estimated using the same negative binomial regression model as for the primary endpoint.
Furthermore, an additional evaluation will be made, where actual concizumab dose is included as 
factors in the model.
The remaining supportive secondary efficacy endpoints will be summarised descriptively by 
treatment regimen. In addition, number of bleeding episodes during 76 weeks of treatment with 
prophylactic concizumab will be analysed using a negative binomial model with log of trial 
duration as offset, providing estimates of the ABR with confidence interval for that particular 
regimen.
17.4.2
Supportive secondary safety endpoints
∀
Number of TEAEs during at least 24 weeks from treatment onset
∀
Number of TEAEs during 76 weeks from treatment onset
∀
Number of TEAEs within 24 hours of rFVIIa administration
∀
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
∀
Occurrence rate 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
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∀
Change from baseline of APTT during 76 weeks from treatment onset
∀
Change from baseline of anti-thrombin (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.
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.
17.4.3
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.
17.4.4
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 (nMxmin) prior to the last dose administration at 24 
weeks
o
Endogenous thrombin potential (nMxmin) prior to the last dose administration at 76
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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17.4.5
Exploratory endpoints
17.4.5.1
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
17.4.5.2
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 VERITAS-PRN® after 24 weeks from treatment onset
∀
Change in 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
VERITAS-PRN®, SF-36v2, SDS and TSQM will be scored according to their respective scoring 
algorithms. Change from visit 2 to visit 9 will be analysed with an ANCOVA model including 
regimen as a factor and baseline score as covariate.
The PRO endpoints will be summarised using descriptive statistics and the remaining 
questionnaires (Hemo-TEM, PGI-C, SIAQ-ISRQ) will be summarised and listed using descriptive 
statistics.
17.5
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. Main part is 
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. 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 CTRs might in such case be issued. A CTR describing results 
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from the main and the 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 100 ng/mL, see Section 3.1.2. Based on these results, it is expected that the 
majority of the patients randomised to the concizumab treatment with 0.15 mg/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. For haemophilia patients with inhibitors 
and who are treated on-demand, expected improved efficacy is considered to be a major benefit in 
participating in this trial. Also, concizumab is administered s.c. and might reduce the burden of 
frequent i.v. injections associated with current treatment options in haemophilia patients with 
inhibitors.
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 several folds higher than the currently anticipated effective plasma 
concentration (mean area under curve [AUC] and Cmax) based on PK modelling.
In a drug–drug interaction study in monkeys, three doses of up to 1 mg/kg of NovoSeven® were 
administered at 2-h intervals, alone or in the presence of a steady state concentration of 
concizumab. Increased concentrations of thrombin–anti-thrombin (TAT) and D-dimer were seen, 
which tended to be additive when both concizumab and eptacog alfa (rFVIIa) were present in 
circulation. No notable clinical observations were made.
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
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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.
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.
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 the 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 
mechanisms33 34. 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 injuries35 36, 37.
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.
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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 
Helsinki 2.
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.
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 qualified person, 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 CTR.
∀
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.
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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 
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.
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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.
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 eptacog alfa (rFVIIa)
∀
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 sites outside the US)
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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, 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 GCP 1
applicable regulatory requirements and the Declaration of Helsinki 2.
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.
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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.
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).
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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
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 CTR for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the CTR (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 38. 
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-information.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the CTR is available. This includes the right not to release the results of interim 
analyses, because the release of such information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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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 Editors38 (sometimes referred to as the Vancouver 
Criteria).
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.
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.
Only applicable 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 EOT 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.
24.2
Retention of human biosamples
This trial will involve collection of human biosamples at visit 1 (screening visit) and at visit 17
(EOT) and these samples are to be stored maximum 15 years from EOT. 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 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 
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participate, while refusing permission for biological specimens to be stored for future exploratory 
analysis.
∀
Human biosamples will be stored at the central laboratory
∀
1.0 mL citrated plasma, 1.2 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 consortia
∀
The human biosamples will be transferred and stored after the EOT at a designated central 
laboratory
∀
Confidentiality and personal data protection will be ensured during storage after the EOT
∀
The human biosamples may be transferred to other countries (not applicable if local 
regulations prohibit export of human biosamples)
∀
The human biosamples will be destroyed at the latest 15 years from EOT
∀
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
can contact the investigator if they wish to be informed about results derived from stored 
human biosamples obtained from their own body, see 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. Remaining 
blood from the samples already collected may be used for further development of Anti-Drug 
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antibody assays, and will not be reported in this trial. The samples will be stored at a central bio-
repository after EOT and until marketing authorisation approval or until the research project 
terminates, but no longer than 15 years from EOT 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 CTR 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 CTR 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 Austria: Arzneimittelgesetz (BGBI. Nr. 185/1983) last amended with BGBl. 
II Nr. 105/2015
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 research for the person lending 
himself thereto and for indemnification of his beneficiaries, except in case of proof, incumbent on 
it, that the prejudice is not attributable to his fault or the fault of any intervening party, without the 
sponsor’s being entitled to call on acts by a third party or the voluntary withdrawal of the person 
who had initially consented to cooperating in the research”.
Only applicable for Poland: Novo Nordisk carries liability for the Trial exclusively in the scope 
defined by the applicable laws and in particular by the Civil Code and the Pharmaceutical Law 
dated 6 September 2001 (uniform version Journal pf Laws of 2008 No. 45 item 271 with 
amendments). In order to support potential claims for liability attributable to the Trial, Novo 
Nordisk and Investigators are covered by the Insurance Policy issued according to applicable Polish 
law.
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27 References
1.
International Conference on Harmonisation. ICH Harmonised Tripatite Guideline. Guideline 
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Protocol
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
135 of 136
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Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third 
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Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular 
Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary 
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CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
2
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
136 of 136
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inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 
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Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2016.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
1 of 138
Protocol
NN7415-4310
A Multi-Centre, Randomised, Open-Label, Controlled Trial 
Evaluating the Efficacy and Safety of Prophylactic 
Administration of Concizumab in Haemophilia A and B 
Patients with Inhibitors
Trial phase: 2
Includes: Protocol Version 1 (15 March 2017); Protocol Amendment no 1 (05 May 2017) for all 
participating countries; Protocol Amendment no 2 (15 November 2017) for all participating countries.
Protocol originator
, Senior International Trial Manager 
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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 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
2 of 138
Table of Contents
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................7
Table of Tables............................................................................................................................................8
List of abbreviations ...................................................................................................................................9
1
Summary............................................................................................................................................16
2
Flow chart ..........................................................................................................................................19
2.1
Visits and assessments ............................................................................................................19
2.2
Explanatory descriptions .........................................................................................................22
3
Background information and rationale for the trial.........................................................................24
3.1
Background information..........................................................................................................24
3.1.1
Haemophilia ..........................................................................................................24
3.1.2
Concizumab...........................................................................................................25
3.2
Rationale for the trial...............................................................................................................28
4
Objective(s) and endpoint(s)..............................................................................................................29
4.1
Objective(s) ............................................................................................................................29
4.1.1
Primary objective...................................................................................................29
4.1.2
Secondary objectives .............................................................................................29
4.2
Endpoint(s) .............................................................................................................................29
4.2.1
Primary endpoint ...................................................................................................29
4.2.2
Secondary endpoints ..............................................................................................29
4.2.2.1
Supportive secondary endpoints .......................................................29
4.2.3
Exploratory endpoints............................................................................................30
4.2.3.1
Exploratory safety endpoints ............................................................30
4.2.3.2
Exploratory patient reported outcome endpoints ...............................30
5
Trial design ........................................................................................................................................32
5.1
Type of trial ............................................................................................................................32
5.1.1
Surgery..................................................................................................................33
5.2
Rationale for trial design .........................................................................................................33
5.3
Treatment of patients...............................................................................................................36
5.3.1
Concizumab arm....................................................................................................37
5.3.1.1
Concizumab prophylactic treatment (main and extension part)..........37
5.3.2
Comparator arm (eptacog alfa (rFVIIa)).................................................................38
5.3.2.1
On-demand treatment (main part).....................................................38
5.3.2.2
Concizumab prophylactic treatment (extension part).........................38
5.3.3
Dose escalation......................................................................................................38
5.3.4
Co-administration of eptacog alfa (rFVIIa).............................................................40
5.3.5
Treatment of bleeding episodes during the trial ......................................................41
5.3.6
Prohibited medication ............................................................................................42
5.4
Treatment after discontinuation of trial product .......................................................................42
5.5
Rationale for treatment............................................................................................................42
6
Trial population .................................................................................................................................43
6.1
Number of patients..................................................................................................................43
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
3 of 138
6.2
Inclusion criteria .....................................................................................................................43
6.3
Exclusion criteria ....................................................................................................................43
6.4
Criteria for premature discontinuation of trial product .............................................................44
6.5
Withdrawal from trial..............................................................................................................44
6.6
Patient replacement .................................................................................................................45
6.7
Rationale for trial population...................................................................................................45
7
Milestones...........................................................................................................................................46
8
Methods and assessments ..................................................................................................................47
8.1
Visit procedures ......................................................................................................................47
8.1.1
Informed consent, genotyping and long-term storage consent .................................49
8.1.2
Screening log, enrolment log, trial card and patient number....................................49
8.1.3
Screening failures and re-screening........................................................................49
8.1.4
Premature discontinuation of trial product..............................................................50
8.1.5
Withdrawal from trial.............................................................................................50
8.1.6
Review/ evaluation of clinical outcome..................................................................50
8.1.7
Visit 1 (Screening part)..........................................................................................51
8.1.8
Training of patients at visit 1, visit 2 and visit 9......................................................51
8.1.9
Treatment period at home ......................................................................................52
8.1.10
Staggered recruitment ............................................................................................52
8.1.11
Treatment period – Main part.................................................................................52
8.1.11.1
Visit 2 (Randomisation) ...................................................................52
8.1.11.2
Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and 
PK visit for concizumab arm)...........................................................54
8.1.11.3
Visit 4, 5, 6, 7 and 8 .........................................................................55
8.1.11.4
Visit 9 ..............................................................................................56
8.1.12
Treatment period – Extension part..........................................................................58
8.1.12.1
Visit 9.1 (PK visit and ONLY patients previously on the eptacog 
alfa (rFVIIa) on-demand arm) ..........................................................58
8.1.12.2
Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) 
on-demand arm)...............................................................................59
8.1.12.3
Visit 10 ............................................................................................59
8.1.12.4
Visit 10.1 (ONLY patients previously on the eptacog alfa 
(rFVIIa) on-demand arm) .................................................................60
8.1.12.5
Visit 11 ............................................................................................61
8.1.12.6
Visit 11.1 (ONLY patients previously on the rFVIIa on-demand 
arm) .................................................................................................62
8.1.12.7
Visit 12, 13, 14 and 15 .....................................................................63
8.1.12.8
Visit 16 ............................................................................................63
8.1.13
Visit 17 (End of trial) - Follow-up part...................................................................64
8.1.14
Unscheduled Visit..................................................................................................65
8.2
Patient related information/assessments...................................................................................65
8.2.1
Demography ..........................................................................................................65
8.2.2
Concomitant illness and medical history other than haemophilia ............................65
8.2.3
Concomitant medication ........................................................................................66
8.2.4
Details of Haemophilia, Haemophilia treatment and bleed history..........................66
8.3
Efficacy assessments...............................................................................................................67
8.3.1
Bleeding episodes ..................................................................................................67
8.4
Safety assessments ..................................................................................................................71
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
4 of 138
8.4.1
Physical examination .............................................................................................71
8.4.2
Body measurements...............................................................................................71
8.4.3
Vital Signs.............................................................................................................72
8.4.4
Electrocardiogram..................................................................................................72
8.4.5
Adverse events.......................................................................................................73
8.4.5.1
Medication error...............................................................................73
8.4.5.2
Adverse events requiring additional data collection ..........................73
8.5
Laboratory assessments...........................................................................................................75
8.5.1
Laboratory assessments for efficacy.......................................................................76
8.5.1.1
Thrombin generation........................................................................76
8.5.1.2
Free TFPI.........................................................................................77
8.5.2
Laboratory assessments for safety ..........................................................................77
8.5.2.1
Urinalysis.........................................................................................77
8.5.2.2
Haematology....................................................................................77
8.5.2.3
Biochemistry....................................................................................78
8.5.2.4
FVIII/FIX activity............................................................................78
8.5.2.5
Coagulation parameters....................................................................79
8.5.2.6
FVIII/FIX inhibitors.........................................................................79
8.5.2.7
Anti-concizumab antibodies .............................................................79
8.5.2.8
Concizumab ELISA .........................................................................81
8.5.2.9
FVII ELISA .....................................................................................82
8.5.2.10
Total TFPI........................................................................................82
8.5.3
Human Biosamples ................................................................................................83
8.6
Other assessments ...................................................................................................................83
8.6.1
Patient reported outcomes ......................................................................................83
8.6.2
Training.................................................................................................................84
8.6.2.1
Concizumab and NovoPen®4............................................................84
8.6.2.2
eptacog alfa (rFVIIa)........................................................................85
8.6.2.3
eDiary..............................................................................................85
8.6.3
Surgery..................................................................................................................85
8.7
Patient compliance..................................................................................................................86
8.8
Treatment compliance.............................................................................................................86
9
Trial supplies......................................................................................................................................87
9.1
Trial products..........................................................................................................................87
9.2
Labelling.................................................................................................................................87
9.3
Storage....................................................................................................................................88
9.4
Drug accountability and destruction ........................................................................................88
9.5
Auxiliary supplies ...................................................................................................................89
10
Interactive voice/web response system ..............................................................................................90
11
Randomisation procedure and breaking of blinded codes................................................................90
11.1
Randomisation ........................................................................................................................90
11.2
Breaking of blinded codes .......................................................................................................90
12
Adverse events, and technical complaints .........................................................................................91
12.1
Definitions ..............................................................................................................................91
12.1.1
Adverse event ........................................................................................................91
12.1.2
Serious adverse event.............................................................................................92
12.1.3
Non-serious adverse event......................................................................................93
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
5 of 138
12.1.4
Medication errors...................................................................................................93
12.1.5
Adverse events requiring additional data collection................................................94
12.1.6
Adverse Events of special interest ..........................................................................95
12.1.7
Technical complaints .............................................................................................99
12.2
Reporting of adverse events.....................................................................................................99
12.3
Follow-up of adverse events..................................................................................................102
12.4
Technical complaints and technical complaint samples..........................................................103
12.4.1
Reporting of technical complaints ........................................................................103
12.4.2
Collection, storage and shipment of technical complaint samples .........................104
12.5
Pregnancies...........................................................................................................................104
12.5.1
Pregnancies in female partners of male patients....................................................104
12.6
Precautions and/or overdose..................................................................................................105
12.7
Rules for putting enrolment on hold ......................................................................................106
12.8
Committees related to safety .................................................................................................106
12.8.1
Novo Nordisk safety committee ...........................................................................106
12.8.2
Data monitoring committee..................................................................................106
13
Case report forms ............................................................................................................................107
13.1
Corrections to case report forms............................................................................................108
13.2
Case report form flow ...........................................................................................................108
13.3
Electronic diary.....................................................................................................................108
14
Monitoring procedures ....................................................................................................................110
15
Data management ............................................................................................................................111
16
Computerised systems .....................................................................................................................112
17
Statistical considerations .................................................................................................................113
17.1
Sample size calculation .........................................................................................................114
17.2
Definition of analysis sets......................................................................................................115
17.3
Primary endpoint...................................................................................................................115
17.3.1
Estimand and primary statistical analysis .............................................................115
17.3.2
Sensitivity analysis ..............................................................................................116
17.3.3
Additional analysis ..............................................................................................116
17.4
Supportive secondary endpoints ............................................................................................117
17.4.1
Supportive secondary efficacy endpoints..............................................................117
17.4.2
Supportive secondary safety endpoints.................................................................117
17.4.3
Supportive secondary pharmacokinetic endpoints.................................................118
17.4.4
Supportive secondary pharmacodynamic endpoints..............................................118
17.4.5
Exploratory endpoints..........................................................................................119
17.4.5.1
Exploratory safety endpoints ..........................................................119
17.4.5.2
Exploratory patient reported-outcome endpoints.............................119
17.5
Interim analysis.....................................................................................................................119
18
Ethics................................................................................................................................................121
18.1
Benefit-risk assessment of the trial ........................................................................................121
18.2
Informed consent ..................................................................................................................123
18.3
Data handling........................................................................................................................123
18.4
Information to patients during trial ........................................................................................124
18.5
Premature termination of the trial and/or trial site..................................................................124
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
6 of 138
19
Protocol compliance.........................................................................................................................125
19.1
Protocol deviations................................................................................................................125
19.2
Prevention of missing data ....................................................................................................125
20
Audits and inspections .....................................................................................................................126
21
Critical documents...........................................................................................................................126
22
Responsibilities.................................................................................................................................128
23
Reports and publications .................................................................................................................129
23.1
Communication of results......................................................................................................129
23.1.1
Authorship...........................................................................................................130
23.1.2
Site-specific publication(s) by investigator(s).......................................................130
23.2
Investigator access to data and review of results ....................................................................130
24
Retention of clinical trial documentation and human biosamples..................................................131
24.1
Retention of clinical trial documentation ...............................................................................131
24.2
Retention of human biosamples.............................................................................................131
24.2.1
Antibody samples ................................................................................................132
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........134
26
Indemnity statement ........................................................................................................................135
27
References ........................................................................................................................................136
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. 
Appendix 1
Patient Reported Outcomes
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
7 of 138
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. 
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......................................27
Figure 5–1 Schematic diagram of the trial design......................................................................................32
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. ...................................................................................................35
Figure 5–3 Dose escalation for one individual patient in the concizumab arm............................................39
Figure 5–4 Dose escalation for one individual patient in the comparator arm.............................................40
Figure 8–1 Visit schedule – concizumab arm. ...........................................................................................47
Figure 8–2 Visit schedule – eptacog alfa (rFVIIa) arm later switching to concizumab.........................47
Figure 12–1 Reporting of AEs ..................................................................................................................101
Figure 17–1 Definition of main and extension part....................................................................................120
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
8 of 138
Table of Tables
Page
Table 5–1
List of products provided by Novo Nordisk .............................................................................36
Table 8–1
Definition of stop of bleeding episode .....................................................................................69
Table 8–2
Definitions of bleeding episodes (cause of bleed) ....................................................................69
Table 8–3
Definition of bleeding episode severity and treatment recommendation ...................................69
Table 9–1
Trial products..........................................................................................................................87
Table 9–2
Storage conditions...................................................................................................................88
Table 17–1 Power in superiority comparison between concizumab prophylaxis and on-demand 
treatment under different assumptions of ABR for concizumab and over-dispersion 
(assuming on-demand ABR=24). ..........................................................................................115
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
9 of 138
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
CCDS
company core data sheet 
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 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
10 of 138
CPoC
clinical proof of concept
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
DRC
data request correction 
DUN
dispensing unit number
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
eITMF
electronic investigator trial master file
ELISA
enzyme-linked immunosorbent assay
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
11 of 138
EMA
european medicines agency
EOT
end of trial
ePRO
electronic patient reported outcome
eptacog alfa 
the name ‘eptacog alfa (rFVIIa)’ will be used throughout 
the protocol and the product is identical to 
rFVIIa,‘NovoSeven®, and ‘NiaStaseRT®’
ETP
endogenous thrombin potential 
FAS
full analysis set
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
FVIIa
activated coagulation factor VII
FVIII
coagulation factor VIII
FVIII:C
plasma activity of factor VIII
FX
coagulation factor X
FXa
activated coagulation factor X
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GHN
global haemophilia network
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
12 of 138
HCP
host cell protein
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
IEC
independent ethics committee
IgG4
immunoglobulin G4
IMP
investigational medicinal product
INN
International Non-Proprietary Names for Pharmaceutical 
Substances 
IRB
institutional review board
ISRQ-SIAQ
Injection Site Reaction Questionnaire – Self-Injection 
Assessment Questionnaire 
ISTH
International Society on Thrombosis and Haemostasis
IT
information technology
i.v.
intravenous(-ly)
IWRS
interactive web response system
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
13 of 138
LBBB
left bundle branch block
LPFV
last patient first visit
LPLV
last patient last visit
mAb
monoclonal antibody
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRA
magnetic resonance angiogram
MRI
magnetic resonance imaging
NOAEL
no observed adverse effect level 
NIMP
non investigational medicinal product
PCD
primary completion date 
PD
pharmacodynamics
PEF
peak expiratory flow
PGI-C
Patient’s Global Impression of Change
PK
pharmacokinetics
PP
per protocol
PRO
patient reported outcome
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
14 of 138
PT
prothrombin time
Q
Inter compartmental clearance
QA
quality assurance
Q4D
every 4th day
eptacog alfa (rFVIIa)
the name ‘eptacog alfa (rFVIIa)’ will be used throughout 
the protocol and the product is identical to ‘NovoSeven®’
sABR
spontaneous annualised bleeding rate
SAE
serious adverse event
SAS
safety analysis set
sBE
spontaneous bleeding episodes
s.c.
subcutaneous(-ly)
SDS
Sheehan Disability Scale
SF-36v2
36-Item Short Form Health Survey
SI
international system of units
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse reaction
TAT
thrombin-antithrombin complex
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
15 of 138
TF
tissue factor
TFPI
tissue factor pathway inhibitor
TG
thrombin generation
TMM
trial materials manual
TSQM
Treatment Satisfaction Questionnaire for Medication 
TVP
trial validation plan
UTN
Universal Trial Number
VERITAS-PRN® 
Validated Hemophilia Regimen Treatment Adherence 
Scale
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
16 of 138
1
Summary
The main objective for the phase 2 trial NN7415-4310, explorer™4, is to assess the efficacy of 
concizumab administered s.c. once daily to prevent bleeding episodes in haemophilia A and B 
patients with inhibitors. Furthermore, this trial aims to assess the longer-term efficacy and safety of 
concizumab in haemophilia A and B patients with inhibitors and to establish the safety of treating 
breakthrough bleeding episodes with recombinant factor VIIa (rFVIIa) in these patients.
Objective(s) and endpoint(s)
Primary objective
∀
To assess the efficacy of concizumab administered s.c. once daily in preventing bleeding 
episodes in haemophilia A and B patients with inhibitors.
Secondary objectives
∀
To assess the longer-term efficacy of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of administering recombinant factor VIIa (rFVIIa) to haemophilia 
patients with inhibitors that are exposed to concizumab
∀
To assess the immunogenicity of concizumab in haemophilia patients with 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
∀
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 dosing
treatment with trial product (or has 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.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
17 of 138
Trial design
The trial is a multi-centre, randomised (2:1), open-label, controlled trial, aiming to evaluate the 
efficacy and safety of concizumab 0.15 mg/kg (with potential dose escalation) administered daily 
s.c. in haemophilia patients with inhibitors. We expect 16 patients to complete treatment in 
concizumab arm (concizumab prophylaxis) and 8 patients in comparator arm (rFVIIa on demand). 
The dose regimen is selected based on relevant PK and TFPI data as well as PK/PD modelling of 
the results from the preceding explorer™ trials. Only on-demand patients will be eligible for the 
trial.
For all patients treated with concizumab (concizumab arm and comparator arm extention part) a 
loading dose of 0,5 mg/kg concizumab will be given as the first dose, followed by one week of 
concizumab dosing 0,15 mg/kg. All patients in treatment with concizumab will in a non-bleeding 
state receive a single dose of 90 μg/kg eptacog alfa (rFVIIa) one week after dosing with 
concizumab. Hereafter, patients will be closely clinically observed at the site for potential safety 
issues for at least 12h and evaluated again at the site after 24h.
The total trial duration for the individual patient will be approximately 86-88 weeks, consisting of a 
2-4 week screening period, a subsequent 76-week treatment period and an 8-week follow-up period.
eptacog alfa (rFVIIa) for treatment of bleeding episodes during the trial will be provided by Novo 
Nordisk. The patient will not be provided with trial product or eptacog alfa (rFVIIa) after end of 
trial.
The trial is split into a main part which lasts 24 weeks for all patients in the trial and an extension 
part which lasts 52 weeks. In the main part, the primary and selected secondary endpoints will be 
analysed when 16 patients have completed a minimum of 24 weeks of concizumab prophylaxis and 
8 patients have completed a minimum of 24 weeks of eptacog alfa (rFVIIa) on-demand or have 
withdrawn. The analysis of the main part of the trial aims to substantiate the clinical proof of 
concept (CPoC) that concizumab has the potential to prevent bleeding episodes in patients with 
haemophilia and inhibitors. The extension part of the trial will provide additional safety and long-
term efficacy data.
Trial population
Number of patients planned to be screened: 28
Number of patients planned to be started on trial product: 26
Number of patients expected to complete the trial: 24
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
18 of 138
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 haemophilia A or B patients with inhibitors aged ≥ 18 years at the time of signing 
informed consent
∀
Patients currently in need of treatment with bypassing agents
Key exclusion criteria
∀
Known or suspected hypersensitivity to trial product(s) or related products
∀
Known inherited or acquired bleeding disorder other than haemophilia
∀
Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX
Key Efficacy assessment
∀
Number of bleeding episodes during at least 24 weeks of treatment onset
Key Safety assessment
∀
Number of treatment emergent adverse events during at least 24 weeks of treatment onset
Trial products
The following products will be used in the trial:
∀
Investigational Medicinal Products:
o
concizumab B, 100mg/mL to be administered s.c. with NovoPen®4 and needles
o
eptacog alfa (rFVIIa), 5mg /vial and histidine (solvent). Reconstituted eptacog alfa 
(rFVIIa) is for intravenous administration and used in the trial at visit 3 and 9.1 for all 
patients with the purpose of investigating the safety of administering eptacog alfa 
(rFVIIa) to haemophilia patients
∀
Non Investigational Medicinal Product:
o
eptacog alfa (rFVIIa) 5 mg /vial and histidine (solvent). Reconstituted eptacog alfa is for 
intravenous administration and used in this trial for treatment of bleeding episodes
3URWRFROY
CONFIDENTIAL


Protocol
UTN: U1111-1179-2925
Date:
15 November 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
3.0
Page:
19 of 138
2
Flow chart
2.1
Visits and assessments
explorerTM4 trial periods
Screening
Treatment main a, b
Treatment extension b
Follow-
up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-
scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
7 days 
after V9
197
225
253
281
309
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w 72w 76w
-
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/ Genotyping and Long-term 
storage consent
●
In/exclusion criteria
●
●g
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and 
bleed history
●
Withdrawal criteria/ Criteria for premature 
discontinuation of trial product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Randomisation (IWRS)
●
EFFICACY
Bleeding episodes h, i
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab) 
●
●l
●j, k, l
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Free TFPI (central lab)  
●
●l
●k, l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
SAFETY
Physical examination
●
●
●k
●
●
●
●
●
●
Body measurements 
●
●m
●k, m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
Vital signs 
●
●n
●k, n
●
●
●
●
●
●n
●n
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
15 November 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
3.0
Page:
20 of 138
explorerTM4 trial periods
Screening
Treatment main a, b
Treatment extension b
Follow-
up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-
scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
7 days 
after V9
197
225
253
281
309
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w 72w 76w
-
84w
Injection site reaction  
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●l
●j, k, l
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Biochemistry (central lab)
●
●l
●k, l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
FVIII/ FIX activity (central lab)
●
●l
●l
Coagulation parameters (central lab)
●
●l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●l
●
●
Coagulation parameters (PT, APTT and Fibrinogen 
(local lab))
●j, k, l
●j
FVIII/FIX  inhibitors (central lab)
●
●l
●l
Anti-concizumab antibodies (ADA) (special lab) o
●
●l
●k, l, p
●p
●p
●p
●p
●p
●l, p
●
●
●
●
●
●
●
●
●
●
●l
●
●
Concizumab  ELISA (special lab)
●l
●j, k, l, p
●p
●p
●p
●p
●p
●l, p
●j
●
●
●
●
●
●
●
●
●
●l
●
●
FVII ELISA (special lab)
●j, k. l
●j
Total TFPI (special lab)
●
●l
●k. l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
TRIAL MATERIAL
IWRS call 
●
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab)r
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (eptacog alfa, histidine)q
●
●w
●k
●
●
●
●
●
●
●
●
●
●
●
Administration of trial product (concizumab)r
●k, s
●k
●d, s 
●
●s
●
Administration of trial product (eptacog alfa)
●k, t
●t
Drug accountability (concizumab)
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Drug accountability (eptacog alfa) 
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product e, u
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires 
●
●
●k
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
15 November 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
3.0
Page:
21 of 138
explorerTM4 trial periods
Screening
Treatment main a, b
Treatment extension b
Follow-
up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-
scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
7 days 
after V9
197
225
253
281
309
337
393
449
505
533
When 
applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w 72w 76w
-
84w
Handout ID card 
●
Training v
●
●
●
●
●
Compliance: eDiary
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
The cells marked in ‘red’ are only for the patients randomised to eptacog alfa (rFVIIa) arm.
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
15 November 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
3.0
Page:
22 of 138
2.2
Explanatory descriptions
Footer
Description
a
There is staggered recruitment for the 4 first patients in the trial on the concizumab arm. 
b
Concizumab administration is performed at home except for visit 2 and visit 3 for patients randomised to concizumab and visit 9 and 9.1 for patients 
randomised to eptacog alfa. Sampling for Free TFPI, Anti-concizumab antibodies, Concizumab ELISA and Total TFPI are done prior to concizumab 
administration.
c
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 and 
visit 9.1 have a PK session of 24 hours and a safety follow up visit the following day. 
d
Visit and procedures only performed for patients randomised to eptacog alfa and switching to concizumab treatment.Visit 9.1 should be performed 7 days (+ 1 
day) after visit 9.
e
For patients being dose escalated on concizumab a phone call is recommended 1 week after first dose of concizumab.
f
Daily dosing preferably at the same time in the morning.
g
Evaluation of the laboratory results obtained from samples taken at screening.
h
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.
i
Eptacog alfa will be given to treat breakthrough bleeding episodes. 
j
Sampling time schedule for thrombin generation, haematology,  coagulation parameters, concizumab ELISA and FVII ELISA: pre-dose (-1 hour), post-dose: 
10 min (±2 min), 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 
eptacog alfa administration.
k
ONLY for patients randomised to concizumab arm. The concizumab dose should be administered first followed by eptacog alfa dose. The interval between the 
concizumab and eptacog alfa should not exceed more than 30 min.
l
At visit 2, visit 3, visit 9 and 16 blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been 
performed.
m
Only body weight should be measured. 
n
Vital signs should be evaluated before and after trial drug administration at visit 2 and visit 3 for concizumab arm and at visit 9 and visit 9.1 for patients in 
eptacog alfa arm switching to concizumab treatment.
o
In case 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 blood samples will be taken and stored for characterisation 
of the antibodies.
p
Blood sampling for anti-concizumab antibodies and concizumab ELISA testing should only be collected for patients on concizumab.
q
If needed dispensing of eptacog alfa, histidine, trial injection kits and Direction For Use (DFU). 
r
First treatment dose of concizumab is a loading dose and will be administered at visit 2 for the concizumab arm and visit 9 for the eptacog arm. 
s
The patient must be in a non-bleeding state at the time of the first concizumab administration and should not have received any bypassing agent drugs,(e.g., 
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eptacog alfa, FEIBA®) for treatment of a bleeding episode within a period of 24h (for eptacog alfa) or 48h (for FEIBA®) prior to first concizumab. Only 
eptacog alfa is allowed after visit 2.
t
Eptacog alfa administered in a non-bleeding state at site at visit 3 for the concizumab arm and at visit 9.1 for the eptacog alfa arm. The concizumab dose 
should be administered first followed by eptacog alfa dose. The interval between the concizumab and eptacog alfa should not exceed more than 30 min.
u
Patient treated with concizumab 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 the investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose 
escalation. 
v
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Patients randomised to eptacog alfa will be re-trained in 
NovoPen®4 and s.c. administration at visit 9 and 9.1. If necessary training can be performed as needed at other visits. The eDiary will be provided to the 
patients at visit 2 if the patient feels capable in s.c. administration and using the eDiary. Further the patients will be trained in recognition of signs/symptoms of 
thrombosis.
w
Only for patients randomised to on-demand arm.
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP 1, applicable regulatory 
requirements,  in accordance with the Declaration of Helsinki 2 and ISO 14155 3.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
The 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). In haemophilia B, it is factor IX (FIX) that is deficient. 
Inheritance is chromosome X-linked; 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 births 4. According to 
the World Federation of Haemophilia global survey of 20145, 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 factor 6. With a deficiency of FVIII or FIX, the degree of activation of 
coagulation FX becomes insufficient. Consequently, the thrombin burst is delayed and insufficient 
for normal haemostasis 7. 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 symptoms 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 into a joint prior to age 4 year. Many children also bleed from other body sites before this 
age is reached 8. For this reason, primary prophylaxis with regular FVIII or FIX injections in the 
non-bleeding state is the recommended treatment from early childhood.
In patients who have developed inhibitors towards FVIII or FIX, replacement therapy is rendered 
ineffective. Though prevalence studies and registry data indicate that the prevalence of inhibitors in 
the haemophiliac population overall has been reported to be between 5% and 7% 9, the prevalence 
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amongst patients with severe haemophilia (FVIII:C < 1%) is higher and has been reported to be up 
to 30% 9, 10. These patients may be treated with bypassing agents, activated FVII (NovoSeven®) and 
activated prothrombin complex concentrate (FEIBA®) given as i.v. injections.
Current treatment options in haemophilia, replacement therapy or bypassing therapy, are hampered 
by the fact that these products must be given as i.v. injections. Furthermore, bypassing agents are
characterized by relatively short half-lives, therefore prophylactic treatment is burdensome. It is
also generally acknowledged that the efficacy profile of bypassing agents is inferior to replacement 
therapy. Consequently, delayed or sub-optimal treatment occurs in a significant number of patients
with inhibitors. 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 Dalton’s.  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)) 10. 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.
Key differentiators of this new mode of action (MoA) and the key benefit of concizumab in patients 
with severe haemophilia A and B with inhibitors is reduced treatment burden due to subcutaneous 
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, explorerTM1) 11, a single dose trial in Japanese healthy subjects (NN7415-3981), 
two multiple dose trials (NN7415-3986, explorerTM2) and (NN7415-4159, explorer™3). When the 
first cohort with 4 (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 trial animal had concizumab plasma concentrations several hundred fold 
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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 (NN7415-4159), explorer™3,
a new 52 week non-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.
The explorer™3 trial was finalised following the completion of cohort 3 (0.8 mg/kg s.c. 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 s.c. every 4 days for 6 weeks). No clinical consequences or 
serious adverse events were seen in the completed cohorts in explorer™3.
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 3–1Individual 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™4.
In a drug–drug interaction study in monkeys (NN215431), three doses of up to 1 mg/kg of 
NovoSeven® were administered at 2h intervals, alone or in the presence of a steady state 
concentration of concizumab. No notable clinical observations were made, no treatment-related 
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adverse findings were seen, i.e. no thrombi or other signs of excessive coagulation. Increased 
concentrations of thrombin–anti-thrombin (TAT) and D-dimer were seen, which tended to be 
additive when both concizumab and eptacog alfa (rFVIIa) were present in circulation.
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 studies with concizumab have been finalised. Key safety and preliminary 
efficacy results from these phase 1 studies support further development of concizumab in 
haemophilia 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 haemophilia A and B patients with inhibitors
4.1.2
Secondary objectives
∀
To assess the longer-term efficacy of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of administering recombinant factor VIIa (rFVIIa) to haemophilia 
patients with inhibitors that are exposed to concizumab
∀
To assess the immunogenicity of concizumab in haemophilia patients with 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
∀
Number of TEAEs within 24 hours of rFVIIa administration
∀
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
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∀
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 anti-thrombin (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
∀
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 (nMxmin) prior to the last dose administration at 24 
weeks 
o
Endogenous thrombin potential (nMxmin) 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
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
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∀
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
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 multi-centre, randomised (2:1), open-label, controlled trial, aiming to evaluate the 
efficacy and safety of concizumab 0.15 mg/kg (with potential dose escalation) administered daily 
s.c. in haemophilia patients with inhibitors. The selected dose regimen is based on relevant PK and 
TFPI data as well as PK/PD modelling of the results from the preceding explorer™ trials. Only   
on-demand patients will be eligible for the trial.
Figure 5–1Schematic diagram of the trial design
The total trial duration for the individual patient will be approximately 86-88 weeks, including a 2-4 
week screening period, a 76 week treatment period, and a follow-up period of 8 weeks, see Figure 
5–1
The trial is split into a main part which lasts 24 weeks for all patients in the trial and an extension 
part which lasts up to 52 weeks. In the main part, the primary and selected secondary endpoints will 
be analysed when 16 patients have completed a minimum of 24 weeks of concizumab prophylaxis
and 8 patients have completed a minimum of 24 weeks of eptacog alfa (rFVIIa) on-demand or have 
withdrawn.
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In the concizumab arm bleeding episodes occurring during the trial will be treated with eptacog alfa 
(rFVIIa). In all patients treated with concizumab a single 90 μg/kg dose of eptacog alfa (rFVIIa)
will be administered in a non-bleeding state one week after dosing with concizumab has been 
initiated. The investigator will evaluate if there are any safety concerns 24 hours post eptacog alfa 
(rFVIIa) administration. Furthermore, the scheduled administration of eptacog alfa (rFVIIa) for the 
first 4 patients entering the trial with concizumab will be staggered.
In the comparator arm, in the main part, patients will receive eptacog alfa (rFVIIa) on-demand 
treatment. After completion of the main part, the patients will continue the trial in the extension part 
being treated with prophylactic concizumab 0.15 mg/kg (with potential dose escalation) s.c. daily 
administration.
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 and damage. Acceptance of storage of human biosamples 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 human biosamples to be stored 
for future exploratory analysis, see Section 8.1.1.
An independent data monitoring committee (DMC) will be established for this trial. The DMC will 
review all safety data from the ongoing trial with concizumab exposure, see Section 12.8.2.
5.1.1
Surgery
Minor surgery is allowed in this trial. Major surgery conducted earlier than one month (30 days) 
prior to trial start is allowed, see exclusion criteria 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™4 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 with inhibitors. A dose escalation design will allow cautious dose escalation in order to 
identify an efficacious and safe concizumab dose for the individual patient. A comparator arm is 
included to assess if concizumab is superior to on-demand treatment. Furthermore, the trial will 
give a possibility to assess safety of co-administration of eptacog alfa (rFVIIa) to the patients 
exposed to the concizumab treatment.
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The duration of 24 weeks for the main part of the trial is deemed necessary in order to obtain 
information on the annualised bleeding rate on concizumab prophylaxis. The duration of the 
extension part of the trial will be 52 weeks and provide further information on efficacy, i.e.
annualised bleeding rate, and also provide additional safety data upon 76 weeks treatment with 
concizumab.
A total of 26 patients previously on-demand (OD) treatment will be randomised into one of the two 
arms, with 16 patients in the concizumab arm and 8 patients in the comparator arm see Figure 5–1. 
Concizumab will be administered s.c. daily for patients randomised to the concizumab arm in the 
main and the extension part of the trial. For patients in the comparator arm in the extension part
treatment will be changed from on-demand with rFVIIa to prophylaxis with concizumab.
The concizumab dose regimens will be starting with 0.15 mg/kg with the possibility to escalate to
0.20 mg/kg and 0.25 mg/kg based on bleeding frequency, see Section 5.3.3.
Daily dosing with concizumab 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 5.3.3.
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Figure 5–2Individual 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.1
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 
                                               
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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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™4. Daily dosing will allow for 
the increase in trough levels and thus better efficacy may be expected with a lower dose.
A loading dose of 0.5 mg/kg concizumab will be given as the first dose, followed by one week of 
concizumab dosing 0.15 mg/kg in order to ensure steady-state levels at the time of eptacog alfa 
(rFVIIa) administration. eptacog alfa (rFVIIa) will be administered one week after initiation of 
dosing with concizumab in a non-bleeding state to assess safety of treatment with eptacog alfa 
(rFVIIa) in patients exposed to concizumab treatment.
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.
5.3
Treatment of patients
The following products will be administered in the trial.
Table 5–1 List of products provided by Novo Nordisk
Compound Name 
Strength
Dosage form
Route of administration
Treatment period
concizumab B a
100 mg/mL
solution for s.c. 
injection in a 3 mL 
cartridge b
Subcutaneous 
administration using
NovoPen®4
For prophylactic 
treatment in 76 weeks 
(for concizumab arm in 
the main part and 
extension part).
For prophylactic 
treatment in 52 weeks 
(for comparator arm in 
the extension part).
eptacog alfa (rFVIIa) a, c
5 mg/vial
Powder for solution 
for i.v. injection
Intravenous 
administration
For treatment of 
breakthrough bleeding 
episodes at the 
discretion of the 
investigator (screening, 
main, extension and 
follow up part). c
Administration of 
doses higher than 
histidine solvent (5 mL)
Prefilled syringes for 
solution for i.v. 
injection 
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90μg/kg to patients 
exposed to concizumab 
is not allowed.
For on-demand 
treatment at the 
discretion of the 
investigator in 24 
weeks for comparator 
arm in the main part. 
In the concizumab arm 
and comparator arm 
after switching to 
concizumab in the 
extension part of the 
study a single 90μg/kg 
dose for initial safety 
assessments in a non-
bleeding state. a
Will be provided for as 
long as patients 
participate in the trial 
(screening, main, 
extension and follow 
up part)
a Investigational medicinal product (IMP)
b Not to be confused with the daily injected volume (~150 μL, depending on dose strength and body weight)
c Non-investigational medicinal product (NIMP)
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 in the Trial Materials Manual, see Section 9.
5.3.1
Concizumab arm
5.3.1.1
Concizumab prophylactic treatment (main and extension part)
Concizumab will be given s.c. once daily 0.15 mg/kg (with potential dose escalation to 0.20 and 
0.25 mg/kg). The dose escalation criteria are described, see Section 5.3.3. The first dose of 
concizumab will be given at the trial site under medical supervision.
A loading dose of 0.5 mg/kg will be given as the first concizumab dose at visit 2 in order to ensure 
steady state levels at the time of the administration of eptacog alfa (rFVIIa) in a non-bleeding state 
at visit 3, see Section 5.3.4.
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The patients will be trained in s.c. administration of concizumab with NovoPen®4 at the screening 
visit and at the first scheduled treatment visit. 
5.3.2
Comparator arm (eptacog alfa (rFVIIa))
5.3.2.1
On-demand treatment (main part)
During the main part of the trial, patients will receive eptacog alfa (rFVIIa) for treatment of 
bleeding episodes, with a dose regimen at the discretion of the investigator.
5.3.2.2
Concizumab prophylactic treatment (extension part)
After completion of the main part, the patients will continue the trial in the extension part and will 
switch to prophylactic treatment with s.c. daily administration of concizumab 0.15 mg/kg (with 
potential dose escalation to 0.20 and 0.25 mg/kg) s.c. daily administration.
The same dose escalation criteria as described below (for the initial concizumab arm) will apply.
A loading dose of 0.5 mg/kg will be given as the first concizumab dose at visit 9 in order to ensure 
steady state levels at the time of the administration of rFVIIa in a non-bleeding state at visit 9.1.
5.3.3
Dose escalation
The dose escalation criteria as described below will apply to all treatment arms.
Bleeding episodes will be assessed during the trial both at scheduled visit 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, bleeding episodes occurring during first 2 weeks should not influence a dose escalation 
decision.
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (or visit 9 when
switching from eptacog alfa (rFVIIa) to concizumab) (first treatment 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.
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Dose 0.15 mg/kg: 
When sBE occurs, the investigator will determine if ≥3 sBEs have occurred within the preceding 12
weeks (including the current sBE). If yes, and if investigator deems it safe, the patient will 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 sooner.
Dose 0.20 mg/kg: 
When 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 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 sooner.
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 due to lack of efficacy, see Section 6.4.
The possibility of dose escalation at unscheduled visits is necessary in order to avoid  bleeding
episodes at inadequate dose level: e.g. if the dose escalation eliciting bleeding episode occurs soon 
after a scheduled visit, the patient will avoid to wait 8 weeks for the next scheduled visit (in the 
extension part).
Figure 5–3Dose escalation for one individual patient in the concizumab arm
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Figure 5–4Dose escalation for one individual patient in the comparator arm
5.3.4
Co-administration of eptacog alfa (rFVIIa)
eptacog alfa (rFVIIa) will be used for treating breakthrough bleeding episodes in this trial; one 
week after initiation of dosing with concizumab, a single 90 μg/kg dose of eptacog alfa (rFVIIa)
will be administered in a non-bleeding state at the trial site under medical supervision to assess 
safety of treatment with eptacog alfa (rFVIIa) in patients exposed to concizumab treatment. 
Hereafter, patients will be closely clinically observed at the site for potential safety issues for at 
least 12h and evaluated again at site after 24h. Between 12h and 24h, the patient must either stay at 
the site or at a hotel or at home if he lives nearby to be able to continue visit 3 or 9.1 the day after.
Dosing of eptacog alfa (rFVIIa) in the first 4 patients randomised to concizumab arm will be 
staggered so that the period between eptacog alfa (rFVIIa) administrations from one patient to 
another is at least 48 hours. If no safety concerns are observed (for example signs and symptoms of
thromboembolism, such as swelling, pain and redness of the leg, shortness of breath, and chest 
pain) by the investigator in the period between the administration of eptacog alfa (rFVIIa) and when 
the next daily concizumab dose is to be given, the investigator allows the individual patient to 
administer concizumab prophylactically at home and if needed, treat breakthrough bleeding 
episodes at home with eptacog alfa (rFVIIa). The patients will receive prophylactic doses of 
concizumab 0.15 mg/kg daily throughout the main part (24 weeks) and the extension part (52 
weeks), unless dose escalation criteria are fulfilled, see Section 5.3.3.
In case safety concerns are raised by an investigator after eptacog alfa (rFVIIa) administration and 
these concerns meet the described criteria for putting enrolment of additional patients on hold, 
dosing in the individual patients will be halted and further recruitment in the trial will be halted, see 
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Section 12.7. In case safety concerns that do not meet the criteria for putting enrolment of additional 
patients on hold are observed by the investigator, dosing in that individual patient will be halted 
until further evaluation. In such cases, all available data will be assessed by the Data Monitoring 
Committee (DMC), see Section 12.8.2.
5.3.5
Treatment of bleeding episodes during the trial
Breakthrough bleeding episodes between visit 1 and visit 2 can be treated with any bypassing agent 
(e.g., eptacog alfa (rFVIIa), FEIBA®) up to a period of 24 hours (for eptacog alfa (rFVIIa)) or 48 
hours (for FEIBA®) prior to first concizumab administration at visit 2. Novo Nordisk will provide 
eptacog alfa (rFVIIa) throughout the trial. The patient can treat himself and then he must call the 
site. The bleeding episode must be recorded in the eCRF.
Breakthrough bleeding episodes between visit 2-3 in the concizumab arm and visit 9-9.1 in the 
comparator arm must be treated with eptacog alfa (rFVIIa). Upon breakthrough bleeding episodes 
in this period the patient must first call the site. The investigator should instruct the patient about 
whether he should go to the site to receive treatment or if he can administer a single dose of eptacog 
alfa (rFVIIa) which is not higher than 90μg/kg without delay to treat the breakthrough bleeding
episode. If the patient is instructed to administer the eptacog alfa (rFVIIa) dose at home, following 
the administration, the patient should immediately go to the site for further clinical evaluation. The 
bleeding episode must be recorded in the electronic Diary (eDiary).
Breakthrough bleeding episodes between visit 3 and visit 16 in the concizumab arm must be treated 
with eptacog alfa (rFVIIa). The patient can treat himself without delay but must inform the site that 
a bleeding episode has occurred. Doses of eptacog alfa (rFVIIa) those are lower than 90μg/kg may 
be used to treat breakthrough bleeding episodes at the discretion of the investigator. Administration 
of doses higher than 90μg/kg to patients exposed to concizumab is not allowed. If a single dose of 
eptacog alfa (rFVIIa) is not sufficient to stop a bleeding episode, the patient should inform the site 
and in agreement with the investigator may administer a second dose of eptacog alfa (rFVIIa) not 
higher than 90μg/kg 2-3h after the first dose has been administered. The same procedure should be 
repeated in case the second dose of eptacog alfa (rFVIIa) is not sufficient to stop the bleeding
episode. If more than three 90μg/kg doses of eptacog alfa (rFVIIa) are needed to stop a bleeding 
episode, the patient should go to the site without delay. The definition and diagnostic criteria of 
DIC, acute myocardial infraction, stroke, deep vein thrombosis, pulmonary embolism and 
peripheral artery occlusion is provided in section 12.1.6. The bleeding episodes must be recorded in 
the eDiary.
Breakthrough bleeding episodes between visit 16 and visit 17 (follow-up part) may be treated with 
eptacog alfa (rFVIIa) or other products at the discretion of the investigator. The patient can treat 
himself with eptacog alfa (rFVIIa) at home without delay. Only eptacog alfa (rFVIIa) will be 
provided by Novo Nordisk. The bleeding episodes must be recorded in the eDiary.
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See Table 5–1 and Table 8–3.
5.3.6
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 anticoagulants (DOACs)
∀
Home treatment (between visit 2 and visit 16) with activated prothrombin complex 
concentrates (FEIBA®)
* 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 (visit 16 or earlier), the patient should be switched to a suitable 
marketed product at the discretion of the investigator. Only eptacog alfa (rFVIIa) will be provided 
by Novo Nordisk. The patient will not be provided with concizumab or eptacog alfa (rFVIIa) after 
end of trial (EOT) (visit 17) by Novo Nordisk.
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 the treatment burden 
compared to the currently approved prophylactic drugs which have to be administered i.v.
Furthermore, the current treatment options for prophylaxis in inhibitor patients do not reduce the 
frequency of breakthrough bleeding episodes to the same extent as prophylaxis with replacement 
therapy in non-inhibitor patients. Concizumab may therefore show a better efficacy profile 
compared to current treatment options in haemophilia A and B patients with inhibitors.
The treatment period during at least 24 weeks (the main part of the trial) is considered necessary for 
providing robust data that allow demonstration of clinical proof of concept and to support decision 
making regarding a phase 3 confirmatory trial. Dosing for additional 52 weeks will provide 
valuable long term efficacy and safety data.
Breakthrough bleeding episodes occur in prophylactic regimens with both bypassing agents and 
replacement therapy. Therefore, it is expected that breakthrough bleeding episodes will occur 
during prophylaxis with concizumab even if clinical proof of concept is demonstrated. 
Consequently, eptacog alfa (rFVIIa) will be provided by Novo Nordisk in this trial for treatment of 
breakthrough bleeding episodes. In order to minimize the likelihood of any unforeseen adverse 
events associated with administration of eptacog alfa (rFVIIa) in these circumstances,
administration of eptacog alfa (rFVIIa) in a controlled setting will be performed at visit 3 or 9.1.
Please refer to the Investigator’s Brochure for further information.
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Version:
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 28
Number of patients planned to start on trial product: 26
Number of patients expected to complete the trial: 24
∀
Preferably 21 haemophilia A patients
∀
Preferably 3 haemophilia B patients
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 the suitability 
for the trial
2. Male haemophilia A or B patients with inhibitors aged ≥ 18 years at the time of signing 
informed consent
3. Patients currently treated on-demand with a minimum of six bleeding episodes during the 24 
weeks (or twelve bleeds during 52 weeks) prior to screening
4. Documented history of high-titer inhibitors towards FVIII or FIX, defined as ≥5 Bethesda Units
5. Patients currently in need of treatment with bypassing agents
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
6. Major surgery conducted within one month prior to the initiation of trial activities or major 
surgery planned to occur during the trial
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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
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 requires 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 measured as estimated Glomerular Filtration Rate (eGFR) ≤ 60 ml/min/1.73 
m2 for serum creatinine measured at screening for patients without evidence of renal damage
12. Platelet count ≤ 100x109/L at screening
13. Fibrinogen level < the lower limit of normal
14. Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX
15. Antithrombin levels below the normal reference range at screening
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 and/or randomised in 
violation of the randomisation 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
7. Lack of efficacy due to neutralizing antibodies
8. 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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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 with inhibitors, is that 
there is a significant unmet medical need in this patient population for
1. A more effective treatment and
2. A treatment which reduces treatment burden.
In addition to this, since most of these patients are likely to have been treated and therefore familiar 
with eptacog alfa (rFVIIa) on-demand treatment, this trial population is considered the most suitable 
for assessing the safety of administering eptacog alfa (rFVIIa) to patients in whom plasma TFPI 
levels are inhibited. 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 are to be 
confirmed.
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Date:
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Version:
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7
Milestones
Planned duration of recruitment period (FPFV-LPFV): 28 weeks
Planned FPFV: 
16-Aug-2017
Planned FPFT: 
30-Aug-2017
Planned LPFV: 
28-Feb-2018
Planned LPLV: 
23-Oct-2019
The total duration of concizumab treatment in this trial is 76 weeks for an individual patient
randomised to concizumab prophylaxis treatment at visit 2.
The total duration of concizumab treatment in the trial is 52 weeks for an individual patient 
randomised to eptacog alfa (rFVIIa) on-demand treatment at visit 2.
EOT is defined as last patient last visit (LPLV).
Recruitment
The screening and randomisation 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 randomisation can be randomised in a 2:1 allocation to either the concizumab 
or the comparator arm within the timelines specified in the flow chart (see Section 2).
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and 
clinicaltrials.jp. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure,
how-we-disclose-trial-information, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors (ICMJE), 12
the Food and Drug Administration Amendment Act (FDAAA), 13 European Commission 
Requirements, 14 15 and other relevant recommendations or regulations. If a patient requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the patient. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
protocol LPFT (visit 2) + 24 weeks corresponding to 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.13
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Version:
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8
Methods and assessments
Assessments to be performed at the scheduled and at the unscheduled visits in the trial are described 
in this section, Figure 8–1, Figure 8–2 and in Section 2.
Figure 8–1Visit schedule – concizumab arm.
Figure 8–2
Visit schedule – eptacog alfa (rFVIIa) arm later switching to concizumab.
8.1
Visit procedures
For each patient the trial can consist of the following scheduled parts and visits depending upon
which arm the patient is randomised to:
Screening Part:
∀
Visit 1 (screening visit)
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Main Part:
∀
Visit 2 (Randomisation and 1st treatment visit with concizumab at site for patients 
randomised to the concizumab-arm)
∀
Home treatment with concizumab daily
∀
Visit 3 (treatment and PK-visit with concizumab and eptacog alfa (rFVIIa) at site only for 
patients randomised to the concizumab-arm - phone visit for patients randomised to the 
eptacog alfa (rFVIIa) on-demand arm)
∀
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 – 1st treatment 
visit with concizumab at site for patients randomised to the eptacog alfa (rFVIIa) arm)
Extension Part:
∀
Visit 9.1 (treatment and PK-visit with concizumab and eptacog alfa (rFVIIa) at site ONLY
for patients randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 9.2 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 10 (Assessment visit, patients treat themselves at home)
∀
Visit 10.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 11 (Assessment visit, patients treat themselves at home)
∀
Visit 11.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on demand-arm)
∀
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, no treatment at home before the visit and End of Treatment)
Follow-up Part:
∀
Visit 17 (Assessment visit and End of Trial)
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Date:
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Version:
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Unscheduled Part:
∀
Unscheduled visits can occur e.g. for dispensing of trial product, dose escalation or 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 and eptacog alfa (rFVIIa) administration, 
NovoPen®4, usage of eDiary, completion of the PRO etc.
8.1.1
Informed consent, genotyping and long-term storage consent
Informed consent must be obtained before any trial related activity at visit 1, 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/or 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 patients screening log, a patients identification code list and a patients 
enrolment log. Only patients who have signed the informed consent form should be included on the 
logs. The patients screening log and patients 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: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
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 to 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:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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If unclear entries or discrepancies in the eDiary or ePRO 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
All assessments to be performed at screening are listed in Section 2.
After informed consent is given, patients will be asked to complete the ePRO questionnaires before 
any other trial related activities are performed according to Section 8.6.1:
∀
Hemo-TEM,
∀
VERITAS-PRN®
Assessment results from physical examination and body measurements, as well as measurements of 
vital signs, urinalysis and 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.
For bleeding episodes that occur in the period from Screening visit (Visit1) to randomisation visit 
(Visit 2), information about the bleeding episode is to be entered in the eCRF at visit 2.
Patients will be provided with eptacog alfa (rFVIIa), trial injection kits and direction for use (DFU) 
to cover the potential eptacog alfa (rFVIIa) treatment after the screening part of the trial and 
investigator will ensure that the patients are capable of treating themselves with eptacog alfa 
(rFVIIa).
Dispensing of eptacog alfa (rFVIIa) should be performed in IWRS.
The patient must 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 at visit 1, visit 2 and visit 9
During visit 1 and visit 2 and visit 9 (comparator arm) 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 (if they are randomised to concizumab) 
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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or at visit 9 (if they are randomised to eptacog alfa (rFVIIa) and switching to concizumab at visit 9). 
Furthermore, patients must be instructed and trained in the importance of reporting all the home 
treatments with concizumab, details of the bleeding episodes and the eptacog alfa (rFVIIa) 
treatments associated with these bleeding episodes in the eDiary. The patient should call the site if 
bleeding episodes occur between visit 1 and 2 for the site to register in the eCRF.
Patients should be trained on how to recognize signs of thromboembolic events, so that the patient
contacts the site without delay.
The site and patient can arrange for additional training whenever needed during the remaining time 
of the trial.
8.1.9
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 (concizumab arm) or when the 
patient is comfortable self-administrating trial product subcutaneously (concizumab) and 
intravenously (eptacog alfa (rFVIIa)).
8.1.10
Staggered recruitment
Dosing of eptacog alfa (rFVIIa) in the first 4 patients randomised to the concizumab arm will be 
staggered until the 4th patient randomised to the concizumab arm has completed visit 3 without any 
safety concerns raised by the investigator. Until this time point, enrolled patients will not be 
randomised until the previous patient randomised to concizumab has completed visit 3 without any 
safety concerns raised by the investigator. Novo Nordisk will as sponsor control and communicate 
the staggered recruitment process.
8.1.11
Treatment period – Main part
8.1.11.1
Visit 2 (Randomisation)
Visit 2 should be scheduled 14 to 28 days after visit 1. The date of visit 2 will be considered as trial 
day 1.
It is important to verify the in/exclusion criteria again and review central laboratory tests from 
screening.
The patients must be in a non-bleeding state and should not have received any bypassing agent 
(e.g., eptacog alfa (rFVIIa), FEIBA®) for treatment of bleeding episodes within a period of 24 hours 
(for eptacog alfa (rFVIIa)) or 48 hours (for FEIBA®) prior to the potential first concizumab 
administration (depending on the treatment arm). After visit 2 only treatment with eptacog alfa 
(rFVIIa) for bleeding episodes is allowed.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments listed in 2, must be performed before potential administration of concizumab
(depending on the treatment arm). Vital signs must be assessed both before (within 1 hour) and after 
concizumab administration. Pre-dose blood sampling must take place no more than 1 hour before 
concizumab administration.
Assessment results from concomitant medication, vital signs, body measurement (weight only) and 
details of adverse events must be entered into the eCRF.
A randomisation and dispensing call must be performed in the IWRS.
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 Trial Materials Manual (TMM) on 
basis of the patient’s current body weight. Investigator will communicate the daily dose of 
concizumab to the patient and record the dose for the coming home treatment period in the eCRF.
For patients randomised to the concizumab arm, the first treatment with the loading dose of 
concizumab will be given.
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.
At the visit the patient will be provided with trial product concizumab and/or eptacog alfa (rFVIIa)
and trial injection kits and an eDiary device to be able to conduct and report home treatment and 
bleeding episodes until next scheduled visit.
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa) during the 
trial as instructed by the investigator. Drug accountability must be performed for eptacog alfa 
(rFVIIa), if applicable according to section 9.4. Unused histidine syringes should be returned at 
every visit and new histidine syringes should be dispensed to the patient.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site. If the patient on concizumab needs to treat a 
bleeding episode with eptacog alfa (rFVIIa) at home, then he must visit the site immediately after.
8.1.11.2
Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and PK visit for 
concizumab arm)
eptacog alfa (rFVIIa) on-demand arm:
Visit 3 for eptacog alfa (rFVIIa) on-demand arm is a phone call scheduled 7 days after visit 2 (with 
a visit window of +1 day).
All relevant assessments listed in Section 2, must be discussed.
Assessment results from concomitant medication and details of adverse events must be entered into 
the eCRF.
concizumab arm:
Visit 3 is to be scheduled 7 days after visit 2 (with a visit window of +1 day) and the visit takes two 
days.
All assessments are listed in Section 2, and must be performed accordingly and recorded in 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:
∀
PGI-C
∀
Hemo-TEM
Pre-dose blood sampling must take place no more than 1 hour before eptacog alfa (rFVIIa)
administration. Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa)
administration.
The concizumab dose should be administered first followed by eptacog alfa dose. eptacog alfa 
(rFVIIa) should be administered to the trial patients at the site under the surveillance of medically 
trained trial site staff. The interval between the concizumab and eptacog alfa dose administration 
should not exceed more than 30 min.  
Samples for thrombin generation, haematology, coagulation parameters, concizumab ELISA and 
FVII ELISA are taken pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
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EudraCT no.: 2016-000510-30
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10 min (±2 min), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (±20 min) and 
24h (±20 min).
The investigator must ensure that all assessments are performed as described in Section 2, The 
Investigator is requested to conclude after 24 hours if it is safe for the patient to continue in the trial 
and record the conclusion in the eCRF prior to administration of the next dose of concizumab.
Recruitment of the first four patients will be staggered according to section 8.1.9.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visits the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until the next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.11.3
Visit 4, 5, 6, 7 and 8
Patients should treat themselves at home according to their individual dosing schedule regardless of 
when visits 4, 5, 6, 7 and 8 are scheduled.
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 will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
PGI-C
∀
Hemo-TEM
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
56 of 138
All assessments are to be performed according to Section 2, and the assessment results from 
concomitant medication, vital signs, body measurement (weight only) and details of adverse events 
must be entered into the eCRF.
Investigator must perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the e-Diary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must, for patients randomised to concizumab arm at visit 2, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visits the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until the next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
At visit 8 patients should be reminded that treatment with concizumab (concizumab arm) must take 
place after the blood sampling at visit 9.
8.1.11.4
Visit 9
Visit 9 is to be scheduled on trial day 169 (24 weeks) with a visit window of ±7days.
Patients randomised to eptacog alfa (rFVIIa) on-demand treatment at visit 2 will now be switched to 
concizumab treatment. At this visit the first treatment (loading dose) with concizumab will take 
place.
Treatment with concizumab must take place after the blood sampling for both the patients on the 
concizumab arm as well as patients on the eptacog alfa (rFVIIa on-demand) arm.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
57 of 138
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
PGI-C
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments are to be performed according to Section 2, and the assessment results from 
physical examination, concomitant medication, vital signs, body measurement (weight only) and 
details of adverse events must be entered into the eCRF.
Investigator must perform compliance check of treatment and reporting of bleeding episodes 
through the available access to collected data from the e-Diary. Based on the assessment of any 
spontaneous bleeding episodes the investigator must, for patients randomised to concizumab arm at 
visit 2, evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in Section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 and eptacog alfa 
(rFVIIa) during the trial as instructed by the investigator. Drug accountability must be performed 
for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned at every 
visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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8.1.12
Treatment period – Extension part
8.1.12.1
Visit 9.1 (PK visit and ONLY patients previously on the eptacog alfa (rFVIIa)
on-demand arm)
Visit 9.1 is to be scheduled on trial day 176 (25 weeks) with a visit window of +1 day and the visit 
takes two days.
All assessments are listed in Section 2, and must be performed accordingly and recorded in the 
eCRF.
Pre-dose blood sampling must take place no more than 1 hour before eptacog alfa (rFVIIa)
administration. Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa)
administration.
The concizumab dose should be taken first followed by eptacog alfa dose. eptacog alfa (rFVIIa)
should be administered at the site under the surveillance of medically trained trial site staff. The 
interval between the concizumab and eptacog alfa dose administration should not exceed more than 
30 min. A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until next scheduled visit.
Samples for thrombin generation, haematology, coagulation parameters, concizumab ELISA and 
FVII ELISA are taken pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 
10 min (±2 min), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9 h (± 10 min) and 12h (±20 min) 
and 24h (±20 min).
The Investigator is requested to conclude after 24 hours if it is safe for the patient to continue in the 
trial and record the conclusion in the eCRF prior to administration of the next dose of concizumab.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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8.1.12.2
Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
Visit 9.2 is to be scheduled on trial day 197 (28 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.3
Visit 10
Visits 10 is to be scheduled on trial day 225 (32 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (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.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.4
Visit 10.1 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
Visit 10.1 is to be scheduled on trial day 253 (36 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.5
Visit 11
Visit 11 is to be scheduled on trial day 281 (40 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.6
Visit 11.1 (ONLY patients previously on the rFVIIa on-demand arm) 
Visit 11.1 is to be scheduled on trial day 309 (44 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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8.1.12.7
Visit 12, 13, 14 and 15
Visits 12, 13, 14 and 15 are to be scheduled on trial day 337 (48 weeks), 393(56 weeks), day 449 
(64 weeks) and day 505 (72 weeks) respectively with a visit window of ±7 days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
At visit 15 patients should be reminded that treatment with concizumab must take place after the 
blood sampling at visit 16.
8.1.12.8
Visit 16
Visit 16 is to be scheduled on trial day 533 (76 weeks) with a visit window of ±7days. Further visit 
16 should be scheduled to be conducted at the last day of treatment with concizumab.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs and details of adverse events must be entered into the eCRF. Treatment with concizumab 
must take place after the blood sampling at this visit.
Investigator must 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 patients can be treated with eptacog alfa (rFVIIa) or other 
products at the discretion of the investigator to treat eventual bleeding episodes. Only eptacog alfa 
(rFVIIa) will be provided by Novo Nordisk during this period.
If necessary, a dispensing call must be performed in the IWRS. At the visit the patient will be 
provided with eptacog alfa (rFVIIa) and trial 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. NovoPen®4 must be returned.
Drug accountability must be performed for concizumab and eptacog alfa (rFVIIa). Unused histidine
syringes should be returned at every visit and new histidine syringes should be dispensed to the 
patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes) arise 
after he has left the site. 
8.1.13
Visit 17 (End of trial) - Follow-up part
Visit 17 is to be scheduled on trial day 589 (84 weeks) with a visit window of minus 7 days.
All assessments are listed in Section 2, 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 must perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data. Patients should be asked if their female partner has become 
pregnant, see Section 12.5.1.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa), unused 
histidine syringes, eDiary device and Trial card. Drug accountability must be performed for eptacog 
alfa (rFVIIa).
End-of-Trial information must be entered in the End-of-Trial form in the eCRF.
Completion or treatment discontinuation (if the trial is not completed) session should be performed 
in IWRS, see Section 10.
8.1.14
Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Section 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 Section 
2. 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 eptacog alfa (rFVIIa), concizumab including dose escalation, see Section 5.3.3.
∀
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, 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 
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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concomitant illness forms in the eCRF except information on haemophilia with inhibitors which is 
to be reported in the haemophilia medical history section of the eCRF.
Medical history is a medical event, other than haemophilia, 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, see Section 6.2 and 6.3.
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. 
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 the concizumab and eptacog alfa 
(rFVIIa), which is taken during the trial, including the screening and follow-up period.
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)
o
Classification of haemophilia type (haemophilia A/B)
o
Severity of haemophilia (severe, moderate or mild)
o
Aetiology of haemophilia (congenital or acquired)
∀
Family history of
o
Haemophilia (Y/N)
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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o
Inhibitors (Y/N)
o
Prothrombotic disorders (Y/N)
o
Thromboembolism (Y/N)
∀
Inhibitor tests taken (Y/N)
o
Date (dd-mmm-yyyy) 
o
Result (BU)
∀
Cut-off for positive inhibitor result
∀
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
∀
Dosing frequency during prophylaxis 
∀
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 eptacog alfa (rFVIIa) 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 during visits to the trial site will be collected in the eCRF.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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When home treatment is initiated at visit 2 all bleeding episodes and injections with concizumab 
and eptacog alfa (rFVIIa) injection occurring outside the trial site should be entered in the eDiary by 
the patient, Section 13.3.
The completed eDiary is considered source data.
For reporting of bleeding episodes as AEs/SAEs, please refer to Section 12. In case of life-
threatening bleeding episode, it should always be reported as an SAE, see Section 12.1.2.
The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with eptacog alfa (rFVIIa):
∀
Start date and time
∀
Stop date and time (see Table 8–1)
∀
Anatomical location
o
Position (left/right)
∀
Cause (see Table 8–2)
o
spontaneous
o
traumatic
o
post-surgical
∀
Severity (see Table 8–3)
o
mild/moderate, severe
o
classification and recording of severe bleeding episodes is the responsibility 
of the investigator
∀
Treatment, if any 
o
eptacog alfa (rFVIIa) administration or other product administration
o
dose, date, stop time
o
other medicinal treatments related to the bleeding episode (pain relieving 
medication, non-medical therapy etc.)
o
record as concomitant medication (section 8.2.3)
∀
Symptoms during bleeding episode(s)
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
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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Only report the bleeding episode as an AE/SAE if fatal, life threatening or evaluated as related to 
trial product, see Section 12.1.1 and 12.1.2.
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 do 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 bleeding 
episodes without compartment syndrome), 
mucosal- or subcutaneous bleeding episodes
Mild/moderate bleeding episodes may occur 
in other anatomical locations  
Mild/moderate bleeding episodes: 
∀
patient must call the site between 
visit 1-2 and visit 3-16 (see 2-3 
and 9-9.1 below)
∀
patient must call the site between 
visit 2-3 or visit 9-9.1 (eptacog 
alfa arm) and if treated at home, 
go to the site immediately after
∀
patient can treat themselves at 
home between visit 16 and visit 
17
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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Category
Definition
Treatment recommendation
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 site immediately if in doubt regarding 
treatment of a bleeding episode and to discuss what other actions may need to be 
taken
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.
Dosing for bleeding episodes with eptacog alfa (rFVIIa) should be documented in the eCRF (visit 1 
to visit 2) and eDiary (visit 2 to visit 17). 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 13.3.
Investigator must instruct the patient not to perform preventive treatment with eptacog alfa (rFVIIa)
after bleeding stop as defined in Table 8–1.
Investigator must instruct the patient to use eptacog alfa (rFVIIa) as rescue medication to treat 
bleeding episode between visit 2 and visit 16, see Section 5.3.5.
Furthermore investigator must instruct the patient to contact the site when a bleeding episode 
occurs. 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:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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For in-between visit administrations of trial drug, patients will self-administer concizumab (and 
eptacog alfa (rFVIIa) as rescue medication) and will record treatment in the 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, breast(s)
∀
Musculoskeletal system
∀
Central and peripheral nervous system
∀
Skin
∀
Lymph node palpation
The investigator must evaluate the results of the examination and classify them 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 one decimal)
The body weight assessed at each visit will be used for calculation of the concizumab dose to be 
administered until next visit.
Measurements will be reported in the eCRF.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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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 in a 
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 visits 2 and visit 3 (for patients randomised to concizumab) and at visit 9 and visit 9.1
(for patients initiating concizumab treatment at visit 9), the measurements are also performed after 
concizumab administration.
The investigator must evaluate the vital signs 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 8.2.2
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.
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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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 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 some 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 Section 12.
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:
Injection site reaction 
Investigation of injection site reactions will be performed locally at all visits after visit 2 until visit 
16 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)
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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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∀
Swelling
∀
Dimpling
∀
Macula
∀
Haematoma
∀
Bleeding
∀
Other (visual reactions)
Any injection site reaction symptom (evaluated at 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.
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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 625 mL will be taken from each patient on the concizumab 
arm and 725 mL from each patient on the eptacog alfa (rFVIIa) arm.
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 at all visits and 
coagulation parameters at visits 3 and 9.1 are to be shipped for analysis at central laboratories or 
further distribution to special laboratories. Haematology samples (all visits) and coagulation 
parameters (visit 3 and 9.1) are to be analysed locally. Ports cannot be used for blood sampling.
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 SI units.
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 
clinically 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/FIX activity, FVIII/FIX inhibitor 
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Version:
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test, Thrombin generation, Free TFPI (TFPI not bound to concizumab), concizumab concentration 
in plasma, anti-concizumab antibodies, Total TFPI and FVII antigen concentration.
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 8.2.3 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 antibodies).
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report (CTR).
Antibody samples and human biosamples, 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 collected at all visits.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa): 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9 h (± 
10 min), 12h (± 20 min) and 24h (± 20 min).
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:
15 November 2017
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Version:
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UTN: U1111-1179-2925
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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 (TFPI not bound to concizumab) will be collected at all visits, pre-dose at visit 2 and 3 
(concizumab arm), visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16.
The free TFPI assay is an enzyme immunoassay measuring levels of free TFPI from 
 
 (named and referred to 
 TOTAL TFPI) and will be used for PD assessments.
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.
The investigator must evaluate the results and record the outcome as:
∀
Normal or abnormal
∀
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.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa), 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9 h (± 
10 min), 12h (± 20 min) and 24h (± 20 min).
∀
Haemoglobin
∀
Erythrocytes (cell count)
∀
Thrombocytes (platelet count)
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Version:
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∀
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
Biochemistry samples are to be sampled and analysed centrally at all visits.
∀
Creatinine
∀
Albumin
∀
Bilirubin; total, direct, indirect
∀
Aspartate aminotransferase (AST)
∀
Alanine aminotransferase (ALT)
∀
Gamma glutamyltransferase (GGT) 
∀
Alkaline phosphatase
∀
C-reactive protein (CRP)
The investigator must evaluate the results of the examination 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/FIX activity
FVIII/FIX activity is to be sampled and analysed centrally at visit 1, visit 9 and visit 16.
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Version:
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∀
FVIII activity level (IU/mL) or
∀
FIX activity level (IU/mL)
8.5.2.5
Coagulation parameters
Coagulation parameters will be performed centrally at all visits with the exception of visit 3 and 
visit 9.1 where the PT, APTT, and Fibrinogen will be performed locally.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa) at 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9h 
(±10 min) and 12h (±20 min) and 24h (± 20 min) locally.
∀
Fibrinogen – centrally and locally
∀
Prothrombin time (incl. INR) (PT) centrally and locally
∀
D-dimer – only centrally
∀
Prothrombin fragment 1+2 – only centrally
∀
Activated partial thromboplastin time (APTT) – centrally and locally
∀
Antithrombin (AT) activity – only centrally
The investigator must evaluate the results of the examination 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)
Coagulation parameters analysed locally are to be entered into the eCRF.
8.5.2.6
FVIII/FIX inhibitors
FVIII/FIX inhibitor level will be measured by the Nijmegen method at visit 1, visit 9 and visit 16. 
∀
FVIII inhibitors (BU) or
∀
FIX inhibitors (BU)
8.5.2.7
Anti-concizumab antibodies
Samples for the determination of anti-drug antibodies collected during the treatment period must be 
drawn at all visits and prior to administering concizumab at visit 2 and 3 (concizumab arm) and 
visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
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Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
Status:
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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.
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 positive for binding antibodies. 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.
The following analyses will be available:
∀
Anti-concizumab antibodies assay
∀
Specificity assay (Anti-concizumab antibodies cross reacting with IgG4 backbone, CDR 
region or S241P mutation)
∀
Anti-concizumab neutralising antibodies assay
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. 
Neutralising antibodies will be analysed and reported at the EOT. 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.
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 
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Date:
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1RYR1RUGLVN
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Version:
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Status:
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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 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 collected at all visits where patients are in treatment with concizumab.
Samples will be collected pre-dose at visit 2 for concizumab arm and visit 9 for eptacog alfa 
(rFVIIa) arm) and visit 16 for both arms.
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Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
Status:
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At visit 3 for concizumab arm and visit 9.1 for eptacog alfa arm samples for concizumab ELISA are 
taken pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 10 min (±2 
min), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (±20 min) and 24h (±20 
min).
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
FVII ELISA
FVII ELISA will be collected at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) pre-
dose eptacog alfa (rFVIIa) and post-dose at 10 min (±2 min), 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 eptacog alfa (rFVIIa) administration.
FVII in plasma will be quantified using a validated enzyme-linked immunosorbent assay (ELISA).
The FVII ELISA will detect the total sum of FVII in a sample, including endogenous FVII, eptacog 
alfa (rFVIIa) and FVII in complex with other molecules e.g. antithrombin. The ELISA has been 
validated for measuring FVII in human citrated plasma samples. Validation follows current 
guidelines for bioanalytical method validation. Bioanalytical data will be reported in a bioanalytical 
report.
8.5.2.10
Total TFPI
Total TFPI ELISA will be collected at all visits. Samples will be collected pre-dose at visit 2 and 3 
(concizumab arm) and visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
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 a 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.
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Date:
15 November 2017
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Version:
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UTN: U1111-1179-2925
Status:
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Data will be reported in ng/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, see Section 2. 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. Plasma 
and serum is taken at visit 1 and 17. DNA for genotyping is only taken at visit 1.
8.6
Other assessments
8.6.1
Patient reported outcomes
A newly developed disease-specific electronic PRO (ePRO) the Hemophilia Treatment Experience 
Measure (Hemo-TEM) - is being validated in this trial. In order to assess the psychometric 
properties of Hemo-TEM, other questionnaires will be provided; see further appendix 1.
The following ePRO questionnaires will be used in the trial:
∀
Hemophilia Treatment Experience Measure (Hemo-TEM)
∀
Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS-PRN®) 16
∀
36-Item Short Form Health Survey (SF-36v2) (4 week recall)17
∀
Patient’s Global Impression of Change (PGI-C)
∀
Sheehan Disability Scale (SDS) 18
∀
Treatment Satisfaction Questionnaire for Medication (TSQM, version II) 19 20 21
∀
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)22
The ePROs should be assessed at the scheduled visits following the order listed below:
∀
visit 1 (Hemo-TEM, VERITAS-PRN®)
∀
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
∀
visit 3 (PGI-C, Hemo-TEM)
∀
visit 4 (PGI-C, Hemo-TEM)
∀
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, SIAQ-ISRQ)
∀
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
∀
visit 16 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
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Date:
15 November 2017
1RYR1RUGLVN
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Version:
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UTN: U1111-1179-2925
Status:
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At visit 1: before any visit-related activities all patients should complete Hemo-TEM and 
VERITAS-PRN®.
At visit 2: before any visit-related activities all patients should complete Hemo-TEM, SF-36v2, 
SDS, TSQM and SIAQ-ISRQ.
At visit 3-8: 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 visits 9, 10 and 16. 
∀
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. 
Exception: Patients randomised to eptacog alfa (rFVIIa) on-demand should not complete the 
ePRO at visit 3 as this is a phone visit.
At visit 9 if the patient has responded “0” or “2” in the PGI-C at all previous visits, the patient 
should complete PGI-C. All patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and 
SIAQ-ISRQ.
At visit 10 and 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and SIAQ-
ISRQ.
The investigator must check the ePROs for potential AEs and SAEs. The completed ePROs should 
be transmitted at each visit to the PRO database by the Investigator.
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 documented in the medical record.
8.6.2.1
Concizumab and NovoPen®4
Direction for use (DFUs) will be available as a 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 the 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 DFUs.
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Version:
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UTN: U1111-1179-2925
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8.6.2.2
eptacog alfa (rFVIIa)
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.
The following should be emphasised for eptacog alfa (rFVIIa):
∀
eptacog alfa (rFVIIa) should be slowly injected intravenously over 2 to 5 minutes
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 eptacog alfa (rFVIIa) treatments 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 duplicate 
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 EOT.
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 eptacog alfa (rFVIIa) 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
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Date:
15 November 2017
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Version:
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UTN: U1111-1179-2925
Status:
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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 of the importance of following the instructions given including 
taking the trial products as prescribed.
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 for the concizumab arm 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 eptacog alfa (rFVIIa) 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. 
Drug accountability will be performed and will be used to assess patient compliance together with 
the patients’ 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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Protocol
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
3.0
UTN: U1111-1179-2925
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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 TMM.
The trial product, concizumab B, appears as clear to slightly opalescent and colourless to slightly 
yellow. The trial product must not be used if it contains visible particles or discoloration.
The reconstituted eptacog alfa (rFVIIa) solution appears clear and colourless. Do not use the 
reconstituted solution if it contains visible particles or if it is discoloured.
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)
100 mg/mL
Solution for injection
s.c. injection
3 mL cartridge
eptacog alfa
(IMP a and NIMP b)
5 mg/vial
Powder for solution
for injection
i.v. injection
Vial
histidine 5 mL
N/A
Solvent for solution 
for injection
i.v. injection
prefilled syringe
a Investigational Medicinal Product (IMP) given as IMP for a single dose at visit 3 and 9.1.
b Non-Investigational Medicinal 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. It will be labelled in accordance with the EMA directive on medical devices annex I 23
and similar national legislation. A description of how to use the device is given in the DFU.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 24, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation.
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The investigator must document that DFUs are given to the patient orally and in writing at the first 
dispensing visit (see 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 (2oC-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)
eptacog alfa
5mg
Store between 2oC-25oC
Do not freeze
Protect from light
For single use
Do not freeze
Protect from light
To be used immediately 
after reconstitution
If not used 
immediately, store in 
refrigerator (2oC-8oC)
for up to 3 hours
histidine 5 mL
Store between 2oC-25oC 
Do not freeze
Protect from light
For single use
N/A
a In-use time for concizumab starts when first dose is administered from an individual cartridge and for eptacog alfa
(rFVIIa) 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.
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 (concizumab and eptacog alfa (rFVIIa) 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 used histidine
syringes which should be discarded at home and not accounted for. Unused histidine syringes 
should be returned at every visit and new histidine syringes should be dispensed to the patient.
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All cartridges (concizumab) and vials (eptacog alfa (rFVIIa)) 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/or 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 product including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Destruction of concizumab and eptacog alfa (rFVIIa) 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 DFUs
∀
For eptacog alfa (rFVIIa) reconstitution and administration: Trial Injection Kit and DFU
Only needles and trial injection kit 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
∀
Randomisation
∀
Medication arrival
∀
Dispensing
∀
Dispensing verification
∀
Treatment discontinuation 
∀
Completion
∀
Drug accountability
∀
Data change
IWRS user manuals will be provided to each trial site.
11 Randomisation procedure and breaking of blinded codes
11.1
Randomisation 
Randomisation will be handed by the IWRS.
All patients included in the screening period and eligible for the trial will enter the trial and be 
randomised at visit 2 in a 2:1 allocation to either concizumab prophylaxis arm or eptacog alfa 
(rFVIIa) on-demand arm.
11.2
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 
∀
Mild – no or transient symptoms, no interference with the patient’s daily activities
∀
Moderate – marked symptoms, moderate interference with the patient’s daily activities
∀
Severe – considerable interference with the patient’s daily activities; unacceptable
∀
Causality 
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Relationship between an AE and the relevant trial product(s): 
∀
Probable - Good reason and sufficient documentation to assume a causal relationship
∀
Possible - A causal relationship is conceivable and cannot be dismissed
∀
Unlikely - The event is most likely related to aetiology other than the trial product
∀
Final outcome 
∀
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
∀
Recovering/resolving - The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the trial 
or has died from another AE
∀
Recovered/resolved with sequelae - The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE
∀
Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged or the outcome is not known
∀
Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported 
as an SAE
∀
Unknown - This term is only applicable if the patient is lost to follow-up
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-threatening a experience
∀
In-patient hospitalisation b or prolongation of existing hospitalisation
∀
A persistent or significant disability or incapacity c
∀
A congenital anomaly or birth defect
∀
Important medical events that may not result in death, be life threatening a or require 
hospitalisation b 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 SAE d
a. The term “life threatening” in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
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b. The term “hospitalisation” is used when a patient:
∀
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay or
∀
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a patient’s ability to conduct normal life functions (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 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 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
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Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1
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, see Section 8.4.5.2
Injection site reactions: 
Any injection site reaction symptom must be recorded on the AE form and the injection site 
reaction form.
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 type 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 will be performed. 
Definition of anaphylaxis (25)
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. dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow [PEF], hypoxemia)
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b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.
hypotonia [collapse], syncope, incontinence)
∀
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. dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
∀
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 treating physician. If according to the investigators judgement, 
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 Events 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:
∀
Platelet count (>100 × 109/L = 0, <100 × 109/L = 1, <50 × 109/L = 2)
∀
Elevated D-dimer (no increase = 0, moderate increase = 2, strong increase = 3)
∀
Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
∀
Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
∀
Calculate score: ≥5 compatible with overt DIC
B) Myocardial infarction is defined according to the “Third Universal Definition of
Myocardical Infarction” (26)
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:
∀
Symptoms of ischemia
∀
New or presumed new significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB)
∀
Development of pathological Q waves in the ECG
∀
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality
∀
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.
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C) Definition of pulmonary embolism:
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 embolism
(27).
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” (28).
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 “Haemorrhagic Infarction”).
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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.
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. A Transient ischemic attack 
(TIA) is a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal 
ischemia, without acute infarction (29).
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 DVT in the lower
extremities27. 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, 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 (30).
12.1.7
Technical complaints
A technical complaint is any written, electronic or oral communication that alledges 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 the pen and the 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 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.
When eptacog alfa (rFVIIa), NovoSeven® is used as IMP, expectedness should be performed 
according to the Company Core Data Sheet (CCDS).
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
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 (eptacog alfa (rFVIIa)) 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.
∀
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 AEs. 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.
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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
∀
Eptacog alfa (rFVIIa) 5 mg/vial, powder for solution for injection in a vial
∀
Histidine 5 mL, solvent for solution for injection in a 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.
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, AESI 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
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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 
Centre, 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.
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 with concizumab at visit 2 or 
visit 9 depending on the arm). At the last scheduled visit (visit 17), 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.
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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: 
∀
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 newborn 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 have not been investigated in clinical trials.
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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 
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
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 
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of the patients and to evaluate the benefit-risk balance. The DMC will have access to the 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.
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:
∀
Pregnancy forms
∀
Technical complaint forms
∀
AE forms
∀
Safety information forms
The paper version of the technical complaint form, AE form, and safety information form must only 
be used to ensure timely reporting when/if the electronic CRF is unavailable.
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) 
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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.
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 eptacog alfa 
(rFVIIa)).
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 EOT visit.
All data entered will be transferred from the device to an electronic database, where it is kept as a 
certified copy of the source data. Data entered in the device will upon confirmation of a successful 
back-up be deleted from the device.
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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.
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 Request Correction (DRC) must be submitted to 
the eDiary vendor. An audit trail will be maintained.
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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 
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. 
Monitoring visits should be scheduled as frequently as needed to support the first 6 patients 
recruited in the trial. 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 
ePROs and eDiaries are completed and reviewed by the investigator at the relevant scheduled visits 
and needed action has been taken and documented, if any.
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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
∀
Demography, see section 8.2.1
∀
Date of visit
Monitors will review the patient’s medical records and other source data (e.g. the 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.
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 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.
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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 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 archiving containing the 
electronic Investigator Trial Master File (eITMF) for each trial site. These CDs or other relevant 
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 FDA 21 CFR Part 11
and ICH E6 (EU directive for personal data protection).1, 31
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.
The eDiary and ePRO 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, 31After trial 
completion, each trial site will be supplied with long-life CDs. These CDs will contain site-specific 
patient records including the patient’s eDiaries and audit trail including any data additions and 
corrections made on each form. The eDiary vendor will furthermore retain and securely store copies 
of all archived documents and data for 15 years or as required by local data retention laws for trial 
data.
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17 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 
17–1 for further information. 
Data from when the on-demand treated patients are transferred to concizumab s.c. prophylaxis will 
not be included in this evaluation. Observations from the extension part in the on-demand arm will 
be summarised separately as well as combined with observations from the main part when reporting 
the extension part data.
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 patients with inhibitors. The objective will be 
assessed when the last of the 24 patients has completed 24 weeks of dosing (or has withdrawn 
before that).
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the ABR of all patients in the concizumab group, irrespective of individual dose 
titration, with the ABR of the patients in the on-demand arm using different sets of observations. 
The primary CPoC criterion aims at evaluating the effect of concizumab when given at the last dose 
level reached for the 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 not be included. Since this evaluation disregards a 
subset of data collected post randomisation, the result should be viewed taking into 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 patients in the concizumab arm with 
the ABR of the patients in the on-demand arm using all data collected after randomisation. 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 part as offset and regimen as factor (concizumab vs. on-demand). For each criterion, 
evidence of effect will be concluded if the 95% confidence interval of the treatment ratio is below 1.
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.
17.1
Sample size calculation
The estimand will be defined as the “if all patients had adhered” estimand.
The treatment ratio between prophylactic s.c. concizumab and on-demand i.v. eptacog alfa (rFVIIa)
during at least 24 weeks for all randomised patients if all patients adhered to trial drug and did not 
initiate alternative treatment options.
This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand i.v. eptacog alfa 
(rFVIIa) under similar conditions as observed in this trial.
The sample size calculation has been determined based on this estimand and the CPoC criteria 
taking the small patient population into account, while also aiming for an acceptably narrow 95% 
confidence interval for the rate ratio.
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be 
accommodated by 16 patients in the concizumab arm and 8 in the comparator arm. 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, annual bleeding rates 
of 24 and 6 are assumed for the on-demand patients and the end dose concizumab regimen, 
respectively. Assuming further over-dispersion of 7, the power for concluding superiority of the 
concizumab regimen becomes approximately 80%. 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 17–1Power in superiority comparison between concizumab prophylaxis and on-demand 
treatment under different assumptions of ABR for concizumab and over-
dispersion (assuming on-demand ABR=24).
Power
Over-dispersion (over 6 months)
ABR (concizumab)
6
7
8
6
89%
82%
75%
7
84%
75%
70%
8
77%
69%
66%
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 7.6 for 
the concizumab regimen. This yields a marginal power of approximately 70% 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). In the 
NN7128-1907 trial in inhibitor patients, larger 1-year over-dispersion values of approximately 21 
and 18, respectively, were observed during an initial 3-month on-demand period and a subsequent 
3-month prophylaxis period. It is expected that the variation in the current trial will be smaller, 
partly due to the longer duration of the trial and partly due to an expected more homogenous patient 
population. Another published trial including inhibitor patients, comparing prophylaxis using 
FEIBA® with on-demand treatment, showed 6-month over-dispersion of 4-5 32. On that background, 
an over-dispersion of 7 over the 24 weeks in 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 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 endpoint will be analysed when the main part of trial has been completed.
17.3.1
Estimand and primary statistical analysis
The estimand for the primary endpoint is the “if all patients had adhered” estimand.
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The treatment ratio between prophylaxis s.c. concizumab and on-demand i.v. eptacog alfa (rFVIIa)
during at least 24 weeks for all randomised patients if all patients adhered to trial drug and did not 
initiate alternative treatment options.
This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand i.v. eptacog alfa 
(rFVIIa) under similar conditions as observed in this trial.
The estimand for the primary endpoint will be estimated using negative binomial regression with 
log of exposure time in main part as offset and regimen as factor, providing an estimate of the ABR 
ratio between regimens (concizumab prophylactic and on-demand eptacog alfa (rFVIIa)) with 
corresponding 95% confidence interval and also actual estimate of the ABR with corresponding 
95% confidence interval for each regimen. 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 estimand will be estimated based on the FAS
and only data collected prior to discontinuation of trial product or initiation of alternative treatment 
options will be used to draw inference.
17.3.2
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 Δ 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 part 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 concizumab 
prophylaxis no longer is superior to on-demand eptacog alfa (rFVIIa). The results of the primary 
analysis will be considered robust if the tipping point is above what is considered clinically
plausible.
17.3.3
Additional analysis
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 of number of bleeding episodes 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, TFPI value prior to the last s.c. dose 
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administration, peak thrombin generation (nM), Endogenous thrombin potential (nMxmin) and 
velocity index (nM/min).
17.4
Supportive secondary endpoints
17.4.1
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 number of spontaneous bleeding episodes during at least 24 weeks from treatment onset will be 
addressed in terms of the same estimand as for the primary endpoint. The estimand will be 
estimated using the same negative binomial regression model as for the primary endpoint.
Furthermore, an additional evaluation will be made, where actual concizumab dose is included as 
factors in the model.
The remaining supportive secondary efficacy endpoints will be summarised descriptively by 
treatment regimen. In addition, number of bleeding episodes during 76 weeks of treatment with 
prophylactic concizumab will be analysed using a negative binomial model with log of trial 
duration as offset, providing estimates of the ABR with confidence interval for that particular 
regimen.
17.4.2
Supportive secondary safety endpoints
∀
Number of TEAEs during at least 24 weeks from treatment onset
∀
Number of TEAEs during 76 weeks from treatment onset
∀
Number of TEAEs within 24 hours of rFVIIa administration
∀
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset
∀
Occurrence rate 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
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∀
Change from baseline of APTT during 76 weeks from treatment onset
∀
Change from baseline of anti-thrombin (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.
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.
17.4.3
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.
17.4.4
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 (nMxmin) prior to the last dose administration at 24 
weeks
o
Endogenous thrombin potential (nMxmin) prior to the last dose administration at 76
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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17.4.5
Exploratory endpoints
17.4.5.1
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
17.4.5.2
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
VERITAS-PRN®, SF-36v2, SDS and TSQM will be scored according to their respective scoring 
algorithms. Change from visit 2 to visit 9 will be analysed with an ANCOVA model including 
regimen as a factor and baseline score as covariate.
The PRO endpoints will be summarised using descriptive statistics and the remaining 
questionnaires (Hemo-TEM, PGI-C, SIAQ-ISRQ) will be summarised and listed using descriptive 
statistics.
17.5
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. Main part is 
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. 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 CTRs might in such case be issued. A CTR describing results 
from the main and the 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.
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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 100 ng/mL, see Section 3.1.2. Based on these results, it is expected that the 
majority of the patients randomised to the concizumab treatment with 0.15 mg/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. For haemophilia patients with inhibitors 
and who are treated on-demand, expected improved efficacy is considered to be a major benefit in 
participating in this trial. Also, concizumab is administered s.c. and might reduce the burden of 
frequent i.v. injections associated with current treatment options in haemophilia patients with 
inhibitors.
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 a drug–drug interaction study in monkeys, three doses of up to 1 mg/kg of NovoSeven® were 
administered at 2-h intervals, alone or in the presence of a steady state concentration of 
concizumab. Increased concentrations of thrombin–anti-thrombin (TAT) and D-dimer were seen, 
which tended to be additive when both concizumab and eptacog alfa (rFVIIa) were present in 
circulation. No notable clinical observations were made.
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
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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.
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.
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 the 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 
mechanisms33 34. 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 injuries35 36, 37.
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.
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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 
Helsinki 2.
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.
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 qualified person, 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 CTR.
∀
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.
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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 
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.
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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.
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 eptacog alfa (rFVIIa)
∀
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 sites outside the US)
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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, 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 GCP 1
applicable regulatory requirements and the Declaration of Helsinki 2.
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.
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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.
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).
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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 
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 CTR for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the CTR (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 38. 
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-information.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the CTR is available. This includes the right not to release the results of interim 
analyses, because the release of such information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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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 Editors38 (sometimes referred to as the Vancouver 
Criteria).
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.
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.
Only applicable 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 EOT 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.
24.2
Retention of human biosamples
This trial will involve collection of human biosamples at visit 1 (screening visit) and at visit 17
(EOT) and these samples are to be stored maximum 15 years from EOT. 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 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 
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participate, while refusing permission for biological specimens to be stored for future exploratory 
analysis.
∀
Human biosamples will be stored at the central laboratory
∀
1.0 mL citrated plasma, 1.2 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 consortia
∀
The human biosamples will be transferred and stored after the EOT at a designated central 
laboratory
∀
Confidentiality and personal data protection will be ensured during storage after the EOT
∀
The human biosamples may be transferred to other countries (not applicable if local 
regulations prohibit export of human biosamples)
∀
The human biosamples will be destroyed at the latest 15 years from EOT
∀
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
can contact the investigator if they wish to be informed about results derived from stored 
human biosamples obtained from their own body, see 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. Remaining 
blood from the samples already collected may be used for further development of Anti-Drug 
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antibody assays, and will not be reported in this trial. The samples will be stored at a central bio-
repository after EOT and until marketing authorisation approval or until the research project 
terminates, but no longer than 15 years from EOT 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 CTR 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 CTR 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 Austria: Arzneimittelgesetz (BGBI. Nr. 185/1983) last amended with BGBl. 
II Nr. 105/2015
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 research for the person lending 
himself thereto and for indemnification of his beneficiaries, except in case of proof, incumbent on 
it, that the prejudice is not attributable to his fault or the fault of any intervening party, without the 
sponsor’s being entitled to call on acts by a third party or the voluntary withdrawal of the person 
who had initially consented to cooperating in the research”.
Only applicable for Poland: Novo Nordisk carries liability for the Trial exclusively in the scope 
defined by the applicable laws and in particular by the Civil Code and the Pharmaceutical Law 
dated 6 September 2001 (uniform version Journal pf Laws of 2008 No. 45 item 271 with 
amendments). In order to support potential claims for liability attributable to the Trial, Novo 
Nordisk and Investigators are covered by the Insurance Policy issued according to applicable Polish 
law.
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Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Vasc Biol. 
2005;25(1):47-56.
38.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2016.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
1 of 143
Protocol
NN7415-4310
A Multi-Centre, Randomised, Open-Label, Controlled Trial 
Evaluating the Efficacy and Safety of Prophylactic 
Administration of Concizumab in Haemophilia A and B 
Patients with Inhibitors
Trial phase: 2
Includes: Protocol Version 1 (15 March 2017); Protocol Amendment no 1 (05 May 2017) for all 
participating countries; Protocol Amendment no 2 (15 November 2017) and Protocol Amendment no 3 (21 
August 2018) for all participating countries.
Protocol originator
, International Trial Manager 
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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:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
2 of 143
Table of Contents
Table of Contents........................................................................................................................................2
Table of Figures ........................................................................................................................................11
Table of Tables..........................................................................................................................................12
List of abbreviations .................................................................................................................................13
1
Summary............................................................................................................................................20
2
Flow chart ..........................................................................................................................................23
2.1
Visits and assessments ............................................................................................................23
2.2
Explanatory descriptions .........................................................................................................26
3
Background information and rationale for the trial.........................................................................28
3.1
Background information..........................................................................................................28
3.1.1
Haemophilia ..........................................................................................................28
3.1.2
Concizumab...........................................................................................................29
3.2
Rationale for the trial...............................................................................................................32
4
Objective(s) and endpoint(s)..............................................................................................................33
4.1
Objective(s) ............................................................................................................................33
4.1.1
Primary objective...................................................................................................33
4.1.2
Secondary objectives .............................................................................................33
4.2
Endpoint(s) .............................................................................................................................33
4.2.1
Primary endpoint ...................................................................................................33
4.2.2
Secondary endpoints ..............................................................................................33
4.2.2.1
Supportive secondary endpoints .......................................................33
4.2.3
Exploratory endpoints............................................................................................34
4.2.3.1
Exploratory safety endpoints ............................................................34
4.2.3.2
Exploratory patient reported outcome endpoints ...............................35
5
Trial design ........................................................................................................................................36
5.1
Type of trial ............................................................................................................................36
5.1.1
Surgery..................................................................................................................37
5.2
Rationale for trial design .........................................................................................................37
5.3
Treatment of patients...............................................................................................................40
5.3.1
Concizumab arm....................................................................................................41
5.3.1.1
Concizumab prophylactic treatment (main and extension part)..........41
5.3.2
Comparator arm (eptacog alfa (rFVIIa)).................................................................42
5.3.2.1
On-demand treatment (main part).....................................................42
5.3.2.2
Concizumab prophylactic treatment (extension part).........................42
5.3.3
Dose escalation......................................................................................................42
5.3.4
Co-administration of eptacog alfa (rFVIIa).............................................................44
5.3.5
Treatment of bleeding episodes during the trial ......................................................45
5.3.6
Prohibited medication ............................................................................................46
5.4
Treatment after discontinuation of trial product .......................................................................46
5.5
Rationale for treatment............................................................................................................46
6
Trial population .................................................................................................................................47
6.1
Number of patients..................................................................................................................47
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
3 of 143
6.2
Inclusion criteria .....................................................................................................................47
6.3
Exclusion criteria ....................................................................................................................47
6.4
Criteria for premature discontinuation of trial product .............................................................48
6.5
Withdrawal from trial..............................................................................................................48
6.6
Patient replacement .................................................................................................................49
6.7
Rationale for trial population...................................................................................................49
7
Milestones...........................................................................................................................................50
8
Methods and assessments ..................................................................................................................51
8.1
Visit procedures ......................................................................................................................51
8.1.1
Informed consent, genotyping and long-term storage consent .................................53
8.1.2
Screening log, enrolment log, trial card and patient number....................................53
8.1.3
Screening failures and re-screening........................................................................53
8.1.4
Premature discontinuation of trial product..............................................................54
8.1.5
Withdrawal from trial.............................................................................................54
8.1.6
Review/ evaluation of clinical outcome..................................................................55
8.1.7
Visit 1 (Screening part)..........................................................................................55
8.1.8
Training of patients at visit 1, visit 2 and visit 9......................................................56
8.1.9
Treatment period at home ......................................................................................56
8.1.10
Staggered recruitment ............................................................................................56
8.1.11
Treatment period – Main part.................................................................................56
8.1.11.1
Visit 2 (Randomisation) ...................................................................56
8.1.11.2
Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and 
PK visit for concizumab arm)...........................................................58
8.1.11.3
Visit 4, 5, 6, 7 and 8 .........................................................................59
8.1.11.4
Visit 9 ..............................................................................................60
8.1.12
Treatment period – Extension part..........................................................................62
8.1.12.1
Visit 9.1 (PK visit and ONLY patients previously on the eptacog 
alfa (rFVIIa) on-demand arm) ..........................................................62
8.1.12.2
Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) 
on-demand arm)...............................................................................63
8.1.12.3
Visit 10 ............................................................................................63
8.1.12.4
Visit 10.1 (ONLY patients previously on the eptacog alfa 
(rFVIIa) on-demand arm) .................................................................64
8.1.12.5
Visit 11 ............................................................................................65
8.1.12.6
Visit 11.1 (ONLY patients previously on the rFVIIa on-demand 
arm) .................................................................................................66
8.1.12.7
Visit 12, 13, 14 and 15, 15.1, 15.2, 15.n............................................67
8.1.12.8
Visit 16 ............................................................................................68
8.1.13
Visit 17 (End of trial) - Follow-up part...................................................................69
8.1.14
Unscheduled Visit..................................................................................................70
8.2
Patient related information/assessments...................................................................................70
8.2.1
Demography ..........................................................................................................70
8.2.2
Concomitant illness and medical history other than haemophilia ............................70
8.2.3
Concomitant medication ........................................................................................71
8.2.4
Details of Haemophilia, Haemophilia treatment and bleed history..........................71
8.3
Efficacy assessments...............................................................................................................72
8.3.1
Bleeding episodes ..................................................................................................72
8.4
Safety assessments ..................................................................................................................76
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
4 of 143
8.4.1
Physical examination .............................................................................................76
8.4.2
Body measurements...............................................................................................76
8.4.3
Vital Signs.............................................................................................................77
8.4.4
Electrocardiogram..................................................................................................77
8.4.5
Adverse events.......................................................................................................78
8.4.5.1
Medication error...............................................................................78
8.4.5.2
Adverse events requiring additional data collection ..........................78
8.5
Laboratory assessments...........................................................................................................80
8.5.1
Laboratory assessments for efficacy.......................................................................81
8.5.1.1
Thrombin generation........................................................................81
8.5.1.2
Free TFPI.........................................................................................82
8.5.2
Laboratory assessments for safety ..........................................................................82
8.5.2.1
Urinalysis.........................................................................................82
8.5.2.2
Haematology....................................................................................82
8.5.2.3
Biochemistry....................................................................................83
8.5.2.4
FVIII/FIX activity............................................................................83
8.5.2.5
Coagulation parameters....................................................................84
8.5.2.6
FVIII/FIX inhibitors.........................................................................84
8.5.2.7
Anti-concizumab antibodies .............................................................84
8.5.2.8
Concizumab ELISA .........................................................................86
8.5.2.9
FVII ELISA .....................................................................................87
8.5.2.10
Total TFPI........................................................................................87
8.5.3
Human Biosamples ................................................................................................88
8.6
Other assessments ...................................................................................................................88
8.6.1
Patient reported outcomes ......................................................................................88
8.6.2
Training.................................................................................................................89
8.6.2.1
Concizumab and NovoPen®4............................................................89
8.6.2.2
eptacog alfa (rFVIIa)........................................................................90
8.6.2.3
eDiary..............................................................................................90
8.6.3
Surgery..................................................................................................................90
8.7
Patient compliance..................................................................................................................91
8.8
Treatment compliance.............................................................................................................91
9
Trial supplies......................................................................................................................................92
9.1
Trial products..........................................................................................................................92
9.2
Labelling.................................................................................................................................92
9.3
Storage....................................................................................................................................93
9.4
Drug accountability and destruction ........................................................................................93
9.5
Auxiliary supplies ...................................................................................................................94
10
Interactive voice/web response system ..............................................................................................95
11
Randomisation procedure and breaking of blinded codes................................................................95
11.1
Randomisation ........................................................................................................................95
11.2
Breaking of blinded codes .......................................................................................................95
12
Adverse events, and technical complaints .........................................................................................96
12.1
Definitions ..............................................................................................................................96
12.1.1
Adverse event ........................................................................................................96
12.1.2
Serious adverse event.............................................................................................97
12.1.3
Non-serious adverse event......................................................................................98
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
5 of 143
12.1.4
Medication errors...................................................................................................98
12.1.5
Adverse events requiring additional data collection................................................99
12.1.6
Adverse Events of special interest ........................................................................100
12.1.7
Technical complaints ...........................................................................................104
12.2
Reporting of adverse events...................................................................................................104
12.3
Follow-up of adverse events..................................................................................................107
12.4
Technical complaints and technical complaint samples..........................................................108
12.4.1
Reporting of technical complaints ........................................................................108
12.4.2
Collection, storage and shipment of technical complaint samples .........................109
12.5
Pregnancies...........................................................................................................................109
12.5.1
Pregnancies in female partners of male patients....................................................109
12.6
Precautions and/or overdose..................................................................................................110
12.7
Rules for putting enrolment on hold ......................................................................................111
12.8
Committees related to safety .................................................................................................111
12.8.1
Novo Nordisk safety committee ...........................................................................111
12.8.2
Data monitoring committee..................................................................................111
13
Case report forms ............................................................................................................................112
13.1
Corrections to case report forms............................................................................................113
13.2
Case report form flow ...........................................................................................................113
13.3
Electronic diary.....................................................................................................................113
14
Monitoring procedures ....................................................................................................................115
15
Data management ............................................................................................................................116
16
Computerised systems .....................................................................................................................117
17
Statistical considerations .................................................................................................................118
17.1
Sample size calculation .........................................................................................................119
17.2
Definition of analysis sets......................................................................................................120
17.3
Primary endpoint...................................................................................................................120
17.3.1
Estimand and primary statistical analysis .............................................................120
17.3.2
Sensitivity analysis ..............................................................................................121
17.3.3
Additional analysis ..............................................................................................121
17.4
Supportive secondary endpoints ............................................................................................122
17.4.1
Supportive secondary efficacy endpoints..............................................................122
17.4.2
Supportive secondary safety endpoints.................................................................122
17.4.3
Supportive secondary pharmacokinetic endpoints.................................................123
17.4.4
Supportive secondary pharmacodynamic endpoints..............................................123
17.4.5
Exploratory endpoints..........................................................................................124
17.4.5.1
Exploratory safety endpoints ..........................................................124
17.4.5.2
Exploratory patient reported-outcome endpoints.............................124
17.5
Interim analysis.....................................................................................................................125
18
Ethics................................................................................................................................................126
18.1
Benefit-risk assessment of the trial ........................................................................................126
18.2
Informed consent ..................................................................................................................128
18.3
Data handling........................................................................................................................128
18.4
Information to patients during trial ........................................................................................129
18.5
Premature termination of the trial and/or trial site..................................................................129
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
6 of 143
19
Protocol compliance.........................................................................................................................130
19.1
Protocol deviations................................................................................................................130
19.2
Prevention of missing data ....................................................................................................130
20
Audits and inspections .....................................................................................................................131
21
Critical documents...........................................................................................................................131
22
Responsibilities.................................................................................................................................133
23
Reports and publications .................................................................................................................134
23.1
Communication of results......................................................................................................134
23.1.1
Authorship...........................................................................................................135
23.1.2
Site-specific publication(s) by investigator(s).......................................................135
23.2
Investigator access to data and review of results ....................................................................135
24
Retention of clinical trial documentation and human biosamples..................................................136
24.1
Retention of clinical trial documentation ...............................................................................136
24.2
Retention of human biosamples.............................................................................................136
24.2.1
Antibody samples ................................................................................................137
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........139
26
Indemnity statement ........................................................................................................................140
27
References ........................................................................................................................................141
Table of Contents........................................................................................................................................2
Table of Figures ........................................................................................................................................11
Table of Tables..........................................................................................................................................12
List of abbreviations .................................................................................................................................13
1
Summary............................................................................................................................................20
2
Flow chart ..........................................................................................................................................23
2.1
Visits and assessments ............................................................................................................23
2.2
Explanatory descriptions .........................................................................................................26
3
Background information and rationale for the trial.........................................................................28
3.1
Background information..........................................................................................................28
3.1.1
Haemophilia ..........................................................................................................28
3.1.2
Concizumab...........................................................................................................29
3.2
Rationale for the trial...............................................................................................................32
4
Objective(s) and endpoint(s)..............................................................................................................33
4.1
Objective(s) ............................................................................................................................33
4.1.1
Primary objective...................................................................................................33
4.1.2
Secondary objectives .............................................................................................33
4.2
Endpoint(s) .............................................................................................................................33
4.2.1
Primary endpoint ...................................................................................................33
4.2.2
Secondary endpoints ..............................................................................................33
4.2.2.1
Supportive secondary endpoints .......................................................33
4.2.3
Exploratory endpoints............................................................................................34
4.2.3.1
Exploratory safety endpoints ............................................................34
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
7 of 143
4.2.3.2
Exploratory patient reported outcome endpoints ...............................35
5
Trial design ........................................................................................................................................36
5.1
Type of trial ............................................................................................................................36
5.1.1
Surgery..................................................................................................................37
5.2
Rationale for trial design .........................................................................................................37
5.3
Treatment of patients...............................................................................................................40
5.3.1
Concizumab arm....................................................................................................41
5.3.1.1
Concizumab prophylactic treatment (main and extension part)..........41
5.3.2
Comparator arm (eptacog alfa (rFVIIa)).................................................................42
5.3.2.1
On-demand treatment (main part).....................................................42
5.3.2.2
Concizumab prophylactic treatment (extension part).........................42
5.3.3
Dose escalation......................................................................................................42
5.3.4
Co-administration of eptacog alfa (rFVIIa).............................................................44
5.3.5
Treatment of bleeding episodes during the trial ......................................................45
5.3.6
Prohibited medication ............................................................................................46
5.4
Treatment after discontinuation of trial product .......................................................................46
5.5
Rationale for treatment............................................................................................................46
6
Trial population .................................................................................................................................47
6.1
Number of patients..................................................................................................................47
6.2
Inclusion criteria .....................................................................................................................47
6.3
Exclusion criteria ....................................................................................................................47
6.4
Criteria for premature discontinuation of trial product .............................................................48
6.5
Withdrawal from trial..............................................................................................................48
6.6
Patient replacement .................................................................................................................49
6.7
Rationale for trial population...................................................................................................49
7
Milestones...........................................................................................................................................50
8
Methods and assessments ..................................................................................................................51
8.1
Visit procedures ......................................................................................................................51
8.1.1
Informed consent, genotyping and long-term storage consent .................................53
8.1.2
Screening log, enrolment log, trial card and patient number....................................53
8.1.3
Screening failures and re-screening........................................................................53
8.1.4
Premature discontinuation of trial product..............................................................54
8.1.5
Withdrawal from trial.............................................................................................54
8.1.6
Review/ evaluation of clinical outcome..................................................................55
8.1.7
Visit 1 (Screening part)..........................................................................................55
8.1.8
Training of patients at visit 1, visit 2 and visit 9......................................................56
8.1.9
Treatment period at home ......................................................................................56
8.1.10
Staggered recruitment ............................................................................................56
8.1.11
Treatment period – Main part.................................................................................56
8.1.11.1
Visit 2 (Randomisation) ...................................................................56
8.1.11.2
Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and 
PK visit for concizumab arm)...........................................................58
8.1.11.3
Visit 4, 5, 6, 7 and 8 .........................................................................59
8.1.11.4
Visit 9 ..............................................................................................60
8.1.12
Treatment period – Extension part..........................................................................62
8.1.12.1
Visit 9.1 (PK visit and ONLY patients previously on the eptacog 
alfa (rFVIIa) on-demand arm) ..........................................................62
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
8 of 143
8.1.12.2
Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) 
on-demand arm)...............................................................................63
8.1.12.3
Visit 10 ............................................................................................63
8.1.12.4
Visit 10.1 (ONLY patients previously on the eptacog alfa 
(rFVIIa) on-demand arm) .................................................................64
8.1.12.5
Visit 11 ............................................................................................65
8.1.12.6
Visit 11.1 (ONLY patients previously on the rFVIIa on-demand 
arm) .................................................................................................66
8.1.12.7
Visit 12, 13, 14 and 15 .....................................................................67
8.1.12.8
Visit 16 ............................................................................................68
8.1.13
Visit 17 (End of trial) - Follow-up part...................................................................69
8.1.14
Unscheduled Visit..................................................................................................70
8.2
Patient related information/assessments...................................................................................70
8.2.1
Demography ..........................................................................................................70
8.2.2
Concomitant illness and medical history other than haemophilia ............................70
8.2.3
Concomitant medication ........................................................................................71
8.2.4
Details of Haemophilia, Haemophilia treatment and bleed history..........................71
8.3
Efficacy assessments...............................................................................................................72
8.3.1
Bleeding episodes ..................................................................................................72
8.4
Safety assessments ..................................................................................................................76
8.4.1
Physical examination .............................................................................................76
8.4.2
Body measurements...............................................................................................76
8.4.3
Vital Signs.............................................................................................................77
8.4.4
Electrocardiogram..................................................................................................77
8.4.5
Adverse events.......................................................................................................78
8.4.5.1
Medication error...............................................................................78
8.4.5.2
Adverse events requiring additional data collection ..........................78
8.5
Laboratory assessments...........................................................................................................80
8.5.1
Laboratory assessments for efficacy.......................................................................81
8.5.1.1
Thrombin generation........................................................................81
8.5.1.2
Free TFPI.........................................................................................82
8.5.2
Laboratory assessments for safety ..........................................................................82
8.5.2.1
Urinalysis.........................................................................................82
8.5.2.2
Haematology....................................................................................82
8.5.2.3
Biochemistry....................................................................................83
8.5.2.4
FVIII/FIX activity............................................................................83
8.5.2.5
Coagulation parameters....................................................................84
8.5.2.6
FVIII/FIX inhibitors.........................................................................84
8.5.2.7
Anti-concizumab antibodies .............................................................84
8.5.2.8
Concizumab ELISA .........................................................................86
8.5.2.9
FVII ELISA .....................................................................................87
8.5.2.10
Total TFPI........................................................................................87
8.5.3
Human Biosamples ................................................................................................88
8.6
Other assessments ...................................................................................................................88
8.6.1
Patient reported outcomes ......................................................................................88
8.6.2
Training.................................................................................................................89
8.6.2.1
Concizumab and NovoPen®4............................................................89
8.6.2.2
eptacog alfa (rFVIIa)........................................................................90
8.6.2.3
eDiary..............................................................................................90
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
9 of 143
8.6.3
Surgery..................................................................................................................90
8.7
Patient compliance..................................................................................................................91
8.8
Treatment compliance.............................................................................................................91
9
Trial supplies......................................................................................................................................92
9.1
Trial products..........................................................................................................................92
9.2
Labelling.................................................................................................................................92
9.3
Storage....................................................................................................................................93
9.4
Drug accountability and destruction ........................................................................................93
9.5
Auxiliary supplies ...................................................................................................................94
10
Interactive voice/web response system ..............................................................................................95
11
Randomisation procedure and breaking of blinded codes................................................................95
11.1
Randomisation ........................................................................................................................95
11.2
Breaking of blinded codes .......................................................................................................95
12
Adverse events, and technical complaints .........................................................................................96
12.1
Definitions ..............................................................................................................................96
12.1.1
Adverse event ........................................................................................................96
12.1.2
Serious adverse event.............................................................................................97
12.1.3
Non-serious adverse event......................................................................................98
12.1.4
Medication errors...................................................................................................98
12.1.5
Adverse events requiring additional data collection................................................99
12.1.6
Adverse Events of special interest ........................................................................100
12.1.7
Technical complaints ...........................................................................................104
12.2
Reporting of adverse events...................................................................................................104
12.3
Follow-up of adverse events..................................................................................................107
12.4
Technical complaints and technical complaint samples..........................................................108
12.4.1
Reporting of technical complaints ........................................................................108
12.4.2
Collection, storage and shipment of technical complaint samples .........................109
12.5
Pregnancies...........................................................................................................................109
12.5.1
Pregnancies in female partners of male patients....................................................109
12.6
Precautions and/or overdose..................................................................................................110
12.7
Rules for putting enrolment on hold ......................................................................................111
12.8
Committees related to safety .................................................................................................111
12.8.1
Novo Nordisk safety committee ...........................................................................111
12.8.2
Data monitoring committee..................................................................................111
13
Case report forms ............................................................................................................................112
13.1
Corrections to case report forms............................................................................................113
13.2
Case report form flow ...........................................................................................................113
13.3
Electronic diary.....................................................................................................................113
14
Monitoring procedures ....................................................................................................................115
15
Data management ............................................................................................................................116
16
Computerised systems .....................................................................................................................117
17
Statistical considerations .................................................................................................................118
17.1
Sample size calculation .........................................................................................................119
17.2
Definition of analysis sets......................................................................................................120
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
10 of 143
17.3
Primary endpoint...................................................................................................................120
17.3.1
Estimand and primary statistical analysis .............................................................120
17.3.2
Sensitivity analysis ..............................................................................................121
17.3.3
Additional analysis ..............................................................................................121
17.4
Supportive secondary endpoints ............................................................................................122
17.4.1
Supportive secondary efficacy endpoints..............................................................122
17.4.2
Supportive secondary safety endpoints.................................................................122
17.4.3
Supportive secondary pharmacokinetic endpoints.................................................123
17.4.4
Supportive secondary pharmacodynamic endpoints..............................................123
17.4.5
Exploratory endpoints..........................................................................................124
17.4.5.1
Exploratory safety endpoints ..........................................................124
17.4.5.2
Exploratory patient reported-outcome endpoints.............................124
17.5
Interim analysis.....................................................................................................................125
18
Ethics................................................................................................................................................126
18.1
Benefit-risk assessment of the trial ........................................................................................126
18.2
Informed consent ..................................................................................................................128
18.3
Data handling........................................................................................................................128
18.4
Information to patients during trial ........................................................................................129
18.5
Premature termination of the trial and/or trial site..................................................................129
19
Protocol compliance.........................................................................................................................130
19.1
Protocol deviations................................................................................................................130
19.2
Prevention of missing data ....................................................................................................130
20
Audits and inspections .....................................................................................................................131
21
Critical documents...........................................................................................................................131
22
Responsibilities.................................................................................................................................133
23
Reports and publications .................................................................................................................134
23.1
Communication of results......................................................................................................134
23.1.1
Authorship...........................................................................................................135
23.1.2
Site-specific publication(s) by investigator(s).......................................................135
23.2
Investigator access to data and review of results ....................................................................135
24
Retention of clinical trial documentation and human biosamples..................................................136
24.1
Retention of clinical trial documentation ...............................................................................136
24.2
Retention of human biosamples.............................................................................................136
24.2.1
Antibody samples ................................................................................................137
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........139
26
Indemnity statement ........................................................................................................................140
27
References ........................................................................................................................................141
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. 
Appendix 1
Patient Reported Outcomes
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
11 of 143
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. 
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......................................31
Figure 5–1 Schematic diagram of the trial design......................................................................................36
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. ...................................................................................................39
Figure 5–3 Dose escalation for one individual patient in the concizumab arm............................................43
Figure 5–4 Dose escalation for one individual patient in the comparator arm.............................................44
Figure 8–1 Visit schedule – concizumab arm. ...........................................................................................51
Figure 8–2 Visit schedule – eptacog alfa (rFVIIa) arm later switching to concizumab.........................51
Figure 12–1 Reporting of AEs ..................................................................................................................106
Figure 17–1 Definition of main and extension part....................................................................................125
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
12 of 143
Table of Tables
Page
Table 5–1
List of products provided by Novo Nordisk.............................................................................40
Table 8–1
Definition of stop of bleeding episode .....................................................................................74
Table 8–2
Definitions of bleeding episodes (cause of bleed) ....................................................................74
Table 8–3
Definition of bleeding episode severity and treatment recommendation ...................................74
Table 9–1
Trial products..........................................................................................................................92
Table 9–2
Storage conditions...................................................................................................................93
Table 17–1 Power in superiority comparison between concizumab prophylaxis and on-demand 
treatment under different assumptions of ABR for concizumab and over-dispersion 
(assuming on-demand ABR=24). ..........................................................................................120
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
13 of 143
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
CCDS
company core data sheet 
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 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
14 of 143
CPoC
clinical proof of concept
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
DRC
data request correction 
DUN
dispensing unit number
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
eITMF
electronic investigator trial master file
ELISA
enzyme-linked immunosorbent assay
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
15 of 143
EMA
european medicines agency
EOT
end of trial
ePRO
electronic patient reported outcome
eptacog alfa 
the name ‘eptacog alfa (rFVIIa)’ will be used throughout 
the protocol and the product is identical to 
rFVIIa,‘NovoSeven®, and ‘NiaStaseRT®’
ETP
endogenous thrombin potential 
FAS
full analysis set
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
FVIIa
activated coagulation factor VII
FVIII
coagulation factor VIII
FVIII:C
plasma activity of factor VIII
FX
coagulation factor X
FXa
activated coagulation factor X
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GHN
global haemophilia network
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
16 of 143
HCP
host cell protein
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
IEC
independent ethics committee
IgG4
immunoglobulin G4
IMP
investigational medicinal product
INN
International Non-Proprietary Names for Pharmaceutical 
Substances 
IRB
institutional review board
ISRQ-SIAQ
Injection Site Reaction Questionnaire – Self-Injection 
Assessment Questionnaire 
ISTH
International Society on Thrombosis and Haemostasis
IT
information technology
i.v.
intravenous(-ly)
IWRS
interactive web response system
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
17 of 143
LBBB
left bundle branch block
LPFV
last patient first visit
LPLV
last patient last visit
mAb
monoclonal antibody
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRA
magnetic resonance angiogram
MRI
magnetic resonance imaging
NOAEL
no observed adverse effect level 
NIMP
non investigational medicinal product
PCD
primary completion date 
PD
pharmacodynamics
PEF
peak expiratory flow
PGI-C
Patient’s Global Impression of Change
PK
pharmacokinetics
PP
per protocol
PRO
patient reported outcome
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
18 of 143
PT
prothrombin time
Q
Inter compartmental clearance
QA
quality assurance
Q4D
every 4th day
eptacog alfa (rFVIIa)
the name ‘eptacog alfa (rFVIIa)’ will be used throughout 
the protocol and the product is identical to ‘NovoSeven®’
sABR
spontaneous annualised bleeding rate
SAE
serious adverse event
SAS
safety analysis set
sBE
spontaneous bleeding episodes
s.c.
subcutaneous(-ly)
SDS
Sheehan Disability Scale
SF-36v2
36-Item Short Form Health Survey
SI
international system of units
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse reaction
TAT
thrombin-antithrombin complex
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
19 of 143
TF
tissue factor
TFPI
tissue factor pathway inhibitor
TG
thrombin generation
TMM
trial materials manual
TSQM
Treatment Satisfaction Questionnaire for Medication 
TVP
trial validation plan
UTN
Universal Trial Number
VERITAS-PRN® 
Validated Hemophilia Regimen Treatment Adherence 
Scale
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
20 of 143
1
Summary
The main objective for the phase 2 trial NN7415-4310, explorer™4, is to assess the efficacy of 
concizumab administered s.c. once daily to prevent bleeding episodes in haemophilia A and B 
patients with inhibitors. Furthermore, this trial aims to assess the longer-term efficacy and safety of 
concizumab in haemophilia A and B patients with inhibitors and to establish the safety of treating 
breakthrough bleeding episodes with recombinant factor VIIa (rFVIIa) in these patients.
Objective(s) and endpoint(s)
Primary objective
∀
To assess the efficacy of concizumab administered s.c. once daily in preventing bleeding 
episodes in haemophilia A and B patients with inhibitors.
Secondary objectives
∀
To assess the longer-term efficacy of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of administering recombinant factor VIIa (rFVIIa) to haemophilia 
patients with inhibitors that are exposed to concizumab
∀
To assess the immunogenicity of concizumab in haemophilia patients with 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
∀
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 dosing
treatment with trial product (or has withdrawn). The extension part of the trial will provide 
additional safety and long-term efficacy data.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
21 of 143
Trial design
The trial is a multi-centre, randomised (2:1), open-label, controlled trial, aiming to evaluate the 
efficacy and safety of concizumab 0.15 mg/kg (with potential dose escalation) administered daily 
s.c. in haemophilia patients with inhibitors. We expect 16 patients to complete treatment in 
concizumab arm (concizumab prophylaxis) and 8 patients in comparator arm (rFVIIa on demand). 
The dose regimen is selected based on relevant PK and TFPI data as well as PK/PD modelling of 
the results from the preceding explorer™ trials. Only on-demand patients will be eligible for the 
trial.
For all patients treated with concizumab (concizumab arm and comparator arm extention part) a 
loading dose of 0,5 mg/kg concizumab will be given as the first dose, followed by one week of 
concizumab dosing 0,15 mg/kg. All patients in treatment with concizumab will in a non-bleeding 
state receive a single dose of 90 μg/kg eptacog alfa (rFVIIa) one week after dosing with 
concizumab. Hereafter, patients will be closely clinically observed at the site for potential safety 
issues for at least 12h and evaluated again at the site after 24h.
The total trial duration for the individual patient will be approximately 86-130 weeks, consisting of
a 2-4 week screening period, a subsequent 76-118 week treatment period and an 8-week follow-up 
period. eptacog alfa (rFVIIa) for treatment of bleeding episodes during the trial will be provided by 
Novo Nordisk. The patient will not be provided with trial product or eptacog alfa (rFVIIa) after end 
of trial.
The trial is 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 94 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 16 patients have completed at least of 24 weeks of concizumab 
prophylaxis and 8 patients have completed 24 weeks of treatment with eptacog alfa (rFVIIa) on-
demand or have withdrawn. The analysis of the main part of the trial aims to substantiate the 
clinical proof of concept (CPoC) that concizumab has the potential to prevent bleeding episodes in 
patients with haemophilia and inhibitors. The extension part of the trial will provide additional 
safety and long-term efficacy data.
Trial population
Number of patients planned to be screened: 28
Number of patients planned to be started on trial product: 26
Number of patients expected to complete the trial: 24
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
22 of 143
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 haemophilia A or B patients with inhibitors aged ≥ 18 years at the time of signing 
informed consent
∀
Patients currently in need of treatment with bypassing agents
Key exclusion criteria
∀
Known or suspected hypersensitivity to trial product(s) or related products
∀
Known inherited or acquired bleeding disorder other than haemophilia
∀
Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX
Key Efficacy assessment
∀
Number of bleeding episodes during at least 24 weeks of treatment onset
Key Safety assessment
∀
Number of treatment emergent adverse events during at least 24 weeks of treatment onset
Trial products
The following products will be used in the trial:
∀
Investigational Medicinal Products:
o
concizumab B, 100mg/mL to be administered s.c. with NovoPen®4 and needles
o
eptacog alfa (rFVIIa), 5mg /vial and histidine (solvent). Reconstituted eptacog alfa 
(rFVIIa) is for intravenous administration and used in the trial at visit 3 and 9.1 for all 
patients with the purpose of investigating the safety of administering eptacog alfa 
(rFVIIa) to haemophilia patients
∀
Non Investigational Medicinal Product:
o
eptacog alfa (rFVIIa) 5 mg /vial and histidine (solvent). Reconstituted eptacog alfa is for 
intravenous administration and used in this trial for treatment of bleeding episodes
3URWRFROY
CONFIDENTIAL


Protocol
UTN: U1111-1179-2925
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
4.0
Page:
23 of 143
2
Flow chart
2.1
Visits and assessments
explorerTM4 trial periods
Screening
Treatment main a, b
Treatment extension b
Follow-up
Visit number c
1
2
3
4-5
6
7-8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13-14
15, 15.1, 
15.2, 15.nw
16
Unscheduled e
17x
Timing of visits (d) f
14 - 28 d before
visit 2
1
8
29-57
85
113-141
169
176
197
225
253
281
309
337
393-449
505-785
Up to
827
When 
applicable
Up to
883
Visit window (d)
14 - 28 d before
visit 2
0
+1
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
Every 
4w
12w
Every 
4w
24w
25w
28w
32w
36w
40w
44w
48 w
Every 8w
Every 8w
Up to  
118w
-
Up to 126w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/ Long-term storage consent
●
In/exclusion criteria
●
●g
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed 
history
●
Withdrawal criteria/ Criteria for premature discontinuation 
of trial product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Randomisation (IWRS)
●
EFFICACY
Bleeding episodes h, i
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab) 
●
●l
●j, k, l
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●l
●
●
Free TFPI (central lab)  
●
●l
●k, l
●
●
●
●l
●
●
●
●
●
●
●
●
●
●l
●
●
SAFETY
Physical examination
●
●
●k
●
●
●
●
●
●
Body measurements 
●
●m
●k, m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
Vital signs 
●
●n
●k, n
●
●
●
●n
●n
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
3URWRFROY


Protocol
UTN: U1111-1179-2925
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
4.0
Page:
24 of 143
explorerTM4 trial periods
Screening
Treatment main a, b
Treatment extension b
Follow-up
Visit number c
1
2
3
4-5
6
7-8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13-14
15, 15.1, 
15.2, 15.nw
16
Unscheduled e
17x
Timing of visits (d) f
14 - 28 d before
visit 2
1
8
29-57
85
113-141
169
176
197
225
253
281
309
337
393-449
505-785
Up to
827
When 
applicable
Up to
883
Visit window (d)
14 - 28 d before
visit 2
0
+1
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
Every 
4w
12w
Every 
4w
24w
25w
28w
32w
36w
40w
44w
48 w
Every 8w
Every 8w
Up to  
118w
-
Up to 126w
Injection site reaction  
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●l
●j, k, l
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●l
●
●
Biochemistry (central lab)
●
●l
●k, l
●
●
●
●l
●
●
●
●
●
●
●
●
●
●l
●
●
FVIII/ FIX activity (central lab)
●
●l
●l
Coagulation parameters (central lab)
●
●l
●
●
●
●l
●
●
●
●
●
●
●
●
●l
●
●
Coagulation parameters (PT, APTT and Fibrinogen (local 
lab))
●j, k, l
●j
FVIII/FIX  inhibitors (central lab)
●
●l
●l
Anti-concizumab antibodies (ADA) (special lab) o
●
●l
●k, l, p
●p
●p
●p
●l, p
●
●
●
●
●
●
●
●
●
●l
●
●
Concizumab  ELISA (special lab)
●l
●j, k, l, p
●p
●p
●p
●l, p
●j
●
●
●
●
●
●
●
●
●l
●
●
FVII ELISA (special lab)
●j,k, l
●j
Total TFPI (special lab)
●
●l
●k, l
●
●
●
●l
●
●
●
●
●
●
●
●
●
●l
●
●
TRIAL MATERIAL
IWRS call 
●
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab)r
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (eptacog alfa, histidine)q
●
●k
●
●
●
●
●
●
●
●
●
●
Administration of trial product (concizumab)r
●k, s
●k
●d, s 
●
● s
●
Administration of trial product (eptacog alfa)
●k, t
●t
Drug accountability (concizumab)
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
Drug accountability (eptacog alfa) 
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product e, u
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires 
●
●
●k
●
●
●
●
●
●z
● aa
REMINDERS
Human biological specimen for storage (central lab)
●
●
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Protocol
UTN: U1111-1179-2925
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
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explorerTM4 trial periods
Screening
Treatment main a, b
Treatment extension b
Follow-up
Visit number c
1
2
3
4-5
6
7-8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13-14
15, 15.1, 
15.2, 15.nw
16
Unscheduled e
17x
Timing of visits (d) f
14 - 28 d before
visit 2
1
8
29-57
85
113-141
169
176
197
225
253
281
309
337
393-449
505-785
Up to
827
When 
applicable
Up to
883
Visit window (d)
14 - 28 d before
visit 2
0
+1
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
Every 
4w
12w
Every 
4w
24w
25w
28w
32w
36w
40w
44w
48 w
Every 8w
Every 8w
Up to  
118w
-
Up to 126w
Handout ID card 
●
Training v
●
●
●
●
●
Compliance: eDiary
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●y
●y
The cells marked in ‘red’ are only for the patients randomised to eptacog alfa (rFVIIa) arm.
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Protocol
UTN: U1111-1179-2925
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
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2.2
Explanatory descriptions
Footer
Description
a
There is staggered recruitment for the 4 first patients in the trial on the concizumab arm. 
b
Concizumab administration is performed at home except for visit 2 and visit 3 for patients randomised to concizumab and visit 9 and 9.1 for patients 
randomised to eptacog alfa. Sampling for Free TFPI, Anti-concizumab antibodies, Concizumab ELISA and Total TFPI are done prior to concizumab 
administration.
c
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 and 
visit 9.1 have a PK session of 24 hours and a safety follow up visit the following day. 
d
Visit and procedures only performed for patients randomised to eptacog alfa and switching to concizumab treatment.Visit 9.1 should be performed 7 days (+ 1 
day) after visit 9.
e
For patients being dose escalated on concizumab a phone call is recommended 1 week after first dose of concizumab.
f
Daily dosing preferably at the same time in the morning.
g
Evaluation of the laboratory results obtained from samples taken at screening.
h
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.
i
Eptacog alfa will be given to treat breakthrough bleeding episodes. 
j
Sampling time schedule for thrombin generation, haematology,  coagulation parameters, concizumab ELISA and FVII ELISA: pre-dose (-1 hour), post-dose: 
10 min (±2 min), 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 
eptacog alfa administration.
k
ONLY for patients randomised to concizumab arm. The concizumab dose should be administered first followed by eptacog alfa dose. The interval between the 
concizumab and eptacog alfa should not exceed more than 30 min.
l
At visit 2, visit 3, visit 9 and 16 blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been 
performed.
m
Only body weight should be measured. 
n
Vital signs should be evaluated before and after trial drug administration at visit 2 and visit 3 for concizumab arm and at visit 9 and visit 9.1 for patients in 
eptacog alfa arm switching to concizumab treatment.
o
In case 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 blood samples will be taken and stored for characterisation 
of the antibodies.
p
Blood sampling for anti-concizumab antibodies and concizumab ELISA testing should only be collected for patients on concizumab.
q
If needed dispensing of eptacog alfa, histidine, trial injection kits and Direction For Use (DFU). 
r
First treatment dose of concizumab is a loading dose and will be administered at visit 2 for the concizumab arm and visit 9 for the eptacog arm. 
s
The patient must be in a non-bleeding state at the time of the first concizumab administration and should not have received any bypassing agent drugs,(e.g., 
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Protocol
UTN: U1111-1179-2925
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT no.: 2016-000510-30
Version:
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eptacog alfa, FEIBA®) for treatment of a bleeding episode within a period of 24h (for eptacog alfa) or 48h (for FEIBA®) prior to first concizumab. Only 
eptacog alfa is allowed after visit 2.
t
Eptacog alfa administered in a non-bleeding state at site at visit 3 for the concizumab arm and at visit 9.1 for the eptacog alfa arm. The concizumab dose 
should be administered first followed by eptacog alfa dose. The interval between the concizumab and eptacog alfa should not exceed more than 30 min.
u
Patient treated with concizumab 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 the investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose 
escalation. 
v
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Patients randomised to eptacog alfa will be re-trained in 
NovoPen®4 and s.c. administration at visit 9 and 9.1. If necessary training can be performed as needed at other visits. The eDiary will be provided to the 
patients at visit 2 if the patient feels capable in s.c. administration and using the eDiary. Further the patients will be trained in recognition of signs/symptoms of 
thrombosis.
w
Only for patients randomised to on-demand arm.
x
Visit repeated every 8 week until patient either discontinues, completes extension or is enrolled into phase 3 programme
y
For patients continuing in a subsequent trial End of Trial must be completed at visit 16. For patients declining participation in the prolongation, End of Trial 
must be completed at visit 17, 8 weeks after End of Treatment.
z
PRO questionnaires should only be completed at 15.1 for patients continuing in the prolongation of the trial.
aa
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: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP 1, applicable regulatory 
requirements,  in accordance with the Declaration of Helsinki 2 and ISO 14155 3.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
The 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). In haemophilia B, it is factor IX (FIX) that is deficient. 
Inheritance is chromosome X-linked; 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 births 4. According to 
the World Federation of Haemophilia global survey of 20145, 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 factor 6. With a deficiency of FVIII or FIX, the degree of activation of 
coagulation FX becomes insufficient. Consequently, the thrombin burst is delayed and insufficient 
for normal haemostasis 7. 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 symptoms 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 into a joint prior to age 4 year. Many children also bleed from other body sites before this 
age is reached 8. For this reason, primary prophylaxis with regular FVIII or FIX injections in the 
non-bleeding state is the recommended treatment from early childhood.
In patients who have developed inhibitors towards FVIII or FIX, replacement therapy is rendered 
ineffective. Though prevalence studies and registry data indicate that the prevalence of inhibitors in 
the haemophiliac population overall has been reported to be between 5% and 7% 9, the prevalence 
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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
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EudraCT no.: 2016-000510-30
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amongst patients with severe haemophilia (FVIII:C < 1%) is higher and has been reported to be up 
to 30% 9, 10. These patients may be treated with bypassing agents, activated FVII (NovoSeven®) and 
activated prothrombin complex concentrate (FEIBA®) given as i.v. injections.
Current treatment options in haemophilia, replacement therapy or bypassing therapy, are hampered 
by the fact that these products must be given as i.v. injections. Furthermore, bypassing agents are
characterized by relatively short half-lives, therefore prophylactic treatment is burdensome. It is 
also generally acknowledged that the efficacy profile of bypassing agents is inferior to replacement 
therapy. Consequently, delayed or sub-optimal treatment occurs in a significant number of patients
with inhibitors. 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 Dalton’s.  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)) 10. 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.
Key differentiators of this new mode of action (MoA) and the key benefit of concizumab in patients 
with severe haemophilia A and B with inhibitors is reduced treatment burden due to subcutaneous 
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, explorerTM1) 11, a single dose trial in Japanese healthy subjects (NN7415-3981), 
two multiple dose trials (NN7415-3986, explorerTM2) and (NN7415-4159, explorer™3). When the 
first cohort with 4 (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 trial animal had concizumab plasma concentrations several hundred fold 
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
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EudraCT no.: 2016-000510-30
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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 (NN7415-4159), explorer™3,
a new 52 week non-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.
The explorer™3 trial was finalised following the completion of cohort 3 (0.8 mg/kg s.c. 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 s.c. every 4 days for 6 weeks). No clinical consequences or 
serious adverse events were seen in the completed cohorts in explorer™3.
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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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
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Figure 3–1Individual 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™4.
In a drug–drug interaction study in monkeys (NN215431), three doses of up to 1 mg/kg of 
NovoSeven® were administered at 2h intervals, alone or in the presence of a steady state 
concentration of concizumab. No notable clinical observations were made, no treatment-related 
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
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EudraCT no.: 2016-000510-30
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adverse findings were seen, i.e. no thrombi or other signs of excessive coagulation. Increased 
concentrations of thrombin–anti-thrombin (TAT) and D-dimer were seen, which tended to be 
additive when both concizumab and eptacog alfa (rFVIIa) were present in circulation.
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 studies with concizumab have been finalised. Key safety and preliminary 
efficacy results from these phase 1 studies support further development of concizumab in 
haemophilia 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: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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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 haemophilia A and B patients with inhibitors
4.1.2
Secondary objectives
∀
To assess the longer-term efficacy of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of concizumab in haemophilia patients with inhibitors
∀
To assess the safety of administering recombinant factor VIIa (rFVIIa) to haemophilia 
patients with inhibitors that are exposed to concizumab
∀
To assess the immunogenicity of concizumab in haemophilia patients with 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
∀
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
∀
Number of TEAEs within 24 hours of rFVIIa administration
∀
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
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
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EudraCT no.: 2016-000510-30
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∀
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
∀
Free TFPI concentration
o
Value prior to the last dose administration at 24 weeks
o
Value prior to the last dose administration after at least 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 after at least 76 
weeks 
o
Endogenous thrombin potential (nMxmin) prior to the last dose administration at 24 
weeks 
o
Endogenous thrombin potential (nMxmin) prior to the last dose administration after 
at least 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 after at least 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:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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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 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
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:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
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5
Trial design
5.1
Type of trial
The trial is a multi-centre, randomised (2:1), open-label, controlled trial, aiming to evaluate the 
efficacy and safety of concizumab 0.15 mg/kg (with potential dose escalation) administered daily 
s.c. in haemophilia patients with inhibitors. The selected dose regimen is based on relevant PK and 
TFPI data as well as PK/PD modelling of the results from the preceding explorer™ trials. Only   
on-demand patients will be eligible for the trial.
Figure 5–1Schematic diagram of the trial design
The total trial duration for the individual patient will be approximately 86-130 weeks, including a 2-
4 week screening period, a 76-118 week treatment period, and a follow-up period of 8 weeks, see 
Figure 5–1
The trial is 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 94 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 16 patients have completed a minimum of 24 weeks of 
concizumab prophylaxis and 8 patients have completed a minimum of 24 weeks of eptacog alfa 
(rFVIIa) on-demand or have withdrawn.
In the concizumab arm bleeding episodes occurring during the trial will be treated with eptacog alfa 
(rFVIIa). In all patients treated with concizumab a single 90 μg/kg dose of eptacog alfa (rFVIIa)
will be administered in a non-bleeding state one week after dosing with concizumab has been 
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
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EudraCT no.: 2016-000510-30
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initiated. The investigator will evaluate if there are any safety concerns 24 hours post eptacog alfa 
(rFVIIa) administration. Furthermore, the scheduled administration of eptacog alfa (rFVIIa) for the 
first 4 patients entering the trial with concizumab will be staggered.
In the comparator arm, in the main part, patients will receive eptacog alfa (rFVIIa) on-demand 
treatment. After completion of the main part, the patients will continue the trial in the extension part 
being treated with prophylactic concizumab 0.15 mg/kg (with potential dose escalation) s.c. daily 
administration.
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 and damage. Acceptance of storage of human biosamples 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 human biosamples to be stored 
for future exploratory analysis, see Section 8.1.1.
An independent data monitoring committee (DMC) will be established for this trial. The DMC will 
review all safety data from the ongoing trial with concizumab exposure, see Section 12.8.2.
5.1.1
Surgery
Minor surgery is allowed in this trial. Major surgery conducted earlier than one month (30 days) 
prior to trial start is allowed, see exclusion criteria 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™4 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 with inhibitors. A dose escalation design will allow cautious dose escalation in order to 
identify an efficacious and safe concizumab dose for the individual patient. A comparator arm is 
included to assess if concizumab is superior to on-demand treatment. Furthermore, the trial will 
give a possibility to assess safety of co-administration of eptacog alfa (rFVIIa) to the patients 
exposed to the concizumab treatment.
The duration of at least 24 weeks for the main part of the trial is deemed necessary in order to 
obtain information on the annualised bleeding rate on concizumab prophylaxis. The duration of the 
extension part of the trial will be up to 94 weeks and provide further information on efficacy, i.e. 
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annualised bleeding rate, and also provide additional safety data upon 76-118 weeks treatment with 
concizumab.
Patients participating in NN7415-4310 will be offered screening for eligibility to participate in the 
subsequent clinical trials for concizumab, following their participation in NN7415-4310 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 subsequent trial and thus may continue prophylactic treatment with concizumab.
A total of 26 patients previously on-demand (OD) treatment will be randomised into one of the two 
arms, with 16 patients in the concizumab arm and 8 patients in the comparator arm see Figure 5–1. 
Concizumab will be administered s.c. daily for patients randomised to the concizumab arm in the 
main and the extension part of the trial. For patients in the comparator arm in the extension part
treatment will be changed from on-demand with rFVIIa to prophylaxis with concizumab.
The concizumab dose regimens will be starting with 0.15 mg/kg with the possibility to escalate to
0.20 mg/kg and 0.25 mg/kg based on bleeding frequency, see Section 5.3.3.
Daily dosing with concizumab 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 5.3.3.
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Figure 5–2Individual 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.1
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 
                                               
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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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™4. Daily dosing will allow for 
the increase in trough levels and thus better efficacy may be expected with a lower dose.
A loading dose of 0.5 mg/kg concizumab will be given as the first dose, followed by one week of 
concizumab dosing 0.15 mg/kg in order to ensure steady-state levels at the time of eptacog alfa 
(rFVIIa) administration. eptacog alfa (rFVIIa) will be administered one week after initiation of 
dosing with concizumab in a non-bleeding state to assess safety of treatment with eptacog alfa 
(rFVIIa) in patients exposed to concizumab treatment.
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.
5.3
Treatment of patients
The following products will be administered in the trial.
Table 5–1 List of products provided by Novo Nordisk
Compound Name 
Strength
Dosage form
Route of administration
Treatment period
concizumab B a
100 mg/mL
solution for s.c. 
injection in a 3 mL 
cartridge b
Subcutaneous 
administration using
NovoPen®4
For prophylactic 
treatment for at least 76 
weeks (for concizumab 
arm in the main part 
and extension part).
For prophylactic 
treatment for at least 52 
weeks (for comparator 
arm in the extension 
part).
eptacog alfa (rFVIIa) a, c
5 mg/vial
Powder for solution 
for i.v. injection
Intravenous 
administration
For treatment of 
breakthrough bleeding 
episodes at the 
discretion of the 
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histidine solvent (5 mL)
Prefilled syringes for 
solution for i.v. 
injection 
investigator (screening, 
main, extension and 
follow up part). c
Administration of 
doses higher than 
90μg/kg to patients 
exposed to concizumab 
is not allowed.
For on-demand 
treatment at the 
discretion of the 
investigator in 24 
weeks for comparator 
arm in the main part. 
In the concizumab arm 
and comparator arm 
after switching to 
concizumab in the 
extension part of the 
study a single 90μg/kg 
dose for initial safety 
assessments in a non-
bleeding state. a
Will be provided for as 
long as patients 
participate in the trial 
(screening, main, 
extension and follow 
up part)
a Investigational medicinal product (IMP)
b Not to be confused with the daily injected volume (~150 μL, depending on dose strength and body weight)
c Non-investigational medicinal product (NIMP)
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 in the Trial Materials Manual, see Section 9.
5.3.1
Concizumab arm
5.3.1.1
Concizumab prophylactic treatment (main and extension part)
Concizumab will be given s.c. once daily 0.15 mg/kg (with potential dose escalation to 0.20 and 
0.25 mg/kg). The dose escalation criteria are described, see Section 5.3.3. The first dose of 
concizumab will be given at the trial site under medical supervision.
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A loading dose of 0.5 mg/kg will be given as the first concizumab dose at visit 2 in order to ensure 
steady state levels at the time of the administration of eptacog alfa (rFVIIa) in a non-bleeding state 
at visit 3, see Section 5.3.4.
The patients will be trained in s.c. administration of concizumab with NovoPen®4 at the screening 
visit and at the first scheduled treatment visit. 
5.3.2
Comparator arm (eptacog alfa (rFVIIa))
5.3.2.1
On-demand treatment (main part)
During the main part of the trial, patients will receive eptacog alfa (rFVIIa) for treatment of 
bleeding episodes, with a dose regimen at the discretion of the investigator.
5.3.2.2
Concizumab prophylactic treatment (extension part)
After completion of the main part, the patients will continue the trial in the extension part and will 
switch to prophylactic treatment with s.c. daily administration of concizumab 0.15 mg/kg (with 
potential dose escalation to 0.20 and 0.25 mg/kg) s.c. daily administration.
The same dose escalation criteria as described below (for the initial concizumab arm) will apply.
A loading dose of 0.5 mg/kg will be given as the first concizumab dose at visit 9 in order to ensure 
steady state levels at the time of the administration of rFVIIa in a non-bleeding state at visit 9.1.
5.3.3
Dose escalation
The dose escalation criteria as described below will apply to all treatment arms.
Bleeding episodes will be assessed during the trial both at scheduled visit 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, bleeding episodes occurring during first 2 weeks should not influence a dose escalation 
decision.
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (or visit 9 when
switching from eptacog alfa (rFVIIa) to concizumab) (first treatment visit) until visit 16 (end of
treatment visit), i.e. a total of up to 116 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.
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Dose 0.15 mg/kg: 
When sBE occurs, the investigator will determine if ≥3 sBEs have occurred within the preceding 12
weeks (including the current sBE). If yes, and if investigator deems it safe, the patient will 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 sooner.
Dose 0.20 mg/kg: 
When 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 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 sooner.
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 due to lack of efficacy, see Section 6.4.
The possibility of dose escalation at unscheduled visits is necessary in order to avoid  bleeding
episodes at inadequate dose level: e.g. if the dose escalation eliciting bleeding episode occurs soon 
after a scheduled visit, the patient will avoid to wait 8 weeks for the next scheduled visit (in the 
extension part).
Figure 5–3Dose escalation for one individual patient in the concizumab arm
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Figure 5–4Dose escalation for one individual patient in the comparator arm
5.3.4
Co-administration of eptacog alfa (rFVIIa)
eptacog alfa (rFVIIa) will be used for treating breakthrough bleeding episodes in this trial; one 
week after initiation of dosing with concizumab, a single 90 μg/kg dose of eptacog alfa (rFVIIa)
will be administered in a non-bleeding state at the trial site under medical supervision to assess 
safety of treatment with eptacog alfa (rFVIIa) in patients exposed to concizumab treatment. 
Hereafter, patients will be closely clinically observed at the site for potential safety issues for at 
least 12h and evaluated again at site after 24h. Between 12h and 24h, the patient must either stay at 
the site or at a hotel or at home if he lives nearby to be able to continue visit 3 or 9.1 the day after.
Dosing of eptacog alfa (rFVIIa) in the first 4 patients randomised to concizumab arm will be 
staggered so that the period between eptacog alfa (rFVIIa) administrations from one patient to 
another is at least 48 hours. If no safety concerns are observed (for example signs and symptoms of 
thromboembolism, such as swelling, pain and redness of the leg, shortness of breath, and chest 
pain) by the investigator in the period between the administration of eptacog alfa (rFVIIa) and when 
the next daily concizumab dose is to be given, the investigator allows the individual patient to 
administer concizumab prophylactically at home and if needed, treat breakthrough bleeding 
episodes at home with eptacog alfa (rFVIIa). The patients will receive prophylactic doses of 
concizumab 0.15 mg/kg daily throughout the main part (at least 24 weeks) and the extension part 
(up to 94 weeks), unless dose escalation criteria are fulfilled, see Section 5.3.3.
In case safety concerns are raised by an investigator after eptacog alfa (rFVIIa) administration and 
these concerns meet the described criteria for putting enrolment of additional patients on hold, 
dosing in the individual patients will be halted and further recruitment in the trial will be halted, see 
Section 12.7. In case safety concerns that do not meet the criteria for putting enrolment of additional 
patients on hold are observed by the investigator, dosing in that individual patient will be halted 
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until further evaluation. In such cases, all available data will be assessed by the Data Monitoring 
Committee (DMC), see Section 12.8.2.
5.3.5
Treatment of bleeding episodes during the trial
Breakthrough bleeding episodes between visit 1 and visit 2 can be treated with any bypassing agent 
(e.g., eptacog alfa (rFVIIa), FEIBA®) up to a period of 24 hours (for eptacog alfa (rFVIIa)) or 48 
hours (for FEIBA®) prior to first concizumab administration at visit 2. Novo Nordisk will provide 
eptacog alfa (rFVIIa) throughout the trial. The patient can treat himself and then he must call the 
site. The bleeding episode must be recorded in the eCRF.
Breakthrough bleeding episodes between visit 2-3 in the concizumab arm and visit 9-9.1 in the 
comparator arm must be treated with eptacog alfa (rFVIIa). Upon breakthrough bleeding episodes 
in this period the patient must first call the site. The investigator should instruct the patient about 
whether he should go to the site to receive treatment or if he can administer a single dose of eptacog 
alfa (rFVIIa) which is not higher than 90μg/kg without delay to treat the breakthrough bleeding
episode. If the patient is instructed to administer the eptacog alfa (rFVIIa) dose at home, following 
the administration, the patient should immediately go to the site for further clinical evaluation. The 
bleeding episode must be recorded in the electronic Diary (eDiary).
Breakthrough bleeding episodes between visit 3 and visit 16 in the concizumab arm must be treated 
with eptacog alfa (rFVIIa). The patient can treat himself without delay but must inform the site that 
a bleeding episode has occurred. Doses of eptacog alfa (rFVIIa) those are lower than 90μg/kg may 
be used to treat breakthrough bleeding episodes at the discretion of the investigator. Administration 
of doses higher than 90μg/kg to patients exposed to concizumab is not allowed. If a single dose of 
eptacog alfa (rFVIIa) is not sufficient to stop a bleeding episode, the patient should inform the site 
and in agreement with the investigator may administer a second dose of eptacog alfa (rFVIIa) not 
higher than 90μg/kg 2-3h after the first dose has been administered. The same procedure should be 
repeated in case the second dose of eptacog alfa (rFVIIa) is not sufficient to stop the bleeding 
episode. If more than three 90μg/kg doses of eptacog alfa (rFVIIa) are needed to stop a bleeding 
episode, the patient should go to the site without delay. The definition and diagnostic criteria of 
DIC, acute myocardial infraction, stroke, deep vein thrombosis, pulmonary embolism and 
peripheral artery occlusion is provided in section 12.1.6. The bleeding episodes must be recorded in 
the eDiary.
Breakthrough bleeding episodes between visit 16 and visit 17 (follow-up part) may be treated with 
eptacog alfa (rFVIIa) or other products at the discretion of the investigator. The patient can treat 
himself with eptacog alfa (rFVIIa) at home without delay. Only eptacog alfa (rFVIIa) will be 
provided by Novo Nordisk. The bleeding episodes must be recorded in the eDiary.
See Table 5–1 and Table 8–3.
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5.3.6
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 anticoagulants (DOACs)
∀
Home treatment (between visit 2 and visit 16) with activated prothrombin complex 
concentrates (FEIBA®)
* 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 (visit 16 or earlier), the patient should be switched to a suitable 
marketed product at the discretion of the investigator. Only eptacog alfa (rFVIIa) will be provided 
by Novo Nordisk. The patient will not be provided with concizumab or eptacog alfa (rFVIIa) after 
end of trial (EOT) (visit 17) by Novo Nordisk.
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 the treatment burden 
compared to the currently approved prophylactic drugs which have to be administered i.v.
Furthermore, the current treatment options for prophylaxis in inhibitor patients do not reduce the 
frequency of breakthrough bleeding episodes to the same extent as prophylaxis with replacement 
therapy in non-inhibitor patients. Concizumab may therefore show a better efficacy profile 
compared to current treatment options in haemophilia A and B patients with inhibitors.
The treatment period during at least 24 weeks (the main part of the trial) is considered necessary for 
providing robust data that allow demonstration of clinical proof of concept and to support decision 
making regarding a phase 3 confirmatory trial. Dosing for up to 94 additional weeks will provide 
valuable long term efficacy and safety data.
Breakthrough bleeding episodes occur in prophylactic regimens with both bypassing agents and 
replacement therapy. Therefore, it is expected that breakthrough bleeding episodes will occur 
during prophylaxis with concizumab even if clinical proof of concept is demonstrated. 
Consequently, eptacog alfa (rFVIIa) will be provided by Novo Nordisk in this trial for treatment of 
breakthrough bleeding episodes. In order to minimize the likelihood of any unforeseen adverse 
events associated with administration of eptacog alfa (rFVIIa) in these circumstances,
administration of eptacog alfa (rFVIIa) in a controlled setting will be performed at visit 3 or 9.1.
Please refer to the Investigator’s Brochure for further information.
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6
Trial population
6.1
Number of patients
Number of patients planned to be screened: 28
Number of patients planned to start on trial product: 26
Number of patients expected to complete the trial: 24
∀
Preferably 21 haemophilia A patients
∀
Preferably 3 haemophilia B patients
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 the suitability 
for the trial
2. Male haemophilia A or B patients with inhibitors aged ≥ 18 years at the time of signing 
informed consent
3. Patients currently treated on-demand with a minimum of six bleeding episodes during the 24 
weeks (or twelve bleeds during 52 weeks) prior to screening
4. Documented history of high-titer inhibitors towards FVIII or FIX, defined as ≥5 Bethesda Units
5. Patients currently in need of treatment with bypassing agents
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
6. Major surgery conducted within one month prior to the initiation of trial activities or major 
surgery planned to occur during the trial
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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
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 requires 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 measured as estimated Glomerular Filtration Rate (eGFR) ≤ 60 ml/min/1.73 
m2 for serum creatinine measured at screening for patients without evidence of renal damage
12. Platelet count ≤ 100x109/L at screening
13. Fibrinogen level < the lower limit of normal
14. Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX
15. Antithrombin levels below the normal reference range at screening
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 and/or randomised in 
violation of the randomisation 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
7. Lack of efficacy due to neutralizing antibodies
8. 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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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 with inhibitors, is that 
there is a significant unmet medical need in this patient population for
1. A more effective treatment and
2. A treatment which reduces treatment burden.
In addition to this, since most of these patients are likely to have been treated and therefore familiar 
with eptacog alfa (rFVIIa) on-demand treatment, this trial population is considered the most suitable 
for assessing the safety of administering eptacog alfa (rFVIIa) to patients in whom plasma TFPI 
levels are inhibited. 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 are to be 
confirmed.
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7
Milestones
Planned duration of recruitment period (FPFV-LPFV): 28 weeks
FPFV: 
16-Aug-2017
FPFT: 
30-Aug-2017
LPFV: 
28-Feb-2018
Planned LPLV: 
31-Jan-2020
The total duration of concizumab treatment in this trial is at least 76 weeks for an individual patient
randomised to concizumab prophylaxis treatment at visit 2.
The total duration of concizumab treatment in the trial is at least 52 weeks for an individual patient 
randomised to eptacog alfa (rFVIIa) on-demand treatment at visit 2.
EOT is defined as last patient last visit (LPLV).
Recruitment
The screening and randomisation 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 randomisation can be randomised in a 2:1 allocation to either the concizumab 
or the comparator arm within the timelines specified in the flow chart (see Section 2).
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and 
clinicaltrials.jp. According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure,
how-we-disclose-trial-information, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors (ICMJE), 12
the Food and Drug Administration Amendment Act (FDAAA), 13 European Commission 
Requirements, 14 15 and other relevant recommendations or regulations. If a patient requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the patient. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
protocol LPFT (visit 2) + 24 weeks corresponding to 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.13
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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8
Methods and assessments
Assessments to be performed at the scheduled and at the unscheduled visits in the trial are described 
in this section, Figure 8–1, Figure 8–2 and in Section 2.
Figure 8–1Visit schedule – concizumab arm.
Figure 8–2
Visit schedule – eptacog alfa (rFVIIa) arm later switching to concizumab.
8.1
Visit procedures
For each patient the trial can consist of the following scheduled parts and visits depending upon
which arm the patient is randomised to:
Screening Part:
∀
Visit 1 (screening visit)
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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Main Part:
∀
Visit 2 (Randomisation and 1st treatment visit with concizumab at site for patients 
randomised to the concizumab-arm)
∀
Home treatment with concizumab daily
∀
Visit 3 (treatment and PK-visit with concizumab and eptacog alfa (rFVIIa) at site only for 
patients randomised to the concizumab-arm - phone visit for patients randomised to the 
eptacog alfa (rFVIIa) on-demand arm)
∀
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 – 1st treatment 
visit with concizumab at site for patients randomised to the eptacog alfa (rFVIIa) arm)
Extension Part:
∀
Visit 9.1 (treatment and PK-visit with concizumab and eptacog alfa (rFVIIa) at site ONLY
for patients randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 9.2 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 10 (Assessment visit, patients treat themselves at home)
∀
Visit 10.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
∀
Visit 11 (Assessment visit, patients treat themselves at home)
∀
Visit 11.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on demand-arm)
∀
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, no treatment at home before the visit and End of Treatment)
Follow-up Part:
∀
Visit 17 (Assessment visit and End of Trial)
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
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Unscheduled Part:
∀
Unscheduled visits can occur e.g. for dispensing of trial product, dose escalation or 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 and eptacog alfa (rFVIIa) administration, 
NovoPen®4, usage of eDiary, completion of the PRO etc.
8.1.1
Informed consent, genotyping and long-term storage consent
Informed consent must be obtained before any trial related activity at visit 1, 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/or 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 patients screening log, a patients identification code list and a patients 
enrolment log. Only patients who have signed the informed consent form should be included on the 
logs. The patients screening log and patients 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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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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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


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
55 of 143
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 to 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 ePRO 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
All assessments to be performed at screening are listed in Section 2.
After informed consent is given, patients will be asked to complete the ePRO questionnaires before 
any other trial related activities are performed according to Section 8.6.1:
∀
Hemo-TEM,
∀
VERITAS-PRN®
Assessment results from physical examination and body measurements, as well as measurements of 
vital signs, urinalysis and 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.
For bleeding episodes that occur in the period from Screening visit (Visit1) to randomisation visit 
(Visit 2), information about the bleeding episode is to be entered in the eCRF at visit 2.
Patients will be provided with eptacog alfa (rFVIIa), trial injection kits and direction for use (DFU) 
to cover the potential eptacog alfa (rFVIIa) treatment after the screening part of the trial and 
investigator will ensure that the patients are capable of treating themselves with eptacog alfa 
(rFVIIa).
Dispensing of eptacog alfa (rFVIIa) should be performed in IWRS.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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The patient must 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 at visit 1, visit 2 and visit 9
During visit 1 and visit 2 and visit 9 (comparator arm) 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 (if they are randomised to concizumab) 
or at visit 9 (if they are randomised to eptacog alfa (rFVIIa) and switching to concizumab at visit 9). 
Furthermore, patients must be instructed and trained in the importance of reporting all the home 
treatments with concizumab, details of the bleeding episodes and the eptacog alfa (rFVIIa) 
treatments associated with these bleeding episodes in the eDiary. The patient should call the site if 
bleeding episodes occur between visit 1 and 2 for the site to register in the eCRF.
Patients should be trained on how to recognize signs of thromboembolic events, so that the patient
contacts the site without delay.
The site and patient can arrange for additional training whenever needed during the remaining time 
of the trial.
8.1.9
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 (concizumab arm) or when the 
patient is comfortable self-administrating trial product subcutaneously (concizumab) and 
intravenously (eptacog alfa (rFVIIa)).
8.1.10
Staggered recruitment
Dosing of eptacog alfa (rFVIIa) in the first 4 patients randomised to the concizumab arm will be 
staggered until the 4th patient randomised to the concizumab arm has completed visit 3 without any 
safety concerns raised by the investigator. Until this time point, enrolled patients will not be 
randomised until the previous patient randomised to concizumab has completed visit 3 without any 
safety concerns raised by the investigator. Novo Nordisk will as sponsor control and communicate 
the staggered recruitment process.
8.1.11
Treatment period – Main part
8.1.11.1
Visit 2 (Randomisation)
Visit 2 should be scheduled 14 to 28 days after visit 1. The date of visit 2 will be considered as trial 
day 1.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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It is important to verify the in/exclusion criteria again and review central laboratory tests from 
screening.
The patients must be in a non-bleeding state and should not have received any bypassing agent 
(e.g., eptacog alfa (rFVIIa), FEIBA®) for treatment of bleeding episodes within a period of 24 hours 
(for eptacog alfa (rFVIIa)) or 48 hours (for FEIBA®) prior to the potential first concizumab 
administration (depending on the treatment arm). After visit 2 only treatment with eptacog alfa 
(rFVIIa) for bleeding episodes is allowed.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments listed in 2, must be performed before potential administration of concizumab
(depending on the treatment arm). Vital signs must be assessed both before (within 1 hour) and after 
concizumab administration. Pre-dose blood sampling must take place no more than 1 hour before 
concizumab administration.
Assessment results from concomitant medication, vital signs, body measurement (weight only) and 
details of adverse events must be entered into the eCRF.
A randomisation and dispensing call must be performed in the IWRS.
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 Trial Materials Manual (TMM) on 
basis of the patient’s current body weight. Investigator will communicate the daily dose of 
concizumab to the patient and record the dose for the coming home treatment period in the eCRF.
For patients randomised to the concizumab arm, the first treatment with the loading dose of 
concizumab will be given.
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.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
58 of 143
At the visit the patient will be provided with trial product concizumab and/or eptacog alfa (rFVIIa)
and trial injection kits and an eDiary device to be able to conduct and report home treatment and 
bleeding episodes until next scheduled visit.
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa) during the 
trial as instructed by the investigator. Drug accountability must be performed for eptacog alfa 
(rFVIIa), if applicable according to section 9.4. Unused histidine syringes should be returned at 
every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site. If the patient on concizumab needs to treat a 
bleeding episode with eptacog alfa (rFVIIa) at home, then he must visit the site immediately after.
8.1.11.2
Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and PK visit for 
concizumab arm)
eptacog alfa (rFVIIa) on-demand arm:
Visit 3 for eptacog alfa (rFVIIa) on-demand arm is a phone call scheduled 7 days after visit 2 (with 
a visit window of +1 day).
All relevant assessments listed in Section 2, must be discussed.
Assessment results from concomitant medication and details of adverse events must be entered into 
the eCRF.
concizumab arm:
Visit 3 is to be scheduled 7 days after visit 2 (with a visit window of +1 day) and the visit takes two 
days.
All assessments are listed in Section 2, and must be performed accordingly and recorded in 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:
∀
PGI-C
∀
Hemo-TEM
Pre-dose blood sampling must take place no more than 1 hour before eptacog alfa (rFVIIa)
administration. Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa)
administration.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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The concizumab dose should be administered first followed by eptacog alfa dose. eptacog alfa 
(rFVIIa) should be administered to the trial patients at the site under the surveillance of medically 
trained trial site staff. The interval between the concizumab and eptacog alfa dose administration 
should not exceed more than 30 min.  
Samples for thrombin generation, haematology, coagulation parameters, concizumab ELISA and 
FVII ELISA are taken pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 
10 min (±2 min), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (±20 min) and 
24h (±20 min).
The investigator must ensure that all assessments are performed as described in Section 2, The 
Investigator is requested to conclude after 24 hours if it is safe for the patient to continue in the trial 
and record the conclusion in the eCRF prior to administration of the next dose of concizumab.
Recruitment of the first four patients will be staggered according to section 8.1.9.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visits the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until the next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.11.3
Visit 4, 5, 6, 7 and 8
Patients should treat themselves at home according to their individual dosing schedule regardless of 
when visits 4, 5, 6, 7 and 8 are scheduled.
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.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
PGI-C
∀
Hemo-TEM
All assessments are to be performed according to Section 2, and the assessment results from 
concomitant medication, vital signs, body measurement (weight only) and details of adverse events 
must be entered into the eCRF.
Investigator must perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data from the e-Diary. Based on the assessment of any spontaneous 
bleeding episodes the investigator must, for patients randomised to concizumab arm at visit 2, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visits the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until the next scheduled visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
At visit 8 patients should be reminded that treatment with concizumab (concizumab arm) must take 
place after the blood sampling at visit 9.
8.1.11.4
Visit 9
Visit 9 is to be scheduled on trial day 169 (24 weeks) with a visit window of ±7days.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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Patients randomised to eptacog alfa (rFVIIa) on-demand treatment at visit 2 will now be switched to 
concizumab treatment. At this visit the first treatment (loading dose) with concizumab will take 
place.
Treatment with concizumab must take place after the blood sampling for both the patients on the 
concizumab arm as well as patients on the eptacog alfa (rFVIIa on-demand) arm.
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1:
∀
PGI-C
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments are to be performed according to Section 2, and the assessment results from 
physical examination, concomitant medication, vital signs, body measurement (weight only) and 
details of adverse events must be entered into the eCRF.
Investigator must perform compliance check of treatment and reporting of bleeding episodes 
through the available access to collected data from the e-Diary. Based on the assessment of any 
spontaneous bleeding episodes the investigator must, for patients randomised to concizumab arm at 
visit 2, evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in Section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 and eptacog alfa 
(rFVIIa) during the trial as instructed by the investigator. Drug accountability must be performed 
for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned at every 
visit and new histidine syringes should be dispensed to the patient.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
62 of 143
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12
Treatment period – Extension part
8.1.12.1
Visit 9.1 (PK visit and ONLY patients previously on the eptacog alfa (rFVIIa)
on-demand arm)
Visit 9.1 is to be scheduled on trial day 176 (25 weeks) with a visit window of +1 day and the visit 
takes two days.
All assessments are listed in Section 2, and must be performed accordingly and recorded in the 
eCRF.
Pre-dose blood sampling must take place no more than 1 hour before eptacog alfa (rFVIIa)
administration. Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa)
administration.
The concizumab dose should be taken first followed by eptacog alfa dose. eptacog alfa (rFVIIa)
should be administered at the site under the surveillance of medically trained trial site staff. The 
interval between the concizumab and eptacog alfa dose administration should not exceed more than 
30 min. A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, to be able to conduct home treatment until next scheduled visit.
Samples for thrombin generation, haematology, coagulation parameters, concizumab ELISA and 
FVII ELISA are taken pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 
10 min (±2 min), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9 h (± 10 min) and 12h (±20 min) 
and 24h (±20 min).
The Investigator is requested to conclude after 24 hours if it is safe for the patient to continue in the 
trial and record the conclusion in the eCRF prior to administration of the next dose of concizumab.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
63 of 143
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.2
Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
Visit 9.2 is to be scheduled on trial day 197 (28 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.3
Visit 10
Visits 10 is to be scheduled on trial day 225 (32 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
64 of 143
Patients will be asked to complete the ePRO questionnaires before any other trial related activities 
are performed according to section 8.6.1.
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.4
Visit 10.1 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
Visit 10.1 is to be scheduled on trial day 253 (36 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
65 of 143
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.5
Visit 11
Visit 11 is to be scheduled on trial day 281 (40 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
66 of 143
current body weight. Investigator will communicate the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.6
Visit 11.1 (ONLY patients previously on the rFVIIa on-demand arm) 
Visit 11.1 is to be scheduled on trial day 309 (44 weeks) with a visit window of ±7days.
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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, for patients initiating concizumab treatment at visit 9, 
evaluate if an escalation of the concizumab doses is needed according to the escalation rules 
described in section 5.3.3. All decisions to escalate the concizumab dose must be recorded in the 
eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
67 of 143
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
8.1.12.7
Visit 12, 13, 14 and 15, 15.1, 15.2, 15.n 
Visits 12, to15.n are to be scheduled with an interval of 8 weeks with a visit window of ±7 days 
until the patient either discontinues treatment or completes visit 16.
If patient declines participation in the prolongation of the extension, visit 16 should be conducted 4 
weeks after visit 15 (see Section 8.1.12.8)
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
At visit 15.1 only patients in the prolongation will be asked to complete the ePRO questionnaires 
before any other trial related activities are performed according to section 8.6.1;
∀
Hemo-TEM
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
68 of 143
∀
SF-36v2
∀
SDS
∀
TSQM
∀
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.
8.1.12.8
Visit 16
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. Further visit 16 should be scheduled to be conducted at the last day 
of treatment with concizumab.
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;
∀
Hemo-TEM
∀
SF-36v2
∀
SDS
∀
TSQM
∀
SIAQ-ISRQ
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs and details of adverse events must be entered into the eCRF. Treatment with concizumab 
must take place after the blood sampling at this visit.
Investigator must 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 patients can be treated with eptacog alfa 
(rFVIIa) or other products at the discretion of the investigator to treat any bleeding episodes. 
Eptacog alfa (rFVIIa) may be requested via IWRS.  Only eptacog alfa (rFVIIa) will be provided by 
Novo Nordisk during this period. If necessary, the patient will be provided with eptacog alfa 
(rFVIIa) and trial injection kits to be able to conduct home treatment until next scheduled visit.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
69 of 143
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 (eptacog 
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 eptacog alfa (rFVIIa) or other products at the discretion of the 
investigator to treat any bleeding episodes. Only eptacog alfa (rFVIIa) will be provided by Novo 
Nordisk during this period. If necessary, the patient will be provided with eptacog alfa (rFVIIa) and 
trial 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. NovoPen®4 must be 
returned. Drug accountability must be performed for concizumab and eptacog alfa (rFVIIa). Unused 
histidine syringes should be returned at every visit and new histidine syringes should be dispensed 
to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes) arise 
after he has left the site.
The End-of-Trial information must be entered in the End-of-Trial form in the eCRF at visit 16 for 
all patients continuing in a subsequent trial with concizumab. 
8.1.13
Visit 17 (End of trial) - Follow-up part
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. 
All assessments are listed in Section 2, 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 must perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data. Patients should be asked if their female partner has become 
pregnant, see Section 12.5.1.
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa), unused 
histidine syringes, eDiary device and Trial card. Drug accountability must be performed for eptacog 
alfa (rFVIIa).
End-of-Trial information must be entered in the End-of-Trial form in the eCRF at visit 17 for all 
patients not continuing in a subsequent trial with concizumab.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
70 of 143
If eptacog alfa (rFVIIa) was requested at visit 16 drug accountability should be performed in IWRS, 
see Section 10.
8.1.14
Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Section 2. 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 Section 
2. 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 replacement of 
eDiary or NovoPen®4.
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 eptacog alfa (rFVIIa), concizumab including dose escalation, see Section 5.3.3.
∀
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, 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 with inhibitors which is 
to be reported in the haemophilia medical history section of the eCRF.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
71 of 143
Medical history is a medical event, other than haemophilia, 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, see Section 6.2 and 6.3.
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. 
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 the concizumab and eptacog alfa 
(rFVIIa), which is taken during the trial, including the screening and follow-up period.
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)
o
Classification of haemophilia type (haemophilia A/B)
o
Severity of haemophilia (severe, moderate or mild)
o
Aetiology of haemophilia (congenital or acquired)
∀
Family history of
o
Haemophilia (Y/N)
o
Inhibitors (Y/N)
o
Prothrombotic disorders (Y/N)
o
Thromboembolism (Y/N)
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
72 of 143
∀
Inhibitor tests taken (Y/N)
o
Date (dd-mmm-yyyy) 
o
Result (BU)
∀
Cut-off for positive inhibitor result
∀
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
∀
Dosing frequency during prophylaxis 
∀
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 eptacog alfa (rFVIIa) 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 during visits to 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 eptacog alfa (rFVIIa) injection occurring outside the trial site should be entered in the eDiary by 
the patient, Section 13.3.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
73 of 143
The completed eDiary is considered source data.
For reporting of bleeding episodes as AEs/SAEs, please refer to Section 12. In case of life-
threatening bleeding episode, it should always be reported as an SAE, see Section 12.1.2.
The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with eptacog alfa (rFVIIa):
∀
Start date and time
∀
Stop date and time (see Table 8–1)
∀
Anatomical location
o
Position (left/right)
∀
Cause (see Table 8–2)
o
spontaneous
o
traumatic
o
post-surgical
∀
Severity (see Table 8–3)
o
mild/moderate, severe
o
classification and recording of severe bleeding episodes is the responsibility 
of the investigator
∀
Treatment, if any 
o
eptacog alfa (rFVIIa) administration or other product administration
o
dose, date, stop time
o
other medicinal treatments related to the bleeding episode (pain relieving 
medication, non-medical therapy etc.)
o
record as concomitant medication (section 8.2.3)
∀
Symptoms during bleeding episode(s)
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 12.1.1 and 12.1.2.
3URWRFROY
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
74 of 143
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 do 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 bleeding 
episodes without compartment syndrome), 
mucosal- or subcutaneous bleeding episodes
Mild/moderate bleeding episodes may occur 
in other anatomical locations  
Mild/moderate bleeding episodes: 
∀
patient must call the site between 
visit 1-2 and visit 3-16 (see 2-3 
and 9-9.1 below)
∀
patient must call the site between 
visit 2-3 or visit 9-9.1 (eptacog 
alfa arm) and if treated at home, 
go to the site immediately after
∀
patient can treat themselves at 
home between visit 16 and visit 
17
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
75 of 143
Category
Definition
Treatment recommendation
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 site immediately if in doubt regarding 
treatment of a bleeding episode and to discuss what other actions may need to be 
taken
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.
Dosing for bleeding episodes with eptacog alfa (rFVIIa) should be documented in the eCRF (visit 1 
to visit 2) and eDiary (visit 2 to visit 17). 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 13.3.
Investigator must instruct the patient not to perform preventive treatment with eptacog alfa (rFVIIa)
after bleeding stop as defined in Table 8–1.
Investigator must instruct the patient to use eptacog alfa (rFVIIa) as rescue medication to treat 
bleeding episode between visit 2 and visit 16, see Section 5.3.5.
Furthermore investigator must instruct the patient to contact the site when a bleeding episode 
occurs. 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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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
76 of 143
For in-between visit administrations of trial drug, patients will self-administer concizumab (and 
eptacog alfa (rFVIIa) as rescue medication) and will record treatment in the 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, breast(s)
∀
Musculoskeletal system
∀
Central and peripheral nervous system
∀
Skin
∀
Lymph node palpation
The investigator must evaluate the results of the examination and classify them 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 one decimal)
The body weight assessed at each visit will be used for calculation of the concizumab dose to be 
administered until next visit.
Measurements will be reported in the eCRF.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
77 of 143
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 in a 
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 visits 2 and visit 3 (for patients randomised to concizumab) and at visit 9 and visit 9.1
(for patients initiating concizumab treatment at visit 9), the measurements are also performed after 
concizumab administration.
The investigator must evaluate the vital signs 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 8.2.2
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.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
78 of 143
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 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 some 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 Section 12.
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:
Injection site reaction 
Investigation of injection site reactions will be performed locally at all visits after visit 2 until visit 
16 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)
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
79 of 143
∀
Swelling
∀
Dimpling
∀
Macula
∀
Haematoma
∀
Bleeding
∀
Other (visual reactions)
Any injection site reaction symptom (evaluated at 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.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
80 of 143
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 768 mL will be taken from each patient on the concizumab 
arm and 868 mL from each patient on the eptacog alfa (rFVIIa) arm.
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 at all visits and 
coagulation parameters at visits 3 and 9.1 are to be shipped for analysis at central laboratories or 
further distribution to special laboratories. Haematology samples (all visits) and coagulation 
parameters (visit 3 and 9.1) are to be analysed locally. Ports cannot be used for blood sampling.
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 SI units.
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 
clinically 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/FIX activity, FVIII/FIX inhibitor 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
81 of 143
test, Thrombin generation, Free TFPI (TFPI not bound to concizumab), concizumab concentration 
in plasma, anti-concizumab antibodies, Total TFPI and FVII antigen concentration.
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 8.2.3 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 antibodies).
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report (CTR).
Antibody samples and human biosamples, 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 collected at all visits.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa): 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9 h (± 
10 min), 12h (± 20 min) and 24h (± 20 min).
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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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
82 of 143
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 (TFPI not bound to concizumab) will be collected at all visits, pre-dose at visit 2 and 3 
(concizumab arm), visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16.
The free TFPI assay is an enzyme immunoassay measuring levels of free TFPI from 
 
 (named and referred to 
 TOTAL TFPI) and will be used for PD assessments.
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.
The investigator must evaluate the results and record the outcome as:
∀
Normal or abnormal
∀
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.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa), 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9 h (± 
10 min), 12h (± 20 min) and 24h (± 20 min).
∀
Haemoglobin
∀
Erythrocytes (cell count)
∀
Thrombocytes (platelet count)
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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∀
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
Biochemistry samples are to be sampled and analysed centrally at all visits.
∀
Creatinine
∀
Albumin
∀
Bilirubin; total, direct, indirect
∀
Aspartate aminotransferase (AST)
∀
Alanine aminotransferase (ALT)
∀
Gamma glutamyltransferase (GGT) 
∀
Alkaline phosphatase
∀
C-reactive protein (CRP)
The investigator must evaluate the results of the examination 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/FIX activity
FVIII/FIX activity is to be sampled and analysed centrally at visit 1, visit 9 and visit 16.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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∀
FVIII activity level (IU/mL) or
∀
FIX activity level (IU/mL)
8.5.2.5
Coagulation parameters
Coagulation parameters will be performed centrally at all visits with the exception of visit 3 and 
visit 9.1 where the PT, APTT, and Fibrinogen will be performed locally.
Further at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) samples are taken pre- and 
post-dose eptacog alfa (rFVIIa) at 10 min (±2 min), 1h (±10 min), 3h (±10 min), 6h (±10 min), 9h 
(±10 min) and 12h (±20 min) and 24h (± 20 min) locally.
∀
Fibrinogen – centrally and locally
∀
Prothrombin time (incl. INR) (PT) centrally and locally
∀
D-dimer – only centrally
∀
Prothrombin fragment 1+2 – only centrally
∀
Activated partial thromboplastin time (APTT) – centrally and locally
∀
Antithrombin (AT) activity – only centrally
The investigator must evaluate the results of the examination 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)
Coagulation parameters analysed locally are to be entered into the eCRF.
8.5.2.6
FVIII/FIX inhibitors
FVIII/FIX inhibitor level will be measured by the Nijmegen method at visit 1, visit 9 and visit 16. 
∀
FVIII inhibitors (BU) or
∀
FIX inhibitors (BU)
8.5.2.7
Anti-concizumab antibodies
Samples for the determination of anti-drug antibodies collected during the treatment period must be 
drawn at all visits and prior to administering concizumab at visit 2 and 3 (concizumab arm) and 
visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
85 of 143
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.
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 positive for binding antibodies. 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.
The following analyses will be available:
∀
Anti-concizumab antibodies assay
∀
Specificity assay (Anti-concizumab antibodies cross reacting with IgG4 backbone, CDR 
region or S241P mutation)
∀
Anti-concizumab neutralising antibodies assay
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. Neutralising antibodies will be analysed and reported at the EOT. 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 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 
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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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 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 collected at all visits where patients are in treatment with concizumab.
Samples will be collected pre-dose at visit 2 for concizumab arm and visit 9 for eptacog alfa 
(rFVIIa) arm) and visit 16 for both arms.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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At visit 3 for concizumab arm and visit 9.1 for eptacog alfa arm samples for concizumab ELISA are 
taken pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 10 min (±2 
min), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (±20 min) and 24h (±20 
min).
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
FVII ELISA
FVII ELISA will be collected at visit 3 (concizumab arm) and 9.1 (eptacog alfa (rFVIIa) arm) pre-
dose eptacog alfa (rFVIIa) and post-dose at 10 min (±2 min), 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 eptacog alfa (rFVIIa) administration.
FVII in plasma will be quantified using a validated enzyme-linked immunosorbent assay (ELISA).
The FVII ELISA will detect the total sum of FVII in a sample, including endogenous FVII, eptacog 
alfa (rFVIIa) and FVII in complex with other molecules e.g. antithrombin. The ELISA has been 
validated for measuring FVII in human citrated plasma samples. Validation follows current 
guidelines for bioanalytical method validation. Bioanalytical data will be reported in a bioanalytical 
report.
8.5.2.10
Total TFPI
Total TFPI ELISA will be collected at all visits. Samples will be collected pre-dose at visit 2 and 3 
(concizumab arm) and visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
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 a 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.
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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
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Data will be reported in ng/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, see Section 2. 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. Plasma 
and serum is taken at visit 1 and 17. DNA for genotyping is only taken at visit 1.
8.6
Other assessments
8.6.1
Patient reported outcomes
A newly developed disease-specific electronic PRO (ePRO) the Hemophilia Treatment Experience 
Measure (Hemo-TEM) - is being validated in this trial. In order to assess the psychometric 
properties of Hemo-TEM, other questionnaires will be provided; see further appendix 1.
The following ePRO questionnaires will be used in the trial:
∀
Hemophilia Treatment Experience Measure (Hemo-TEM)
∀
Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS-PRN®) 16
∀
36-Item Short Form Health Survey (SF-36v2) (4 week recall)17
∀
Patient’s Global Impression of Change (PGI-C)
∀
Sheehan Disability Scale (SDS) 18
∀
Treatment Satisfaction Questionnaire for Medication (TSQM, version II) 19 20 21
∀
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)22
The ePROs should be assessed at the scheduled visits following the order listed below:
∀
visit 1 (Hemo-TEM, VERITAS-PRN®)
∀
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
∀
visit 3 (PGI-C, Hemo-TEM)
∀
visit 4 (PGI-C, Hemo-TEM)
∀
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, SIAQ-ISRQ)
∀
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
∀
visit 15.1 or 16 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
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Version:
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At visit 1: before any visit-related activities all patients should complete Hemo-TEM and 
VERITAS-PRN®.
At visit 2: before any visit-related activities all patients should complete Hemo-TEM, SF-36v2, 
SDS, TSQM and SIAQ-ISRQ.
At visit 3-8: 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 visits 9, 10 and 15.1 or 16. 
∀
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. 
Exception: Patients randomised to eptacog alfa (rFVIIa) on-demand should not complete the 
ePRO at visit 3 as this is a phone visit.
At visit 9 if the patient has responded “0” or “2” in the PGI-C at all previous visits, the patient 
should complete PGI-C. All patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and 
SIAQ-ISRQ.
At visit 10 and 15.1 or 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and 
SIAQ-ISRQ.
The investigator must check the ePROs for completeness. The completed ePROs should be 
transmitted at each visit to the PRO database by the Investigator.
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 documented in the medical record.
8.6.2.1
Concizumab and NovoPen®4
Direction for use (DFUs) will be available as a 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 the 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 DFUs.
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8.6.2.2
eptacog alfa (rFVIIa)
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.
The following should be emphasised for eptacog alfa (rFVIIa):
∀
eptacog alfa (rFVIIa) should be slowly injected intravenously over 2 to 5 minutes
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 eptacog alfa (rFVIIa) treatments 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 duplicate 
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 EOT.
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 eptacog alfa (rFVIIa) 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
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Version:
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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 of the importance of following the instructions given including 
taking the trial products as prescribed.
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 for the concizumab arm 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 eptacog alfa (rFVIIa) 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. 
Drug accountability will be performed and will be used to assess patient compliance together with 
the patients’ 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 TMM.
The trial product, concizumab B, appears as clear to slightly opalescent and colourless to slightly 
yellow. The trial product must not be used if it contains visible particles or discoloration.
The reconstituted eptacog alfa (rFVIIa) solution appears clear and colourless. Do not use the 
reconstituted solution if it contains visible particles or if it is discoloured.
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)
100 mg/mL
Solution for injection
s.c. injection
3 mL cartridge
eptacog alfa
(IMP a and NIMP b)
5 mg/vial
Powder for solution
for injection
i.v. injection
Vial
histidine 5 mL
N/A
Solvent for solution 
for injection
i.v. injection
prefilled syringe
a Investigational Medicinal Product (IMP) given as IMP for a single dose at visit 3 and 9.1.
b Non-Investigational Medicinal 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. It will be labelled in accordance with the EMA directive on medical devices annex I 23
and similar national legislation. A description of how to use the device is given in the DFU.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 24, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation.
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Version:
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The investigator must document that DFUs are given to the patient orally and in writing at the first 
dispensing visit (see 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 (2oC-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)
eptacog alfa
5mg
Store between 2oC-25oC
Do not freeze
Protect from light
For single use
Do not freeze
Protect from light
To be used immediately 
after reconstitution
If not used 
immediately, store in 
refrigerator (2oC-8oC)
for up to 3 hours
histidine 5 mL
Store between 2oC-25oC 
Do not freeze
Protect from light
For single use
N/A
a In-use time for concizumab starts when first dose is administered from an individual cartridge and for eptacog alfa
(rFVIIa) 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.
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 (concizumab and eptacog alfa (rFVIIa) 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 used histidine
syringes which should be discarded at home and not accounted for. Unused histidine syringes 
should be returned at every visit and new histidine syringes should be dispensed to the patient.
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Version:
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All cartridges (concizumab) and vials (eptacog alfa (rFVIIa)) 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/or 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 product including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Destruction of concizumab and eptacog alfa (rFVIIa) 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 DFUs
∀
For eptacog alfa (rFVIIa) reconstitution and administration: Trial Injection Kit and DFU
Only needles and trial injection kit provided by Novo Nordisk must be used for administration of 
trial product.
For further guidance please see the TMM.
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Date:
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Version:
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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
∀
Randomisation
∀
Medication arrival
∀
Dispensing
∀
Dispensing verification
∀
Treatment discontinuation 
∀
Completion
∀
Drug accountability
∀
Data change
IWRS user manuals will be provided to each trial site.
11 Randomisation procedure and breaking of blinded codes
11.1
Randomisation 
Randomisation will be handed by the IWRS.
All patients included in the screening period and eligible for the trial will enter the trial and be 
randomised at visit 2 in a 2:1 allocation to either concizumab prophylaxis arm or eptacog alfa 
(rFVIIa) on-demand arm.
11.2
Breaking of blinded codes
Not applicable for this trial.
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Date:
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Version:
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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 
∀
Mild – no or transient symptoms, no interference with the patient’s daily activities
∀
Moderate – marked symptoms, moderate interference with the patient’s daily activities
∀
Severe – considerable interference with the patient’s daily activities; unacceptable
∀
Causality 
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Relationship between an AE and the relevant trial product(s): 
∀
Probable - Good reason and sufficient documentation to assume a causal relationship
∀
Possible - A causal relationship is conceivable and cannot be dismissed
∀
Unlikely - The event is most likely related to aetiology other than the trial product
∀
Final outcome 
∀
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
∀
Recovering/resolving - The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the trial 
or has died from another AE
∀
Recovered/resolved with sequelae - The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE
∀
Not recovered/not resolved - The condition of the patient has not improved and the 
symptoms are unchanged or the outcome is not known
∀
Fatal - This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported 
as an SAE
∀
Unknown - This term is only applicable if the patient is lost to follow-up
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-threatening a experience
∀
In-patient hospitalisation b or prolongation of existing hospitalisation
∀
A persistent or significant disability or incapacity c
∀
A congenital anomaly or birth defect
∀
Important medical events that may not result in death, be life threatening a or require 
hospitalisation b 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 SAE d
a. The term “life threatening” in the definition of SAE refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
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b. The term “hospitalisation” is used when a patient:
∀
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay or
∀
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a patient’s ability to conduct normal life functions (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 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 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
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Version:
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Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1
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, see Section 8.4.5.2
Injection site reactions: 
Any injection site reaction symptom must be recorded on the AE form and the injection site 
reaction form.
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 type 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 will be performed. 
Definition of anaphylaxis (25)
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. dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow [PEF], hypoxemia)
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b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.
hypotonia [collapse], syncope, incontinence)
∀
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. dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
∀
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 treating physician. If according to the investigators judgement, 
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 Events 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:
∀
Platelet count (>100 × 109/L = 0, <100 × 109/L = 1, <50 × 109/L = 2)
∀
Elevated D-dimer (no increase = 0, moderate increase = 2, strong increase = 3)
∀
Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
∀
Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
∀
Calculate score: ≥5 compatible with overt DIC
B) Myocardial infarction is defined according to the “Third Universal Definition of
Myocardical Infarction” (26)
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:
∀
Symptoms of ischemia
∀
New or presumed new significant ST-segment–T wave (ST–T) changes or new left
bundle branch block (LBBB)
∀
Development of pathological Q waves in the ECG
∀
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality
∀
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.
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C) Definition of pulmonary embolism:
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 embolism
(27).
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” (28).
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 “Haemorrhagic Infarction”).
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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.
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. A Transient ischemic attack 
(TIA) is a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal 
ischemia, without acute infarction (29).
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 DVT in the lower
extremities27. 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, 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 (30).
12.1.7
Technical complaints
A technical complaint is any written, electronic or oral communication that alledges 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 the pen and the 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 patient not enrolling into a new trial. 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 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.
When eptacog alfa (rFVIIa), NovoSeven® is used as IMP, 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
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 (eptacog alfa (rFVIIa)) 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.
∀
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 AEs. 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.
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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
∀
Eptacog alfa (rFVIIa) 5 mg/vial, powder for solution for injection in a vial
∀
Histidine 5 mL, solvent for solution for injection in a 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.
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, AESI 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
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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 
Centre, 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.
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 with concizumab at visit 2 or 
visit 9 depending on the arm). At the last scheduled visit (visit 17), 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.
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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: 
∀
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 newborn 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 have not been investigated in clinical trials.
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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 
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.
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 data, and 
will provide recommendations on trial continuation, modification or termination.
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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.
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:
∀
Pregnancy forms
∀
Technical complaint forms
∀
AE forms
∀
Safety information forms
The paper version of the technical complaint form, AE form, and safety information form must only 
be used to ensure timely reporting when/if the electronic CRF is unavailable.
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.
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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.
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 eptacog alfa 
(rFVIIa)).
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 EOT visit.
All data entered will be transferred from the device to an electronic database, where it is kept as a 
certified copy of the source data. Data entered in the device will upon confirmation of a successful 
back-up be deleted from the device.
The eDiary will have built in edit checks and reminders to ensure that all relevant questions are 
answered. 
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eDiary data transferred to the electronic database will be viewable to relevant trial site staff and 
Novo Nordisk personnel on a secure, password protected web portal.
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 Request Correction (DRC) must be submitted to 
the eDiary vendor. An audit trail will be maintained.
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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 
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. 
Monitoring visits should be scheduled as frequently as needed to support the first 6 patients 
recruited in the trial. 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 
ePROs and eDiaries are completed and reviewed by the investigator at the relevant scheduled visits 
and needed action has been taken and documented, if any.
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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
∀
Demography, see section 8.2.1
∀
Date of visit
Monitors will review the patient’s medical records and other source data (e.g. the 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.
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 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.
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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 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 archiving containing the 
electronic Investigator Trial Master File (eITMF) for each trial site. These CDs or other relevant 
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 FDA 21 CFR Part 11 
and ICH E6 (EU directive for personal data protection).1, 31
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.
The eDiary and ePRO 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, 31After trial 
completion, each trial site will be supplied with long-life CDs. These CDs will contain site-specific 
patient records including the patient’s eDiaries and audit trail including any data additions and 
corrections made on each form. The eDiary vendor will furthermore retain and securely store copies 
of all archived documents and data for 15 years or as required by local data retention laws for trial 
data.
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17 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 
17–1 for further information. 
Data from when the on-demand treated patients are transferred to concizumab s.c. prophylaxis will 
not be included in this evaluation. Observations from the extension part in the on-demand arm will 
be summarised separately as well as combined with observations from the main part when reporting 
the extension part data.
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 product 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 patients with inhibitors. The objective will be 
assessed when the last of the 24 patients has completed 24 weeks of dosing (or has withdrawn 
before that).
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the ABR of all patients in the concizumab group, irrespective of individual dose 
titration, with the ABR of the patients in the on-demand arm using different sets of observations. 
The primary CPoC criterion aims at evaluating the effect of concizumab when given at the last dose 
level reached for the 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 not be included. Since this evaluation disregards a 
subset of data collected post randomisation, the result should be viewed taking into account the 
potential bias. The second CPoC criterion aims at evaluating the effect of concizumab when given 
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as an escalation regimen. Hence, this will compare the ABR of patients in the concizumab arm with 
the ABR of the patients in the on-demand arm using all data collected after randomisation. 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 and regimen as factor (concizumab vs. on-demand). For each criterion, 
evidence of effect will be concluded if the 95% confidence interval of the treatment ratio is below 1.
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.
17.1
Sample size calculation
The estimand will be defined as the “if all patients had adhered” estimand.
The treatment ratio between prophylactic s.c. concizumab and on-demand i.v. eptacog alfa (rFVIIa)
during at least 24 weeks for all randomised patients if all patients adhered to trial drug and did not 
initiate alternative treatment options.
This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand i.v. eptacog alfa 
(rFVIIa) under similar conditions as observed in this trial.
The sample size calculation has been determined based on this estimand and the CPoC criteria 
taking the small patient population into account, while also aiming for an acceptably narrow 95% 
confidence interval for the rate ratio.
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be 
accommodated by 16 patients in the concizumab arm and 8 in the comparator arm. 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, annual bleeding rates 
of 24 and 6 are assumed for the on-demand patients and the end dose concizumab regimen, 
respectively. Assuming further over-dispersion of 7, the power for concluding superiority of the 
concizumab regimen becomes approximately 80%. 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 17–1Power in superiority comparison between concizumab prophylaxis and on-demand 
treatment under different assumptions of ABR for concizumab and over-
dispersion (assuming on-demand ABR=24).
Power
Over-dispersion (over 6 months)
ABR (concizumab)
6
7
8
6
89%
82%
75%
7
84%
75%
70%
8
77%
69%
66%
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 7.6 for 
the concizumab regimen. This yields a marginal power of approximately 70% 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). In the 
NN7128-1907 trial in inhibitor patients, larger 1-year over-dispersion values of approximately 21 
and 18, respectively, were observed during an initial 3-month on-demand period and a subsequent 
3-month prophylaxis period. It is expected that the variation in the current trial will be smaller, 
partly due to the longer duration of the trial and partly due to an expected more homogenous patient 
population. Another published trial including inhibitor patients, comparing prophylaxis using 
FEIBA® with on-demand treatment, showed 6-month over-dispersion of 4-5 32. On that background, 
an over-dispersion of 7 over the 24 weeks in 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 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 endpoint will be analysed when the main part of trial has been completed.
17.3.1
Estimand and primary statistical analysis
The estimand for the primary endpoint is the “if all patients had adhered” estimand.
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The treatment ratio between prophylaxis s.c. concizumab and on-demand i.v. eptacog alfa (rFVIIa)
during at least 24 weeks for all randomised patients if all patients adhered to trial drug and did not 
initiate alternative treatment options.
This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand i.v. eptacog alfa 
(rFVIIa) under similar conditions as observed in this trial.
The estimand for 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 and regimen as 
factor. The offset for first CPoC criterion of patients in concizumab arm 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 of patients in concizumab arm 
is the log of the individual exposure time in the main part. For both criteria and patients in the on-
demand arm, the offset is the log of the exposure time in the main part. The analysis provides an 
estimate of the ABR ratio between regimens (concizumab prophylactic and on-demand eptacog alfa 
(rFVIIa)) with corresponding 95% confidence interval and also actual estimate of the ABR with 
corresponding 95% confidence interval for each regimen. 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 estimand will be 
estimated based on the FAS and only data collected prior to discontinuation of trial product or 
initiation of alternative treatment options will be used to draw inference.
17.3.2
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 Δ 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 part 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 concizumab 
prophylaxis no longer is superior to on-demand eptacog alfa (rFVIIa). The results of the primary 
analysis will be considered robust if the tipping point is above what is considered clinically
plausible.
17.3.3
Additional analysis
An additional evaluation of the primary endpoint will be made, including the actual concizumab 
dose level (interpreted as the patients 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 
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at the different dose levels of concizumab (0.15, 0.20 and 0.25 mg/kg). Furthermore, 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 of number of bleeding episodes 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, TFPI value prior to the last s.c. dose administration, peak thrombin generation (nM), 
Endogenous thrombin potential (nMxmin) and velocity index (nM/min).
17.4
Supportive secondary endpoints
17.4.1
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 number of spontaneous bleeding episodes during at least 24 weeks from treatment onset will be 
addressed in terms of the same estimand as for the primary endpoint. The estimand will be 
estimated using the same negative binomial regression model as for the primary endpoint.
Furthermore, an additional evaluation will be made, where actual concizumab dose is included as 
factors in the model.
The remaining supportive secondary efficacy endpoints will be summarised descriptively by 
treatment regimen. In addition, number of bleeding episodes during at least 76 weeks of treatment 
with prophylactic concizumab will be analysed using a negative binomial model with log of trial 
duration as offset, providing estimates of the ABR with confidence interval for that particular 
regimen.
17.4.2
Supportive secondary safety endpoints
∀
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
∀
Number of TEAEs during at least 76 weeks from treatment onset
∀
Number of TEAEs within 24 hours of rFVIIa administration
∀
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
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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 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.
TEAE is defined as an event that has onset after randomisation 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 safety follow-up period (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. Relations to Novo Nordisk marketed products 
used by patients in the trial, such as eptacog alpha, is reported as described in section 12.2 of the 
protocol 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.
17.4.3
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 after at least 76 weeks
The pharmacokinetic endpoints will be summarised and listed.
17.4.4
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 after at least 76 weeks
∀
Thrombin generation
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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 after at least 76 
weeks
o
Endogenous thrombin potential (nMxmin) prior to the last dose administration at 24 
weeks
o
Endogenous thrombin potential (nMxmin) prior to the last dose administration after 
at least 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 after at least 76 weeks
The PD endpoints will be summarized and listed.
17.4.5
Exploratory endpoints
17.4.5.1
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
17.4.5.2
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
VERITAS-PRN®, SF-36v2, SDS and TSQM will be scored according to their respective scoring 
algorithms. Change after 24 weeks of treatment onset for SF-36v2, SDS and TSQM from visit 2 to 
visit 9 will be analysed with an ANCOVA model including regimen as a factor and baseline score 
as covariate.
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The PRO endpoints will be summarised using descriptive statistics and the remaining 
questionnaires (Hemo-TEM, PGI-C, SIAQ-ISRQ) will be summarised and listed using descriptive 
statistics.
17.5
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. For patients in 
the concizumab s.c. prophylaxis arm, main part is 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. For patients in the on-demand arm, the main part consists of 
observations from randomisation until transfer to concizumab s.c. prophylaxis treatment or 
withdrawal from trial, whichever comes first. All observations for these patients after transfer to 
concizumab treatment are regarded as extension part 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 CTRs might in such case be issued. A CTR describing results from the 
main and the 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 100 ng/mL, see Section 3.1.2. Based on these results, it is expected that the 
majority of the patients randomised to the concizumab treatment with 0.15 mg/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. For haemophilia patients with inhibitors 
and who are treated on-demand, expected improved efficacy is considered to be a major benefit in 
participating in this trial. Also, concizumab is administered s.c. and might reduce the burden of 
frequent i.v. injections associated with current treatment options in haemophilia patients with 
inhibitors.
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 a drug–drug interaction study in monkeys, three doses of up to 1 mg/kg of NovoSeven® were 
administered at 2-h intervals, alone or in the presence of a steady state concentration of 
concizumab. Increased concentrations of thrombin–anti-thrombin (TAT) and D-dimer were seen, 
which tended to be additive when both concizumab and eptacog alfa (rFVIIa) were present in 
circulation. No notable clinical observations were made.
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
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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.
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.
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 the 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 
mechanisms33 34. 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 injuries35 36, 37.
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.
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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 
Helsinki 2.
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.
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 qualified person, 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 CTR.
∀
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.
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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 
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.
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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.
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 eptacog alfa (rFVIIa)
∀
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 sites outside the US)
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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, 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 GCP 1
applicable regulatory requirements and the Declaration of Helsinki 2.
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.
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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.
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).
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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 
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 CTR for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the CTR (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 38. 
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-information.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the CTR is available. This includes the right not to release the results of interim 
analyses, because the release of such information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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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 Editors38 (sometimes referred to as the Vancouver 
Criteria).
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.
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.
Only applicable 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 EOT 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.
24.2
Retention of human biosamples
This trial will involve collection of human biosamples at visit 1 (screening visit) and at visit 17
(EOT) and these samples are to be stored maximum 15 years from EOT. 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 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 
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participate, while refusing permission for biological specimens to be stored for future exploratory 
analysis.
∀
Human biosamples will be stored at the central laboratory
∀
1.0 mL citrated plasma, 1.2 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 consortia
∀
The human biosamples will be transferred and stored after the EOT at a designated central 
laboratory
∀
Confidentiality and personal data protection will be ensured during storage after the EOT
∀
The human biosamples may be transferred to other countries (not applicable if local 
regulations prohibit export of human biosamples)
∀
The human biosamples will be destroyed at the latest 15 years from EOT
∀
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
can contact the investigator if they wish to be informed about results derived from stored 
human biosamples obtained from their own body, see 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. Remaining 
blood from the samples already collected may be used for further development of Anti-Drug 
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antibody assays, and will not be reported in this trial. The samples will be stored at a central bio-
repository after EOT and until marketing authorisation approval or until the research project 
terminates, but no longer than 15 years from EOT 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 CTR 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 CTR 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 Austria: Arzneimittelgesetz (BGBI. Nr. 185/1983) last amended with BGBl. 
II Nr. 105/2015
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 research for the person lending 
himself thereto and for indemnification of his beneficiaries, except in case of proof, incumbent on 
it, that the prejudice is not attributable to his fault or the fault of any intervening party, without the 
sponsor’s being entitled to call on acts by a third party or the voluntary withdrawal of the person 
who had initially consented to cooperating in the research”.
Only applicable for Poland: Novo Nordisk carries liability for the Trial exclusively in the scope 
defined by the applicable laws and in particular by the Civil Code and the Pharmaceutical Law 
dated 6 September 2001 (uniform version Journal pf Laws of 2008 No. 45 item 271 with 
amendments). In order to support potential claims for liability attributable to the Trial, Novo 
Nordisk and Investigators are covered by the Insurance Policy issued according to applicable Polish 
law.
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
141 of 143
27 References
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International Organization for Standardization. ISO 14155:2011, Clinical investigation of 
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Soucie JM, Evatt B, Jackson D. Occurrence of hemophilia in the United States. The 
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White GC, 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J, et al. 
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of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
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The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March laying down 
Community procedures for the authorisation and supervision of medicinal products for 
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Protocol
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
142 of 143
human and veterinary use and establishing a European Medicines Agency, article 57. 
Official Journal of the European Communities. April 2001.
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Duncan NA, Kronenberger WG, Roberson CP, Shapiro AD. VERITAS-PRN: a new 
measure of adherence to episodic treatment regimens in haemophilia. Haemophilia. 
2010;16(1):47-53.
17.
Maruish ME. User's manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated2013.
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Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin 
Psychopharmacol. 1996;11 Suppl 3:89-95.
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Atkinson MJ, et al. Validation of a general measure of treatment satisfaction, the Treatment 
Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic 
disease. Health Qual Life Outcomes. 2004;2:12.
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Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical construct validity of the 
treatment satisfaction questionnaire for medication (TSQM version II) among outpatient 
pharmacy consumers. Value Health. 2005;8 Suppl 1:S9-S24.
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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 
patients on antihypertensive medications. Health Qual Life Outcomes. 2009;7:36.
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Keininger D, Coteur G. Assessment of self-injection experience in patients with rheumatoid 
arthritis: psychometric validation of the Self-Injection Assessment Questionnaire (SIAQ). 
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Council Directive 93/42/EEC of 14 June 1993 concerning medical devices. Official Journal 
L 1692 12/07/1993.
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European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products (ENTR/F/2/AM/an D[2010] 
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Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et 
al. Second symposium on the definition and management of anaphylaxis: summary report--
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7.
26.
Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third 
universal definition of myocardial infarction. Circulation. 2012;126(16):2020-35.
27.
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.
28.
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.
29.
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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CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
4.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no.: 2016-000510-30
Page:
143 of 143
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.
30.
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.
31.
U.S. Food and Drug Administration. Code of Federal Regulations, 21 CFR Part 11, 
Electronic Records, Electronic Signatures. 2009 2009.
32.
Leissinger C, Gringeri A, Antmen B, Berntorp E, Biasoli C, Carpenter S, et al. Anti-
inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 
2011;365(18):1684-92.
33.
Levi M, Keller TT, van GE, ten CH. Infection and inflammation and the coagulation system. 
Cardiovasc Res. 2003;60(1):26-39.
34.
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-
21.
35.
Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. 
Arterioscler Thromb Vasc Biol. 2004;24(6):1015-22.
36.
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.
37.
Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Vasc Biol. 
2005;25(1):47-56.
38.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2016.
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CONFIDENTIAL


Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
1 of 14
Appendix 1
NN7415-4310
A Multi-Centre, Randomised, Open-Label, Controlled Trial 
Evaluating the Efficacy and Safety of Prophylactic Administration 
of Concizumab in Haemophilia A and B Patients with Inhibitors
Trial phase: 2
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
3URWRFRODSS[
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:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
2 of 14
Table of Contents
Page
Table of Contents........................................................................................................................................2
1
Hemophilia Treatment Experience Measure (Hemo-TEM)...............................................................3
2
Validated Hemophilia Regimen Treatment Adherence Scale - PRN (VERITAS-PRN®)..................6
3
36-Item Short Form Health Survey (SF-36v2) (standard)..................................................................8
4
Patient’s Global Impression of Change (PGI-C) ................................................................................9
5
Sheehan Disability Scale (SDS)..........................................................................................................10
6
Treatment Satisfaction Questionnaire for Medication (TSQM, version II).....................................11
7
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ (SIAQ-ISRQ)...............................14
3URWRFRODSS[
CONFIDENTIAL


Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
3 of 14
1
Hemophilia Treatment Experience Measure (Hemo-TEM)
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Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
4 of 14
3URWRFRODSS[
CONFIDENTIAL


Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
5 of 14
3URWRFRODSS[
CONFIDENTIAL


Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
6 of 14
2
Validated Hemophilia Regimen Treatment Adherence Scale - PRN 
(VERITAS-PRN®)
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CONFIDENTIAL


Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
7 of 14
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CONFIDENTIAL


Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
8 of 14
3
36-Item Short Form Health Survey (SF-36v2) (standard)
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Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
9 of 14
4
Patient’s Global Impression of Change (PGI-C)
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Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
10 of 14
5
Sheehan Disability Scale (SDS)
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Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
11 of 14
6
Treatment Satisfaction Questionnaire for Medication (TSQM, 
version II)
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Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
12 of 14
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CONFIDENTIAL


Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
13 of 14
3URWRFRODSS[
CONFIDENTIAL


Concizumab
CONFIDENTIAL
Date:
05 May 2017
Novo Nordisk
Trial ID: NN7415-4310
Version:
2.0
Protocol - Appendix 1
Status:
Final
EudraCT No.: 2016-000510-30
Page:
14 of 14
7
Injection Site Reaction Questionnaire (ISRQ) domain of SIAQ 
(SIAQ-ISRQ)
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CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
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CONFIDENTIAL


Protocol Amendment no. 1
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
1 of 6
Protocol Amendment
no 1
to Protocol, version 1
dated 15 March 2017
Trial ID: NN7415-4310
A Multi-Centre, Randomised, Open-Label, Controlled Trial Evaluating the Efficacy and 
Safety of Prophylactic Administration of Concizumab in Haemophilia A and B Patients with 
Inhibitors
Trial phase: 2
Applicable to all countries
Amendment originator:
 - Senior International Trial Manager
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: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
2 of 6
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 1
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
3 of 6
1
Introduction including rationale for the protocol amendment
This protocol amendment has been prepared to address VHP1081 requirements to clarify individual 
discontinuation criteria, holding rules for the trial, protocol deviations and patient eligibility 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 5.3.3 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 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 and/or randomised 
in violation of the randomisation 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
7. Lack Loss of efficacy due to neutralizing antibodies
8. 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.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 1
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
4 of 6
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 
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.
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 …
Patient eligibility 6: 
Section 1 Summary
Only Both on-demand and prophylaxis patients will be eligible for the trial. 
Section 2.1 Visits and assessments
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CONFIDENTIAL


Protocol Amendment no. 1
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
5 of 6
Section 2.2 Explanatory descriptions
Section 4.2.3.2 Exploratory patient reported outcome endpoints
Change in VERITAS-Pro® or VERITAS-PRN® after 24 weeks from treatment onset
Change in VERITAS-Pro® or VERITAS-PRN® after 76 weeks from treatment onset
Section 5.1 Type of trial 
Only Both on-demand and prophylaxis patients will be eligible for the trial. 
Section 5.2 Rationale for trial design
A total of 26 patients previously on prophylaxis (PPX) or on-demand (OD) treatment will be 
randomised into one of the two arms, with 16 patients in the concizumab arm and 8 patients in the 
comparator arm ..
Section 6.2 Inclusion criteria
3. For pPatients currently treated on-demand with, a minimum of six bleeding episodes during the 
24 weeks (or twelve bleeds during 52 weeks) prior to screening
Section 8.1.7 Visit 1 (Screening part)
After informed consent is given, patients will be asked to complete the ePRO questionnaires before 
any other trial related activities are performed according to Section 8.6.1:
!
Hemo-TEM,
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 1
CONFIDENTIAL
Date:
05 May 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
6 of 6
!
VERITAS-Pro® or VERITAS-PRN®
Section 8.6.1 Patient reported outcomes 
The following ePRO questionnaires will be used in the trial:
!
Hemophilia Treatment Experience Measure (Hemo-TEM) 
!
Validated Hemophilia Regimen Treatment Adherence Scale - Prophylaxis (VERITAS-Pro®)
or Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS-PRN®) 16
The ePROs should be assessed at the scheduled visits following the order listed below:
!
visit 1 (Hemo-TEM, VERITAS-Pro® or VERITAS-PRN®)
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) or VERITAS-PRN® (if 
the patient at baseline receives on-demand treatment).
Section 17.4.5.2 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 VERITAS-Pro® or VERITAS-PRN® after 24 weeks from treatment onset
!
Change in VERITAS-Pro® or VERITAS-PRN® after 76 weeks from treatment onset
VERITAS-Pro® or VERITAS-PRN®, SF-36v2, SDS and TSQM will be scored according to their 
respective scoring algorithms. Change from visit 2 to visit 9 will be analysed with an ANCOVA 
model including regimen as a factor and baseline score as covariate.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
1 of 12
Protocol Amendment
no 2
to Protocol, version 2
dated 05 May 2017
Trial ID:NN7415-4310
A Multi-Centre, Randomised, Open-Label, Controlled Trial Evaluating the Efficacy and
Safety of Prophylactic Administration of Concizumab in Haemophilia A and B Patients with
Inhibitors
Trial phase: 2
Applicable to all countries
Protocol Amendment originator
- Senior International Trial Manager
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:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
2 of 12
Table of Contents
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................4
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
3 of 12
1
Introduction including rationale for the protocol amendment
This protocol amendment has been prepared to address: 
!
Section 2.2, 8.1.11.2, 8.1.12.1 and 8.5.2.8 ‘Concizumab ELISA’ updated due to concizumab 
PK has been added to the trial in order to obtain PK-profile of daily dosing with concizumab 
after initiation of multiple dosing
!
Section 4.2.3.2 and Section 17.4.5.2 ‘Exploratory patient reported-outcome endpoints’ 
updated as VERITAS-PRN is not assessed at visit 9 and visit 16 and PGI-C is not assessed 
at visit 1 and visit 16
!
Section 5.3.6 ‘Prohibited medication’ is updated because the use of anti-fibrinolytics is 
commonly local/topical use in dental procedures or dental surgery and thus not seen as 
compromising patient safety or trial conclusions. 
A single systemic dose may be needed: 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’ updated to provide clarity on when a patient is 
considered to be positive for binding antibodies as this is difficult to interpret with current 
text in version 2.0 of the protocol if reader is not in possession of thorough knowledge on 
the different tests described
!
Section 9.4 ‘Drug accountability and destruction’ updated to ensure solvent does not reach 
expiry date in patient’s custody this includes clarification in relevant visits described in 
section 8 
o
8.1.11.1; 8.1.11.2; 8.1.11.3; 8.1.11.4; 8.1.12.1; 8.1.12.2; 8.1.12.3; 8.1.12.4; 8.1.12.5; 
8.1.12.6; 8.1.12.7; 8.1.12.8; 8.1.13
!
Section 18.1 ‘Benefit-risk assessment of the trial’ updated to specify the minimum 
difference in plasma concentration between the NOAEL in non-haemophilic animals and 
highest anticipated plasma concentration in phase 2
!
Clarifications and corrections which are seen as being minor
o
List of abbreviations; Figure 8-1 and Figure 8-2; Section 2.1; 2.2; 3.1.1; 4.2.3.2; 
8.1.11.2; 8.1.12.1; 8.1.12.8; 8.5; 8.5.1.2; 12.7
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
4 of 12
2
Changes
List of abbreviations
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-PRN® 
Validated Hemophilia Regimen Treatment Adherence Scale
Section 2.1 Visits and assessments
explorerTM4 trial periods
Screeni
ng
Treatment main a, b
Treatment extension b
Follo
w-up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d 9.2d
10
10.1d
11
11.1d
12
13
14 15
16
Un-
schedul
ed e
17
Timing of visits (d) f
14 to 28 
d 
before
visit 2
1
8
29
57
85
113
141
169
176
7 days 
after 
V9
197
225
253
281
309
337
393 449 505 533
When 
applica
ble
589
Visit window (d)
14 to 28 
d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7 ±7 ±7
Not 
applica
ble
-7
Treatment week (w)
0
1w
4w
8w
12w 16w 20w 24w 25w 28w 32w 36w 40w 44w 48w 56w 64
w
72
w 76w
-
84w
PATIENT RELATED 
INFO/ASSESSMENTS
Informed consent/ Genotyping and 
Long-term storage consent
●
In/exclusion criteria
●
●g
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia 
treatment and bleed history
●
Withdrawal criteria/ Criteria for 
premature discontinuation of trial 
product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Randomisation (IWRS)
●
EFFICACY
Bleeding episodes h, i
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab) 
●
●l
●j, k, l
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Free TFPI (central lab)  
●
●l
●k, l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
SAFETY
Physical examination
●
●
●k
●
●
●
●
●
●
Body measurements 
●
●m
●k, m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m ●m
●m
●m
Vital signs 
●
●n
●k, n
●
●
●
●
●
●n
●n
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction  
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
5 of 12
explorerTM4 trial periods
Screeni
ng
Treatment main a, b
Treatment extension b
Follo
w-up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d 9.2d
10
10.1d
11
11.1d
12
13
14 15
16
Un-
schedul
ed e
17
Timing of visits (d) f
14 to 28 
d 
before
visit 2
1
8
29
57
85
113
141
169
176
7 days 
after 
V9
197
225
253
281
309
337
393 449 505 533
When 
applica
ble
589
Visit window (d)
14 to 28 
d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7 ±7 ±7
Not 
applica
ble
-7
Treatment week (w)
0
1w
4w
8w
12w 16w 20w 24w 25w 28w 32w 36w 40w 44w 48w 56w 64
w
72
w 76w
-
84w
Urinalysis (local lab)
●
Haematology (local lab)
●
●l
●j, k, l
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Biochemistry (central lab)
●
●l
●k, l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
FVIII/ FIX activity (central lab)
●
●l
●l
Coagulation parameters (central lab)
●
●l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●l
●
●
Coagulation parameters (PT, APTT 
and Fibrinogen (local lab))
●j, k, l
●j
FVIII/FIX  inhibitors (central lab)
●
●l
●l
Anti-concizumab antibodies (ADA) 
(special lab) o
●
●l
●k, l, p
●p
●p
●p
●p
●p
●l, p
●
●
●
●
●
●
●
●
●
●
●l
●
●
Concizumab  ELISA (special lab)
●l
●j, k, l,
p
●p
●p
●p
●p
●p
●l, p
●j
●
●
●
●
●
●
●
●
●
●l
●
●
FVII ELISA (special lab)
●j, k, l
●j
Total TFPI (special lab)
●
●l
●k, l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
TRIAL MATERIAL
IWRS call 
●
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab)r
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (eptacog alfa, 
histidine)q
●
●w
●k
●
●
●
●
●
●
●
●
●
●
●
Administration of trial product 
(concizumab)r
●k, s
●k
●d, s 
●
●s
●
Administration of trial product 
(eptacog alfa)
●k, t
●t
Drug accountability (concizumab)
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Drug accountability (eptacog alfa) 
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product e, u
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires 
●
●
●k
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for 
storage (central lab)
●
●
Handout ID card 
●
Training v
●
●
●
●
●
Compliance: eDiary
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
6 of 12
Section 2.2 Explanatory descriptions
Footer ‘d’: Visit and procedures only performed for patients randomised to eptacog alfa and 
switching to concizumab treatment. Visit 9.1 should be performed 7 days (+ 1 day) after visit 9.
Footer ‘j’: Sampling time schedule for thrombin generation, haematology,  coagulation parameters,  
concizumab ELISA and FVII ELISA: pre-dose (-1 hour), post-dose: 10 min (±2 min), 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 eptacog alfa administration.
Footer ‘k’: ONLY for patients randomised to concizumab arm. The concizumab dose should be 
administered first followed by eptacog alfa dose. The interval between the concizumab and eptacog 
alfa should not exceed more than 30 min. 
Footer ‘l’: At visit 2, visit 3, visit 9 and 16 blood samples should be collected pre-dose. Patients 
must not treat themselves with concizumab until sampling has been performed.
Footer ‘t’: Eptacog alfa administered in a non-bleeding state at site at visit 3 for the concizumab 
arm and at visit 9.1 for the eptacog alfa arm. The concizumab dose should be administered first 
followed by eptacog alfa dose. The interval between the concizumab and eptacog alfa should not 
exceed more than 30 min. 
Administration of trial product (concizumab): Dot and ‘s’ footnote added to visit 16 
Section 3.1.1 Haemophilia
Haemophilia is classified as “severe”, “moderate” or “mild” according to the plasma activity level
of the affected coagulation factor. 
Section 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-PRN® after 24 weeks from treatment onset
!
Change in 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
!
Status of Change in PGI-C after 24 weeks from treatment onset
!
Change in PGI-C 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. 
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
7 of 12
Section 5.3.6 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 anticoagulants (DOACs)
!
Home treatment (between visit 2 and visit 16) with activated prothrombin complex 
concentrates (FEIBA®)
* Local/topical use is allowed. Use of single systemic doses in severe bleeding episodes, after careful benefit risk 
evaluation, is allowed.
Section 8; Figure 8-1 and Figure 8-2.
Figure 8.1
Figure 8.2
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
8 of 12
Section 8.1.11.1 Visit 2 (Randomisation)
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa) during the 
trial as instructed by the investigator. Drug accountability must be performed for eptacog alfa 
(rFVIIa), if applicable according to section 9.4. Unused histidine syringes should be returned at 
every visit and new histidine syringes should be dispensed to the patient.
Section 8.1.11.2 Visit 3 (Phone call for eptacog alfa (rFVIIa) on-demand arm and PK visit for 
concizumab arm)
Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa) administration dosing.
The concizumab dose should be administered first followed by eptacog alfa dose. eptacog alfa 
(rFVIIa) should be administered to the trial patients at the site under the surveillance of medically 
trained trial site staff. The interval between the concizumab and eptacog alfa dose administration 
should not exceed more than 30 min. Patient should continue his daily concizumab injections 
regardless of eptacog alfa (rFVIIa) administration.
Samples for thrombin generation, haematology, coagulation parameters, concizumab ELISA and 
FVII ELISA are taken pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 
10 min (±2 min), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (±20 min) and 
24h (±20 min).
The investigator must ensure that all assessments are performed as described in Section 2, The 
Investigator is requested to conclude after 24 hours if it is safe for the patient to continue in the trial 
and record the conclusion in the eCRF prior to administration of the before next dose of with  
concizumab is given the day after.
…
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
Section 8.1.11.3 Visit 4, 5, 6, 7 and 8
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
Section 8.1.11.4 Visit 9
The patient will be asked to return all used, partly used and unused concizumab and eptacog alfa 
(rFVIIa) during the trial as instructed by the investigator. Drug accountability must be performed 
for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned at every 
visit and new histidine syringes should be dispensed to the patient.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
9 of 12
Section 8.1.12.1 Visit 9.1 (PK visit and ONLY patients previously on the eptacog alfa (rFVIIa) 
on-demand arm)
Vital signs are assessed within 1 hour before and after eptacog alfa (rFVIIa) administration dosing.
The concizumab dose should be taken first followed by eptacog alfa dose. eptacog alfa (rFVIIa) 
should be administered at the site under the surveillance of medically trained trial site staff. The 
interval between the concizumab and eptacog alfa dose administration should not exceed more than 
30 min. Patient should continue his daily concizumab injections regardless of eptacog alfa (rFVIIa) 
administration.
…
Samples for thrombin generation, haematology, coagulation parameters, concizumab ELISA and 
FVII ELISA are taken pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 
10 min (±2 min), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9 h (± 10 min) and 12h (±20 min) 
and 24h (±20 min).
The Investigator is requested to conclude after 24 hours if it is safe for the patient to continue in the 
trial and record the conclusion in the eCRF prior to administration of before the next dose of 
concizumab is given the day after.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
Section 8.1.12.2 Visit 9.2 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
Section 8.1.12.3 Visit 10
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
Section 8.1.12.4 Visit 10.1 (ONLY patients previously on the eptacog alfa (rFVIIa) on-demand 
arm)
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
10 of 12
Section 8.1.12.5 Visit 11
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
Section 8.1.12.6 Visit 11.1 (ONLY patients previously on the rFVIIa on-demand arm) 
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
Section 8.1.12.7 Visit 12, 13, 14 and 15
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine syringes should be dispensed to the patient.
Section 8.1.12.8 Visit 16
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs and details of adverse events must be entered into the eCRF. Treatment with concizumab 
must take place after the blood sampling at this visit.
The patient will be asked to return all used, partly used and unused concizumab cartridges and 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. NovoPen®4 must be 
returned. Drug accountability must be performed for concizumab and eptacog alfa (rFVIIa). Unused 
histidine syringes should be returned at every visit and new histidine syringes should be dispensed 
to the patient.
Section 8.1.13 Visit 17 (End of trial) - Follow-up part
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa), unused 
histidine syringes, eDiary device and Trial card. Drug accountability must be performed for eptacog 
alfa (rFVIIa).
Section 8.5 Laboratory assessments
An approximate total blood volume of 625725 mL will be taken from each patient on the 
concizumab arm and 725625 mL from each patient on the eptacog alfa (rFVIIa) arm.
Section 8.5.1.2 Free TFPI
Free TFPI (TFPI not bound to concizumab) will be collected at all visits, pre-dose at visit 2 and 3 
(concizumab arm), and visit 9 and 9.1 (eptacog alfa (rFVIIa) arm) and visit 16.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
11 of 12
Section 8.5.2.7 Anti-concizumab antibodies
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 positive for binding antibodies. 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.
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.
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.
Section 8.5.2.8 Concizumab ELISA
Concizumab ELISA will be collected at all visits whereexcept at screening patients are in treatment 
with only for the concizumab arm.
Samples will be collected pre-dose at visit 2 and 3 for concizumab arm and visit 9 and 9.1 for 
eptacog alfa (rFVIIa) arm) and visit 16 for both arms.
At visit 3 for concizumab arm and visit 9.1 for eptacog alfa arm samples for concizumab ELISA are 
taken pre-dose eptacog alfa (rFVIIa) (-1 hour) and post-dose eptacog alfa (rFVIIa): 10 min (±2 
min), 1h (± 10 min), 3h (± 10 min), 6h (± 10 min), 9h (± 10 min), 12h (±20 min) and 24h (±20 min).
Section 9.4 Drug accountability and destruction
Drug accountability of all trial products (concizumab and eptacog alfa (rFVIIa) 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 used histidine
syringes which should be discarded at home and not accounted for. Unused histidine syringes 
should be returned at every visit and new histidine syringes should be dispensed to the patient.
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 
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*
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 November 2017
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT no: 2016-000510-30
Page:
12 of 12
!
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 17.4.5.2 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 VERITAS-PRN® after 24 weeks from treatment onset
!
Change in 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
!
Status of Change in PGI-C after 24 weeks from treatment onset
!
Change in PGI-C after 76 weeks from treatment onset
Section 18.1 Benefit-risk assessment of the trial
Risks
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.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
1 of 31
Protocol Amendment
no 3
to Protocol, final version 3
dated 15 November 2017
Trial ID: NN7415-4310
A Multi-Centre, Randomised, Open-Label, Controlled Trial Evaluating the Efficacy and
Safety of Prophylactic Administration of Concizumab in Haemophilia A and B Patients with 
Inhibitors
Trial phase: 2
Applicable to all countries
Amendment originator:
, International Trial Manager
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: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
2 of 31
Table of Contents  
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment and informed consent ......................3
2
Changes ................................................................................................................................................6
2.1
Protocol ....................................................................................................................................6
2.2
Informed Consent....................................................................................................................28
2.2.1
Master Informed Consent.......................................................................................28
2.2.2
Genotyping and Long-term Storage of Human Samples Informed Consent 
(page 4 last paragraph)...........................................................................................30
2.2.3
Female partner of a Male Subject in Case of an Abnormal Pregnancy Informed 
Consent (page 3 last paragraph) .............................................................................30
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
3 of 31
1
Introduction including rationale for the protocol amendment and 
informed consent
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. Further more 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 towards concizumab (ADA) 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 (Figures 5-3 and 5-4), 5.3.3, 5.3.4, 5.5, 7 and 17.5 (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 the subsequent clinical trials for concizumab provided 
that either the study site participates in the subsequent trial programme or the patient can be
transferred to a participating site.  
Sections 4.2.2.1, 4.2.3.2, 17.4.1, 17.4.2, 17.4.3, 17.4.4 and 17.4.5.2 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 76 weeks in total. 
Section 5.2, ‘Rationale of the trial design’ has been updated with an option ofor 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 8 (Figures 8-1 and 8-2), 8.1, 8.1.12.7, 8.1.12.8, 8.1.13 and 8.5 are updated to include the 
additional visits and blood volume 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 5 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 8.1.14‘Premature discontinuation of trial product’ has been updated as well as 
‘Unscheduled Visit’ to provide the option of following patients who has permanently prematurely 
discontinue trial product due to a safety concern after visit 17 (End of trial). The purpose of the 
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
4 of 31
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 8.1.12.7 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. Furthermore the section has 
been updated to accommodate the latest requirements in regards to Novo Nordisk assessment of AE 
expectedness. 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, 17.3.1 and 17.3 ‘Statistical considerations’ has been updated due to technical details 
related to selection of bleeds and estimation of offset has been added
Section 17.4.5.2, 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 118 weeks
of treatment and be given the possibility to participate in a subsequent trial with concizumab if he is 
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
5 of 31
eligible and site continues in the trial or he can be transferred to a participating site. Furthermore 
has the GDPR (patient confidentiality) standard text been added as required.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
6 of 31
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 dosing 
treatment with trial product (or has 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 86-88-130 weeks, consisting 
of a 2-4 week screening period, a subsequent 76-118 week treatment period and an 8-week follow-
up period. eptacog alfa (rFVIIa) for treatment of bleeding episodes during the trial will be provided 
by Novo Nordisk. The patient will not be provided with trial product or eptacog alfa (rFVIIa) after 
end of trial.
The trial is 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 94 52 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 16 patients have completed a minimum at least of 24 weeks of 
concizumab prophylaxis and 8 patients have completed a minimum of 24 weeks of treatment with 
eptacog alfa (rFVIIa) on-demand or have withdrawn. The analysis of the main part of the trial aims 
to substantiate the clinical proof of concept (CPoC) that concizumab has the potential to prevent 
bleeding episodes in patients with haemophilia and inhibitors. The extension part of the trial will 
provide additional safety and long-term efficacy data.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
UTN: U1111-1179-2925
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT No.: 2016-000510-30
Version:
1.0
Page:
7 of 31
Section 2 Flow chart with deletions (strike through)
explorerTM4 trial periods
Screening
Treatment main a,b
Treatment extension b
Follow-up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
197
225
253
281
309
337
393
449
505
533
When applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w
72w
76w
-
84w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/ Long-term storage consent
●
In/exclusion criteria
●
●g
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Randomisation (IWRS)
●
EFFICACY
Bleeding episodes h, i
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Thrombin generation (central lab) 
●
●l
●j, k, l
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Free TFPI (central lab)  
●
●l
●k, l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
SAFETY
Physical examination
●
●
●k
●
●
●
●
●
●
Body measurements 
●
●m
●k, m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
●m
Vital signs 
●
●n
●k, n
●
●
●
●
●
●n
●n
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●
Adverse events 
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Injection site reaction  
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Urinalysis (local lab)
●
Haematology (local lab)
●
●l
●j, k, l
●
●
●
●
●
●l
●j
●
●
●
●
●
●
●
●
●
●l
●
●
Biochemistry (central lab)
●
●l
●k, l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
FVIII/ FIX activity (central lab)
●
●l
●l
Coagulation parameters (central lab)
●
●l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●l
●
●
Coagulation parameters (PT, APTT and Fibrinogen (local lab))
●j, k, l
●j
FVIII/FIX  inhibitors (central lab)
●
●l
●l
Anti-concizumab antibodies (ADA) (special lab) o
●
●l
●k, l, p
●p
●p
●p
●p
●p
●l, p
●
●
●
●
●
●
●
●
●
●
●l
●
●
Concizumab  ELISA (special lab)
●l
●j, k, l, p
●p
●p
●p
●p
●p
●l, p
●j
●
●
●
●
●
●
●
●
●
●l
●
●
FVII ELISA (special lab)
●j, k, l
●j
Total TFPI (special lab)
●
●l
●k, l
●
●
●
●
●
●l
●
●
●
●
●
●
●
●
●
●
●l
●
●
TRIAL MATERIAL
IWRS call 
●
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (concizumab)r
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Dispensing visit (eptacog alfa, histidine)q
●
●w
●k
●
●
●
●
●
●
●
●
●
●
●
Administration of trial product (concizumab)r
●k, s
●k
●d, s 
●
●s
●
Administration of trial product (eptacog alfa)
●k, t
●t
Drug accountability (concizumab)
●k
●k
●k
●k
●k
●k
●k
●
●
●
●
●
●
●
●
●
●
●
●
Drug accountability (eptacog alfa) 
●
●k
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
New dose of trial product e, u
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
PRO questionnaires 
●
●
●k
●
●
●
●
●
●
●
●
REMINDERS
Human biological specimen for storage (central lab)
●
●
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
UTN: U1111-1179-2925
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT No.: 2016-000510-30
Version:
1.0
Page:
8 of 31
explorerTM4 trial periods
Screening
Treatment main a,b
Treatment extension b
Follow-up
Visit number c
1
2
3
4
5
6
7
8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13
14
15
16
Un-scheduled e
17
Timing of visits (d) f
14 to 28 d 
before
visit 2
1
8
29
57
85
113
141
169
176
197
225
253
281
309
337
393
449
505
533
When applicable
589
Visit window (d)
14 to 28 d 
before
visit 2
0
+1
±7
±7
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
4w
8w
12w
16w
20w
24w
25w
28w
32w
36w
40w
44w
48w
56w
64w
72w
76w
-
84w
Handout ID card 
●
Training v
●
●
●
●
●
Compliance: eDiary
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
End of treatment
●
End of trial
●
Section 2 Flow chart with updates (italics)
4310 trial periods
Screening
Treatment main a, b
Treatment extension b
Follow-up
Visit number c
1
2
3
4-5
6
7-8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13-14
15, 15.1, 
15.2, 15.nw
16
Unscheduled e
17x
Timing of visits (d) f
14 - 28 d before
visit 2
1
8
29-57
85
113-141
169
176
197
225
253
281
309
337
393-449
505-785
Up to
827
When applicable
Up to
883
Visit window (d)
14 - 28 d before
visit 2
0
+1
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
Every 4w
12w
Every 4w
24w
25w
28w
32w
36w
40w
44w
48 w
Every 8w
Every 8w
Up to  118w
-
Up to 126w
PATIENT RELATED INFO/ASSESSMENTS
Informed consent/ Long-term storage consent
●
In/exclusion criteria
●
●g
Demography
●
Concomitant illness/Medical history
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Details of Haemophilia/Haemophilia treatment and bleed history
●
Withdrawal criteria/ Criteria for premature discontinuation of trial product
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Randomisation (IWRS)
●
EFFICACY
Bleeding episodes h, i
●
●
●
●
●
●
●
●
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Thrombin generation (central lab) 
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Free TFPI (central lab)  
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SAFETY
Physical examination
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Body measurements 
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Vital signs 
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ECG
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Adverse events 
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Injection site reaction  
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Urinalysis (local lab)
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Haematology (local lab)
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Biochemistry (central lab)
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FVIII/ FIX activity (central lab)
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Coagulation parameters (central lab)
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Coagulation parameters (PT, APTT and Fibrinogen (local lab))
●j, k, l
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FVIII/FIX  inhibitors (central lab)
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●l
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Anti-concizumab antibodies (ADA) (special lab) o
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3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
UTN: U1111-1179-2925
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT No.: 2016-000510-30
Version:
1.0
Page:
9 of 31
4310 trial periods
Screening
Treatment main a, b
Treatment extension b
Follow-up
Visit number c
1
2
3
4-5
6
7-8
9
9.1d
9.2d
10
10.1d
11
11.1d
12
13-14
15, 15.1, 
15.2, 15.nw
16
Unscheduled e
17x
Timing of visits (d) f
14 - 28 d before
visit 2
1
8
29-57
85
113-141
169
176
197
225
253
281
309
337
393-449
505-785
Up to
827
When applicable
Up to
883
Visit window (d)
14 - 28 d before
visit 2
0
+1
±7
±7
±7
±7
+1
±7
±7
±7
±7
±7
±7
±7
±7
±7
Not 
applicable
-7
Treatment week (w)
0
1w
Every 4w
12w
Every 4w
24w
25w
28w
32w
36w
40w
44w
48 w
Every 8w
Every 8w
Up to  118w
-
Up to 126w
Concizumab  ELISA (special lab)
●l
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FVII ELISA (special lab)
●j,k, l
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Total TFPI (special lab)
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TRIAL MATERIAL
IWRS call 
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Dispensing visit (concizumab)r
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Dispensing visit (eptacog alfa, histidine)q
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Administration of trial product (concizumab)r
●k, s
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Administration of trial product (eptacog alfa)
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Drug accountability (concizumab)
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Drug accountability (eptacog alfa) 
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New dose of trial product e, u
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PRO questionnaires 
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REMINDERS
Human biological specimen for storage (central lab)
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Handout ID card 
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Training v
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Compliance: eDiary
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End of treatment
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End of trial
●y
●y
Footer
Description
a
There is staggered recruitment for the 4 first patients in the trial on the concizumab arm. 
b
Concizumab administration is performed at home except for visit 2 and visit 3 for patients randomised to concizumab and visit 9 and 9.1 for patients 
randomised to eptacog alfa. Sampling for Free TFPI, Anti-concizumab antibodies, Concizumab ELISA and Total TFPI are done prior to concizumab 
administration.
c
The duration of the visits will last according to patient’s individual training need on concizumab administration, NovoPen®4, eDiary training etc. Visit 3 and 
visit 9.1 have a PK session of 24 hours and a safety follow up visit the following day. 
d
Visit and procedures only performed for patients randomised to eptacog alfa and switching to concizumab treatment.Visit 9.1 should be performed 7 days (+ 1 
day) after visit 9.
e
For patients being dose escalated on concizumab a phone call is recommended 1 week after first dose of concizumab.
f
Daily dosing preferably at the same time in the morning.
g
Evaluation of the laboratory results obtained from samples taken at screening.
h
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.
i
Eptacog alfa will be given to treat breakthrough bleeding episodes. 
j
Sampling time schedule for thrombin generation, haematology,  coagulation parameters, concizumab ELISA and FVII ELISA: pre-dose (-1 hour), post-dose: 
10 min (±2 min), 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 
eptacog alfa administration.
k
ONLY for patients randomised to concizumab arm. The concizumab dose should be administered first followed by eptacog alfa dose. The interval between the 
concizumab and eptacog alfa should not exceed more than 30 min.
l
At visit 2, visit 3, visit 9 and 16 blood samples should be collected pre-dose. Patients must not treat themselves with concizumab until sampling has been 
performed.
m
Only body weight should be measured. 
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
UTN: U1111-1179-2925
Date:
28 August 2018
Status:
Final
1RYR1RUGLVN
Trial ID: NN7415-4310
EudraCT No.: 2016-000510-30
Version:
1.0
Page:
10 of 31
n
Vital signs should be evaluated before and after trial drug administration at visit 2 and visit 3 for concizumab arm and at visit 9 and visit 9.1 for patients in 
eptacog alfa arm switching to concizumab treatment.
o
In case 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 blood samples will be taken and stored for characterisation 
of the antibodies.
p
Blood sampling for anti-concizumab antibodies and concizumab ELISA testing should only be collected for patients on concizumab.
q
If needed dispensing of eptacog alfa, histidine, trial injection kits and Direction For Use (DFU). 
r
First treatment dose of concizumab is a loading dose and will be administered at visit 2 for the concizumab arm and visit 9 for the eptacog arm. 
s
The patient must be in a non-bleeding state at the time of the first concizumab administration and should not have received any bypassing agent drugs,(e.g., 
eptacog alfa, FEIBA®) for treatment of a bleeding episode within a period of 24h (for eptacog alfa) or 48h (for FEIBA®) prior to first concizumab. Only 
eptacog alfa is allowed after visit 2.
t
Eptacog alfa administered in a non-bleeding state at site at visit 3 for the concizumab arm and at visit 9.1 for the eptacog alfa arm. The concizumab dose 
should be administered first followed by eptacog alfa dose. The interval between the concizumab and eptacog alfa should not exceed more than 30 min.
u
Patient treated with concizumab 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 the investigator judges that next scheduled visit is too late an unscheduled visit should be performed for dose 
escalation. 
v
Home treatment training must take place at visit 2 at the latest and whenever needed afterwards. Patients randomised to eptacog alfa will be re-trained in 
NovoPen®4 and s.c. administration at visit 9 and 9.1. If necessary training can be performed as needed at other visits. The eDiary will be provided to the 
patients at visit 2 if the patient feels capable in s.c. administration and using the eDiary. Further the patients will be trained in recognition of signs/symptoms of 
thrombosis.
w
Only for patients randomised to on-demand arm.
x
Visit repeated every 8 week until patient either discontinues, completes extension or is enrolled into phase 3 programme
y
For patients continuing in a subsequent trial End of Trial must be completed at visit 16. For patients declining participation in the prolongation, End of Trial 
must be completed at visit 17, 8 weeks after End of Treatment.
z
PRO questionnaires should only be completed at 15.1 for patients continuing in the prolongation of the trial.
aa
PRO questionnaires should only be completed at visit 16 for patients not continuing in the prolongation of the trial
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
11 of 31
Section 4.2.2.1 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
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
!
Number of TEAEs within 24 hours of rFVIIa administration
!
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
!
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: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
12 of 31
!
Peak thrombin generation (nM) prior to the last dose administration after at least 76 weeks 
!
Endogenous thrombin potential (nMxmin) prior to the last dose administration at 24 weeks 
!
Endogenous thrombin potential (nMxmin) 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
!
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
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.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
13 of 31
Section 5.1 Type of trial (Figure 5-1)
Section 5.1 Type of trial 
The total trial duration for the individual patient will be approximately 86-88-130 weeks, including 
a 2-4 week screening period, a 76-118 week treatment period, and a follow-up period of 8 weeks, 
see Figure 5-1 
The trial is 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 52 94 weeks. In the main part, the primary and selected secondary 
endpoints will be analysed when 16 patients have completed a minimum of 24 weeks of 
concizumab prophylaxis and 8 patients have completed a minimum of 24 weeks of eptacog alfa 
(rFVIIa) on-demand or have withdrawn.
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 annualised bleeding rate on concizumab prophylaxis. The duration of the 
extension part of the trial will be up to 94 52 weeks and provide further information on efficacy, i.e. 
annualised bleeding rate, and also provide additional safety data upon 76-118 weeks treatment with 
concizumab.
Patients participating in NN7415-4310 will be offered screening for eligibility to participate in the 
subsequent clinical trials for concizumab, following their participation in NN7415-4310 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 subsequent trial and thus may continue prophylactic treatment with concizumab.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
14 of 31
Section 5.3 Treatment of patients (Table 5-1)
Compound Name 
Strength
Dosage form
Route of 
administration
Treatment period
concizumab B a
100 
mg/mL
solution for s.c. 
injection in a 3 
mL cartridge b
Subcutaneous 
administration 
using NovoPen®4
For prophylactic 
treatment in for at 
least 76 weeks (for 
concizumab arm in 
the main part and 
extension part).
For prophylactic 
treatment in for at 
least 52 weeks (for 
comparator arm in 
the extension part).
eptacog alfa (rFVIIa) 
a, c
5 mg/vial
Powder for 
solution for i.v. 
injection
Intravenous 
administration
For treatment of 
breakthrough 
bleeding episodes 
at the discretion of 
the investigator 
(screening, main, 
extension and 
follow up part). c
Administration of 
doses higher than 
90μg/kg to patients 
exposed to 
concizumab is not 
allowed.
For on-demand 
treatment at the 
discretion of the 
investigator in 24 
weeks for 
comparator arm in 
the main part. 
In the concizumab 
arm and 
comparator arm 
after switching to 
concizumab in the 
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
15 of 31
extension part of 
the study a single 
90μg/kg dose for 
initial safety 
assessments in a 
non-bleeding state. 
a
Will be provided 
for as long as 
patients participate 
in the trial 
(screening, main, 
extension and 
follow up part)
Section 5.3.3 Dose escalation 
All spontaneous bleeding episodes (sBEs) are counted from 2 weeks after visit 2 (or visit 9 when 
switching from eptacog alfa (rFVIIa) to concizumab) (first treatment visit) until visit 16 (end of 
treatment visit), i.e. a total of 74 of up to 116 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: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
16 of 31
Section 5.3.3 Dose escalation (Figure 5-3)
Section 5.3.3 Dose escalation (Figure 5-4)
Section 5.3.4 Co-administration of eptacog alfa (rFVIIa)
The patients will receive prophylactic doses of concizumab 0.15 mg/kg daily throughout the main 
part (at least 24 weeks) and the extension part (52 up to 94 weeks), unless dose escalation criteria 
are fulfilled, see Section 5.3.3.
Section 5.5 Rationale for treatment
The treatment period during at least 24 weeks (the main part of the trial) is considered necessary for 
providing robust data that allow demonstration of clinical proof of concept and to support decision 
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
17 of 31
making regarding a phase 3 confirmatory trial. Dosing for up to 94 additional 52 weeks will provide 
valuable long term efficacy and safety data.
Section 7 Milestones
Planned FPFV: 
10-Aug-2017
Planned FPFT: 
30-Aug-2017
Planned LPFV: 
09-Mar-2018
Planned LPLV: 
23-Oct-2019 31-Jan-2020
The total duration of concizumab treatment in this trial is at least 76 weeks for an individual patient 
randomised to concizumab prophylaxis treatment at visit 2.
The total duration of concizumab treatment in the trial is at least 52 weeks for an individual patient 
randomised to eptacog alfa (rFVIIa) on-demand treatment at visit 2.
Section 8 Methods and assessments (Figure 8-1) 
Section 8 Methods and assessments (Figure 8-2) 
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
18 of 31
Section 8.1 Visit procedures 
Extension Part:
!
Visit 9.1 (treatment and PK-visit with concizumab and eptacog alfa (rFVIIa) at site ONLY 
for patients randomised to the eptacog alfa (rFVIIa) on-demand arm)
!
Visit 9.2 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
!
Visit 10 (Assessment visit, patients treat themselves at home)
!
Visit 10.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on-demand arm)
!
Visit 11 (Assessment visit, patients treat themselves at home)
!
Visit 11.1 (Assessment visit, patients treat themselves at home - ONLY for patients 
randomised to the eptacog alfa (rFVIIa) on demand-arm)
!
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).
Section 8.1.12.7 Visit 12, 13, 14 and 15, 15.1, 15.2, 15.n
Visits 12, to15.n 13, 14 and 15 are to be scheduled with an interval of 8 weeks on trial day 337 (48 
weeks), 393(56 weeks), day 449 (64 weeks) and day 505 (72 weeks) respectively with a visit 
window of ±7 days until the patient either discontinues treatment or completes visit 16.
If patient declines participation in the prolongation of the extension, visit 16 should be conducted 4 
weeks after visit 15 (see Section 8.1.12.8)
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs, body measurement (weight only) and details of adverse events must be entered into the 
eCRF.
3URWRFRO$PHQGPHQWJORE
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
19 of 31
Investigator must 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 to the escalation rules described in section 5.3.3. All decisions to escalate the concizumab 
dose must be recorded in the eCRF.
A dispensing call must be performed in the IWRS.
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 the daily dose of concizumab to the patient and 
record the dose for the coming home treatment period in the eCRF.
At the visit the patient will be provided with concizumab and/or eptacog alfa (rFVIIa) and trial 
injection kits, if necessary, 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. Drug accountability must be 
performed for concizumab and eptacog alfa (rFVIIa). Unused histidine syringes should be returned 
at every visit and new histidine should be dispensed to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes or 
any sign of thrombosis) arise after he has left the site.
At visit 15.1 only patients in the prolongation will be asked to complete the ePRO questionnaires 
before any other trial related activities are performed according to section 8.6.1;
!
Hemo-TEM
!
SF-36v2
!
SDS
!
TSQM
!
SIAQ-ISRQ
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 8.1.12.8 Visit 16
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) 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
20 of 31
with a visit window of ± 7days. Further visit 16 should be scheduled to be conducted at the last day 
of treatment with concizumab.
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
!
Hemo-TEM
!
SF-36v2
!
SDS
!
TSQM
!
SIAQ-ISRQ
All assessments are listed in Section 2, and the assessment results from concomitant medication, 
vital signs and details of adverse events must be entered into the eCRF. Treatment with concizumab 
must take place after the blood sampling at this visit.
Investigator must 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 patients can be treated with eptacog alfa 
(rFVIIa) or other products at the discretion of the investigator to treat any bleeding episodes.
Eptacog alfa (rFVIIa) may be requested via IWRS.  Only eptacog alfa (rFVIIa) will be provided by 
Novo Nordisk during this period. If necessary, the patient will be provided with eptacog alfa 
(rFVIIa) and trial injection kits to be able to conduct home treatment until next scheduled 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 (eptacog 
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 eptacog alfa (rFVIIa) or other products at the discretion of the 
investigator to treat any bleeding episodes. Only eptacog alfa (rFVIIa) will be provided by Novo 
Nordisk during this period. If necessary, the patient will be provided with eptacog alfa (rFVIIa) and 
trial injection kits to be able to conduct home treatment until next scheduled visit.
In the period from visit 16 to visit 17 patients can be treated with eptacog alfa (rFVIIa) or other 
products at the discretion of the investigator to treat eventual bleeding episodes. Only eptacog alfa 
(rFVIIa) will be provided by Novo Nordisk during this period.
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
21 of 31
If necessary, a dispensing call must be performed in the IWRS. At the visit the patient will be 
provided with eptacog alfa (rFVIIa) and trial 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 
eptacog alfa (rFVIIa) during the trial as instructed by the investigator. NovoPen®4 must be 
returned. Drug accountability must be performed for concizumab and eptacog alfa (rFVIIa). Unused 
histidine syringes should be returned at every visit and new histidine syringes should be dispensed 
to the patient.
The patient must be instructed to call the site if any questions or issues (e.g. bleeding episodes) arise 
after he has left the site.
The End-of-Trial information must be entered in the End-of-Trial form in the eCRF at visit 16 for 
all patients continuing in a subsequent trial with concizumab.
Section 8.1.13 Visit 17 (End of trial) – Follow-up part 
Visit For patients not enrolled into a subsequent trial with concizumab 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.
All assessments are listed in Section 2, 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 must perform compliance check of treatment and reporting of bleeding episodes 
through reviewing collected data. Patients should be asked if their female partner has become 
pregnant, see Section 12.5.1.
The patient will be asked to return all used, partly used and unused eptacog alfa (rFVIIa), unused 
histidine syringes, eDiary device and Trial card. Drug accountability must be performed for eptacog 
alfa (rFVIIa).
End-of-Trial information must be entered in the End-of-Trial form in the eCRF at visit 17 for all 
patients not continuing in a subsequent trial with concizumab. .
Completion or treatment discontinuation (if the trial is not completed) session should be performed 
in IWRS If eptacog alfa (rFVIIa) was requested at visit 16 drug accountability should be performed 
in IWRS, see Section 10.
Section 8.1.14 Unscheduled Visit
Unscheduled visits can be performed at any time during the trial as listed in Section 2. Unscheduled 
visits may be performed after visit 17 at the discretion of the investigator for patients who has 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
22 of 31
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 Section 
2. 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 replacement of 
eDiary or NovoPen®4 .
Section 8.5 Laboratory assessments
An approximate total blood volume of 768 625 mL will be taken from each patient on the 
concizumab arm and 868 725 mL from each patient on the eptacog alfa (rFVIIa) arm.
Section 8.5.2.7 Anti-concizumab antibodies 
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. Neutralising antibodies will be analysed and reported at the EOT. 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®)
!
visit 2 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 3 (PGI-C, Hemo-TEM)
!
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, SIAQ-ISRQ)
!
visit 10 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
!
visit 1615.1 or 16 (Hemo-TEM, SF-36v2, SDS, TSQM, SIAQ-ISRQ)
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
23 of 31
Section 8.6.1 Patient reported outcome
At visit 3-8: 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 visits 9, 10 and 15.1or 16.
!
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 10 and 15.1or 16 all patients should complete Hemo-TEM, SF-36v2, SDS, TSQM and 
SIAQ-ISRQ.
Section 8.6.1 Patient reported outcome 
The investigator must check the ePROs for completeness. potential AEs and SAEs. The completed 
ePROs should be transmitted at each visit to the PRO database by the Investigator.
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 into a new trial. The events 
must be recorded in the applicable eCRF forms in a timely manner, see timelines below and Figure 
12-1
Section 12.2 Reporting of adverse events 
When eptacog alfa (rFVIIa), NovoSeven® is used as IMP, expectedness should be performed 
according to the Company Core Data Sheet (CCDS) is performed according to the following 
reference documents: Investigator’s Brochure; current version and any updates thereto.
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
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
24 of 31
Section 17 Statistical considerations
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 treatment bleed is defined as a new bleeding 
episode.
Data collected among permanently prematurely discontinued from trial product 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 17.3.1 Estimand and primary statistical analysis 
The estimand for the primary endpoint will be estimated using negative binomial regression with 
log of exposure time in (the included observational period of the main part) as offset and regimen 
as factor. The offset for first CPoC criterion of patients in concizumab arm 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 of patients in 
concizumab arm is the log of the individual exposure time in the main part. For both criteria and 
patients in the on-demand arm, the offset is the log of the exposure time in the main part. The 
analysis provides, providing an estimate of the ABR ratio between regimens (concizumab 
prophylactic and on-demand eptacog alfa (rFVIIa)) with corresponding 95% confidence interval 
and also actual estimate of the ABR with corresponding 95% confidence interval for each regimen. 
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 estimand will be estimated based on the FAS and only data collected prior to 
discontinuation of trial product or initiation of alternative treatment options will be used to draw 
inference.
Section 17.3.3 Additional analysis 
An additional evaluation of the primary endpoint will be made, including the actual concizumab 
dose level (interpreted as the patients 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, an series of
analyseis analyses with individual steady state PK/PD assessments included as covariates in the 
negative binomial regression model as specified for the primary analysis of number of bleeding 
episodes 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 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
25 of 31
concizumab trough level, TFPI value prior to the last s.c. dose administration, peak thrombin 
generation (nM), Endogenous thrombin potential (nMxmin) and velocity index (nM/min).
17.4.1 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
Section 17.4.1 Supportive secondary efficacy endpoints 
The remaining supportive secondary efficacy endpoints will be summarised descriptively by 
treatment regimen. In addition, number of bleeding episodes during at least 76 weeks of treatment 
with prophylactic concizumab will be analysed using a negative binomial model with log of trial 
duration as offset, providing estimates of the ABR with confidence interval for that particular 
regimen.
Section 17.4.2 Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during at least 24 weeks from 
treatment onset
!
Number of TEAEs during at least 76 weeks from treatment onset
!
Number of TEAEs within 24 hours of rFVIIa administration
!
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
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
26 of 31
Adverse Events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding .
TEAE is defined as an event that has onset from the first exposure to treatment after randomisation  
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 safety follow-up period (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. 
Relations to Novo Nordisk marketed products used by patients in the trial, such as eptacog alpha, is 
reported as described in section 12.2 of the protocol and not reported in the report of the trial
Section 17.4.3 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 after at least 76 weeks
Section 17.4.4 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 (nMxmin) prior to the last dose administration at 24 weeks 
!
Endogenous thrombin potential (nMxmin) 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 17.4.5.2 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
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
27 of 31
!
Status of PGI-C after 24 weeks from treatment onset
VERITAS-PRN®, SF-36v2, SDS and TSQM will be scored according to their respective scoring 
algorithms. Change after 24 weeks of treatment onset for SF-36v2, SDS and TSQM from visit 2 to 
visit 9 will be analysed with an ANCOVA model including regimen as a factor and baseline score 
as covariate.
Section 17.5 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. For patients in 
the concizumab s.c. prophylaxis arm, main Main part is 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. For patients in the on-demand arm, the main part consists of 
observations from randomisation until transfer to concizumab s.c. prophylaxis treatment or 
withdrawal from trial, whichever comes first. All observations for these patients after transfer to 
concizumab treatment are regarded as extension part 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 CTRs might in such case be issued. A CTR describing results from the 
main and the 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. 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
28 of 31
Section 17.5 Interim analysis (Figure 17-1)
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 either inject one dose of concizumab daily for up to 
76 118 weeks (concizumab treatment), or receive on-demand treatment with eptacog alfa for 
bleeding episodes in the first 24 weeks of the trial (on-demand treatment), before switching to daily 
concizumab treatment for the remaining period (52 56 - 94 weeks). If you experience a bleeding 
episode during treatment with concizumab, you will treat this with eptacog 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. If you are receiving on-demand treatment, you will 
receive eptacog alfa for on-demand treatment of your bleeding episodes during the first 24 weeks of 
the trial. 
After 52 or 76 weeks of treatment with concizumab Once you have treated yourself daily with 
concizumab for a period of 56-118 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 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
29 of 31
visit 16 and be followed for an additional 8 weeks before completing the trial. During this period 
you will be provided with eptacog alfa for the 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 90 up to 130
weeks depending on when you started in the trial. During this time you will have 17 or 21between 
16 to 26 planned visits to your trial site. The duration of each visit at the site may vary depending 
upon 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 4 to 16):
Concizumab Treatment 
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 5 depending on 
when you started in the trial. You will receive concizumab to take home at each visit and eptacog 
alfa at visits 3, 6, 9, 10, 11 and 12 to 16, or at an unscheduled visit if 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 6 questionnaires related to your 
quality of life, well-being and treatment at visits 4 to 10 and 5 questionnaires at visit 1615.1. 
On-demand Treatment 
Visit 9.2 occurs approximately 3 weeks after visit 9.1. Visits 10 to 12 are scheduled approximately 
4 weeks apart and visits 12 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 extra planned visits will be up to 5 depending on 
when you started in the trial. 
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 2 questionnaires related to your quality of 
life, well-being and treatment at visits 4 to 8 and 5 questionnaires at visit 10 and 1615.1. 
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CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
28 August 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
30 of 31
Follow-up visit (Visit 17):
This visit will only happen if you do not continue in a new trial.
Concizumab & On-demand Treatment
There will be a period of approximately 8 weeks between visit 16 and 17 (follow-up and end of trial 
visit). Blood will be drawn for analysis, vital signs measured, details of any other medications you 
may be taking recorded and a physical examination performed. You will return the electronic diary 
and any remaining eptacog alfa. At the final visit, you and your trial doctor will discuss the best 
alternatives for your future treatment. Novo Nordisk will not offer any free medication, additional 
care or continued treatment with the trial products after the completion of the 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 625 up to 768 mL for patients receiving concizumab 
treatment and 725 up to 868 mL for patients receiving on-demand treatment 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.
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].>
2.2.2
Genotyping and Long-term Storage of Human Samples Informed Consent
<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].>
2.2.3
Female partner of a Male Subject in Case of an Abnormal Pregnancy Informed 
Consent
<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 
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Protocol Amendment no 3
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Date:
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Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
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more information about your rights, or if you wish to make a complaint, you can contact [Data 
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03196284 
Sponsor trial ID: 
NN7415-4310 
Official title of study: 
A Multi-Centre, Randomised, Open-Label, Controlled Trial 
Evaluating the Efficacy and Safety of Prophylactic 
Administration of Concizumab in Haemophilia A and B 
Patients with Inhibitors 
Document date: 
24 June 2020 
 


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


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
1 of 16
Statistical Analysis Plan
Trial ID: NN7415-4310
A Multi-Centre, Randomised, Open-Label, Controlled Trial
Evaluating the Efficacy and Safety of Prophylactic
Administration of Concizumab in Haemophilia A and B
Patients with 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.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
2 of 16
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..........................................................................................................8
2.3
Primary endpoint.......................................................................................................................8
2.3.1
Estimand and primary statistical analysis .................................................................8
2.3.2
Sensitivity analysis ..................................................................................................9
2.3.3
Additional analysis ..................................................................................................9
2.4
Supportive secondary endpoints ..............................................................................................10
2.4.1
Supportive secondary efficacy endpoints................................................................10
2.4.2
Supportive secondary safety endpoints...................................................................10
2.4.3
Supportive secondary pharmacokinetic endpoints...................................................11
2.4.4
Supportive secondary pharmacodynamic endpoints................................................11
2.4.5
Exploratory endpoints............................................................................................12
2.4.5.1
Exploratory safety endpoints ............................................................12
2.4.5.2
Exploratory patient reported-outcome endpoints...............................12
2.5
Interim analysis.......................................................................................................................12
3
Changes to the statistical analyses planned in the protocol..............................................................13
3.1
Definition of rebleed ...............................................................................................................13
3.2
Clarification of bleeding episodes for primary endpoint...........................................................14
3.3
Clarification of initiation of alternative treatment options ........................................................14
3.4
Offset definition for negative binomial regression for primary endpoint...................................14
3.5
Sensitivity analysis for primary endpoint.................................................................................14
3.6
Additional analyses for primary endpoint ................................................................................15
3.7
Clarification of analyses for supportive secondary endpoints ...................................................15
3.8
Definition of TEAE.................................................................................................................15
3.9
Causal relation between eptacog alfa and AE...........................................................................15
3.10
Exploratory analyses of patient reported outcome endpoints....................................................16
3.11
Main part definition for subjects on eptacog alfa on-demand ...................................................16
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
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Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
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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
eptacog alfa 
the name ‘eptacog alfa (rFVIIa)’ will be used throughout 
the document and the product is identical to 
rFVIIa,‘NovoSeven®, and ‘NiaStaseRT®’
FAS
full analysis set
FVIIa
activated coagulation factor VII
Hemo-TEM 
Hemophilia Treatment Experience Measure
i.v.
intravenous(-ly)
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PGI-C
Patient’s Global Impression of Change
PK
pharmacokinetics
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
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PRO
patient reported outcome
PT
prothrombin time
s.c.
subcutaneous(-ly)
SAS
safety analysis set
SDS
Sheehan Disability Scale
SF-36v2
36-Item Short Form Health Survey
SIAQ-ISRQ
Injection Site Reaction Questionnaire domain of Self-
Injection Assessment 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
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
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1
Introduction
1.1
Trial information
NN7415-4310, explorerTM4, is a multicentre, randomised, open-label, controlled trial where daily 
treatment with concizumab is evaluated against on-demand treatment in a population of 
Haemophilia A and B patients with 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, Randomised, Open-
Label, Controlled Trial Evaluating the Efficacy and Safety of Prophylactic Administration of 
Concizumab in Haemophilia A and B Patients with Inhibitors, version 3, 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. 
Data from when the on-demand treated patients are transferred to concizumab subcutaneous (s.c.)
prophylaxis will not be included in this evaluation. Observations from the extension part in the on-
demand arm will be summarised separately as well as combined with observations from the main 
part when reporting the extension part data.
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-bleeds. 
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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
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Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
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Clinical proof of concept
The statistical analysis of the collected data aims to establish clinical proof of concept (CPoC) that 
concizumab is efficacious in preventing bleeding episodes in haemophilia patients with inhibitors. 
The objective will be assessed when the last of the 24 patients has completed 24 weeks of dosing 
(or has withdrawn before that).
Two criteria will be evaluated in a hierarchical fashion in support of CPoC comprising a 
comparison of the annualised bleeding rate (ABR) of all patients in the concizumab group, 
irrespective of individual dose titration, with the ABR of the patients in the on-demand arm using 
different sets of observations. The primary CPoC criterion aims at evaluating the effect of 
concizumab when given at the last dose level reached for the 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 not be 
included. Since this evaluation disregards a subset of data collected post randomisation, the result 
should be viewed taking into 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 patients in the concizumab arm with the ABR of the patients in the on-demand arm 
using all data collected after randomisation. 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 and regimen as factor (concizumab vs. on-demand). For each criterion, 
evidence of effect will be concluded if the 95% confidence interval of the treatment ratio is below 1.
Clinical arguments for the hierarchical test approach
Concizumab exhibits non-linear pharmacokinetics (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.
2.1
Sample size calculation
The estimand will be defined as the “if all patients had adhered” estimand.
The treatment ratio between prophylactic s.c. concizumab and on-demand intravenous (i.v.) eptacog 
alfa (rFVIIa) during at least 24 weeks for all randomised patients if all patients adhered to trial drug 
and did not initiate alternative treatment options.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
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EudraCT No.: 2016-000510-30
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This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand i.v. eptacog alfa 
(rFVIIa) under similar conditions as observed in this trial.
The sample size calculation has been determined based on this estimand and the CPoC criteria 
taking the small patient population into account, while also aiming for an acceptably narrow 95% 
confidence interval for the rate ratio.
Sufficient inference on bleeding episodes for the primary CPoC criterion is judged to be 
accommodated by 16 patients in the concizumab arm and 8 in the comparator arm. 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, annual bleeding rates 
of 24 and 6 are assumed for the on-demand patients and the end dose concizumab regimen, 
respectively. Assuming further over-dispersion of 7, the power for concluding superiority of the 
concizumab regimen becomes approximately 80%. The power under varying values of true ABR 
and over-dispersion for the primary CPoC criterion are shown below in Table 2–1.
Table 2–1 Power in superiority comparison between concizumab prophylaxis and on-demand 
treatment under different assumptions of ABR for concizumab and over-
dispersion (assuming on-demand ABR=24).
Power
Over-dispersion (over 6 months)
ABR (concizumab)
6
7
8
6
89%
82%
75%
7
84%
75%
70%
8
77%
69%
66%
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 7.6 for 
the concizumab regimen. This yields a marginal power of approximately 70% 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 coagulation factor FVIII or coagulation factor IX 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). In the NN7128-1907 trial in inhibitor patients, larger 1-year over-
dispersion values of approximately 21 and 18, respectively, were observed during an initial 3-month 
on-demand period and a subsequent 3-month prophylaxis period. It is expected that the variation in 
the current trial will be smaller, partly due to the longer duration of the trial and partly due to an 
expected more homogenous patient population. Another published trial including inhibitor patients, 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
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EudraCT No.: 2016-000510-30
Page:
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comparing prophylaxis using FEIBA® with on-demand treatment, showed 6-month over-dispersion 
of 4-5 32. On that background, an over-dispersion of 7 over the 24 weeks in 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 endpoint will be analysed when the main part of trial has been completed.
2.3.1
Estimand and primary statistical analysis
The estimand for the primary endpoint is the “if all patients had adhered” estimand.
The treatment ratio between prophylaxis s.c. concizumab and on-demand i.v. eptacog alfa (rFVIIa) 
during at least 24 weeks for all randomised patients if all patients adhered to trial drug and did not 
initiate alternative treatment options. To initiate alternative treatment options in this respect is 
defined as stopping concizumab or eptacog alfa on-demand treatment and initiating alternative 
treatment options.
This estimand is a de jure estimand assessing the expected added benefit a patient can achieve if 
continuing treatment with prophylactic s.c. concizumab as compared to on-demand i.v. eptacog alfa 
(rFVIIa) under similar conditions as observed in this trial.
The estimand for the primary endpoint will be estimated using negative binomial regression with 
log of exposure time in the included observational period of the main part as offset and regimen as 
factor. The offset for first CPoC criterion of patients in concizumab arm 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 of patients in concizumab arm 
is the log of the individual exposure time in the main part. For patients in the on-demand arm
regardless of criterion, the offset is the log of the exposure time in the main part. The analysis 
provides an estimate of the ABR ratio between regimens (concizumab prophylactic and on-demand 
eptacog alfa (rFVIIa)) with corresponding 95% confidence interval and also actual estimate of the 
ABR with corresponding 95% confidence interval for each regimen. This analysis has the 
underlying assumption that the missing data mechanism is “missing at random”, i.e. missing at 
random (MAR). Under this assumption, the statistical behaviour of the missing data (given the 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
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observed responses and the mean value structure) is assumed to be the same as for the observed 
data. The estimand will be estimated based on the FAS and only data collected prior to 
discontinuation of trial product or initiation of alternative treatment options will be used to draw 
inference.
2.3.2
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 Δ to the observed bleeding episodes in the 
main part of the trial of the concizumab patients before analysing the data. The offset is maintained 
as being the exposure during the main part 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 concizumab prophylaxis no longer is superior to on-demand eptacog alfa (rFVIIa). The results 
of the primary analysis will be considered robust if the tipping point is above what is considered 
clinically 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 and using log of exposure time excluding those days as the offset. 
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.
2.3.3
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/pharmacodynamics (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 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
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trough level at visit 9, maximum plasma concentration (Cmax) of concizumab throughout the trial, 
tissue factor pathway inhibitor (TFPI) value prior to the last s.c. dose administration, peak thrombin 
generation (nM), Endogenous thrombin potential (nM*min) and velocity index (nM/min) prior to 
the last dose administration at 24 weeks. This model will only include observations from subjects 
exposed to concizumab.
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 number of spontaneous bleeding episodes during at least 24 weeks from treatment onset will be 
addressed in terms of the same estimand as for the primary endpoint The estimand will be 
estimated using the same negative binomial regression model as for 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 for patients treated with concizumab 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
!
Number of TEAEs within 24 hours of rFVIIa administration
!
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
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
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UTN: U1111-1179-2925
Status:
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EudraCT No.: 2016-000510-30
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!
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.
TEAE is defined as an event that has onset after randomisation 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 eptacog alpha, 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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
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EudraCT No.: 2016-000510-30
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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 Hemophilia Treatment Experience Measure (Hemo-TEM) after 24 weeks from 
treatment onset
!
Change in Hemo-TEM after 76 weeks from treatment onset
!
Change in 36-Item Short Form Health Survey (SF-36v2) after 24 weeks from treatment 
onset
!
Change in SF-36v2 after 76 weeks from treatment onset
!
Change in Sheehan Disability Scale (SDS) after 24 weeks from treatment onset
!
Change in SDS after 76 weeks from treatment onset
!
Change in Treatment Satisfaction Questionnaire for Medication (TSQM) after 24 weeks 
from treatment onset
!
Change in TSQM after 76 weeks from treatment onset
!
Change in Injection Site Reaction Questionnaire domain of Self-Injection Assessment 
Questionnaire (SIAQ-ISRQ) after 24 weeks from treatment onset
!
Change in SIAQ-ISRQ after 76 weeks from treatment onset
!
Status of Patient’s Global Impression of Change (PGI-C) after 24 weeks from treatment 
onset
Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS-PRN®), SF-36v2, SDS and 
TSQM will be scored according to their respective scoring algorithms. Change after 24 weeks from
treatment onset for SF-36v2, SDS and TSQM will be analysed with an ANCOVA model including 
regimen (concizumab or eptacog alfa) as a factor and baseline score as covariate. The VERITAS-
PRN questionnaire is only taken at visit 1 so no ANCOVA is performed for it.
All the patient reported outcome (PRO) endpoints will be summarised using descriptive statistics.
The PRO-questionnaires (Hemo-TEM, PGI-C, SIAQ-ISRQ) will not be analysed with an 
ANCOVA.
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. For patients in 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
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the concizumab s.c. prophylaxis arm, main part is 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. For patients in the on-demand arm, the main part consists of 
observations from randomisation until transfer to concizumab s.c. prophylaxis treatment or 
withdrawal from trial, whichever comes first. All observations for these patients after transfer to 
concizumab treatment is regarded as extension part 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 trial reports might in such case be issued. A clinical trial report 
describing results from the main and the 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
3
Changes to the statistical analyses planned in the protocol
3.1
Definition of rebleed
Section 17 page 113 in the protocol describes the definition of a re-bleed. The text below is a 
clarification of this definitionincluded in section 2of this document. Words written with italic 
font is added words and strikethrough words are deleted words.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
14 of 16
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 treatment is defined as a new bleeding episode.
3.2
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.
3.3
Clarification of initiation of alternative treatment options
Section 17.3.1 of the protocol describes the estimand which is the “if all patients had adhered” 
estimand. In the definition below it is mentioned that it is mentioned that it includes “all randomised 
patients if all patients adhered to trial drug and did not initiate alternative treatment options.” In 
section 2.3.1the definition of initiation alternative treatment options is clarified.
3.4
Offset definition for negative binomial regression for primary endpoint
Section 17.3.1 of the protocol defines the offset of the negative binomial regression as log of 
exposure time in the main period.For patients in the concizumab arm, this definition only accounts 
for the second CPoC criterion.The offset should reflect the observation period which differs for 
subjects in theconcizumab treatment arm for thefirst CPoCwhich has been further clarified in 
section 2.3.1of this document.
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after randomisation. 
The offset for first CPoC criterion of patients in concizumab arm 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 of patients in concizumab arm 
is the log of the individual exposure time in the main part. For both criteria and patients in the on-
demand arm, the offset is the log of the exposure time in the main part.
3.5
Sensitivity analysis for primary endpoint
Section 17.3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 in section 
17.3.2 how additional sensitivity analyses will be performed.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
15 of 16
Since the first 2 weeks of the concizumab treatment is considered as a run-in period therefore an 
additional sensitivity analysis forCPoC criterion 2 is described in section 2.3.2where 
observations for the first 2 weeks of treatment are excluded.
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 analysis excluding these 
bleeding episodes will be performed as described in section 2.3.2of this document.
3.6
Additional analyses for primary endpoint
Section 17.3.3 of the protocol describes the additional analyses of the primary endpoint. Section 
2.3.3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. The section also clarifies how the series of additional 
analyses will be performed with each of the PK/PD variables taken prior to last dose at 24 weeks.
3.7
Clarification of analyses for supportive secondary endpoints
In section 17.4.1 of the protocol the analyses for the supportive secondary endpoints are defined. In 
section 2.4.1of this document it is further clarified thatthe analyses are performed using 
observations from concizumab patients at the last dose level as well as throughout the escalation 
regimen.
3.8
Definition of TEAE
In section 17.4.2 a TEAE is defined as “an event that has onset from the first exposure to treatment 
until the last visit in the trial.” Since the trial design is concizumab s.c. prophylaxis with on-demand 
treatment of bleeds with eptacog alfa versus placebo with on-demand treatment of with eptacog alfa 
then first exposure for the eptacog alfa on-demand arm is actually at randomisation. To treat each 
arm similarly TEAE is defined as an event that has onset after randomisationas defined in section 
2.4.2of this document.
3.9
Causal relation between eptacog alfa and AE 
On the adverse event (AE)case report form for the trial it is possible to fill in causality to rVIIa. 
The form states that rVIIa causality is only applicable for rVIIa administered at visit 3and 9.1. 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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 October 2018
1RYR1RUGLVN
Trial ID: NN7415-4310
Version:
1.0
UTN: U1111-1179-2925
Status:
Final
EudraCT No.: 2016-000510-30
Page:
16 of 16
3.10
Exploratory analyses of patient reported outcome endpoints
In section 17.4.5.2 of the protocol the endpoints for patient reported outcomes are described. In 
section2.4.5.2of this document it is clarified that ANCOVA will not be performed for the 
VERITAS-PRN scores since they are only supplied by visit 1 and for Hemo-TEM, PGI-C, SIAQ-
ISRQ since they do not supply scores. 
3.11
Main part definition for subjects on eptacog alfa on-demand
In section 17 of the protocol it is specified that “Data from when theon-demand treated patients are 
transferred to concizumab s.c. prophylaxis will not be included in this evaluation. Observations 
from the extension part in the on-demand arm will be summarised separately as well as combined 
with observations from the main part when reporting the extension part data.”  However insection 
17.5 of the protocol it is stated that “Main part is 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.”
Section 2.5of this document has been updated to clarify that the main part for the on-demand 
treated patients is defined to end when they are transferred to concizumab s.c. prophylaxis 
treatment.
CONFIDENTIAL