Efficacy and Safety of Concizumab Prophylaxis in Patients With Haemophilia A or B With Inhibitors
Phase: PHASE3
Conditions: Haemophilia A With Inhibitors, Haemophilia B With Inhibitors
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04083781 
Sponsor trial ID: 
NN7415-4311 
Official title of study: 
Efficacy and safety of concizumab prophylaxis in patients with 
haemophilia A or B with inhibitors 
Document date: 
18-June-2021 
*Document date refers to the date on which the document was most recently updated. 

Protocol 
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Date: 
18 June 2021 Novo Nordisk 
Trial ID: NN7415-4311 
Version: 
7.0 
Status: 
Final 
Page: 
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Protocol 
explorer7
Protocol title: 
Efficacy and Safety of Concizumab prophylaxis in patients with 
haemophilia A or B with inhibitors 
Substance: Concizumab 
Universal Trial Number: U1111-1225-9670 
EUdraCT Number: 2018-004889-34 
Trial phase: 3a 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
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 No unpublished information contained herein may be 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 No unpublished information contained herein may be 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.
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 

Protocol 
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Trial ID: NN7415-4311 
Version: 
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Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document 
Date 
Applicable in country (-ies) and/or 
site(s) 
Updated protocol, version 7.0 
18 June 2021 
All countries 
Updated protocol, version 6.0 
25 March 2021 
All countries 
Updated protocol, version 5.0 
18 January 2021 
Poland 
Updated protocol, version 4.0 
08 July 2020 
All countries 
Updated protocol, version 3.0 
06 July 2020 
All countries, not submitted 
Updated protocol, version 2.0 
06 June 2019 
All countries 
Original protocol, version 1.0 
03 June 2019 
All countries, not submitted 
Protocol version 7.0 (18-June-2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.1 
Overall rationale for preparing protocol version 7.0 
The protocol has been amended to reflect changes to the definition of the primary analysis cut-off. 
After the last patient has been randomised, any patient that due to the COVID-19 pandemic is 
prevented from restarting the new dosing regimen will no longer be used to determine the primary 
analysis cut-off and the 56-week cut-off. As the primary analysis cut-off determines the subsequent 
activities for close-out and reporting of the main part of the trial the modification of the primary 
analysis cut-off will ensure continuity of the overall concizumab development programme and 
thereby not delay access to treatment with a potential to address an unmet medical need. 
Due to the modification of the primary analysis cut-off the amendment is considered to be 
substantial. 
Section # and name 
Description of change 
Rationale 
Section 2 - Flowchart 
Footnote for vital signs measured at 
V4a1 changed from ‘o’ to ‘p’ 
The footnote has been corrected. 
Section 4.3.2.2 - Supportive 
secondary endpoints 
Footnote ‘d’ has been deleted 
The footnote was added by mistake 
in the previous version of the 
protocol 
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Section 5.1 – Overall design 
Modification of the primary analysis 
cut-off and the 56-week cut-off 
To ensure continuity of the 
concizumab development 
programme despite the COVID-19 
pandemic in order to not delay 
access to treatment with a potential 
to address an unmet medical need.  
Section 6.2 – Exclusion criteria 
Footnote re-added to exclusion 
criteria #2 
The footnote had mistakenly been 
taken out in the previous version of 
the protocol.  
Disclosure 
The contents of all local amendments are included in this version of the protocol. The changes are 
specified in the column ‘Implementation in protocol version 4.0 and any update thereof’ below. 
Local 
amendment 
number 
Date 
Applicable in 
country (-ies) 
and/or site(s) 
Brief rationale 
Implementation in updated 
protocol version 4.0 and any 
update thereof 
1.0 
11-Sep-2019
Japan 
PMDA required an update of the 
text in Section 5.1.1 (Dose 
escalation) and Section 9.2.3 
(Bleeding episode). The aim of 
the update is to clarify the criteria 
for dose escalation considering all 
available laboratory results 
(including coagulation 
parameters) to ensure the safety 
of the patient. As well as, a clear 
explanation on how the patient 
should treat bleeding episodes 
beforehand.  
This amendment has not been 
fully implemented in this 
updated protocol Section 
5.1.1 has been deleted since 
the described dose escalation 
option has been removed 
hence the changes outline in 
the amendment is no longer 
applicable.  
The changes outlined in 
Section 5.2.3 have been 
implemented by updating the 
text as follows: 
If an additional dose is 
needed because a single dose 
was insufficient to treat the 
bleed, the patient must come 
to the site. 
The changes outlined in 
Section 9.2.3 have been 
implemented by updating the 
text as follows: 
In case a patient cannot get in 
contact with the site, bleeds 
must be treated according to 
local standards as previously 
agreed with the 
investigator. 
1.0 
09-Oct-2019
Turkey 
The protocol was updated to 
comply with local reimbursement 
rules in Turkey. 
Amended Sections 5.2.2, 
5.2.3,5.2.4 and 7.1 have been 
implemented in Appendix 10 
– Country-specific
requirements in this updated
protocol.
2.0 
N/A 
N/A 
Not in use. 
N/A 
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Trial ID: NN7415-4311 
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Status: 
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Local 
amendment 
number 
Date 
Applicable in 
country (-ies) 
and/or site(s) 
Brief rationale 
Implementation in updated 
protocol version 4.0 and any 
update thereof 
3.0 
27-Nov-2019
Spain/ 
Site 
 
The rationale for this amendment, 
is to ensure that at the selected 
site, patients participating in 
NN7415-4311 (explorer 7) will 
be offered to consent to take part 
in a site-specific sub-study to 
evaluate the use of rotational 
thrombelastometry (ROTEM) 
parameters as a possible marker 
for evaluation of concizumab. 
Appendix 10 – Country-
specific requirements/ 
ROTEM Sub-Study has been 
added to reflect the text as 
specified in this local 
amendment. 
4.0 
N/A 
N/A 
Not in use. 
N/A 
5.0 
N/A 
N/A 
Not in use. 
N/A 
6.0 
26-Nov-2019
Russia 
Local legal requirements on how 
to conduct Clinical trials in 
Russia were included in the 
protocol.  
Amendment implemented in 
Appendix 10 – Country-
specific requirements 
7.0 
15-Jan-2020
Czech 
Republic 
This Protocol Amendment 7 was 
created to comply with 
requirements from the Czech 
Regulatory Authority (SUKL) 
concerning exclusion of HAwI 
patients aged 12−17 years. This 
amendment is applicable for the 
Czech Republic only. 
Amendment implemented in 
Appendix 10 – Country-
specific requirements. In 
addition, this requirement will 
be reflected in the eCRF for 
sites in Czech Republic.  
8.0 
24-Mar-2020
South Korea 
The protocol was updated to 
comply with local reimbursement 
rules for South Korea 
Amendment implemented in 
Appendix 10 – Country-
specific requirements 
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Table of Contents 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 5 
1 Synopsis ........................................................................................................................................................ 8 
2 Flowchart ................................................................................................................................................... 12 
2.1 
Pharmacokinetic (PK)/Pharmacodynamic (PD) sampling flowchart for patients enrolled or 
reinitiated after the treatment pause .................................................................................................. 20 
3 Introduction ............................................................................................................................................... 21 
3.1 
Trial rationale .................................................................................................................................... 21 
3.2 
Background ....................................................................................................................................... 21 
3.3 
Benefit-risk assessment ..................................................................................................................... 22 
4 Objectives and endpoints .......................................................................................................................... 25 
4.1 
Primary, secondary and exploratory objectives ................................................................................ 25 
4.1.1 
Primary objective ............................................................................................................... 25 
4.1.2 
Secondary objectives ......................................................................................................... 25 
4.1.3 
Exploratory objectives ....................................................................................................... 25 
4.2 
Estimands .......................................................................................................................................... 25 
4.3 
Primary, secondary and exploratory endpoints ................................................................................. 26 
4.3.1 
Primary endpoint ............................................................................................................... 26 
4.3.2 
Secondary endpoints .......................................................................................................... 26 
4.3.2.1 
Key secondary endpoints ............................................................................... 26 
4.3.2.2 
Supportive secondary endpoints .................................................................... 27 
4.3.3 
Exploratory endpoints........................................................................................................ 30 
5 Trial design ................................................................................................................................................ 32 
5.1 
Overall design ................................................................................................................................... 32 
5.2 
Treatment of patients ........................................................................................................................ 34 
5.2.1 
Concizumab prophylaxis ................................................................................................... 34 
5.2.2 
On-demand treatment ........................................................................................................ 35 
5.2.3 
Treatment of break-through bleeding episodes ................................................................. 35 
5.2.4 
Treatment during screening and follow-up period ............................................................ 37 
5.3 
Patient and trial completion .............................................................................................................. 37 
5.4 
End of trial definition ........................................................................................................................ 37 
5.5 
Scientific rationale for trial design .................................................................................................... 37 
5.6 
Justification for dose ......................................................................................................................... 38 
5.7 
Rationale for Trial Population .......................................................................................................... 38 
6 Trial population ......................................................................................................................................... 40 
6.1 
Inclusion criteria ............................................................................................................................... 40 
6.2 
Exclusion criteria .............................................................................................................................. 40 
6.3 
Screen failures ................................................................................................................................... 41 
6.4 
Randomisation criteria ...................................................................................................................... 41 
7 Treatments ................................................................................................................................................. 42 
7.1 
Treatments administered ................................................................................................................... 42 
7.1.1 
Medical devices ................................................................................................................. 42 
7.1.2 
Investigational medical device (in vitro diagnostic device) .............................................. 43 
7.2 
Method of treatment assignment ....................................................................................................... 43 
7.3 
Blinding ............................................................................................................................................ 44 
7.4 
Preparation/Handling/Storage/Accountability .................................................................................. 44 
7.5 
Treatment compliance ....................................................................................................................... 45 
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7.6 
Concomitant medication ................................................................................................................... 46 
7.6.1 
Prohibited medication ........................................................................................................ 46 
7.7 
Treatment after the end of the trial .................................................................................................... 46 
8 Discontinuation/Withdrawal criteria ...................................................................................................... 47 
8.1 
Discontinuation of trial treatment ..................................................................................................... 47 
8.1.1 
Temporary discontinuation of concizumab in relation to COVID-19 ............................... 47 
8.1.2 
Sponsor-initiated discontinuation of trial product in relation to the treatment pause ........ 48 
8.2 
Withdrawal from the trial .................................................................................................................. 48 
8.2.1 
Replacement of patients..................................................................................................... 49 
8.3 
Lost to follow-up............................................................................................................................... 49 
9 Trial assessments and procedures............................................................................................................ 50 
9.1 
Patient related information/assessments ........................................................................................... 51 
9.1.1 
Demography ...................................................................................................................... 51 
9.1.2 
Details of Haemophilia ...................................................................................................... 51 
9.1.3 
Haemophilia Treatment and Bleed History ....................................................................... 52 
9.1.4 
Target Joints ...................................................................................................................... 52 
9.2 
Efficacy assessments ......................................................................................................................... 52 
9.2.1 
eDiary ................................................................................................................................ 52 
9.2.2 
Treatment with concizumab .............................................................................................. 53 
9.2.3 
Bleeding episodes .............................................................................................................. 54 
9.2.4 
Sport activity ..................................................................................................................... 56 
9.2.5 
Physical activity tracker (ActiGraph) ................................................................................ 56 
9.2.6 
Patient-reported outcome questionnaires ........................................................................... 58 
9.2.7 
Clinical efficacy laboratory assessments ........................................................................... 59 
9.3 
Adverse events .................................................................................................................................. 61 
9.3.1 
Time period and frequency for collecting AE and SAE information ................................ 61 
9.3.1.1 
Adverse event of special interest .................................................................... 62 
9.3.2 
Method of detecting AEs and SAEs .................................................................................. 63 
9.3.3 
Follow-up on AEs and SAEs ............................................................................................. 63 
9.3.4 
Regulatory reporting requirements for SAEs .................................................................... 63 
9.3.5 
Reporting requirement for safety information related to the physical activity tracker ...... 63 
9.3.6 
Disease-related events and/or disease-related outcomes and other information not 
qualifying as an AE or SAE .............................................................................................. 63 
9.3.7 
Technical complaints ......................................................................................................... 64 
9.3.8 
Treatment of overdose ....................................................................................................... 64 
9.3.9 
Trial stopping rules ............................................................................................................ 64 
9.4 
Safety assessments ............................................................................................................................ 64 
9.4.1 
Concomitant illness and Medical History ......................................................................... 65 
9.4.2 
Physical examinations ....................................................................................................... 65 
9.4.3 
Body measurements ........................................................................................................... 65 
9.4.4 
Vital signs .......................................................................................................................... 66 
9.4.5 
Electrocardiogram (ECG) .................................................................................................. 66 
9.4.6 
Clinical safety laboratory assessments .............................................................................. 67 
9.4.7 
Immunogenicity assessments ............................................................................................ 68 
9.4.8 
Hypersensitivity reaction ................................................................................................... 69 
9.4.9 
Injection site reactions ....................................................................................................... 70 
9.5 
Pharmacokinetics .............................................................................................................................. 70 
9.6 
Pharmacodynamics ........................................................................................................................... 71 
9.7 
Human Biological Specimen for storage .......................................................................................... 71 
9.7.1 
Genetics ............................................................................................................................. 71 
9.7.2 
Biomarkers ........................................................................................................................ 71 
9.8 
Health economics .............................................................................................................................. 71 
9.9 
Surgery .............................................................................................................................................. 72 
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10 Statistical considerations .......................................................................................................................... 73 
10.1 Sample size determination ................................................................................................................ 73 
10.2 Definition of analysis sets ................................................................................................................. 74 
10.3 Statistical analyses ............................................................................................................................ 74 
10.3.1 
Primary endpoint ............................................................................................................... 75 
10.3.2 
Secondary endpoints .......................................................................................................... 76 
10.3.2.1 
Key secondary endpoints ............................................................................... 76 
10.3.2.2 
Supportive secondary endpoints .................................................................... 77 
10.3.3 
Exploratory endpoints........................................................................................................ 77 
10.3.4 
Interim analyses ................................................................................................................. 77 
10.3.5 
Sequential safety analysis and safety monitoring .............................................................. 77 
10.3.6 
Explorative statistical analysis for pharmacogenetics and biomarkers ............................. 78 
10.4 Pharmacokinetic and/or pharmacodynamic modelling ..................................................................... 78 
11 References .................................................................................................................................................. 79 
12 Appendices ................................................................................................................................................. 82 
Appendix 1 
Abbreviations and Trademarks .............................................................. 82 
Appendix 2 
Clinical laboratory tests ......................................................................... 85 
Appendix 3 
Blood sampling in patients below 18 years of age................................. 87 
Appendix 4 
Trial governance considerations ............................................................ 89 
Appendix 5 
Adverse events: definitions and procedures for recording, 
evaluation, follow-up, and reporting ...................................................... 97 
Appendix 6 
Sports ratings by activity ..................................................................... 104 
Appendix 7 
Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting ..................................................... 106 
Appendix 8 
AEs, ADEs, SAEs, SADEs, USADEs and device deficiencies: 
Definitions and procedures for recording, evaluating, follow-up, 
and reporting in medical device studies ............................................... 108 
Appendix 9 
Retention of human biosamples ........................................................... 113 
Appendix 10 Country-specific requirements ............................................................. 115 
Appendix 11 Breakthrough bleed treatment guidance .............................................. 118 
Appendix 12 Flowcharts applicable for patients enrolled before the treatment 
pause and who have permanently discontinued treatment prior to 
restart ................................................................................................... 121 
 
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1 
Synopsis 
Rationale: 
The purpose of this phase 3 trial is to establish the effect and investigate safety of daily 
subcutaneous treatment with concizumab prophylaxis when given to adult and adolescent 
haemophilia patients with inhibitors. 
Objectives and endpoints: 
Primary objective 
• To compare the effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with 
bypassing agents) in reducing the number of bleeding episodes in adult and adolescent patients 
with haemophilia A or B with inhibitors. 
Primary endpoint 
Endpoint title 
Time frame  
Unit 
The number of treated 
spontaneous and traumatic 
bleeding episodes  
On demand (arm 1) 
• From randomisation (week 0) up until start 
of concizumab treatment (at least 24 
weeks)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the primary 
analysis cut-off (at least 32 weeks) 
Count 
 
Secondary objectives 
• To compare the patient-reported outcomes (PROs) after treatment with concizumab prophylaxis 
vs no prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors 
• To investigate the safety of concizumab prophylaxis in adult and adolescent patients with 
haemophilia A or B with inhibitors 
• To investigate the PK and PD parameters of concizumab prophylaxis in adult and adolescent 
patients with haemophilia A or B with inhibitors 
Key secondary endpoints 
Endpoint title 
Time frame  
Unit 
Health economics 
Change in SF36v2 bodily 
pain  
From start of treatment (week 0a) until week 24  
Score 
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Change in SF36v2 physical 
functioning  
From start of treatment (week 0a) until week 24  
Score 
aDefined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen 
Estimand: 
The five components of the estimand for the primary endpoint are as follows: 
• Endpoint:  
• On demand (arm 1): The number of treated spontaneous and traumatic bleeding episodes 
from randomisation (week 0) up until start of concizumab treatment (at least 24 weeks)  
• Concizumab (arm 2): The number of treated spontaneous and traumatic bleeding episodes 
from start of the new concizumab dosing regimen (week 0) up until the primary analysis 
cut-off (at least 32 weeks)  
• Treatment regimens: Either a) on demand treatment with intravenous replacement with factor-
containing products, or b) PPX treatment regimen with subcutaneous concizumab consisting of 
an initial loading dose of 1.0 mg/kg, followed by an initial daily dose of 0.20 mg/kg (during the 
dose adjustment period), followed by a maintenance dose of either 0.15, 0.20 or 0.25 mg/kg 
where breakthrough bleeds are treated with intravenous replacement with factor-containing 
products. 
• Population-level summary: The treatment ratio of the ABRs between the two treatment 
regimens. 
• Intercurrent events: 1) permanent treatment discontinuation, 2) temporary treatment 
discontinuation after restart of the trial, 3) use of factor-containing products not related to 
treatment of a bleed and 4) minor surgery. 
• Target patient population: HAwI and HBwI patients treated on demand prior to entering trial 
4311. 
Utilizing these five components, the estimand for the primary objective can be described as the 
treatment ratio of the ABRs for treated spontaneous or traumatic bleeding episodes up until the 
primary analysis cut-off between the two treatment regimens in the target patient population while 
patients are adhering to the allocated treatment regimen. 
The strategies for how to account for the intercurrent events in the estimand are as follows: 
1. Permanent treatment discontinuation. For this intercurrent event, the data from the period 
after permanent discontinuation of trial treatment are not included. It is to be noted that for 
patients in the on demand arm, permanent treatment discontinuation will mean initiation of 
PPX. 
2. Temporary treatment discontinuation after restart of the trial. For this intercurrent event the 
‘treatment policy’ strategy is used meaning that the data from this period are included. 
3. Use of factor products not related to treatment of a bleed. For this intercurrent event, the 
data during this period are not included. 
4. Minor surgery. For this intercurrent event the ‘treatment policy’ strategy is used. 
Overall design: 
This is a prospective, multicentre, open label clinical trial with four arms. The trial aims to evaluate 
the effect and safety of daily concizumab prophylaxis administered s.c. in patients with haemophilia 
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with inhibitors. Initially, patients were assigned to randomisation or to allocation into non-
randomised treatment arms based on their treatment regimen before the trial. Patients restarting the 
trial after the pause will enter the same arm as they were initially randomised or allocated to. New 
patients will be randomised to arms 1 or 2, if they fulfil the randomisation criteria, or allocated to 
arm 4.  
The trial consists of a main part (24 or 32 weeks), an extension part (up to 136 weeks) and a safety 
follow-up part (7 weeks). The main part of the trial is completed for a patient when the patient has 
completed at least 24 weeks of participation (arm 1) or 32 weeks of participation (arms 2, 3 and 4). 
After the main part of the trial, all patients will be offered to continue in the extension part of the 
trial and receive treatment with concizumab for up to an additional 136 weeks.  
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 suitability for 
the trial. 
• Male aged ≥12 years at the time of signing informed consent. 
• Congenital Haemophilia A or B of any severity with documented history of inhibitor (≥0.6 BU). 
• Patient has been prescribed, or in need of, treatment with bypassing agents in the last 24 weeks 
prior to screening (for patients not previously enrolled in NN7415-4310 (explorer 4)). 
Key exclusion criteria: 
• Known or suspected hypersensitivity to any constituent of the trial product or related products. 
• Known inherited or acquired coagulation disorder other than congenital haemophilia. 
• Ongoing or planned Immune Tolerance Induction treatment. 
• History of thromboembolic diseasea. Current clinical signs of, or treatment for thromboembolic 
disease. Patients who in the judgement of the investigator are considered at high risk of 
thromboembolic eventsb.  
aIncludes arterial and venous thrombosis including myocardial infarction, pulmonary embolism, cerebral 
infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events and peripheral artery 
occlusion. 
bThromboembolic risk factors could include, but are not limited to, hypercholesterolemia, diabetes mellitus, 
hypertension, obesity, smoking, family history of thromboembolic events, arteriosclerosis, other conditions associated 
with increased risk of thromboembolic events. 
Number of patients: 
Number of patients planned to be screened: 155 
Number of patients planned to be started on trial product: 136 
Of note, patients who were screen-failed at Sponsor’s decision due to the treatment pause are 
allowed to be re-screened; in that case they will count twice in the number of screened patients.  
Treatment groups and duration: 
Duration of treatment will be up to 160 weeks. 
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The following trial products will be supplied by Novo Nordisk A/S: 
• concizumab 40 mg/ml in prefilled PDS290 pen-injector 
• concizumab 100 mg/ml in prefilled PDS290 pen-injector 
The trial products will be administered subcutaneously. 
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2 
Flowchart 
Flowcharts for patients enrolled or reinitiated after the treatment pause 
The below flowchart is applicable for patients who reinitiate treatment with concizumab after the treatment pause or for new patients enrolled in the trial 
after the treatment pause. Patients enrolled in the trial before the treatment pause and who will not reinitiate treatment with concizumab must follow the 
flowchart in Appendix 12. 
Treatment  
arm 1 
Main Part 
Extension Part 
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3aa 
V  
4a NA V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a 
V 
9a.1 
V 
9a.2 
V 
9a.3 
V 
10a 
V 
10a.1 
V  
11a 
V 
11a.1 
V  
12a 
V 
12a.1 
V  
13a 
V  
14a 
V  
15a 
V  
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V  
26a 
V  
27a 
Treatment  
arm 2, 3 and 4 
Main Part 
Extension Part  
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3a 
V  
4a 
V  
4a.1 
V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a NA 
V 
9a.2 NA 
V 
10a NA 
V  
11a NA 
V  
12a 
NA 
V  
13a 
V 
14a 
V 
15a 
V 
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V 
26a 
V  
27a 
Timing of Visit 
(Weeks) 
-3 0b 
1 
4 
6c 
8 
12 16 20 24 
25 
28 
30c 
32 
36 
40 
44 
48 
52 
56 
64 
72 
80 
88 
96 104 112 120 128 136 144 152 160 
167 
Visit Window 
(Days) 
±0 ±0 ±1 ±3 ±7c ±3 ±3 ±3 ±3 ±3 
±1 
±3 
±7c ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
SUBJECT 
RELATED 
INFORMATION 
AND 
ASSESSMENTS 
 
Informed 
Consent  
Xd Xe 
 
 
 
 
 
 
 
Xf  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VV-CLIN-121085
1.0
VV-TMF-4536529
1.0

Protocol 
      
Date: 
18 June 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
13 of 125 
 
Treatment  
arm 1 
Main Part 
Extension Part 
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3aa 
V  
4a NA V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a 
V 
9a.1 
V 
9a.2 
V 
9a.3 
V 
10a 
V 
10a.1 
V  
11a 
V 
11a.1 
V  
12a 
V 
12a.1 
V  
13a 
V  
14a 
V  
15a 
V  
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V  
26a 
V  
27a 
Treatment  
arm 2, 3 and 4 
Main Part 
Extension Part  
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3a 
V  
4a 
V  
4a.1 
V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a NA 
V 
9a.2 NA 
V 
10a NA 
V  
11a NA 
V  
12a 
NA 
V  
13a 
V 
14a 
V 
15a 
V 
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V 
26a 
V  
27a 
Timing of Visit 
(Weeks) 
-3 0b 
1 
4 
6c 
8 
12 16 20 24 
25 
28 
30c 
32 
36 
40 
44 
48 
52 
56 
64 
72 
80 
88 
96 104 112 120 128 136 144 152 160 
167 
Visit Window 
(Days) 
±0 ±0 ±1 ±3 ±7c ±3 ±3 ±3 ±3 ±3 
±1 
±3 
±7c ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Concomitant 
illness 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Details of 
Haemophilia 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haemophilia 
treatment and 
bleed history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Target Joints 
X Xh 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
discontinuation 
criteria 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Withdrawal 
criteria 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomisation 
 
Xj  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFFICACY  
 
Bleeding 
Episode 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VV-CLIN-121085
1.0
VV-TMF-4536529
1.0

Protocol 
      
Date: 
18 June 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
14 of 125 
 
Treatment  
arm 1 
Main Part 
Extension Part 
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3aa 
V  
4a NA V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a 
V 
9a.1 
V 
9a.2 
V 
9a.3 
V 
10a 
V 
10a.1 
V  
11a 
V 
11a.1 
V  
12a 
V 
12a.1 
V  
13a 
V  
14a 
V  
15a 
V  
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V  
26a 
V  
27a 
Treatment  
arm 2, 3 and 4 
Main Part 
Extension Part  
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3a 
V  
4a 
V  
4a.1 
V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a NA 
V 
9a.2 NA 
V 
10a NA 
V  
11a NA 
V  
12a 
NA 
V  
13a 
V 
14a 
V 
15a 
V 
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V 
26a 
V  
27a 
Timing of Visit 
(Weeks) 
-3 0b 
1 
4 
6c 
8 
12 16 20 24 
25 
28 
30c 
32 
36 
40 
44 
48 
52 
56 
64 
72 
80 
88 
96 104 112 120 128 136 144 152 160 
167 
Visit Window 
(Days) 
±0 ±0 ±1 ±3 ±7c ±3 ±3 ±3 ±3 ±3 
±1 
±3 
±7c ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Body 
Measurementsk 
X 
X 
 
X  
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Thrombin 
generation 
 
Xl 
X 
X  
X 
X 
X 
X 
Xl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sport activity 
 
X  
 
 
 
 
 
Xg 
 
 
Xh  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concizumab 
ELISAm 
 
Xl 
X Xn 
 
X 
X 
X 
X 
Xl 
X 
Xn 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Free TFPI 
 
Xl 
X 
X 
 
X 
X 
X 
X 
Xl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAFETY 
 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site 
Reaction 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
Parameters 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
Factorso 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-121085
1.0
VV-TMF-4536529
1.0

Protocol 
      
Date: 
18 June 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
15 of 125 
 
Treatment  
arm 1 
Main Part 
Extension Part 
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3aa 
V  
4a NA V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a 
V 
9a.1 
V 
9a.2 
V 
9a.3 
V 
10a 
V 
10a.1 
V  
11a 
V 
11a.1 
V  
12a 
V 
12a.1 
V  
13a 
V  
14a 
V  
15a 
V  
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V  
26a 
V  
27a 
Treatment  
arm 2, 3 and 4 
Main Part 
Extension Part  
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3a 
V  
4a 
V  
4a.1 
V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a NA 
V 
9a.2 NA 
V 
10a NA 
V  
11a NA 
V  
12a 
NA 
V  
13a 
V 
14a 
V 
15a 
V 
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V 
26a 
V  
27a 
Timing of Visit 
(Weeks) 
-3 0b 
1 
4 
6c 
8 
12 16 20 24 
25 
28 
30c 
32 
36 
40 
44 
48 
52 
56 
64 
72 
80 
88 
96 104 112 120 128 136 144 152 160 
167 
Visit Window 
(Days) 
±0 ±0 ±1 ±3 ±7c ±3 ±3 ±3 ±3 ±3 
±1 
±3 
±7c ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Haematology 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
X 
 
 
 
 
 
 
 
Xg 
 
 
 
Xh 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Vital signs 
X 
X 
X 
X 
Xp 
X 
X 
X 
X 
X 
X 
X 
Xp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-
concizumab 
antibodiesm 
X Xh 
 
Xh 
 
Xh Xh Xh Xh X 
 
 
 
Xh 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
FVIII/FIX 
inhibitor 
analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Total TFPI 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OTHER 
ASSESSMENTS 
 
PRO 
questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-121085
1.0
VV-TMF-4536529
1.0

Protocol 
      
Date: 
18 June 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
16 of 125 
 
Treatment  
arm 1 
Main Part 
Extension Part 
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3aa 
V  
4a NA V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a 
V 
9a.1 
V 
9a.2 
V 
9a.3 
V 
10a 
V 
10a.1 
V  
11a 
V 
11a.1 
V  
12a 
V 
12a.1 
V  
13a 
V  
14a 
V  
15a 
V  
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V  
26a 
V  
27a 
Treatment  
arm 2, 3 and 4 
Main Part 
Extension Part  
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3a 
V  
4a 
V  
4a.1 
V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a NA 
V 
9a.2 NA 
V 
10a NA 
V  
11a NA 
V  
12a 
NA 
V  
13a 
V 
14a 
V 
15a 
V 
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V 
26a 
V  
27a 
Timing of Visit 
(Weeks) 
-3 0b 
1 
4 
6c 
8 
12 16 20 24 
25 
28 
30c 
32 
36 
40 
44 
48 
52 
56 
64 
72 
80 
88 
96 104 112 120 128 136 144 152 160 
167 
Visit Window 
(Days) 
±0 ±0 ±1 ±3 ±7c ±3 ±3 ±3 ±3 ±3 
±1 
±3 
±7c ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
SF36 V2.0 
Health 
Survey 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient 
preference 
questionnaire 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS 
Short Form 
Upper 
Extremity 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS 
Numeric 
Rating Scale 
- Pain 
Intensity 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haemophilia 
Treatment 
Experience 
Measure 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haem-A-
QoLq 
X Xr 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-121085
1.0
VV-TMF-4536529
1.0

Protocol 
      
Date: 
18 June 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
17 of 125 
 
Treatment  
arm 1 
Main Part 
Extension Part 
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3aa 
V  
4a NA V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a 
V 
9a.1 
V 
9a.2 
V 
9a.3 
V 
10a 
V 
10a.1 
V  
11a 
V 
11a.1 
V  
12a 
V 
12a.1 
V  
13a 
V  
14a 
V  
15a 
V  
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V  
26a 
V  
27a 
Treatment  
arm 2, 3 and 4 
Main Part 
Extension Part  
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3a 
V  
4a 
V  
4a.1 
V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a NA 
V 
9a.2 NA 
V 
10a NA 
V  
11a NA 
V  
12a 
NA 
V  
13a 
V 
14a 
V 
15a 
V 
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V 
26a 
V  
27a 
Timing of Visit 
(Weeks) 
-3 0b 
1 
4 
6c 
8 
12 16 20 24 
25 
28 
30c 
32 
36 
40 
44 
48 
52 
56 
64 
72 
80 
88 
96 104 112 120 128 136 144 152 160 
167 
Visit Window 
(Days) 
±0 ±0 ±1 ±3 ±7c ±3 ±3 ±3 ±3 ±3 
±1 
±3 
±7c ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
PGI-S on 
physical 
functioning  
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xh  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGI-C on 
physical 
functioning 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xh  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TRIAL 
MATERIAL 
 
Administration of 
Trial Product (on 
site) 
 
X 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose 
Adjustments 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Dispensing 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug 
Accountability  
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
VV-CLIN-121085
1.0
VV-TMF-4536529
1.0

Protocol 
      
Date: 
18 June 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
18 of 125 
 
Treatment  
arm 1 
Main Part 
Extension Part 
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3aa 
V  
4a NA V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a 
V 
9a.1 
V 
9a.2 
V 
9a.3 
V 
10a 
V 
10a.1 
V  
11a 
V 
11a.1 
V  
12a 
V 
12a.1 
V  
13a 
V  
14a 
V  
15a 
V  
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V  
26a 
V  
27a 
Treatment  
arm 2, 3 and 4 
Main Part 
Extension Part  
Follow-
up 
Visits  
(V) 
V  
1a 
V  
2a 
V  
3a 
V  
4a 
V  
4a.1 
V  
5a 
V  
6a 
V  
7a 
V  
8a 
V  
9a NA 
V 
9a.2 NA 
V 
10a NA 
V  
11a NA 
V  
12a 
NA 
V  
13a 
V 
14a 
V 
15a 
V 
16a 
V  
17a 
V  
18a 
V  
19a 
V 
20a 
V 
21a 
V 
22a 
V  
23a 
V  
24a 
V  
25a 
V 
26a 
V  
27a 
Timing of Visit 
(Weeks) 
-3 0b 
1 
4 
6c 
8 
12 16 20 24 
25 
28 
30c 
32 
36 
40 
44 
48 
52 
56 
64 
72 
80 
88 
96 104 112 120 128 136 144 152 160 
167 
Visit Window 
(Days) 
±0 ±0 ±1 ±3 ±7c ±3 ±3 ±3 ±3 ±3 
±1 
±3 
±7c ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
REMINDERS 
 
Human 
biological 
specimen for 
storaget 
Xu 
 
 
 
 
 
X 
 
 
Xg 
 
 
 
Xh 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
actGraph 
dispensingv 
X 
 
 
 
 
 
 
Xg 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
actiGraph 
collectionv 
 
X 
 
 
 
 
 
 
 
Xg 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand out 
Direction for Use 
 
Xh 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand out patient 
ID card and 
patient material 
X Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand out eDiary 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
End of Trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Footnote  
a) Phone visit is allowed for patients randomised to arm 1 (on-demand patient) 
b) Week 0 is the time of trial restart  
c) Visit will take place after the concizumab exposure levels are available according to in Section 9.2.2 
d) Only patients enrolled after the treatment pause will sign the Informed Consent at visit 1a 
e) Only patients enrolled in the trial before the treatment pause and allocated to arm 2, 3 and 4, will re-consent at Visit 2a 
f) 
Only patients enrolled in the trial before the treatment pause and randomised to arm 1, will re-consent at visit 9a 
g) Only applicable for arm 1 patients, who are receiving concizumab at Visit 9a 
h) Only applicable for patients in arm 2, 3 and 4, who are receiving concizumab at visit 2a 
i) 
Only applicable for patients enrolled in the trial before treatment pause. Site must ensure patients do not violate discontinuation criteria according to Section 8.1 before 
reinitiating dosing with concizumab 
j) 
Patients randomised to arm 2 before the treatment pause will not be re-randomised at visit 2a  
k) Weight only, except at visit 1 where height is measured   
l) 
For patients having concizumab dosing at visit 2a there will be a 24-hour PK session at visit 2a and 9a. Please see details for PK sampling in Section 2.1. For on-demand 
patients (arm 1) only the pre-dose sample will be taken 
m) Sample is taken pre-dose. Patients must not inject trial medication on this visit day before the sample is taken 
n) Concizumab plasma concentration for dose adjustment (visit 4a for arm 2-4 and visit 9a.2 for arm 1) will be analysed using the concizumab ELISA in vitro diagnostic (IVD) 
device 
o) Only one sample to be taken, either factor VIII for HA patients or factor IX for HB patients 
p) Only applicable for patients having site visit due to dose-escalation 
q) Only for patients above ≥ 17 years old (at visit 1a) 
r) 
Only applicable for patients enrolled in the trial before the treatment pause  
s) 
Site visit must be performed in case of dose escalation. Phone visit is allowed for patients having dose de-escalation or dose unchanged. See section 9.2.2 for further details  
t) 
A separate Informed Consent Form must be signed before any samples are taken. See section 9.7 for further details  
u) Whole blood for DNA is only taken at screening 
v) See Section 9.2.5 for further details 
 
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2.1 
Pharmacokinetic (PK)/Pharmacodynamic (PD) sampling flowchart for patients enrolled or reinitiated after the treatment pause 
The below flowchart is only applicable for patients who enrolled in or reinitiated the trial after the treatment pause. Patients who were enrolled in the trial 
before the treatment pause and who discontinued prior to restart must follow the flowcharts in Appendix 12. 
 
Visit 2a and Visit 9a (PK/PD profile only applicable for patients on concizumab treatment from visit 2a)a 
PK sampling timepoint (hours) 
Pre-dose 
3 hours 
6 hours 
9 hours 
24 hours 
 Sampling window  
-1 − 0 hours 
±30 min 
±30 min 
±1 hour 
±3 hours 
 PK ASSESSMENTS 
 
 
 
 
 
Concizumab ELISA 
X 
X 
X 
X 
X 
Free TFPI 
X 
X 
X 
X 
X 
Thrombin generation 
X 
 
X 
 
X 
aFor patients who had a full 24-hour PK/PD profile measured at visit 2 prior to the treatment pause, only pre-dose (i.e. prior to loading dose) and 24-hour post-dose samples should be taken 
at visit 2a 
 
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3 
Introduction 
3.1 
Trial rationale 
Concizumab is a therapeutic monoclonal antibody that is being developed for prophylaxis treatment 
of bleeding episodes in haemophilia A (HA) and haemophilia B (HB). It is a new treatment concept 
involving inhibition of TFPI and has the potential to treat HA and HB patients with or without 
inhibitors. Concizumab is intended for subcutaneous administration. 
Concizumab aspires to address the high unmet medical need in haemophilia patients by offering a 
s.c. administered bleeding prophylaxis in a pen-injector. Concizumab is not expected to be effective 
in the treatment of bleeding episodes, and breakthrough bleeds would therefore require a 
coagulation factor or bypassing treatment. 
Due to the mode of action of concizumab and existing clinical data showing a similar response 
across haemophilia subtypes, the clinical development of concizumab is conducted in parallel for 
HA and HB, i.e., HA and HB patients are included in the same trials.  
3.2 
Background 
Haemophilia is an inherited bleeding disorder characterised by an increased bleeding tendency, 
typically in weight bearing joints. HA is caused by a partial or complete deficiency of blood 
coagulation factor VIII (FVIII). In HB, it is factor IX (FIX) that is deficient. Inheritance is 
chromosome X-linked; therefore, the disease mainly affects males. The incidence is estimated to be 
about 1 in 5,000 live male births for HA2 and 1 in 25,000 live male births for HB. According to the 
World Federation of Haemophilia global survey of 2017, about 196,706 persons are diagnosed with 
haemophilia worldwide.3 Of these, about 80% have HA. 
Haemophilia is classified as “severe”, “moderate” or “mild” according to the plasma activity of the 
affected coagulation factor.4 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.5 If formed, the haemostatic plug 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 often occurs spontaneously and is the most 
frequent symptom of the disease. Recurrent bleeding episodes in the same location, most commonly 
a weight bearing joint, lead to chronic arthropathy, muscular atrophy and deformities. Treatment of 
bleeding episodes as they manifest (on-demand treatment) may delay arthropathy but does not 
prevent it. 
The most common complication of replacement therapy in HA and to a lesser extent HB is 
development of inhibitory antibodies against FVIII and or FIX respectively. These binding 
antibodies might neutralise the effect of exogenous FVIII or FIX and are then called inhibitors. In 
patients who have developed clinically relevant inhibitors towards FVIII or FIX, replacement 
therapy is rendered ineffective. 
Of the 196,706 people diagnosed with haemophilia, 6,290 have a clinically identified inhibitor 
corresponding to a prevalence of approximately 3.2%. According to the World Federation of 
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Haemophilia global survey of 2017, the inhibitor prevalence is highest in HA accounting for 94% of 
the inhibitor cases. Inhibitors in HB are very rare with a reported global prevalence of 342 cases.3 
Bleeding episodes in inhibitor patients may be treated intravenously with bypassing agents, 
activated FVII or an activated prothrombin complex concentrate (aPCC) given as intravenous 
injections. 
The majority of current replacement therapy with coagulation factor VIII and IX or bypassing 
treatment options are hampered by the fact that most of these products must be given as intravenous 
injections. A new therapeutic agent that can be administered subcutaneously in small volume will 
represent a major improvement in the treatment convenience and thereby compliance of these 
patients in a prophylaxis setting. 
Concizumab is a humanised recombinant monoclonal antibody (mAb) of the immunoglobulin G4 
(IgG4) isotype with a molecular weight of 149 kilo Daltons. To prevent formation of half-
antibodies, the serine at position 241 in the heavy chain has been replaced with a proline (S241P 
(Kabat annotation)). Concizumab is directed against the tissue factor pathway inhibitor (TFPI), 
which is involved in down-regulation of the initiation of the coagulation cascade. Concizumab 
prevents TFPI from binding to and blocking the active site of the coagulation factor Xa (FXa). This 
compensates for the limited FXa generation in the absence of a functional FIXa/FVIIIa complex in 
haemophilia. When the TFPI inhibitory activity is reduced, the FXa produced by the coagulation 
factor VIIa (FVIIa)/tissue factor (TF) complex will result in sufficient generation of thrombin to 
achieve haemostasis. More information about the physiological role of TFPI and the mode of action 
of concizumab is provided in the Investigator’s Brochure (IB). 
The key differentiator to current treatment options is thus a new mode of action (MoA), and the key 
benefit of concizumab in patients with HA, HB, HAwI and HBwI is a reduced treatment burden due 
to subcutaneous administration potentially leading to better adherence, more patients on 
prophylactic treatment and ultimately potentially better disease outcome. 
The concizumab clinical development programme in patients ≥12 years of age comprises four 
phase 1 trials, two phase 2 trials, two phase 3 trials and a non-interventional study. Details on the 
individual trials are provided in the IB. Phase 3 clinical trials were initiated in October 2019; trial 
NN7415-4307 (explorer 8) in patients with HA and HB and trial NN7415-4311 (explorer 7) in 
patients with HAwI and HBwI. In February and March 2020, 5 serious thromboembolic events 
were reported in 3 patients included in the phase 3 trials (2 patients in trial 4307 and 1 patient in 
trial 4311). As a result of the occurrence of these events, clinical development was paused and 
investigations to understand what may have contributed to the non-fatal thromboembolic events 
were conducted. The findings from the investigations have led Novo Nordisk to implement a 
number of changes to the trial protocols (as reflected by this protocol amendment (protocol version 
3.0)) to reduce the risk that additional patients treated with concizumab will experience 
thromboembolic events. The changes have been accepted by the external independent Data 
Monitoring Committee. 
3.3 
Benefit-risk assessment 
Concizumab is under development for the prevention of bleeding episodes, including long-term 
prophylaxis, in patients with haemophilia A and B, regardless of inhibitor status. Until recently, all 
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available haemophilia treatment options required frequent intravenous administration of pro-
coagulant compounds. However, a monoclonal antibody therapy emicizumab (Hemlibra®) has now 
been approved for subcutaneous prophylaxis in HA patients with and without inhibitors. Inhibition 
of TFPI is a potential new option for the treatment of patients with haemophilia. Concizumab is 
administered subcutaneously, thus potentially improving convenience compared to clotting factor 
prophylaxis. Concizumab does not itself involve the risk of inhibitor formation against FVIII or 
FIX. Therefore, concizumab could represent a major improvement over current treatment options. 
As observed for other pro-coagulant compounds, there is a potential risk of thrombosis due to 
exaggerated pharmacology. Thromboembolic events were observed in toxicity studies in 
non-human non-haemophiliac primates at high concizumab exposures. In pathological conditions, 
in which TF is expressed more extensively than considered physiological, e.g. advanced 
atherosclerosis, cancer, crush injury, or septicaemia, the risk of developing thrombosis and 
disseminated intravascular coagulation (DIC) may be increased by anti-TFPI treatment.6, 7 Vascular 
changes observed in the nonclinical toxicity studies were shown to be mediated by disposition of 
immune complexes (ICs). This is the result of an overwhelmed clearance of ICs, containing 
concizumab and antibodies against concizumab. Similar changes, if they occur in humans, could 
lead to organ damage and potentially become life-threatening. It is, however, generally recognised 
that animal studies are limited in their ability to predict human immune responses to a therapeutic 
protein. 
No significant thromboembolic events or signs of DIC were reported in the phase 1 or phase 2 
concizumab clinical trials with an exposure time of up to 102 weeks for the individual patient in the 
phase 2 trials. After initiation of the phase 3 clinical trials, 5 serious thromboembolic events (all 
non-fatal) were reported in 3 patients; the events were of different pathological aetiology, i.e. 
arterial and venous. All events occurred within 3 months of concizumab treatment initiation. All 
3 patients experiencing thromboembolic events had different types of thromboembolic risk factors 
and all 3 patients had used breakthrough bleed treatment just before the onset of symptoms for the 
thromboembolic event. In 2 of the cases, either a relatively high dose or prolonged treatment with 
factor product was reported. The concizumab exposure levels for these 2 patients were also among 
the highest levels observed across the phase 2 trials (4310 and 4255) and the phase 3 trials (4307 
and 4311), and it was also noted that overall, the concizumab exposure levels in phase 3 at the 
0.25 mg/kg dose-level were higher than expected. For the remaining patient, a possible/potential 
renal infarct prior to trial entry is being assessed (not confirmed). The findings from the 
investigations of the cases have led Novo Nordisk to make several changes to the trial protocols to 
reduce the risk that additional patients treated with concizumab will experience thromboembolic 
events.  
These changes include:  
• A new guidance for treatment of mild and moderate breakthrough bleeds, with specific guidance 
for use of the lowest dose of factor product or bypassing agent while on concizumab PPX (see 
Section 5.2.3). 
• That patients must contact the site when they have a suspected bleed (see Section 5.2.3). 
• A new concizumab dosing regimen including an initial daily dose of 0.20 mg/kg concizumab 
(instead of 0.25 mg/kg). Criteria for an increase or decrease in the daily maintenance dose to 
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0.25 mg/kg or 0.15 mg/kg, respectively (based on concizumab exposure levels at the week 4 
visit) are provided. The loading dose remains 1.0 mg/kg (see Section 5.2.1). 
• Elective major surgery is no longer allowed (see Section 9.9). 
• Trial stopping rule requiring urgent evaluation by the Novo Nordisk Safety Committee and 
consultation with the DMC in case of one (instead of two) significant thromboembolic event, 
DIC, TMA or death of trial patient which may be related to the trial product (see Section 9.3.9). 
Anaphylactic reactions towards therapeutic mAbs have been reported but are rare.8 Acute 
generalised hypersensitivity reactions are generally known to occur within the first few hours after 
the infusion or injection and may include headache, nausea, vomiting, dizziness, sweating, flushing, 
change in blood pressure and difficulties in breathing. In rare cases, the reaction may be 
life-threatening. No serious hypersensitivity reactions have been reported in the phase 1 and main 
part of phase 2 clinical trials with concizumab. A severe hypersensitivity reaction in a patient with 
HBwI has been reported in a phase 3 clinical trial with concizumab (prior to the treatment pause). 
TFPI is an inhibitor of tissue factor (TF) which is the most potent initiator of coagulation. In 
addition to its role in coagulation, TF is involved in a variety of coagulation-independent processes, 
including inflammation.6, 9 Therefore, in pathophysiological conditions with increased TF 
expression, e.g. infection, sepsis, inflammation, and crush injuries, there may be a potential risk of 
adverse reactions due to potentiation of inflammatory response. No AEs indicating an increased 
inflammatory response due to concizumab treatment has been reported. 
When the coagulation system is excessively activated, not only thrombosis, but also bleeding could 
potentially occur due to consumption of coagulation factors. This has not been observed in clinical 
trials with concizumab. 
With the implementation of mitigations to minimise the risk of thromboembolic events in the restart 
of the phase 3 trials, concizumab is considered to still have the potential for a favourable benefit-
risk profile within all haemophilia subtypes.  
More detailed information about the identified and potential benefits as well as the potential risks of 
concizumab can be found in the IB. 
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4 
Objectives and endpoints 
4.1 
Primary, secondary and exploratory objectives 
4.1.1 
Primary objective 
• To compare the effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with 
bypassing agents) in reducing the number of bleeding episodes in adult and adolescent patients 
with haemophilia A or B with inhibitors 
4.1.2 
Secondary objectives 
• To compare the patient-reported outcomes (PROs) after treatment with concizumab prophylaxis 
vs no prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors 
• To investigate the safety of concizumab prophylaxis in adult and adolescent patients with 
haemophilia A or B with inhibitors 
• To investigate the PK and PD parameters of concizumab prophylaxis in adult and adolescent 
patients with haemophilia A or B with inhibitors 
4.1.3 
Exploratory objectives 
• To explore treatment preference for concizumab prophylaxis versus no prophylaxis or previous 
prophylaxis treatment in adult and adolescent patients with haemophilia A or B with inhibitors 
4.2 
Estimands 
The five components of the estimand for the primary endpoint are as follows: 
• Endpoint:  
• On demand (arm 1): The number of treated spontaneous and traumatic bleeding episodes 
from randomisation (week 0) up until start of concizumab treatment (at least 24 weeks)  
• Concizumab (arm 2): The number of treated spontaneous and traumatic bleeding episodes 
from start of the new concizumab dosing regimen (week 0) up until the primary analysis 
cut-off (at least 32 weeks)  
• Treatment regimens: Either a) on demand treatment with intravenous replacement with factor-
containing products, or b) PPX treatment regimen with subcutaneous concizumab consisting of 
an initial loading dose of 1.0 mg/kg, followed by an initial daily dose of 0.20 mg/kg (during the 
dose adjustment period), followed by a maintenance dose of either 0.15, 0.20 or 0.25 mg/kg 
where breakthrough bleeds are treated with intravenous replacement with factor-containing 
products. 
• Population-level summary: The treatment ratio of the ABRs between the two treatment 
regimens. 
• Intercurrent events: 1) permanent treatment discontinuation, 2) temporary treatment 
discontinuation after restart of the trial, 3) use of factor-containing products not related to 
treatment of a bleed and 4) minor surgery. 
• Target patient population: HAwI and HBwI patients treated on demand prior to entering trial 
4311. 
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Utilizing these five components, the estimand for the primary objective can be described as the 
treatment ratio of the ABRs for treated spontaneous or traumatic bleeding episodes up until the 
primary analysis cut-off between the two treatment regimens in the target patient population while 
patients are adhering to the allocated treatment regimen. 
The strategies for how to account for the intercurrent events in the estimand are as follows: 
1. Permanent treatment discontinuation. For this intercurrent event, the data from the period 
after permanent discontinuation of trial treatment are not included. It is to be noted that for 
patients in the on demand arm, permanent treatment discontinuation will mean initiation of 
PPX. 
2. Temporary treatment discontinuation after restart of the trial. For this intercurrent event the 
‘treatment policy’ strategy is used meaning that the data from this period are included. 
3. Use of factor products not related to treatment of a bleed. For this intercurrent event, the 
data during this period are not included. 
4. Minor surgery. For this intercurrent event the ‘treatment policy’ strategy is used. The 
definition of minor surgery is outlined in Table 14. 
4.3 
Primary, secondary and exploratory endpoints 
4.3.1 
Primary endpoint 
Endpoint title 
Time frame  
Unit 
The number of treated 
spontaneous and traumatic 
bleeding episodes  
On demand (arm 1) 
• From randomisation (week 0) up until start 
of concizumab treatment (at least 
24 weeks)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the primary 
analysis cut-off (at least 32 weeks) 
Count 
4.3.2 
Secondary endpoints 
4.3.2.1 
Key secondary endpoints 
Endpoint title 
Time frame  
Unit 
Health economics 
Change in SF36v2 bodily 
pain  
From start of treatment (week 0a) until week 24  
Score 
Change in SF36v2 physical 
functioning  
From start of treatment (week 0a) until week 24  
Score 
aDefined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen 
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4.3.2.2 
Supportive secondary endpoints 
Endpoint title 
Time frame  
Unit 
Effect 
Number of treated 
spontaneous bleeding 
episodes 
On demand (arm 1) 
• From randomisation (week 0) up until start 
of concizumab treatment (at least 24 weeks)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the primary 
analysis cut-off (at least 32 weeks) 
Count 
Number of treated 
spontaneous and traumatic 
joint bleeds  
On demand (arm 1) 
• From randomisation (week 0) up until start 
of concizumab treatment (at least 24 weeks)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the primary 
analysis cut-off (at least 32 weeks) 
Count 
Number of treated 
spontaneous and traumatic 
target joint bleeds 
On demand (arm 1) 
• From randomisation (week 0) up until start 
of concizumab treatment (at least 24 weeks)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the primary 
analysis cut-off (at least 32 weeks) 
Count 
Safety 
Number of 
thromboembolic events 
On demand (arm 1 main part) 
• From randomisation to on demand treatment 
up until start of concizumab treatmentd 
Concizumab (arms 2-4) 
• Before the pausec: From start of concizumab 
treatment (week 0b) up until 7 weeks after 
the treatment was paused 
as well as 
• After the pausec: From start of concizumab 
treatment (week 0a) up until the primary 
analysis cut-off (at least 32 weeks) 
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Endpoint title 
Time frame  
Unit 
Concizumab (arm 1 extension part) 
• From start of the new concizumab dosing 
regimen (visit 9a) up until the primary 
analysis cut-off 
Number of 
thromboembolic events 
Concizumab 
• Before the pausec: From start of treatment 
(week 0b) up until 7 weeks after the 
treatment was paused  
as well as 
• After the pausec: From start of concizumab 
treatment up until the end of trial (week 
167) 
 
Number of hypersensitivity 
type reactions  
On demand (arm 1 main part) 
• From randomisation to on demand treatment 
up until start of concizumab treatmentd  
Concizumab (arms 2-4) 
• Before the pausec: From start of concizumab 
treatment (week 0b) up until 7 weeks after 
the treatment was paused 
as well as 
• After the pausec: From start of concizumab 
treatment (week 0a) up until the primary 
analysis cut-off (at least 32 weeks) 
Concizumab (arm 1 extension part) 
• From start of the new concizumab dosing 
regimen (visit 9a) up until the primary 
analysis cut-off 
Count 
Number of hypersensitivity 
type reactions  
Concizumab 
• Before the pausec: From start of treatment 
(week 0b) up until 7 weeks after the 
treatment was paused 
as well as 
• After the pausec: From start of concizumab 
treatment up until the end of trial 
(week 167) 
 
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Endpoint title 
Time frame  
Unit 
Number of injection site 
reactions 
On demand (arm 1 main part) 
• From randomisation to on demand treatment 
up until start of concizumab treatmentd  
Concizumab (arms 2-4) 
• Before the pausec: From start of concizumab 
treatment (week 0b) up until 7 weeks after 
the treatment was paused 
as well as 
• After the pausec: From start of concizumab 
treatment (week 0a) up until the primary 
analysis cut-off (at least 32 weeks) 
Concizumab (arm 1 extension part) 
• From start of the new concizumab dosing 
regimen (visit 9a) up until the primary 
analysis cut-off 
Count 
Number of injection site 
reactions 
Concizumab 
• Before the pausec: From start of treatment 
(week 0b) up until 7 weeks after the 
treatment was paused 
as well as 
• After the pausec: From start of concizumab 
treatment up until the end of trial (week 
167) 
 
Number of patients with 
antibodies to concizumab  
Concizumab (arms 2-4) 
• Before the pausec: From start of concizumab 
treatment (week 0b) up until 7 weeks after 
the treatment was paused 
as well as 
• After the pausec: From start of concizumab 
treatment (week 0a) up until the primary 
analysis cut-off (at least 32 weeks) 
Concizumab (arm 1 extension part) 
• From start of the new concizumab dosing 
regimen (visit 9a) up until the primary 
analysis cut-off 
Count 
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Endpoint title 
Time frame  
Unit 
Number of patients with 
antibodies to concizumab  
Concizumab 
• Before the pausec: From start of treatment 
(week 0b) up until 7 weeks after the 
treatment was paused   
as well as 
• After the pausec: From start of concizumab 
treatment up until the end of trial (week 
167) 
 
Pharmacokinetic and pharmacodynamic endpoints 
Pre-dose (trough) 
concizumab plasma 
concentration (Ctrough) 
Prior to the concizumab administration at week 24 
(after restart)  
ng/mL 
Pre-dose thrombin peak  
Prior to the concizumab administration at week 24 
(after restart)  
nmol/L 
Pre-dose free TFPI 
concentration 
Prior to the concizumab administration at week 24 
(after restart)  
ng/mL 
Maximum concizumab 
plasma concentration 
(Cmax)  
From 0 to 24 hours where 0 is time of the 
concizumab dose at week 24 (after restart) 
ng/mL 
Area under the concizumab 
plasma concentration-time 
curve (AUC)  
From 0 to 24 hours where 0 is time of the 
concizumab dose at week 24 (after restart) 
ng*hr/mL 
aDefined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen 
bDefined as time of randomisation to on-demand administration or time of start of the initial concizumab dosing 
regimen (0.25 mg/kg/day). 
cDefined as the pause in the concizumab clinical development programme during March to August 2020, while 
thromboembolic events were investigated 
 
4.3.3 
Exploratory endpoints 
Endpoint title 
Time frame 
Unit 
Patient reported outcomes 
Patient preference assessed by 
questionnaire  
Week 24  
% 
Change in patient’s treatment 
burden using the Hemo-TEM total 
score 
From baseline (week 0a) until week 24  
Score 
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Endpoint title 
Time frame 
Unit 
Change in PROMIS Short Form 
v2.0 -Upper Extremity 7a 
From baseline (week 0a) until week 24  
Score 
Change in PROMIS Numeric 
Rating Scale v.1.0 – Pain Intensity 
1a 
From baseline (week 0a) until week 24  
Score 
Change in Haem-A-QoL total score From baseline (week 0a) until week 24  
Score 
Change in Haem-A-QoL physical 
health domain score 
From baseline (week 0a) until week 24  
Score 
Physical activity measured by accelerometer 
Change in time spend in moderate 
to vigorous physical activity 
(MVPA) per day  
From baseline to end of the main part 
(week 24 for the on-demand arm and week 
32 for the concizumab arms)  
Minutes per 
day 
aDefined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. 
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5 
Trial design 
5.1 
Overall design 
This is a prospective, multicentre, open label clinical trial with four arms. The trial aims to evaluate 
the effect and safety of daily concizumab prophylaxis administered s.c. in patients with HAwI and 
HBwI. Initially, patients were randomised to concizumab PPX or no PPX or assigned into the non-
randomised treatment arms, based on their treatment regimen before entering the trial. After the 
restart of the trial, the patients will enter the treatment arm they were initially assigned to. New 
patients eligible for arms 1 and 2 will be randomised to concizumab PPX or no PPX. The main part 
of the trial is completed for a patient when the patient has completed at least 24 weeks of 
participation (screening period not included) for patients in arm 1 or 32 weeks of participation 
(screening period not included) for patients in arms 2,3 and 4. After the main part of the trial, all 
patients will be offered to continue in the extension part of the trial and receive treatment with 
concizumab for up to an additional 128 weeks (arms 2−4) or 136 weeks (arm 1); Figure 1. 
A primary analysis cut-off is defined as when all patients in arm 1 have completed visit 9/9a (or 
withdrawn) and all patients in arm 2 have completed visit 10a (or withdrawn). Furthermore, a 
56-week cut-off is defined as when all patients in arms 2, 3 and 4 have completed visit 13a (or 
permanently discontinued treatment). At this 56-week cut-off, an additional evaluation will be made 
assessing bleed related endpoints and safety.  
After the last patient has been randomised, any patient that due to the COVID-19 pandemic is 
prevented from restarting the new dosing regimen will no longer be used to determine the primary 
analysis cut-off and the 56-week cut-off.  
After up to 128/136 weeks in extension part the patient will enter the safety follow-up part of the 
trial. The patient will receive his last dose at home on the day prior to visit 26a. The follow-up part 
of the trial lasts for 7 weeks and the patient will continue to report bleeding episodes until visit 27a.  
In this version of the protocol, patients not already enrolled at the time of the re-start, will be 
defined as new patients recruited from the non-interventional study NN7415-4322 (explorer 6) and 
from outside the concizumab programme. New patients can belong to the following categories: 
• patients who were in screening phase at the time of the pause 
• patients entering from NN7415-4322 (explorer 6) 
• new patients coming from outside the concizumab programme. 
All of the above-mentioned new patients will start the trial at visit 1a (screening visit). 
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Note: aThe individual maintenance dose will be either 0.15, 0.20 or 0.25 mg/kg concizumab (see Section 9.2.2). 
Abbreviations: OnD = on demand; PPX = prophylaxis; V = visit 
Figure 1 
Trial design 
The randomisation between the treatment arms 1 and 2 is stratified according to haemophilia type 
and bleeding frequency during the 24 weeks prior to screening; see Section 7.2. Upon restart, 
patients will enter the treatment arm they were originally randomised or assigned to. New patients, 
including patients who were in screening at the time of the pause, will be randomised or allocated to 
treatment, as outlined below.  
Treatment arms 1 and 2: 
Approximately 51 patients (27 HAwI and 24 HBwI), previously treated on-demand, will be 
randomised 1:2 to no prophylaxis versus concizumab prophylaxis. Patients will be stratified by the 
haemophilia type and the bleeding frequency. 
Patients randomised to arm 1 before the pause were instructed to continue their on demand 
treatment and report data until trial restart. It is expected that all of these patients will have 
completed at least 24 weeks of on demand treatment when restarting the trials. Upon completion of 
the main part, the arm 1 patients will start the new concizumab dosing regimen (see Section 5.2.1) 
and receive up to 136 weeks of concizumab PPX in the extension part of the trial.  
Patients randomised to arm 2 before the pause have discontinued their concizumab treatment 
and received available standard of care during the pause. Upon restart, patients who do not fulfil 
any discontinuation criteria (see Section 8) will receive the new concizumab dosing regimen from 
visit 2a (described in Section 5.2.1). 
New patients eligible for arms 1 and 2 will be recruited to fulfill the protocol target numbers. New 
patients eligible for arms 1 and 2 will be randomised as outlined in Section 7.2. 
Treatment arm 3: 
The HAwI and HBwI patients enrolled into the concizumab phase 2 trial (NN7415-4310 
(explorer 4)) at time of transfer will be offered enrolment into arm 3 (approximately 25 patients). It 
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is required that these patients are on concizumab prophylaxis up until enrolment into the trial. These 
patients will continue concizumab PPX and have a combined visit 1 and 2. All patients from 4310 
were transferred to trial 4311 before the pause. Upon restart, patients will receive the new 
concizumab dosing regimen. 
Treatment arm 4: 
Arm 4 will include approximately 60 patients previously on prophylaxis with by-passing agents as 
well as any on-demand patients who are screened at a timepoint where the required number of 
patients in arms 1 and 2 have been randomised. These patients will, if eligible, be enrolled into the 
trial and will initiate concizumab prophylaxis at visit 2a. Patients restarting in arm 4 as well as new 
patients allocated to arm 4 will receive the new concizumab dosing regimen.  
Patients who were enrolled before the pause 
Patients who were randomised or allocated to treatment in this trial before the pause, should re-enter 
the trial as outlined in Table 1 
Table 1 
Visit overview for patients restarting this trial 
Allocation before the pause 
Allocation at restart 
Arm 1 
Arm 1 - visit 9a 
Arm 2 
Arm 2 - visit 2a 
Arm 3 
Arm 3 - visit 2a 
Arm 4 
Arm 4 - visit 2a 
Note: Visit 9a is the first visit in the extension part for arm 1. At visit 9a, the patients in arm 1 will start concizumab 
PPX.  
Table 2 below summarises the expected numbers of randomised/enrolled patients in each arm. In 
total 136 patients are expected to be enrolled; this includes patients enrolled before as well as after 
the pause. The aim is to have approximately 15 unique HAwI and HBwI adolescent patients defined 
as patients between ≥12 to <18 years at trial start. 
Table 2 
Randomisation/enrolment overview 
 
Number of patients randomised/enrolled  
Arm 1 
Arm 2 
Arm 3 
Arm 4 
(PPX or on-demand) 
HAwI 
9 
18 
Up to 15 
 
60 
HBwI 
8 
16 
Up to 10 
 
5.2 
Treatment of patients 
5.2.1 
Concizumab prophylaxis 
When patients are randomised/allocated to concizumab prophylaxis they will receive a loading dose 
of 1.0 mg/kg concizumab at visit 2a (arm 2, 3 and 4) or visit 9a (arm 1) followed by an initial daily 
dose of 0.20 mg/kg concizumab from treatment day 2.Within an initial 5−8-week dose adjustment 
period on 0.20 mg/kg concizumab, the patients can be increased or decreased in dose to 0.25 mg/kg 
or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 4a.1 or 9a.3 and will 
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be based on the concizumab exposure level measured at the previous visit 4a or 9a.2. Patients who 
have concizumab exposure levels of 200−4000 ng/mL will stay at 0.20 mg/kg concizumab. The 
new concizumab dosing regimen is shown schematically in Figure 2 and explained in further detail 
in Section 9.2.2.  
 
Abbreviation: LD = loading dose 
Notes: Concizumab exposure level is measured at V4a/9a.2; Potential dose adjustment will take place at V4a.1/9a.3. 
Figure 2 
Concizumab dosing regimen upon re-initiation of trial 
Doses, including the loading dose, given at PK/PD visits (i.e. visit 2a and 9a) will be administered 
at the site; all other injections may be administered at home by the patient or caregiver. 
Prior to visit 2a, patients must be in a non-bleeding state 48 hour prior to the visit however patients 
are allowed to have treatment for up to 24 hours prior to visit 2a, except for treatment with aPCC 
and ByClot® where the wash-out is 48 hours prior to visit 2a.  
For patients coming from a PPX treatment regimen, a wash-out of aPCC and ByClot® for 48 hours 
is required. For other factor-containing products, a wash-out of 2 half-lives of the given product is 
required. 
A pre-filled, multi-dose pen-injector for the drug administration will be provided by Novo Nordisk, 
details can be found in Section 7.1.1. 
Use of factor-containing products not associated to a bleed is not allowed, except for diagnostic 
procedures, intramuscular injections (e.g. vaccinations) and minor surgery, e.g. dental treatment, 
endoscopies etc. 
5.2.2 
On-demand treatment 
Patients in arm 1 will continue on-demand treatment with their usual bypassing product until visit 9 
(end of main part for arm 1). Patients included prior to the treatment pause will re-start the trial at 
visit 9a; see Section 5.1. Novo Nordisk will not provide or reimburse on-demand treatment for 
patients in arm 1. In the extension part, patients in arm 1 will receive daily concizumab 
subcutaneous injections (see Section 5.2.1). 
5.2.3 
Treatment of break-through bleeding episodes 
The patient must contact the site when they have a suspected bleed, see Section 9.2.3 for further 
details. 
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Novo Nordisk will not provide or reimburse bypassing treatment for bleeding episodes. Any bleeds 
occurring in the trial can be treated with the patient’s usual factor-containing product taking the 
treatment guidance in Appendix 11 into consideration. Table 3 provides a tabular overview of the 
guidance on management of mild and moderate bleeds. 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. 
For treatment of bleeds with aPCC (FEIBA®), the dose must not exceed a single dose of 50 U/kg, 
and not exceed 100 U/kg within 24 hours. The first treatment should be at the hospital, with 
observation if the patient for a minimum of 24 hours. If there are no safety concerns, the patient can 
continue with FEIBA® treatment for breakthrough bleeds at home. Single dose home treatment 
must not exceed 50 U/kg. If an additional dose is needed because a single dose was insufficient to 
treat the bleed, the patient must come to the site.  
For treatment of bleeds with ByClot®, the dose must not exceed 60 µg/kg, and not exceed 90 µg/kg 
within 24 hours. Additional dose can be given at an interval of 8 hours or longer. The first treatment 
should be at the hospital, with observation of the patient for a minimum of 24 hours. If there are no 
safety concerns, the patient can continue with ByClot® treatment for breakthrough bleeds at home. 
Single dose home treatment must not exceed 60 µg/kg. If an additional dose is needed because a 
single dose was insufficient to treat the bleed, the patient must come to the site. 
Table 3 
Guidance on management of mild and moderate bleeds during concizumab PPX 
 
rFVIIa 
aPCC 
ByClot® 
Contact 
centre (PI)  
The patient must contact the centre before initiating treatment of a bleeding episode. If more doses 
are needed, the patient should contact the centre before each dose. 
First dosea  
90 µg/kg 
Single dose must not exceed 
50 U/kg, and not exceed 
100 U/kg within 24 hours 
Single dose must not exceed 
60 µg/kg ByClot®, and not exceed 
90 µg/kg ByClot® within 24 hours 
Second dose  
90 µg/kg 
At investigator’s discretion 
Additional dose can be given at an 
interval of 8 hours or longer 
Dose interval 
Time between first and second dose must not be shorter than stated in local labellingb 
Anti-
fibrinolytics  
Local/topical use is allowed. 
Use of single systemic doses 
is allowed after careful 
benefit-risk evaluation 
Not recommended 
Not recommended 
Notes: aLowest dose in accordance with local labelling. bThe interval between the two doses could be increased based 
on clinical case-by-case judgment keeping in mind that early breakthrough bleed control remains crucial. 
Severe and life-threatening bleeding episodes 
From a patient safety perspective, specific recommendations for the management of severe and 
life-threatening bleeding episodes (see definition in Table 10) are not considered feasible as such 
management often poses several complex clinical challenges that need to be addressed case by case 
by the treating physicians hereby tailoring and securing the optimal treatment, which in some cases 
may be high factor replacement doses for extended periods of time. In the rare event of a severe 
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(life-threatening) bleed the patient should be in immediate and close contact to the investigator and 
be treated with relevant doses of factor containing products at the discretion of the investigator. 
Please see Section 9.2.3 and Appendix 11 for further instructions on bleeding episodes. 
5.2.4 
Treatment during screening and follow-up period 
Patients should follow their normal prophylaxis schedule or on-demand regimen during the 
screening period and follow-up period. Treatments will not be reimbursed by Novo Nordisk. Bleeds 
during screening and follow-up should be treated as per standard local practice. 
5.3 
Patient and trial completion 
Approximately 155 patients will be screened to achieve that at least 51 patients are randomly 
assigned to either no prophylaxis or trial product in the treatment arms 1 and 2. To achieve that up 
to 85 patients are assigned to prophylaxis with concizumab in treatment arms 3 and 4; please see 
Table 2. For definition of screen failures; see Section 6.3. 
Trial period completion for a patient: 
Trial period completion for a patient is defined as when the patient has completed visit 27a, or at the 
global end of trial date 20 June 2024 whichever comes first. 
Treatment period completion for a patient: 
Treatment period completion for a patient is defined as when the patient has completed visit 26a. 
5.4 
End of trial definition 
The end of trial is defined as the date of the last visit of the last patient in the trial or 20 June 2024 
whichever comes first. 
5.5 
Scientific rationale for trial design 
The trial design follows to the extent possible requirements and makes use of applicable elements 
outlined in the EMA guidelines on the clinical investigation of recombinant and human plasma-
derived factor VIII/IX products in terms of; endpoints, patient population, sample size, eligibility 
criteria, exposure time, PK and immunogenicity assessment etc. 
The primary objective of the trial is to compare concizumab prophylaxis (arm 2) compared to no 
prophylaxis (arm 1, on-demand treatment) in preventing bleeding episodes in HAwI and HBwI 
patients. Superiority to on-demand has been chosen as regulatory authorities have traditionally 
required a comparison of prophylaxis versus no prophylaxis for registration of haemophilia 
products for prophylaxis. The superiority analysis aims to demonstrate the effect of concizumab for 
HAwI and HBwI patients combined. The PD/PK effect of concizumab is expected to be comparable 
across haemophilia types. A separate superiority analysis for HBwI alone is not considered feasible, 
given the rarity of the disease. The combined analysis is also justified given the similarity of the 
diseases, the concizumab mode of action, and the comparability of the data from HAwI and HBwI 
in phase 2. 
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Patients to be included in the on-demand arm of the trial will be coming from on-demand treatment 
regimens at their clinics reflecting local standards of care. After completion of the main part of the 
trial, all patients will be offered concizumab prophylaxis in the extension part for up to an 
additional 136 weeks. 
Due to the treatment pause (described in Section 3.2), and subsequent restart of the trial, the original 
randomisation cannot be maintained after the treatment pause. The impact of potential resulting bias 
will be assessed with sensitivity analyses. 
5.6 
Justification for dose 
Upon restart, the dosing regimen for this phase 3 trial is a loading dose of 1.0 mg/kg concizumab 
s.c. on the first day of treatment, followed by an initial daily dose of 0.20 mg/kg concizumab. 
Within the initial 5−8-week dose adjustment period on 0.20 mg/kg concizumab, the patients can be 
increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab (or they can stay on 
0.20 mg/kg); this will be based on the concizumab exposure level at visit 4a/9a.2 (see 
Section 9.2.2). 
The reduction in the initial daily dose as compared to the previous maintenance dose of 0.25 mg/kg, 
is based on the finding that 2 of the 3 patients experiencing thromboembolic events were among the 
patients with the highest concizumab exposure level observed. Furthermore, the concizumab 
exposure levels observed in phase 3 on the original dosing regimen (0.25 mg/kg/day) were higher 
than expected based on the phase 2 results as well as population PK modelling. The safety of the 
initial daily dose of 0.20 mg/kg is supported by results from the phase 2 trials, since the exposure 
range observed in phase 2 covers the exposure range predicted when restarting all patients on daily 
dosing with 0.20 mg/kg concizumab. The exposure ratio between the initial daily dose of 
0.20 mg/kg and the exposure level at the no adverse effect level (NOAEL) in the nonclinical studies 
is given in the Investigator’s Brochure.  
Some patients will need to increase or decrease the daily dose to 0.25 or 0.15 mg/kg; this will be 
based on the exposure level after 4 weeks of concizumab PPX (see Section 9.2.2). The target of 
concizumab exposure levels above 200 ng/mL emanates from an exploratory exposure-response 
analysis performed based on the phase 2 trials (NN7415-4255 (explorer 5) and NN7415-4310 
(explorer 4) main part data, indicating a lower ABR with exposure levels above 200 ng/mL. The 
upper limit of 4000 ng/mL is a precaution to avoid patients reaching very high exposure levels. 
Despite the lack of data showing that high exposure per se is causative of thromboembolic events, 
the evaluations of the thromboembolic events suggests that the concizumab exposure in 
combination with other risk factors could contribute to thrombosis.  
5.7 
Rationale for Trial Population 
The trial population is defined in Section 6. The eligibility criteria have been defined to allow 
inclusion of patients from the non-interventional study NN7415-4322 (explorer 6) and trial 
NN7415-4310 (explorer 4), and of patients who were screen-failed at Sponsor’s decision due to the 
treatment pause as well as new patients. Additionally, the eligibility criteria were defined to ensure 
that the resulting population will be homogeneous in terms of unmet medical needs. 
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Patients with HAwI and HBwI who are treated with bypassing agents comprise the population for 
this Phase 3 study. Although the initial severity of a patient’s haemophilia may be directly related to 
his endogenous FVIII or FIX activity, the treatment of patients of any severity (mild, moderate, or 
severe) with clinically relevant inhibitors is similar (i.e., with bypassing agents). In such cases the 
initial severity of haemophilia is no longer prognostic for the risk of bleeding, therefore this will not 
be used to determine eligibility. Instead, the eligibility is defined based on the need for bypassing 
treatment. In addition, patients previously treated on demand are required to have a minimum 
bleeding frequency 12 bleeds/year prior to study entry to be eligible for enrolment in the 
randomized arms. This is to select a group of patients who have a high, unmet medical need and to 
enable detection of a clinically and statistically significant difference in bleeding rates in this subset 
of the population, compared to concizumab prophylaxis. 
The exclusion criteria are defined to ensure safety of the patients. Due to the pro-coagulant nature 
of the drug, patients at increased risk of thromboembolic events according to the Investigator’s 
discretion are excluded from the trials. Patients receiving ITI are not eligible because ITI typically 
requires administration of long term frequent, high doses of FVIII, and safety of concomitant use of 
concizumab under these conditions has not been established. 
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6 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
6.1 
Inclusion criteria 
Patients are eligible to be included in the trial only if all of the following criteria apply: 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial. 
2. Male aged ≥12 years at the time of signing informed consent. 
3. Body weight >25 kg at screening. 
4. Congenital Haemophilia A or B of any severity with documented history of inhibitor 
(≥0.6 BU). 
5. Patient has been prescribed, or in need of, treatment with bypassing agents in the last 
24 weeks prior to screening (for patients not previously enrolled in NN7415-4310). 
6.2 
Exclusion criteria  
Patients are excluded from the trial if any of the following criteria apply: 
1. Known or suspected hypersensitivity to any constituent of the trial product or related 
products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 
However, this is not applicable for patients who were screen failed at Sponsor’s decision 
due to the treatment pausea. 
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 5 half-lives or 30 days from screening, whichever is longer (not applicable 
for patients from NN7415-4310). 
4. Platelets ≤ 100x109/L at screening. 
5. Fibrinogen below laboratory lower normal limit at screening. 
6. Hepatic dysfunction defined as AST and/or ALT > 3 times the upper limit combined with 
total bilirubin > 1,5 times the upper limit at screening. 
7. Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) ≤ 30 ml/min/1.73 
m2 for serum creatinine measured at screening. 
8. Known inherited or acquired coagulation disorder other than congenital haemophilia. 
9. History of thromboembolic diseaseb. Current clinical signs of or treatment for 
thromboembolic disease. Patients who in the judgement of the investigator are considered at 
high risk of thromboembolic eventsc. 
10. A known systemic inflammatory condition requiring systemic treatment at screening. 
11. Treatment with emicizumab within 180 days before screening. 
12. Ongoing or planned Immune Tolerance Induction treatment. 
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13. Any disorder, except for conditions associated with haemophilia, which in the investigator’s 
opinion might jeopardise patient’s safety or compliance with the protocol. 
aFor patients in Poland, refer to country-specific exceptions in Appendix 10 bIncludes arterial and venous thrombosis 
including myocardial infarction, pulmonary embolism, cerebral infarction/thrombosis, deep vein thrombosis, other 
clinically significant thromboembolic events and peripheral artery occlusion. cThromboembolic risk factors could 
include, but are not limited to, hypercholesterolemia, diabetes mellitus, hypertension, obesity, smoking, family history 
of thromboembolic events, arteriosclerosis, other conditions associated with increased risk of thromboembolic events. 
6.3 
Screen failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
eligible for participation according to in/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet 
requirements from regulatory authorities. Minimal information to be collected during the screening 
period includes demography, screen failure details, eligibility criteria, and any SAEs. A screen 
failure session must be made in the IWRS. 
Individuals who do not meet the criteria for participation in this trial may not be re-screened unless 
the patient was screen failed at Sponsor’s decision due to the treatment pause (for country-specific 
exceptions, please refer to Appendix 10). Re-sampling is not allowed if the patient has failed one of 
the inclusion criteria or fulfilled one of the exclusion criteria related to laboratory parameters. 
However, in case of technical issues (e.g. haemolysed or lost), re-sampling is allowed for the 
affected parameters. 
6.4 
Randomisation criteria  
To be randomised into arm 1 or arm 2 in this trial, one of following randomisation criteria must be 
answered "yes". 
Randomisation criteria: 
1. On-demand patient transferred from NN7415-4322 (explorer 6) 
or 
2. On-demand patient who has ≥6 documented treated bleeds in the last 24 weeks or ≥12 
treated bleeds during 52 weeks before screening. 
 
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7 
Treatments 
7.1 
Treatments administered 
Trial product must only be used, if it appears almost clear and colourless to slightly yellow. 
Table 4 
Trial products provided by Novo Nordisk A/S 
Trial product name: 
 
Concizumab C 40 mg/ml 
(IMP, test product) 
Concizumab C 100 mg/ml 
(IMP, test product) 
Dosage form: 
 
Solution for injection 
Solution for injection 
Route of administration: 
Subcutaneous 
Subcutaneous 
Initial (loading) dose - dose at day one: 
1.0 mg/kg 
1.0 mg/kg 
Dosing instructions daily dose from day 
2 and onwards: 
Initially 0.20 mg/kg followed by 
0.15, 0.20 or 0.25 mg/kg  
Initially 0.20 mg/kg followed by 
0.15, 0.20 or 0.25 mg/kg  
Packaging 
 
Prefilled Pen-injector (PDS290 
pen-injector) 
Prefilled Pen-injector (PDS290 
pen-injector) 
The investigator must document that directions for use is given to the patient orally and in writing at 
the first dispensing visit. The investigator, or a person designated by the investigator/institution, will 
train the patient in the correct use of the investigational product. See Section 7.1.1 for further 
details.  
Other haemostatic medication including treatment used for breakthrough bleeds and prophylactic 
treatment for the screening and follow-up period will not be supplied or reimbursed by Novo 
Nordisk. 
Needles for the pen injector will be delivered as auxiliary. Only needles provided by Novo Nordisk 
must be used for administration of trial product. 
7.1.1 
Medical devices 
Only the Prefilled pen-injector, Concizumab PDS290 pen-injector, is to be used for administration 
of the trial product, concizumab, in this trial. 
Table 5 
Pen-injector and strengths 
Investigational Medicinal Product 
Route of administration 
Strength 
Cartridge volume 
Dosage increment 
Concizumab (in prefilled Pen-
injector PDS290 pen) 
For subcutaneous use 
40mg/ml 
1.5 ml 
0.3 mg 
Concizumab (in prefilled Pen-
injector PDS290 pen) 
For subcutaneous use 
100mg/ml 
1.5 ml 
0.75 mg 
 
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Training in the Concizumab PDS290 pen-injector 
The patients must be trained according to the Directions for Use (DFU) in how to handle the 
concizumab PDS290 pen-injector. Patient training must be documented in the patients’ medical 
records. Training must be repeated, based on patients’ needs as judged by the investigator, during 
the trial at regular intervals to ensure correct use of the PDS290 pen-injector. The following should 
be emphasised: 
• Trial product must be administered subcutaneously either in the abdomen or in the thigh. 
• Always use a new needle for each injection as this will prevent contamination and ensure 
correct dosing. 
• The needle should be kept in the skin while counting slowly to 10 after the dose counter has 
returned to zero. If the needle is removed too early, then the full dose may not have been 
delivered. 
• Remember the scale drum does not reflect the dose in mg. Refer to the conversion table in the 
Trials Materials Manual for the correct dose. Incorrect dose setting may lead to under-
/overdosing. 
• Remind the patient to consult the DFU or contact the site if in doubt on how to use the 
pen-injector. 
 
7.1.2 
Investigational medical device (in vitro diagnostic device) 
The concizumab-ELISA is an enzyme-linked immunosorbent assay (ELISA) intended to quantitate 
the concentration of concizumab in human citrated plasma from patients included in the 
concizumab clinical trials. The concizumab-ELISA has been used throughout the clinical 
development programme for measuring concizumab exposure (PK). The concentration of 
concizumab in human citrated plasma measured by this assay will also be used as the point of 
reference for dose adjustments in the phase 3 clinical trials for concizumab. Samples collected 
specifically for dose adjustment will be analysed using the concizumab-ELISA in vitro diagnostic 
(IVD) device. All other samples will be analysed using the concizumab-ELISA. FDA has approved 
an investigational device exemption for concizumab-ELISA measurements to be used for dose 
adjustment. Risk management documentation for the concizumab-ELISA IVD is available in the 
IB.  
7.2 
Method of treatment assignment 
All screened patients will receive a unique subject number at the screening visit, which will be 
assigned to the patient throughout the trial. Patients who were screen-failed at Sponsor’s decision 
due to the treatment pause and who are re-screened at trial restart will receive a new unique subject 
number. 
Patients meeting the randomisation criteria will be centrally randomised using an IWRS and 
assigned to the next available treatment according to randomisation schedule. Trial product will be 
dispensed/allocated at the trial visits summarised in the flowchart in Section 2. 
Stratification of the randomised on-demand patients into treatment arms 1 and 2 will be performed 
in the IWRS.  
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The stratification variables are: 
• haemophilia type (HAwI, HBwI) 
• bleeding frequency during the 24 weeks prior to screening (<9 bleeding episodes, ≥9 bleeding 
episodes) 
7.3 
Blinding 
This is an open-label trial where the trial product is packed open-label; however, the specific 
treatment for a patient will be assigned using IWRS. The site will access the IWRS before the start 
of trial product administration for each patient. 
7.4 
Preparation/Handling/Storage/Accountability 
Only patients enrolled in the trial may receive trial product and only authorised site staff may 
supply or administer trial product.  
Instructions on home treatment of patients and handling of auxiliaries are described in the latest 
version of the DFU. Authorised site staff having the responsibility for patient training and 
administering trial product at site will be requested to follow the similar instructions in the latest 
version of the Trial Materials Manual. 
Long term storage and in use storage  
Table 6 
Trial product storage conditions 
Trial product name 
Storage conditions 
(not-in-use) 
In-use conditions 
In-use timea 
Concizumab 40 mg/ml 
Do not freeze 
Store in refrigerator (2 °C – 8 °C) 
Protect from light 
Do not refrigerate 
Store at 8 °C - 30 °C 
Protect from light 
Use within 28 days 
 
28 days 
Concizumab 100 mg/ml 
aIn-use time for concizumab starts when first dose is administered from the pen-injector. 
Any changes to trial product storage conditions will be communicated to all sites in the latest 
version of the Trial Materials Manual. 
Drug accountability of all trial products received is the responsibility of the investigator. The patient 
will be asked to return all used, partly used and unused trial products as specified in the flowchart 
Section 2.  
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 the status of 
screening and randomisation. 
• The investigator must confirm that appropriate temperature conditions have been maintained 
during transit for all trial products received and any discrepancies are reported and resolved 
before use of the trial products. 
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• All trial products must be stored in a secure, controlled, and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
• The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. Additional details regarding handling of temperature deviations 
can be found in the Trial Materials Manual.  
• 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 is responsible for drug accountability and record maintenance (i.e. receipt, 
accountability and final disposition records). 
• All concizumab containing pen-injectors must be accounted for as used, partly used or unused. 
• Destruction of concizumab can be performed on an ongoing basis and will be done according to 
local procedures after accountability is finalised by the site and reconciled by the monitor.  
• Destruction of trial products must be documented in the IWRS.  
• All returned, expired or damaged trial products (for technical complaint samples see Appendix 
7) must be stored separately from non-allocated trial products. No temperature monitoring is 
required. 
• Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the trial site.  
For country-specific requirements; please refer to Appendix 10. 
7.5 
Treatment 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. Training of the patient should be documented accordingly. 
When patients are dosed at the site, they will receive trial product directly from the investigator or 
designee, under medical supervision. The date and time of each dose administered at the site will be 
recorded in the patient medical records.  
When patients self-administer trial product(s) at home, compliance with trial product administration 
will be assessed and the assessment documented in patient medical records at each dispensing visit 
where information is available. If any suspicion of non-compliance arises, apart from occasionally 
missed doses, the site must enter into a dialogue with the patient, re-emphasizing the importance of 
compliance and uncover barriers to compliance. This dialogue must be documented.  
Compliance will be assessed by cross checking the following sources and comparing these to the 
expected use:  
• Drug accountability information; counting returned trial product 
• Review of prophylaxis treatment diaries 
• Patient’s body weight measured at last site visit  
• Investigators input to concizumab daily dose at last visit 
• Questioning of subjects 
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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 are 
collected. If missing data do occur, the reason will be collected via the protocol deviation process, 
see Appendix 4. 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). 
7.6 
Concomitant medication 
Any medication other than the trial product concizumab that the patient is receiving at the time of 
the first visit or receives during the trial must be recorded along with: 
• Trade name or generic name 
• Indication  
• Dates of administration including start and stop dates or continuation. 
Changes in concomitant medication must be recorded at each visit. If a change is due to an 
AE/SAE, then this must be reported according to Section 9.3.  
Concomitant haemostatic medication must be collected regardless of the duration and relation to a 
bleed. The haemostatic medication will primarily be collected in the eDiary and StudyWorks, 
please see Section 9.2.3 for details. 
7.6.1 
Prohibited medication 
• Heparin, except for sealing of central venous access ports according to local practice 
• Vitamin-K antagonists 
• Direct oral anti-coagulants (DOACs) 
• Emicizumab 
• Anti-fibrinolytics, except for local/topical use. Use of single systemic doses is allowed after 
careful benefit-risk evaluation. 
7.7 
Treatment after the end of the trial 
When discontinuing trial products, either at the scheduled end of treatment visit or if trial product is 
discontinued, the patient should be transferred to a suitable marketed product at the discretion of the 
investigator. 
 
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8 
Discontinuation/Withdrawal criteria  
8.1 
Discontinuation of trial treatment 
The patient may be discontinued from trial product at any time during the trial at the discretion of 
the investigator for safety, behavioural, compliance or administrative reasons. 
Efforts must be made so that patients, who discontinue trial product, attend and complete all 
scheduled visit procedures according to the flowchart in Section 2. Patients should stay in the trial 
irrespective of lack of adherence to the treatment, lack of adherence to visit schedule or missing 
assessments. Only patients who withdraw consent will be considered as withdrawn from the trial. 
Patients must be educated about the continued scientific importance of their data, even if they 
discontinue trial product.  
The patient must be discontinued from trial product, if the following applies: 
1. Included in the trial in violation of the inclusion and/or exclusion criteria 
2. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product 
3. Incapacity or unwillingness to follow the trial procedures 
4. Significant thromboembolic eventa 
5. Event of Disseminated Intravascular Coagulation (DIC) 
6. Event of Thrombotic Microangiopathy (TMA) 
7. Event of severe or serious hypersensitivity reaction related to concizumab 
aThe definition of a significant thromboembolic events is provided in Appendix 5. For venous thromboembolic events 
where treatment of concizumab has been discontinued, re-initiation of concizumab can be considered by the 
investigator in the extension part of the trial, after the patient has fully recovered. The investigator must contact and 
agree with Novo Nordisk before reinitiating concizumab treatment.  
See the flowchart in Section 2 for data to be collected at the time of treatment discontinuation and 
follow-up and for further evaluations that need to be completed. 
The primary reason for 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. 
8.1.1 
Temporary discontinuation of concizumab in relation to COVID-19 
Regular testing for COVID-19 will not be part of the protocol, but will be done at the investigator’s 
discretion only. Testing should be performed according to the locally recommended testing 
methodology. 
In case a patient is tested positive for ongoing COVID-19 infection prior to the first concizumab 
dose, then visit 2a/9a (allocation/randomisation visit) should be postponed until a negative 
COVID-19 result exists or the patient has fully recovered from the COVID-19 infection as judged 
by the investigator. During the trial, in the case a patient is tested positive for ongoing COVID-19, 
concizumab should be paused immediately and not restarted until the patient tests negative again or 
has fully recovered from COVID-19 as judged by the investigator. In the interim period, patients 
should be treated as per judgement of the investigator. 
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If access to COVID-19 testing is limited, then the pause and postponement should be based on a 
strong suspicion, as judged by the investigator. 
A positive COVID-19 test, or suspicion of COVID-19, is considered an AE and should be reported 
as such following the procedures in Section 9.3 and Appendix 5. 
In case of a suspected thromboembolic event, it is encouraged to perform a COVID-19 test. If a 
thromboembolic event is diagnosed, COVID-19 testing must be performed. Additionally, analysis 
for COVID-19 antibodies may be performed; see Section 9.4.6. 
8.1.2 
Sponsor-initiated discontinuation of trial product in relation to the treatment pause 
All patients enrolled in the trial at the time of the treatment pause were temporarily discontinued 
from treatment with concizumab.  
The following must be documented in the eCRF in relation to the treatment pause:  
• For all patients:  
• The stop date of concizumab treatment after announcement of the treatment pause 
• For patients who reinitiate treatment with concizumab after the treatment pause: 
• The date of signing the addendum to the informed consent form (see Appendix 4) 
• The start date of the initiation of the new concizumab dosing regimen. 
Patients enrolled in the trial before the treatment pause and who will not reinitiate treatment with 
concizumab will consequently have permanently discontinued from treatment and must follow the 
flowchart in Section 2.  
If a patient decides to withdraw consent prior to trial restart, the investigator should ask the patient 
if he, as soon as possible, is willing to have assessments performed according to visit 9. If the 
patient withdraws consent after visit 9, then he should have assessments performed according to 
visit 26 (last treatment visit in the extension part of the trial). See the flowchart in Section 2 for data 
to be collected. For further instructions concerning withdrawals; see Section 8.2.  
8.2 
Withdrawal from the trial 
A patient may withdraw consent at any time at his own request, or at the request of the patient's 
parent or the patient's legally acceptable representative (LAR). 
If a patient withdraws consent prior to visit 9a/10a (last treatment visit in the main part of the trial), 
the investigator should ask the patient if he is willing, as soon as possible, to have assessment 
performed according to visit 9a/10a. If the patient withdraws consent after visit 9a/10a, he should 
have assessment performed according to visit 26a (last treatment visit in the extension part of the 
trial). See the flowchart in Section 2 for data to be collected. 
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. 
If a patient withdraws from the trial, he may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical records. 
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If the patient withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
Although a patient is not obliged to give his reason(s) for withdrawing, 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 withdrawal must be specified in the end of trial form in 
the eCRF. 
8.2.1 
Replacement of patients 
Patients who discontinue trial product or withdraw from the trial will not be replaced. 
8.3 
Lost to follow-up 
A patient will be considered lost to follow-up if he repeatedly fails to return for scheduled visits and 
is unable to be contacted by the trial site. 
The following actions must be taken if a patient fails to return to the trial site for a required visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as possible 
and counsel the patient on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the patient wishes to and/or should continue in the trial. 
• Before a patient is deemed lost to follow-up, the investigator must make every effort to regain 
contact with the patient (where possible, at least three telephone calls and, if necessary, a 
certified letter to the patient's last known mailing address or local equivalent methods). These 
contact attempts should be documented in the patient's source document. 
• Should the patient continue to be unreachable, he will be considered to have withdrawn from the 
trial with a primary reason of lost to follow-up. 
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9 
Trial assessments and procedures 
Figure 3 provides a visit schedule overview. Trial procedures and their timing are summarised in 
details in the flowchart in Section 2. 
 
Note: aFor patients who had a 24-hour PK/PD profile measured at visit 2 prior to the treatment pause, only pre-dose 
(i.e. prior to loading dose) and 24-hour post-dose samples should be taken at visit 2a 
Figure 3 
Overview of trial visits 
Informed consent must be obtained before any trial related activity, see Appendix 4. This applies 
for patients restarting the trial as well as for patients in arm 1 who start concizumab treatment. 
All screening evaluations must be completed and reviewed to confirm that potential patients meet 
all eligibility criteria. 
The investigator will maintain a screening log to record details of all patients screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
At screening, patients will be provided with an ID card stating that they are participating in a trial 
and giving contact details of relevant trial site staff.  
Adherence to the trial design requirements, including those specified in the flowchart, is essential 
and required for trial conduct. 
Review of completeness of the diaries, laboratory reports etc. must be documented either on the 
documents or in the patient's source documents. If clarification of entries or discrepancies in the 
diary or PRO instruments is needed, the patient must be questioned, and a conclusion made in the 
patient's source documents. Care must be taken not to bias the patient. Any necessary changes to the 
eDiary data should be requested to the vendor and documented accordingly. See Section 9.2.6 for 
further instructions on review of PRO questionnaires.  
The maximum amount of blood collected from each patient upon trial restart (after the treatment 
pause, including the screening, main, extension and follow-up parts) will be approximately 850 mL 
depending on which treatment arm the patient is allocated to. In addition, for patients enrolled in the 
trial prior to the treatment pause, the total amount of blood collected will depend on the number of 
site visits the patient attended with an average of 28 mL of blood collected per site visit.   
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Blood sampling in adolescent patients aged 12-17 years must be performed according to local 
guidelines. The blood volume taken in patients below 18 years should not exceed 3 % of the total 
volume during a 4-week period and should not exceed 1 % at any single time point.10 See Appendix 
3 for further details concerning blood sampling in adolescent patients. 
Shared assessments and data transfer from NN7415-4310 (explorer 4) and NN7415-4322 
(explorer 6) 
For patients enrolled into this trial from NN7415-4310 (explorer 4) and NN7415-4322 (explorer 6) 
assessments related to the patient´s end of trial and screening visit, respectively, will be baseline 
assessments for this trial when feasible. The data will automatically be transferred to the database 
for this trial.  
For patients transferring from NN7415-4310 (explorer 4), the following assessments are in scope: 
• Laboratory data (End of Trial). See the laboratory manual for details on laboratory sampling for 
patients who are transferred.  
• Details of Haemophilia (screening) 
• Haemophilia Treatment and Bleed History (screening) 
• ECG (screening) 
• PROs (collected at visit 15.1) 
For patients transferring from NN7415-4322 (explorer 6), the following assessments are in scope: 
• Details of Haemophilia (screening) 
• Physical Activity Tracker (screening) 
For patients who have previously participated in NN7415-4310 (explorer 4) and NN7415-4322 
(explorer 6) following information will be collected in the eCRF: 
• Trial ID for previous trial 
• Subject number in previous trial 
9.1 
Patient related information/assessments 
9.1.1 
Demography 
Demography will be recorded in the eCRF at screening and consists of: 
• Date of birth (according to local regulation) 
• Sex 
• Ethnicity (according to local regulation) 
• Race (according to local regulation) 
9.1.2 
Details of Haemophilia  
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 or B) 
• Family history of 
o Haemophilia 
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o Prothrombotic disorders 
o Thromboembolism 
o Inhibitors  
• Inhibitor tests taken (date, result (BU)) 
• Cut-off for positive inhibitor result 
• Deficiency factor level 
9.1.3 
Haemophilia Treatment and Bleed History 
The following information on haemophilia treatment and bleed history 12 months prior to screening 
should be recorded in the eCRF: 
• Type of treatment/regiment 
o Prophylaxis or on-demand 
o Start date 
o Stop date 
• Number of bleeding episodes 
o If possible, specify number of spontaneous bleeding episodes. 
• Coagulation factor product(s) 
o Brand name, or if the brand is not known, the type of product, (plasma derived or 
recombinant) 
• Dosage used for prophylaxis (for prophylaxis patients only) 
• Dosing frequency during prophylaxis (for prophylaxis patients only) 
• Approximate dose to treat a bleeding episode 
• Approximate number of doses to treat a bleeding episode 
9.1.4 
Target Joints 
All current target joints, including number of bleedings during the last 12 months, must be 
registered. A target joint is defined as three or more spontaneous bleeds into a single joint within a 
consecutive 6-month period. Where there have been ≤ 2 bleeds into the joint within a consecutive 
12-month period the joint is no longer considered a target joint. Surgical joint bleeds should not be 
included in the target joint count. 
Following information will be collected in the eCRF: 
• Location 
• Position (left/right) 
• Number of bleeding episodes the last 12 months 
9.2 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart in Section 2. 
9.2.1 
eDiary 
Novo Nordisk will provide the patient with an eDiary for electronic recording of following 
assessments: 
• Treatment with concizumab, see Section 9.2.2 
• Bleeding episodes including treatment of bleeds, see Section 9.2.3 
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• PRO questionnaires see Section 9.2.6 
• Health economic questions see Section 9.8 
The eDiary and related support services will be supplied by a vendor working under the direction 
and supervision of Novo Nordisk.  
Patients or patient’s caregiver will be trained in the use of the eDiary by the investigator or 
delegated personnel before entering of any data. The eDiary will be dispensed to the patient at visit 
2a (unless an eDiary has already been dispensed). After visit 2a and onwards, data will be entered 
by the patient or patient´s caregiver in the eDiary at home. The patient should bring his eDiary at all 
visits to ensure the eDiary is working properly. The eDiary will be returned by the patient at the end 
of trial visit (visit 27a). 
For data collected in the eDiary, the investigator must review treatment data, bleeding episodes and 
specific PRO´s, as specified in Section 9.2.6. The review should be documented accordingly. It is 
the responsibility of the investigator to instruct the patient about the timelines for timely completion 
of the eDiary. 
If the investigator finds it necessary to amend or correct eDiary data, the patient must be consulted, 
and outcome documented prior to requesting the actual data change. A Data Correction Request 
must be submitted to the eDiary vendor. An audit trail will be maintained. 
All data entered will be transferred from the eDiary to an electronic database, where it is kept as a 
certified copy of the source data by the eDiary vendor. Data entered in the eDiary will upon 
confirmation of a successful back-up be deleted from the eDiary. 
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. 
From the re-start of the trial, and if allowed according to local regulations, patients will be offered 
to use an app (Bring Your Own device) that can be downloaded to the patient’s own smartphone 
instead of the handheld eDiary device currently used in the trial. It is voluntary for the patients if 
they want to use the app, and an addendum to the Informed Consent Form must be signed before 
use. If it is not possible for the patient to use the app e.g., due to technical or other issues, then the 
patient will use/continue to use the provisioned device. The patient can start using the app solution 
at any time during the trial.  
9.2.2 
Treatment with concizumab 
For in-between visit administrations of trial drug, patients will self-administer concizumab and will 
record their treatment in the eDiary which will be reviewed at each visit by trial site staff in 
StudyWorks and periodically by the sponsor staff. 
In addition, the following items will be recorded in the eCRF at scheduled visits: 
• Injection site location for the last dose taken prior to visit 
• Time of last dose the day before the visit 
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Adjusting the concizumab dose based on concizumab exposure level 
As depicted in Figure 2, the daily concizumab maintenance dose can be decreased to 0.15 mg/kg or 
increased to 0.25 mg/kg (or the patients can stay on 0.20 mg/kg); this will be based on the 
concizumab exposure level from the sample taken at visit 4a (arms 2, 3 and 4) or visit 9a.2 (arm 1). 
The concizumab exposure level will be communicated to the investigator via a report from the 
central laboratory. Based on that exposure level, the investigator can/must call the patient for an 
additional dose adjustment visit, i.e., visit 4a.1 (arms 2, 3 and 4) or visit 9a.3 (arm 1) to adjust the 
dose as outlined in Table 7. 
Table 7 
Dose adjustment based on concizumab exposure level 
Concizumab 
exposure level 
Type of visit 
Visit windowa 
Action  
>4000 ng/mL 
Site or 
phone visit 
allowed 
2 working days from receipt of the 
laboratory report on the concizumab 
exposure level to patient contact 
The investigator must decrease the 
daily maintenance dose to 0.15 mg/kg 
200-4000 ng/mL 
Phone visit 
1 week from receipt of the laboratory 
report on the concizumab exposure 
level.  
The patient must be informed that no 
dose adjustment was needed. Also, the 
investigator must document that the 
report from the central laboratory was 
received and that no action was needed. 
<200 ng/mL 
Site visit 
required 
1 week from receipt of the laboratory 
report on the concizumab exposure 
level.  
Note: this visit cannot be earlier than 
6 weeks after the previous dispensing 
visit 2a (arms 2−4) or 9a (arm 1).  
The investigator can increase the daily 
maintenance dose to 0.25 mg/kg 
concizumab, if there are no safety 
concerns based on available laboratory 
parameters, clinical picture and 
medical history of the patient. 
aVisit window for 4a.1/9a.3 must not exceed the timing of visit (weeks) and visit window (days) defined in the 
flowchart in Section 2 
 
Data on dose adjustment will be collected in the eCRF. No additional dose adjustments may be 
performed. 
9.2.3 
Bleeding episodes 
At all visits the patients/or patient’s caregiver must be asked if all bleeding episodes, both treatment 
requiring and non-treatment requiring, have been recorded in the eDiary, including treatment of 
bleeds (if applicable), since the last visit. After visit 2a bleeding episodes must be recorded either in 
the eDiary (if treated at home) or in the eCRF (if treated at the trial site). Information about 
bleeding episodes prior to visit 2a (screening period) will be recorded in eCRF. 
The investigator must instruct the patient to contact the site before administering breakthrough 
bleed therapy to ensure breakthrough medication is administered when applicable, taking the 
treatment guidance in Appendix 11 into consideration. The trial site should be informed of the 
details of all bleeding episodes, including those that are treated outside of the trial site. All contacts 
to the patient must be recorded in the patient’s medical record. In case a patient cannot get in 
contact with the site, bleeds must be treated as previously agreed with the investigator. 
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The following must be recorded for any bleeding episode, including bleeding episodes that do not 
require treatment with factor products: 
• Start date and time 
• Stop date and time (see Table 8 for definitions) 
• Anatomical location(s) 
• Cause (see Table 9 for definitions) 
o spontaneous 
o traumatic 
o post-surgical 
• Severity (see Table 10 for definitions) 
o mild/moderate, severe (classification and recording of severe bleeding episodes is 
the responsibility of the investigator) 
o Severity of bleeding episodes must be evaluated by the investigator according to 
Table 9 and reported in StudyWorks by site 
• Contact between patient and site prior to every bleed treatment not administered at the 
haemophilia clinic (recorded in StudyWorks by investigator) 
• Treatment, if any 
o product administration(s)  
▪ Type of treatment (brand name and concentration) will be entered in 
StudyWorks by site 
▪ Amount of treatment in mL, date and time of injection will be entered by the 
patient 
o other medicinal treatments related to the bleeding episode (tranexamic acid, pain 
relieving medication etc.) will be entered in the eCRF by site 
• Symptoms during bleeding episodes  
o Pain  
o Pain intensity 
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, (see Section 9.3), if one of the following criteria 
are fulfilled: 
• The event is, in the investigator's opinion, of greater intensity, frequency, or duration than 
expected for the individual patient. 
• The investigator considers that there is a reasonable possibility that the event was related to 
treatment with the investigational product. 
• The event was life-threatening or resulted in death. 
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Table 8 
Definition of stop of bleed 
Stop time is: 
When the patient/parent or LAR experiences/observes signs of cessation of the 
active bleed 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 9 
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 10 
Definition of bleeding episode severity  
Category 
Definition 
 
Mild/Moderate 
 
Examples: uncomplicated musculoskeletal bleeds (joint, muscular bleeds without 
compartment syndrome), mucosal- or subcutaneous bleeds 
Mild/moderate bleeds may occur in other anatomical locations 
 
 
Severe 
 
Examples: intracranial, retroperitoneal, iliopsoas and internal neck bleeds; muscle bleeds with 
compartment syndrome; bleeds associated with a significant decrease in the haemoglobin level 
(>3g/dl) 
Severe bleeds may occur in other anatomical locations 
Bleeding episodes that require hospitalisation 
All life-threatening bleeding episodes 
 
9.2.4 
Sport activity 
Patients will be interviewed by the site staff about any sport activity practiced during the previous 
month. The sports activity rating, according to the list found in Appendix 6, will be recorded in the 
eCRF on visits according to the flowchart in Section 2. 
9.2.5 
Physical activity tracker (ActiGraph) 
In this trial, data on physical activity will be collected. Historically, people with haemophilia were 
discouraged from participation in sports, given the perceived risk of sports associated trauma and 
subsequent haemorrhage and morbidity. Recent studies have since documented physical, medical 
and psychosocial benefits of exercise and appropriate sports activities (non-collision, non-contact 
sports) in people with haemophilia. Patients with haemophilia who engage in physical activity 
experience improvements in proprioception, muscle strength and joint health (stabilisation, range of 
motion, pain and bleed protection.11-19 
Physical activity data will be collected using a small wrist worn physical activity tracker from 
ActiGraph designed for documenting physical activity and approved for clinical research (FDA 
class II grade). Data will be collected and transferred to Novo Nordisk from the physical activity 
tracker without site or patient interaction by a small data hub placed at the patient's home. Data can 
also be transferred at the trial site. The patient and the trial site will be blinded to the physical 
activity data which are collected. During the course of the trial, the trial site will have access to data 
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on patients wearing compliance and it is recommended that the trial site encourages the patient e.g. 
via phone and/or email to wear the physical activity tracker, if not done so. 
When to use ActiGraph 
The ActiGraph activity tracker will only be used in the main part of the trial.  
Phase 2 patients 
Patients already enrolled in arm 3 from phase 2, NN7415-4310 (explorer 4), before the treatment 
pause, should not wear the physical activity tracker. 
Remaining patients 
The instruction below includes new patients, patients currently in the trial and patients enrolled 
from NN7415-4322 (explorer 6). 
Baseline measurement: 
• Patients who already have a baseline measurement either from NN7415-4322 (explorer 6) or 
this trial (patients who started treatment before the treatment pause) will not have a new 
baseline measurement taken. Patients who were in screening at the time of the treatment pause 
and who are re-starting the trial will have a new baseline measurement taken.  
• For new patients or patients who do not have a sufficient baseline measurement from NN7415-
4322 (explorer 6), the physical activity tracker will be handed out to the patient at screening 
(visit 1a). The patients will be instructed to wear the tracker for approximately two consecutive 
weeks or as much as possible to establish a baseline value. The patient will be instructed to 
return the activity tracker at visit 2a. 
Efficacy Measurement: 
• To investigate the effect of concizumab daily PPX on patients physical activity, the patients will 
be instructed to wear the physical activity tracker for eight consecutive weeks or as much as 
possible at the end of the patient’s main part of the trial (weeks 16−24 for arm 1 and weeks 
24−32 for arm 2 and 4 patients).  
• Patients who are restarting the trial at visit 2a and already have an ActiGraph measurement 
(from before the treatment pause) will be asked to repeat the ActiGraph activity measurement at 
visit 9a. 
• Arm 1 patients who have already completed the main part of the trial and is re-starting the trial 
at visit 9a will not be asked to repeat any measurements.  
Table 11 shows an overview of when to use the ActiGraph physical activity tracker in this trial. 
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Table 11 
Physical Activity Tracker handout overview  
Treatment arm 
Patients trial history 
Baseline 
Measurement 
Wear-period in trial 
Arm 1 
Patients with no or insufficient baseline 
measurement who will start the trial at visit 
1a 
Visits 1a – 2a 
Visits 7a – 9a 
Patients with baseline measurement who will 
start the trial at visit 1a 
N/A 
Visits 7a – 9a 
Patients who will re-start trial at visit 9a 
N/A 
N/A 
Arms 2 and 4 
Patients with no or insufficient baseline 
measurement who will start the trial at visit 
1a 
Visits 1a – 2a 
Visits 9a – 10a 
Patients with baseline measurement who will 
start trial at visit 1a 
N/A 
Visits 9a – 10a 
Patients who will re-start trial at visit 2a 
N/A 
Visits 9a – 10a 
Arm 3 
Patients who re-start the trial in arm 3 
N/A 
N/A 
 
Instructions to patients 
The site staff should instruct the patient according to the following recommendations: 
• The physical activity tracker should be worn on the non-dominant arm 
• The physical activity tracker should be firmly attached to the wrist and the tracker should not be 
able to slide up and down when the arm moves 
• The patient should wear the physical activity tracker as much as possible, preferably 24 hours 
per day 
• The patient should wear the physical activity tracker as much as possible for approximately 
eight consecutive weeks between relevant visits  
• The physical activity tracker should be returned to the site according to the flowchart in 
Section 2 
The measurements from the physical activity tracker are summarised into daily measures 
representing different aspects of physical activity.  
All safety information and/or other issues judged by the investigator to be related to wearing the 
activity monitor should be reported by the site directly to the manufacturer 
(support@actigraphcorp.com).  
9.2.6 
Patient-reported outcome questionnaires 
This trial includes eight Patient-Reported Outcome (PRO) questionnaires, see Table 12.  
PRO questionnaires will be completed, if available in local language, by the patient (not the 
caregiver) in accordance the trial flow chart in Section 2. PRO-questionnaires will be completed as 
ePROs by the patient using the same eDiary except for Haem-A-QoL (all countries) and PROMIS 
(some countries) which will be completed on paper. 
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At visit 2a and visit 9a, patients must complete the PRO questionnaires on the day of the site visit, 
preferably before any other assessments. For the remaining visits, patients should preferably 
complete the PRO questionnaires on the day of the visit before any other assessments. 
Patients re-entering the trial after the treatment pause should fill out all forms according to the 
flowchart in Section 2. For these patients, previous treatment will be defined as the treatment they 
received during the concizumab treatment pause. The site staff must inform the patients about this 
'previous treatment' definition prior to completing the questionnaires. 
Review of PROs 
The review of the PRO´s should be documented in the patient’s source documents. 
PRO questionnaires reported on paper, the Haem-A-QOL (and PROMIS in some countries) must be 
reviewed by the investigator to ensure that all AE´s are reported. In addition, the electronically 
reported Hemo-TEM questionnaires must be reviewed by the investigator to ensure that AE´s 
concerning injection site reactions are recorded in the eCRF at the investigator’s discretion. The 
electronically questionnaire will be available in the eDiary web portal, StudyWorks. The other 
electronically reported PRO questionnaires do not have to be reviewed by the investigator. 
Table 12 
Overview of PRO questionnaires 
PRO questionnaire as per flow 
chart 
Name of questionnaire 
Concept 
SF-36 V2.0 Health Survey 
36 Item Short Form Health Survey 
(SF-36 v2) 
Generic health state measure, capturing 
physical and mental health. 
Patient preference 
questionnaire 
Haemophilia Patient Preference 
Questionnaire (H-PPQ) 
Patient’s haemophilia treatment preference 
PROMIS Short Form Upper 
Extremity 
PROMIS Short Form v. 2.0 Upper 
Extremity 7a 
Physical functioning in upper limbs 
PROMIS Numeric Rating Scale 
- Pain Intensity 
PROMIS Numeric Rating Scale v. 1.0 
Pain Intensity1a 
Average pain intensity experienced 
Haemophilia Treatment 
Experience Measure 
Haemophilia Treatment Experience 
Measure (Hemo-TEM) 
Haemophilia specific treatment burden 
Haem-A-QOL) 
Haemophilia Quality of Life 
Questionnaire for Adults 
Haemophilia specific HRQoL, capturing 
physical, emotional and social components 
of HRQoL. For patients ≥ 17 years only 
(at visit 1a) 
PGI-S on physical functioning  
Patient Global Impression of Severity 
(PGI-S) on physical functioning 
Physical functioning level (overall) 
PGI-C on physical functioning 
Patient Global Impression of Change 
(PGI-C) on physical functioning 
Change in physical functioning level 
(overall) 
9.2.7 
Clinical efficacy laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 and Appendix 3, must be 
conducted in accordance with the flowcharts in Section 2 and Section 2.1 and the laboratory 
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manual. The laboratory will provide instructions on sampling, handling of samples, labelling and 
shipment of samples. 
For the efficacy laboratory paraments (concizumab ELISA, Thrombin generation, Free TFPI) a 
PK/PD profile will be made at visit 2a and visit 9a, for all patients receiving concizumab at visit 2a 
(patients in arms 2, 3 and 4). See PK/PD sampling flowchart in Section 2.1 for further details. 
Concizumab-ELISA 
Concizumab-ELISA PK profile and trough will be performed as specified in the flowchart see 
Sections 2 and 2.1. Samples for assessment of concizumab trough values will be collected pre-dose 
when patients are assigned to concizumab prophylaxis, i.e. patients in arm 1 will only have baseline 
samples taken in the main part of the trial. Patients must be instructed to take their daily dose of 
concizumab after the initial blood sampling have taken place when visiting the site. See Section 9.5 
for further details. 
Validation of the assay followed current bioanalytical guidelines for method validation. The sample 
taken at visit 4a/9a.2, to determine whether the dose should be adjusted, will be communicated 
directly to the investigator via a report from the central laboratory (see Section 9.2.2). All other 
results will be reported to the sites and in a bioanalytical report after the primary analysis cut-off 
and at the end of the extension part. 
Thrombin generation 
The Thrombin Generation Assay (TGA) will be performed as specified in the flowcharts in 
Sections 2 and 2.1. 
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. 
Thrombin generation results will be reported at the primary analysis cut-off and at the end of the 
extension part. 
Free TFPI 
Free TFPI will be measured as specified in the flowcharts in Sections 2 and 2.1. 
Free TFPI measures TFPI not bound to concizumab. This enzyme-linked immunosorbent assay 
(ELISA) test will be sampled for at all assessment visits, including 24-hour PK visit. For details 
please see pharmacokinetics Section 9.5. 
The assay is commercially available from 
 (
). 
Free TFPI results will be reported at the primary analysis cut-off of the trial and at the end of the 
extension part. 
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9.3 
Adverse events 
The definitions of AEs and SAEs can be found in Appendix 5 for the IMP and on demand 
treatment, and in Appendix 8 for the investigational medical device. 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE. 
9.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs will be collected from the first trial-related activity after obtaining informed consent and 
until end of trial visit, at the time points specified in the flowchart. 
All SAEs will be recorded and reported to Novo Nordisk or designee within 24 hours, as indicated 
in Appendix 5 for the IMP and on demand treatment, and in Appendix 8 for the investigational 
medical device. The investigator must submit any updated SAE data to Novo Nordisk within 
24 hours of it being available. 
Investigators are not obligated to actively seek for AE or SAE in former trial patients. However, if 
the investigator learns of any SAE, including a death, at any time after a patient has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the investigational trial product or trial participation, the investigator 
must promptly notify Novo Nordisk. 
The method of recording, evaluating and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 5 for the IMP and on demand 
treatment, and in Appendix 8 for the investigational medical device. 
Timelines for reporting of AEs, including AESIs are listed in Figure 4. 
Some AEs require additional data collection via a specific event form. This includes medication 
errors observed during the trial. The relevant specific events are listed in Table 13 and the reporting 
timelines in Figure 4. 
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Figure 4 
Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
Table 13 
AEs requiring additional data collection (via specific event form) and AESIsa 
Event type 
AE requiring additional event form 
AESI 
Thromboembolic events 
 
X 
Hypersensitivity reaction 
X 
 
Injection site reaction 
X 
 
Medication error 
X 
 
aRefer to Section 9.3.6 for reporting details 
9.3.1.1 
Adverse event of special interest 
The AESIs for this trial are thromboembolic events as listed in Table 13 and must be reported 
according to Figure 4. 
In this trial, the following AEs fulfil the AESI criteria: 
• Thromboembolic events including but not limited to, 
o disseminated intravascular coagulation (DIC) 
o thrombotic microangiopathy (TMA) 
o myocardial infarction 
o pulmonary embolism  
o stroke  
o deep vein thrombosis  
o other clinically significant thromboembolic events and peripheral artery occlusion  
The AESIs must be reported on an AE form and a safety information form. 
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The definitions and further information on additional testing on the AESIs and AE requiring 
additional data collection can be found in Appendix 5. 
9.3.2 
Method of detecting AEs and SAEs 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the patient is the preferred method to inquire about events. 
9.3.3 
Follow-up on AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs, and non-serious AESIs will be followed until resolution, 
stabilization, or if the event is otherwise explained (e.g. chronic condition) or the patient is lost to 
follow-up as defined in Section 8.3. Further information on follow-up procedures is given in 
Appendix 5 for the IMP and on demand treatment, and in Appendix 8 for the investigational 
medical device. 
9.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a trial product 
under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/ Independent Ethics Committee (IEC), and 
investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory requirements 
and Novo Nordisk policy and forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs), from Novo Nordisk will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
9.3.5 
Reporting requirement for safety information related to the physical activity 
tracker 
All safety information and/or other issues judged by the investigator to be related to wearing the 
activity monitor should be reported by the site directly to the manufacturer 
(support@actigraphcorp.com). If the patient is on a Novo Nordisk product within the haemophilia 
indication, the safety information must also be reported to Novo Nordisk. 
9.3.6 
Disease-related events and/or disease-related outcomes and other information not 
qualifying as an AE or SAE 
The following Disease-Related Events (DREs) are common in patients with haemophilia and can be 
serious/life-threatening: 
• Bleeding episodes 
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Bleeding episodes in relation to AE/SAEs 
Because bleeding episodes are associated with the disease under study, they will not be reported 
according to the standard process for reporting of AEs/SAEs, even though the bleeding episode 
(event) may meet the definition of an AE/SAE unless they meet the criteria as specified below.  
Note: The event must be recorded and reported as an AE/SAE if one of the following applies: 
• The event is, in the investigator's opinion, of greater intensity, frequency, or duration than 
expected for the individual patient. 
• The investigator considers that there is a reasonable possibility that the event was related to 
treatment with the investigational product. 
• The event was life-threatening or resulted in death. 
9.3.7 
Technical complaints 
The investigator must assess whether a technical complaint is related to an AE. 
The definitions, reporting process and timelines for reporting for technical complaints can be found 
in Appendix 7. 
9.3.8 
Treatment of overdose 
In the event of an overdose, the investigator should closely monitor the patient for overdose-related 
AE/SAE and laboratory abnormalities and symptomatic medical treatment according to the clinical 
condition should be applied as relevant. Decisions regarding dose interruptions or modifications 
will be made by the investigator based on the clinical evaluation of the patient. 
The overdose must be reported as medication error. Refer to Section 9.3.1 for further details. 
For more information on overdose, also consult the current version of the concizumab IB. 
9.3.9 
Trial stopping rules 
If one of the below mentioned criteria is fulfilled, the Novo Nordisk Safety Committee will urgently 
evaluate all available data and decide on further actions: 
• Significant thromboembolic event 
• Event of DIC 
• Event of TMA 
• Death of trial patient which may be related to the trial product 
If enrolment is put on temporary hold, relevant data will be submitted to regulatory authorities, 
according to local regulations, to support restart of enrolment. 
9.4 
Safety assessments  
Planned timepoints for all safety assessments are provided in the flowchart Section 2. 
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9.4.1 
Concomitant illness and Medical History 
A concomitant illness is any illness 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 exposure to 
trial product.  
Medical history is a medical event that the patient has experienced in the past.  
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the Medical History/Concomitant Illness form if it is present at screening. Any new finding 
fulfilling the AE definition (see Appendix 5) during the trial and any clinically significant 
worsening from baseline (visit 1/1a) must be reported as an AE (see Section 9.3). 
Recording of haemophilia arthropathy in medical history must be performed. 
9.4.2 
Physical examinations 
The physical examination includes the following: 
• General appearance 
• Head, ears, eyes, nose, throat, neck 
• Respiratory system 
• Cardiovascular system 
• Gastrointestinal system including mouth 
• Genito-Urinary system 
• Musculoskeletal system 
• Central and peripheral nervous system 
• Skin 
• Lymph node palpation 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
The investigator must evaluate the results of the examination and record the outcome in the eCRF 
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 Medical History (Section 9.4) 
o if observed after screening: report an AE/SAE (Section 9.3). 
9.4.3 
Body measurements 
Body measurements will be assessed according to the flowchart in Section 2. 
• Height (cm), at screening 
• Body Weight (kg), with 1 decimal at all visits 
The body weight assessed at each visit will be used for determination of the concizumab dose to be 
administered until next visit. 
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Measurements will be reported in the eCRF. 
9.4.4 
Vital signs 
• Oral, Rectal, Axillary, Ear or Skin temperature (°C), pulse rate (beats/min), respiratory rate, as 
well as diastolic and systolic blood pressure (mmHg) will be assessed as specified in the 
flowchart in Section 2. 
• Blood pressure and pulse measurements or vital signs assessment should be preceded by at least 
5 minutes of rest for the patient in a quiet setting without distractions (e.g. television, cell 
phones). 
• Blood pressure at screening will consist of 3 diastolic and systolic blood pressure measurements 
with intervals of at least 1 minute. All three readings must be entered in the eCRF and the 
average of the 3 blood pressure readings will be recorded on or calculated in the eCRF. At the 
subsequent visits, the blood pressure should only be measured once. 
• Blood pressure and pulse measurements will be assessed in sitting position, if applicable with a 
completely automated device. Manual techniques will be used only if an automated device is 
not available. 
The investigator must evaluate the results and classify the outcome as either: 
• Normal or abnormal 
• If abnormal the investigator must: 
o Specify the abnormality  
o Record if the result is clinically significant (Yes/No) 
o If observed before or at screening: record as concomitant illness/Medical History 
(Section 9.4.1) 
o If observed after screening: report an AE/SAE (Section 9.3) 
Measurements will be reported in the eCRF. 
9.4.5 
Electrocardiogram (ECG) 
For patients in arms 1, 2 and 4, an ECG must be taken according to flowchart 2. For patients in 
arm 3, the data collected in phase 2 will be reused. 
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 concomitant illness/Medical History 
(Section 9.4.1) 
o If observed after screening: report an AE/SAE (Section 9.3) 
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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9.4.6 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 and Appendix 3, must be 
conducted in accordance with the laboratory manual and the flowchart in Section 2. The laboratory 
will provide instructions on sampling, handling of samples, labelling and shipment of samples. 
For the clinical safety laboratory assessments: Coagulation parameters, Haematology, Biochemistry 
and Urinalysis the investigator must evaluate the results and classify the outcome as either:  
• Normal or abnormal 
• If abnormal the investigator must:  
o Specify the abnormality  
o Record if the result is clinically significant (Yes/No) 
o If observed before or at screening: record as concomitant illness/Medical History 
(Section 9.4.1) 
o If observed after screening: report an AE/SAE (Appendix 5) 
For clinical safety laboratory assessments FVIII/FIX activity and FVIII/FIX inhibitors investigator 
will only evaluate the results according to inclusion/exclusion criteria. 
Above mentioned measurements, except urinalysis, will be reported to the sites by the central 
laboratory on an ongoing basis. 
If deemed relevant as per the investigator’s discretion, Novo Nordisk may perform blood analyses 
for COVID-19 antibodies. These analyses will be performed at a special laboratory and will only be 
performed if back-up material from other samples are available. No additional blood sampling will 
be performed. The results from such tests will be reported directly to site(s) via Novo Nordisk. 
Concizumab ELISA (PK ELISA and ELISA IVD) 
Concizumab will be quantified using a validated enzyme-linked immunosorbent assay (ELISA). 
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 
concizumab present in the calibration, quality control and test samples correlate with the obtained 
signal strength.  
Validation of the assay has been performed following current bioanalytical guidelines for method 
validation. Additional assay validation of the concizumab ELISA IVD, specifically with regards to 
assay precision, has been performed to support the Investigational Device Exemption. 
Plasma concizumab concentrations will be measured pre-dosing (trough) as specified in the 
flowchart in Section 2. Samples for assessment of concizumab trough values will be collected pre-
dose to concizumab prophylaxis. Patients must be instructed to take their daily dose of concizumab 
after the blood sampling have taken place when visiting the site. 
The sample taken at visit 4a (arm 2, 3, 4) and visit 9a.2 (arm 1) is to determine whether the dose 
should be adjusted. The sample is analysed using the concizumab ELISA IVD. These results (in 
ng/mL) will be communicated directly to the investigator by the central laboratory (see 
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Section 9.2.2). All other samples will be analysed using the concizumab PK ELISA. The ELISA 
data will be reported in a bioanalytical report after the end of the trial at the latest.  
Safety laboratory data evaluation 
In the event of confirmed central laboratory test results including one or more of below: 
• platelets <LLN (central lab) 
• fibrinogen < LLN (central lab) 
• any other laboratory parameters of concern to the investigator 
It is recommended that the investigator considers clinical evaluation of the patient and determine if 
further medical action is needed. 
Total TFPI 
Total TFPI ELISA sampling will be performed according to the flowchart in Section 2. 
The total TFPI level (free TFPI and concizumab bound TFPI) will be included as an exploratory 
biomarker assessment. The assay is a classic sandwich ELISA, where TFPI is captured via a 
polyclonal anti-TFPI antibody. This antibody binds to a region distant to the binding site of 
concizumab hence both, free TFPI and concizumab bound TFPI will be captured. Detection is done 
using a monoclonal antibody targeting TFPI. This antibody will not bind to the concizumab epitope 
of TFPI. Results will be reported in ng/mL TFPI. 
9.4.7 
Immunogenicity assessments 
Samples for the determination of anti-drug antibodies will be collected according to the flowchart in 
Section 2. All patients will have samples drawn at V1/V1a, but only patients randomised/allocated 
to concizumab treatment (arms 2, 3 and 4) will have samples drawn at the remaining indicated 
timepoints in the main part of the trial. In the extension part of the trial, samples must be drawn for 
all patients (arms 1−4). Sampling should always take place prior to administration of concizumab. 
In case of suspected hypersensitivity reaction requiring systemic treatment, additional blood 
samples are to be collected; refer to Section 9.4.8. 
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 or the S241P 
mutation. Furthermore, positive samples will be characterised for neutralising activity using a 
neutralising ADA assay. All antibody assays are validated according to international guidelines and 
recommendations. 
The following data will be available: 
• Anti-concizumab antibodies 
• Anti-concizumab antibody titres 
• Anti-concizumab binding antibodies cross-reacting with IgG4 backbone or S241P mutation 
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• Anti-concizumab neutralising antibodies 
The samples will be analysed and reported to sites at the primary analysis cut-off and at end of 
extension part (end of trial). A detailed description of the assay methods will be included in the 
antibody analysis report at the end of the trial. 
Patients positive for binding antibodies at end of follow-up may be followed outside this protocol. 
9.4.8 
Hypersensitivity reaction 
If suspicion of a hypersensitivity reaction occurs, patients should be instructed to contact the site 
staff as soon as possible for further guidance, see Appendix 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 locally 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 month after 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. 
The following additional tests can be performed locally or at special laboratories if deemed 
relevant: 
• Anti-concizumab IgE antibodies 
• Anti-concizumab antibodies (additional to scheduled time points) 
• Anti-Host Cell Proteins (HCP) antibodies 
• Anti-HCP IgE antibodies 
• Basophil activation results 
• Prick test/intra-dermal test 
• Complement test results 
• Tryptase (total and/or mature tryptase) 
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In case laboratory samples for severe hypersensitivity reactions are analysed at special laboratories, 
the results from the analysis will be reported directly to site(s) via Novo Nordisk. 
Hypersensitivity reactions including test results should be reported as an AE requiring additional 
data collection, see Section 9.3.1  
9.4.9 
Injection site reactions 
Injection site reactions must be recorded on the AE form and the injection site reaction form. Signs 
and symptoms of injection site reactions include but are not limited to pain, numbness, itching, 
burning, redness, induration, swelling, dimpling, macula, haematoma and bleeding. 
9.5 
Pharmacokinetics 
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 correlate 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. 
The concizumab ELISA will be used to evaluate exposure and pharmacokinetics of concizumab. 
For patients dosed with concizumab from visit 2a (patients in arms 2, 3 and 4), two 24-hour PK/PD-
sessions will be conducted at visits 2a and 9a. The concizumab dose will be administered in the 
abdomen and blood samples will be drawn pre-dosing, 3, 6, 9 and 24 hours after dosing. Care must 
be taken to ensure the 24-hour sample is drawn before the next daily dose of concizumab is 
administered. At the day of visit 9a patients should not dose themselves at home; the dose will be 
administered at site followed by blood sampling. The dose should be taken at site in the abdomen 
and care must be taken to ensure the 24-hour sample is drawn before the next daily dose of 
concizumab is given.  
For patients who had a 24-hour PK profile measured at visit 2 prior to the treatment pause, a new 
24-hour PK profile at visit 2a should not be conducted after restart of the trial. For these patients, 
only pre-dose and 24-hour post-dose samples should be taken at visit 2a. Care must be taken to 
ensure the 24-hour sample is drawn before the next daily dose of concizumab is administered. 
Following items must be recorded in the eCRF: 
• Time of lab samples taken 
• Time of concizumab dose 
• Injection site location 
See Section 2.1 for the specific timepoints for the PK analysis. 
In addition to the two PK/PD sessions, pre-dose concizumab levels (Ctrough) will be measured 
throughout the concizumab treatment period. These blood samples must be drawn prior to trial 
product administration as specified in the flowchart in Section 2. If the patient has taken the daily 
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dose of concizumab before collection of the concizumab ELISA sample, then visit 4a (arm 2, 3, 4) 
and visit 9a.2 (arm 1) should be rescheduled. 
9.6 
Pharmacodynamics 
Pharmacodynamics assessments Thrombin Generation, and Free TFPI are described in 
Section 9.2.7 For patients dosed with concizumab from visit 2a (patients in arms 2, 3 and 4), two 
24-hour PK/PD-sessions will be conducted at visits 2a and 9a; see Section 9.5 for further details. 
9.7 
Human Biological Specimen for storage 
9.7.1 
Genetics 
Whole blood samples for DNA genotyping will be collected according to the flowchart in Section 2 
for future analysis and long-term storage from patients who have consented to participate in this 
part of the trial. Participation in the genetic research is optional. Patients who do not wish to 
participate in the genetic research may still participate in the trial. 
In the event of sample handling failure, a replacement genetic blood sample may be requested from 
the patient.  
Genetic samples will not be evaluated by the investigator. 
Patients who had a sample taken at visit 1 before the treatment pause should not have that sample 
re-taken upon trial restart.  
Please refer to Appendix 9 for further information regarding the genetic research. Details on 
processes for collection, shipment and destruction of these samples can be found in the laboratory 
manual. 
9.7.2 
Biomarkers 
Serum and plasma samples will be collected according to the flowchart in Section 2 for future 
exploratory laboratory analysis and long-term storage from patients where additional consent has 
been obtained. Patients who do not wish to participate in this research may still participate in the 
trial. 
Biomarker samples will not be evaluated by the investigator. 
Patients who had a sample taken at visit 1 before the treatment pause should not have that sample 
re-taken upon trial restart.  
Please refer to Appendix 9 for further information regarding the biomarker research and details on 
processes for collection, shipment and destruction of these samples can be found in the laboratory 
manual. 
9.8 
Health economics  
A set of eDiary screens assembled in a monthly diary will be made available to the patient every 30 
days. The screens are designed to collect: 
• Number of school or workdays missed 
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• Number of days where a patient used an aid to move around 
• How many days in-home professional nursing was needed. 
The monthly diary will be completed by the patient in the eDiary. 
9.9 
Surgery 
Minor surgical procedures are allowed during the trial (for surgery definitions see Table 14). 
Planned major surgery is not allowed. 
Local/topical use of antifibrinolytics e.g. tranexamic acid is allowed. Use of single systemic doses is 
allowed after careful benefit-risk evaluation. 
During the perioperative period patients should continue daily concizumab prophylaxis. 
Table 14 
Surgery definitions 
Category 
Definition 
Examples 
Major surgery: 
Any invasive operative procedure that 
requires ≥3 doses of bypassing therapy 
and/or where any one or more of the 
following occur 
A body cavity is entered  
A mesenchyme barrier (e.g. pleura, 
peritoneum or dura mater) is crossed  
A fascia plane is opened  
An organ is removed  
Normal anatomy is operatively altered  
Minor surgery: 
Any invasive operative procedure where 
only the skin, the mucous membranes or 
superficial connective tissue is 
manipulated 
Implanting of central venous access 
devices (ports, central venous catheter, 
pumps and other central venous access 
devices) in subcutaneous tissue 
Skin biopsies  
Simple dental procedures 
Ear tube/drain insertion 
Circumcision 
Port insertion in paediatric patients 
For surgery the following should be recorded in the eCRF: 
• Type of Surgery 
• Data and stop time and dose of preventive treatment (haemostatic medication). 
• Other treatments during surgery (concomitant medication) 
• Indication of surgery 
• Anatomical Location of surgery 
• Date of surgery 
• Start and stop time of surgery 
In the instance of acute major surgery, it is recommended to pause concizumab at the discretion of 
the investigator. 
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10 Statistical considerations  
10.1 
Sample size determination 
The estimand for the primary endpoint will for patients in arms 1 and 2 be addressed based on the 
Full Analysis Set (FAS; see Section 10.2) using negative binomial regression. 
The sample size calculation has been determined based on the above estimand. In the calculation 
the treatment duration is set to 24 weeks for patients in arm 1 and 32 weeks for patients in arm 2. Of 
note, expected differences in observation periods and efficacy in patients exposed before the pause 
is not accounted for in the sample size calculations. 
The trial will be powered for confirming superiority of the concizumab prophylaxis versus no 
prophylaxis (on-demand) using a significance level of 5%. 
The power for concluding superiority of concizumab prophylaxis over no prophylaxis (on-demand) 
treatment for the estimand is at least 88% having 42 patients, allocated in a 2:1 manner to either 
concizumab prophylaxis (n=28) or no prophylaxis (on-demand) (n=14) to the trial and assuming a 
yearly overdispersion of 13, an ABR of 18 during on demand treatment and an ABR of 3 to 5 on the 
new concizumab regimen.  
ABR assumptions 
For the on-demand inhibitor patients, an average ABR of 18 is considered appropriate, based on 
previous trials (Table 15). 
Table 15 
Annualised bleeding rate assumptions for inhibitor patients treated on-demand 
Regimen 
Compound 
Study 
N 
ABR 
On-demand 
Novoseven 
NN1731-3562a 
72 
17.1 
 
Novoseven 
NN7128-1907b 
23 
29.8 
 
Novoseven 
NN7025-3601c 
51 
7.9e 
 
NovoSeven 
NN7415-4310d 
9 
21 
aNN1731-3562 CTR. bNN7128-1907 CTR. cNN7025-3601 CTR. dNN7415-4310 (explorer 4) main part internal result 
meeting presentation. eThe ABR is estimated: mean number of bleeding episodes per patient per 19.6 months 
((12.9/19.6)*12=7.9). 
Also, considering a FEIBA® median ABR 28.7 in the on-demand arm of the randomised FEIBA® 
prophylaxis trial20, an assumed ABR of 18 seems reasonable and conservative for the inhibitor on-
demand population. An ABR for concizumab prophylaxis of approximately 3−5 bleeds/year is 
expected. 
Over-dispersion assumptions 
A yearly over-dispersion of 13 is deemed realistic based on experience from previous trials. 
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Power 
Assuming an ABR of 18 for the on-demand arm and an ABR between 3 and 7 for the concizumab 
arm (arm 2), a yearly over-dispersion varying between 11 and 15 and performing 
10,000 simulations of each group will produce different scenarios of power for superiority tabulated 
in Table 16 below. 
Table 16 
Power for superiority for 42 patients randomised 2:1 assuming an ABR for the 
on-demand treatment of 18 
Power 
Yearly over-dispersion  
ABR concizumab 
11 
13 
15 
3 
98% 
97% 
94% 
4 
96% 
93% 
90% 
5 
92% 
88% 
83% 
6 
86% 
80% 
75% 
7 
78% 
70% 
65% 
When evaluating the power of the negative binomial analysis with logarithm of exposure time as 
offset and treatment as factor, annual bleeding rates of 18 and 3-5 are assumed for the on-demand 
patients and concizumab exposed patients, respectively. Assuming further a yearly over-dispersion 
of 13, the power for concluding superiority of concizumab prophylaxis becomes at least 88% with 
28 patients in the concizumab arm and 14 in the comparator arm. 
Expected withdrawal pattern 
Since treatment options for haemophilia patients with inhibitors are limited, the completion rate for 
this trial is expected to be high with less than 17% withdrawing or discontinuing treatment 
prematurely. In order to account for potential withdrawal patients, in particular in relation to other 
endpoints in this trial, a total of 51 patients will be randomised to ensure a high likelihood of having 
at least 42 patients completing arms 1 and 2. 
10.2 
Definition of analysis sets 
• Safety analysis set (SAS): All patients exposed to concizumab PPX or randomised to OnD.  
• Full analysis set (FAS): All patients randomised to concizumab PPX or OnD or allocated to 
arm 3 or 4.  
10.3 
Statistical analyses 
The statistical analysis plan (SAP) was updated prior to the first patient restarting the trial, to reflect 
the changes made in protocol amendment #4, and includes a more technical and detailed elaboration 
of the statistical analyses.  
As described in Section 5.1, several evaluations will be made prior to the end of this trial. This 
section will describe the analyses of the primary and key secondary endpoints at the primary 
analysis cut-off focusing on arms 1 and 2 
The bleed rate is defined as the number of treated bleeds over the respective observation periods. As 
a general rule, a treated bleed is defined as any bleed where a factor-containing product is reported 
between the start and stop time of a bleed. Multiple bleeding locations occurring at the same time 
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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) 
starting within 72 hours after stopping treatment of a previous treated bleeding episode (or re-bleed) 
at the same anatomical location. Note that there can be more than one re-bleed related to the same 
bleed. If a bleeding episode occurs in the same location more than 72 hours after stopping treatment 
of a previous bleeding episode (or re-bleed) in the same location, the bleed is defined as a new 
bleeding episode. 
The significance level is 5%. The primary endpoint is analysed using negative binomial regression. 
Superiority of concizumab prophylaxis over no prophylaxis will be concluded if the two-sided 95% 
confidence interval of the treatment ratio is below 1. 
In order to maintain the type 1 error for the key secondary endpoints, the hypotheses related to 
bleeds, SF36v2 physical functioning and SF36v2 bodily pain endpoints will be subject to a 
hierarchical testing. If a hypothesis is confirmed, the significance level will be reallocated to the 
next hypothesis in the hierarchy and then that hypothesis will be tested at the 5% significance level. 
This process will be repeated until no further hypotheses can be confirmed. All three tests will be 
for superiority hypotheses. The order of the hierarchy will be the primary endpoint followed by 
change from baseline in SF36v2 Bodily pain followed by the change from baseline in SF36v2 
Physical functioning. 
10.3.1 
Primary endpoint 
The primary endpoint is defined in Section 4.3.1.  
‘The estimand associated with this endpoint will be addressed comparing the number of treated 
bleeds between arms 1 and 2 based on the FAS using negative binomial regression with the 
patient’s number of bleeds analysed as a function of the randomized treatment regimen, type of 
haemophilia (HAwI or HBwI) and bleeding frequency (<9 or ≥ 9 bleeding episodes during the past 
24 weeks prior to screening) and the logarithm of the length of the observation period included as 
an offset in the model. For this analysis patients will contribute as follows: 
• in arm 1 with the observation period from randomisation to start on the new concizumab dosing 
regimen in the extension part or permanent treatment discontinuation 
• in arm 2 (exposed to the new concizumab dosing regimen) with the observation period from 
start on the new concizumab dosing regimen until the primary analysis cut off or permanent 
treatment discontinuation 
• in arm 2 (patients who has not restarted) with the observation period from the start of the initial 
dosing regimen until permanent treatment discontinuation 
The primary analysis will also account for the different intercurrent events as described in the 
estimand. 
From the statistical model, an estimate of the rate ratio of the ABR between the treatment regimens 
(concizumab prophylaxis and no prophylaxis) with corresponding 95% confidence interval and a p-
value for the test for superiority will be provided. Also, estimates of the actual ABRs with 
corresponding 95% confidence intervals will be provided for arms 1 and 2. To the extent the 
statistical model allows, separate estimates for HBwI and HAwI will be provided.’ 
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Sensitivity analyses 
The below sensitivity analyses will be implemented to further investigate the different assumptions 
that go into the above estimand and statistical methodology. Note that as different strategies are 
implemented to address some of the intercurrent events, these analyses address a slightly different 
estimand.  
• The number of treated bleeds will be analysed with a multiple imputation technique where the 
number of treated bleeds for patients that are not exposed to the new concizumab dosing 
regimen are imputed based on treated bleeds observed on the initial dosing regimen. The 
imputation technique and inference drawn will be based on the methods detailed by Keene et al 
(2014).21  
• A tipping point analysis using a similar method as described above. Patients only exposed to the 
initial dosing regimen of 0.25 mg/kg/day will be modelled with an increasing bleeding rate until 
the conclusion of superiority is changed. The data used will be the same as in the primary 
analysis and the offset period will be kept fixed within this analysis 
• The primary analysis will also be repeated using all concizumab exposure in arm 2 up until the 
primary analysis cut-off, irrespective of the dosing regimen. Hence, in this sensitivity analysis 
the initial and the new concizumab dosing regimen are both included (to maximise the amount 
of data used) and compared with arm 1 (OnD). 
• A statistical analysis using a model similar to the one used for the primary analysis but 
including an interaction term between treatment and a factor differentiating between patients 
randomised before and after the pause will be performed.  
• In order to investigate the effect of excluding observed data a model where all intercurrent 
events will be handled by use of the treatment policy strategy will be fitted. The model will be 
similar to the primary analysis but where the patient’s bleeds and observation time collected 
post permanent treatment discontinuation (the first intercurrent event) and collected during 
periods with unallowed use of factor products not related to treatment of a bleed (the third 
intercurrent event) will be used. This analysis will be performed using the FAS. 
• In order to not rely on the model assumptions of the primary analysis a non-parametric Van 
Elteren test to compare the mean ABR in the two randomised groups will be done. This is done 
using the FAS where patients contribute with observation time as described under 
Section 10.3.1. 
Further sensitivity analyses can be specified in the SAP. 
10.3.2 
Secondary endpoints 
10.3.2.1 
Key secondary endpoints 
The key secondary endpoints are defined in Section 4.3.2.1. 
The two key secondary endpoints based on SF-36v2 will be analysed including all patients in the 
FAS where patients contribute with observation time as described under Section 10.3.1. In order to 
incorporate the patients from the original randomisation that have not restarted, statistical analysis 
will be implemented as a statistical model using multiple imputations where the subjects without 
any available SF-36v2 measurements at scheduled visits will have their SF-36v2 value imputed 
from the available information from the treatment group the subject has been randomised to. For 
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subjects that have no observations on the new dosing regimen, the baseline value before the initial 
randomisation will be used. Subjects without any post-randomisation measurements contribute to 
the analysis, as the missing values will be imputed. The analysis will be implemented as follows. 
• For all patients the baseline value will be set to either the value obtained just prior to the re-start 
and if that is missing, the value prior to the initial randomisation. 
• In the first step, intermittent missing values are imputed using a Markov Chain Monte Carlo 
method, in order to obtain a monotone missing data pattern. This imputation is done for each 
treatment group separately and 1000 copies of the dataset will be generated. 
• In the second step, for each of the 1000 copies of the dataset, an analysis of variance model with 
stratification factors as factors and baseline SF-36v2 value as covariate is fitted to the change in 
SF-36v2 from baseline to week 4 for each treatment group separately. The estimated 
parameters, and their variances, from these models are used to impute values at week 4 for 
subjects in each treatment group, based on stratification factors and baseline SF-36v2. 
• In the third step, for each of the 1000 copies of the dataset, missing values at week 8 are 
imputed in the same way as for week 4 but now also including the SF-36v2 values at week 4 in 
the model. This stepwise procedure is then repeated sequentially for week 16 and 24 and in each 
step the SF-36v2 values in previous weeks are also included in the model. 
• For each of the complete data sets, the change from baseline to week 24 is analysed using an 
analysis of variance model with treatment and stratification factors as factors, and baseline SF-
36v2 as a covariate. 
The estimates and standard deviations for the 1000 data sets are pooled to one estimate and 
associated standard deviation using Rubin’s rule. From these the 95% confidence interval for the 
treatment difference is calculated together with a p-value for the test of superiority. 
10.3.2.2 
Supportive secondary endpoints 
Analyses of supportive secondary endpoints will be detailed in the SAP. 
10.3.3 
Exploratory endpoints 
Analyses of exploratory endpoints will be detailed in the SAP. 
10.3.4 
Interim analyses 
No formal interim analyses are planned. 
As stated under Section 5.1 several evaluations are to be made during the conduct of the trial: 
• at the primary analysis cut-off 
• at the 56-week cut-off 
• at the end of the extension part 
After the initial evaluation at the primary analysis cut-off no further confirmatory conclusions can 
be made.  
10.3.5 
Sequential safety analysis and safety monitoring 
A Data Monitoring Committee (DMC) will be established to review and evaluate accumulating data 
from the trial in order to protect the safety of the patients. 
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The DMC members will not have direct contact with any Novo Nordisk staff involved with the trial 
except for Novo Nordisk global safety. Details in relation to DMC can be seen in Appendix 4. 
10.3.6 
Explorative statistical analysis for pharmacogenetics and biomarkers 
N/A 
10.4 
Pharmacokinetic and/or pharmacodynamic modelling 
The concizumab concentration measurements obtained in this trial will be subject to exploratory PK 
modelling analysis performed by Quantitative Clinical Pharmacology, Novo Nordisk. 
A previously developed PK model for concizumab will be applied to the PK data. If necessary, 
alternative models can be considered for an accurate description of the PK profile. Further 
exploratory population PK modelling can potentially be a joint analysis of data from multiple trials 
including investigation of covariate factors. Relevant PK endpoints will be derived from the model 
parameter estimates. 
Selected PD measurements may be used for exploratory PK/PD analyses and if deemed feasible, 
population PK/PD and exposure-response modelling may be performed. 
A more technical and detailed elaboration of the population PK, population PK/PD and exposure-
response analyses will be given in a prospective modelling analysis plan. 
The results of the final analyses will be reported separately from the CTR. If relevant, selected 
model-derived results may be summarised in the CTR. 
 
 
 
 
 
 
 
 
 
 
 
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11 References 
1. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
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 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
2. 
Soucie JM, Evatt B, Jackson D. Occurrence of hemophilia in the United States. The 
Hemophilia Surveillance System Project Investigators. Am J Hematol. 1998;59(4):288-94. 
3. 
World Federation of Hemophilia.   Report on the annual global survey 2017. October 2018. 
4. 
Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003;361(9371):1801-9. 
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Hoffman M, Monroe III. A cell-based model of hemostasis. Thrombosis and haemostasis. 
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Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. 
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Descotes J, Gouraud A. Clinical immunotoxicity of therapeutic proteins. Expert Opin Drug 
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Levi M, Keller TT, van GE, ten CH. Infection and inflammation and the coagulation system. 
Cardiovasc Res. 2003;60(1):26-39. 
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Mulder K, Cassis F, Seuser DR, Narayan P, Dalzell R, Poulsen W. Risks and benefits of 
sports and fitness activities for people with haemophilia. Haemophilia. 2004;10 Suppl 
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Gomis M, Querol F, Gallach JE, González LM, Aznar JA. Exercise and sport in the 
treatment of haemophilic patients: a systematic review. Haemophilia. 2009;15(1):43-54. 
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Soucie JM, Cianfrini C, Janco RL, Kulkarni F, Hambleton J, Evatt B, et al. Joint range-of-
motion limitations among young males with hemophilia: prevalence and risk factors. Blood. 
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Tiktinsky R, Falk B, Heim M, Martinovitz U. The effect of resistance training on the 
frequency of bleeding in haemophilia patients: a pilot study. Haemophilia. 2002;8(1):22-7. 
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Hilberg T, Herbsleb M, Puta C, Gabriel HH, Schramm W. Physical training increases 
isometric muscular strength and proprioceptive performance in haemophilic subjects. 
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Mazloum V, Rahnama N, Khayambashi K. Effects of therapeutic exercise and hydrotherapy 
on pain severity and knee range of motion in patients with hemophilia: a randomized 
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Gupta S, Siddiqi AE, Soucie JM, Manco-Johnson M, Kulkarni R, Lane H, et al. The effect 
of secondary prophylaxis versus episodic treatment on the range of motion of target joints in 
patients with haemophilia. Br J Haematol. 2013;161(3):424-33. 
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Querol F, Pérez-Alenda S, Gallach J, Devís-Devís J, Valencia-Peris A, Moreno L. 
Haemophilia: exercise and sport. Punts Med Esport. 2011;46(169):29-39. 
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Antunes SV, Tangada S, Stasyshyn O, Mamonov V, Phillips J, Guzman-Becerra N, et al. 
Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the 
treatment of haemophilia A and B with inhibitors. Haemophilia. 2014;20(1):65-72. 
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Keene ON, Roger JH, Hartley BF, Kenward MG. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharmaceutical Statistics. 2014;13(4):258-
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Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
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version. 09 Nov 2016. 
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Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
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De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
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Engl J Med. 2004;351(12):1250-1. 
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Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
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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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726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
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1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
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Donald M. Arnold M, MSc, Christopher J. Patriquin, MD, MSc, and  Ishac Nazy, PhD. 
Thrombotic microangiopathies: a general approach to diagnosis and management. CMAJ 
. 2017 Jan 30. p. E153–E9. 
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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 
Fam Med. 2007;5(1):57-62. 
33. 
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. 
34. 
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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Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the 
value of this statement as an educational tool for neurologists. Stroke. 2009;40(6):2276-93. 
 
 
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12 Appendices 
Appendix 1 
Abbreviations and Trademarks 
ABI 
ankle-brachial index  
ABR 
Annual Bleeding Rate 
aPPC 
activated prothrombin complex concentrate 
 
ADA 
anti drug antibodies 
ADE 
adverse device effect 
AE 
Adverse Event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
Area under the curve 
Cmax 
maximum concentration 
Ctrough 
trough level concentration 
CLAE 
clinical laboratory adverse event 
CRF 
case report form 
eCRF 
electronic case report form 
eGFR 
estimated Glomerular Filtration Rate 
CNS 
central nervous sstem 
COVID-19 
Coronavirus disease 2019 
CT 
computerised tomopraphy 
CTR 
clinical trial report 
DFU 
Direction For Use 
DIC 
Disseminated Intravascular Coagulation 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DRE 
disease related event 
DUN 
dispensing unit number 
DVT 
deep vein thrombosis 
ECG 
Electrocardiogram 
EOT 
End of trial 
ETP 
Endogenous Thrombin potential 
FAS 
Full Analysis Set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FPFV 
first patient first visit 
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GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HA 
Haemophilia A 
HAwI 
Haemophilia A with inhibitors 
Haem-A-QoL 
Haemophilia Quality of Life Quesionnaire for Audult 
HB 
Haemophilia B 
HBwI 
Haemophilia B with inhibitors 
HCP 
Host Cell Protein 
Hemo-TEM 
Haemophilia Treatment Experience Measure 
H-PPQ 
Haemophilia Patient Preference Questionnaire 
IB 
Investigators Broshure 
IC 
Immune Complex 
ICH 
International Council for Harmonisation 
ICMJE 
International of Committe Medicinal Journal Editors 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
institutional review board 
IRT 
Item response theory 
IVD 
in vitro diagnostic 
IWRS 
interactive web response system 
LAR 
legally acceptable representative 
LLN 
Lover limit of normal 
LPFT 
Last Patient First Treatment 
MAR 
missing at random 
MI 
Myocardial infarction 
MIDF 
monitor-initiated discrepancy form 
MMRM 
mixed-effect model for repeated measurements 
MRA 
Magnetic Resonance Angiography 
MRI 
Magnetic resonance imaging 
MSE 
Missing Score Evaluation 
MVPA 
Moderate to Vigorous Physical Activity 
NIS 
Non-interventional Study 
OD 
On-demand 
PCD 
primary completion date 
PD 
Pharmacodynamic 
PF 
physical functioning  
PGI-C 
Patient Global Impression of Change 
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PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PPX 
prophylaxis 
PRO 
patient-reported outcome 
SADE 
serious adverse device effect  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
safety analysis set  
SUSAR 
suspected unexpected serious adverse reaction 
TF 
Tissue Factor 
TFPI 
Tissue Factor Pathway Inhibitor 
TMA 
Thrombotic Microangiopathy 
ULN 
upper limit of normal 
URL 
upper reference limit  
USADE 
unanticipated serious adverse device effect  
 
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Appendix 2 
Clinical laboratory tests 
• The tests detailed in Table 17 and Table 18 will be performed by central or designated 
special laboratories. 
• Additional tests may be performed at any time during the trial as determined necessary by 
the investigator or required by local regulations. Only laboratory samples specified in the 
protocol should 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. 
• 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 except 
for results from Human biosamples. 
• Laboratory samples will be destroyed no later than at finalisation of the clinical trial report 
except for samples as described in Appendix 9.  
• Human biosamples for retention will be stored as described in Appendix 9. 
• All laboratory samples should be taken pre-dosing and as specified in the flowchart in 
Section 2 
Table 17 
Protocol-required efficacy laboratory assessments 
Laboratory assessments 
Parameters 
Thrombin generation 
 
 
 
 
 
Concizumab ELISA IVD 
Concizumab ELISA 
Free TFPI 
Thrombin lag time  
Velocity index 
Endogenous thrombin potential 
Endogenous Thrombin Potential ratio 
Thrombin peak 
Time to peak 
Concizumab plasma concentration for dose adjustment 
Concizumab plasma concentration 
Free TFPI 
Table 18 
Protocol-required safety laboratory assessments 
Laboratory assessments 
Parameters 
Haematology 
Erythrocytes 
Haemoglobin 
Leucocytes 
Thrombocytes (platelets) 
Differential Leucocytes count: Lymphocytes, monocytes, neutrophils, 
Eosinophils and Basophiles 
Biochemistrya 
Alanine Aminotransferase (ALT)  
Albumin 
Alkaline phosphatase 
Aspartate Aminotransferase (AST) 
Creatinine 
Bilirubin (total) 
C-reactive protein (CRP) 
Gamma-glutamyl transferase (GGT) 
Urinalysis (screening only) 
pH, glucose, protein, bilirubin, by dipstick 
Antibodies 
Anti-concizumab binding antibodies 
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Laboratory assessments 
Parameters 
Anti-concizumab ab crossreacting w S241P 
Anti-concizumab ab crossreacting w IgG4 
Anti-concizumab binding antibodies titre 
Anti-concizumab neutralising antibodies 
FVIII inhibitors (for HAwI) 
FIX inhibitors (for HBwI only)  
Coagulation Factors (screening 
only) 
Factor VIII activity (for HAwI only) 
Factor IX activity (for HBwI only) 
Coagulation parameters  
Antithrombin Plasma 
D-Dimer 
Prothrombin Fragments 1 + 2 in Plasma 
Fibrinogen 
Activated Partial Thromboplastin Time 
Prothrombin Time 
INR 
Total TFPI 
Human biological specimen for 
storage  
Plasma 
Serum 
Whole Blood (for DNA genotyping) 
Other tests 
estimated Glomerular Filtration Rate (eGFR) test calculated by the central 
laboratory based on the creatinine value using the CKD-EPI equation 
Notes: aDetails of required actions and follow-up assessments for increased liver parameters including any 
discontinuation criteria are given in 8.1 and Appendix 5 (Hy’s Law). 
All trial-required laboratory assessments will be performed by a central laboratory or designated 
special laboratories. 
Laboratory sampling for patients from NN7415-4310 (explorer 4): 
Results from selected laboratory samples, from patients transferring from NN7415-4310 
(explorer 4) taken at EOT, will be transferred to this trial. Some samples must be taken again at the 
combined visit 1/visit 2. A detailed overview of which samples to take once/twice is specified in the 
laboratory manual. 
 
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Appendix 3 
Blood sampling in patients below 18 years of age 
Blood sampling in adolescent patients aged 12−17 years must be performed according to local 
guidelines. The blood volume taken in patients below 18 years should not exceed 3% of the total 
volume during a 4-week period and should not exceed 1% at any single time point.10 
In order to adhere to this guideline blood sampling in adolescent patients must be performed based 
on the patient’s weight and blood volume, Table 19, the blood sample prioritisation list, Table 20 
and the laboratory manual. 
Table 19 shows the approximate blood volume in adolescents (12−17 years) weighing ≥25 kg and 
the maximum blood sampling volumes to be collected at one single time point and during a 4-week 
period. It is assumed that the blood volume is 80 ml pr. kg. 
Table 19 
Total blood volumes and maximum blood sampling volumes according to body 
weight (kg) 
Body weight (kg) 
Blood volume (ml) 
according to body weight 
(kg) 
Maximum blood sampling 
volume at one single time point 
(ml) 
Maximum blood 
sampling within 4 weeks 
(ml) 
25 - 29 
2000 - 2320 
20.0 - 23.2 
60.0 – 69.6 
30 - 34 
2400 - 2720 
24.0 – 27.2 
72.0 - 81.6 
35 - 39 
2800 - 3120 
28.0 – 31.2 
84.0 – 93.6 
40 - 44 
3200 - 3520 
32.0 – 35.2 
96.0 – 100.6 
45 - 49 
3600 - 3920 
36.0 – 39.2 
108.0 – 117.6 
50 - 54 
4000 - 4320 
40.0 – 43.2 
120.0 – 129.6 
55 - 59 
4400 - 4720 
44.0 – 47.2 
132.0 – 141.6 
60 - 64 
4800 - 5120 
48.0 – 51.2 
144.0 – 153.6 
65 - 69 
5200 - 5520 
52.0 – 55.2 
156.0 – 165.6 
70 - 74 
5600 - 5920 
56.0 – 59.2 
168.0 – 177.6 
75 - 79 
6000 - 6320 
60.0 – 63.2 
180.0 – 189.6 
≥80 
6400 
64.0 
192.0 
 
Table 20 shows the blood sample prioritisation list that should be followed for adolescent patients. 
Blood samples should be drawn in the below mentioned order, highest priority sample assigned. If 
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deemed necessary by the investigator for safety reasons, the order may be changed. Please refer to 
the current version of the Laboratory Manual for further details. 
Table 20 
Blood sample prioritisation list 
Priority 
Laboratory parameter 
1 
Coagulation parameters 
2 
Haematology 
3 
Biochemistry 
4 
Concizumab ELISA 
5 
Concizumab Immunology 
6 
Free TFPI 
7 
TGA 
8 
Human Biological Specimen for future research 
9 
Coagulation back-up 
 
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Appendix 4 
Trial governance considerations 
1) Regulatory and ethical considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki22 and applicable ICH Good Clinical Practice (GCP) 
Guideline.23 
o Applicable laws and regulations 
• The protocol, informed consent form, IB (as applicable) and other relevant documents (e.g. 
advertisements), must be submitted to an IRB/IEC and reviewed and approved by the 
IRB/IEC before the trial is initiated. 
• Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the clinical trial report according to national requirements. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
safety hazard to trial patients. 
• Before a trial site is allowed to start screening patients, written notification from Novo 
Nordisk must be received. 
• The investigator will be responsible for: 
o providing written summaries of the status of the trial annually or more frequently 
in accordance with the requirements, policies, and procedures established by the 
IRB/IEC and/or regulatory authorities 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o providing oversight of the conduct of the trial at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
o ensuring submission of the clinical trial report (CTR) synopsis to the IRB/IEC. 
2) Financial disclosure 
Investigators and sub investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest. 
3) Informed consent process 
• The investigator or his/her representative will explain the nature of the trial to the patient 
and/or the patient’s LAR and answer all questions regarding the trial. This includes the use 
of an impartial witness where required according to local requirements. 
• The investigator must ensure the patient ample time to come to a decision whether or not to 
participate in the trial. 
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• Patients must be informed that their participation is voluntary. 
• Patients or their LAR will be required to sign and date a statement of informed consent that 
meets the requirements of local regulations, ICH guidelines23, Declaration of Helsinki22 and 
the IRB/IEC or trial site. 
• Whenever possible informed consent/assent must also be obtained by the 
minor/incapacitated patient. The informed consent/assent must be signed by patients below 
legal age according to local regulations. 
• In addition to the information given to the patient’s LAR, the minor/incapacitated patient 
must be given information according to his/her capacity to understand, always taking into 
consideration the minor’s/patient’s presumed willingness to participate in a clinical trial.  
• The medical record must include a statement that written informed consent was obtained 
before any trial related activity and the date when the written consent was obtained. The 
authorised person obtaining the informed consent must also sign and date the informed 
consent form before any trial related activity. 
• The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task of informing to a medically qualified person, in 
accordance with local requirements. 
• Patients and/or their LAR must be re-consented to the most current version of the informed 
consent form(s) during their participation in the trial. 
• For patients who were enrolled before the treatment pause, an addendum to the informed 
consent form must be signed by the patients and/or their LAR before reinitiating dosing with 
concizumab. 
• A copy of the informed consent form(s) must be provided to the patient or the patient’s 
LAR. 
• If the minor reaches legal age while participating in the trial and has only signed an age 
specific informed consent/assent form, the patient has to re-consent to the informed consent 
form signed by the patient’s LAR. 
Long term Storage of human samples 
• If allowed according to local law the patient will be asked to sign a separate consent form 
that addresses taken additional blood samples for Biomarkers and genetic testing (DNA) for 
long term storage of human samples and/or the use of samples for optional explanatory 
research. The objectives of the explanatory research must be explained to each patient. 
• This separate informed consent form should be signed by the patient and/or patient’s LAR if 
they consent to have additional sample taking for later biomarker and genotype analysis. 
The patient/ the patient’s LAR has the option to abstain from this part while still 
participating in the trial. 
4) Information to patients during trial 
The site will be offered a communication package for the patient during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the patients. The written information will be translated and 
adjusted to local requirements and distributed to the patient at the discretion of the investigator. The 
patient may receive a “welcome to the trial letter” and a “thank you for your participation letter” 
after completion of the trial. Further the patient may receive other written information during the 
trial. 
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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. 
5) Data protection 
• Patients will be assigned a 6-digit unique identifier, a subject number. Any patient records or 
datasets that are transferred to Novo Nordisk will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred. 
• The patient and any biological material obtained from the patient will be identified by 
patient number, visit number and trial ID. Appropriate measures such as encryption or 
leaving out certain identifiers will be enforced to protect the identity of patients as required 
by local, regional and national requirements. 
• The patient must be informed that his personal trial-related data will be used by Novo 
Nordisk in accordance with local data protection law. The disclosure of the data must also 
be explained to the patient. 
• The patient must be informed that his medical records may be examined by auditors or other 
authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities. 
6) Committee structure 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal safety committee. 
Data monitoring committee 
The data monitoring committee (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 done in order to protect the safety of the patients and to evaluate the benefit-risk balance. 
The DMC will have access to unblinded trial data, and will provide recommendations on trial 
continuation, modification or termination. 
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter. 
7) Publication policy 
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 investigators 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 
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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 clinical trial report for this trial. 
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed 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 patient to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the clinical trial report is available. This 
includes the right not to release the results of interim analyses, because the release of such 
information may influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. 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. 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.24 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned 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. 
Site-specific publication(s) by investigator(s) 
For a multicentre 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. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
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is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
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. 
Individual investigators will have their own research patients' data. 
8) Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements such as those of the International 
Committee of Medical Journal Editors (ICMJE)25, the Food and Drug Administration Amendment 
Act (FDAAA)26, European Commission Requirements27-29 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. 
The Primary Completion Date (PCD) is the last assessment of the primary endpoint and is for this 
trial Last Patient First Treatment (LPFT) + 32 weeks corresponding to visit 10a. If the last patient is 
withdrawn early, the PCD is considered the date when the last patient would have completed visit 
10a. The PCD determines the deadline for results disclosure at clinicaltrials.gov according to 
FDAAA. 
9) Data quality assurance 
Case Report Forms (CRFs) 
• Novo Nordisk or designee is responsible for the data management of this trial including 
quality checking of the data. 
• All patient data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory and diary data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• The following will be provided as paper CRFs to be used when access to the eCRF is 
revoked or the eCRF is temporarily unavailable: 
o AE forms  
o Safety information forms  
o Technical complaint forms (also to be used to report complaints that are not patient 
related, e.g. discovered at trial site before allocation) 
• 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 when the investigator signed the eCRF, the eCRF must be 
signed and dated again by the investigator. 
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• The investigator must ensure that data are recorded in the eCRF as soon as possible, 
preferably within 5 working days after the visit. Once data have been entered, it will be 
available to Novo Nordisk for data verification and validation purposes. 
Monitoring 
• The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data 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). 
• Trial monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of patients are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is 
being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to trial sites. 
• Monitors will review the patient’s medical records and other source data e.g. the diaries and 
paper PROs, to ensure consistency and/or identify omissions compared to the eCRF. 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor and the implications of the deviation must be reviewed and discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
10) Source documents 
All data entered in the eCRF must be verifiable in source documentation other than the eCRF. 
• Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the trial site. 
• Data reported on the paper CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records. Also, current medical records must be available.  
• It must be possible to verify patient’s medical history related to haemophilia in source 
documents such as patient’s medical record. 
• The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who was contacted. 
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• Definition of what constitutes source data can be found in a source document agreement at 
each trial site. There will only be one source document defined at any time for any data 
element. 
11) Retention of clinical trial documentation 
• Records and documents, including signed informed consent forms, pertaining to the conduct 
of this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No 
records may be transferred to another location or party without written notification to Novo 
Nordisk. 
• The investigator must be able to access his/her trial documents without involving Novo 
Nordisk in any way. If applicable, electronic CRF and other patient data will be provided in 
an electronic readable format to the investigator before access is revoked to the systems 
and/or electronic devices supplied by Novo Nordisk. Site-specific CRFs and other patient 
data (in an electronic readable format or as paper copies or prints) must be retained by the 
trial site. If the provided electronic 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. 
• Patient’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice 
12) Trial and site closure 
Novo Nordisk reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of Novo Nordisk. If the trial is suspended or 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. 
Trial sites will be closed upon trial completion. A trial site is considered closed when all required 
documents and trial supplies have been collected and a trial site closure visit has been performed. 
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by Novo Nordisk or investigator may include but are not 
limited to: 
• failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, Novo Nordisk procedures or GCP guidelines 
• inadequate recruitment of patients by the investigator 
• discontinuation of further trial product development. 
13) 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 
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staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the patients. 
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions. 
The investigator 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 that 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). 
14) 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. 
15) Web-portal for document exchange 
During the trial a web-portal will be used for document exchange between Novo Nordisk and the 
sites. The web-portal is not an archiving tool but could be used as a temporary archiving place 
during the trial as judged by the investigator.  
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Appendix 5 
Adverse events: definitions and procedures for 
recording, evaluation, follow-up, and reporting 
AE definition 
• An AE is any untoward medical occurrence in a clinical trial patient that is temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
• An AE can be any unfavourable and unintended sign, including an abnormal laboratory finding, symptom or 
disease (new or exacerbated) temporally associated with the use of a medicinal product. 
 
Events meeting the AE definition 
• Any abnormal laboratory test results or safety assessments, including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator. 
• A CLAE: a clinical abnormal laboratory finding 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. 
• Abuse: Persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied by harmful 
physical or psychological effects (e.g. overdose with the intention to cause harm. 
• Misuse: Situations where the medicinal product is intentionally and inappropriately used not in accordance with 
the protocol or the terms of the marketing authorisation.  
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition. 
• Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms or the clinical sequelae of a suspected overdose of trial product regardless of intent. 
• A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE. 
Such instances will be captured in the efficacy assessments. However, the signs, symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition. 
Events NOT meeting the AE definition  
• Pre-existing conditions, anticipated day-to-day fluctuations of pre-existing conditions, including those identified 
during screening or other trial procedures performed before exposure to trial product.  
Note: pre-existing conditions should be recorded as medical history/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. 
 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
• Results in death 
• Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient was at risk of death at 
the time of the event. It does not refer to an event which hypothetically might have caused death, if it were more 
severe. 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Hospitalisation signifies that the patient has been detained at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious. 
• Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
Note: 
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• 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.  
• Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• This definition is not intended to include experience of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle), 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
• Important medical event: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations. This includes important medical events that may not be immediately life-threatening or result in 
death or hospitalisation but may jeopardise the patient or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should usually be considered 
serious and reported as SAEs using the important medical event criterion. 
• The following adverse events must always be reported as SAEs using the important medical event criterion, if 
no other seriousness criteria are applicable: 
• suspicion of transmission of infectious agents via the trial product. 
• risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x 
Upper Normal Limit (UNL) and total bilirubin >2 x UNL, where no alternative aetiology exists (Hy's law). 
 
Description of AEs requiring additional data collection (via specific event form) and AESIs  
AESIs 
An AESI is an event, which in the evaluation of safety, has a special focus due to requirements from regulatory 
authorities.  
In this trial, the following AEs fulfil the AESI criteria: 
Thromboembolic events including but not limited to, 
• 
disseminated intravascular coagulation (DIC) (A), 
• 
thrombotic microangiopathy (TMA)(B) 
• 
myocardial infarction (C), 
• 
pulmonary embolism (D), 
• 
stroke (E), 
• 
deep vein thrombosis (F), 
• 
other clinically significant thromboembolic events (G) and peripheral artery occlusion (see below H), see 
definitions below 
In case of suspicion of thromboembolic events, further investigations and appropriate medical treatment should be 
initiated. Additionally, it is encouraged to perform a COVID-19 test in the case of a suspected thromboembolic 
event. If a thromboembolic event is diagnosed, COVID-19 testing must be performed.  
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 
 
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B) Definition of thrombotic microangiopathy, as defined below: 
Thrombotic microangiopathies (TMA) are a group of disorders characterized by microangiopathic hemolytic anemia, 
thrombocytopenia and microthrombi leading to ischemic tissue injury that can affect e.g. the kidneys and the central 
nervous system. 
TMA is a clinicopathologic diagnosis. The constellation of thrombocytopenia, anemia and red blood cell 
fragmentation (i.e. schistocytes) on the blood film is consistent with a diagnosis of TMA. The finding of concomitant 
anemia and thrombocytopenia should prompt a request for a peripheral blood film to look for red blood cell 
fragmentation. 
If TMA is suspected the following laboratory assessment workup is suggested: standard hematology, hemolytic 
parameters (reticulocytes, hemoglobin, bilirubin, LDH, haptoglobin), Direct Anti-Globulin (DAT) test (also referred 
to as Coombs test), peripheral blood smear to look for schistocytes, creatinine, ADAMTS13 Antigen and 
ADAMTS13 Antibody.30  
 
C) Myocardial infarction is defined according to the “Third Universal Definition of Myocardical Infarction”31 
Criteria for acute myocardial infarction - The term acute myocardial infarction (MI) should be used when there is 
evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Under these 
conditions any one of the following criteria meets the diagnosis for MI:  
• 
Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin (cTn)] with at least 
one value above the 99th percentile upper reference limit (URL) and with at least one of the following: 
o 
Symptoms of ischemia 
o 
New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle branch 
block (LBBB) 
o 
Development of pathological Q waves in the ECG 
o 
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
o 
Identification of an intracoronary thrombus by angiography or autopsy 
 
Criteria for prior myocardial infarction - Any one of the following criteria meets the diagnosis for prior MI: 
• 
Pathological Q waves with or without symptoms in the absence of non-ischemic causes. 
• 
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the 
absence of a non-ischemic cause. 
• 
Pathological findings of a prior MI. 
 
Recurrent myocardial infarction - Incident MI is defined as the individual’s first MI. When features of MI occur in 
the first 28 days after an incident event, this is not counted as a new event for epidemiological purposes. If 
characteristics of MI occur after 28 days following an incident MI, it is considered to be a recurrent MI. 
 
D) 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.32 
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 
 
E) 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”.33 
 
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: 
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pathological, imaging or other objective evidence of cerebral, spinal cord or retinal focal ischemic injury in a defined 
vascular distribution or clinical evidence of cerebral, spinal cord or retinal focal ischemic injury based on symptoms 
persisting 24 hours or until death, and other aetiologies 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”. 
 
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.34 
 
F) Definition of deep vein thrombosis:  
The “Clinical Practice Guideline from the American Academy of Family Physicians and the American College of 
Physicians” on diagnosis of venous thromboembolism recommends ultrasound scanning for patients with 
intermediate or high pre-test probability of deep vein thrombosis (DVT) in the lower extremities.32 Accordingly, 
venous thrombosis should be demonstrated by compression ultrasound, duplex ultrasound, colour Doppler imaging 
or venography (phlebography). 
 
G) 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 related to a central 
venous access device is not considered a clinically significant thromboembolic event unless evaluated as such by the 
investigator. 
 
H) Definition of peripheral artery occlusion:  
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Clinical signs of acute arterial occlusion verified by ankle-brachial index (ABI) test, Doppler and ultrasound 
(Duplex) imaging, computerised tomographic angiography, Magnetic Resonance 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 
 
AEs 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. 
 
Hypersensitivity type reactions: 
In cases where clinical signs of a severe and immediate hypersensitivity reaction resembling a type 
I hypersensitivity reaction is present, additional blood should be sampled for central laboratory assessment of 
anti-drug IgE antibodies and anti-drug binding antibodies. See Section 9.4.8 for further guidance on additional 
laboratory testing to be performed. Attention should be given to clinical signs and symptoms of hypersensitivity 
reactions of type II and III. Common clinical signs and symptoms characteristic for these types of reactions may 
include, but are not limited to: fever/malaise, cutaneous eruptions, arthralgia, lymphadenopathy, itching, headaches 
and myalgia. Related laboratory findings may include but are not limited to: mild proteinuria or haematuria, 
leukopenia or leucocytosis, decreased complement levels or increased complement split products and transient 
elevations of serum creatinine levels.  
In case of suspected severe systemic hypersensitivity reactions, dosing with concizumab should be stopped 
immediately and treatment at the discretion of the treating physician initiated. 
 
Injection site reactions: 
Any injection site reaction symptom must be reported on the AE form and the injection site reaction form, refer to 
Section 9.4.9. 
 
Investigation of injection site reactions will be performed locally at all visits when patients are receiving treatment 
with concizumab PPX based on patient feedback and by following visual inspections of injection sites for 
concizumab administration. The affected area should be evaluated in cm or inches using a ruler. In the event of a 
local reaction, assessments 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. 
 
Medication error: 
A medication error is an unintended failure in the trial drug process that leads to, or has the potential to lead to, harm 
to the patient, such as: 
• Administration of wrong drug or use of wrong device. 
Note: Use of wrong DUN is not considered a medication error unless it results in administration of wrong drug. 
• Wrong route of administration, such as intramuscular instead of subcutaneous. 
•  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. 
 
AE and SAE recording 
• The investigator will record all relevant AE/SAE information in the eCRF. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical 
information. In such cases, the diagnosis (not the individual signs/symptoms) will be documented as the AE/SAE.  
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g. hospital 
progress notes, laboratory and diagnostics reports) related to the event. 
• There may be instances when copies of source documents (e.g. medical records) for certain cases are requested by 
Novo Nordisk. In such cases, all patient identifiers, with the exception of the subject number, will be redacted on 
the copies of the source documents before submission to Novo Nordisk. 
• 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. For sign-off of SAE related forms refer to “SAE reporting via paper CRF” later in this section. 
• Novo Nordisk products used as concomitant medication if an AE is considered to have a causal relationship with a 
Novo Nordisk marketed product used as concomitant medication in the trial, it is important that the suspected 
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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. 
 
Assessment of severity 
The investigator will assess intensity for each event reported during the trial and assign it to one of the following 
categories:  
• Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not interfering with 
everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• Severe: An event that prevents normal everyday activities.  
Note: Severe is a category used for rating the intensity of an event; and both an AE and SAE can be assessed as 
severe. An event is defined as ‘serious’ when it meets at least one of the outcomes described in the definition of an 
SAE and not when it is rated as severe. 
 
Assessment of causality 
The investigator is obligated to assess the relationship between trial product and the occurrence of each AE/SAE. 
Relationship between an AE/SAE and the relevant trial product should be assessed as: 
• 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. 
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, as well as the 
temporal relationship of the event to trial product administration will be considered and investigated. 
The investigator should use the IB for the assessment. For each AE/SAE, the investigator must document in the 
medical records that he/she has reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal information to include in 
the initial report. However, it is important that the investigator always makes an assessment of causality for 
every event before the initial transmission of the SAE data. 
The investigator may change his/her opinion of causality in light of follow-up information and send a follow-up 
report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
Final outcome 
The investigator will select the most appropriate 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 a fatal outcome must be reported 
as an SAE. 
• Unknown: This term is only applicable if the patient is lost to follow-up. 
 
Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations 
as medically indicated or as requested by Novo Nordisk to elucidate the nature and/or causality of the AE or SAE as 
fully as possible (e.g. severe hypersensitivity reactions). This may include additional laboratory tests (e.g. skin prick 
test) or investigations, histopathological examinations, or consultation with other health care professionals. 
If a patient dies during participation in the trial or during a recognised follow-up period, the investigator should 
provide Novo Nordisk with a copy of autopsy report including histopathology. 
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New or updated information will be recorded in the eCRF. 
 
SAE reporting via eCRF 
• Relevant forms (AE and safety information form) must be completed in the eCRF.  
• For reporting and sign-off timelines, see box below.  
• If the eCRF is unavailable for more than 24 hours, then the site will use the paper AE form and if the eCRF is 
unavailable for more than 5 calendar days then the site will use the safety information form (see box below). 
• The site will enter the SAE data into the eCRF as soon as it becomes available, see 9.3.1. 
• After the trial is completed at a given site, the eCRF will be decommissioned to prevent the entry of new data or 
changes to existing data. If a site receives a report of a new SAE from a patient or receives updated data on a 
previously reported SAE after eCRF decommission, then the site can report this information on a paper AE and 
safety information form (see box below) or to Novo Nordisk by telephone. 
 
SAE reporting via paper CRF 
• Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk either by fax, e-mail 
or courier. 
• Initial notification via telephone is acceptable, although it does not replace the need for the investigator to 
complete the AE and safety information form within the designated reporting time frames (as illustrated in 
Figure 4 in Section 9.3): 
• AE form within 24 hours. 
• Safety information form within 5 calendar days.  
• Both forms must be signed within 7 calendar days. 
Contact details for SAE reporting can be found in the investigator trial master file. 
 
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Appendix 6 
Sports ratings by activity  
As per US National Hemophilia Foundation brochure for haemophilia patients, PlayingItSafe. 
 
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Appendix 7 
Technical complaints: Definition and procedures for 
recording, evaluation, follow-up and reporting 
Technical complaint definition  
• A technical complaint is any written, electronic or oral communication that alleges product (medicine or device) 
defects. The technical complaint may be associated with an AE but does not concern the AE itself. 
• Technical complaints include the definition of device deficiency, please refer to Appendix 8  
Examples of technical complaints: 
• Problems with the physical or chemical appearance of trial products (e.g. discoloration, 
particles or contamination). 
• Problems with packaging material including labelling. 
• Problems related to medical devices (e.g. to the injection mechanism, dose setting 
mechanism, push button or interface between the pen-injector and the needle). 
• Problems related to concizumab-ELISA (e.g. uncertain results). 
 
Time period for detecting technical complaints  
All technical complaints, which occur from the time of receipt of the product at trial site until the time of the last 
usage of the product, must be collected for products predefined on the technical complaint form.  
 
Reporting of technical complaints to Novo Nordisk 
Contact details (fax, e-mail and address) for Customer Complaint Center – refer to Attachment I 
Technical complaints must be reported on a separate technical complaint form: 
▪ 
For concizumab pen-injector: One technical complaint form must be completed for each affected DUN 
▪ 
For concizumab-ELISA: One technical complaint form must be completed for each onset 
For medical device under investigation (concizumab-ELISA), evaluate on the technical complaint form if the 
technical complaint could have led to an SAE. If the technical complaint on a medical device under investigation 
could have led to an SAE, a device deficiency that could have led to an SAE form must be completed as described in 
Appendix 8. 
 
Timelines for reporting of technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the eCRF within: 
▪ 
24 hours if could have led to an SAE (for concizumab-ELISA) 
▪ 
24 hours if related to an SAE 
▪ 
5 calendar days for all other technical complaints 
 
If the eCRF is unavailable or when reporting a technical complaint that is not patient related, the information must be 
provided on a paper form by fax, e-mail or courier to Customer Complaint Center, Novo Nordisk, within the same 
timelines as stated above. When the eCRF becomes available again, the investigator must enter the information on 
the technical complaint form in the eCRF. 
 
 
Follow-up of technical complaints  
The investigator is responsible for ensuring that new or updated information will be recorded on the originally 
completed form 
 
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Collection, storage and shipment of technical complaint samples – not applicable for concizumab-ELISA 
The investigator must collect the technical complaint sample and all associated parts that were packed in the same 
DUN and notify the monitor within 5 calendar days of obtaining the sample at trial site. The sample and all 
associated parts must be sent as soon as possible to Customer Complaint Center, Novo Nordisk, together with a copy 
of the completed technical complaint form. The technical complaint sample should contain the batch, code or lot 
number and, if available, the DUN. If the technical complaint sample is unobtainable, the reason must be stated on 
the technical complaint form. If several samples are shipped in one shipment, the sample and the corresponding 
technical complaint form should be kept together. 
Storage of the technical complaint sample must be done in accordance with the conditions prescribed for the product. 
 
Reporting of technical complaints for Novo Nordisk products not included in technical complaint form 
Technical complaints on Novo Nordisk products not included in the technical complaint form should be reported to 
local Novo Nordisk affiliate with a reference to trial ID. 
 
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Appendix 8 
AEs, ADEs, SAEs, SADEs, USADEs and device 
deficiencies: Definitions and procedures for recording, evaluating, 
follow-up, and reporting in medical device studies 
 
Definition of AE and adverse device effects 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory finding) in trial patients, users, or other persons, whether or not 
related to the medical device under investigation and whether anticipated or unanticipated. This 
definition includes events related to the medical device under investigation or comparator and 
events related to the procedures involved. For users or other persons, this definition is restricted to 
events related to medical devices under investigation or comparators. 
 
An adverse device effect (ADE) is an AE related to the use of a medical device under investigation. 
This definition includes any AEs resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the medical device under 
investigation as well as any event resulting from use error or from intentional misuse of the medical 
device under investigation or comparator if the comparator is a medical device. See the current 
edition of the investigator’s brochure and any updates hereof for the anticipated ADEs. 
Definition of SAE, serious adverse device effect and unanticipated serious adverse device 
effect  
An SAE is an AE that fulfils at least one of the following criteria: 
1. Results in death  
2. Leads to serious deterioration in the health of the patient, user or other person that either results 
in: 
a. A life-threatening illness or injury. The term ‘life-threatening' refers to an event in which 
the patient was at risk of death at the time of the event. It does not refer to an event 
which hypothetically might have caused death, if it were more severe. 
b. Persistent or significant disability/incapacity: A permanent impairment of a body 
structure or a body function including chronic diseases. 
c. In-patient or prolonged hospitalisation, planned hospitalisation for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE. 
d. Important medical event: Medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure or a body function. 
3. Congenital anomaly/birth defect: Results in foetal distress, foetal death or a congenital 
abnormality or birth defect including physical or mental impairment. 
 
Serious adverse device effect 
A serious adverse device effect (SADE) is an adverse device effect that has resulted in any of the 
consequences characteristic of an SAE. 
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Unanticipated serious adverse device effect 
A unanticipated serious adverse device effect (USADE) is a serious adverse device effect which by 
its nature, incidence, severity or outcome has not been identified in the current risk assessment 
analysis report (see Section 3.3). 
Anticipated serious adverse device effect is an effect which by its nature, incidence, severity or 
outcome has been identified in the risk assessment.  
Definition of serious health threat 
A serious health threat is a signal from any adverse event or device deficiency that indicates an 
imminent risk of death or a serious deterioration in the health in trial participants, users or other 
persons, and that requires prompt remedial action for other participants, users or other persons. This 
would include events that are of significant and unexpected nature such that they become alarming 
as a potential serious health hazard or possibility of multiple deaths occurring at short intervals. 
Definition of device deficiency 
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. Device deficiencies include malfunctions, use errors, 
and the inadequacy of the information supplied by the manufacturer, including labelling.  
This definition includes device deficiencies related to the medical device under investigation. 
Device deficiency is part of technical complaint definition, please refer to Appendix 7. 
Recording and follow-up of AE and/or SAE and device deficiencies 
AE, SAE and device deficiency recording 
When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory reports, and diagnostics reports) related to 
the event.  
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. 
There may be instances when copies of source documents (e.g., medical records) for certain cases 
are requested by Novo Nordisk. In such cases, all participant identifiers, with the exception of the 
subject ID, will be redacted on the copies of the source documents before submission to Novo 
Nordisk.  
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the study at the latest.  
The investigator will then record all relevant AE/SAE/device deficiency information in the patient’s 
medical records, in accordance with the investigator’s normal clinical practice and on the 
appropriate form of the CRF.  
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For device deficiencies, it is very important that the investigator describes any corrective actions 
taken to prevent recurrence of the event. 
Assessment of severity 
The investigator will make an assessment of severity for each AE/SAE/device deficiency reported 
during the trial and assign it to one of the following categories:  
• Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities.  
Note: An AE that is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe.  
An event is defined as ‘serious’ when it meets at least one of the criteria described in the definition 
of an SAE, NOT when it is rated as severe. 
Assessment of causality 
The investigator is obligated to assess the relationship between medical device under investigation, 
the procedure and each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine relationship. 
 
Relationship between an AE/SAE and the medical device under investigation and the procedure 
should be assessed as: 
• Causal: when relationship is beyond any doubt 
• Probable: when relationship seems relevant and/or the event cannot be explained by another 
cause 
• Possible: when relationship is weak but cannot be ruled out 
• Not related: when relationship can be excluded 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to the use of the medical device under investigation, 
will be considered and investigated. 
The investigator will also consult the investigator’s brochure in his/her assessment. 
For each AE/SAE, the investigator must document in the medical records that he/she has reviewed 
the AE/SAE and has provided an assessment of causality for AE or SAE. 
There may be situations in which an AE/SAE has occurred, and the investigator has minimal 
information to include in the initial report to Novo Nordisk. However, it is very important that the 
investigator always makes an assessment of causality for every event before the initial transmission 
of the SAE data. 
The investigator may change his/her opinion of causality in light of follow-up information and send 
an AE/SAE follow-up report with the updated causality assessment.  
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The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Final outcome 
The investigator will select the most appropriate outcome: 
• Recovered/resolved: The patient has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed when first documented. 
• Recovering/resolving: The condition is improving, and the patient is expected to recover from 
the event. This term may be applicable in case of chronic conditions, cancer of AEs ongoing at 
time of death (where death is due to another AE). Note: for SAEs, this term is only applicable if 
the patient has completed the follow-up period and is expected to recover. 
• Recovered/resolved with sequelae: the patient has recovered from the condition but with 
lasting effect due to 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 no known.  
Note: this term may be applicable in case of chronic conditions, cancer or AEs ongoing at time 
of death (where death is due to another AE). 
• Fatal: This term is only applicable if the patient died from a condition related to the 
reported AE. Outcome of other reported AEs in a patient before he/she died should be 
assessed as ‘recovered/resolved’, ‘recovering/resolving’, ‘recovered/resolved with sequelae’ or 
‘not recovered/not resolved’. An AE with a fatal outcome must be reported as an SAE. 
• Unknown: This term is only applicable if the patient is lost to follow-up. 
Follow-up of AE/SAE/device deficiency 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE/SAE/device deficiency as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other health 
care professionals. 
New or updated information will be recorded in the originally completed CRF. 
The investigator will submit any updated SAE data to Novo Nordisk within 24 hours of receipt of 
the information. 
Reporting of SAEs, Serious Device Deficiencies that could have led to an SAE and serious 
health threats 
Relevant CRFs (AE and safety information forms, device deficiency that could have led to an SAE 
form) must be forwarded to Novo Nordisk in accordance with Appendix 4 (Data protection). 
Initial notification via telephone is acceptable, although it does not replace the need for the 
investigator to complete the AE, device deficiency that could have led to an SAE and safety 
information form within the designated reporting time frames: 
• AE and device deficiency that could have led to an SAE form within 24 hours 
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• Safety information form within 5 calendar days  
• Both forms must be signed within 7 calendar days after first knowledge by the investigator. 
 
A suspicion of a serious health threat must be indicated in the SAE form or in the device deficiency 
that could have led to an SAE form.  
For device deficiency that could have led to an SAE, a technical complaint form must also be 
completed, refer to Appendix 7. 
 
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Appendix 9 
Retention of human biosamples 
The trial will involve collection of human biosamples to be stored in a central archive. 
1) Biosamples for future research (Biomarkers and Genetics) 
1.2 ml citrated plasma, 1.0 ml serum and /or 2.0 ml whole blood (DNA for genotyping) will be 
obtained from patients/LARs who have consented to this part of the trial.  
Biomarkers 
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 biosamples may 
also include biomarkers that are unknown at present or have not been included in the scientific 
hypotheses at initiation of the trial. 
Only Novo Nordisk staff and biorepository personnel will have access to the stored samples. For all 
retained samples the patient’s identity will remain confidential and the samples will be identified 
only by subject number, visit number and or date and trial identification number. No direct 
identification of the patient will be stored together with the samples. The biosamples may be 
transferred to other countries. 
In the event that the collected biosamples (blood) 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 biosamples obtained from their own body. 
Use/Analysis of DNA 
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity and 
progression of disease. Variable response to therapy may be due to genetic determinants that impact 
drug absorption, distribution, metabolism and excretion, mechanism of action of the drug, disease 
aetiology, and/or molecular subtype of the disease being treated. Therefore, where local regulations 
and IRB/IEC allow, a blood sample will be collected for DNA analysis from consenting patients. 
DNA samples will be used for research related to trial product or indication and related diseases. 
Genetic research may consist of the analysis of one or more candidate genes, or the analysis of 
genetic markers throughout the genome or analysis of the entire genome (as appropriate). 
The samples may be analysed as part of a multi-trial assessment of genetic factors involved in the 
response to trial product or product treatments of this class to understand trial disease or related 
conditions. 
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2) Antibodies and PK/PD samples 
Antibodies and PK/PD samples may be retained 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 antibody and PK/PD assays and will not be reported in this trial. Residual samples may also be 
used to generate reagents for in study validation or control of future assay performance inside or 
outside this trial. Selected samples would be pooled, and not be traceable to any individual. Pooling 
would not be done if it prevented retention of sufficient sample material for possible further 
characterisation of antibody responses in this trial. 
3) Storage and destruction 
The samples will be stored at Novo Nordisk and/or at a central bio-repository after end of trial and 
until marketing authorisation approval or until the research project terminates, but no longer than 15 
years from end of trial after which they will be destroyed. 
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Appendix 10 Country-specific requirements 
Algeria: Legal age of majority is 19 years old. Biogenic testing and biobanking not allowed. 
Czech Republic: Within the adolescent population (patients aged 12-17 years) only haemophilia B 
patients with an inhibitor will be included in this clinical trial. The eCRF for sites in Czech 
Republic will have this text added to the eCRF page where all inclusion criteria for the trial are 
listed.  
France: The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 2004 art. 
88 I, IX, Journal Officiel of 11 August 2004. "The sponsor is responsible for identification of the 
harmful consequences of the biomedical the research for the person lending himself thereto and for 
indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice is 
not attributable to his fault of or the faults 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. 
India: In India, Novo Nordisk will provide or reimburse the patients treatment for bleeds during the 
entire trial including the screening and follow-up parts. 
Japan: The legal age in Japan is 20 or above. The head of the trial site or the trial product storage 
manager assigned by the head of the trial site (a pharmacist in principle) is responsible for control 
and accountability of the trial products. 
Mexico: Should the subject his/her family members parents or legal representative decide to 
withdraw the consent for participation in the trial, the subject will be entitled to receive appropriate, 
free of charge medical care and/or trial drug during the follow up period of the protocol when it will 
be established with certainty that no untoward medical consequences of the subject participation in 
the research occurred. 
Poland: In Poland, non-randomised patients that withdrew consent from the trial due to the 
treatment pause are eligible to be re-screened under the following circumstances:  
• no alternative effective treatment option is available for the patient 
• decision to re-screen a withdrawn patient must be based upon medical and ethical evaluation 
and approved by the medical team in Novo Nordisk HQ.  
 
Note that patients who re-enter the trial must follow the same treatment arm as they withdrew from. 
Patients that withdrew consent but were re-screened and re-entered into the trial will have a link 
between the previous subject ID and the new subject ID and thus only count as one patient.  
Russia: The trial should be conducted in compliance with the protocol and Ministry of Healthcare 
of Russian Federation‘ order # 200n from April 01, 2016 “Approval of rules of good clinical 
practice” and legal requirements of Russian Federation regulating circulating of medicines. 
South Africa: Genetic testing and biobanking not allowed.  
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South Korea: The legal age is above or equal to 19 years. In South Korea, Novo Nordisk will 
provide or reimburse the patients treatment for bleeds during the entire trial including the screening 
and follow-up parts. In addition, Novo Nordisk will provide or reimburse patients on-demand 
treatment if patients are randomised to arm 1. 
Turkey: In Turkey Novo Nordisk will provide or reimburse the patients treatment for bleeds during 
the entire trial including the screening and follow-up parts. In addition, Novo Nordisk will provide 
or reimburse patients on-demand treatment if patients are randomised to arm 1. 
Rotational thrombelastometry (ROTEM) Sub-Study: Applicable for site 
(Spain). 
Four sites in four countries will participate in a ROTEM sub-study in either protocols 
NN7415-4307 and/or NN7415-4311. The purpose of this sub-study is to evaluate the use of 
ROTEM parameters as possible marker for evaluation of concizumab. 
ROTEM enables the evaluation of haemostatic potential in whole blood, providing multiple 
parameters to describe clot formation and strength. ROTEM evaluation has the potential of being 
used to evaluate the haemostatic effect of treatment with concizumab in patients with haemophilia. 
The selected trial sites have extensive experience with ROTEM evaluation, as well as a thorough 
understanding of concizumab treatment from clinical trials. The number of sites will be limited to 
reduce assay variation, as ROTEM is known to show a high degree of user-dependent variation in 
the evaluation of patients with haemophilia.  
The ROTEM parameters will be compared to PK parameter and thrombin generation parameter 
from the two clinical trials, NN7415-4307 and NN7415-4311, and thus sampling for ROTEM 
evaluation will take place at the same time as sampling for thrombin generation for subject treated 
with concizumab. As the ROTEM assay is for research purpose only, the evaluation of the ROTEM 
parameters will be exploratory only, and not be part of the formal statistical evaluation as per 
protocol. 
Sampling for ROTEM will take place in the main part at each visit where Thrombin Generation 
sampling takes place (please see flowchart Section 2). In addition, thrombin generation sampling 
will be added to timepoint 3 hours, please see Table 21 below. This means that ROTEM sampling 
will be take place at pre-dose, 3 hours, and 6 hours (when a PK profile is taken). 
The collection will involve an additional blood collection tube of 2 ml per time point for the PK 
profile (V2a and V9a), and 2 ml at the other visits where thrombin generation is taken in the main 
part for arms 2−4 (32 weeks). The total additional sampling for subjects agreeing to take part will 
be 30 ml.  
For patients that are currently in the trial and is restarting concizumab treatment at visit 2a, ROTEM 
sampling will be repeated. These patients will not have a PK profile at visit 2a but ROTEM samples 
will be taken in the main part at each visit where Thrombin Generation sampling takes place and at 
visit 9a. The total volume for sampling for these subjects will be higher depending on how many 
samples that were taken prior to the treatment pause (maximum 60 ml).  
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Trial ID: NN7415-4311 
Version: 
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Status: 
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The details of the ROTEM assay method will be outlined in a separate laboratory manual, 
applicable for only the selected sites participating in the ROTEM sub-study and covered by this 
amendment. 
Table 21 
Pharmacokinetic (PK)/ Pharmacodynamic (PD) sampling flowchart 
 
Visit 2a and Visit 9a (PK/PD profile only applicable for patients on 
concizumab treatment from visit 2a)  
PK sampling timepoint 
(hours)a 
Pre-dose 
3 hours 
6 hours 
9 hours 
24 hours 
 Sampling window  
-1 − 0 hours 
±30 min 
±30 min 
±1 hour 
±3 hours 
 PK ASSESSMENTS 
 
 
 
 
 
Concizumab ELISA 
X 
X 
X 
X 
X 
Free TFPI 
X 
X 
X 
X 
X 
Thrombin generation 
X 
X 
X 
 
X 
ROTEM samples 
X 
X 
X 
 
 
Note: aIf the patient has already completed the PK profile at visit 2 before the treatment pause, the PK profile will not be repeated at 
visit 2a. Then the patient will only have the ROTEM sampling performed at visit 9a and at the other visits where thrombin generation 
is assessed in the main part of the trial. 
All patients participating in the ROTEM sub-study must signed a separate informed consent form.  
Applicable for site 
 (Spain) only: Participants must be aged ≥18 years at the time of signing the 
informed consent. 
Applicable for the other sites: If participations below 18 years are included in the ROTEM 
sub-study, the site must ensure that the blood volumes listed in Appendix 3 are adhered to. The 
sampling for ROTEM is lowest priority. 
VV-CLIN-121085
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CONFIDENTIAL

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CONFIDENTIAL 
Date: 
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Trial ID: NN7415-4311 
Version: 
7.0 
     
Status: 
Final 
     
Page: 
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Appendix 11 Breakthrough bleed treatment guidance 
The investigator must instruct the patient on how to treat breakthrough bleeds. 
The investigator must ensure that patients are instructed to contact the site before administering 
breakthrough bleed treatment to ensure that treatment is administered when and as applicable. 
Treatment of mild or moderate breakthrough bleeds with bypassing agents 
In case a patient experiences a mild or moderate treatment-requiring bleed, the investigator should 
instruct the patient to treat the bleed taking the guidance on doses and dose intervals in Table 22 
into consideration. 
For treatment of bleeds with aPCC (FEIBA®), the dose must not exceed a single dose of 50 U/kg, 
and not exceed 100 U/kg within 24 hours. The first treatment should be at the hospital, with 
observation if the patient for a minimum of 24 hours. If there are no safety concerns, the patient can 
continue with FEIBA® treatment for breakthrough bleeds at home. Single dose home treatment 
must not exceed 50 U/kg. If an additional dose is needed because a single dose was insufficient to 
treat the bleed the patient must some to the site.  
For treatment of bleeds with ByClot®, the dose must not exceed 60 µg/kg, and not exceed 90 µg/kg 
within 24 hours. Additional dose can be given at an interval of 8 hours or longer. The first treatment 
should be at the hospital, with observation of the patient for a minimum of 24 hours. If there are no 
safety concerns, the patient can continue with ByClot® treatment for breakthrough bleeds at home. 
Single dose home treatment must not exceed 60 µg/kg. If an additional dose is needed because a 
single dose was insufficient to treat the bleed, the patient must come to the site. 
Table 22 
Guidance on management of mild and moderate bleeds during concizumab PPX 
 
rFVIIa 
aPCC 
ByClot® 
Contact 
centre (PI)  
The patient must contact the centre before initiating treatment of a bleeding episode. If more doses 
are needed, the patient should contact the centre before each dose. 
First dosea  
90 µg/kg 
Single dose must not exceed 
50 U/kg, and not exceed 
100 U/kg within 24 hours 
Single dose must not exceed 
60 µg/kg ByClot®, and not exceed 
90 µg/kg ByClot® within 24 hours 
Second dose  
90 µg/kg 
At investigator’s discretion 
Additional dose can be given at an 
interval of 8 hours or longer 
Dose interval 
Time between first and second dose must not be shorter than stated in local labellingb 
Anti-
fibrinolytics  
Local/topical use is allowed. 
Use of single systemic doses 
is allowed after careful 
benefit-risk evaluation 
Not recommended 
Not recommended 
Notes: aLowest dose in accordance with local labelling.  bThe interval between the two doses could be increased based 
on clinical case-by-case judgment keeping in mind that early breakthrough bleed control remains crucial. 
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Trial ID: NN7415-4311 
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Status: 
Final 
     
Page: 
119 of 125 
 
 
Severe and life-threatening bleeding episodes 
From a patient safety perspective, specific recommendations for the management of severe and 
life-threatening bleeding episodes (see definition in Table 10 in the protocol) are not considered 
feasible as such management often poses several complex clinical challenges that need to be 
addressed case by case by the treating physicians hereby tailoring and securing the optimal 
treatment, which in some cases may be high factor replacement doses for extended periods of time. 
In the rare event of a severe (life-threatening) bleed the patient should be in immediate and close 
contact to the investigator and be treated with relevant doses of factor containing products at the 
discretion of the investigator. 
Investigator−patient interactions and training 
It is important that patients are trained in the management of bleeds. New and updated training 
material for both site staff and patients has been developed, see overview in Table 23. 
Table 23 
Overview of documents for investigator and patient training. 
Investigators & Site Staff 
Patients 
Patient bleed treatment plan 
Guidance for management of bleeds. 
Updated Informed Consent Forms 
Updated Patient Handbook 
Trial ID patient card – key instructions to the patient on how to 
proceed when suspecting a bleed. 
Patient-specific bleed treatment plan 
Investigative sites are encouraged to create a patient-specific plan for breakthrough bleed treatment 
such that all involved investigators are aligned in the treatment instructions to the patient when the 
patient contacts the site. 
Patient education on management of bleeds 
Adequate management of breakthrough bleeds is important for the patient’s safety and overall 
disease outcome, and to the outcome of the trial. The investigator must educate the patient on 
adequate management of bleeds before (re-)start of concizumab treatment (i.e., visit 2a (arms 2−4) 
or visit 9a (arm 1)). The training conversation with the patient must be documented in the patient 
medical records and should as a minimum cover the below points: 
• Introduce management of bleeds during concizumab prophylaxis as described in Sections 5.2.2 
and 9.2.2 
• Explain need for a cautious treatment approach while avoiding undertreatment 
• Provide rationale to the patient for a close patient to site contact 
• Instruct patients to contact site before every bleed treatment dose 
• Discuss practicalities of contacts to the investigational site i.e. when, how and whom  
to contact 
• Describe to the patient the difference between traumatic and spontaneous bleed 
• Discuss severe bleeds and surgical procedures with the patient 
• Explain what products the patient should use for treatment of bleeds and how 
• Touch on dose levels and intervals between dosing 
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Date: 
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Trial ID: NN7415-4311 
Version: 
7.0 
     
Status: 
Final 
     
Page: 
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• Explain how to record bleeds and bleed treatment in the eDiary 
• Introduce the patient information material and explain how to use it. 
Investigator’s responsibilities regarding patient information material 
The investigator must hand out all approved supportive material to the patient for him to bring 
home. The purpose of the patient information material is to help the patient remember trial 
instructions and procedures, as well as to serve as documentation. 
Furthermore, the investigator has the following responsibilities: 
• Provide information to the patient in accordance with the latest version of the informed consent 
form, particularly Section 5 ‘What are the possible side effects or harms of taking part?’. 
• Hand out the Patient Handbook to the patient and ensure that the patient is familiar with the 
content of the current version of the Patient Handbook to an extent that allows the patient to 
comply with the trial procedures. The Patient Handbook is developed as a tool for patients 
describing the trial and the connected trial procedures in layman terms, and it is recommended 
to put emphasis on following sections: 
o Bleeds 
o Treatment of bleeds 
o Thromboembolic events  
o Electronic Diary  
• Hand out the Trial ID patient card, which carries key instructions to the patient on how to 
proceed when suspecting a bleed. 
Investigator’s responsibilities concerning reporting of bleeding episodes 
Patients must report all bleeding episodes and bleed treatment in eDiaries when bleeds and 
treatment occur away from the investigational site. When occurring at the investigational site, 
circumstances of the bleed and the bleed treatment will be reported in the eCRF. 
• Whenever recording a bleed in the eDiary, patients will receive a reminder on the eDiary device 
to contact investigator 
• Investigator must report in the eCRF or eDiary-portal StudyWorks whether a patient-
investigator contact was established before treating the bleed. The investigator must also report 
treatment type for each treatment  
• Investigator is requested to perform a rating of the severity of each bleeding episode reported 
and report the severity in StudyWorks or in the eCRF as applicable 
VV-CLIN-121085
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Date: 
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Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
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Appendix 12 Flowcharts applicable for patients enrolled before the treatment pause and who have 
permanently discontinued treatment prior to restart 
The below flowchart is only applicable for those patients enrolled in the trial before the treatment pause and who have permanently discontinued from 
treatment prior to restart. Patients who enrolled in the trial or reinitiated treatment after the treatment pause must follow the flowcharts in Section 2. 
 
Main Part 
Extension Part 
 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
9.1 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Visit 
15 
Visit 
16 
Visit 
17 
Visit 
18 
Visit 
19 
Visit 
20 
Visit 
21 
Visit 
22 
Visit 
23 
Visit 
24 
Visit 
25 
Visit 
26 
Visit 
27 
Visit 
1a 
2b 
3c 
4 
5 
6 
7 
8 
9b 
9.1d 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Timing of Visit (Weeks) 
-3 
0 
1 
4 
8 
12 
16 
20 
24 
25 
32 
40 
48 
56 
64 
72 
80 
88 
96 
104 
112 
120 
128 
136 
144 
152 
160 
167 
Visit Window (Days) 
±0 
±0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 SUBJECT RELATED 
INFORMATION AND 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/exclusion Criteria 
X 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant illness 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Details of Haemophilal 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haemophilia treatment and 
bleed historyl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Target Joints 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment discontinuation 
criteria 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Withdrawal criteria 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-121085
1.0
VV-TMF-4536529
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Protocol 
      
Date: 
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Status: 
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Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
122 of 125 
 
 
 
Main Part 
Extension Part 
 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
9.1 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Visit 
15 
Visit 
16 
Visit 
17 
Visit 
18 
Visit 
19 
Visit 
20 
Visit 
21 
Visit 
22 
Visit 
23 
Visit 
24 
Visit 
25 
Visit 
26 
Visit 
27 
Visit 
1a 
2b 
3c 
4 
5 
6 
7 
8 
9b 
9.1d 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Timing of Visit (Weeks) 
-3 
0 
1 
4 
8 
12 
16 
20 
24 
25 
32 
40 
48 
56 
64 
72 
80 
88 
96 
104 
112 
120 
128 
136 
144 
152 
160 
167 
Visit Window (Days) 
±0 
±0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bleeding episode 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body measurementse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Thrombin generation 
 
Xb 
X 
X 
X 
X 
X 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sport activity 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concizumab ELISAf 
 
Xb 
X 
X 
X 
X 
X 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Free TFPI 
 
Xb 
X 
X 
X 
X 
X 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site reaction 
 
x 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
 
ECGl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Parameters 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation factors  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-concizumab antibodies 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
VV-CLIN-121085
1.0
VV-TMF-4536529
1.0

Protocol 
      
Date: 
18 June 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
123 of 125 
 
 
 
Main Part 
Extension Part 
 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
9.1 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Visit 
15 
Visit 
16 
Visit 
17 
Visit 
18 
Visit 
19 
Visit 
20 
Visit 
21 
Visit 
22 
Visit 
23 
Visit 
24 
Visit 
25 
Visit 
26 
Visit 
27 
Visit 
1a 
2b 
3c 
4 
5 
6 
7 
8 
9b 
9.1d 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Timing of Visit (Weeks) 
-3 
0 
1 
4 
8 
12 
16 
20 
24 
25 
32 
40 
48 
56 
64 
72 
80 
88 
96 
104 
112 
120 
128 
136 
144 
152 
160 
167 
Visit Window (Days) 
±0 
±0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
FVIII/FIX inhibitors 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Total TFPI 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 OTHER ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 v2 Health Survey 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Patient preference 
questionnaire 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS Short Form Upper 
Extremity 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
PROMIS Numeric Rating 
Scale -Pain Intensity 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Haemophilia Treatment 
Experience Measure 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haem-A-QoLg 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PGI-S on physical 
functioning  
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGI-C on physical 
functioning  
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 TRIAL MATERIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of trial 
product (on site) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensing visit 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
VV-CLIN-121085
1.0
VV-TMF-4536529
1.0

Protocol 
      
Date: 
18 June 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
124 of 125 
 
 
 
Main Part 
Extension Part 
 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
9.1 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Visit 
15 
Visit 
16 
Visit 
17 
Visit 
18 
Visit 
19 
Visit 
20 
Visit 
21 
Visit 
22 
Visit 
23 
Visit 
24 
Visit 
25 
Visit 
26 
Visit 
27 
Visit 
1a 
2b 
3c 
4 
5 
6 
7 
8 
9b 
9.1d 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Timing of Visit (Weeks) 
-3 
0 
1 
4 
8 
12 
16 
20 
24 
25 
32 
40 
48 
56 
64 
72 
80 
88 
96 
104 
112 
120 
128 
136 
144 
152 
160 
167 
Visit Window (Days) 
±0 
±0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Drug accountability 
 
 X 
 
 
X 
 
X 
  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 REMINDERS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Human biological specimen 
for storagei 
Xj 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
ActiGraph 
dispensing/collection 
Xh 
 
 
 
 
 
Xh 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand out of Direction for Use 
 
Xk 
 
 
 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand out patient ID card and 
patient material 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
End of trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Footnote 
a) Only for patients from phase 2 (NN7415-4310, explorer 4): Visits 1 and 2 must be on same day. Patients will receive their first dose in this trial on the combined visit 1/visit 2 day. Assessments applicable for both visits 1 and 2 
should only be performed once. Some assessments will also be transferred directly from phase 2, see Section 9. 
b) For patients having concizumab dosing at visit 2 there will be a 24-hour PK-session at visits 2 and 9. Please see details for PK sampling in Section 2.1. For on-demand patients (arm 1) only the pre-dose sample will be taken. 
c) Phone visit is allowed for patients enrolled from NN7415-4310 (explorer 4), arm 3, and patients randomised to arm 1 (on-demand patient). 
d) Only for patients randomised to the on-demand treatment 
e) Weight only, except at visit 1 where height is measured 
f) Sample is taken pre-dose. Patients must not inject before the sample is taken. 
g) Only for patients above ≥ 17 years old 
h) Patients from phase 2, NN7415-4310 (explorer 4) should not use the ActiGraph tracker. For patients coming from NN7415-4322 (explorer 6), ActiGraph tracker should only be dispensed at visit 7. New patients should have the 
tracker at visits 1 and visit 7. See Section 9.2.5 for further details. 
VV-CLIN-121085
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VV-TMF-4536529
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Protocol 
      
Date: 
18 June 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4311 
      
Version: 
7.0 
Page: 
125 of 125 
 
 
Footnote 
i) A separate Informed Consent Form must be signed before any samples are taken. See section 9.7 for further details.   
j) Whole blood for DNA is only taken at screening. 
k) Only for patients receiving concizumab at visit 2. 
l) Only for patients is arms 1,2 and 4 who did not participate in NN7415-4310 (explorer 4) and NN7415-4322 (explorer 6).    
 
Pharmacokinetic (PK)/ Pharmacodynamic (PD) sampling flowchart for patients enrolled before the treatment pause and discontinued prior to 
restart 
The below flowchart is only applicable for those patients enrolled in the trial before the treatment pause and who have discontinued prior to restart. Patients 
who enrolled in or reinitiated the trial after the treatment pause must follow the flowcharts in Section 2. 
 
Visit 2 and Visit 9 (PK/PD profile only applicable for patients on concizumab treatment from visit 2)  
PK sampling timepoint (hours) 
Pre-dose 
3 hoursa 
6 hoursa 
9 hoursa 
24 hours 
 Sampling window  
-1- 0 hours 
±30 min 
±30 min 
±1 hour 
±3 hours 
 PK ASSESSMENTS 
 
 
 
 
 
Concizumab Elisa 
X 
X 
X 
X 
X 
Free TFPI 
X 
X 
X 
X 
X 
Thrombin generation 
X 
 
X 
 
 X 
aPatients coming from NN7415-4310 (explorer 4) should only have PK/PD sampling, pre-dose and after 24 hours at visit 2.  
At visit 9 all patients (arms 2, 3 and 4) should have a full PK profile. 
 
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