Efficacy and Safety of Concizumab Prophylaxis in Patients With Haemophilia A or B Without Inhibitors
Phase: PHASE3
Conditions: Haemophilia A Without Inhibitors, Haemophilia B Without Inhibitors
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04082429 
Sponsor trial ID: 
NN7415-4307 
Official title of study: 
Efficacy and safety of concizumab prophylaxis in patients with 
haemophilia A or B without inhibitors (explorer8) 
Document date: 
25-March-2021 
*Document date refers to the date on which the document was most recently updated. 

Protocol 
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Trial ID: NN7415-4307 
Version: 
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Protocol 
explorer8
Protocol title: 
Efficacy and Safety of Concizumab prophylaxis in patients with 
haemophilia A or B without inhibitors 
Substance: Concizumab 
Universal Trial Number: U1111-1225-9722 
EUdraCT Number: 2018-004891-36 
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 No unpublished information contained herein may be 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 No unpublished information contained herein may be 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: NN7415-4307 
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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 5.0 
25 March 2021 
All countries 
Updated protocol, version 4.0 
06 July 2020 
All countries 
Updated protocol, version 3.0 
17 December 2019 
All countries 
Updated protocol, version 2.0 
06 June 2019 
All countries 
Original protocol, version 1.0 
03 June 2019 
All countries, not submitted 
Protocol version 5.0 (25-Mar-2021) 
This amendment is considered to be non-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 5.0 
The protocol has been amended to further reflect upon the concizumab ELISA in vitro diagnostic 
(IVD) device specifically used for samples collected for dose adjustment, as introduced and 
approved with amendment 4.0. Moreover, the FDA has approved an investigational device 
exemption (IDE) to use the concizumab-ELISA for dose adjustment.  
Furthermore, a number of corrections and minor adjustments have been implemented throughout 
the protocol for clarification purposes. Due to the clarifying and corrective nature of the updates, 
and as the use of the IVD in the trial already has been approved in a previous amendment, this 
amendment is considered non-substantial. 
Section # and name 
Description of change 
Rationale 
Section 1 - Synopsis 
Updated in alignment with changes 
specified below. 
For alignment 
Section 2 – Flowchart 
Assessment of Target joints at visit 
10a has been removed. 
In version 4.0 of the protocol the 
trial design was updated to have two 
different timepoints for end of main 
for on demand (arm 1) and 
concizumab (arm 2-4). The target 
joint assessment at V9 which was 
meant as a concizumab baseline 
assessment for arm 1 was by mistake 
moved to both V9a (arm 1) and 
V10a (arms 2-4), but not needed for 
arms 2-4, since their baseline is at 
V2a where they start concizumab. 
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Trial ID: NN7415-4307 
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Section 2 – Flowchart 
Footnote f) has been removed and 
subsequent footnotes are adjusted 
accordingly. 
The information on details of 
haemophilia and haemophilia 
treatment and bleed history should 
be collected for all patients 
Section 2 – Flowchart 
Footnote added for concizumab 
ELISA: the ELISA IVD is 
performed on Visits 4a and 9a.2. 
Concizumab plasma concentration 
for dose adjustment will be analysed 
using the concizumab ELISA IVD. 
Section 4.2 – Estimands 
Correction of typo in the brief sum-
up of the estimand: 
For the previous PPX treatment 
(study 4322): From the point in time 
where PPX treatment is stable and 
up until start of concizumab 
treatment.  
Corrected to: For the previous PPX 
treatment (study 4322): From the 
point in time where PPX treatment is 
stable and up until the end of the 
study.  
To align with the detailed 
specification of the estimand in 
Section 4.2 and in the synopsis, 
Section 1. 
Section 4.3.1 – Primary endpoints 
The mentioning of arm 4 in the 
primary endpoints is deleted.  
The estimands used to address the 
two primary objectives includes the 
primary endpoints, see Section 4.2. 
In particular, it is only the two 
randomised arms (arms 1 and 2) that 
are to be compared. In Section 4.3.1 
the primary endpoints are also 
specified but unfortunately here arm 
4 was included as part of the 
endpoint. That was a mistake 
because arm 4 was clearly never 
intended to be included when 
addressing the primary objective 
which is also clear from the 
statistical analyses specified in 
Section 10.3.1. Instead with respect 
to arm 4 there are separate estimands 
(and thereby separate endpoints – 
called the confirmatory secondary 
endpoints) to address the two 
secondary efficacy objectives. 
Section 4.3.2.2 – Supportive 
secondary endpoints 
For secondary endpoints for effect, 
treated joint bleeds and treated target 
joint bleeds have been clarified to 
treated spontaneous and traumatic 
joint bleeds and treated spontaneous 
and traumatic target joint bleeds.  
For clarification. 
Section 4.3.2.2 – Supportive 
secondary endpoints 
The mentioning of arm 4 in 
supportive secondary endpoint for 
efficacy/effect has been deleted. 
To align with the primary endpoints. 
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Trial ID: NN7415-4307 
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Section 4.3.2.2 – Supportive 
secondary endpoints 
Concizumab (arm 1) has been 
included for supportive secondary 
endpoints for safety. 
To include all patients treated with 
concizumab up until the 
confirmatory analysis cut-off. 
Section 4.3.2.2 – Supportive 
secondary endpoints 
For the secondary endpoints for 
safety (concizumab arm 2-4) the 
time frame after treatment pause has 
been clarified. 
For clarification. 
Section 4.3.2.2 – Supportive 
secondary endpoints 
On demand (arm 1 main part) 
removed from the supportive 
secondary endpoint; Number of 
patients with antibodies to 
concizumab. 
Correction, as concizumab 
antibodies are not assessed for on 
demand (arm 1 main part).  
Section 5.1 – Overall design 
Figure 1: Minor text update. 
For clarification. 
Section 5.1 – Overall design 
The patient will receive his last dose 
on the day prior to visit 26a instead 
of on the day of Visit 26a. 
To align with the flowchart and 
protocol requirements of patients not 
injecting medication on the day of 
the visit before blood samples are 
taken, in order to ensure blood 
samples are collected pre-dose.  
Section 5.1 – Overall design 
The 56-week cut-off has been further 
defined. 
For clarification. 
Section 5.2.1 – Concizumab 
prophylaxis 
For patients on prior PPX, wash-out 
period of aPCC, ByClot® and other 
products, has been clarified. 
For clarification. 
Section 5.2.1 – Concizumab 
prophylaxis 
Use of factor-product PPX before 
intramuscular injections (e.g. 
vaccinations) allowed. 
To allow use of factor PPX before 
intramuscular injections (e.g. 
vaccinations), which is common 
practice in many centres. 
Section 5.2.3 – Treatment of break-
through bleeding episodes 
Table 3: It is clarified that the patient 
must contact the centre before 
initiating treatment of a bleeding 
episode.  
For clarification.  
Section 5.2.3 – Treatment of break-
through bleeding episodes 
Footnote b and c from Table 3, 
updated to body text in front of the 
table. 
For clarification. 
Section 5.2.3 – Treatment of break-
through bleeding episodes 
Section of Severe and life-
threatening bleeding episodes added 
in alignment with Appendix 11 
(Breakthrough bleed treatment 
guidance).   
For clarification. 
Section 5.3 – Patient and trial 
completion 
Number of patients planned to be 
screened has been adjusted from 161 
to 180. 
To adjust for patients who were 
screen failed at Sponsor’s decision 
due to the treatment pause, and the 
replacement of withdrawn patients 
following the treatment pause. 
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Section 7.1.2 - Investigational 
medical device (in vitro diagnostic 
device) 
Section added to the protocol. 
Concizumab plasma concentration 
for dose adjustment will be analysed 
using the concizumab ELISA IVD.  
Section 8.1.1 - Temporary 
discontinuation of concizumab in 
relation to COVID-19 
Text edit to allow COVID-19 to be 
considered as resolved based either 
on a negative PCR test or a clinical 
judgement. 
To comply with local practises for 
handling of COVID-19, and to 
account for possible false positive 
COVID-19 tests in the time after 
resolved disease. 
Section 9 – Trial assessments and 
procedures 
Sentence deleted: Any additional 
transfer of relevant data from 
NN7415-4322 (explorer 6) to be 
used for analyses in this trial will be 
specified in the SAP. 
All data needed will be transferred as 
appropriate. There is no need for 
further specification.  
Section 9.2.2 – Treatment with 
concizumab 
Time frame for visit windows 
specified. 
For clarification. 
Section 9.2.5 – Physical activity 
tracker (ActiGraph) 
Description of safety reporting for 
the activity tracker has been added.  
For clarification. 
Section 9.2.6 – Patient-reported 
outcome questionnaires 
Mandatory completion of PRO 
questionnaires on the day of the visit 
at visit 2a and visit 9a. 
Change is included to emphasize the 
importance of completing visit 2a 
and visit 9a PRO questionnaires on 
the day of the visit and hereby ensure 
data quality and integrity. For the 
Hemo-TEM questionnaire, the 
patient is asked to think about their 
current treatment while answering 
the questionnaire and therefore, it is 
important to have the questionnaires 
administered just before the patients 
start concizumab treatment (v2a for 
arms 2,3 and 4; v9a for arm 1) for a 
baseline measure based on their pre-
concizumab treatment.  
Section 9.2.7 – Clinical efficacy 
laboratory assessments 
Primary analysis cut-off corrected to 
confirmatory analyses cut-off for 
reporting of thrombin generation 
results. 
For clarification. 
Section 9.3 - Adverse events 
Reference to Appendix 8 has been 
added. 
To cover adverse device effects 
related to the concizumab ELISA 
IVD. 
Section 9.3.5 - Reporting 
requirement for safety information 
related to the physical activity 
tracker 
New section has been added to the 
protocol  
Description of safety reporting for 
the activity tracker has been added to 
the protocol for clarification. 
Section 9.3.6 - Disease-related 
events and/or disease-related 
outcomes and other information not 
qualifying as an AE or SAE 
To clarify that bleeds recorded as 
AE/SAE also are reported as bleeds 
in the bleed diary. 
 
To avoid any contradiction (between 
Section 9.2.3 and 9.3.6) potentially 
resulting in bleeding episodes only 
being recorded as AE/SAE and not 
also as bleeding episodes in 
accordance with Section 9.2.3. 
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Trial ID: NN7415-4307 
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9.3.7 - Technical complaints 
Figure 5 deleted and reference to 
Appendix 7 added regarding 
timelines for reporting of technical 
complaints. 
Figure deleted as it did not 
sufficiently cover timelines for the 
investigational medical device. 
Timelines added in Appendix 7. 
Section 9.4.6 - Clinical safety 
laboratory assessments 
Exception on urinalysis for reporting 
to the sites by the central laboratory 
is added. 
For clarification. 
Section 9.4.6 - Clinical safety 
laboratory assessments 
Section for concizumab ELISA (PK 
ELISA and ELISA IVD) added 
To describe samples collected for 
analysis of plasma concizumab 
exposure using the concizumab 
ELISA IVD and validation of the 
assay 
 
Section 9.5 - Pharmacokinetics 
Specified that visit 4a (arm 2, 3, 4) 
and visit 9a.2 (arm 1) should be re-
scheduled if the patient has taken the 
daily dose of concizumab before 
collection of the concizumab ELISA 
sample 
To clarify the importance that the 
patient has not taken his daily dose 
before coming to the clinic. Dosing 
should be performed after blood 
collection for dose adjustment. 
Section 9.9 - Surgery 
Sentence added: In the instance of 
acute major surgery, it is 
recommended to pause concizumab 
at the discretion of the investigator. 
For clarification 
Section 10.3 – Statistical analyses 
Simplification of the sentence for 
multiple bleeding episodes: 
Multiple bleeding locations 
occurring from the same event (e.g., 
due to a bicycle accident) or at the 
same time point will be counted as 
one bleeding episode.  
Data are not collected on whether 
bleeding episodes in multiple 
locations occur from the same event. 
However, if there are any such, they 
will occur at the same time point and 
this is still collected and taken into 
account. 
Section 10.3.2.1 – Confirmatory 
secondary endpoints 
Correction of typo. “No” changed to 
“previous” in the following 
sentence: 
The estimated ratio of ABR between 
the treatment regimens (concizumab 
prophylaxis versus no previous 
prophylaxis) with corresponding 
95% confidence interval and also 
estimates of the actual ABRs with 
corresponding 95% confidence 
intervals in each treatment period 
will be presented.  
For alignment with the confirmatory 
secondary endpoints and the 
estimands addressing the two 
secondary efficacy objectives  
described in Sections 4.3.2.1, 4.2  
and in the synopsis, Section 1. 
Appendix 1 - Abbreviations and 
Trademarks 
Abbreviations list updated 
New abbreviations used throughout 
the protocol  
Appendix 2 – Clinical laboratory 
tests 
Specification of pre-dose sampling 
of laboratory tests 
For clarification 
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Appendix 2 - Clinical laboratory 
tests 
Concizumab ELISA IVD added to 
Table 17 for protocol-required 
efficacy laboratory assessments 
To cover the concizumab ELISA 
IVD device 
Appendix 4 - Trial governance 
considerations 
Updated description of responsibility 
for Novo Nordisk safety committee:  
To clarify the responsibility of the 
internal safety committee 
Appendix 7 - Technical complaints: 
Definition and procedures for 
recording, evaluation, follow-up and 
reporting 
Technical complaints on 
investigational medical device has 
been included and reference to new 
appendix 8 added 
To cover the concizumab ELISA in 
vitro diagnostic device 
Appendix 8 - AEs, ADEs, SAEs, 
SADEs, USADEs and device 
deficiencies: Definitions and 
procedures for recording, evaluating, 
follow-up, and reporting in Medical 
device studies 
New Appendix has been added the 
protocol  
To cover adverse device effects 
related to the concizumab ELISA 
IVD  
Appendix 11 - Breakthrough bleed 
treatment guidance 
Table 22: It is clarified that the 
patient must contact the centre 
before initiating treatment of a 
bleeding episode.  
For clarification  
Appendix 11 - Breakthrough bleed 
treatment guidance 
Footnote b and c from Table 3, 
updated to body text in front of the 
table 
For clarification 
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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 
18-Jul-2019 
Israel 
It was decided that the genetic 
testing and biobank part will be 
omitted from the protocol. 
Amendment implemented in 
appendix 10 – Country-
specific requirements 
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 
08-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 
09-Jul-2019 
Germany/ 
Site 
 
The rationale for this amendment, 
is to ensure that at selected sites, 
patients participating in 
NN7415-4307 (explorer 8) 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. 
 
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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 selected sites, 
patients participating in 
NN7415-4307 (explorer 8) 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 
09-Jul.2019 
Sweden/ 
Site 
 
The rationale for this amendment, 
is to ensure that at selected sites, 
patients participating in NN7415-
4307 (explorer 8) 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. 
 
 
5.0 
14-Nov-2019 
UK/ 
Site 
 
The rationale for this amendment, 
is to ensure that at selected sites, 
patients participating in NN7415-
4307 (explorer 8) 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.  
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 
N/A 
N/A 
Not in use 
N/A 
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............................................................................................................................................ 10 
1 Synopsis ...................................................................................................................................................... 13 
2 Flowchart ................................................................................................................................................... 19 
2.1 
Pharmacokinetic (PK)/Pharmacodynamic (PD) sampling flowchart ............................................... 26 
3 Introduction ............................................................................................................................................... 27 
3.1 
Trial rationale .................................................................................................................................... 27 
3.2 
Background ....................................................................................................................................... 27 
3.3 
Benefit-risk assessment ..................................................................................................................... 28 
4 Objectives and endpoints .......................................................................................................................... 31 
4.1 
Primary, secondary and exploratory objectives ................................................................................ 31 
4.1.1 
Primary objectives ............................................................................................................. 31 
4.1.2 
Secondary objectives ......................................................................................................... 31 
4.1.3 
Exploratory objectives ....................................................................................................... 31 
4.2 
Estimands .......................................................................................................................................... 31 
4.3 
Primary, secondary and exploratory endpoints ................................................................................. 34 
4.3.1 
Primary endpoints .............................................................................................................. 34 
4.3.2 
Secondary endpoints .......................................................................................................... 34 
4.3.2.1 
Confirmatory secondary endpoints ................................................................ 34 
4.3.2.2 
Supportive secondary endpoints .................................................................... 35 
4.3.3 
Exploratory endpoints........................................................................................................ 40 
5 Trial design ................................................................................................................................................ 41 
5.1 
Overall design ................................................................................................................................... 41 
5.2 
Treatment of patients ........................................................................................................................ 43 
5.2.1 
Concizumab prophylaxis ................................................................................................... 43 
5.2.2 
On-demand treatment ........................................................................................................ 44 
5.2.3 
Treatment of break-through bleeding episodes ................................................................. 44 
5.2.4 
Treatment during screening and follow-up period ............................................................ 46 
5.3 
Patient and trial completion .............................................................................................................. 46 
5.4 
End of trial definition ........................................................................................................................ 46 
5.5 
Scientific rationale for trial design .................................................................................................... 46 
5.5.1 
Rationale for non-inferiority margin ................................................................................. 48 
5.6 
Justification for dose ......................................................................................................................... 48 
5.7 
Rationale for Trial Population .......................................................................................................... 49 
6 Trial population ......................................................................................................................................... 50 
6.1 
Inclusion criteria ............................................................................................................................... 50 
6.2 
Exclusion criteria .............................................................................................................................. 50 
6.3 
Screen failures ................................................................................................................................... 51 
6.4 
Randomisation criteria ...................................................................................................................... 51 
7 Treatments ................................................................................................................................................. 52 
7.1 
Treatments administered ................................................................................................................... 52 
7.1.1 
Medical devices ................................................................................................................. 52 
7.1.2 
Investigational medical device (in vitro diagnostic device) .............................................. 53 
7.2 
Method of treatment assignment ....................................................................................................... 53 
7.3 
Blinding ............................................................................................................................................ 54 
7.4 
Preparation/Handling/Storage/Accountability .................................................................................. 54 
7.5 
Treatment compliance ....................................................................................................................... 55 
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7.6 
Concomitant medication ................................................................................................................... 56 
7.6.1 
Prohibited medication ........................................................................................................ 56 
7.7 
Treatment after the end of the trial .................................................................................................... 56 
8 Discontinuation/Withdrawal criteria ...................................................................................................... 57 
8.1 
Discontinuation of trial treatment ..................................................................................................... 57 
8.1.1 
Temporary discontinuation of concizumab in relation to COVID-19 ............................... 57 
8.1.2 
Sponsor-initiated discontinuation of trial product in relation to the treatment pause ........ 58 
8.2 
Withdrawal from the trial .................................................................................................................. 58 
8.2.1 
Replacement of patients..................................................................................................... 59 
8.3 
Lost to follow-up............................................................................................................................... 59 
9 Trial assessments and procedures............................................................................................................ 60 
9.1 
Patient related information/assessments ........................................................................................... 61 
9.1.1 
Demography ...................................................................................................................... 61 
9.1.2 
Details of Haemophilia ...................................................................................................... 62 
9.1.3 
Haemophilia Treatment and Bleed History ....................................................................... 62 
9.1.4 
Target Joints ...................................................................................................................... 63 
9.2 
Efficacy assessments ......................................................................................................................... 63 
9.2.1 
eDiary ................................................................................................................................ 63 
9.2.2 
Treatment with concizumab .............................................................................................. 64 
9.2.3 
Bleeding episodes .............................................................................................................. 65 
9.2.4 
Sport activity ..................................................................................................................... 67 
9.2.5 
Physical activity tracker (ActiGraph) ................................................................................ 67 
9.2.6 
Patient-reported outcome questionnaires ........................................................................... 69 
9.2.7 
Clinical efficacy laboratory assessments ........................................................................... 70 
9.3 
Adverse events .................................................................................................................................. 71 
9.3.1 
Time period and frequency for collecting AE and SAE information ................................ 71 
9.3.1.1 
Adverse event of special interest .................................................................... 72 
9.3.2 
Method of detecting AEs and SAEs .................................................................................. 73 
9.3.3 
Follow-up on AEs and SAEs ............................................................................................. 73 
9.3.4 
Regulatory reporting requirements for SAEs .................................................................... 73 
9.3.5 
Reporting requirement for safety information related to the physical activity tracker ...... 73 
9.3.6 
Disease-related events and/or disease-related outcomes and other information not 
qualifying as an AE or SAE .............................................................................................. 74 
9.3.7 
Technical complaints ......................................................................................................... 74 
9.3.8 
Treatment of overdose ....................................................................................................... 74 
9.3.9 
Trial stopping rules ............................................................................................................ 74 
9.4 
Safety assessments ............................................................................................................................ 75 
9.4.1 
Concomitant illness and Medical History ......................................................................... 75 
9.4.2 
Physical examinations ....................................................................................................... 75 
9.4.3 
Body measurements ........................................................................................................... 76 
9.4.4 
Vital signs .......................................................................................................................... 76 
9.4.5 
Electrocardiogram (ECG) .................................................................................................. 76 
9.4.6 
Clinical safety laboratory assessments .............................................................................. 77 
9.4.7 
Immunogenicity assessments ............................................................................................ 78 
9.4.8 
Hypersensitivity reaction ................................................................................................... 79 
9.4.9 
Injection site reactions ....................................................................................................... 80 
9.5 
Pharmacokinetics .............................................................................................................................. 80 
9.6 
Pharmacodynamics ........................................................................................................................... 81 
9.7 
Human Biological Specimen for storage .......................................................................................... 81 
9.7.1 
Genetics ............................................................................................................................. 81 
9.7.2 
Biomarkers ........................................................................................................................ 81 
9.8 
Health economics .............................................................................................................................. 83 
9.9 
Surgery .............................................................................................................................................. 83 
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10 Statistical considerations .......................................................................................................................... 85 
10.1 Sample size determination ................................................................................................................ 85 
10.2 Definition of analysis sets ................................................................................................................. 87 
10.3 Statistical analyses ............................................................................................................................ 88 
10.3.1 
Primary endpoint ............................................................................................................... 89 
10.3.2 
Secondary endpoints .......................................................................................................... 90 
10.3.2.1 
Confirmatory secondary endpoints ................................................................ 90 
10.3.2.2 
Supportive secondary endpoints .................................................................... 91 
10.3.3 
Exploratory endpoints........................................................................................................ 91 
10.3.4 
Interim analyses ................................................................................................................. 91 
10.3.5 
Sequential safety analysis and safety monitoring .............................................................. 91 
10.3.6 
Explorative statistical analysis for pharmacogenetics and biomarkers ............................. 91 
10.4 Pharmacokinetic and/or pharmacodynamic modelling ..................................................................... 91 
11 References .................................................................................................................................................. 93 
12 Appendices ................................................................................................................................................. 95 
Appendix 1 
Abbreviations and Trademarks .............................................................. 95 
Appendix 2 
Clinical laboratory tests ......................................................................... 98 
Appendix 3 
Blood sampling in patients below 18 years of age............................... 100 
Appendix 4 
Trial governance considerations .......................................................... 102 
Appendix 5 
Adverse events: definitions and procedures for recording, 
evaluation, follow-up, and reporting .................................................... 110 
Appendix 6 
Sports ratings by activity ..................................................................... 117 
Appendix 7 
Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting ..................................................... 119 
Appendix 8 
AEs, ADEs, SAEs, SADEs, USADEs and device deficiencies: 
Definitions and procedures for recording, evaluating, follow-up, 
and reporting in medical device studies ............................................... 121 
Appendix 9 
Retention of human biosamples ........................................................... 126 
Appendix 10 Country-specific requirements ............................................................. 128 
Appendix 11 Breakthrough bleed treatment guidance .............................................. 131 
Appendix 12 Flowcharts applicable for patients enrolled before the treatment 
pause and who have permanently discontinued treatment prior to 
restart ................................................................................................... 135 
 
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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 without inhibitors. 
Objectives and endpoints: 
Primary objectives 
• To compare the effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with 
factor) in reducing the number of bleeding episodes in adult and adolescent patients with 
haemophilia A without inhibitors 
• To compare effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with 
factor) in reducing the number of bleeding episodes in adult and adolescent patients with 
haemophilia B without inhibitors 
Primary endpoints 
Endpoint title 
Time frame  
Unit 
For haemophilia A patients 
without inhibitors:  
The number of treated 
spontaneous and traumatic 
bleeding episodes 
On demand (arm 1) 
• From randomisation after the pause 
(week 0) up until start of concizumab 
treatment (week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses cut-off (at least 32 weeks)  
Count 
For haemophilia B patients 
without inhibitors:  
The number of treated 
spontaneous and traumatic 
bleeding episodes 
On demand (arm 1) 
• From randomisation after the pause 
(week 0) up until start of concizumab 
treatment (week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses cut-off (at least 32 weeks) 
Count 
 
Secondary objectives 
• To compare the effect of concizumab prophylaxis to the patients’ previous prophylaxis 
treatment in reducing the number of bleeding episodes in adult and adolescent patients with 
haemophilia A without inhibitors 
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• To compare the effect of concizumab prophylaxis to the patients’ previous prophylaxis 
treatment in reducing the number of bleeding episodes in adult and adolescent patients with 
haemophilia B without inhibitors 
• To investigate the safety of concizumab prophylaxis in adult and adolescent patients with 
haemophilia A or B without inhibitors 
• To investigate the PK and PD parameters of concizumab prophylaxis in adult and adolescent 
patients with haemophilia A or B without inhibitors 
Confirmatory secondary endpoints 
Endpoint title 
Time frame  
Unit 
Effect 
For haemophilia A patients 
without inhibitors: The 
number of treated 
spontaneous and traumatic 
bleeding episodes   
Arm 4 patients who have been on stable PPX at 
least 24 weeks in study 4322 
• For previous PPX (study 4322): From the point 
in time where PPX treatment is stablea and up 
until the end of study. 
• For concizumab PPX (trial 4307): From the 
point in time where the concizumab 
maintenance dose is confirmed, increased or 
decreased and up until the confirmatory 
analyses cut-off (at least 24 weeks). 
Count 
For haemophilia B patients 
without inhibitors: The 
number of treated 
spontaneous and traumatic 
bleeding episodes  
Arm 4 patients who have been on stable PPX at 
least 24 weeks in study 4322 
• For previous PPX (study 4322): From the point 
in time where PPX treatment is stablea and up 
until the end of study. 
• For concizumab PPX (trial 4307): From the 
point in time where the concizumab 
maintenance dose is confirmed, increased or 
decreased and up until the confirmatory 
analyses cut-off (at least 24 weeks). 
Count 
aStable is defined as the time after an initial period on PPX treatment of at least 24 weeks 
Estimands: 
The five components of the estimand for the primary objective for HA patients are as follows: 
Endpoint:  
• On demand (arm 1): The number of treated spontaneous and traumatic bleeding episodes from 
randomisation after the pause (week 0) up until start of concizumab treatment (week 24) 
• 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 confirmatory analyses 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 
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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 randomised 
treatment regimens. 
• Intercurrent events: 1) permanent treatment discontinuation, 2) temporary treatment 
discontinuation, 3) use of factor-containing products not related to treatment of a bleed and 4) 
minor surgery.  
• Target patient population: HA patients previously treated on demand before entering the trial. 
The same five components apply for the estimand for HB patients where HA in the target patient 
population is substituted with HB. 
Utilizing these five components, the estimand for the primary objectives can be described as the 
treatment ratio of the ABRs for treated spontaneous or traumatic bleeding episodes up until the 
confirmatory analyses cut-off between the two randomised 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 primary 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 and there will be no 
imputation of missing data. 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. 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 and there will be no imputation of missing data. 
4) Minor surgery. For this intercurrent event the ‘treatment policy’ strategy is used. 
The five components of the estimand for the secondary efficacy endpoints addressing the secondary 
efficacy objectives are as follows for HA patients: 
• Endpoint: 
Arm 4 patients who have been on stable PPX for at least 24 weeks in study 4322:  
• For previous PPX (study 4322): The number of treated spontaneous or traumatic bleeding 
episodes from the point in time where PPX is stable and up until the end of study. 
• For concizumab PPX (trial 4307): The number of treated spontaneous or traumatic bleeding 
episodes from the point in time where the concizumab maintenance dose is confirmed, increased 
or decreased and up until the confirmatory analyses cut-off. 
• Treatment regimens: a) intravenous PPX treatment with factor-containing products and 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) 
and followed by a maintenance dose of either 0.15, 0.20 or 0.25 mg/kg. During both treatment 
regimens, breakthrough bleeds can be treated intravenously with factor-containing products. 
• Population-level summary: The treatment ratio of the ABRs between the two treatment 
regimens. 
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• Intercurrent events: 1) permanent treatment discontinuation in trial 4307, 2) temporary 
treatment discontinuation, 3) use of factor products not related to treatment of a bleed in trial 
4307, 4) minor surgery, and 5) major surgery (during the non-interventional study 4322). 
• Target patient population: HA patients on stable PPX treatment for at least 24 weeks in the 
non-interventional study 4322 and have started the concizumab maintenance dose PPX regimen 
(i.e., completed the dose adjustment period). 
The same five components apply for the estimand for HB patients where HA in the target patient 
population is substituted with HB. 
Utilizing these five components, the estimand for the secondary efficacy objectives can be 
described as the treatment ratio of the ABRs for treated spontaneous or traumatic bleeding episodes: 
• For the previous PPX treatment (study 4322): From the point in time where PPX treatment is 
stable and up until the end of the study.  
• For concizumab PPX (trial 4307): from the point in time where the maintenance dose is 
confirmed, escalated or de-escalated and up until the confirmatory analyses cut-off.  
between the two PPX treatment regimens in the target patient population while patients are adhering 
to the allocated treatment regimens. 
The strategies for how to account for the intercurrent events in the estimand are as follows: 
1. Permanent treatment discontinuation. This intercurrent event is only applicable when a 
patient is part of trial 4307 (after the dose adjustment period) because if permanent PPX 
treatment discontinuation occurs for a patient in the non-interventional study 4322 then this 
patient is not part of the target patient population. If the intercurrent event occurs in trial 
4307 then the data from the period after permanent discontinuation of trial treatment are not 
included and there will be no imputation of missing data. 
2. Temporary treatment discontinuation. 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 in trial 4307. For this intercurrent 
event, the data during this period are not included and there will be no imputation of missing 
data. 
4. Minor surgery. For this intercurrent event the ‘treatment policy’ strategy is used.  
5. Major surgery: This intercurrent event is only applicable when a patient is part of the 
non-interventional study 4322 because planned major surgery is not allowed in trial 4307 
after restart. Thus, for a fair comparison this intercurrent event will be handled by use of the 
‘hypothetical strategy’ meaning that the data, from the start of the major surgery and until 
the stop date when post-surgical period has ended and the patient resumes the regular 
treatment regimen, will be excluded.  
Overall design: 
This is a prospective, multicentre, open label clinical trial with two randomised arms and two non-
randomised arms. The trial aims to evaluate the effect and safety of daily concizumab prophylaxis 
administered s.c. in patients with haemophilia without inhibitors. After screening patients will be 
assigned to randomisation or to allocation into non-randomised treatment arms based on their 
treatment regimen before the trial. Patients who were randomised to arms 1 and 2 before the pause 
will enter arm 4 when restarting the trial. Patients who were allocated to arms 3 and 4 before the 
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pause will re-enter the arm they were initially allocated to. The randomisation into arms 1 and 2 will 
be restarted with new patients after the treatment pause.  
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 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 severe haemophilia A (FVIII <1%) or B (FIX ≤2%). 
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. 
• 
Presence of confirmed inhibitors ≥ 0.6 BU at screening. 
• 
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: 180 
Number of patients planned to be started on trial product: 158 
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.  
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Treatment groups and duration: 
Duration of treatment will be up to 160 weeks. 
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 arms 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
Concomitant 
illness 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 arms 
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 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Details of 
Haemophilia 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haemophilia 
treatment and 
bleed history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Target Joints 
X 
Xe 
 
 
 
 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
discontinuation 
criteria 
 
Xh 
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 
 
Xi  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
Body 
Measurementsj 
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 
 
Xk 
X 
X 
 
X 
X 
X 
X 
Xk 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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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 arms 
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 
Sport activity 
 
X  
 
 
 
 
 
Xf 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concizumab 
ELISAl 
 
Xk 
X 
Xm 
 
X 
X 
X 
X 
Xk 
X 
Xm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Free TFPI 
 
Xk 
X 
X 
 
X 
X 
X 
X 
Xk 
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 
Factorsn 
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 
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 
 
 
 
 
 
 
 
Xf 
 
 
 
Xg 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
VV-CLIN-143484
1.0
VV-TMF-4359489
1.0

Protocol 
      
Date: 
25 March 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4307 
      
Version: 
5.0 
Page: 
22 of 138 
 
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 arms 
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 
Vital signs 
X 
X 
X 
X 
Xo 
X 
X 
X 
X 
X 
X 
X 
Xo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-
concizumab 
antibodiesl 
X 
Xg 
 
Xg 
 
Xg Xg Xg Xg 
X 
 
 
 
Xg 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
FVIII/FIX 
inhibitor 
analysis 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF36 V2.0 
Health 
Survey 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient 
preference 
questionnaire 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS 
Short Form 
Upper 
Extremity 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS 
Numeric 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-143484
1.0
VV-TMF-4359489
1.0

Protocol 
      
Date: 
25 March 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4307 
      
Version: 
5.0 
Page: 
23 of 138 
 
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 arms 
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 
Rating Scale 
- Pain 
Intensity 
Haemophilia 
Treatment 
Experience 
Measure 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haem-A-
QoLp 
X 
Xq 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGI-S on 
physical 
functioning  
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xg  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGI-C on 
physical 
functioning 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xg  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TRIAL 
MATERIAL 
 
Administration 
of Trial Poduct 
(on site) 
 
Xg 
 
 
 
 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose 
Adjustmentr 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug 
Dispensing 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
VV-CLIN-143484
1.0
VV-TMF-4359489
1.0

Protocol 
      
Date: 
25 March 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4307 
      
Version: 
5.0 
Page: 
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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 arms 
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 
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 
storages 
Xt 
 
 
 
 
 
X 
 
 
Xf 
 
 
 
Xg 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
actGraph 
dispensingu 
X 
 
 
 
 
 
 
Xf 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
actiGraph 
collectionu 
 
X 
 
 
 
 
 
 
 
Xf 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand out 
Direction for 
Use 
 
Xg 
 
 
 
 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand out 
patient ID card 
and patient 
material 
X 
Xq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand out 
eDiary 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
End of Trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
VV-CLIN-143484
1.0
VV-TMF-4359489
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Protocol 
      
Date: 
25 March 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4307 
      
Version: 
5.0 
Page: 
25 of 138 
 
 
 
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 Section 9.2.2 
d) Only patients enrolled in the trial after the treatment pause, will sign the Informed Consent at visit 1a 
e) Only patients enrolled in the trial before the treatment pause, will re-consent at visit 2a 
f) 
Only applicable for patients in arm 1, who are receiving concizumab at visit 9a 
g) Only applicable for patients in arm 2, 3 and 4, who are receiving concizumab at visit 2a 
h) Only applicable for patients enrolled in the trial before treatment pause. Site must ensure patients do not violate discontinuation criteria according to Section 8 before 
reinitiating dosing with concizumab. 
i) 
Patients randomised to arm 1 and 2 before the treatment pause will not be re-randomised at visit 2a  
j) 
Weight only, except at visit 1 where height is measured  
k) 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 
l) 
Sample is taken pre-dose. Patients must not inject trial medication on this visit day before the sample is taken. 
m) 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 
n) Only one sample to be taken, either factor VIII for HA patients or factor IX for HB patients 
o) Only applicable for patients having site visit due to dose-escalation 
p) Only for patients above ≥17 years old (at visit 1a) 
q) Only applicable for patients enrolled in the trial before the treatment pause 
r) 
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  
s) 
A separate Informed Consent Form must be signed before any samples are taken. See Section 9.7 for further details  
t) 
Whole blood for DNA is only taken at screening 
u) See Section 9.2.5 for further details 
 
 
VV-CLIN-143484
1.0
VV-TMF-4359489
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Protocol 
      
Date: 
25 March 2021 
Status: 
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Novo Nordisk 
Trial ID: NN7415-4307 
      
Version: 
5.0 
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2.1 
Pharmacokinetic (PK)/Pharmacodynamic (PD) sampling flowchart 
 
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 
VV-CLIN-143484
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VV-TMF-4359489
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CONFIDENTIAL 
Date: 
25 March 2021 
Novo Nordisk 
Trial ID: NN7415-4307 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
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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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Trial ID: NN7415-4307 
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Haemophilia global survey of 2017, the inhibitor prevalence is highest in HA accounting for 94% of 
the inhibitor cases.3 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 
4.0)) 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 
VV-CLIN-143484
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25 March 2021 
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Trial ID: NN7415-4307 
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Status: 
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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). 
• Continuation of previous PPX for up to two weeks after initiation of concizumab dosing is no 
longer allowed (see Section 5.2.1) 
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• 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 
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 objectives 
• To compare the effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with 
factor) in reducing the number of bleeding episodes in adult and adolescent patients with 
haemophilia A without inhibitors 
• To compare effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with 
factor) in reducing the number of bleeding episodes in adult and adolescent patients with 
haemophilia B without inhibitors 
4.1.2 
Secondary objectives 
• To compare the effect of concizumab prophylaxis to the patients’ previous prophylaxis 
treatment in reducing the number of bleeding episodes in adult and adolescent patients with 
haemophilia A without inhibitors 
• To compare the effect of concizumab prophylaxis to the patients’ previous prophylaxis 
treatment in reducing the number of bleeding episodes in adult and adolescent patients with 
haemophilia B without inhibitors 
• To investigate the safety of concizumab prophylaxis in adult and adolescent patients with 
haemophilia A or B without inhibitors 
• To investigate the PK and PD parameters of concizumab prophylaxis in adult and adolescent 
patients with haemophilia A or B without inhibitors 
4.1.3 
Exploratory objectives 
• To compare the patient-reported outcomes (PRO) in adult and adolescent patients with 
haemophilia A or B without inhibitors treated with concizumab prophylaxis to the PROs in 
patients treated with no prophylaxis 
• To explore treatment preference for concizumab prophylaxis versus no prophylaxis or previous 
prophylaxis treatment in adult and adolescent patients with haemophilia A or B without 
inhibitors 
4.2 
Estimands 
The five components of the estimand for the primary objective for HA patients are as follows: 
• Endpoint:  
• On demand (arm 1): The number of treated spontaneous and traumatic bleeding episodes from 
randomisation after the pause (week 0) up until start of concizumab treatment (week 24) 
• 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 confirmatory analyses 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 
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where breakthrough bleeds are treated with intravenous replacement with factor-containing 
products. 
• Population-level summary: The treatment ratio of the ABRs between the two randomised 
treatment regimens. 
• Intercurrent events: 1) permanent treatment discontinuation, 2) temporary treatment 
discontinuation, 3) use of factor-containing products not related to treatment of a bleed (see 
Section 5.2.1) and 4) minor surgery.  
• Target patient population: HA patients previously treated on demand before entering the trial. 
The same five components apply for the estimand for HB patients where HA in the target patient 
population is substituted with HB. 
Utilizing these five components, the estimand for the primary objectives can be described as the 
treatment ratio of the ABRs for treated spontaneous or traumatic bleeding episodes up until the 
confirmatory analyses cut-off between the two randomised 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 primary 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 and there will be no 
imputation of missing data. 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. 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 and there will be no imputation of missing data. 
4) Minor surgery. For this intercurrent event the ‘treatment policy’ strategy is used. The 
definition of minor surgery is outlined in Table 14. 
The five components of the estimand for the secondary efficacy endpoints addressing the secondary 
efficacy objectives are as follows for HA patients: 
• Endpoint:  
Arm 4 patients who have been on stable PPX for at least 24 weeks in study 4322:  
• For previous PPX (study 4322): The number of treated spontaneous or traumatic bleeding 
episodes from the point in time where PPX is stable and up until the end of study. 
• For concizumab PPX (trial 4307): The number of treated spontaneous or traumatic bleeding 
episodes from the point in time where the concizumab maintenance dose is confirmed, increased 
or decreased and up until the confirmatory analyses cut-off. 
• Treatment regimens: a) intravenous PPX treatment with factor-containing products and 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) 
and followed by a maintenance dose of either 0.15, 0.20 or 0.25 mg/kg. During both treatment 
regimens, breakthrough bleeds can be treated intravenously with factor-containing products. 
• Population-level summary: The treatment ratio of the ABRs between the two treatment 
regimens. 
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• Intercurrent events: 1) permanent treatment discontinuation in trial 4307, 2) temporary 
treatment discontinuation, 3) use of factor products not related to treatment of a bleed in trial 
4307, 4) minor surgery, and 5) major surgery (during the non-interventional study 4322). 
• Target patient population: HA patients on stable PPX treatment for at least 24 weeks in the 
non-interventional study 4322 and have started the concizumab maintenance dose PPX regimen 
(i.e., completed the dose adjustment period). 
The same five components apply for the estimand for HB patients where HA in the target patient 
population is substituted with HB. 
Utilizing these five components, the estimand for the secondary efficacy objectives can be 
described as the treatment ratio of the ABRs for treated spontaneous or traumatic bleeding episodes: 
• For the previous PPX treatment (study 4322): From the point in time where PPX treatment is 
stable and up until the end of the study.  
• For concizumab PPX (trial 4307): from the point in time where the maintenance dose is 
confirmed, escalated or de-escalated and up until the confirmatory analyses cut-off.  
between the two PPX treatment regimens in the target patient population while patients are adhering 
to the allocated treatment regimens. 
The strategies for how to account for the intercurrent events in the estimand are as follows: 
1. Permanent treatment discontinuation. This intercurrent event is only applicable when a 
patient is part of trial 4307 (after the dose adjustment period) because if permanent PPX 
treatment discontinuation occurs for a patient in the non-interventional study 4322 then this 
patient is not part of the target patient population. If the intercurrent event occurs in trial 
4307 then the data from the period after permanent discontinuation of trial treatment are not 
included and there will be no imputation of missing data. 
2. Temporary treatment discontinuation. 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 in trial 4307. For this intercurrent 
event, the data during this period are not included and there will be no imputation of missing 
data. 
4. Minor surgery. For this intercurrent event the ‘treatment policy’ strategy is used. The 
definition of minor surgery is outlined in Table 14. 
5. Major surgery: This intercurrent event is only applicable when a patient is part of the 
non-interventional study 4322 because planned major surgery is not allowed in trial 4307 
after restart. Thus, for a fair comparison this intercurrent event will be handled by use of the 
‘hypothetical strategy’ meaning that the data, from the start of the major surgery and until 
the stop date when post-surgical period has ended and the patient resumes the regular 
treatment regimen, will be excluded. The definition of major surgery is outlined Table 14. 
 
 
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4.3 
Primary, secondary and exploratory endpoints 
4.3.1 
Primary endpoints 
Endpoint title 
Time frame  
Unit 
For haemophilia A patients 
without inhibitors:  
The number of treated 
spontaneous and traumatic 
bleeding episodes 
On demand (arm 1) 
• From randomisation after the pause 
(week 0) up until start of concizumab 
treatment (week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses cut-off (at least 32 weeks) 
Count 
For haemophilia B patients 
without inhibitors:  
The number of treated 
spontaneous and traumatic 
bleeding episodes 
On demand (arm 1) 
• From randomisation after the pause 
(week 0) up until start of concizumab 
treatment (week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses cut-off (at least 32 weeks) 
Count 
4.3.2 
Secondary endpoints 
4.3.2.1 
Confirmatory secondary endpoints 
Endpoint title 
Time frame  
Unit 
Effect 
For haemophilia A patients 
without inhibitors: The 
number of treated 
spontaneous and traumatic 
bleeding episodes   
Arm 4 patients who have been on stable PPX at 
least 24 weeks in study 4322 
• For previous PPX (study 4322): From the point 
in time where PPX is stablea and up until the 
end of study. 
• For concizumab PPX (trial 4307): From the 
point in time where the concizumab 
maintenance dose is confirmed, increased or 
decreased and up until the confirmatory 
analyses cut-off (at least 24 weeks). 
Count 
For haemophilia B patients 
without inhibitors: The 
number of treated 
spontaneous and traumatic 
bleeding episodes  
Arm 4 patients who have been on stable PPX at 
least 24 weeks in study 4322 
• For previous PPX (study 4322): From the point 
in time where PPX is stablea and up until the 
end of study. 
• For concizumab PPX (trial 4307): From the 
point in time where the concizumab 
Count 
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maintenance dose is confirmed, increased or 
decreased and up until the confirmatory 
analyses cut-off (at least 24 weeks). 
aStable is defined as the time after an initial period on PPX treatment of at least 24 weeks 
4.3.2.2 
Supportive secondary endpoints 
Endpoint title 
Time frame  
Unit 
Effect 
For haemophilia A patients 
without inhibitors: Number of 
treated spontaneous bleeding 
episodes   
On demand (arm 1) 
• From randomisation after the pause 
(week 0) up until start of concizumab 
treatment (week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses cut-off (at least 32 weeks) 
Count 
For haemophilia B patients 
without inhibitors: Number of 
treated spontaneous bleeding 
episodes   
On demand (arm 1) 
• From randomisation after the pause 
(week 0) up until start of concizumab 
treatment (week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses cut-off (at least 32 weeks) 
Count 
For haemophilia A patients 
without inhibitors: Number of 
treated spontaneous and 
traumatic joint bleeds   
On demand (arm 1) 
• From randomisation after the pause 
(week 0) up until start of concizumab 
treatment (week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses cut-off (at least 32 weeks) 
Count 
For haemophilia B patients 
without inhibitors: Number of 
treated spontaneous and 
traumatic joint bleeds   
On demand (arm 1) 
• From randomisation after the pause 
(week 0) up until start of concizumab 
treatment (week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses cut-off (at least 32 weeks) 
Count 
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Endpoint title 
Time frame  
Unit 
For haemophilia A patients 
without inhibitors: Number of 
treated spontaneous and 
traumatic target joint bleeds   
On demand (arm 1) 
• From randomisation after the pause 
(week 0) up until start of concizumab 
treatment (week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses cut-off (at least 32 weeks) 
Count 
For haemophilia B patients 
without inhibitors: Number of 
treated spontaneous and 
traumatic target joint bleeds   
On demand (arm 1) 
• From randomisation after the pause (week 
0) up until start of concizumab treatment 
(week 24)  
Concizumab (arm 2) 
• From start of the new concizumab dosing 
regimen (week 0) up until the confirmatory 
analyses 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 pauseb: From start of 
concizumab treatment (week 0c) up until 
7 weeks after the treatment was paused 
as well as 
• After the pauseb: From start of concizumab 
treatment (week 0a) up until the 
confirmatory analyses cut-off (at least 32 
weeks) 
Concizumab (arm 1 extension part) 
• From start of concizumab treatment 
(visit 9a) up until the confirmatory analysis 
cut-off 
Count 
Number of thromboembolic 
events 
Concizumab 
• Before the pauseb: From start of treatment 
(week 0c) up until 7 weeks after the 
treatment was paused 
Count 
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Endpoint title 
Time frame  
Unit 
as well as 
• After the pauseb: 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 pauseb: From start of 
concizumab treatment (week 0c) up until 
7 weeks after the treatment was paused 
as well as 
• After the pauseb: From start of concizumab 
treatment (week 0a) up until the 
confirmatory analyses cut-off (at least 32 
weeks) 
Concizumab (arm 1 extension part) 
• From start of concizumab treatment 
(visit 9a) up until the confirmatory analysis 
cut-off 
Count 
Number of hypersensitivity 
type reactions  
Concizumab 
• Before the pauseb: From start of treatment 
(week 0c) up until 7 weeks after the 
treatment was paused 
as well as 
• After the pauseb: From start of concizumab 
treatment up until the end of trial (week 167) 
Count 
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 pauseb: From start of 
concizumab treatment (week 0c) up until 
7 weeks after the treatment was paused 
Count 
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Endpoint title 
Time frame  
Unit 
as well as 
• After the pauseb: From start of concizumab 
treatment (week 0a) up until the 
confirmatory analyses cut-off (at least 32 
weeks) 
Concizumab (arm 1 extension part) 
• From start of concizumab treatment 
(visit 9a) up until the confirmatory analysis 
cut-off 
Number of injection site 
reactions 
Concizumab 
• Before the pauseb: From start of treatment 
(week 0c) up until 7 weeks after the 
treatment was paused 
as well as 
• After the pauseb: From start of concizumab 
treatment up until the end of trial (week 
167) 
Count 
Number of patients with 
antibodies to concizumab  
Concizumab (arms 2-4) 
• Before the pauseb: From start of 
concizumab treatment (week 0c) up until 
7 weeks after the treatment was paused 
as well as 
• After the pauseb: From start of concizumab 
treatment (week 0a) up until the 
confirmatory analyses cut-off (at least 32 
weeks) 
Concizumab (arm 1 extension part) 
• From start of concizumab treatment 
(visit 9a) up until the confirmatory analysis 
cut-off 
Count 
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Endpoint title 
Time frame  
Unit 
Number of patients with 
antibodies to concizumab  
Concizumab 
• Before the pauseb: From start of treatment 
(week 0c) up until 7 weeks after the 
treatment was paused 
as well as 
• After the pauseb: From start of concizumab 
treatment up until the end of trial (week 
167) 
Count 
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 after the pause or time of start of the new concizumab 
dosing regimen. 
bDefined as the pause in the concizumab clinical development programme during March to August 2020, while 
thromboembolic events were investigated. 
cDefined as time of the initial randomisation to on-demand administration or time of start of the previous concizumab 
dosing regimen (0.25 mg/kg/day). 
dSafety will be described separately for patients randomised to on demand treatment before the pause. 
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4.3.3 
Exploratory endpoints 
Endpoint title 
Time frame  
Unit 
Patient reported outcomes 
Change in SF-36v2 bodily 
pain  
From baseline (week 0a) until week 24 
Score 
Change in SF-36v2 physical 
functioning  
From baseline (week 0a) until week 24 
Score 
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 
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 after the pause 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 two randomised arms and two non-
randomised arms. The trial aims to evaluate the effect and safety of daily concizumab prophylaxis 
administered s.c. in patients with HA and HB. Patients will be randomised to concizumab PPX or 
no PPX or assigned into the non-randomised treatment arms, based on their treatment regimen 
before entering the trial. Upon restart, patients who were randomised to arms 1 or 2 before the 
pause will enter arm 4. Patients who were allocated to arms 3 and 4 before the pause will re-enter 
the arm they were initially allocated to. The randomisation into arms 1 or 2 will be restarted with 
new patients. The main part of the trial is completed for a patient when the patient has completed 
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 confirmatory analyses cut-off will be defined as when all patients in arm 1 have completed visit 
9a (or withdrawn) and all patients in arms 2 and 4 have completed visit 10a (or withdrawn). This 
will ensure that all patients in arms 2 and 4 have completed the dose adjustment period and at least 
an additional 24 weeks of concizumab PPX on their final maintenance dose (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 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 previously participated in NN7415-4255 (explorer 5) 
• 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); 
bAdditional patients on OnD treatment or patients on PPX with factor replacement, patients from explorer5 enrolled 
after the treatment pause and patients randomised to arms 1 or 2 before the treatment pause. 
Abbreviations: OnD = on demand; PPX = prophylaxis; V = visit 
Figure 1 
Trial design 
The randomisation between the treatment arms 1 and 2 will be stratified according to haemophilia 
type and bleeding frequency during the 24 weeks prior to screening; see Section 7.2. 
Treatment arms 1 and 2: 
Approximately 60 patients (24 HA and 36 HB patients), previously treated on-demand, will be 
randomised 1:2 to no prophylaxis versus concizumab prophylaxis. 
Patients randomised to arm 1 before the pause were instructed to continue their on demand 
treatment and report data until trial restart. Patients who were randomised to arms 1 and 2 prior to 
the treatment pause should re-enter the trial in arm 4. Instead 60 new patients will be identified to 
be randomised into arms 1 or 2. 
Treatment arm 3: 
The HA patients enrolled into the concizumab phase 2 trial NN7415-4255 (explorer 5) were offered 
enrolment into arm 3. These patients continued concizumab PPX and had a combined visit 1 and 2. 
Upon trial restart, these patients will receive the new concizumab dosing regimen. After the initial 
dose adjustment period, patients will receive at least 24 weeks of treatment on their final 
maintenance dose (main part). Subsequently, these patients will be offered up to 128 weeks of 
concizumab PPX (extension part). 
Patients who were in NN7415-4255 (explorer 5) at the time of the treatment pause, and who have 
now completed explorer 5, will be offered screening in this trial and should enter arm 4 (visit 1a) as 
outlined below. 
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Treatment arm 4:  
Arm 4 will include at least 60 patients (30 HA and 30 HB patients) previously on prophylaxis with 
factor products with a minimum of 24 weeks observation in NN7415-4322 (explorer 6).  
In addition, arm 4 will also include: 
• Patients who were randomised to arms 1 and 2 before the treatment pause 
• HA patients who were in NN7415-4255 (explorer 5) at the time of the treatment pause, and who 
have now completed explorer 5 
• On demand patients included after arms 1 and 2 are closed 
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 4 - visit 2a 
Arm 2 
Arm 4 - visit 2a 
Arm 3 
Arm 3 - visit 2a 
Arm 4 
Arm 4 - visit 2a 
 
Table 2 below summarises the expected numbers of randomised/enrolled patients in each arm. In 
total 158 patients are expected to be enrolled. The aim is to have approximately 21 HA and 14 HB 
unique adolescent patients defined as patients between ≥12 to <18 years at trial start. 
Table 2 
Randomisation/enrolment overview 
 
Minimum number of patients randomised/enrolled  
Arm 1 
Arm 2 
Arm 3 
Arm 4 
Minimum number of PPX patients from 
NN7415-4322 (explorer 6) with at least 24 weeks 
observation period on stable PPX 
HA 
8 
16 
10 
30 
HB 
12 
24 
N/A 
30 
Note: In addition to the 60 patients needed for the confirmatory secondary analysis (within-patient comparison), arm 4 
will also include patients who were randomised to arms 1 or 2 before the treatment pause, HA patients from NN7415-
4255 (explorer 5) included after the treatment pause as well as on demand patients included after arms 1 and 2 are 
closed.  
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 
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9a.3 and will 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 
can 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, 
an interval of 2 half-lives from the given factor product to first concizumab dose 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 replacement therapy until visit 
9a (end of main part). 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). 
As noted in Section 5.1, Patients randomised to arm 1 before the pause will go to arm 4 upon restart 
of the trial. Thus, additional patients will be randomised to arm 1 (and 2) when restarting the trials. 
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 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, the dose must not exceed a single dose of 50 U/kg aPCC (FEIBA®), and 
not exceed 100 U/kg within 24 hours. 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 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, the dose must not exceed 60 µg/kg ByClot®, and not exceed 90 µg/kg 
ByClot® 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 
 
FVIII 
SHL 
FVIII 
EHL 
FIX 
SHL 
FIX 
EHL 
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  
20 IU/kg 
20 IU/kg 
30 IU/kg 
30 IU/kg 
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  20 IU/kg 
20 IU/kg 
30 IU/kg 
At 
investigator’s 
discretion 
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. 
Abbreviations: SHL=standard half-life, EHL=extended half-life 
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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 
(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 specified in Section 5.2.3. 
5.3 
Patient and trial completion 
Approximately 180 patients will be screened to achieve that at least 60 patients are randomly 
assigned to either no prophylaxis or trial product in the treatment arms 1 and 2. To achieve that up 
to 98 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 for patients with HA is to show the effect of concizumab prophylaxis (arm 2) 
is superior to no prophylaxis (arm 1, on-demand treatment) in adult and adolescent patients. The 
primary objective for patients with HB is to show the effect of concizumab prophylaxis (arm 2) is 
superior to no prophylaxis (arm 1, on-demand treatment). The first confirmatory secondary 
objective for HA patients aims at showing that the effect of concizumab prophylaxis is non-inferior 
to standard of care prophylaxis treatment. The first confirmatory secondary objective for HB 
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patients aims at showing that the effect of concizumab prophylaxis is non-inferior to standard of 
care prophylaxis treatment. 
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.  
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5.5.1 
Rationale for non-inferiority margin  
Within this trial a secondary confirmatory hypothesis is tested comparing patients previous PPX 
treatment with concizumab administration using a non-inferiority approach. The non-inferiority 
margin associated with this hypothesis is determined using the 95%-95% fixed margin approach as 
described in the FDA guidance.10 In the lack of placebo-controlled trials within haematology, a 
historical effect measure based on bleeding episodes has been estimated in a pooled analysis 
between on demand and PPX treatment. This analysis was conducted on 20 trials selected based on 
a literature search where both PPX treatment and on demand treatment is used. The treatment ratio 
(on demand over PPX treatment) and associated 95% confidence interval for ABR was estimated to 
7.47 [5.90;9.46]. By setting the non-inferiority margin at 2, approximately 60% of the effect will be 
preserved  
With this non-inferiority margin, in this rare disease indication, it will be possible to have sufficient 
number of patients to investigate the effect of concizumab PPX in patients previously treated with 
PPX. The choice of the non-inferiority margin is influenced by the expected PPX population in this 
global trial, where highly variable bleeding phenotype can be expected, as described above and 
observed in the phase 2. 
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.  
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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 
NN7415-4255 (explorer 5), 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.  
The patient population has been defined based on severity of haemophilia, because severity is 
known to correlate with the endogenous factor activity and the bleeding phenotype in patients 
without inhibitors. This is to select patients who have a high medical need or a bleeding frequency 
of 5 per 24 weeks. 
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. Pre-existing inhibitors or development of inhibitors during 
the trial would complicate and treatment of breakthrough bleeds in the affected patient. Therefore, 
patients with existing inhibitor or at risk for reoccurrence of inhibitor are excluded. 
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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 severe haemophilia A (FVIII < 1%) or moderate/severe B (FIX ≤ 2%).  
5. Documented treatment with coagulation factor containing product in the last 24 weeks (not 
applicable for NN7415-4255 (explorer 5) patients enrolled prior to the treatment pause). 
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 pause.  
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 NN7415-4255 patients enrolled prior to the treatment pause). 
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 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.  
10. A known systemic inflammatory condition requiring systemic treatment at screening. 
11. Treatment with emicizumab within 180 days before screening.  
12. Presence of confirmed inhibitor ≥0.6 BU at screening. 
13. Known history of inhibitors ≥0.6 BU in the last 5 years according to the medical records. 
14. Any disorder, except for conditions associated with haemophilia, which in the 
investigator’s opinion might jeopardise patient’s safety or compliance with the protocol. 
aIncludes arterial and venous thrombosis including myocardial infarction, pulmonary embolism, cerebral 
infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events and peripheral artery 
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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. 
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. 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 ≥5 documented treated bleeds in the last 24 weeks or ≥10 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 
 
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 
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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. 
The stratification variables are: 
• haemophilia type (HA, HB) 
• bleeding frequency during the 24 weeks prior to screening (<9 bleeding episodes, ≥9 bleeding 
episodes) 
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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. 
• 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.  
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• 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 
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. 
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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 Appendix 12.  
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 Appendix 12 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 after restart will not be replaced. 
Patients who were initially randomised to arms 1 or 2 before the pause will be transferred to arm 4 
when restarting the trial (see Section 5.1). Therefore, additional patients will be randomised to meet 
the required number for the primary analysis. Additionally, the required number of patients in 
NN7415-4322 (explorer 6) subsequently entering arm 4 will be ensured for the confirmatory 
secondary analysis.  
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 950 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.11 See Appendix 
3 for further details concerning blood sampling in adolescent patients. 
Shared assessments and data transfer from NN7415-4255 (explorer 5) and NN7415-4322 
(explorer 6) 
For patients enrolled into this trial from NN7415-4255 (explorer 5) 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 NN7415-4255 (explorer 5) before the pause, 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 visit 15.1) 
For previous NN7415-4255 (explorer 5) patients enrolled after the pause, there will be no shared 
assessments. These patients will have assessments made according to the flowchart in Section 2 
(visit 1a). 
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 NN7415-4255 (explorer 5) 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) 
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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  
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 
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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 
• 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. 
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The eDiary will have built in edit checks and reminders, to ensure that all relevant questions are 
answered. eDiary data transferred to the electronic database will be viewable to relevant trial site 
staff and Novo Nordisk personnel on a secure, password protected web portal. 
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 
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 
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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. 
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 
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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. 
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  
 
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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).12-20 
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 
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, NN7415-4255 (explorer 5), before the treatment 
pause, should not wear the physical activity tracker. 
Patients from NN7415-4255 (explorer 5) that were not enrolled in the trial at the time of the 
treatment pause should wear the tracker as described below. 
Remaining patients 
The instruction below includes new patients, patients currently in the trial, patients enrolled from 
NN7415-4322 (explorer 6) and patients from NN7415-4255 (explorer 5) who were not enrolled 
prior to the treatment pause. 
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 
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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. 
Table 11 shows an overview of when to use the ActiGraph physical activity tracker in this trial. 
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 
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.  
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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. 
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. 
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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 
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 
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results will be reported to the sites and in a bioanalytical report after the confirmatory analyses 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 confirmatory analyses 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 confirmatory analyses cut-off of the trial and at the end of 
the extension part. 
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. 
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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. 
 
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) 
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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. 
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 
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(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 
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 
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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. 
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 a AE/SAE (Section 9.3). 
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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. 
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 
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o Record if the result is clinically significant? (Yes/No) 
o If observed before or at Screening: record as concomitant illness/Medical History 
(Section 9.4.1) 
o If observed after screening: report and 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. 
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. 
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Plasma concizumab concentrations will be measured pre-dosing (trough) as specified in the 
flowchart in Section 22. 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 
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 
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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 
• Anti-concizumab neutralising antibodies 
The samples will be analysed and reported to sites at the confirmatory analyses 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 
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• 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) 
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. 
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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 
dose of concizumab before collection of the concizumab ELISA sample, then visit 4a (arm 2, 3, 4) 
or 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. 
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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. 
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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 
• 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.  
Haemophilia A and haemophilia B patients undergoing minor surgical procedures should be 
managed in accordance with local standard of care. Coagulation factor replacement therapy using 
either regular or extended half-life products are allowed and should be used in accordance with 
local label. 
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 replacement 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 
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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 objectives 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 estimand for the primary and 
confirmatory secondary objectives. In the below calculations it is assumed that the treatment 
duration is 24 weeks for patients in arms 1 and 32 weeks for patients in arm 2. For the comparison 
of previous PPX to concizumab PPX in arm 4 it is assumed that the treatment duration is 38 weeks 
(estimated from NN7415-4322 (explorer 6)) on the previous PPX regimen and 24 weeks on the 
concizumab maintenance dose. 
When evaluating the power of the negative binomial analysis with exposure time as offset and 
treatment as factor, annual bleeding rates of 24 and 18 are assumed for the no-prophylaxis HA 
patients, and the no-prophylaxis HB patients, respectively. An ABR of 3-5 is expected for 
concizumab prophylaxis. Assuming further a yearly over-dispersion of 13, the power for concluding 
superiority of concizumab prophylaxis versus no-prophylaxis for HA patients becomes at least 82% 
with 21 patients (14 in the concizumab arm and 7 in the comparator arm). The power for concluding 
superiority of concizumab prophylaxis versus no prophylaxis for HB patients becomes at least 79% 
with 33 patients (22 in the concizumab arm and 11 in the comparator arm). When evaluating the 
power of the negative binomial analysis (with exposure time as offset and treatment as factor and 
incorporating within-subject repeated measurements using an unstructured covariance matrix) with 
respect to showing non-inferiority of concizumab prophylaxis vs previous prophylaxis in a within-
patient comparison the assumptions are: Concizumab ABR of 3−5, an ABR for previous 
prophylaxis of 4, a noninferiority margin of 2.0 on the relative scale, a sample size of 30 and a 
yearly over-dispersion of 13, and a patient’s frailty for experiencing bleeds in the first period (on 
previous PPX) and the second period (on concizumab PPX) is fully correlated. With these 
assumptions the power will be at least 79% to show non-inferiority for each haemophilia subtype. 
ABR assumptions 
Based on the available studies and sources, a representative mean ABR on on-demand treatment for 
the severe haemophilia A patients of 24 bleeds/year and for the haemophilia B patients of 
18 bleeds/year is considered appropriate (see Table 15). 
Table 15 
Annualised bleeding rate recorded in prior Novo Nordisk studies conducted in 
different haemophilia subpopulations treated on-demand 
Regimen 
Population 
Study 
N 
ABR 
 
On demand 
HA 
NN7088-3859a 
12 
32.35 
HA 
NN7008-3568b 
19 
24 
HB 
NN7999-3747c 
13 
17.6 
Note: The ABR is recorded in prior Novo Nordisk studies conducted in different haemophilia subpopulations. 
aNN7088-3859 CTR extension 1, EOT 14.2.78; bNN7008-3568 CTR, EOT 14.2.65; cNN7999-3747 CTR, EOT 14.2.45 
It is the expectation to show an ABR for concizumab prophylaxis of approximately 3-5 bleeds/year. 
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Over-dispersion assumptions 
A yearly over-dispersion of 13 is deemed realistic based on experience from previous trials. 
Power 
Primary endpoint 
Assuming ABRs of 24 and 18 for the no-prophylaxis HA patients, and the no-prophylaxis HB 
patients, respectively, an ABR between 3 and 7 for the concizumab arm (arm 2) for both HA and 
HB patients, a yearly over dispersion varying between 11 and 15 and performing 10,000 
simulations of each group will produce different scenarios of power in superiority tabulated in 
Table 16 below. 
Table 16 
Power for superiority for patients with HA and HB respectively 
 Power (HAa/HBb) 
Yearly over-dispersion 
ABR concizumab 
11 
13 
15 
3 
94%/95% 
91%/92% 
88%/89% 
4 
92%/91% 
87%/86% 
83%/83% 
5 
87%/85% 
82%/79% 
78%/74% 
6 
83%/77% 
75%/70% 
70%/64% 
7 
76%/68% 
70%/62% 
66%/56% 
aFor HA, power is calculated with 21 patients randomised 2:1 assuming an ABR for the on-demand treatment of 24 
bFor HB, power is calculated with 33 patients randomised 2:1 assuming an ABR for the on-demand treatment of 18 
When evaluating the power of the negative binomial analysis with exposure time as offset and 
treatment regimen as factor, annual bleeding rates of 24 and 3−5 are assumed for the haemophilia A 
patient (or 18 and 3-5 for the haemophilia B patient) on no prophylaxis and on concizumab 
prophylaxis, respectively. Assuming further a yearly over-dispersion of 13, the power for 
concluding superiority of concizumab prophylaxis becomes at least 82% with 14 patients in the 
concizumab and 7 patients in the comparator arm for haemophilia A (or at least 79% with 22 
patients in the concizumab arm and 11 patients in the comparator arm for haemophilia B; see 
Table 16). 
Confirmatory secondary endpoint 
When evaluating the negative binomial analysis (with exposure time as offset, treatment as factor 
and incorporating within-subject repeated measurements using of an unstructured covariance 
structure) with respect to showing non-inferiority of concizumab prophylaxis vs previous 
prophylaxis in a within-patient comparison, the power of showing non-inferiority is at least 79% 
with a concizumab ABR of 3-5, an ABR for previous prophylaxis of 4, a non-inferiority margin of 
2.0 on the relative scale, a sample size of 30, a yearly over-dispersion of 13 and assuming a 
patient’s frailty for experiencing bleeds in the first period (on previous PPX) and the second period 
(on concizumab PPX) is fully correlated (i.e. a correlation of 1). Other scenarios with different 
assumptions are displayed in Table 17 below including scenarios where the assumption of a 
correlation of 1 is lowered to 0.8. 
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Table 17 
Power to demonstrate non-inferiority separately for patients with HA or HB 
 
 
 
Non-inferiority margin on relative scale 
Correlationa 
ABR on 
concizumab 
ABR on previous 
prophylaxis 
1.5 
1.8 
2.0 
 
 
 
 
 
 
1.0 
 
3 
2 
6% 
21% 
33% 
4 
95% 
99% 
>99% 
6 
>99% 
>99% 
>99% 
 
5 
2 
~0% 
~0% 
~0% 
4 
25% 
61% 
79% 
6 
97% 
>99% 
>99% 
 
7 
2 
~0% 
~0% 
~0% 
4 
0% 
6% 
17% 
6 
50% 
87% 
95% 
 
 
 
 
 
 
0.8 
 
3 
2 
5% 
12% 
18% 
4 
66% 
83% 
89% 
6 
96% 
99% 
>99% 
 
5 
2 
~0% 
~0% 
~0% 
4 
14% 
33% 
46% 
6 
71% 
89% 
95% 
 
7 
2 
~0% 
~0% 
~0% 
4 
~0% 
5% 
11% 
6 
26% 
55% 
71% 
a The spearman correlation between a patient’s frailty for experiencing bleeds in the first and the second treatment 
period. 
Combined power 
Assuming that the confirmatory secondary endpoint is independent of the primary endpoint the 
combined power becomes at least 82%*79% = 65% for haemophilia A patients and at least 62% for 
haemophilia B patients. 
Expected frequency and pattern of missing data 
Since treatment options for haemophilia patients are limited and there is a general tendency to 
continue with the treatment regimen, the completion rate for this study is expected to be high with 
less than 15 % withdrawing or discontinuing treatment prematurely. The study will randomise 24 
patients with haemophilia A and 36 with haemophilia B to account for potential withdrawals in 
particular in relation to other endpoints in this trial. 
10.2 
Definition of analysis sets 
The following analysis sets are defined: 
• Safety analysis set (SAS): All patients exposed to concizumab PPX or randomised to OnD.  
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• Full analysis set (FAS): All patients randomised to the new concizumab PPX dosing regimen or 
OnD after the treatment pause or allocated to arm 3 or 4 with the new concizumab PPX dosing 
regimen.  
For both analysis sets, the specific treatment arms refer to the treatment arms the patients enter after 
restart. 
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, several evaluations will be made prior to the end of this trial. This section 
will describe the analyses of the primary and the secondary confirmatory endpoints at the 
confirmatory analyses cut-off focusing on the randomised arms as well the within-subject 
comparison in arm 4 of the confirmatory secondary endpoints. 
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 
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 Type-I error for testing the two confirmatory hypotheses related to bleeds will be preserved by 
using hierarchical testing. The tests will be evaluated separately for the two patient populations, i) 
patients with haemophilia A and ii) patients with haemophilia B. The conclusion from the trial will 
be drawn for each of the two populations separately, i.e. the conclusion from one population does 
not influence the conclusion from the other population. Correction for multiplicity between the two 
populations is therefore not considered relevant. The type 1 error will be controlled for the two 
hypothesis within one population, as described below. 
The overall significance level is 5%. 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. 
The primary endpoint is analysed using negative binomial regression. Superiority of concizumab 
prophylaxis over no prophylaxis in the patient population will be concluded if the two-sided 95% 
confidence interval of the treatment ratio is below 1. 
If superiority is concluded for the primary endpoint the confirmatory secondary hypothesis will be 
tested with a significant level of 5%. The confirmatory secondary hypothesis aims at comparing the 
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bleeding rate during concizumab treatment with the bleeding rate on the patients’ previous 
prophylaxis. 
10.3.1 
Primary endpoint 
The primary endpoint is defined in Section 4.3.1. 
The estimand for the primary endpoint for patients with haemophilia A will be addressed comparing 
the number of treated bleeds between the randomised arms (arm 1 and 2) based on the FAS 
including information obtained from the restart of the trial to when the patient permanently 
discontinues treatment or completes the confirmatory analyses cut-off using negative binomial 
regression, where the patients’ number of bleeds will be analysed with treatment and bleeding 
frequency (<9, ≥ 9 bleeding episodes during the past 24 weeks prior to screening) as factors, and 
logarithm of exposure time as offset. The estimated ratio of ABR between the treatment regimens 
(concizumab prophylaxis and no prophylaxis) with corresponding 95% confidence interval, p-value 
for the test for superiority and also estimates of the actual ABRs with corresponding 95% 
confidence intervals in each treatment arm will be presented. The primary analysis will also account 
for the different intercurrent events as described under the estimand. 
The analysis of the primary endpoint for patients with haemophilia B will be done in a similar way 
as described for haemophilia A patients. 
Sensitivity analysis 
Several sensitivity analyses will be implemented by haemophilia type to further investigate the 
different assumptions that goes into the above estimand and statistical methodology. Note that some 
of these sensitivity analyses are implemented by altering the strategy for a given intercurrent event 
and hence addresses a slightly different estimand. 
• In order to investigate the missing at random (MAR) assumption, a tipping point analysis will 
be implemented where patients that permanently discontinue treatment before 24 weeks for arm 
1 or before 32 for arm 2 will be modelled with an increasing bleeding rate until the conclusion 
of superiority is changed. Those patients that permanently discontinues treatment before 24 
weeks for arm 1 or before 32 weeks for arm 2 will have the offset period fixed at 24 or 32 
weeks, respectively. Any patient that permanently discontinues treatment before the 
confirmatory analyses cut-off but after 24 weeks for arm 1 or after 32 weeks for arm 2 will not 
be considered to have missing data for the purpose of this tipping point analysis. 
• 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 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 including information obtained from the restart of the trial to when the patient 
permanently discontinues treatment or completes the confirmatory analyses cut-off. 
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• In order to investigate the impact of the initial randomisation prior to the clinical pause, the 
primary analyses will be re-run where patients from the initial randomisation are included. For 
patients randomised to on-demand all information from the point of the initial randomisation to 
the time of restart will be included. For patients randomised to the initial concizumab regimen 
all information collected from the time of randomisation until treatment discontinuation will be 
included. 
Further sensitivity analyses can be specified in the SAP. 
10.3.2 
Secondary endpoints 
10.3.2.1 
Confirmatory secondary endpoints 
The confirmatory secondary endpoint for haemophilia A patients is defined in Section 4.3.2.1.  
Only the subset of patients from the FAS that entered the maintenance period in arm 4 and who 
were on a stable PPX regimen for at least 24 weeks in NN7415-4322 (explorer 6) will contribute to 
the analysis. The analysis will be done using a negative binomial regression, where the patients’ 
number of bleeds will be analysed with exposure time as offset, treatment and bleeding frequency 
(<9, ≥9 bleeding episodes during the past 24 weeks prior to screening) as factors and within-subject 
repeated measurements will be incorporated using of an unstructured covariance structure. The 
estimated ratio of ABR between the treatment regimens (concizumab prophylaxis versus previous 
prophylaxis) with corresponding 95% confidence interval and also estimates of the actual ABRs 
with corresponding 95% confidence intervals in each treatment period will be presented. 
Non-inferiority will be confirmed if the upper limit of 95% confidence interval is below 2.0. 
A similar approach will be used for haemophilia B patients. 
Sensitivity analyses 
The below sensitivity analyses will be implemented by haemophilia type to further investigate the 
underlying assumptions of the above statistical analyses. Note that as different strategies are 
implemented to address some of the intercurrent events, this analysis addresses a slightly different 
estimand: 
• In order to investigate the missing at random (MAR) assumption, a tipping point analysis will 
be implemented where patients that permanently discontinue concizumab treatment after the 
dose is decreased, increased or confirmed and before 24 weeks of treatment have been observed 
will be modelled with an increasing bleeding rate until the conclusion of non-inferiority is 
changed. For those patients that permanently discontinues treatment before 24 weeks on 
maintenance dose, the offset period will be fixed at 24 weeks. For any patient that permanently 
discontinues treatment before the confirmatory analyses cut-off but after 24 weeks on 
maintenance dose will not be considered to have missing data for the purpose of this tipping 
point analysis.  
• 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 confirmatory secondary analysis but where the patient’s bleeds and observation 
time collected post permanent treatment discontinuation (the first intercurrent event) and 
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collected during periods with 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. 
Further sensitivity analyses can be specified in the SAP. 
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 confirmatory analyses cut-off 
• at the 56-week cut-off 
• at the end of the extension part 
After the initial evaluation at the confirmatory analyses 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. 
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. 
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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. 
5. 
Hoffman M, Monroe III. A cell-based model of hemostasis. Thrombosis and haemostasis. 
2001;85(6):958-65. 
6. 
Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Vasc Biol. 
2005;25(1):47-56. 
7. 
Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. 
Arterioscler Thromb Vasc Biol. 2004;24(6):1015-22. 
8. 
Descotes J, Gouraud A. Clinical immunotoxicity of therapeutic proteins. Expert Opin Drug 
Metab Toxicol. 2008;4(12):1537-49. 
9. 
Levi M, Keller TT, van GE, ten CH. Infection and inflammation and the coagulation system. 
Cardiovasc Res. 2003;60(1):26-39. 
10. 
US Food and Drug Administration. Guidance for industry: Non-Inferiority Clinical Trials to 
Establish Effectiveness. 2016. 
11. 
EU guideline. Ethical considerations for clinical trials on medicinal products conducted with 
minors, Revision 1. 18 September 2017. 
12. 
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 
4:161-3. 
13. 
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. 
14. 
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. 
2004;103(7):2467-73. 
15. 
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. 
16. 
Hilberg T, Herbsleb M, Puta C, Gabriel HH, Schramm W. Physical training increases 
isometric muscular strength and proprioceptive performance in haemophilic subjects. 
Haemophilia. 2003;9(1):86-93. 
17. 
Harris S, Boggio LN. Exercise may decrease further destruction in the adult haemophilic 
joint. Haemophilia. 2006;12(3):237-40. 
18. 
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 
controlled trial. Int J Prev Med. 2014;5(1):83-8. 
19. 
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. 
20. 
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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21. 
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013. 
22. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016. 
23. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2017. 
24. 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1. 
25. 
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
Trials Registration and Results Information Submission". 21 September 2016. 
26. 
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. 
27. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
28. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
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. 
29. 
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. 
30. 
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. 
31. 
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. 
32. 
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. 
33. 
Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition 
and evaluation of transient ischemic attack: a scientific statement for healthcare 
professionals from the American Heart Association/American Stroke Association Stroke 
Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular 
Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary 
Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the 
value of this statement as an educational tool for neurologists. Stroke. 2009;40(6):2276-93. 
 
 
 
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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 
NI 
Non-inferiority  
NIS 
Non-interventional Study 
OD 
On-demand 
PCD 
primary completion date 
PD 
Pharmacodynamic 
PF 
physical functioning 
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PGI-C 
Patient Global Impression of Change 
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 18 and Table 19 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 18 
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 19 
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 HA) 
FIX inhibitors (for HB only)  
Coagulation Factors  
Factor VIII activity (for HA only) 
Factor IX activity (for HB 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 NN7415-4255 (explorer 5): 
Only applicable for patients that were transferred prior to the treatment pause: Results from selected 
laboratory samples, from patients transferring from NN7415-4255 (explorer 5) taken at EOT, will 
be transferred to this trial.  
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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.11 
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 20, the blood sample prioritisation list, Table 21 
and the laboratory manual. 
Table 20 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 20 
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 21 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 21 
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 
Coagulation Factors (FVIII/FIX) and inhibitors 
9 
Human Biological Specimen for future research 
10 
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 Helsinki21 and applicable ICH Good Clinical Practice (GCP) 
Guideline.22 
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 guidelines22, Declaration of Helsinki21 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.23 
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)24, the Food and Drug Administration Amendment 
Act (FDAAA)25, European Commission Requirements26-28 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. 
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• 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. 
• 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 
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must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the patients. 
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.29 
 
C) Myocardial infarction is defined according to the “Third Universal Definition of Myocardical Infarction”30 
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.31 
 
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”.32 
 
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 etiologies excluded 
Note: CNS infarction includes haemorrhagic infarctions, types I and II; see “Haemorrhagic 
Infarction” 
 
Definition of ischemic stroke: An episode of neurological dysfunction caused by focal cerebral, spinal or retinal 
infarction. Note: Evidence of CNS infarction is defined above. 
 
Definition of silent CNS infarction: Imaging or neuropathological evidence of CNS infarction, without a history of 
acute neurological dysfunction attributable to the lesion. 
 
Definition of intracerebral haemorrhage: A focal collection of blood within the brain parenchyma or ventricular 
system that is not caused by trauma. Note: Intracerebral haemorrhage includes parenchymal haemorrhages after CNS 
infarction, types I and II - see “Haemorrhagic Infarction”). 
 
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.33 
 
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.31 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. 
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H) Definition of peripheral artery occlusion: 
Clinical signs of acute arterial occlusion verified by ankle-brachial index (ABI) test, Doppler and ultrasound 
(Duplex) imaging, computerised tomographic angiography, Magnetic Resonance 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. 
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• 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 
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. 
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• 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. 
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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Trial ID: NN7415-4307 
Version: 
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Status: 
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Page: 
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Appendix 10 Country-specific requirements  
Algeria: Legal age of majority is 19 years old. Biogenic testing and biobanking not allowed. 
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. 
Israel: With reference to Sections 9.7.1, 9.7.2 and Appendix 9: No patients from Israel will 
participate in the optional biobank part of the trial, and no genetic testing will be performed.  
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. 
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”. 
South Africa: Genetic testing and biobanking not allowed. 
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 
 (Germany), site 
 (Spain), site 
 (Sweden) and site
 (UK). 
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Four sites in four countries will participate in a ROTEM sub-study in either protocols 
NN7415-4307 (explorer 8) and/or NN7415-4311 (explorer 7). 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 ROTEM evaluation will be added to the trial at four sites.  
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 (explorer 8) and NN7415-4311 (explorer 7), 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 22 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).  
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. 
 
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Table 22 
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.  
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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 factor products 
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 23 
into consideration. 
For treatment of bleeds with 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. 
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Table 23 
Guidance on management of mild and moderate bleeds during concizumab PPX 
 
FVIII 
SHL 
FVIII 
EHL 
FIX 
SHL 
FIX 
EHL 
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  
20 IU/kg 
20 IU/kg 
30 IU/kg 
30 IU/kg 
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  
20 IU/kg 
20 IU/kg 
30 IU/kg 
At 
investigator’s 
discretion 
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. 
Abbreviations: SHL=standard half-life, EHL=extended half-life 
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 24. 
Table 24 
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. 
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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 5.2.3 
and 9.2.3 
• 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 
• 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. 
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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 
 
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 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 
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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 
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 
FVIII/FIX inhibitors 
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 
 
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Version: 
5.0 
Page: 
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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 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 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 
 
 
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 
 
VV-CLIN-143484
1.0
VV-TMF-4359489
1.0

Protocol 
      
Date: 
25 March 2021 
Status: 
Final 
Novo Nordisk 
Trial ID: NN7415-4307 
      
Version: 
5.0 
Page: 
138 of 138 
 
 
 
Footnote 
a) Only for patients from phase 2 (NN7415-4255, explorer 5): 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 NN7415-4255 (explorer 5), 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, NN7415-4255 (explorer 5) 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. 
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 NN74154255 (explorer 5) and NN7415-4322 (explorer 6). 
Pharmacokinetic (PK)/ Pharmacodynamic (PD) sampling flowchart 
 
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 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 
*Patients coming from NN7415-4255 (explorer 5) 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. 
 
VV-CLIN-143484
1.0
VV-TMF-4359489
1.0