Clinical trial NCT05082116
Conditions: Haemophilia A
Sponsor: Novo Nordisk A/S
Start date: 2021-09-27; Completion date: 2022-12-28
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study investigates how well the medicine called turoctocog alfa pegol (N8-GP) works in previously treated Chinese patients with severe haemophilia A.

Participants will be treated with N8-GP. This is a medicine that doctors can already prescribe in other countries.

The medicine will be injected into a vein (intravenous injections) and blood samples will be collected.

The study will last for about 7-8 months. Participants will have between 8 and 15 visits to the clinic and possibly a number of phone calls with the study doctor.

Detailed description:

Arms: arm 1: All patients will receive prophylaxis with 50 IU/kg N8-GP every 4 days for a treatment period of at least 28 weeks (with the possibility of switching to twice-weekly dosing during the treatment period at the discretion of the investigator).
Interventions: intervention 1: turoctocog alfa pegol (N8-GP)
Intervention descriptions: intervention 1: N8-GP will be injected into a vein (intravenous injections) every 4 days in at least 28 weeks

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol
Sponsor name:
Novo Nordisk A/S
NCT number
NCT05082116
Sponsor trial ID:
NN7088-4595
Official title of study:
A multi-centre, open-label trial evaluating efficacy, safety and 
pharmacokinetics of turoctocog alfa pegol (N8-GP) when used 
for treatment and prophylaxis of bleeding episodes in 
previously treated Chinese patients with haemophilia A
Document date*:
05 Jul 2021
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content.


Link
Link
List of contents
Protocol ...............................................................................................................................................
Protocol attachment ...........................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Turoctocog alfa pegol (N8-GP)
Trial ID: NN7088-4595
Clinical Trial Report
Appendix 16.1.1
21 March 2023
1.0
Final
16.1.1 Protocol and protocol amendments
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Protocol
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Trial ID: NN7088-4595
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Protocol
Protocol title: A multi-centre, open-label trial evaluating efficacy, safety and 
pharmacokinetics of turoctocog alfa pegol (N8-GP) when used for treatment 
and prophylaxis of bleeding episodes in previously treated Chinese patients 
with haemophilia A
Substance name: turoctocog alfa pegol (N8-GP)
Universal Trial Number: U1111-1235-5905
EudraCT Number: 2020-003001-58
Trial phase: 3b
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.


Protocol
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 Protocol amendment summary of changes table
DOCUMENT HISTORY
Document version
Date
Applicable in country(-ies) 
and/or site(s) 
Updated protocol with 
protocol amendment 3
05 Jul 2021
CN
Updated protocol with 
protocol amendment 2
22 Jan 2021
CN
Updated protocol with 
protocol amendment 1
28 Sep 2020
CN
Original Protocol
01 Jul 2020
CN
Protocol version 4.0 (05 Jul 2021)
Overall rationale for preparing protocol version 4.0:
The overall rationale for preparing the protocol, version 4.0 is to include neurological assessment
categories that had been missed to include in prior protocol version, for the patients who have not 
had visit 2a at the time of implementation of protocol version 4.0 and clarifications on 
discontinuation of trial treatment and FVIII inhibitors. List changes in chronological order:
Section # and name
Description of change
Brief rationale
Section 4.1.4 Treatment of 
bleeding episodes
Section 6.5.1 Prohibited 
Medication
Section 7.1 Discontinuation of
trial treatment
Section 8.1.1 Bleeding 
Episodes
Update of exception criteria 
for discontinuation of trial 
treatment
The exception criteria on the 
use of other FVIII product 
between visit 2a and 2b does 
not apply for the trial, hence 
removed 
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Section # and name
Description of change
Brief rationale
Section 8.2.1.1 Neurological 
examination
Update to neurological 
examination criteria
Addition of missed categories 
for neurological examination
Section 8.6.1 FVIII inhibitors
Clarification on analysis of 
FVIII inhibitors
Clarification
Section 10.6 
Appendix 6: Neurological 
examination checklist
Update to neurological 
examination checklist
Addition of missed categories 
for neurological examination
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Table of Contents   
Page
Protocol amendment summary of changes table...........................................................................................2 
Table of Contents..............................................................................................................................................4 
1 
Protocol summary.....................................................................................................................................8 
1.1 
Synopsis.........................................................................................................................................8 
1.2 
Flowchart .....................................................................................................................................13 
2 
Introduction.............................................................................................................................................19 
2.1 
Trial rationale...............................................................................................................................19 
2.2 
Background..................................................................................................................................19 
2.3 
Benefit-risk assessment................................................................................................................21 
2.3.1 
Risk assessment .........................................................................................................21 
2.3.2 
Benefit assessment.....................................................................................................25 
2.3.3 
Overall benefit-risk conclusion..................................................................................25 
3 
Objectives and endpoints........................................................................................................................25 
3.1 
Primary and secondary objectives ...............................................................................................25 
3.2 
Primary and secondary endpoints ................................................................................................26 
3.2.1 
Primary endpoint........................................................................................................26 
3.2.2 
Secondary endpoints..................................................................................................26 
3.2.2.1 
Secondary efficacy endpoints..............................................................26 
3.2.2.2 
Secondary safety endpoints.................................................................26 
3.2.2.3 
Secondary pharmacokinetic endpoints................................................27 
4 
Trial design ..............................................................................................................................................27 
4.1 
Overall design..............................................................................................................................27 
4.1.1 
Treatment of patients .................................................................................................29 
4.1.2 
Maximum dose and daily administration of N8-GP ..................................................29 
4.1.3 
Prophylaxis ................................................................................................................29 
4.1.4 
Treatment of bleeding episodes .................................................................................30 
4.1.5 
Treatment for surgery ................................................................................................31 
4.1.5.1 
Administration of N8-GP on the day of surgery .................................32 
4.1.6 
Treatment during screening and follow-up periods...................................................32 
4.2 
Scientific rationale for trial design...............................................................................................32 
4.3 
Justification for dose....................................................................................................................32 
4.4 
End of trial definition...................................................................................................................33 
5 
Trial population.......................................................................................................................................33 
5.1 
Inclusion criteria ..........................................................................................................................33 
5.2 
Exclusion criteria.........................................................................................................................33 
5.3 
Lifestyle considerations ...............................................................................................................34 
5.4 
Screen failures..............................................................................................................................34 
6 
Treatments...............................................................................................................................................35 
6.1 
Treatments administered..............................................................................................................35 
6.2 
Preparation/handling/storage/accountability................................................................................36 
6.3 
Measures to minimise bias: Randomisation and blinding ...........................................................37 
6.4 
Treatment compliance..................................................................................................................38 
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6.4.1 
In-use time .................................................................................................................38 
6.5 
Concomitant medication..............................................................................................................38 
6.5.1 
Prohibited Medication................................................................................................39 
6.6 
Dose modification........................................................................................................................39 
6.7 
Treatment after end of trial ..........................................................................................................39 
7 
Discontinuation of trial treatment and patient withdrawal ................................................................40 
7.1 
Discontinuation of trial treatment ................................................................................................40 
7.1.1 
Temporary discontinuation of trial treatment ............................................................41 
7.2 
Patient withdrawal from the trial .................................................................................................42 
7.2.1 
Replacement of patients.............................................................................................42 
7.3 
Lost to follow-up .........................................................................................................................42 
8 
Trial assessments and procedures .........................................................................................................43 
8.1 
Efficacy assessments....................................................................................................................43 
8.1.1 
Bleeding Episodes......................................................................................................43 
8.1.1.1 
Definition of severity of bleeding episodes.........................................44 
8.1.1.2 
Definition of Haemostatic Response:..................................................45 
8.1.1.3 
Classification of a bleeding episode....................................................45 
8.1.2 
Clinical efficacy laboratory assessments ...................................................................45 
8.1.3 
Surgery.......................................................................................................................45 
8.1.3.1 
Definition of surgery...........................................................................46 
8.1.3.2 
Haemostatic response during surgery..................................................46 
8.1.3.3 
Surgery visit ........................................................................................46 
8.2 
Safety assessments.......................................................................................................................47 
8.2.1 
Physical examinations................................................................................................47 
8.2.1.1 
Neurological examination ...................................................................48 
8.2.2 
Vital signs ..................................................................................................................48 
8.2.3 
Electrocardiograms ....................................................................................................49 
8.2.4 
Clinical safety laboratory assessments.......................................................................49 
8.3 
Adverse events and serious adverse events..................................................................................50 
8.3.1 
Time period and frequency for collecting AE and SAE information ........................50 
8.3.2 
Method of detecting AEs and SAEs ..........................................................................51 
8.3.3 
Follow-up of AEs and SAEs......................................................................................51 
8.3.4 
Regulatory reporting requirements for SAEs.............................................................51 
8.3.5 
Pregnancy...................................................................................................................52 
8.3.6 
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE........................................................................................................................52 
8.3.7 
Technical complaints.................................................................................................52 
8.4 
Treatment of overdose .................................................................................................................53 
8.5 
Pharmacokinetics.........................................................................................................................53 
8.5.1 
Visit 2a for patients undergoing PK assessments ......................................................53 
8.5.2 
Visit 2b for patients undergoing PK assessments......................................................54 
8.5.3 
Visit 7 for patients undergoing PK assessments........................................................54 
8.6 
Immunogenicity assessments.......................................................................................................55 
8.6.1 
FVIII inhibitors..........................................................................................................55 
8.6.2 
Anti-N8-GP antibodies ..............................................................................................56 
8.6.3 
Anti-PEG antibodies..................................................................................................57 
8.6.4 
Anti-HCP antibodies..................................................................................................57 
8.7 
Diary ............................................................................................................................................57 
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8.8 
Home treatment training ..............................................................................................................58 
9 
Statistical considerations ........................................................................................................................58 
9.1 
Statistical hypotheses...................................................................................................................58 
9.2 
Sample size determination...........................................................................................................58 
9.3 
Populations for analyses ..............................................................................................................58 
9.4 
Statistical analyses .......................................................................................................................59 
9.4.1 
General considerations...............................................................................................59 
9.4.2 
Primary endpoint........................................................................................................59 
9.4.3 
Secondary endpoints..................................................................................................61 
9.4.3.1 
Secondary efficacy endpoints..............................................................61 
9.4.3.2 
Secondary safety endpoints.................................................................63 
9.4.3.3 
Secondary pharmacokinetic endpoints................................................64 
9.4.4 
Other safety analyses .................................................................................................67 
9.4.5 
Other analyses............................................................................................................67 
10 Supporting documentation and operational considerations ...............................................................68 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ...........................................68 
10.1.1 
Regulatory and ethical considerations .......................................................................68 
10.1.2 
Financial disclosure ...................................................................................................69 
10.1.3 
Informed consent process ..........................................................................................69 
10.1.4 
Information to patients during trial............................................................................70 
10.1.5 
Data protection...........................................................................................................70 
10.1.6 
Committees structure.................................................................................................70 
10.1.6.1 
Novo Nordisk safety committee..........................................................70 
10.1.7 
Dissemination of clinical trial data ............................................................................71 
10.1.8 
Data quality assurance ...............................................................................................71 
10.1.8.1 
Case report forms ................................................................................71 
10.1.8.2 
Monitoring...........................................................................................72 
10.1.8.3 
Protocol compliance............................................................................72 
10.1.9 
Source documents......................................................................................................73 
10.1.10 
Retention of clinical trial documentation...................................................................74 
10.1.11 
Trial and site closure..................................................................................................74 
10.1.12 
Responsibilities..........................................................................................................75 
10.1.13 
Indemnity statement...................................................................................................76 
10.1.14 
Publication policy ......................................................................................................76 
10.1.14.1 
Communication of results ...................................................................77 
10.1.14.2 
Authorship...........................................................................................77 
10.1.14.3 
Site-specific publication(s) by investigator(s).....................................78 
10.1.14.4 
Investigator access to data and review of results.................................78 
10.2 
Appendix 2: Clinical laboratory tests ..........................................................................................79 
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-
up, and reporting..........................................................................................................................81 
10.3.1 
Definition of AE ........................................................................................................81 
10.3.2 
Definition of an SAE .................................................................................................82 
10.3.3 
Description of AESIs and AEs requiring additional data collection..........................83 
10.3.4 
Recording and follow-up of AE and/or SAE.............................................................85 
10.3.5 
Reporting of SAEs.....................................................................................................88 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information..........................90 
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10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting ...............................................................................................................91 
10.5.1 
Definition of technical complaint ..............................................................................91 
10.5.2 
Recording and follow-up of technical complaints.....................................................91 
10.6 
Appendix 6: Neurological examination checklist........................................................................93 
10.7 
Appendix 12: Country-specific requirements..............................................................................95 
10.8 
Appendix 13: Abbreviations........................................................................................................96 
10.9 
Appendix 14: Protocol amendment history .................................................................................98 
11 References..............................................................................................................................................100 
Protocol attachment I: Global list of key staff and relevant departments and suppliers.
Protocol attachment II: Country list of key staff and relevant departments.
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1
Protocol summary
1.1
Synopsis
Rationale:
To accumulate sufficient exposure to N8-GP in order to document efficacy for treatment and 
prevention of bleeding episodes and to evaluate safety (including immunogenicity) and 
pharmacokinetics (PK) in previously treated Chinese patients with severe haemophilia A (FVIII 
activity <1%).
Objectives and endpoints:
Primary objective
x
To evaluate the clinical efficacy of N8-GP in bleeding prophylaxis (number of bleeding 
episodes during prophylaxis) in Chinese adolescent and adult patients with severe 
haemophilia A previously treated with other FVIII products
Primary endpoint
Endpoint title
Time frame
Unit
Number of bleeding episodes
From start of treatment until visit 7
Count
Secondary objectives
In Chinese adolescent and adult patients with severe haemophilia A previously treated with other 
FVIII products:
x
To evaluate the clinical efficacy of N8-GP when used for treatment of bleeding episodes
x
To evaluate the consumption of N8-GP
x
To evaluate the immunogenicity of N8-GP
x
To evaluate the general safety of N8-GP
x
To evaluate the pharmacokinetic properties of N8-GP
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Secondary efficacy endpoints
Endpoint title
Time frame
Unit
Haemostatic effect of N8-GP when 
used for treatment of bleeding 
episodes, assessed on a four-point 
scale for haemostatic response 
(excellent, good, moderate and 
none)
From start of treatment until visit 7
Count
Consumption of N8-GP for 
treatment of bleeding episodes 
From start of treatment until visit 7
IU/kg/bleed
Consumption of N8-GP for 
prophylaxis 
From start of treatment until visit 7
IU/kg/year
FVIII trough activity during 
prophylaxis
From start of treatment (excluding 
the first exposure) until visit 7
IU/mL
Secondary safety endpoints
Endpoint title
Time frame
Unit
Incidence rate of confirmed FVIII 
inhibitors ≥0.6 BU
From start of treatment until visit 7
Rate
Number of adverse events (AEs)
From start of treatment until end of 
trial
Count
Number of serious adverse events 
(SAEs)
From start of treatment until end of 
trial
Count
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Secondary pharmacokinetic endpoints
Endpoint title
Time frame
Unit
FVIII activity 30 min post-injection 
(C30min)
Single-dose: 30 min ± 5 min post-
injection at visit 2a
Steady-state: 30 min ± 5 min post-
injection at visit 7
IU/mL
Incremental recovery (IR)
Single-dose: 30 min ± 5 min post-
injection at visit 2a
Steady-state: 30 min ± 5 min post-
injection at visit 7
(IU/mL)/(IU/kg)
Area under the curve (AUC)
Single-dose: 0−inf post-injection at 
visit 2a
Steady-state: 0−96 h post-injection 
at visit 7
h*(IU/mL)
Terminal half-life (t½)
Single-dose: 0−96 h post-injection 
at visit 2a
Steady-state: 0−96 h post-injection 
at visit 7
h
Clearance (CL)
Single-dose: 0−96 h post-injection 
at visit 2a
Steady-state: 0−96 h post-injection 
at visit 7
mL/h/kg
FVIII trough activity 96 h post-
injection (C96h)
Single-dose: 96 h ± 8 h post-
injection at visit 2a
Steady-state: 96 h ± 8 h post-
injection at visit 7
IU/mL
Overall design:
This trial is a multi-centre, open-label, non-randomised, single-arm phase 3b trial.
The trial population consists of previously treated Chinese patients t12 years of age with severe 
haemophilia A (FVIII activity <1%).
Inclusion criteria are:
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 Chinese patient with severe congenital haemophilia A with a FVIII activity <1% 
according to medical records.
3. Aged ≥12 years at the time of signing informed consent.
4. History of at least 150 exposure days (EDs) to other FVIII products1.
5. The patient and/or caregiver is capable of assessing a bleeding episode, keeping a diary, 
performing home treatment of bleeding episodes and otherwise following the trial procedures at
the discretion of the investigator.
1 Prophylaxis, prevention, on-demand and treatment during surgery counts as exposure days. If not possible to count the 
actual number of exposures in the medical chart, the investigator should make a written statement with an estimate 
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based on e.g., patient age, treatment frequency, medical history, discussion with previous doctor/transfer note and other 
relevant information. This statement should be filed either with the patient chart or separately with the investigator trial 
file.
The criteria will be assessed at the investigator's discretion unless otherwise stated.
Exclusion criteria are:
1. Known or suspected hypersensitivity to trial product or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 5 half-lives or 30 days from screening, whichever is longer.
4. Known history of FVIII inhibitors based on existing medical records, laboratory report reviews 
and patient and/or caregiver interviews.
5. Current FVIII inhibitors ≥0.6 BU.
6. Congenital or acquired coagulation disorder other than haemophilia According to medical 
records.
7. HIV positive, defined by medical records, with CD4+ count d200/PL and a viral load 
>200 particles/μl or >400000 copies/mL within 6 months of the trial entry. If the data are not 
available in medical records within last 6 months, then the test must be performed at screening 
visit.
8. Previous significant thromboembolic events (e.g. myocardial infarction, cerebrovascular disease 
or deep venous thrombosis) as defined by available medical records.
9. Hepatic dysfunction defined as aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) >3 times the upper limit of normal combined with total bilirubin 
>1.5 times the upper limit of normal at screening, as defined by central laboratory.
10. Renal impairment defined as estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2
for serum creatinine measured at screening, as defined by central laboratory.
11. Platelet count <50×109/L at screening based on central laboratory values at screening.
12. Ongoing immune modulating or chemotherapeutic medication.
13. Any disorder, except for conditions associated with haemophilia A, which in the investigator`s 
opinion might jeopardise the patient`s safety or compliance with the protocol.
14. Mental incapacity, unwillingness or language barriers precluding adequate understanding or 
cooperation.
The criteria will be assessed at the investigator's discretion unless otherwise stated.
Patients are screened at visit 1 and baseline assessments are performed at visit 2a which will take 
place approximately two weeks after visit 1. At visit 2a trial product is administered for the first 
time to all patients. Some patients will undergo single-dose PK assessments until visit 2b, which is 
4 days after visit 2a. From visit 2b the treatment period consists of an additional 4 visits (visits 3-6)
taking place 4, 8, 12, and 20 weeks after visit 2a. An end of treatment visit (visit 7) is placed 
28 weeks after visit 2a. Patients who underwent single-dose PK assessments at visit 2a will undergo 
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steady-state PK assessments at visit 7. An end of trial (follow-up) visit (P8) is placed 30 days after
the end of treatment visit (visit 7) (visit windows are not included in this description).
Major and minor surgery is allowed in the trial.
Number of patients:
Thirty-six (36) patients are planned to be included in the trial. At least 30 patients must complete 
the trial with t50 EDs to N8-GP (including treatment of bleeding episodes) during a period of
≥6 months (≥28 weeks) of prophylaxis with N8-GP. Among these, at least 12 patients will complete 
single-dose and steady-state PK assessments.
Treatment groups and duration:
All patients will receive prophylaxis with 50 IU/kg N8-GP every 4 days for a treatment period of at 
least 28 weeks (with the possibility of switching to twice-weekly dosing during the treatment period 
at the discretion of the investigator). Bleeding episodes will be treated with bolus injection(s) of 
20−75 IU/kg N8-GP.
Dosing recommendation guidance for surgery recommends FVIII activity level of 30-60% for 
minor surgery and 80-100% for major surgery, until adequate wound healing is ensured.
Data monitoring committee: No
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1.2
Flowchart
Protocol 
Sections
Screening
Baselinea, b
Treatment period
End of 
treatment
Discontinuation 
of treatment
End of trial 
(Follow up)
Surgery
Visit
V1
V2a
V2b
V3 V4 V5 V6
V7
V7a
P8
Timing of Visit (Weeks)
-2
0
4 days 
after visit 
2a
4
8
12
20
28
30D
Visit Window (Days)
-7
0
0
±7
±7
±7
±7
+7
+5
Informed Consent and Demography
10.1.3
X
Eligibility Criteria
5.1, 5.2
X
X
Discontinuation Criteria
7, 7.1
X
X
X
X
X
X
Medical History/Concomitant Illness
8.2,
X
X
History of surgery
8.2,
X
Details of Haemophilia
8.2,
X
Haemophilia treatment and bleed history
8.2,
X
Date and time of last coagulation factor 
administration
8.2,
X
X
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Protocol 
Sections
Screening
Baselinea, b
Treatment period
End of 
treatment
Discontinuation 
of treatment
End of trial 
(Follow up)
Surgery
Visit
V1
V2a
V2b
V3 V4 V5 V6
V7
V7a
P8
Timing of Visit (Weeks)
-2
0
4 days 
after visit 
2a
4
8
12
20
28
30D
Visit Window (Days)
-7
0
0
±7
±7
±7
±7
+7
+5
Concomitant Medication
6.5
X
X
X
X
X
X
X
X
X
X
Body Measurements
8.2.1
X
X
X
X
X
X
X
X
Height
8.2.1
X
Weight
8.2.1
X
X
X
X
X
X
X
X
BMI
8.2.1
X
Physical Examination
8.2.1
X
X
X
X
X
Neurological examination
8.2.1.1
X
X
Xh
Xh
Xh
Target Joint
8.2.1
X
X
X
X
X
Vital Signs
8.2.2
X
X
X
X
X
X
X
X
ECG
8.2.3
X
X
X
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Protocol 
Sections
Screening
Baselinea, b
Treatment period
End of 
treatment
Discontinuation 
of treatment
End of trial 
(Follow up)
Surgery
Visit
V1
V2a
V2b
V3 V4 V5 V6
V7
V7a
P8
Timing of Visit (Weeks)
-2
0
4 days 
after visit 
2a
4
8
12
20
28
30D
Visit Window (Days)
-7
0
0
±7
±7
±7
±7
+7
+5
Adverse Event
8.3
X
X
X
X
X
X
X
X
X
Bleeding Episode
8.1.1
X
X
X
X
X
X
X
X
Technical Complaints
10.5,8.3.7
X
X
X
X
X
X
X
X
X
Laboratory Assessments
8.1.2, 8.2.4, 10.2
X
X
X
X
X
X
X
X
X
Haematology
10.2
X
X
X
X
X
X
X
X
Biochemistry
10.2
X
X
X
X
X
X
X
X
Urinalysis
10.2
X
X
Coagulation parameter
10.2
X
Factor VIII Chromogenic Activity
10.2
Xc
Xc
Xc
Xc
Xc
Xc
X
Xc
Hepatitis
10.2
X
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Protocol 
Sections
Screening
Baselinea, b
Treatment period
End of 
treatment
Discontinuation 
of treatment
End of trial 
(Follow up)
Surgery
Visit
V1
V2a
V2b
V3 V4 V5 V6
V7
V7a
P8
Timing of Visit (Weeks)
-2
0
4 days 
after visit 
2a
4
8
12
20
28
30D
Visit Window (Days)
-7
0
0
±7
±7
±7
±7
+7
+5
HIVd
10.2
X
Factor VIII Inhibitor in Plasma
10.2,8.6.1
Xe
Xe
Xf
Xf
Xf
Xf
Xf
Xf
Anti-N8-GP antibodies
8.6.2
X
X
X
X
X
X
X
X
Anti-PEG antibodies
8.6.3
X
X
X
Anti-HCP antibodies
8.6.4
X
Xg
PKb
1.2 8.5
Xe
X
Administration of Trial Product
4.1.1
X
X
X
X
X
X
X
X
Drug Dispensing
6.2
X
X
X
X
X
X
X
X
X
Dispensing Visit
6.2
X
X
X
X
X
X
X
Drug Accountability
6.2, 6.4
X
X
X
X
X
X
X
X
X
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Protocol 
Sections
Screening
Baselinea, b
Treatment period
End of 
treatment
Discontinuation 
of treatment
End of trial 
(Follow up)
Surgery
Visit
V1
V2a
V2b
V3 V4 V5 V6
V7
V7a
P8
Timing of Visit (Weeks)
-2
0
4 days 
after visit 
2a
4
8
12
20
28
30D
Visit Window (Days)
-7
0
0
±7
±7
±7
±7
+7
+5
IWRS session
6.2, 6.3
X
X
X
X
X
X
X
X
X
Hand Out and Instruct in Diary
8.7
X
X
X
X
X
X
Home treatment training
8.8
X
X
Training in Devices
8.8
X
X
Footnotes
Description
a
All screening assessments must be completed and evaluated by the investigator before the patient can be included in the trial.
b
Refer to Table 1-1 for patients that will participate in PK assessments
c
To be measured pre-injection and 30 min (±10min) post-injection.  
d
If positive HIV test, then a HIV polymerase chain reaction (PCR) viral load assessment should be performed
e
Time from last treatment with current FVIII product should be at least 96 hours. The blood sample should be taken before any injection of N8-GP, if applicable.
f
Time from last treatment with N8-GP should be at least 96 hours. The blood sample should be taken before any injection of N8-GP, if applicable.
g
Only to be assessed in case of an acute severe allergic/anaphylactic reaction.
h
Neurological assessments should not be performed for the assessments not performed at baseline (visit 2a).
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Table 1-1
Flowchart for patients having PK evaluated at Visit 2a and Visit 7
Day(s)
0
0
1
2
3
4
Nominal Time
Pre-dose
0
30
1 hr
4 hrs
12 hrs
24 hrs
48 hrs
72 hrs
96 hrs
Visit Window
-1h
r 5 min
r 5 min
r 30 min
r30 min
+ 8 hrs
+ 8 hrs
+ 8 hrs
+ 8 hrs
Concomitant medication
X
X
X
X
X
X
X
X
X
X
Adverse Events
Xh
X
X
X
X
X
X
X
X
Vital signs
X
X
X
FVIII activity  
X
X
X
X
X
X
X
X
X
Administration of N8-GP
X
Footnotes
Description
h
Only applicable at visit 7
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2
Introduction
2.1
Trial rationale
No Chinese haemophilia patients have yet been exposed to N8-GP as there were no patients from 
China included in the global N8-GP clinical development programme (NN7088, pathfinder™).
The rationale for this Phase 3b trial is to assess the effect of N8-GP in Chinese patients with severe 
haemophilia A (FVIII activity <1%) previously treated with other FVIII product(s) (PTPs). The aim 
is to accumulate sufficient exposure data in order to evaluate efficacy and safety of N8-GP in 
treatment and prevention of bleeding episodes and to obtain N8-GP PK data in this patient 
population.
The results of this trial will supplement results from the global N8-GP clinical development 
programme (pathfinder™).
2.2
Background
Haemophilia A is a rare, recessive X-linked congenital bleeding disorder caused by mutation in the 
blood-coagulation factor VIII (FVIII) gene on the long arm of the X-chromosome. The prevalence 
globally is approximately 1 in 5,000 male births.1 According to the World Federation of Hemophilia 
(WFH), there are globally over 184,000 identified haemophilia patients of which 150,000 are 
diagnosed with haemophilia A.2
A meta-analysis in China has shown a prevalence of haemophilia of 5.5 per 100,000 males (3.6 per 
100,000 males+females) and about 71% of these suffer from haemophilia A.3 However, according 
to the WFH, about 12,500 patients with haemophilia A were registered in China in 2016.2 Thus,
only about 1/3 of the anticipated number of patients with haemophilia A in China are diagnosed4
and there’s a large number of patients who are either undiagnosed or untreated.
The most common manifestation of haemophilia A is bleeding into joints. Repeated bleeding into 
the same joint, referred to as a target joint, can prevent healing and thus cause chronic inflammation 
and musculoskeletal pain, reduced range of motion and diminished quality of life.5 Incorrect or 
delayed diagnosis of haemophilia due to low disease awareness in the past years and the associated 
suboptimal treatment result in a high disease burden to the patients and their families as well to the 
society.6 According to consensus of Chinese experts, about 70% of children with haemophilia suffer 
from joint disability when they have reached adulthood.7 In the past years, however, the standard of 
care is rapidly improving in China and prophylaxis is becoming more and more available to the 
patients. 
However, many patients consider prophylaxis to be a major burden as treatment requires frequent 
intravenous injections to maintain protective factor activity levels.1, 8-11 Prophylaxis requires 
repeated venous access, which can be difficult and traumatic to obtain in some patients.12, 13 In 
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addition, prophylactic treatment can be time consuming. While prophylaxis is the standard of care 
for haemophilia, patients often face challenges integrating prophylaxis dosing into their daily life. 
Thus, therapies that require less frequent dosing may reduce the overall burden of prophylaxis. 
Currently, there are no extended half-life rFVIII products available in China, therefore Chinese 
patients will still be facing the above-mentioned barriers. 
With the well-established knowledge of N8-GP efficacy and PK properties obtained from the 
comprehensive global clinical development program in severe haemophilia A patients across all age 
groups,14-16 N8-GP provides a new treatment option to significantly reduce the dosing frequency 
associated with regular prophylaxis, which fulfils the urgent unmet needs in Chinese patients.
Turoctocog alfa pegol (in this protocol referred to as ‘N8-GP’), a 40-kDa glycoPEGylated human 
recombinant coagulation factor VIII (rFVIII) with an extended half-life, has been developed to offer 
patients with haemophilia A a more effective and less burdensome treatment versus standard FVIII 
products. N8-GP has improved PK properties including a 1.6-fold increase in terminal half-life 
compared with standard FVIII products, which offers the possibility of achieving FVIII levels in the 
range of moderate haemophilia A with a less-burdensome every fourth day treatment regimen.14-16
With a better overall PK profile and the ability to sustain higher FVIII levels than standard 
therapies, N8-GP has the potential to improve prophylaxis and simplify management of bleeds as 
well as perioperative haemostatic control in patients with haemophilia A. 
N8-GP has been approved in US, EU, Japan, Canada and Switzerland for on-demand and 
prophylaxis for patients with haemophilia A. The Global Regulatory file is based on the results 
from a comprehensive global clinical development programme (pathfinder™) including 270 unique 
PTPs (202 adults/adolescents and 68 children) with severe haemophilia A who have been exposed 
to N8-GP with a total of 79,446 EDs corresponding to 882 patient years of exposure (PYE). 
Overall, the haemostatic effect of N8-GP on prevention and treatment of bleeds was high and 
consistent across all phase 3 trials and age groups. Adults and adolescents had a median ABR of 
1.18, and a median annualised spontaneous bleeding rate (AsBR) of 0.00, respectively, while 40% 
did not experience any bleeding episodes during prophylactic treatment with N8-GP in the pivotal 
parts of the Phase 3 trial. Another clinical benefit of N8-GP was observed in the treatment of 
bleeds. The overall success rate for the first treatment of a bleeding episode evaluated within 8 
hours was 88 %.15, 16 The vast majority of the bleeds were resolved with 1‒2 injections. In addition,
N8-GP was shown to provide haemostatic control during surgery (trial 3860), as the success rate for 
perioperative treatment was 96% in 45 major surgeries. Through the clinical development 
programme, N8-GP has demonstrated a safety profile similar to that of currently approved FVIII 
products. N8-GP was well tolerated, the AE pattern was considered typical for the patient 
population, and no safety concerns related to N8-GP have been identified. Across the clinical 
development programme of N8-GP, no discernible pattern has been observed when the response to 
N8-GP with regards to PK profile, efficacy (prevention and treatment of bleeds) and safety has been 
analysed by country, race, or ethnicity. 
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2.3
Benefit-risk assessment
Main benefits and risks are described in the below sections. More detailed information about the 
known and expected benefits and risks and reasonably expected adverse events of N8-GP
(turoctocog alfa pegol) may be found in the investigator’s brochure).17
2.3.1
Risk assessment
Based on previous experience and knowledge from completed and ongoing phase 3 trials with N8-
GP, development of inhibitory antibodies and allergic reactions have been classified as identified 
risks.
See Section 7.2 of the investigator’s brochure17 for further information on identified and potential 
risks with use of N8-GP and FVIII products.
Potential risk of clinical 
significance
Summary of data/rationale for 
risk
Mitigation strategy
Trial treatment: N8-GP
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Identified risks
Development of inhibitory antibodies
Allergic reactions
Potential risks
Thromboembolic events
The main safety issues identified 
with use of FVIII products are 
immunogenicity and lack of efficacy 
due to formation of neutralising 
antibodies against FVIII.
See Section 7.2.1.1 of the 
investigator’ brochure17 for further 
details on identified risks, and
Section 6.4.2.3 of the investigator’s 
brochure17 for results on inhibitor 
development in the N8-GP clinical 
trial programme.
As with any intravenous product, 
allergic hypersensitivity reactions 
cannot be excluded. Allergic type 
hypersensitivity reactions, including 
anaphylaxis, have been observed in 
patients treated with marketed FVIII 
products.
For results on allergic reactions 
reported in the N8-GP clinical trial 
programme, see Section 6.4.2.3 of 
the investigator’s brochure.17
Thromboembolic events is 
considered an important potential 
risk considering the fact that supra-
physiologically elevated 
procoagulant levels may be 
associated with an increased risk of 
venous thrombosis.
Few thromboembolic events have 
been observed in the N8-GP clinical 
trial programme; see Section 6.4.2.3 
of the investigator’s brochure.17
For previously treated patients with 
no history of FVIII inhibitor 
development, the risk of inhibitor 
formation is low. As per inclusion 
criteria no.4 (see Section 5.1), only 
patients with a history of at least 
150 EDs to other FVIII products are 
eligible. Also, exclusion criteria no. 
4 excludes patients with a known 
history of FVIII inhibitors (Section 
5.2). If reduced efficacy from 
treatment is suspected an assessment 
for FVIII inhibitors should be 
performed (see Section 8.6.1.
Patients are monitored carefully for 
allergic type hypersensitivity 
reactions, including anaphylaxis.
Allergic type hypersensitivity 
reactions must be treated as per local 
practice and as per investigator’s
discretion.
Thromboembolic events are 
monitored closely.
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Long-term potential effects of PEG 
accumulation in the choroid plexus 
of the brain and other tissues/organs.
There has been no indication of PEG 
accumulation after N8-GP treatment 
non-clinically or clinically. The 
possible clinical consequences of 
potential PEG accumulation are 
currently unknown.
Potential effects of PEG 
accumulation are monitored closely.
Long-term safety including potential 
effects of PEG accumulation in the 
choroid plexus of the brain
and other tissues/organs are 
monitored in the clinical trials and 
post-marketing.
Trial procedures
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Intravenous injection (i.v.) 
Physical examination and body 
measurements
Risk of COVID-19 infection in 
relation to participation in the trial.
Wrong route of administration, e.g., 
intramuscular instead of intravenous
No risks are expected to be 
associated with standard physical 
examination. Burden 
(embarrassment, discomfort, 
distress) associated with 
examinations that are related to 
sexual development (e.g., in 
adolescents) can be expected.
Patients and caregivers may be 
exposed to the risk of COVID-19
transmission and infection in relation 
to site visits if an outbreak is 
ongoing in the country.
If a patient is tested positive for 
COVID-19
Administration of trial product at 
sites are performed by trained staff.
The previously treated patients 
and/or caregivers have experience 
with i.v. injection and will be trained 
by site staff in use of trial product.
As this assessment is performed by 
physicians familiar with the patient 
population the burden is expected to 
be low.
The risk of COVID-19 transmission 
in relation to site visits is overall 
considered to be low. To minimize 
the risk as much as possible, the 
following measures have been taken:
On-site visits will be well-prepared 
and as short as possible. Physical 
contact between patients and site 
staff will be limited to the extent 
possible, and protective measures 
will be implemented such as masks 
sanitizers etc.
The risk of COVID-19 transmission 
in relation to site visits is overall 
considered to be low, however if a 
patient is tested positive for COVID-
19 then the investigator must ensure 
proper medical care and if possible 
site visits can be converted to 
telephone visits and if the patient 
recovers in time for the primary 
endpoint visit then the investigator 
should encourage the patient to visit 
the site for the primary endpoint 
visit. All necessary precautions must 
be taken for the site visit.
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2.3.2
Benefit assessment
N8-GP has a longer half-life compared to standard FVIII coagulation products and thus has the 
potential to improve the quality of life for haemophilia A patients by offering a convenient 
prophylaxis treatment with a reduced treatment burden from less frequent injections.
2.3.3
Overall benefit-risk conclusion
No clinical safety issues have been identified that precludes further clinical development of N8-GP.
AEs from the clinical trials that have been evaluated to be related to N8-GP are consistent with 
what has been observed, and what is expected, with use of other FVIII products. The potential 
benefits of N8-GP are considered to outweigh the identified and potential risks.
Taking into account the measures taken to minimise risk to patients participating in this trial, the 
potential risks identified in association with use of N8-GP are justified by the anticipated benefits 
that may be afforded to patient with haemophilia A.
3
Objectives and endpoints
3.1
Primary and secondary objectives
Primary objective
x
To evaluate the clinical efficacy of N8-GP in bleeding prophylaxis (number of bleeding 
episodes during prophylaxis) in Chinese adolescent and adult patients with severe 
haemophilia A previously treated with other FVIII products
Secondary objectives
In Chinese adolescent and adult patients with severe haemophilia A previously treated with other 
FVIII products,
x
To evaluate the clinical efficacy of N8-GP when used for treatment of bleeding episodes
x
To evaluate the immunogenicity of N8-GP
x
To evaluate the general safety of N8-GP
x
To evaluate the consumption of N8-GP
x
To evaluate the pharmacokinetic properties of N8-GP
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3.2
Primary and secondary endpoints
3.2.1
Primary endpoint
Endpoint title
Time frame
Unit
Number of bleeding episodes
From start of treatment until visit 7
Count
3.2.2
Secondary endpoints
3.2.2.1
Secondary efficacy endpoints
Endpoint title
Time frame
Unit
Haemostatic effect of N8-GP when 
used for treatment of bleeding 
episodes, assessed on a four-point 
scale for haemostatic response 
(excellent, good, moderate and 
none)
From start of treatment until visit 7
Count
Consumption of N8-GP for 
treatment of bleeding episodes 
From start of treatment until visit 7
IU/kg/bleed
Consumption of N8-GP for 
prophylaxis 
From start of treatment until visit 7
IU/kg/year
FVIII trough activity during 
prophylaxis
From start of treatment (excluding 
the first exposure) until visit 7
IU/mL
3.2.2.2
Secondary safety endpoints
Endpoint title
Time frame
Unit
Incidence rate of confirmed FVIII 
inhibitors ≥0.6 BU
From start of treatment until visit 7
Rate
Number of adverse events (AEs)
From start of treatment until end of 
trial
Count
Number of serious adverse events 
(SAEs)
From start of treatment until end of 
trial
Count
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3.2.2.3
Secondary pharmacokinetic endpoints
Endpoint title
Time frame
Unit
FVIII activity 30 min post-injection 
(C30min)
Single-dose: 30 min ± 5 min post-
injection at visit 2a
Steady-state: 30 min ± 5 min post-
injection at visit 7
IU/mL
Incremental recovery (IR)
Single-dose: 30 min ± 5 min post-
injection at visit 2a
Steady-state: 30 min ± 5 min post-
injection at visit 7
(IU/mL)/(IU/kg)
Area under the curve (AUC)
Single-dose: 0−inf post-injection at 
visit 2a
Steady-state: 0−96 h post-injection 
at visit 7
h*(IU/mL)
Terminal half-life (t½)
Single-dose: 0−96 h post-injection 
at visit 2a
Steady-state: 0−96 h post-injection 
at visit 7
h
Clearance (CL)
Single-dose: 0−96 h post-injection 
at visit 2a
Steady-state: 0−96 h post-injection 
at visit 7
mL/h/kg
FVIII trough activity 96 h post-
injection (C96h)
Single-dose: 96 h ± 8 h post-
injection at visit 2a
Steady-state: 96 h ± 8 h post-
injection at visit 7
IU/mL
4
Trial design
4.1
Overall design
This trial is a multi-centre, open-label, non-randomised, single-arm phase 3b trial evaluating the 
clinical efficacy, safety (including immunogenicity) and PK of N8-GP when used for treatment and 
prevention (prophylaxis) of bleeding episodes in Chinese patients t12 years of age with severe 
haemophilia A (FVIII activity <1%). This trial design is overall similar to the design of the 
completed global, pivotal pathfinderTM2 trial in adult and adolescent previously treated patients 
with severe haemophilia A (trial NN7088-3859). 
Thirty-six (36) Chinese PTPs with severe haemophilia A, aged t12 years and with ≥150 exposure 
days (EDs) to other FVIII product(s), will receive prophylaxis with 50 IU/kg N8-GP every 4 days
(with the possibility of switching to twice-weekly dosing during the treatment period at the 
discretion of the investigator). Bleeding episodes will be treated with bolus injection(s) of 20-75
IU/kg N8-GP.
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The treatment period in the trial will be at least 28 weeks with N8-GP prophylaxis every 4 days 
where ≥50 EDs to N8-GP (including treatment of bleeding episodes) must be obtained. The 
screening period will be 2 weeks and the follow-up period will be 30 days.
At least 30 patients must complete the trial with ≥50 EDs to N8-GP (including treatment of 
bleeding episodes) and ≥6 months (≥28 weeks) of prophylaxis.
An overview of the trial design is given in Figure 4-1.
Figure 4-1
Overview of trial design
Efficacy of N8-GP prophylaxis (prevention of bleeds) will be assessed by the number of 
spontaneous and traumatic bleeding episodes observed (annualised bleeding rate). In addition, 
trough levels of the surrogate efficacy parameter, FVIII activity, will be evaluated.
The haemostatic effect of N8-GP in the treatment of bleeding episodes will be based on the 
treatment of all bleeding episodes (spontaneous and traumatic bleeding episodes) during 
prophylaxis (breakthrough bleeds), and will be assessed by total number, severity, cause of bleed,
and by location of bleed (including target joints). The haemostatic response to N8-GP will be 
assessed using a four-point scale (excellent, good, moderate and none response) by counting 
excellent and good as success and moderate and none as failure. Amount and number of injections 
of N8-GP per bleeding episode will also be evaluated.
Major and minor surgery is allowed in the trial, and the haemostatic effect and consumption of N8-
GP in relation to surgery will be evaluated.
Fifteen (15) of the 36 enrolled patients will participate in PK assessments to obtain at least 12 
patients with two PK profiles of N8-GP (one single-dose PK profile and one steady-state PK 
profile). The single-dose PK assessments will be performed at first exposure to N8-GP after a 
preceding wash-out period of at least 4 days (96 hours). The steady-state PK assessments will be 
performed approximately 28 weeks after start of prophylaxis.
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4.1.1
Treatment of patients
Patients will receive N8-GP as prophylaxis, for treatment of bleeding episodes, and in relation to 
surgery.
The trial product is N8-GP (turoctocog alfa pegol) produced by Novo Nordisk. The trial product is a 
recombinant FVIII product and is a lyophilised powder in vials, which is reconstituted with solvent 
for injection (see Section 6.1 for further details). Trial product will be administered as intravenous 
injections (i.v.) at home by the patient and/caregiver, at the trial site, or in exceptional cases in 
another clinic/hospital. To be able to train patients on home treatment of N8-GP at least the first 
treatment should be at the trial site.
Table 4-1
Treatment regimens
Treatment 
regimen
Age 
(years)
Dose (IU/kg)
Dose frequency
Prophylaxis
≥12
50
Once every 4 days
(can be changed to twice-
weekly at investigator's 
discretion)
Treatment of 
bleeds
≥12
20-75
When necessary
Surgery
≥12
At investigator’s 
discretion
Pre-dose and when necessary
4.1.2
Maximum dose and daily administration of N8-GP
The maximum dose to be administered to a patient within 24 hours is 200 IU/kg. The dose is 
recommended to be divided and only considered under exceptional circumstance such as serious 
trauma or severe bleed. The maximum dose per injection must not exceed 100 IU/kg BW.
4.1.3
Prophylaxis
The N8-GP prophylaxis regimen chosen for this trial is based on clinical data from the global trial 
in adolescent and adult patients (pathfinderTM2, NN7088-3859) where prophylaxis with 50 IU/kg 
N8-GP every 4 days was associated with low ABRs. 
For prophylaxis, one single bolus dose of 50 IU/kg N8-GP will be administered i.v. every 4 days 
(96 hours interval). During the treatment period, a shortening of the dosing interval for prophylaxis 
to twice-weekly dosing may be undertaken at the investigator’s discretion, if deemed necessary for 
the individual patient. If the dosing regimen is changed to twice weekly, doses should be separated 
with at least 3 calendar days and no more than 4 calendar days. Other changes of the dose or dosing 
interval for prophylaxis are not allowed in the trial. However, extra doses of N8-GP can be 
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administered if a patient experiences a treatment-requiring bleeding episode (see Section 4.1.4) or 
in case of surgery (see Section 4.1.5).
If a bleeding episode occurs on a planned prophylaxis dosing day before administration of the 
prophylaxis dose, or if a bleeding episode extends into such a day, the bleeding episode must be 
treated with the full prophylaxis dose (this dose should be recorded as treatment of a bleeding 
episode). The patient should at all times follow the original prophylaxis dosing scheme unless a 
dose has already been given to treat a bleeding episode during the same day.
4.1.4
Treatment of bleeding episodes
A treatment-requiring bleeding episode is defined as a bleed that requires treatment with N8-GP. If 
a patient experiences a treatment-requiring bleeding episode it must be treated as soon as it is 
identified. The investigator must always be contacted in case of a severe bleed and the patient 
should visit the site within 24 hours, or when possible. Mild/moderate bleeding episodes can be 
treated at home without contacting the site. Treatment should be started as soon as a bleed is 
identified. 
For treatment of a mild or moderate bleeding episode, for example a joint bleed, N8-GP i.v. bolus 
injections at doses between 20-75 IU/kg BW should be administered to achieve a desired dose level 
based on the severity and location of the bleeding episode. Each unit of N8-GP will raise the FVIII 
level with approximately 2%. The required dose within the 20-75 IU/kg BW dosing range is
determined by the investigator for every patient, using the recommendations in the World 
Federation of Haemophilia (WFH) guideline, FVIII activity should not fall below the lower range 
for the given plasma activity level (in % of normal or IU/dl) until the bleeding episode is resolved.
The effect of initial N8-GP dose on the clinical symptoms should be closely monitored and the need 
for a second dose should be evaluated within 8 hours after the initial N8-GP dose. If further doses 
are considered necessary to treat the bleeding episode, the patient is recommended to contact the 
investigator.
Any dose used for treatment of a bleed must be recorded as treatment of bleed and not as a 
prophylaxis dose. When the bleed has resolved (e.g. pain reduction and no increase in swelling), the 
patient can resume the prophylaxis dosing regimen.
If a bleeding episode occurs on a planned prophylaxis dosing day before administration of the 
prophylaxis dose, or if a bleeding episode extends into such a day, the bleeding episode must be 
treated with the full prophylaxis dose (this dose should be recorded as treatment of a bleeding 
episode). The patient should at all times follow the original prophylaxis dosing scheme unless a 
dose has already been given to treat a bleeding episode during the same day.
If a haemostatic response cannot be achieved after 48 hours using adequate doses of N8-GP
treatment when treating bleeding episodes, another FVIII product may be used at the discretion of 
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the investigator. The use of other FVIII products will result in discontinuation of the patient 
(exception: current FVIII product is allowed until 96 hours before visit 2a).
4.1.5
Treatment for surgery
Major and minor surgery can be performed while participating in the trial. Use of FVIII products 
other than N8-GP for surgery is not allowed. Patients undergoing surgical procedures will receive 
trial product as bleeding preventive treatment according to standard practice at the trial site and/or
at the investigator’s discretion.
For dosing guidance in patients who need to undergo surgical procedures during the trial, 
investigators could refer to Table 4-2 and WFH guidelines.18 As these guidelines are 
recommendations, non-compliance with them will not require any protocol deviations. Achieving 
higher FVIII activity levels may be necessary depending on type of surgery and standard practice at 
the trial site. The rationale is to replace the FVIII activity in these patients up to FVIII activity 
levels that are effective in preventing bleeding during and after surgery.
Table 4-2
Guide for dosing for surgery
Type of surgical 
procedure
FVIII activity to achieve
(%) (IU/dL)
Frequency of doses (hours)/ Duration of treatment (days)
Minor surgery 
(including tooth 
extraction)
30-60
Repeat every 24 hours if needed until adequate wound 
healing is achieved.
Major surgery
80-100
(pre-and postoperative)
Maintain factor VIII level by repeat injection every 8-24
hours until adequate wound healing is achieved, then adjust 
therapy for at least 7 more days to maintain a FVIII activity 
of 30% to 60% (IU/dL)
The specific treatment for each patient is decided by the investigator in collaboration with the
surgeon. Surgery can be done at the trial site, in another clinical department of the site, or at another 
hospital. If a surgery takes place at another location than at the trial site, the surgeon must be 
informed that the patient is participating in the trial, and the investigator should give instructions to 
the surgeon about the dosing treatment, the handling of the trial product and the efficacy and safety 
evaluation. It must be ensured that there is enough available trial product for the surgery, including 
the post-operative period. Please note the medication that is not permitted during the trial and 
surgery, see Section 6.5.1.
The maximum dose to be administered to a patient within 24 hours is 200 IU/kg. The dose is 
recommended to be divided and only considered under exceptional circumstance such us serious 
trauma or severe bleed.
See Section 8.1.3.1 for definitions of major and minor surgery.
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4.1.5.1
Administration of N8-GP on the day of surgery
Patients undergoing surgical procedures will receive trial product as bleeding preventive treatment 
according to standard practice at the trial site and/or at the investigator’s discretion.
Preventive treatment with trial product should be administered before any surgical procedures are 
undertaken, including potential anaesthesia to avoid bleeding when being anaesthetised.
See Table 4-2 for dosing guidance for surgery.
4.1.6
Treatment during screening and follow-up periods
Patients should follow their normal treatment regimen during the screening and follow-up periods. 
Treatments will not be reimbursed by Novo Nordisk during these periods. Bleeds that occur during 
the screening and follow-up periods should be treated as per standard local practice and will not be 
assessed.
4.2
Scientific rationale for trial design
This trial is a Phase 3b trial with a trial design overall similar to the global, pivotal pathfinderTM2
trial in adult and adolescent patients with severe haemophilia A (trial NN7088-3859), which is also 
in accordance with recommendations from Centre of Drug Evaluation (CDE) and guidelines. 
The chosen trial design will provide information on efficacy, safety (including immunogenicity) 
and PK of N8-GP when used for prophylaxis and treatment of bleeding episodes in previously 
treated Chinese patients with severe haemophilia A (FVIII activity <1%), complementing the data 
collected in global pathfinder™2 trial. 
Prophylaxis of bleeding episodes is the primary goal of therapy and must be the goal of all 
haemophilia care programmes until a cure is available.18
The trial will generate efficacy and safety data from ≥50 EDs and ≥6 months of prophylaxis to N8-
GP for each patient completing the trial, equivalent to at least 28 weeks of prophylaxis.
The trial will not be controlled by a placebo group as it is considered unethical to administer an 
ineffective treatment to patients with haemophilia.
The rationale for choosing a multi-centre design is to ensure a sufficient screening pool of patients 
with a rare disorder.
4.3
Justification for dose
This trial design is overall similar to the global, pivotal pathfinderTM2 trial design. The frequency 
for the prophylaxis treatment regimen and the dose levels for prophylaxis and treatment of bleeding 
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episodes is identical to what was used in the pathfinderTM2 trial. The treatment for major and minor 
surgery is identical to what was used in the pathfinderTM3 trial (NN7088-3860).
4.4
End of trial definition
A patient is considered to have completed the trial if he has completed all visits of the trial 
including the last visit. The end of the trial is defined as the date of the last visit of the last patient in 
the trial.
5
Trial population
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1
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 Chinese patient with severe congenital haemophilia A with a FVIII activity <1% 
according to medical records.
3. Aged ≥12 years at the time of signing informed consent.
4. History of at least 150 exposure days (EDs) to other FVIII products1.
5. The patient and/or caregiver is capable of assessing a bleeding episode, keeping a diary, 
performing home treatment of bleeding episodes and otherwise following the trial procedures at 
the discretion of the investigator.
1 Prophylaxis, prevention, on-demand and treatment during surgery counts as exposure days. If not possible to count the 
actual number of exposures in the medical chart, the investigator should make a written statement with an estimate 
based on e.g., patient age, treatment frequency, medical history, discussion with previous doctor/transfer note and other 
relevant information. This statement should be filed either with the patient chart or separately with the investigator trial 
file.
The criteria will be assessed at the investigator's discretion unless otherwise stated.
5.2
Exclusion criteria
Patients are excluded from the trial if any of the following criteria apply:
1. Known or suspected hypersensitivity to trial product or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 5 half-lives or 30 days from screening, whichever is longer.
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4. Known history of FVIII inhibitors based on existing medical records, laboratory report reviews 
and patient and/or caregiver interviews.
5. Current FVIII inhibitors ≥0.6 BU.
6. Congenital or acquired coagulation disorder other than haemophilia According to medical 
records.
7. HIV positive, defined by medical records, with CD4+ count d200/PL and a viral load 
>200 particles/μl or >400000 copies/mL within 6 months of the trial entry. If the data are not 
available in medical records within last 6 months, then the test must be performed at screening 
visit. .
8. Previous significant thromboembolic events (e.g. myocardial infarction, cerebrovascular disease 
or deep venous thrombosis) as defined by available medical records.
9. Hepatic dysfunction defined as aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) >3 times the upper limit of normal combined with total bilirubin 
>1.5 times the upper limit of normal at screening, as defined by central laboratory.
10. Renal impairment defined as estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2
for serum creatinine measured at screening, as defined by central laboratory.
11. Platelet count <50×109/L at screening based on central laboratory values at screening.
12. Ongoing immune modulating or chemotherapeutic medication.
13. Any disorder, except for conditions associated with haemophilia A, which in the investigator`s 
opinion might jeopardise the patient`s safety or compliance with the protocol.
14. Mental incapacity, unwillingness or language barriers precluding adequate understanding or 
cooperation.
The criteria will be assessed at the investigator's discretion unless otherwise stated.
5.3
Lifestyle considerations
Normal lifestyle is considered to be restricted for PK patients when they will undergo PK 
assessments at visit 2a and visit 7 where blood sampling will be performed during a 96-hour period. 
It is not required that the patient stays overnight. See the flowchart in Section 1.2 for patients 
having PK evaluated at Visit 2a and Visit 7, and Section 8.5 for how PK assessments are performed.
5.4
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 includes demography, screen failure 
details, eligibility criteria, and laboratory results. A screen failure session must be made in the 
interactive web response system (IWRS).
Individuals who do not meet the criteria for participation in this trial may not be rescreened. Re-
sampling is not allowed if the patient has failed one of the inclusion criteria or fulfilled one of the 
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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
Treatments
6.1
Treatments administered
Investigational medicinal product (IMP)
The following trial product will be supplied by Novo Nordisk:
x
turoctocog alfa pegol (N8-GP) 2000 IU/vial as a sterile, freeze-dried powder in a single-use 
vial of 2000 IU/vial to be reconstituted with 4.3 mL of 0.9% sodium chloride (NaCl) for i.v. 
injection. 
The reconstituted solution must not be further diluted. It is recommended to use the trial product 
immediately after reconstitution.
The trial product should be administered as a slow bolus i.v. injection over approximately 2 minutes 
(from start to completion of injection) for all trial product administrations.
Trial drug will be administered as i.v. injections at sites or at home by the patient and/or caregiver 
themselves.
The investigator must document that directions for use are given to the patient/caregiver verbally 
and in writing at the first dispensing visit (visit 2a) (see Section 1.2).
Table 6-1
Investigational medicinal product provided by Novo Nordisk A/S
Trial product name:
Turoctocog alfa pegol (N8-GP), 2000 IU/vial.
Dosage form
Solution for injection.
Route of administration 
Intravenous (i.v.).
Dosing instructions
Prophylaxis: 50 IU/kg every 4 days.
Treatment of bleeds: 20-75 IU/kg bolus injections.
Minor surgery (dosing guidelines): 50-75 IU/kg N8-GP or a dose 
sufficient to increase the FVIII level to 100% (IU/dL) prior to the 
surgery.
Major surgery (dosing guidelines): Maintain factor VIII level at 80-
100% (IU/dL) by repeat injection every 8-24 hours until adequate wound 
healing, then adjust therapy for at least 7 more days to maintain a FVIII 
activity of 30-60% (IU/dL).
Packaging
Vial with freeze-dried powder to be reconstituted with 0.9% sodium 
chloride.
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Non-investigational medicinal products (NIMP)
Sodium chloride 0.9% solution will be used to reconstitute the IMP. Sodium chloride 0.9% will 
come in a syringe with scale label (the NIMP) and will be provided by Novo Nordisk.
Auxiliary supplies
All medical devices used in this trial will be provided by Novo Nordisk such as needles, butterflies, 
syringes, sterile swabs, and vial adapters.
Only needles and syringes provided and/or approved by Novo Nordisk must be used for 
administration of trial product.
6.2
Preparation/handling/storage/accountability
Only patients enrolled in the trial may receive trial product (IMP and NIMP), and only the trial 
doctor and authorised site staff may supply and administer trial product.
Instructions for trial product storage, in-use conditions and in-use time will be available from the 
label and from the trial materials manual (TMM).
x
Acceptable temperature ranges and conditions for storage and handling of trial product when 
not in use and when in use are described in the TMM.
x
Each site will be supplied with sufficient trial products for the trial on an ongoing basis. 
Trial product will be distributed to the sites according to screening and inclusion.
x
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all trial products received, and that any discrepancies are 
reported and resolved before use of the trial products.
x
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 delegated site staff.
x
The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. If so, this trial product must not be dispensed to any patient 
before it has been evaluated and approved for further use by Novo Nordisk. Additional 
details regarding handling of temperature deviations can be found in the TMM.
x
The investigator or designee is responsible for drug accountability and for recording 
maintenance (i.e. receipt, accountability and final disposition records).
x
The investigator or designee must instruct the patient in what to return at next visit.
x
The patient must return all used, partly used and unused trial product including empty 
packaging materials during the trial as instructed by the investigator or designee.
x
Drug accountability for N8-GP (IMP) and sodium chloride 0.9% syringe (NIMP) is
performed on a dispensing unit number (DUN) level using the IWRS drug accountability 
module to account for the status of each DUN.
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x
Destruction of trial products 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.
x
All returned, unused, expired or damaged trial products (for technical complaint samples, 
see Section 10.5) must be stored separately from non-allocated trial products. No 
temperature monitoring is required.
x
Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the site.
6.3
Measures to minimise bias: Randomisation and blinding
All screened patients will receive a unique patient number at the screening visit, which will be 
assigned to the patient throughout the trial.
This is an open-label trial.
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6.4
Treatment compliance
Drug treatment compliance
Throughout the trial, the investigator will remind the patients to follow the trial procedures and 
requirements to encourage patient compliance.
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 source documents.
When patients self-administer trial product(s) at home, compliance with trial product administration 
will be assessed and the assessment documented in source documents at each visit where 
information is available. Any missed dose should be discussed with the patient and followed up to 
ensure patient is compliant to trial product and trial procedures. If any suspicion of non-compliance 
arises i.e., the patient missed ≥5 doses of any consecutive 25 doses 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:
x
Drug accountability information; counting returned trial product, visual inspection of vials
x
Review of dosing diaries
x
Questioning of patients
Treatment start dates, stop dates and all doses will be recorded in the electronic case report form 
(eCRF).
6.4.1
In-use time
Investigator/investigator designee must train the subject on in-use time of the trial product at first 
dispensing, At each site visit investigator/ investigator designee must review use of trial product
with the subject and document in the subject medical record if the subject exceeds in-use time of the 
trial product.
6.5
Concomitant medication
Any medication or vaccine (including over the counter or prescription medicines, vitamins, and/or 
herbal supplements) other than the trial product(s) that the patient is receiving at the time of the first 
visit or receives during the trial must be recorded along with:
x
Trade name or generic name
x
Indication 
x
Start and stop dates
x
Total daily dose 
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Changes in concomitant medication must be recorded at each visit. If a change in concomitant 
medication is due to an AE/SAE, then this must be reported according to Section 8.3.
6.5.1
Prohibited Medication
The following medications are not allowed during the course of the trial until after the End of 
Treatment visit. 
x
Bypassing products: activated recombinant factor VII (rFVIIa), plasma-derived prothrombin 
complex concentrates (pd-PCC) and plasma-derived activated prothrombin complex 
concentrates (pd-aPCC).
x
Coagulation Factors: FVIII, FIX and FVII-containing products other than N8-GP and other 
FVIII-containing products like fresh frozen plasma or cryoprecipitate (exception: current 
FVIII is allowed until 96 hours before Visit 2a).
x
Anti-coagulants such as Heparin and vitamin-K antagonists. Heparin is allowed for sealing 
of central venous access devices according to local practice.
6.6
Dose modification
Treatment with N8-GP for prophylaxis, treatment of bleeding episodes, and surgery is found in 
Sections 4.1.3, 4.1.4 and 4.1.5, respectively.
The possibility of changing the prophylaxis regimen in an individual patient from every 4 days 
dosing with 50 IU/kg N8-GP to twice-weekly dosing with 50 IU/kg N8-GP at the discretion of the 
investigator is described in Section 4.1.3.
6.7
Treatment after end of trial
When discontinuing trial product at visit 7 or 7a (i.e., before the End of trial/Follow-up visit), the 
patient should be transferred to a suitable marketed product at the discretion of the investigator.
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7
Discontinuation of trial treatment and patient
withdrawal
Treatment of a patient may be discontinued at any time during the trial at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons.
Even if treatment with trial product has been discontinued, the patient should continue to follow the 
planned visit schedule until having completed the end of treatment visit (Visit 7). Efforts must be 
made to have the patients who discontinue trial product attend and complete all scheduled visit 
procedures according to Section 1.2. Patients should stay in the trial irrespective of lack of 
adherence to the treatment, lack of adherence to visit schedule or missing assessments.
If the patient, who has been discontinued from treatment with trial product, declines the request to
continue in the trial, then efforts must be made to have the patient attend Visit 7a (discontinuation 
of treatment visit) (see Section 1.2).
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.
7.1
Discontinuation of trial treatment
A patient who does not fulfil the eligibility criteria (inclusion/exclusion criteria) must not be 
included in the trial. Inclusion in violation of any of the eligibility criteria is non-compliant with 
Good Clinical Practice (GCP) procedures and must be reported to the sponsor without delay. This 
will be handled as an important protocol deviation, and the independent ethics committee (IEC)/ 
institutional review board (IRB) and regulatory authorities must be notified according to local 
requirements. If there are no safety concerns for the patient, trial treatment may be continued or 
resumed at the discretion of the investigator after agreement with the sponsor´s global medical 
expert.
A patient may be discontinued from treatment with N8-GP at the discretion of the investigator due 
to a safety concern. 
The trial product must be discontinued, if any of the following applies for the patient:
1. Simultaneous use of an approved or non-approved investigational medicinal product in 
another clinical trial.
2.
Haemostasis not achievable with N8-GP: The bleed cannot be controlled after 48 hours 
using adequate doses of N8-GP.
3. FVIII inhibitor (≥0.6 and ≤5 BU) as confirmed by re-testing by Central Laboratory that 
makes treatment (prophylaxis and/or treatment of bleeding episodes) with N8-GP clinically 
ineffective. see section 8.6
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4. FVIII inhibitor (>5 BU) as confirmed by re-testing by Central Laboratory.
5. Allergy/anaphylaxis to the trial product.
6. Use of Coagulation Factors FVIII, FIX and FVII-containing products other than N8-GP and 
other FVIII-containing products such as fresh frozen plasma or cryoprecipitate (Exception:
FVIII is allowed until 96 hours before visit 2a).
7. Incapacity or unwillingness to follow the trial procedures.
8. Use of Anti-coagulants such as Heparin and vitamin-K antagonists (Heparin is allowed for 
sealing of central venous access devices according to local practice).
See Section 1.2 for data to be collected at the time of treatment discontinuation (discontinuation of 
treatment visit; Visit 7a) and follow-up and for any further evaluations that need to be completed.
The purpose of the end of trial (follow-up) visit is to collect information about adverse events. For 
convenience of the patient the visit can be performed as a telephone contact.
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.
If a patient discontinues treatment prior to Visit 7, Visit 7a should be performed as soon as possible
after the last dose of trial product has been administered, and prior to starting treatment with another 
marketed product. The follow-up visit (Visit P8) should be performed 30 +5 days after the last dose 
of trial product has been administered. Even if treatment with trial product has been discontinued, 
after Visit P8 the patient should continue to follow the planned visit schedule until having 
completed the end of treatment visit (Visit 7).
After Visit 7a, the following procedures/assessments should not be performed for patients who 
discontinue treatment:
x
Trial product administration
x
FVIII activity
x
Medication error
x
Technical complaint
x
Drug dispensing and drug accountability
7.1.1
Temporary discontinuation of trial treatment
Temporary discontinuation of treatment with trial product is not allowed in the trial.
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7.2
Patient withdrawal from the trial
A patient may withdraw consent at any time at his own request or at the request of the caregiver.
If a patient withdraws consent, the investigator must ask the patient for willingness, as soon as 
possible, to have assessments performed according to Visit 7a (discontinuation of treatment visit). 
See Section 1.2 for data to be collected at Visit 7a (discontinuation of treatment visit) after 
treatment with trial product has been discontinued.
Final drug accountability must be performed even if the patient is not able to come to the site. A 
treatment discontinuation session must be made in the IWRS.
If the patient withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent.
If a patient withdraws from the trial, the patient may request destruction of any samples taken and 
not tested, and the investigator must document this in the medical record.
Although a patient is not obliged to give the 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.
7.2.1
Replacement of patients
Patients who discontinue trial product or withdraw from the trial will not be replaced.
7.3
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 site.
The following actions must be taken if a patient fails to return to the site for a required visit:
x
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.
x
Before a patient is deemed lost to follow-up, the investigator or designee 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.
x
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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8
Trial assessments and procedures
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowcharts in Section 1.2.
Informed consent must be obtained before any trial related activity, see Section 10.1.3.
All screening evaluations must be completed and reviewed to confirm that potential patients meet 
all inclusion criteria and none of the exclusion 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 a card stating that they are participating in a trial and 
giving contact details of relevant site staff that can be contacted in case of emergency.
Adherence to the trial design requirements, including those specified in the flowchart in Section 1.2,
is essential and required for trial conduct.
Review of e.g., diaries and laboratory reports must be documented either on the documents or in the 
patient's source documents. If clarification of entries or discrepancies in the documents 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
Repeat samples may be taken for technical issues and unscheduled samples or assessments may be 
taken for safety reasons. Refer to Appendix 2 for further details on laboratory samples.
8.1
Efficacy assessments
Planned time points for all efficacy assessments are provided in the flowcharts in Section 1.2.
8.1.1
Bleeding Episodes
From Visit 2a (inclusion of the patient and first administration of trial product) and during the entire 
trial period all treatment-requiring bleeding episodes (also referred to as ‘bleeding episodes’ or 
‘bleeds’) must be entered by the patient or caregiver in the patient’s diary. In case a patient is 
unable to enter a bleeding episode in the diary or is hospitalised, the investigator will report the 
bleeding episode in the eCRF (refer to Section 8.7 for reporting in the diary and eCRF).
If a patient experiences a bleeding episode at home, treatment with N8-GP should be initiated 
irrespective of severity of the bleeding episode (refer to Section 8.8 for training in home treatment).
If the bleed is mild/moderate, the treatment responsibility is with the patient, patient’s caregiver(s) 
and/or the investigator. For severe bleeding episodes, the treatment responsibility is always with the 
investigator and the patient should contact the site for further instructions. Treatment of severe 
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bleeding episodes should be initiated as soon as possible by the patient or caregiver. It is the 
responsibility of the investigator to assess the severity of the bleeding episodes and to ensure that all 
data is recorded correctly in the patient’s diary.
Any discrepancy observed by the investigator or site staff must be documented in the patient's 
medical record and the patient must be retrained on completion of the diary completion, if required.
Joint bleeds are either categorised as target joint or non-target joint bleeds. Target joints are defined 
as 3 or more bleeding episodes in the same joint within 6 months. When there has been no bleed in 
the same joint for 12 months, such a joint is no longer considered a target joint.
A need for haemostatic rescue therapy with another FVIII product will be assessed by the 
investigator via phone or during the site visit. Patients treated with FVIII products other than N8-GP
must be discontinued from treatment with N8-GP (exception: the patient’s current FVIII product is 
allowed until 96 hours before visit 2a).
8.1.1.1
Definition of severity of bleeding episodes
x
Mild/Moderate: Bleeding episodes that are uncomplicated joint bleeds, muscular bleeds 
without compartment syndrome, mucosal- or subcutaneous bleeds
x
Severe: All intracranial, retroperitoneal, iliopsoas and neck bleeds must be categorised as 
severe. Muscle bleeds with compartment syndrome and bleeds associated with a significant 
decrease in the haemoglobin level (>3g/dl) should also be reported as severe. These bleeding 
episodes must be treated immediately or at the local emergency room and the site staff must 
be contacted. The details of severe bleeding episodes must be entered in the diary or if the 
patient is unable to fill in the diary or hospitalized, the investigator or site staff can enter the 
data in the eCRF. Traumatic bleeds at other locations than described above can always be 
considered severe at the investigator’s discretion.
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8.1.1.2
Definition of Haemostatic Response:
x Excellent: abrupt pain relief and/or unequivocal improvement in objective signs of bleeding 
within approximately 8 hours after a single infusion. 
x Good: definite pain relief and/or improvement in signs of bleeding within approximately 8 
hours after one infusion, but possible requiring more than one infusion for complete resolution 
x Moderate: probable or slight beneficial effect within approximately 8 hours after the first 
infusion; usually requiring more than one infusion 
x None: no improvement, or worsening of symptoms 
8.1.1.3
Classification of a bleeding episode
Table 8-1
Definitions of bleeding episodes
Category
Comment
Spontaneous
Not linked to a specific event
Traumatic
Caused by a specific, known action or event (e.g. injury or exercise)
Surgical bleed
Bleeds after surgery from the surgical wound. Bleeding episodes during surgery does not fall 
under this category and will be evaluated in the surgical haemostatic evaluation
8.1.2
Clinical efficacy laboratory assessments
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowcharts in Section 1.2 and the laboratory manual.
8.1.3
Surgery
Surgical procedures should be performed by a surgeon in collaboration with the investigator.
Surgery should preferably be scheduled early in the week and early in the day for optimal 
conditions, e.g., support from the blood bank. Access to sufficient quantities of N8-GP should be 
ensured before undertaking surgery.
Blood samples for analysis of FVIII activity will be collected on the day of surgery; pre-dosing 
(trough) and 30±5 min (recovery) post-administration of the dose for surgery. These sampling time 
points are relative to completion of N8-GP administration, and actual time must be documented. 
The analysis of plasma FVIII activity will be performed using a chromogenic assay at a central 
laboratory selected by Novo Nordisk.
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8.1.3.1
Definition of surgery
Surgery type
Definition
Major surgery 
Major surgery is any invasive operative procedure where any one or more of the following occur
A body cavity is entered.
A mesenchymal barrier (e.g. pleura, peritoneum or dura) is crossed.
A fascial plane is opened.
An organ is removed.
Normal anatomy is operatively altered
These procedures may be performed using general anaesthesia, spinal anaesthesia, epidural 
anaesthesia, conscious sedation or with a combination of these modalities
Minor surgery 
Minor surgery is any invasive operative procedure in which only skin, mucous membranes, or 
superficial connective tissue is manipulated. Examples of minor surgery include vascular cutdown 
for catheter/fistula placement, implanting pumps or CVAD in subcutaneous tissue, biopsies or 
placement of probes, leads, or catheters requiring the entry into a body cavity only through a 
needle/guidewire.
Dental surgery will be classified as minor or major based on above definitions
8.1.3.2
Haemostatic response during surgery
Table 8-2
Haemostatic response during surgery
Category
Definition
Excellent
blood loss less than expected
Good
blood loss as expected
Moderate
blood loss more than expected
None
uncontrolled bleeding
This evaluation must be performed by the surgeon and the investigator should ensure to document it in the eCRF.
8.1.3.3
Surgery visit
Surgery must be performed at a dedicated surgery visit. See Section 1.2 for procedures and 
assessments to be performed during a surgery visit.
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8.2
Safety assessments
Planned time points for all safety assessments are provided in Section 1.2.
A concomitant illness is any illness that is already present at the time point from which AEs are 
collected 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 experienced prior to the time point from which 
AEs are collected.
In case of an abnormal and clinically significant finding fulfilling the definition of a concomitant 
illness or medical history, the investigator must record the finding on the Medical History/ 
Concomitant Illness form.
8.2.1
Physical examinations
The physical examinations will be performed according to local procedure and will include:
x
General appearance
x
Ears, eyes, nose, throat and neck
x
Respiratory system
x
Cardiovascular system
x
Gastrointestinal system, including mouth
x
Musculoskeletal system
x
Central and peripheral nervous system (general evaluation)
x
Skin
x
Lymph node palpation
Target joints: Patients will be asked about number and location of target joints. Target joints are 
defined as 3 or more bleeding episodes in the same joint within 6 months.
Any changes in the examination between the visits which fulfil the criteria of an AE must be 
recorded as such (see Appendix 3 in Section 10.3).
Clinically significant findings present at screening must be documented as concomitant illness and 
during the trial as AEs.
Investigators should pay special attention to clinical signs related to previous serious illnesses.
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Body weight
Body weight will be measured in kilos (kg) with one decimal without shoes and wearing only light 
clothing. Body weight should be measured preferably at the same time of the day and by using the 
same calibrated scale throughout the trial, if possible.
Height
Height is measured without shoes in centimetres or inches and recorded in the eCRF to nearest ½ 
cm or ¼ inch.
Body Mass Index
Body mass index will be calculated by the investigator at the screening visit 1 and documented in 
the subject medical record.
8.2.1.1
Neurological examination
The following neurological examinations will be performed by the investigator (haematologist) or 
an appropriately trained designee under their supervision upon the outline specified in Appendix 6
(this outline has been developed with guidance from a neurologist):
x
General neurology including level of consciousness
x
Cranial nerves in relation to sight including reaction to light, visual fields and acuity, and 
eye movements, facial sensation and movement, hearing, palate sound and tongue 
movement, and trapezius muscle function
x
Tone of upper and lower extremity right and left
x
Strength of upper and lower extremity right and left
x
Reflexes of the biceps, triceps, knee and ankle right and left
x
Sensory aspect of cold, pin prick, light touch and proprioception (toe up/down)
x
Gait with regards to walking, running, on heels and toes, tandem (toe/heel walk), stand/hop 
on one leg/foot right and left, and Romberg sign
x
Coordination and Fine Motor including finger-to-nose, rapid index finger tab and rapid 
finger movement right and left
If a patient have not had a specific neurological examination at baseline (visit 2a) then that
examination item should not be performed during subsequent visits as per flowchart Table 1-1.
8.2.2
Vital signs
Before measurement of vital signs the patient must rest comfortably for at least three minutes and 
all measurements should, if possible, be performed using the same method and position (e.g. sitting 
or lying down) throughout the trial for each individual patient.
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Vitals signs include assessment of:
x
Body temperature (according to local standard practice)
x
Pulse
x
Blood pressure
x
Respiratory rate (resp./min)
Elevated BP is defined as a systolic BP >160 mmHg or a diastolic BP >95 mmHg. Decreased BP is 
defined as a systolic BP <90 mmHg or a decrease from pre-dose of more than 30 mmHg.
Results of vital signs must be reported in the eCRF. Clinically significant findings present at 
screening must be documented as concomitant illness and during the trial as AEs.
8.2.3
Electrocardiograms
12-lead ECG will be obtained at the screening visit and at the end of treatment visit. For the ECG 
recording, the patients must be resting and in a horisontal position. Any irregularities observed 
during the ECG, e.g. cough, should either induce a re-run of the ECG and/or be annotated in the 
eCRF page with description of the occurrence. Printouts must include date, time, patient’s 
identification, and initials of the investigator, and at least 2 complexes for each lead and a single 
rhythm strip of 6 beats. Electronic capture of these measurements may also be performed.
The evaluation should be made by the investigator or delegated to a cardiologist.
Results of the ECG recording must be reported in the eCRF. Clinically significant findings present 
at screening must be documented as concomitant illness.
8.2.4
Clinical safety laboratory assessments
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and Section 1.2). An investigator must sign, date and 
categorise the laboratory results. Categorisation will be either “normal”, “out of normal range, not 
clinically significant” or “out of normal range, clinically significant”. Clinically significant findings 
at Visits 1 and 2a must be recorded as Concomitant Illness, while clinically significant findings 
from Visit 2b until Visit 7 (included) must be recorded as AEs. Abnormalities should only be 
recorded as AEs if not present or worsened from baseline/previous assessments. Laboratory results 
are considered as source data and must be signed and dated by the investigator to verify that the 
data has been reviewed and that any AEs have been reported. 
The administration of N8-GP will be performed after collection of all blood samples for the 
laboratory tests, except the recovery samples which must be collected 30 minutes after 
administration of N8-GP.
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8.3
Adverse events and serious adverse events
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE.
The definition of AEs and SAEs can be found in Appendix 3, along with a description of AEs 
requiring additional data collection.
Some AEs require additional data collection on a specific event form. This always includes 
medication error, misuse and abuse of IMP. The relevant events, together with AESIs, are listed in 
Table 8-3.
Table 8-3
AEs requiring additional data collection (serious and non-serious AEs) and 
AESIs
Event type
AE requiring additional data 
collection
AESIs
Medication error
X
Misuse and abuse
X
Hypersensitivity
X
FVIII inhibitors
X
CNS-related AEs
X
Renal or hepatic AEs
X
Thromboembolic events
X
A detailed description of the events mentioned in the above table can be found in Appendix 3.
8.3.1
Time period and frequency for collecting AE and SAE information
All AEs and SAEs must be collected from the first administration of trial product at Visit 2a and 
until the end of the trial (follow-up visit) at the time points specified in the flowchart in Section 1.2.
Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix 3. All SAEs must be recorded and reported to Novo Nordisk or designee 
within 24 hours, and 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 trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk.
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8.3.2
Method of detecting AEs and SAEs
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 3.
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.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or the 
patient is lost to follow-up as described in Section 7.3. Further information on follow-up and final
outcome of events is given in Appendix 3.
8.3.4
Regulatory reporting requirements for SAEs
Prompt notification by the investigator to Novo Nordisk or designee 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, IRB/IEC, and investigators. This also includes suspected unexpected serious 
adverse reactions (SUSAR).
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 investigator's brochure17 and will notify the IRB/IEC, if appropriate according to local 
requirements.
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8.3.5
Pregnancy 
Details of pregnancies in female partners of male patient will be collected after first exposure to 
trial product and until end of trial (follow-up) visit.
If a female partner of a male patient becomes pregnant and the outcome of the pregnancy is 
abnormal, the investigator should inform Novo Nordisk within 14 calendar days of learning of the 
abnormal outcome and should follow the procedures outlined in Appendix 4.
8.3.6
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE
The following disease-related events (DREs) are common in patients with haemophilia A and can 
be serious/life threatening:
x
Bleeding episodes.
Bleeding episodes
Because bleeding episodes are typically associated with the disease under study, they will not be 
reported according to the standard process for reporting of AEs/SAEs, even though the episodes 
may meet the definition of an AE/SAE. These episodes will be recorded in the patient diary and 
eCRF. These DREs will be monitored by Novo Nordisk on a routine basis.
Note: The bleeding episode must be recorded and reported both as a DRE and as an AE/SAE if one 
of the following applies:
x
The bleeding episode is, in the investigator's opinion, of greater intensity, frequency, or 
duration than expected for the individual patient.
x
The investigator considers that there is a reasonable possibility that the bleeding episode was 
related to treatment with the IMP.
x
The bleeding episode is considered life-threatening (see Appendix 4 for definition of life-
threatening).
x
The bleeding episode results in death.
8.3.7
Technical complaints
Technical complaints will be collected for all products listed on the technical complaint form.
Instructions for reporting technical complaints can be found in Appendix 5.
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form.
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8.4
Treatment of overdose
Accidental overdose must be reported as a medication error. Intentional overdose must be reported 
as misuse and abuse, please refer to Section 8.3 and Appendix 3 for further details.
In the event of an overdose, the investigator should closely monitor the patient for overdose-related 
AE/SAE.
For more information on overdose, also consult the current version of the turoctocog alfa pegol 
(N8-GP) investigator's brochure.17
8.5
Pharmacokinetics
Patients will be administered a single i.v. bolus injection of 50 IU/kg of N8-GP at Visit 2a and at 
Visit 7. The PK sessions extends over 96 hours. Overnight stay is not required. After completion of 
the PK sessions the patients will return to prophylaxis treatment with the next visit in line. 
Patients must not have received current FVIII product for at least 4 days (96 hours) prior to the 
administration of trial product for the single-dose PK session at visit 2a, (i.e., a wash-out period of 
at least 96 hours must be applied before visit 2a).
There is no wash-out period for the steady-state PK session at visit 7, however administration of 
trial product at visit 7 should be approximately 96 hours after the previous N8-GP dose. 
Patients must not be actively bleeding during the pharmacokinetic sessions.
The lines/tubes must be flushed immediately after administration of the trial product.
The pharmacokinetic endpoints (see Section 3.2.2.3) will be based on assessments performed from 
1 hour prior to and up to 96 hours after administration of N8-GP at Visit 2a (single-dose PK 
assessments) and Visit 7 (steady-state PK assessments) (see flowchart for PK assessments in
Section 1.2).
8.5.1
Visit 2a for patients undergoing PK assessments
Visit 2a should take place as soon as possible upon confirmation of eligibility approximately 2 
weeks after the screening visit (Visit 1). Overnight stay is not required during the PK evaluation. 
At Visit 2a the patients will receive their first dose of N8-GP (50 IU/kg) at the site and nine PK 
samples will be taken during the following 96 hours. If a bleeding episode occurs between Visit 2a 
and 2b the patient must contact the site and preferably come to the site for treatment with N8-GP.
Further blood sampling for PK will be stopped. If the patient experiences a bleeding episode at 
home that requires immediate treatment, or if the investigator judges it as necessary, the patient 
must treat himself at home with his previous FVIII product. Treatment with previous FVIII product 
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must lead to immediate stop of PK assessments and the patient must be discontinued from treatment 
with trial product.
Assessments at visit 2a are outlined in Section 1.2 and additional assessments and sampling for PK 
patients are outlined in Table 1-1.
The lines must be flushed immediately after administration of the trial product.
Samples taken pre-dose may be taken from the same arm as the one used for N8-GP administration.
The samples taken 30 min post dose must not be taken from the same vein as used for 
administration of N8-GP.
8.5.2
Visit 2b for patients undergoing PK assessments
The second dose of N8-GP will be administered at the site after the last PK sample in relation to 
Visit 2a is taken.
Assessments at visit 2b are outlined in Section 1.2 and additional assessments and sampling for PK 
patients are outlined in Table 1-1.
8.5.3
Visit 7 for patients undergoing PK assessments
Patients who underwent a single-dose PK assessment at Visit 2a must also undergo a steady-state 
PK assessment at Visit 7. The steady-state PK session should be performed approximately 96 hours
after the previous N8-GP dose. Overnight stay is not required during the PK evaluation. Blood 
sampling for PK should be stopped if a treatment requiring bleeding episode occurs during the PK 
session.
Samples taken pre-dose may be taken from the same arm as the one used for N8-GP administration.
The lines used for injection must be flushed immediately after administration of the trial product.
The samples taken 30 min post dose must not be taken from the same vein as previously used for 
administration of N8-GP.
Assessments at visit 7 and additional assessments and sampling for PK patients are outlined in
Section 1.2.
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8.6
Immunogenicity assessments
8.6.1
FVIII inhibitors
All patients will be examined for the development of FVIII inhibitors at scheduled visits (see 
Section 1.2). If FVIII inhibitor development is suspected (e.g., increased number of bleeding 
episodes, bleeding episodes difficult to treat, N8-GP recovery and trough levels below expected 
values) during the course of the trial, additional inhibitor tests can be taken. All inhibitor tests must 
be analysed by the central laboratory.
A positive inhibitor test is defined as t0.6 BU. In the event that a previously inhibitor negative 
patient has a positive inhibitor test (t0.6 BU), the patient will be requested to visit the site for 
additional sampling preferably within 2 weeks. In addition, the following tests should be performed:
anti-N8-GP antibodies, anti-PEG antibodies, FVIII trough (pre-dose), FVIII recovery (30 min post-
dose) and lupus anticoagulant. These samples should preferably be taken prior to any change of 
treatment, and after approximately 96 hours wash-out period. If the second (confirmatory) inhibitor 
test is also positive, the patient must be discontinued from trial treatment if FVIII inhibitor >5 BU 
or if FVIII inhibitor ≥0.6 and ≤5 BU that makes treatment (prophylaxis or treatment of bleeding 
episodes) with N8-GP clinically ineffective, by discontinuing trial product and attending the 
discontinuation of treatment visit (visit 7a) within 1 week after the result is available.
If the second (confirmatory) inhibitor test is positive and ≤5 BU and the investigator judges that the 
inhibitor does not clinically interfere with N8-GP treatment (prophylaxis or treatment of bleeding 
episodes), the patient can stay in the trial and continue treatment as per-protocol treatment.
A patient has inhibitor (≥0.6 BU) if the patient has been tested positive for inhibitors at two 
consecutive test samples performed at the central laboratory preferably with no more than 2 weeks 
between the tests.
For patients discontinued from treatment with N8-GP: A follow-up visit must be scheduled 
30(+5) days after the discontinuation of treatment (Visit 7a) and additional follow-up contact(s) 
(e.g., phone calls) may be arranged as long as clinically warranted up to 3 months after the EOT 
Visit.
For patients continuing in the trial with inhibitor (≥0.6 and ≤5 BU): the patient must follow per-
protocol treatment schedule and the scheduled visits as described in Section 1.2. Additional visits 
can be scheduled if closer monitoring is needed. Closer monitoring is highly recommended but this 
decision will be at investigator’s discretion. In the event of a concern about reduced treatment 
efficacy a PK session may be performed. Blood sampling during the PK profile session can be 
performed at the following time points: pre-dose, 30 minutes (± 10 min), 24h (± 8 hours), 
48h (± 8 hours), 72h (± 8 hours) and 96h (± 8 hours). 
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A confirmed positive inhibitor is considered to have disappeared if the inhibitor titre is <0.6 BU on 
2 consecutive inhibitor tests (performed at 2 consecutive visits) and the FVIII recovery is ≥66% of 
expected values. A patient with repeated positive inhibitor test result will count only once in the 
determination of the inhibitor incidence rate.
Patients who develop an inhibitor should be classified as high responders (peak inhibitor titre 
>5 BU), low responders (peak inhibitor titre ≤5 BU), and whether the inhibitor is transient 
(disappearing (inhibitor titre <0.6 BU on ≥2 consecutive measurements) spontaneously within 6 
months without a change in treatment regimen), or not.
All per protocol inhibitor laboratory samples are to be analysed in the central laboratory, and only 
these results will be used in the data analyses.
Any single positive inhibitor test must be reported as an AESI (see Section 10.3.3).
If the second (confirmatory) inhibitor test is positive then the event must be reported as an SAE (see 
Section 10.3.5).
Blood samples for measurement of inhibitors towards FVIII will be analysed according to the 
Nijmegen modification of the Bethesda assay.15 Any sampling for the inhibitor test must be 
performed at least 96 hours after last administration of N8-GP to allow for maximum wash-out of 
the drug. 
The patient may discontinue the trial including an EOT Visit and FU Visits or remain in the trial as 
described above. A patient having an initial positive inhibitor test and a second negative inhibitor 
test will be regarded as inhibitor negative and can continue in the trial.
If more than two patients are verified inhibitor positive an unscheduled Safety Committee Meeting 
will be called by Global Safety – and a decision whether to continue, modify or stop the trial will 
made.
In the event that a patient is discontinued from trial treatment due to development of inhibitors,
Novo Nordisk A/S will cover costs of associated treatment if the inhibitor development is 
considered a trial related injury in accordance with Chinese law. 
8.6.2
Anti-N8-GP antibodies
N8-GP binding antibodies will be assessed using a radioimmunoassay that is validated according to 
internationally recognised guidelines.19-23 Samples measured above the assay cut-point of antibody 
reactivity will be subject to a confirmation test, where the presence of anti-N8-GP antibodies will be 
confirmed by addition of excess of unlabelled N8-GP and cross-reactivity to rFVIII will be 
measured using excess of unlabelled rFVIII. Only samples positive in the confirmatory assay will 
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be characterised as anti-N8-GP or anti-rFVIII antibody positive. The analyses will take place at the 
end of the trial.
8.6.3
Anti-PEG antibodies
Anti-PEG antibodies will be measured at baseline and at end of treatment using a direct ELISA
validated according to internationally recognised guidelines.19-23 Samples measured above the assay 
cut-point of antibody reactivity will be subject to a confirmation test, where the presence of 
anti-PEG antibodies will be confirmed by addition of excess of unlabelled PEG. The analysis will 
take place at the end of the trial.
8.6.4
Anti-HCP antibodies
All patients at baseline and subsequently any patient who experiences an acute severe 
allergic/anaphylactic reaction (see Section 10.3.3 for definition) that cannot be assigned to
anti-N8-GP antibodies will be assessed for anti-HCP antibodies. The blood sample for assessment 
of anti-HCP antibodies should be drawn within 4 weeks (and preferably 2-4 weeks) after the AE of 
acute severe allergic/anaphylactic reaction.
8.7
Diary
The patient/caregiver will be provided with a diary for recording of bleeding episodes and the home 
treatment hereof. All the treatments, administered at home (see section 8.8 and 8.1.1) must also be 
recorded in the diary. All bleeding episodes including the bleeding episodes that are experienced 
while at site must be recorded in the diary. At visit 1, the patient/caregiver will receive the first 
diary and they will be trained in the use by the investigator.
The diary is split into a bleed and a treatment diary. The diaries must be returned at every scheduled 
visit and new diaries will be handed out to the patient/caregiver. During trial site visits, the diaries
must be reviewed together with the patient/caregiver and evaluate together with the 
patient/caregiver the correctness of the haemostatic efficacy for treatment of bleeds. The severity 
rating of the bleeding episode and the treatment type must be entered by the trial site staff, if 
necessary, into the diaries. Afterwards the diary data must be recorded in the eCRF by the 
investigator or the designee.
Patient diaries must be reviewed by the investigator at every scheduled visit to ensure that AEs, 
including any change in health and concomitant medication, are reported. Furthermore, the diaries
must also be reviewed for accuracy, completeness and consistency with the requirements defined in 
this protocol, see section 6.4. This review must be documented in the patient's medical record.
Only the patient or caregiver is allowed to change entries in the diary except for the severity rating 
and treatment type if they are entered into the diary by the site.
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If clarification of entries or discrepancies in the diary that are entered by the patient is needed, the 
patient must be questioned, and a conclusion made in the patient's medical record. Care must be 
taken not to bias the patient. A correction is done by both changing the entry in the paper diary and 
the entry in the eCRF.
8.8
Home treatment training
Home treatment training with injection of N8-GP (turoctocog alfa pegol) can start after injections of 
the first dose at the trial site, and should continue until the patient or caregiver is comfortable with 
the reconstitution and injection process. The training must be documented in the medical records.
A home treatment guide for the reconstitution and injection process must be handed-out to the 
patient or caregiver at every dispensing visit.
If the patient does not follow the planned dosing schedule, the investigator must retrain the patient 
and/or caregiver.
9
Statistical considerations 
9.1
Statistical hypotheses
No confirmatory hypotheses are planned to be tested due to the low number of patients to be 
included in this trial.
9.2
Sample size determination
No formal sample size calculations have been performed. Based on meeting communication with 
CDE and with the supplement data from the global pivotal trial NN7088-3859 which also included 
Asian patients, a total number of 30 Chinese patients to complete this trial is considered sufficient 
to evaluate efficacy and safety in the Chinese population.
Fifteen (15) patients will participate in PK assessments sessions to ensure at least 12 patients with 
complete single-dose and steady-state PK profiles.
9.3
Populations for analyses
All patients exposed to N8-GP in this trial will be included in the full analysis set and the safety 
analysis set.
Exceptional outlier pharmacokinetic profiles and/or individual plasma FVIII activities may be 
excluded when analysing pharmacokinetic endpoints based on the FAS. The rules to exclude data 
points from analysis of pharmacokinetic endpoints are described in the statistical analysis plan 
(SAP), and the decision of data exclusion will be made during a review prior to database lock. Any 
excluded data points will be documented in the database lock minutes and also in the clinical trial 
report (CTR).
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9.4
Statistical analyses
The statistical analysis plan (SAP) will be finalised prior to first-patient-first visit (FPFV), and it 
will include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary endpoint. There are no confirmatory secondary endpoints specified in 
this trial.
9.4.1
General considerations
Novo Nordisk will be responsible for the statistical analyses.
Summaries for continuous endpoints will include total number (N), mean (SD), median and 
min/max, and for pharmacokinetic endpoints also geometric mean and coefficient of variation 
(CV%). Summaries for categorical endpoints will include N, number (n) and percentages (%) for 
each outcome category.
In general, all summaries and analyses will also be prepared by age subgroup (12-17 and 18-70
years of age).
9.4.2
Primary endpoint
Endpoint title
Time frame
Unit
Number of bleeding episodes
From start of treatment until visit 7
Count
The primary endpoint will be analysed by a Poisson regression model allowing for over-dispersion 
(using Pearson’s chi-square divided by the degrees of freedom) with the logarithm of duration of
actual prophylaxis treatment with N8-GP used as offset. Estimates of the annualised bleeding rate 
(ABR) will be provided with 95% confidence intervals.
Only the observed bleeding episodes will be counted and the offset will be the duration of actual 
prophylaxis treatment with N8-GP.
A sensitivity analysis based on negative binomial regression model with the logarithm of duration
of actual prophylaxis treatment with N8-GP used as offset will also be performed.
Another sensitivity analysis will be performed imputing the number of bleeding episodes for 
patients that discontinue treatment. For patients prematurely discontinuing treatment, the number of 
bleeding episodes counting in the analysis will be imputed up to what they could be expected to 
have had if they had completed the trial on treatment. If e.g. a patient withdraws after 2 months with 
3 bleeding episodes, but the patient should have been in the study for 6 months, then this patient 
will in the analysis count as having had 9 bleeding episodes in 6 months. This is similar to last 
observation carried forward (LOCF) and will avoid positive bias occurring from patients with many 
bleeding episodes withdrawing early. For patients withdrawing within 1 month this method is 
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considered to give too uncertain LOCF values, hence imputation will not be attempted for such 
patients. Instead only the observed bleeds and the observed duration will be used.
ABRs will be summarised in total, by cause of bleed, and by location of bleed (including ABR in 
baseline target joints).
Bleeding episodes in relation to surgery will not be included in the analysis.
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9.4.3
Secondary endpoints
9.4.3.1
Secondary efficacy endpoints
Endpoint title
Time frame
Unit
Haemostatic effect of N8-GP when 
used for treatment of bleeding 
episodes, assessed on a four-point 
scale for haemostatic response 
(excellent, good, moderate and 
none) by counting excellent and 
good as success and moderate and 
none as failure.
From start of treatment until visit 7
Count
Consumption of N8-GP for 
treatment of bleeding episodes 
From start of treatment until visit 7
IU/kg/bleed
Consumption of N8-GP for 
prophylaxis 
From start of treatment until visit 7
IU/kg/year
FVIII trough activity during 
prophylaxis
From start of treatment (excluding 
the first exposure) until visit 7
IU/mL
Haemostatic effect of N8-GP
Haemostatic effect of N8-GP when used for treatment of bleeding episodes is assessed as 
success/failure based on a four-point scale for haemostatic response (excellent, good, moderate and 
none). Excellent and good counts as success and moderate and none as failures. In addition, any 
bleeding episodes with missing response information will be counted as failures. 
Specifically, this will be done by a logistic regression. The analysis will be performed by use of 
Proc Genmod in SAS. Correlation within patients will be taken into account using a Generalized 
Estimation Equations approach with a working correlation matrix with a compound symmetry 
structure.
Response as measured by the four point scale will also be summarised and listed.
A sensitivity analysis will be performed similar to the primary analysis but only analysing bleeding 
episodes with recorded responses (i.e. not counting any bleeding episodes with missing response as 
failures).
The haemostatic effect will be summarised in total, by cause of bleed and by location of bleed 
(including haemostatic effect in target joints).
Haemostatic effect for bleeding episodes in relation to surgery will not be included in the analysis.
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Consumption of N8-GP for treatment of bleeding episodes
The number of injections per bleed will be summarised and listed.
The number of IU/Kg per bleed will be summarised and listed. 
Consumption of N8-GP for prophylaxis
The number of injections for prophylaxis will be summarised and listed.
The number of IU/Kg per month and per year will be summarised and listed.
FVIII trough activity during prophylaxis
The trough and recovery FVIII activity levels will be analysed by a mixed model on the log-
transformed plasma FVIII activity with age group as fixed effect and patient as a random effect. 
The mean trough and recovery levels will be presented back-transformed to the natural scale 
together with the 95% confidence interval.
The following rules will be implemented for the analysis of trough and recovery levels:
x
Pre-dose and post-dose values will be excluded if post-dose activity is ≤ pre-dose activity.
x
Pre-dose and post-dose values taken more than ±2 days outside of dosing interval will be 
excluded. 
x
Pre-dose and post-dose values taken less than twice the prophylaxis treatment interval after 
last treatment of a bleeding episode will be excluded.
x
Pre-dose and post-dose values taken within 2 weeks after surgery will be excluded.
x
Pre-dose and post-dose values taken in relation to the first exposure will be excluded.
x
FVIII activity measured in defrosted plasma samples will be excluded.
Furthermore, trough and recovery (30 minutes post-dose) levels measured at scheduled visits will 
be summarised and listed. Incremental recoveries will be calculated and presented in summary 
tables and plots.
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9.4.3.2
Secondary safety endpoints
Endpoint title
Time frame
Unit
Incidence rate of confirmed FVIII 
inhibitors ≥0.6 BU
From start of treatment until visit 7
Rate
Number of adverse events (AEs)
From start of treatment until end of 
trial
Count
Number of serious adverse events 
(SAEs)
From start of treatment until end of 
trial
Count
Incidence Rate of Confirmed FVIII-inhibitors t0.6 BU
A patient is said to have FVIII-inhibitors if two consecutive tests, preferably within 2 weeks, are 
positive (≥0.6 BU). The rate of inhibitors will be reported and a 1-sided 97.5% upper confidence 
limit will be provided based on an exact calculation for a binomial distribution. For the calculation 
of the inhibitor rate the nominator will include all patients with neutralising antibodies while the 
denominator will include all patients with a minimum of 50 exposures plus any patients with less 
than 50 exposures but with neutralising inhibitors.
Adverse Events (AEs) and Serious Adverse Events (SAEs) reported during the trial
Treatment emergent AEs (TEAEs defined as AEs occurring after dosing with trial product) and 
treatment emergent SAEs (TESAEs) will be summarised by frequency of events and frequency of 
patients with any event. Similar summaries cross-classified by severity and by causal relation to 
trial product will be made. 
Furthermore, listings will be provided displaying all TEAEs and TESAEs including pertinent  
clinical information.
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9.4.3.3
Secondary pharmacokinetic endpoints
Table 9-1
Definition and calculation of PK Parameters
Title
Time frame
Unit
Details
Incremental Recovery
30 min ± 5 min post-
injection at visit 2a and visit 
7
(IU/mL)/(IU/kg) The incremental recovery is calculated 
by subtracting the FVIII activity 
(IU/mL) measured in plasma at time 0 
from that measured at time 30 min after 
dosing and dividing this difference by 
the dose injected at time 0 expressed as 
IU/kg BW
FVIII activity 30 min post-
injection (C30min)
30 min ± 5 min post-
injection at visit 2a and visit 
7
IU/mL
The FVIII activity recorded 30 min 
after end of injection. Expected to be 
the maximum FVIII activity observed.
FVIII trough activity 96 h 
post-injection (C96h)
96 h ± 8 h post-injection at 
visit 2a and visit 7
IU/mL
The FVIII activity recorded 
immediately before next dose is given. 
Expected to be the minimum FVIII 
activity observed.
AUC(0-inf)
0−96 h post-injection at 
visit 2a and visit 7
h*(IU/mL)
Area under the activity versus time 
profile from time zero to infinity. 
Measure of total plasma exposure. 
AUC(0-inf) = AUC(0-t) + C(t) / λz ,
where C(t) is the last measurable 
activity.
AUC(0-t)
0−96 h post-injection at 
visit 2a and visit 7
h*(IU/mL)
Area under the plasma activity versus 
time profile from time zero to the last 
measurable activity. Measure of plasma 
exposure in the time interval 0 to last 
measurable activity.
AUC(0-t) is calculated using the linear 
trapezoidal method from time 0 to the 
time for the last measurable activity. 
The activity at time 0 will be estimated
by log-linear back extrapolation of the 
two initial post-administration 
activities. If the second value is not 
lower than the first value, the 
concentration at time 0 will be defined 
as the highest of these two.
AUC(0-96h)
0−96 h post-injection at 
visit 2a and visit 7
h*(IU/mL)
AUC(0-96h) is calculated using the linear 
trapezoidal activities. If FVIII activities 
are not available up to 96 hours post-
dose, the area under the missing 
terminal part of the curve will be
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Title
Time frame
Unit
Details
determined by interpolation or 
extrapolation using a similar principle 
as for AUC(0-inf), where the terminal 
elimination rate constant, λZ, is used 
given that there are sufficient 
measurements for the determination of 
the terminal elimination rate constant.
Accumulation ratio 
0−96 h post-injection at 
visit 7
Accumulation ratio is calculated as 
AUC(0-96h) at steady state/AUC(0-96h) at
single dose.
Terminal half-life (t½)
0−96 h post-injection at 
visit 2a and visit 7
h
t½ = ln(2) / λz, where λz is the terminal 
elimination rate. The terminal 
elimination rate will be estimated using 
linear regression on the terminal part of 
the log(activity) versus time profile.
Clearance (CL)
0−96 h post-injection at 
visit 2a and visit 7
mL/h/kg
CL= Dose / AUC.
Using AUC(0-inf) for single dose and 
AUC(0-96h) for steady state.
Vz
0−96 h post-injection at 
visit 2a and visit 7
mL/kg
Apparent volume of distribution based 
on the terminal phase. 
Vz = CL/λz
Vss
0−96 h post-injection at 
visit 7
mL/kg
Apparent volume of distribution at 
steady-state. 
Vss = CL*MRT
%extrap
0−96 h post-injection at 
visit 2a and visit 7
%
Percentage of AUC(0-inf) determined by 
extrapolation.
AUC(t-inf)/(AUC(0-inf))
MRT
0−96 h post-injection at 
visit 2a and visit 7
h
Mean Residence Time.
MRT = AUMC/AUC(0-inf), where 
AUMC is the area under the first 
moment curve, i.e. the area under the 
curve t∙C(t), calculated with the same 
method as AUC(0-inf) (linear trapezoidal 
method + extrapolated area) 
λz
0−96 h post-injection at 
visit 2a and visit 7
1/h
Terminal elimination rate constant.
The terminal elimination rate constant 
will be estimated using linear regression 
on the terminal part of the log(activity) 
versus time profile
Single dose PK will be based on the PK session at visit 2a, and steady state PK will be based on the 
PK session at visit 7.
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The PK parameters will be calculated using plasma FVIII activity obtained from the chromogenic 
assay. The PK parameters will be derived according to a non-compartmental method, as described
in Table 9-1. The actual time points will be used in the calculations.
If any profiles and/or individual plasma FVIII activities are excluded from the primary 
pharmacokinetic analysis, a sensitivity pharmacokinetic analysis will also be performed and 
reported based on all observed data. The primary pharmacokinetic analysis is based on the full 
analysis set excluding outliers. 
Specifically, which data points and profiles that will be excluded will be defined prior to database 
lock. It should exclude profiles with pre-dosing activity > 5% (possibly indicating inadequate wash 
out) at visit 2a and profiles that are not indicative of a normal intravenously injection (i.e. clearly 
increasing plasma FVIII activity initially). If a patient is treated with an additional dose during the 
PK session, the plasma FVIII activities after the occurrence will then be excluded.  Furthermore, if 
the profile shows indications of an additional dose (e.g. clearly increased plasma FVIII activity), the 
plasma FVIII activities after the occurrence will then also be excluded. 
All pharmacokinetic endpoints (except MRT, Vss, Vz, percentage of AUC(0-inf) determined by 
extrapolation and terminal elimination rate constant) will be analysed using mixed effects model on 
log-transformed parameters including patient as random effect. Estimates of each endpoint with 
95% confidence intervals will be provided back-transformed to the natural scale. 
Individual and mean PK profiles will be presented graphically.
Furthermore, the mean PK endpoints will be summarised and individual PK endpoints will be 
listed.
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9.4.4
Other safety analyses
Changes in vital signs (blood pressures, pulse, temperature, respiratory rate)
These endpoints will be presented in summary tables and plots.
Other safety parameters
All additional safety parameters such as laboratory parameters, vital signs, ECG and physical 
examinations will be presented in summary tables and plots.
9.4.5
Other analyses
Surgery
In relation to surgery the following will be recorded:
x
Haemostatic effect evaluated on the four-point scale (excellent, good, moderate and none) 
and assessed by the investigator/surgeon on the day of surgery (Day 1) and on the last day in 
the post-operative period the patient is at the trial/surgery site.
x
Loss of blood and requirements for transfusion on the day of surgery (Day 1) and during the 
post-operative period Days 2-7 or until the last day the patient is at the trial/surgery site, 
whatever comes first.
All records will be summarised and listed.
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10 Supporting documentation and operational considerations
10.1
Appendix 1: Regulatory, ethical, and trial oversight considerations
10.1.1
Regulatory and ethical considerations
This trial will be conducted in accordance with the protocol and with the following:
x
Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki24 and applicable ICH Good Clinical Practice (GCP) Guideline.25
x
Any trial procedure conducted in China mainland should comply with “Regulations on 
management of Human Genetic Resources of People’s Republic of China” and relative 
guideline.
x
Applicable laws and regulations.
x
The protocol, informed consent form, investigator’s brochure (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.
x
Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the CTR according to national requirements.
x
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.
x
Before a site is allowed to start screening patients, written notification from Novo Nordisk 
must be received.
The investigator will be responsible for:
x
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.
x
notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures.
x
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.
x
ensuring submission of the CTR synopsis to the IRB/IEC.
x
reporting any potential serious breaches to the sponsor immediately after discovery.
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10.1.2
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.
10.1.3
Informed consent process
x
The investigator or his/her representative will explain the nature of the trial to the patient 
and/or the patient’s caregiver and answer all questions regarding the trial. This includes the 
use of an impartial witness where required according to local requirements.
x
The investigator must ensure the patient ample time to come to a decision whether or not to 
participate in the trial.
x
Patients must be informed that their participation is voluntary.
x
Patients must be informed about their privacy rights. 
x
Patients or their caregiver will be required to sign and date a statement of informed consent 
that meets the requirements of local regulations, ICH guidelines,25 Declaration of Helsinki24
and the IRB/IEC or site.
x
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.
x
The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements.
x
Patients and/or their caregiver must be re-consented to the most current version of the 
informed consent form(s) during their participation in the trial.
x
A copy of the informed consent form(s) must be provided to the patient or the patient’s 
caregiver.
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10.1.4
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 “thank you for your participation letter” after completion of the trial. Further, 
the patient may receive other written information during the trial.
All written information to patients must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
10.1.5
Data protection
x
Patients will be assigned a 6-digit unique identifier, a patient number. Any patient records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the patient are transferred to Novo Nordisk.
x
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.
x
The patient must be informed about his/her privacy rights, including that his/her 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.
x
The patient must be informed that his/her medical records may be examined by auditors or 
other authorised staff appointed by Novo Nordisk, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
10.1.6
Committees structure
10.1.6.1
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. The safety committee may recommend 
unblinding of any data for further analysis, and in this case an internal trial-independent ad hoc
group will be established in order to maintain the blinding of the trial staff.
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10.1.7
Dissemination of clinical trial data
Information of the trial will be disclosed at ‘chinadrugtrials.org.cn’, ‘clinicaltrials.gov’,
www.clinicaltrialsregister.eu, ‘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)26, the Food and Drug Administration Amendment Act (FDAAA)27, European Commission 
Requirements28-30 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 + 28 weeks, corresponding to visit 7 (end of treatment visit). If the 
last patient is withdrawn early (i.e., withdraws informed consent), the PCD is considered the date 
when this last patient would have completed visit 7. The PCD determines the deadline for results 
disclosure at clinicaltrials.gov according to FDAAA.
10.1.8
Data quality assurance
10.1.8.1
Case report forms
x
Novo Nordisk or designee is responsible for the data management of this trial including 
quality checking of the data.
x
All patient data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or
electronically signing the eCRF.
x
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
Safety information forms
o
Technical complaint forms
o
AE forms 
x
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.
x
The investigator must ensure that data is recorded in the eCRF as soon as possible, 
preferably within 5 working days after the visit. Once data has been entered, it will be 
available to Novo Nordisk for data verification and validation purposes.
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10.1.8.2
Monitoring
x
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 site staff 
should be available for discussions at monitoring visits and between monitoring visits (e.g. 
by telephone).
x
Trial monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site staff 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.
x
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 sites.
x
Monitors will review the patient’s medical records and other source data, e.g. the diaries, to 
ensure consistency and/or identify omissions compared to the eCRF.
10.1.8.3
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay 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.
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10.1.9
Source documents
All data entered in the eCRF must be verifiable in source documentation other than the eCRF.
If source data is entered directly in a paper CRF, each data entry or clear series of data entries must 
be signed and dated separately by the site staff making the entry.
x
All data entered in the eCRF must be verifiable in source documentation other than the
eCRF.
x
The original of the completed diaries must not be removed from the site, unless they form 
part of the CRF and a copy is kept at the site.
x
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the site.
x
Data reported on a 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.
x
It must be possible to verify patient’s medical history in source documents, such as patient’s 
medical record.
x
The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested, and who was contacted.
x
Definition of what constitutes source data can be found in a source document agreement at 
each site. There will only be one source document defined at any time for any data element.
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10.1.10
Retention of clinical trial documentation
x
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. 
x
The investigator must be able to access his/her trial documents without involving Novo 
Nordisk in any way. If applicable, electronic CRF (eCRF) and other patient data will be 
provided in an electronic readable format to the investigator before access is revoked to the 
systems 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 site. A copy 
of all data will be stored by Novo Nordisk.
x
Patient’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
x
Site specific data should only be stored at site.
x
Long term storage of Chinese Patients’ Trial Data is not allowed in other entities.
10.1.11
Trial and site closure
Novo Nordisk reserves the right to close the 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.
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial supplies have been collected and a site closure visit has been performed.
The investigator may initiate 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 site by Novo Nordisk or investigator may include but are not 
limited to:
x
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.
x
inadequate recruitment of patients by the investigator.
x
discontinuation of further trial product development.
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10.1.12
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 site. If any tasks are delegated, the investigator must 
maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the patients.
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 staff must have sufficient English skills according to their assigned 
task(s).
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10.1.13
Indemnity statement 
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with Chinese law and regulations.
10.1.14
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 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial.
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10.1.14.1
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 subject 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 CTR is available. This includes the 
right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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.
10.1.14.2
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.31
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 site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.
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10.1.14.3
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 
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.
10.1.14.4
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 and will be 
provided with the randomisation code after results are available.
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10.2
Appendix 2: Clinical laboratory tests
The assessments detailed in Table 10-1 and Table 10-2 will be performed by the central laboratory
(except for urinalysis; see below).
At visits where it is not possible to perform the required blood sampling, re-scheduling of the visit 
within the visit (see Section 1.2) should be done. The timing of sampling in relation to trial drug 
administration should always be followed.
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 central lab will communicate to the investigator abnormal values of parameters not requested in 
the protocol but identified by the laboratory equipment and/or their processes according to their lab 
SOPs. These data will not be transferred to the trial database. The investigator should review such 
values for AEs and report these according to this protocol.
The investigator must review all laboratory results for concomitant illnesses and AEs.
Urinalysis will be performed locally with sticks provided by the central laboratory. Results of 
urinalysis should be recorded in the eCRF. Results from the urinalysis other than those listed in 
Table 10-2 should not be reported to Novo Nordisk. Clinically significant findings must be recorded 
as concomitant illness at screening and as AEs at the following visits if it is a new finding or a 
change relative to a previous visit.
Laboratory samples will be destroyed no later than at finalisation of the CTR.
The inhibitor samples will be stored at a central laboratory after end of trial and until marketing 
authorisation approval or until the research project terminates, after which they will be destroyed.
Table 10-1
Protocol-required efficacy laboratory assessments
Laboratory assessments
Parameters
FVIII activity
x
Chromogenic assay using PSS as calibrator
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Table 10-2
Protocol-required safety laboratory assessments
Laboratory assessments
Parameters
Antibody assessments
x
FVIII inhibitors
x
Anti-N8-GP
x
Anti-PEG
x
Anti-HCP 
Haematology
x
Erythrocytes
x
Haemoglobin
x
Leucocytes
x
Thrombocytes
Biochemistry
x
Alanine Aminotransferase (ALT) 
x
Albumin
x
Alkaline phosphatase
x
Aspartate Aminotransferase (AST)
x
Bilirubin, total
x
C-reactive protein (CRP)
x
Creatinine
x
Urea
Serology
x
Hepatitis B surface antigen (HBsAg)
x
Hepatitis C virus antibody
x
HIV 1+2 screen (if positive test, then a confirmatory test is performed. If the 
confirmatory test is also positive, then assessment of viral load is performed)
x
CD4+ T cell count (only at screening)
Coagulation parameters
x
aPTT
x
INR
x
PT
x
Lupus anticoagulant
Urinalysis (dip stick)
x
pH
x
Protein
x
Glucose
x
Bilirubin
x
Blood
Other tests
x
eGFR calculated by the central laboratory based on the creatinine value using 
the MDRD or the Schwartz equation depending on the age of the patient
Notes:
Details of required actions for increased liver parameters are given in Section 10.3 (Hy’s Law).
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10.3
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, 
follow-up, and reporting
10.3.1
Definition of AE
AE definition
An AE is any untoward medical occurrence in a clinical trial patient that is temporally associated 
with the use of an investigational medicinal product (IMP), whether or not considered related to 
the IMP.
An AE can therefore be any unfavorable and unintended sign, including an abnormal laboratory 
finding, symptom or disease (new or exacerbated) temporally associated with the use of an IMP.
Events meeting the AE definition
x
Any abnormal laboratory test results or safety assessments considered clinically 
significant in the medical and scientific judgment of the investigator, including events that 
have worsened from prior to the time point from which AEs are collected
x
Conditions detected or diagnosed after IMP administration even though it may have been 
present prior to the time point from which AEs are collected 
x
Exacerbation/worsening of a chronic or intermittent condition including either an increase 
in frequency and/or intensity of the condition
x
Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction
x
Signs, symptoms or the clinical sequelae of a suspected overdose of IMP regardless of 
intent
A "lack of efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE. 
Also, 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 
x
Conditions present prior to the time point from which AEs are collected and anticipated 
day-to-day fluctuations of these conditions, including those identified during screening or 
other trial procedures performed before exposure to IMP.
Note: Conditions present or occurring prior to the time point from which AEs are 
collected should be recorded as concomitant illness/medical history.
x
Medical or surgical procedures (e.g. endoscopy, appendectomy). The condition that leads 
to the procedure is the AE.
x
Medical or surgical procedures not preceded by an AE or worsening of a known 
condition.
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10.3.2
Definition of an SAE
An SAE is an AE that fulfils at least one of the following criteria:
a. Results in death
b. 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.
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation
x
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 seriousness criteria, 
the event is serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
x
Hospitalisation for elective treatment (e.g. elective medical or surgical procedures) of a 
condition that was present prior to the time point from which AEs are collected, and that 
did not worsen, is not considered an AE.
Note: 
x Hospitalisations for administrative, trial related, social and convenience reasons do not 
constitute AEs and should therefore not be reported as AEs or SAEs.
x
Hospital admissions for medical or surgical procedures, planned before trial inclusion, are not 
considered AEs or SAEs. 
d. Results in persistent or significant disability/incapacity
x
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
x
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.
e. Is a congenital anomaly/birth defect
f. Important medical event:
x 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 subject 
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.
x The following adverse events must always be reported as SAEs using the important medical 
event criterion if no other seriousness criteria are applicable:
x Suspicion of transmission of infectious agents via the IMP 
x Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x UNL and total bilirubin >2 x UNL where no alternative aetiology exists (Hy's 
law)
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10.3.3
Description of AESIs and AEs requiring additional data collection 
Description of AESIs and AEs requiring additional data collection (on specific event form) 
AESIs
FVIII inhibitor development
CNS-related AEs
CNS-related adverse events, including but not limited to any learning and behavioural deficits.
Renal or hepatic AEs
Renal or hepatic adverse events including new onset of renal or hepatic disorder or impairment.
Thromboembolic events
Thromboembolic events (clinical signs or laboratory indications of arterial and venous 
thrombosis including myocardial infarction, pulmonary embolism, cerebral infarction/thrombosis, 
deep vein thrombosis, other clinically significant thromboembolic events and peripheral artery 
occlusion) are defined as follows:
x
Definition of an acute, evolving, or recent myocardial infarction
Either one of the following two criteria satisfies the diagnosis for an acute, evolving or recent 
myocardial infarction:
1. Typical rise and gradual fall in troponin T or more rapid rise and fall in creatine kinase, muscle 
and brain or biochemical markers of myocardial necrosis with at least one of the following:
a. Ischaemic symptoms
b. Subsequent development of pathologic Q waves on the ECG
c. ECG changes indicative of ischaemia (ST segment elevation or depression)
d. Coronary artery intervention (e.g. angioplasty)
2. Pathologic findings of an acute myocardial infarction (i.e., pathologic findings of an acute 
myocardial infarction will be defined when criteria a and b below are fulfilled):
a. Increase in troponin T above the "diagnostic" limit: i.e. > 0.03 μg/L
b. Patients with:
o
ST-segment elevation: New ST-segment elevation at the J point in two or more 
contiguous leads with the cut-off points >= 0.2mV in leads V1, V2 or V3 and 0,1 mV in 
other leads (contiguity in the frontal plane is defined by the lead sequence aVL, I inverted 
aVR, II, aVF, III)
o
No ST-segment elevation: ST-segment depression and or T-wave inversion in two or 
more contiguous leads >= 0.1 mV 
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x
Definition of pulmonary embolism
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:
1.
Positive findings in ventilation/perfusion scan
2.
Positive findings in a spiral(helical) computed tomography or angiography
3.
Positive findings in a magnetic resonance imaging
4.
Positive findings in a pulmonary angiography
x
Definition of cerebral thrombosis/infarction
Acute neurological injury that persists for at least 24 hours and occurs as a result of either a 
thrombosis or embolic process, diagnosed by at least one of the following:
x
Computerised tomography
x
Magnetic resonance scan
x
Magnetic resonance angiogram
x
Cerebral angiography
x
Deep vein thrombosis
Venous thrombosis demonstrated by compression ultrasound, duplex ultrasound, or colour 
Doppler imaging.
x
Definition of other clinically significant thromboembolic events
Sign or suspicion of clinically significant thromboembolic event, e.g. visceral arterial 
embolus/thrombus, extremity arterial embolus/thrombus or portal venous thrombosis.
Superficial thrombophlebitis is not considered a clinically significant thromboembolic event 
unless evaluated so by the investigator.
x
Peripheral artery occlusion
Clinical signs of acute arterial occlusion verified by either ankle-brachial index test, Doppler or 
ultrasound (Duplex) imaging, computed tomographic angiography, magnetic resonance 
angiography, or conventional angiography.
Adverse events requiring additional data collection
Medication error
A medication error is an unintended failure in the IMP treatment process that leads to, or has the 
potential to lead to, harm to the patient, such as:
x
administration of wrong drug.
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug. 
x
wrong route of administration, such as intramuscular instead of subcutaneous.
x
accidental administration of a lower or higher dose than intended. The administered dose 
must deviate from the intended dose to an extent where clinical consequences for the trial 
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patient were likely to happen as judged by the investigator, although they did not 
necessarily occur.
Misuse and abuse
x
Situations where the IMP is intentionally and inappropriately used not in accordance with 
the protocol (e.g. overdose to maximise effect).
x
Persistent or sporadic, intentional excessive use of an IMP which is accompanied by 
harmful physical or psychological effects (e.g. overdose with the intention to cause harm).
Medication error, misuse and abuse must always be reported as an AE (e.g. accidental overdose, 
intentional overdose or other) on a separate AE form, and a medication error, misuse and abuse 
form must be completed. In case of a medication error and/or misuse and abuse resulting in a 
clinical consequence, this must be reported on an additional AE form.
Hypersensitivity
Hypersensitivity type reactions, incl. anaphylactic reactions.
Clinical criteria for diagnosing anaphylaxis
Anaphylaxis is highly likely when two or more of the following occur rapidly after exposure to a 
likely allergen for that patient (minutes to several hours):
x
Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush, swollen lips-
tongue- uvula)
x
Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia)
x
Reduced Blood pressure or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence)
x
Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
10.3.4
Recording and follow-up of AE and/or SAE
AE and SAE recording
x
The investigator will record all relevant AE/SAE information in the eCRF.
x
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.
x
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 (see Section 8.3 for details).
x
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 
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exception of the patient number, will be redacted on the copies of the source documents 
before submission to Novo Nordisk.
x
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 “AE and 
SAE reporting via paper CRF” later in this section.
x
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 severity for each event reported during the trial and assign it to one of 
the following categories:
x
Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities.
x
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.
x
Severe: An event that prevents normal everyday activities.
Note: An AE that is assessed as severe should not be confused with a SAE. Both AEs and 
SAEs can be assessed as severe.
Assessment of causality
x The investigator is obligated to assess the relationship between IMP and the occurrence of each 
AE/SAE.
x Relationship between an AE/SAE and the relevant IMP(s) should be assessed as:
x
Probable - Good reason and sufficient documentation to assume a causal relationship.
x
Possible - A causal relationship is conceivable and cannot be dismissed.
x
Unlikely - The event is most likely related to aetiology other than the IMP.
x Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk 
factors, as well as the temporal relationship of the event to IMP administration, will be 
considered and investigated.
x The investigator should use the investigator’s brochure17 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.
x 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.
x The investigator may change his/her opinion of causality, in light of follow-up information, 
and update the causality assessment in the CRF.
x The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
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Final outcome
The investigator will select the most appropriate outcome:
x
Recovered/resolved: The patient has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed when first documented
x
Recovering/resolving: The condition is improving, and the patient is expected to recover 
from the event. This term may be applicable in cases of chronic conditions, cancer or AEs 
ongoing at time of death (where death is due to another AE).
x
Note: For SAEs, this term is only applicable if the patient has completed the follow-up
period and is expected to recover.
x
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.
x
Not recovered/not resolved: The condition of the patient has not improved, and the 
symptoms are unchanged, or the outcome is not known. 
Note: This term may be applicable in cases of chronic conditions, cancer or AEs ongoing 
at time of death (where death is due to another AE).
x
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.
x
Unknown: This term is only applicable if the patient is lost to follow-up.
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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.
New or updated information will be recorded in the eCRF.
10.3.5
Reporting of SAEs
SAE reporting via eCRF
x
Relevant forms (AE and safety information form) must be completed in the eCRF.
x
For reporting and sign-off timelines, see Figure 10-1.
x
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).
x
The site will enter the SAE data into the eCRF as soon as it becomes available.
x
After the trial is completed, the trial database will be locked, and 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.
AE and SAE reporting via paper CRF
x
Relevant CRF forms (AE and safety information form) must be forwarded to Novo 
Nordisk in accordance with Section 10.1.5.
x
For SAEs, 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 timelines (as illustrated in Figure 10-1):
x
AE form within 24 hours
x
Safety information form within 5 calendar days
x
Both forms must be signed within 7 calendar days after first knowledge by the investigator.
x The specific event form for AEs requiring additional data collection within 14 calendar days
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Figure 10-1
Decision tree for determining the event type and the respective forms to 
complete with associated timelines
Contact details for SAE reporting can be found in the investigator trial master file.
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10.4
Appendix 4: Contraceptive guidance and collection of pregnancy information
Collection of pregnancy information
Male patients with partners who become pregnant
x
Investigator will attempt to collect pregnancy information on any female partner who 
becomes pregnant while male patient is participating in this trial. The pregnancy should be 
documented in the medical record of the male patient. Only in case of abnormal outcome 
(e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) of the pregnancy and in case the male patient receives IMP, should the 
investigator inform Novo Nordisk.
x
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to Novo Nordisk within 14 calendar days of learning of the abnormal outcome of 
the partner’s pregnancy (see Figure 10-2). Information on the status of the mother and child 
will be included.
x
Generally, follow-up will be 1 month following the delivery date. 
Pregnancy outcome?
After birth/
termination 
of pregnancy
No additional action
Normal outcome
Paternal form ≤ 14 calendar days
Maternal form 1a*1 ≤ 14 calendar days
Maternal form 1b*1 ≤ 14 calendar days
Maternal form 2*1 ≤ 14 calendar days
Abnormal outcome *1
Pregnancy verified
for female partner
 *1Further information collected on Maternal form 1a, 1b and 2 form from the 
female partner of male subjects requires signing of specific informed consent.
Non-serious AEs in the foetus/newborn that are considered related to the male 
subjects treatment with IMP and all SAEs in the foetus/newborn must be 
reported to Novo Nordisk following the timelines in  Figure 10.1.
For male subjects
Document in 
subjects medical 
records
Figure 10-2
Decision tree for determining the forms to complete with associated timelines 
for pregnancy
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10.5
Appendix 5: Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting
10.5.1
Definition of technical complaint
Technical complaint definition 
x
A technical complaint is any written, electronic or oral communication that alleges 
product (medicine or device) defects. The technical complaint may be associated with an 
AE but does not concern the AE itself.
Examples of technical complaints:
x
Problems with the physical or chemical appearance of trial products (e.g. discoloration, 
particles or contamination)
x
Problems with packaging material including labelling
Time period for detecting technical complaints 
All technical complaints which occur from the time of receipt of the product at site until the time 
of the last usage of the product must be collected for products predefined on the technical 
complaint form. 
10.5.2
Recording and follow-up of technical complaints
Reporting of technical complaints to Novo Nordisk
Contact details for Customer Complaint Center, please refer to Attachment I.
Technical complaints must be reported on a separate technical complaint form:
1. One technical complaint form must be completed for each affected DUN.
2. If DUN is not available, a technical complaint form for each batch, code or lot number must 
be completed.
Timelines for reporting of technical complaints to Novo Nordisk
The investigator must complete the technical complaint form in the eCRF within:
x
24 hours if related to an SAE
x
5 days calendar for all other technical complaints
If the eCRF is unavailable, or when reporting a technical complaint on a trial product that is not 
yet allocated to patient, the information must be provided on a paper form 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.
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Follow-up of technical complaints 
The investigator is responsible for ensuring that new or updated information will be recorded on 
the originally completed form.
Collection, storage and shipment of technical complaint samples
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 
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.
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10.6
Appendix 6: Neurological examination checklist
Unless otherwise stated, each aspect of the neurological examination will be categorised into 
normal, abnormal or not evaluated. 
General 
Level of consciousness
Cranial Nerves
Pupillary reaction to light
Visual fields
Visual acuity (normal, corrected, abnormal, not evaluated)
Eye movements
Facial sensation
Facial movement (smile)
Hearing (finger rub)
Palate/gag (say “ahhh”)
Tongue movement
Trapezius (shoulder shrug)
Tone
Upper Extremity Left 
Upper Extremity Right
Lower Extremity Left
Lower Extremity Right
Strength
Upper Extremity Left
Upper Extremity Right
Lower Extremity Left
Lower Extremity Right
Reflexes
Biceps Left
Biceps Right
Triceps Left
Triceps Right
Knee Left
Knee Right
Ankle Left
Ankle Right
Sensory
Cold
Pin prick
Light touch
Proprioception (toe up/down)
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Gait
Gait walking       
Gait running
Gait on heels
Gait on toes
Tandem (toe/heel walk)
Stand on one leg (right)
Stand on one leg (left)
Hop on one foot (right)
Hop on one foot (left)
Rhomberg sign (normal [absent], abnormal [present], not applicable)
Coordination and Fine Motor
Finger-to-nose (right)       
Finger-to-nose (left)
Rapid index finger tap (right)       
Rapid index finger tap (left)       
Rapid finger movement (right)
Rapid finger movement (left)
Adapted from Paediatric Stroke Outcome Measure (PSOM)32
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10.7
Appendix 12: Country-specific requirements
The following items are applicable for China.
Item
Section 
Section title 
Local requirement
1
5.1 and 
5.2
Inclusion/Exclusion 
criteria
The criteria will be assessed at the investigator's 
discretion unless otherwise stated.
2
10.1
Appendix 1:
Regulatory, ethical, and 
trial oversight 
considerations
Any trial procedure conducted in China mainland 
should comply with“Regulations on management of 
Human Genetic Resources of People’s Republic of 
China” and relative guideline.
http://www.gov.cn/zhengce/content/2019-
06/10/content_5398829.htm
3
10.1.10
Retention of clinical 
trial documentation
Site specific data should only be stored at site.
Long term storage of Chinese Patients’ Trial Data is 
not allowed in other entities.
4
10.5
Appendix 12: Country-
specific requirements
The samples which are tested at central lab will be 
destroyed as biological waste according to local 
regulation and lab manual. The laboratory samples 
for Chinese patients will be destroyed no later than 
the finalization of the clinical trial report, or 
according to local regulatory requirement. 
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10.8
Appendix 13: Abbreviations
ABR
annualised bleeding rate
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BP
blood pressure
CRF
case report form
CTR
clinical trial report
DFU
directions for use
DMC
data monitoring committee
DRE
disease related event
DUN
dispensing unit number
ECG
electrocardiogram
eCRF
electronic case report form
ED
exposure day
eGFR
estimated glomerular filtration rate
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FDAAA
FDA Amendments Act
GCP
Good Clinical Practice
HCP
host cell protein
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
i.v.
intravenous(ly)
IWRS
interactive web response system
LAR
legally acceptable representative (also referred to as ‘caregiver’)  
LOCF
last observation carried forward
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LPLV
last patient last visit
MDRD
Modification of Diet in Renal Disease
MIDF
monitor-initiated discrepancy form
NIMP
non-investigational medical product
PCD
primary completion date
PEG
polyethylene glycol
PTP
previously treated patient
rFVIII
recombinant factor VIII
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment emergent AE
TMM
trial materials manual
WFH
World Federation of Hemophilia
WOCBP
woman of child bearing potential
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10.9
Appendix 14: Protocol amendment history
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents.
Protocol version 2.0 (28 Sep 2020)
The overall rationale for preparing the protocol version 2.0 was to correct inconsistencies and 
editorial errors observed.
Section # and name
Description of change
Brief rationale
Synopsis section 1.1 and Section 5.2 
Exclusion criteria
Exclusion criterion 7 updated
The criterion updated for more 
clarity.
Section 1.2 Flow chart and Table 1-1
Addition of Height, weight and BMI 
to the flow chart. Deletion of drug 
dispensing at visit 7 and other minor 
updates
Added for clear instruction on 
assessments and duplicate 
coagulation parameter assessment 
removed and other typographical 
errors corrected
Section 4.1.1 Treatment of patients
Section 8.1.1.1 Definition of severity 
of bleeding episodes
Section 8.5.1 visit 2a for patients 
undergoing PK assessments.
Section 8.5.3 visit 7 for patients 
undergoing PK assessments
Section 8.7 Diary
Section 8.8 Home treatment training
Section 10.17 Dissemination of 
clinical trial data
Minor updates
Typo corrected and minor 
information added
Section 6.1 Treatments administered
Some text deleted
Text deleted to align with trial 
material manual
Section 6.3 Measures to minimise 
bias: Randomisation and blinding
Some text deleted
Section updated to reflect the actual 
scenario in the trial.
Section 6.4.1 In-use time
New section added
Added to highlight importance of in-
use time of the trial product
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Section # and name
Description of change
Brief rationale
Section 7.1 Discontinuation of trial 
treatment
Errors corrected in this section
Section updated and errors corrected.
Section 7.2 Patient withdrawal from 
the trial 
Text corrected
Text aligned with section 7.1 and 
duplicate text removed
Section 8.2.1 physical examination
Additional information on Height, 
Weight and BMI assessments added
Information was missed previously
Section 8.2.3 Clinical safety 
laboratory assessments
Duplicate text deleted
Duplicate text deleted as the text is 
already available in appendix 2.
Section 8.6.1 FVIII inhibitors
Text added with information about 
inhibitor liability and some text 
corrected
Text added for more clarity
Section 10.2, Appendix 2
Blood volume in table 10.1 and 10.2 
corrected and other minor updates
Information corrected
Section 10.3.3 Description of AESI 
and AEs requiring additional data 
collection
Definition of anaphylactic reaction 
updated
Missing text added
Section 10.3.5 Reporting of SAEs
Figure 10.1 updated with missing 
timelines
Typo corrected
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11 References
1.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. 
Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1-47.
2.
World Federation of Hemophilia. Report on the annual global survey 2016. October 2017.
3.
Qu Y, Nie X, Yang Z, Yin H, Pang Y, Dong P, et al. The prevalence of hemophilia in 
mainland China: a systematic review and meta-analysis. Southeast Asian J Trop Med Public 
Health. 2014;45(2):455-66.
4.
Yan-Ji Q, Huan Y, Yuan-jie P, Xiao-lu N, Peng D, Si-yan Z. Treatment status and economic 
burden of people with hemophilia in mainland China: a systematic review. Chin J Evid-
based Med. 2013;13(2):182-9.
5.
Mulder K, Llinás A. The target joint. Haemophilia. 2004;10 Suppl 4:152-6.
6.
Xue F, Zhou ZP, Yang RC. [Survey of medical care and prognosis in patients with severe 
hemophilia A from certain cities in China]. Zhonghua Xue Ye Xue Za Zhi. 2011;32(7):481-
3.
7.
Thrombosis and Hemostasis Group. Consensus of Chinese expert on the diagnosis and 
treatment of haemophilia (version 2017). Chin J Hematol. 2016;37(5):364-74.
8.
Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. 
Prophylaxis versus episodic treatment to prevent joint disease in boys with severe 
hemophilia. N Engl J Med. 2007;357(6):535-44.
9.
Fischer K, Collins P, Björkman S, Blanchette V, Oh M, Fritsch S, et al. Trends in bleeding 
patterns during prophylaxis for severe haemophilia: observations from a series of 
prospective clinical trials. Haemophilia. 2011;17(3):433-8.
10.
Collins PW. Personalized prophylaxis. Haemophilia. 2012;18 Suppl 4:131-5.
11.
Jimenez-Yuste V, Auerswald G, Benson G, Lambert T, Morfini M, Remor E, et al. 
Achieving and maintaining an optimal trough level for prophylaxis in haemophilia: the past, 
the present and the future. Blood Transfus. 2014;12(3):314-9.
12.
Valentino LA, Kapoor M. Central venous access devices in patients with hemophilia. Expert 
Rev Med Devices. 2005;2(6):699-711.
13.
Gregg SC, Murthi SB, Sisley AC, Stein DM, Scalea TM. Ultrasound-guided peripheral 
intravenous access in the intensive care unit. J Crit Care. 2010;25(3):514-9.
14.
Tiede A, Brand B, Fischer R, Kavakli K, Lentz SR, Matsushita T, et al. Enhancing the 
pharmacokinetic properties of recombinant factor VIII: first-in-human trial of 
glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost.
2013;11(4):670-8.
15.
Giangrande P, Andreeva T, Chowdary P, Ehrenforth S, Hanabusa H, Leebeek FW, et al. 
Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe 
haemophilia A. Thromb Haemost. 2017;117(2):252-61.
16.
Meunier S, Alamelu J, Ehrenforth S, Hanabusa H, Abdul Karim F, Kavakli K, et al. Safety 
and efficacy of a glycoPEGylated rFVIII (turoctocog alpha pegol, N8-GP) in paediatric 
patients with severe haemophilia A. Thromb Haemost. 2017;117(9):1705-13.
17.
Novo Nordisk A/S. Investigator's brochure, turoctocog alfa pegol (N8-GP) (NN7088), 
edition 11 (23-Sep-2019), or updates hereof.
18.
World Federation of Hemophilia. Guidelines for the Management of Hemophilia (second 
edition). 2012.
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Trial ID: NN7088-4595
Version:
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19.
Mire-Sluis AR, Barrett YC, Devanarayan V, Koren E, Liu H, Maia M, et al. 
Recommendations for the design and optimization of immunoassays used in the detection of 
host antibodies against biotechnology products. Journal of Immunological Methods. 
2004;289(1-2):1-16.
20.
Shankar G, Devanarayan V, Amaravadi L, Barrett YC, Bowsher R, Finco-Kent D, et al. 
Recommendations for the validation of immunoassays used for detection of host antibodies 
against biotechnology products. Journal of Pharmaceutical and Biomedical Analysis. 
2008;48(5):1267-81.
21.
European Medicines Agency. Guideline on Immunogenicity assessment of therapeutic 
proteins (CHMP/BMWP/14327/2006 Rev 1). 18 May 2017.
22.
Food and Drug Administration CDER and CBER. FDA. Guidance for Industry. 
Immunogenicity Testing of Therapeutic Protein Products - Developing and Validating 
Assays for Anti-drug Antibody Detection. U.S. Department of Health and Human Services. 
Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center 
for Biologics Evaluation and Research (CBER). January 2019. Jan 2019.
23.
United States Pharmacopeia. Immunogenicity Assays - Design and Validation of 
Immunoassays to Detect Anti-drug Antibodies. 2017.
24.
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.
25.
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016.
26.
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.
27.
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.
28.
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.
29.
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.
30.
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.
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31.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
32.
Kitchen L, Westmacott R, Friefeld S, MacGregor D, Curtis R, Allen A, et al. The pediatric 
stroke outcome measure: a validation and reliability study. Stroke. 2012;43(6):1602-8.
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16.1.01 
Protocol Attachment 
Protocol Attachment I is located in the Trial Master File. 
If applicable, Protocol Attachment II is also located in the Trial Master File. 
Content: Global key staff and Country key staff. 
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Turoctocog alfa pegol (N8-GP)
Trial ID: NN7088-4595
Clinical Trial Report
Appendix 16.1.1
21 March 2023
1.0
Final
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan
Sponsor name:
Novo Nordisk A/S
NCT number
NCT05082116
Sponsor trial ID:
NN7088-4595
Official title of study:
A multi-centre, open-label trial evaluating efficacy, safety and 
pharmacokinetics of turoctocog alfa pegol (N8-GP) when used 
for treatment and prophylaxis of bleeding episodes in 
previously treated Chinese patients with haemophilia A
Document date*
29 January 2021
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header of Page 2 is the date of compilation of the documents and not of an update to content.


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Turoctocog alfa pegol (N8-GP)
Trial ID: NN7088-4595
Clinical Trial Report
Appendix 16.1.9
21 March 2023
1.0
Final
16.1.9 Documentation of statistical methods
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
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EudraCT No: 2020-003001-58
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Statistical Analysis Plan
NN7088-4595
A multi-centre, open-label trial evaluating efficacy, safety 
and pharmacokinetics of turoctocog alfa pegol (N8-GP) when 
used for treatment and prophylaxis of bleeding episodes in 
previously treated Chinese patients with haemophilia A
Author:
 Principal Statistician
2132 Biostatistics Biopharm 2
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Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
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Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
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EudraCT No: 2020-003001-58
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Table of contents
Page
Table of contents...............................................................................................................................................2 
Table of figures.................................................................................................................................................3 
Table of tables...................................................................................................................................................3 
Version history..................................................................................................................................................4 
1 
Introduction...............................................................................................................................................5 
1.1 
Objectives and endpoints...............................................................................................................5 
1.2 
Trial design ....................................................................................................................................5 
2 
Statistical hypotheses ................................................................................................................................7 
3 
Sample size determination........................................................................................................................7 
4 
Analysis sets...............................................................................................................................................7 
5 
Statistical analyses.....................................................................................................................................8 
5.1 
General considerations...................................................................................................................8 
5.2 
Subject disposition.........................................................................................................................8 
5.3 
Primary endpoint analysis..............................................................................................................9 
5.4 
Secondary endpoints analysis ........................................................................................................9 
5.4.1 
Secondary efficacy endpoints ......................................................................................9 
5.4.1.1 
Haemostatic effect of N8-GP ..............................................................10 
5.4.1.2 
Consumption of N8-GP for treatment of bleeding episodes ...............10 
5.4.1.3 
Consumption of N8-GP for prophylaxis .............................................10 
5.4.1.4 
FVIII trough activity during prophylaxis ............................................11 
5.4.2 
Secondary safety endpoints........................................................................................11 
5.4.2.1 
Incidence Rate of Confirmed FVIII-inhibitors t0.6 BU.....................12 
5.4.2.2 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
reported during the trial.......................................................................12 
5.4.3 
Secondary pharmacokinetic endpoints ......................................................................12 
5.5 
Exploratory endpoints analysis....................................................................................................15 
5.6 
Other safety analyses ...................................................................................................................15 
5.7 
Other analyses..............................................................................................................................15 
5.8 
Interim analyses...........................................................................................................................15 
5.8.1 
Data monitoring committee .......................................................................................15 
6 
Supporting documentation.....................................................................................................................16 
6.1 
Appendix 1 List of abbreviations.................................................................................................16 
6.2 
Appendix 3: Definition and calculation of endpoints, assessments and derivations ...................17 
7 
References................................................................................................................................................18 
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Statistical Analysis Plan
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Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
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Table of figures
Page
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Table of tables
Page
Table 1 
SAP Version History Summary.....................................................................................................4 
Table 2 
Definition and calculation of PK Parameters...............................................................................12 
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Statistical Analysis Plan
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Date:
29 January 2021
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Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
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Version history
This Statistical Analysis Plan (SAP) for trial NN7088-4595 is based on the protocol A multi-centre, 
open-label trial evaluating efficacy, safety and pharmacokinetics of turoctocog alfa pegol (N8-GP) 
when used for treatment and prophylaxis of bleeding episodes in previously treated Chinese 
patients with haemophilia A, version 3.0 dated 21Jan2021.
Table 1
SAP Version History Summary
SAP Version
Approval 
Date
Change
Rationale
1
Not Applicable
Original version
2
A few re-wordings 
in Sections 5.3, 
5.4.2 and 5.4.3
Addition of ECG to 
Section 5.6 Other 
safety analyses
Clarification of existing text
In order to accommodate a request from 
China Center for Drug Evaluation
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Statistical Analysis Plan
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Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
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UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
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1
Introduction
The rationale for this Phase 3b trial is to assess the effect of N8-GP in Chinese patients with severe 
haemophilia A (FVIII activity <1%) previously treated with other FVIII product(s) (PTPs). The aim 
is to accumulate sufficient exposure data in order to evaluate efficacy and safety of N8-GP in 
treatment and prevention of bleeding episodes and to obtain N8-GP PK data in this patient 
population.
Specifications of tables, figures and listings (TFL) and other specifications not included in this SAP 
will be described in the mock TFL.
1.1
Objectives and endpoints
Primary objective
x
To evaluate the clinical efficacy of N8-GP in bleeding prophylaxis (number of bleeding 
episodes during prophylaxis) in Chinese adolescent and adult patients with severe 
haemophilia A previously treated with other FVIII products
Secondary objectives
In Chinese adolescent and adult patients with severe haemophilia A previously treated with other 
FVIII products,
x
To evaluate the clinical efficacy of N8-GP when used for treatment of bleeding episodes
x
To evaluate the immunogenicity of N8-GP
x
To evaluate the general safety of N8-GP
x
To evaluate the consumption of N8-GP
x
To evaluate the pharmacokinetic properties of N8-GP
1.2
Trial design
This trial is a multi-centre, open-label, non-randomised, single-arm phase 3b trial evaluating the 
clinical efficacy, safety (including immunogenicity) and PK of N8-GP when used for treatment and 
prevention (prophylaxis) of bleeding episodes in Chinese patients ≥12 years of age with severe 
haemophilia A (FVIII activity <1%). This trial design is overall similar to the design of the 
completed global, pivotal pathfinderTM2 trial in adult and adolescent previously treated patients 
with severe haemophilia A (trial NN7088-3859). 
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Statistical Analysis Plan
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Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
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Thirty-six (36) Chinese PTPs with severe haemophilia A, aged ≥12 years and with ≥150 exposure 
days (EDs) to other FVIII product(s), will receive prophylaxis with 50 IU/kg N8-GP every 4 days
(with the possibility of switching to twice-weekly dosing during the treatment period at the 
discretion of the Investigator). Bleeding episodes will be treated with bolus injection(s) of 20-75
IU/kg N8-GP.
The treatment period in the trial will be at least 28 weeks with N8-GP prophylaxis every 4 days 
where ≥50 EDs to N8-GP (including treatment of bleeding episodes) must be obtained. The 
screening period will be 2 weeks and the follow-up period will be 30 days.
At least 30 patients must complete the trial with ≥50 EDs to N8-GP (including treatment of
bleeding episodes) and ≥6 months (≥28 weeks) of prophylaxis.
Please refer to the protocol for more details.
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Statistical Analysis Plan
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Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
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2
Statistical hypotheses
No confirmatory hypotheses are planned to be tested due to the low number of patients to be 
included in this trial.
3
Sample size determination
No formal sample size calculations have been performed. Based on meeting communication with 
CDE and with the supplement data from the global pivotal trial NN7088-3859 which also included 
Asian patients, a total number of 30 Chinese patients to complete this trial is considered sufficient 
to evaluate efficacy and safety in the Chinese population.
Fifteen (15) patients will participate in PK assessments sessions to ensure at least 12 patients with 
complete single-dose and steady-state PK profiles.
4
Analysis sets
All patients exposed to N8-GP in this trial will be included in the full analysis set (FAS) and the 
safety analysis set (SAS).
Exceptional outlier pharmacokinetic profiles and/or individual plasma FVIII activities may be 
excluded when analysing pharmacokinetic endpoints based on the FAS. The rules to exclude data 
points from analysis of pharmacokinetic endpoints are described in this SAP, and the decision of
data exclusion will be made during a review prior to database lock. Any excluded data points will 
be documented in the database lock minutes and also in the clinical trial report (CTR).
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Statistical Analysis Plan
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Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
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5
Statistical analyses
5.1
General considerations
Novo Nordisk will be responsible for the statistical analyses. The statistical analysis plan (SAP) will 
be finalised prior to first patient first visit.
Summaries for continuous endpoints will include total number (N), mean (SD), median and 
min/max, and for pharmacokinetic endpoints also geometric mean and coefficient of variation 
(CV%). Summaries for categorical endpoints will include N, number (n) and percentages (%) for 
each outcome category.
In general, all summaries and analyses will also be prepared by age subgroup (12-17 and 18-70
years of age).
FVIII activities below lower limit of quantification (LLOQ) will be set to half the value of the 
LLOQ.
All bleeding endpoints will be evaluated based on bleeding episodes requiring treatment with N8-
GP. Non-treatment requiring bleeding episodes will only be listed. Bleeding episodes in relation to
surgery will also only be listed, i.e. not included in the analysis of bleeding endpoints. 
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 and only one haemostatic response will be 
considered for the bleeding episode. In case different responses were registered for different 
bleeding locations in such a bleeding episode, the worst response will be used in the analysis.
A re-bleed is defined as a worsening of symptoms in the same location after an initial period of 
improvement, either on treatment or within 72 hours after stopping treatment. If a bleed occurs in 
the same location later than 72 hours after stopping the treatment it is considered a new bleed. Re-
bleeds will only be considered for joint bleeds since the specific location for other bleeds e.g. in 
subcutaneous are not captured in the database.
In the sub analyses of annualised bleeding rate where there are less than 5 patients in a sub-group, 
model based estimation will not be done. If no bleedings occur in a sub-group, then the confidence 
interval will not be calculated.
For patients that discontinue treatment with N8-GP, data after visit P8 will only be included in 
listings and clearly marked. For secondary safety endpoints separate summary tables for data 
relating to the period after visit P8 will be prepared if such data is available for 5 or more patients.
5.2
Subject disposition
See mock TFLs.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
9 of 18
5.3
Primary endpoint analysis
Endpoint title
Time frame
Unit
Number of bleeding episodes 
From start of treatment until visit 7
Count
The primary endpoint will be analysed by a Poisson regression model allowing for over-dispersion 
(using Pearson’s chi-square divided by the degrees of freedom) with the logarithm of duration of
actual prophylaxis treatment with N8-GP used as offset. Estimates of the annualised bleeding rate 
(ABR) will be provided with 95% confidence intervals.
Only the observed bleeding episodes will be counted and the offset will be the duration of actual 
prophylaxis treatment with N8-GP.
A sensitivity analysis based on negative binomial regression model with the logarithm of duration 
of actual prophylaxis treatment with N8-GP used as offset will also be performed.
Another sensitivity analysis will be performed imputing the number of bleeding episodes for 
patients that discontinue treatment. For patients prematurely discontinuing treatment, the number of 
bleeding episodes counting in the analysis will be imputed up to what they could be expected to 
have had if they had completed the trial on treatment. If e.g. a patient withdraws after 2 months with 
3 bleeding episodes, but the patient should have been in the study for 6 months, then this patient 
will in the analysis count as having had 9 bleeding episodes in 6 months. This is similar to last
observation carried forward (LOCF) and will avoid positive bias occurring from patients with many 
bleeding episodes withdrawing early. For patients withdrawing within 1 month this method is 
considered to give too uncertain LOCF values, hence imputation will not be attempted for such 
patients. Instead only the observed bleeds and the observed duration will be used.
ABRs will be summarised in total, by cause of bleed, and by location of bleed (including ABR in 
baseline target joints).
Bleeding episodes in relation to surgery will not be included in the analysis.
5.4
Secondary endpoints analysis
5.4.1
Secondary efficacy endpoints
Endpoint title
Time frame
Unit
Haemostatic effect of N8-GP when 
used for treatment of bleeding 
episodes, assessed on a four-point 
scale for haemostatic response 
From start of treatment until visit 7
Count
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
10 of 18
(excellent, good, moderate and 
none) by counting excellent and
good as success and moderate and 
none as failure.
Consumption of N8-GP for 
treatment of bleeding episodes 
From start of treatment until visit 7
IU/kg/bleed
Consumption of N8-GP for 
prophylaxis 
From start of treatment until visit 7
IU/kg/year
FVIII trough activity during 
prophylaxis
From start of treatment (excluding 
the first exposure) until visit 7
IU/mL
5.4.1.1
Haemostatic effect of N8-GP
Haemostatic effect of N8-GP when used for treatment of bleeding episodes is assessed as 
success/failure based on a four-point scale for haemostatic response (excellent, good, moderate and 
none). Excellent and good counts as success and moderate and none as failures. In addition any 
bleeding episodes with missing response information will be counted as failures.
Specifically this will be done by a logistic regression. The analysis will be performed by use of Proc 
Genmod in SAS. Correlation within patients will be taken into account using a Generalized 
Estimation Equations approach with a working correlation matrix with a compound symmetry 
structure.
Response as measured by the four point scale will also be summarised and listed.
A sensitivity analysis will be performed similar to the primary analysis but only analysing bleeding 
episodes with recorded responses (i.e. not counting any bleeding episodes with missing response as 
failures).
The haemostatic effect will be summarised in total, by cause of bleed and by location of bleed
(including haemostatic effect in target joints).
Haemostatic effect for bleeding episodes in relation to surgery will not be included in the analysis.
5.4.1.2
Consumption of N8-GP for treatment of bleeding episodes
The number of injections per bleed will be summarised and listed.
The number of IU/Kg per bleed will be summarised and listed. 
5.4.1.3
Consumption of N8-GP for prophylaxis
The number of injections for prophylaxis will be summarised and listed.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
11 of 18
The number of IU/Kg per month and per year will be summarised and listed.
5.4.1.4
FVIII trough activity during prophylaxis
The trough and recovery levels will be analysed by a mixed model on the log-transformed plasma 
concentrations with age group as fixed effect and patient as a random effect. The mean trough and 
recovery levels will be presented back-transformed to the natural scale together with the 95% 
confidence interval.
The following rules will be implemented for the analysis of trough and recovery levels:
x
Pre-dose and post-dose values will be excluded if post-dose activity is ≤ pre-dose activity.
x
Pre-dose and post-dose values taken more than ±2 days outside of dosing interval will be
excluded.
x
Pre-dose and post-dose values taken less than twice the prophylaxis treatment interval after
last treatment of a bleeding episode will be excluded.
x
Pre-dose and post-dose values taken within 2 weeks after surgery will be excluded.
x
Pre-dose and post-dose values taken in relation to the first exposure will be excluded.
x
FVIII activity measured in defrosted plasma samples will be excluded.
Furthermore, trough and recovery (30 minutes post-dose) levels measured at scheduled visits will 
be summarised and listed. Incremental recoveries will be calculated and presented in summary 
tables and plots.
5.4.2
Secondary safety endpoints
Endpoint title
Time frame
Unit
Incidence rate of confirmed FVIII 
inhibitors ≥0.6 BU
From start of treatment until visit 7
Rate
Number of adverse events (AEs)
From start of treatment until end of 
trial
Count
Number of serious adverse events 
(SAEs)
From start of treatment until end of 
trial
Count
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
12 of 18
5.4.2.1
Incidence Rate of Confirmed FVIII-inhibitors t0.6 BU
A patient is said to have FVIII-inhibitors if two consecutive tests, preferably within 2 weeks, are 
positive (≥0.6 BU). The rate of inhibitors will be reported and a 1-sided 97.5% upper confidence 
limit will be provided based on an exact calculation for a binomial distribution. For the calculation 
of the inhibitor rate the numerator will include all patients with neutralising antibodies while the 
denominator will include all patients with a minimum of 50 exposures plus any patients with less 
than 50 exposures but with neutralising inhibitors.
5.4.2.2
Adverse Events (AEs) and Serious Adverse Events (SAEs) reported during the 
trial
Treatment emergent AEs (TEAEs defined as AEs occurring after dosing with trial product) and 
treatment emergent SAEs (TESAEs) will be summarised by frequency of events and frequency of 
patients with any event. Similar summaries cross-classified by severity and by causal relation to 
trial product will be made. 
Furthermore, listings will be provided displaying all TEAEs and TESAEs including pertinent  
clinical information.
5.4.3
Secondary pharmacokinetic endpoints
Table 2
Definition and calculation of PK Parameters
Title
Time frame
Unit
Details
Incremental Recovery
30 min ± 5 min post-
injection at visit 2a and visit 
7
(IU/mL)/(IU/kg) The incremental recovery is calculated 
by subtracting the FVIII activity 
(IU/mL) measured in plasma at time 0 
from that measured at time 30 min after 
dosing and dividing this difference by 
the dose injected at time 0 expressed as 
IU/kg BW
FVIII activity 30 min post-
injection (C30min)
30 min ± 5 min post-
injection at visit 2a and visit 
7
IU/mL
The FVIII activity recorded 30 min 
after end of injection. Expected to be 
the maximum FVIII activity observed.
FVIII trough activity 96 h 
post-injection (C96h)
96 h ± 8 h post-injection at 
visit 2a and visit 7
IU/mL
The FVIII activity recorded 
immediately before next dose is given. 
Expected to be the minimum FVIII 
activity observed.
AUC(0-inf)
0−96 h post-injection at 
visit 2a and visit 7
h*(IU/mL)
Area under the activity versus time 
profile from time zero to infinity. 
Measure of total plasma exposure. 
AUC(0-inf) = AUC(0-t) + C(t) / λz ,
where C(t) is the last measurable 
activity.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
13 of 18
Title
Time frame
Unit
Details
AUC(0-t)
0−96 h post-injection at 
visit 2a and visit 7
h*(IU/mL)
Area under the plasma activity versus 
time profile from time zero to the last 
measurable activity. Measure of plasma 
exposure in the time interval 0 to last 
measurable activity.
AUC(0-t) is calculated using the linear 
trapezoidal method from time 0 to the 
time for the last measurable activity. 
The activity at time 0 will be estimated 
by log-linear back extrapolation of the 
two initial post-administration 
activities. If the second value is not 
lower than the first value, the 
concentration at time 0 will be defined 
as the highest of these two.
AUC(0-96h)
0−96 h post-injection at 
visit 2a and visit 7
h*(IU/mL)
AUC(0-96h) is calculated using the linear 
trapezoidal activities. If FVIII activities 
are not available up to 96 hours post-
dose, the area under the missing 
terminal part of the curve will be
determined by interpolation or 
extrapolation using a similar principle 
as for AUC(0-inf), where the terminal 
elimination rate constant, λZ, is used 
given that there are sufficient 
measurements for the determination of 
the terminal elimination rate constant.
Accumulation ratio 
0−96 h post-injection at 
visit 7
Accumulation ratio is calculated as 
AUC(0-96h) at steady state/AUC(0-96h) at
single dose.
Terminal half-life (t½)
0−96 h post-injection at 
visit 2a and visit 7
h
t½ = ln(2) / λz, where λz is the terminal 
elimination rate. The terminal 
elimination rate will be estimated using 
linear regression on the terminal part of 
the log(activity) versus time profile.
Clearance (CL)
0−96 h post-injection at 
visit 2a and visit 7
mL/h/kg
CL= Dose / AUC.
Using AUC(0-inf) for single dose and 
AUC(0-96h) for steady state.
Vz
0−96 h post-injection at 
visit 2a and visit 7
mL/kg
Apparent volume of distribution based 
on the terminal phase.
Vz = CL/λz
Vss
0−96 h post-injection at 
visit 7
mL/kg
Apparent volume of distribution at 
steady-state. 
Vss = CL*MRT
%extrap
0−96 h post-injection at 
visit 2a and visit 7
%
Percentage of AUC(0-inf) determined by 
extrapolation.
AUC(t-inf)/(AUC(0-inf))
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
14 of 18
Title
Time frame
Unit
Details
MRT
0−96 h post-injection at 
visit 2a and visit 7
h
Mean Residence Time.
MRT = AUMC/AUC(0-inf), where 
AUMC is the area under the first 
moment curve, i.e. the area under the 
curve t∙C(t), calculated with the same 
method as AUC(0-inf) (linear trapezoidal 
method + extrapolated area) 
λz
0−96 h post-injection at 
visit 2a and visit 7
1/h
Terminal elimination rate constant.
The terminal elimination rate constant 
will be estimated using linear regression 
on the terminal part of the log(activity) 
versus time profile
Single dose PK will be based on the PK session at visit 2a, and steady state PK will be based on the 
PK session at visit 7.
The PK parameters will be calculated using plasma FVIII activity obtained from the FVIII 
chromogenic assay. The PK parameters will be derived according to a non-compartmental method, 
as described in Table 2. The actual time points will be used in the calculations.
If any profiles and/or individual plasma FVIII activities are excluded from the primary 
pharmacokinetic analysis, a sensitivity pharmacokinetic analysis will also be performed and 
reported based on all observed data. The primary pharmacokinetic analysis is based on the full 
analysis set excluding outliers. 
Specifically which data points and profiles that will be excluded will be defined prior to database 
lock. It should exclude profiles with pre-dosing activity > 5% (possibly indicating inadequate wash
out) at visit 2a and profiles that are not indicative of a normal intravenously injection (i.e. clearly 
increasing plasma FVIII activities initially). If a patient is treated with an additional dose during the 
PK session, the plasma FVIII activities after the occurrence will then be excluded.  Furthermore, if 
the profile shows indications of an additional dose (e.g. clearly increased plasma FVIII activity), the 
plasma FVIII activities after the occurrence will then also be excluded. 
All pharmacokinetic endpoints (except MRT, Vss, Vz, percentage of AUC(0-inf) determined by 
extrapolation and terminal elimination rate constant) will be analysed using mixed effects model on 
log-transformed parameters including patient as random effect. Estimates of each endpoint with 
95% confidence intervals will be provided back-transformed to the natural scale.
Individual and mean PK profiles will be presented graphically by subject and by visit.
Furthermore, the mean PK endpoints will be summarised and individual PK endpoints will be 
listed.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
15 of 18
5.5
Exploratory endpoints analysis
Not applicable.
5.6
Other safety analyses
Changes in vital signs (blood pressures, pulse, temperature, respiratory rate)
These endpoints will be presented in summary tables and plots.
Other safety parameters
All additional safety parameters such as laboratory parameters, ECG and physical examinations will 
be presented in summary tables, plots and listings as appropriate.
5.7
Other analyses
Surgery
In relation to surgery the following will be recorded:
x
Haemostatic effect evaluated on the four-point scale (excellent, good, moderate and none) 
and assessed by the investigator/surgeon on the day of surgery (Day 1) and on the last day in 
the post-operative period the patient is at the trial/surgery site.
x
Loss of blood and requirements for transfusion on the day of surgery (Day 1) and during the 
post-operative period Days 2-7 or until the last day the patient is at the trial/surgery site, 
whatever comes first.
All records will be summarised and listed. 
5.8
Interim analyses
No interim analysis is planned.
5.8.1
Data monitoring committee
Refer to protocol Section 9.6
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
16 of 18
6
Supporting documentation
6.1
Appendix 1 List of abbreviations
ABR
Annualised bleeding rate
AE
Adverse event
AUC
Area under the curve
BU
Bethesda unit
C30min
FVIII activity at 30 min post injection
CDE 
Centre of Drug Evaluation 
CI
Confidence interval
CL 
Total clearance
CTR
Clinical trial report
ED
Exposure day
FAS
Full analysis set
FVIII
Coagulation factor eight
LLOQ
Lower limit of quantification
LOCF
Last observation carried forward
MRT
Mean residence time
N8-GP
Glycopegylated recombinant coagulation factor VIII (NCC 0129-0000-1003)
PK
Pharmacokinetics
PTP
Previously treated patient
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Safety analysis set
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
17 of 18
SD
Standard deviation
t½
Terminal half life
TE
Treatment emergent
TFL 
Tables, figures and listings
6.2
Appendix 3: Definition and calculation of endpoints, assessments and derivations
Not applicable
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 January 2021
Novo Nordisk
Trial ID: NN7088-4595
Version:
2.0
UTN: U1111-1235-5905
Status:
Final
EudraCT No: 2020-003001-58
Page:
18 of 18
7
References
Not applicable
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