Ability of a Virtual-reality Based Solution Aiming to Reduce Patient Burden Related to Repetitive Intravenous Perfusions. A Proof-of-concept Study in Hemophilia Patients Receiving Prophylactic Factor VIII or Factor IX Infusions
Phase: NA
Conditions: Hemophilia
Sponsor: Takeda

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DoL-x Poc 
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INTERVENTIONAL STUDY WITH MINIMAL RISKS AND 
CONSTRAINTS 
PROTOCOL TAK-660-4013 
Title: 
Ability of a virtual-reality based solution aiming to reduce patient 
burden related to repetitive intravenous perfusions. A proof-of-concept 
study in haemophilia patients receiving prophylactic Factor VIII or 
Factor IX infusions 
Protocol Short Title: DoL-x Poc 
Protocol Version 
and Date 
TAK-660-4013, Version 3.0, 28 February 2023 
Registration No.: 
 NCT05437211 
Active Substance: 
Not applicable 
Medicinal Product: 
Not applicable 
Product Reference: 
Not applicable 
Sponsor 
Takeda France SAS 
112 avenue Kléber 
75116 Paris, France 
Country of Study: 
France 
Takeda Study Lead:  
 Rare Diseases – France 
This document contains confidential and proprietary information of Takeda and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Takeda. 
For non-commercial use only

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PROTOCOL SIGNATURE PAGE – INVESTIGATOR 
Investigator Acknowledgement 
I have read this protocol for Takeda Study (protocol number: TAK-660-4013). 
Title: Ability of a virtual-reality based solution aiming to reduce patient burden related 
to repetitive intravenous perfusions. A proof-of-concept study in haemophilia patients 
receiving prophylactic Factor VIII or Factor IX infusions 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with the Declaration of Helsinki, Good Clinical Practice and with the applicable 
regulatory requirements, including the reference method MR-001. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
Dr. 
 
 
 
 
 
France 
03-mars-2023
Signature: 
 Date: 
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CONTACT INFORMATION 
 
 
Protocol Author: 
 
 Rare Diseases 
TAKEDA France SAS 
112 avenue Kléber 
75116 Paris 
France 
 
Mobile 
 
 
 
Medical Writer: 
 
 
Dr 
 
Auxesia 
8 allée des geraniums 
69150 Décines-Charpieu 
France 
 
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STUDY SYNOPSIS 
FOR INTERVENTIONAL STUDY WITH MINIMAL RISKS AND CONSTRAINTS 
Protocol Number, Version and Date: 
Protocol Number: TAK-660-4013; Version 3.0; 28 February 2023 
Protocol Title: 
Ability of a virtual-reality based solution aiming to reduce patient burden related to repetitive 
intravenous perfusions. A proof-of-concept study in haemophilia patients receiving prophylactic Factor 
VIII or Factor IX infusions 
Protocol Short Title: DoL-x Poc 
Duration of Study (planned): 
-
Test phase of the study (to validate the proper functioning of the hardware and software solution, and
its appropriation by patients and caregivers): 6 months
-
Clinical study itself: 7 months (inclusions: 6 months; patient follow-up: 4 weeks)
Background and Rationale 
The treatment of some medical conditions is based on intensive intravenous therapy that may lead to a real 
treatment burden for patients (pain, anxiety, decrease in quality of life…) and relatives, and then to treatment 
avoidance and poor adherence which can contribute to poor medical outcomes. 
Research Question 
In this context, this proof-of-concept study is designed to assess the ability of a virtual-reality based solution 
aiming to reduce the treatment burden in patients and relatives. The studied population will be haemophilia 
patients receiving prophylactic Factor VIII or Factor IX infusions. 
Objectives 
Primary objective 
To describe the evolution of the treatment burden in haemophilia patients receiving prophylactic Factor VIII or 
Factor IX infusions, under a virtual-reality based solution, as well as for patient relatives and health care 
professionals 
Secondary objectives 
-
To describe the satisfaction of patients, relatives, and health care professionals with the virtual-reality
based solution
-
To describe the tolerance of the virtual-reality based solution
Exploratory objective 
To describe the evolution of drug therapies used by patients for pain and anxiety, under the virtual-reality based 
solution 
Study Design 
This is an interventional (with minimal risks and constraints), prospective, national, and multicentre proof-of- 
concept study designed to describe, in France, the evolution of the treatment burden of haemophilia patients 
receiving prophylactic Factor VIII or Factor IX infusions, using a virtual-reality based solution, as well as for 
patient relatives and health care professionals. 
The duration of the clinical study will be 4 weeks for each patient enrolled. 
The virtual-reality based solution to be studied is provided in a medical device CE marked and specifically 
developed by Deepsen, a French company specialized in e-health solutions to reduce pain. 
The studied solution comprises: 
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- 
A mobile phone application including explanation on the different steps to be followed to perform 
infusions in satisfactory conditions, notably as regards safety, as well as VAS for pain and anxiety to 
be complete between the inclusion and the Week 4 visit 
- 
A 3D mask (to be used during infusions) including 
o 
Simulation of infusions themselves (before infusion) 
o 
A relaxing and distracting content (during and after infusions) 
The content of the different parts of the studied solution is adapted to the person who will be in charge of the 
infusions when not performed by the healthcare professional (patient or family). 
Before the clinical study itself, a test phase will be conducted in a limited number of patients (n=8) to validate 
the proper functioning of the hardware and software solution, and its appropriation by patients and caregivers 
(learning agility, understanding of modules and objectives, and actions to be taken if technical problems). This 
phase will be conducted at the Lyon centre (National Reference Centre for Haemophilia and other rare bleeding 
disorders) that will be also involved in the study itself. This test phase will consist of a single visit for patients 
These patients will be allowed to participate in the clinical study itself, after a period of 4 months minimum 
with no use of the virtual-reality based solution. These patients will be selected to present different 
characteristics in terms of age and autonomy with Factor VIII infusions (2 patients for each of the 4 following 
subgroups: autonomous children, autonomous adults, non-autonomous children, and non-autonomous adults). 
During the clinical study itself, included patients will be followed up for 4 weeks, with the following steps: 
1. Inclusion visit: 
a. 
Firstly, Factor VIII or Factor IX infusion performed at hospital as usual, with no use of the virtual- 
reality based solution, and baseline evaluation 
b. Secondly, training with the virtual-reality based solution 
2. Evaluations at the time of the following infusions, using the virtual-reality based solution (at home 
with or without the help of a nurse, or at hospital according to usual practices) 
3. Final visit at hospital 4 weeks after inclusion, for evaluations at the time of the last infusion during 
follow-up. 
The virtual-reality based solution to be studied could lead clinicians to changes in the current management of 
haemophilia patients (e.g.: potential decrease in analgesics or anxiolytics). This study is therefore through (and 
in accordance with) the reference MR-001 method defined in France for interventional studies with minimal 
risks and constraints (This category of studies id defined in the decree of April 12th, 2018; NOR: 
SSAP1810239A; JORF No 0089, dated on 2018, April 17). 
Study Population (clinical study) 
Haemophilia patients over the age of 6 years, receiving prophylactic Factor VIII or Factor IX infusions, included 
by 6 French haemophilia treatment centres (Lyon Reference Centre; Clermont Ferrand, Bordeaux, Toulouse, 
Nantes, and Strasbourg) 
Two groups of patients will be defined according to their autonomy with Factor VIII or Factor IX infusions 
according to physician opinion 
- 
Autonomy acquired or in the process of being acquired 
- 
Non-autonomy 
Patient Inclusion / Exclusion Criteria (clinical study) 
Inclusion criteria 
- 
Male patient over the age of 6 years, with diagnosed Congenital Haemophilia A or B, whatever the 
severity is 
- 
Patient under long-term prophylaxis with intravenous Factor VIII or Factor IX infusions 
- 
Patient (or the legal guardians if patient age <18 years) able and willing to give written informed 
consent and to comply with the requirements of the study protocol 
- 
Patient affiliated to the national social security or beneficiary to such insurance. 
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Exclusion criteria 
- 
Patient with known or suspected hypersensitivity to virtual-reality based tools 
- 
Patient with central venous line for the administration of Factor VIII or Factor IX 
- 
Patient (and the legal guardians if patient age <18 years) with history of unreliability or non- 
cooperation (including for completion of self-reported questionnaires) 
- 
Patient (and the legal guardians if patient age <18 years) with insufficient comprehension of French 
language 
- 
Patient participating in another clinical trial 
- 
Patient deprived of his liberty by judicial or administrative order 
NB: patients with haemophilia A having participated in the test phase of the study could be included in the 
clinical study itself after a 4-month period with no use of the virtual-reality based solution. 
Data Sources / Data Collection 
Visit data when available as documented in patients’ records will be entered by investigators in the eCRF 
(patient and disease characteristics, drugs taken for pain and anxiety). 
Data related to treatment burden over time and satisfaction with the virtual-reality based solution will be entered 
by patients and/or relatives 
- 
On paper questionnaires at the inclusion and Week 4 visits 
- 
On a specific module of the virtual-reality based solution at the time of each Factor VIII or Factor IX 
infusion between the inclusion and Week 4 visits. 
Variables (Exposures, Outcomes and/or Endpoints) 
Related to Primary objective 
Before each Factor VIII or Factor IX infusion 
- 
Anxiety (patients and relatives) using an Anxiety Visual Analogue Scale (A-VAS). 
o 
Absolute and relative variation 
o 
Decrease of 2 points out of 10 in the A-VAS 
After each Factor VIII or Factor IX infusion 
- 
Pain (patients) using a Pain Visual Analogue Scale (P-VAS). 
o 
Absolute and relative variation 
o 
Decrease of 2 points out of 10 in the P-VAS 
- 
Anxiety (patients and relatives) using an Anxiety Visual Analogue Scale (A-VAS). 
o 
Absolute and relative variation 
o 
Decrease of 2 points out of 10 in the A-VAS 
At inclusion and at end of follow-up (week 4) 
- 
Quality of life measured with the European Quality of Life 5 Dimensions 3‐ levels (EQ‐ 5D‐ 3L 
questionnaire (patients and relatives) - one scale for adults and one scale for children (EQ-5D-Y) 
o 
Absolute and relative variation 
o 
Decrease of 2 points out of 10 in the VAS 
- 
Anxiety using the State-Trait Anxiety Inventory STAI-Y (patients and relatives) including 2 types of 
anxiety: State and Trait. 20 items for each type of anxiety (score from 20 to 80) 
o 
Absolute and relative variation 
o 
Decrease of at least one level of anxiety state (STAI-S) severity. Severity is defined as a score 
on STAI-S 20-35 (very low) 36-45 (low) 46-55 (moderate) 56-65 (high) 66-80 (very high) 
- 
Depression using PHQ-9 Depression Severity (patients and relatives): 9 items (score from 0 to 27). 
o 
Absolute and relative variation 
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o 
Decrease of at least one level of depression severity. Severity is defined as a score on PHQ- 
9: 0-5 (none) 5-10 (mild) 10-15 (moderate) 15-20 (moderately severe) 20-27 (severe). 
- 
Adherence to infusions using MMAS-4 
o 
Absolute variation and changes in classes (0-1: low adherence; 2-3: medium adherence; 4: 
high adherence) 
o 
Score at 4 (high adherence) at the end of follow-up. 
At the end of follow-up (week 4) 
- 
Adherence to virtual-reality based solution at the end of follow-up using MMAS-4 
o 
Score in classes (0-1: low adherence; 2-3: medium adherence; 4: high adherence). 
- 
Global Impression of Change (GIC) Scale at the end of follow-up (patients, relatives and caregivers) 
o 
Value at 3 or more. 
Related to secondary objectives: 
At the end of follow-up (week 4) 
- 
Satisfaction, Willingness to Continue the virtual-reality based solution: Patient, Caregiver and relatives 
using a 4-point Likert scale 
o 
Score at 3 or 4 (satisfied or very satisfied) 
- 
Preference for the virtual-reality based solution: Patient Caregiver and relatives using a binary question 
o 
Preference for the virtual-reality based solution versus no virtual-reality based solution 
- 
Incidents related to the virtual-reality based solution, adverse events related to the infusions of Factor 
VIII or Factor IX, or VR-based solution, serious adverse events 
Related to exploratory objective 
Drug therapies used by patients for pain and anxiety at inclusion and end of follow-up 
Sample size: 
Test phase of the study 
A total of 8 patients (2 patients in each of the 4 following subgroups: autonomous children, autonomous adults, 
non-autonomous children, and non-autonomous adults) are required to test the hardware and software solution. 
Study part two (clinical study itself) 
This clinical study requires 34 subjects to detect an absolute difference (evolution between before and after the 
virtual-reality based solution) with an effect size of 0.5 (ratio difference/standard deviation) which is considered 
to be a medium effect size. Power is set at 80% and the significance level at 5% two-sided. As an example, the 
study has a sufficient power to detect a difference of 2±4 points on the anxiety or pain scales. With 17 patients 
in the acquired autonomy or without autonomy subgroups (i.e.,50% of the total population for each subgroup) 
and the same hypotheses, the effect size is expected to increase from 0.5 to 0.7. 
Data Analysis 
Means absolute variation before and after the virtual-reality based solution will be described using an analysis 
of covariance adjusted on baseline value and group (acquired autonomy or without autonomy). This model will 
estimate the LSMeans with the associated two-sided 95% confidence interval and p value. If the p value is 
significant for at least one endpoint among pain, anxiety, depression or quality of life, this proof-of-concept 
study will be considered as positive. 
The percentage of responder patients for each scale (pain, anxiety, depression, quality of life, adherence to 
treatment, satisfaction, willingness to continue and preference) will be presented with the associated 95% two- 
sided exact confidence interval. 
Patient and disease characteristics will be described at inclusion: patient age at diagnosis and inclusion, 
haemophilia severity according to the residual level of Factor VIII or Factor IX, disease complications over the 
last 12 months (haemorrhagic events, synovitis, chronic arthritis), Factor VIII or Factor IX infusions [age at 
first infusion, inhibitors’ history, immune tolerance (yes/no, success or failure), current number of weekly 
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infusions], daily use of analgesics and/or NSAIDs for at least 3 months, socio-professional activity and 
education level of patients (or parents). 
Study Limitations and Potential Sources of Bias 
For this proof-of-concept study, no representativeness of the studied population is required. After the test phase 
conducted in 8 patients, only a limited number of 34 eligible patients will be included (17 patients with acquired 
autonomy and 17 patients without autonomy). No handling for multiplicity is considered for the analysis of the 
different endpoints. 
However, 
- 
The 6 participating centres, fully involved in the management of haemophilia patients and prophylactic 
Factor VIII or Factor IX infusions, will be in different French areas (Lyon Reference Centre; Clermont 
Ferrand, Bordeaux, Toulouse, Nantes, and Strasbourg) 
- 
Physicians will be asked to include consecutive eligible patients from the study implementation. 
Safety Monitoring 
Potential adverse events related to the virtual-reality based solution are, for example, nausea, headaches, or 
visual disturbances. 
Adverse events/ incidents will be collected and securely reported according to the usual reporting process 
provided by current regulations: 
- 
To be reported to Takeda France Pharmacovigilance: 
o 
Adverse effects that may be related to the infusions of Factor VIII or Factor IX (whatever the 
drug is) 
o 
Adverse effects that may be related to the VR-based solution 
o 
All serious adverse events (related or not related to the infusions of Factor VIII or Factor IX, 
or VR-based solution) 
- 
To be reported to Deepsen: 
o 
Incidents that may be related to the mobile phone application or 3D mask device incidents 
Consent, Protection, and Ethics 
Before inclusion in each study step, patients (and/or the legal guardians) will be informed about the content of 
the study, and sign a written informed consent provided by investigators. Several Consent Forms are defined 
according to the age classes of patients, for each phase of the study: 6-18 et ≥18 years for the test phase; 6-12, 
12-18 et ≥18 years for the clinical study itself. 
Only identifying numbers of the patient and the virtual-reality based solution provided will appear on eCRF 
and self-reported questionnaires. Physicians will keep a list of codes to identify patients and their medical files. 
This list will never be conveyed to the sponsor. 
Indirect personal data on patients collected on the virtual-reality based solution during the study will be securely 
transferred to the CRO mandated by the Sponsor (daily automated transfer). 
According to French relevant regulations, the sponsor will submit the study protocol and any accompanying 
material to be provided to the subject / legal guardians (such as patient written informed consent) to an 
independent Medical Ethics Committee which will be randomly assigned. According to French regulation, this 
study is interventional research at minimal risks which contains only minimal risks and constraints. This 
category was formerly called “common care research”. 
No data will be conveyed outside the European Union. 
Data Management 
An electronic data capture (EDC) system will be used for the study: 
- 
eCRF to collect data from investigators 
- 
ePRO developed as a specific module of the virtual-reality based solution to collect subject’s data 
between the inclusion and Week 4 visits. 
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At inclusion and Week 4 visits, paper self-reported questionnaires will be completed by patients and/or relatives. 
To ensure confidentiality and security of the data, personal logins and passwords will be used. This process 
allows the restriction of system access to authorized personnel only. The list of authorized personnel will be 
documented. The system will ensure a traceability of any data modified, the date of modification, the reason for 
modification and identification of the corresponding user via the audit-trail. Each confirmation or correction of 
data must be performed by authorized site staff on the eCRF with the reason of correction. 
After completion and cleaning process of data and before database lock, each eCRF will be signed by the 
investigator using electronic signature function available on the eCRF (entering login and password). This 
action will ensure that the investigator confirm the accuracy, completeness, legibility of the data collected on 
the eCRF. 
To ensure confidentiality and security of the data, personal logins will be used by patients on the virtual-reality 
based solution. Collection of patient indirect personal data between the inclusion and Week 4 visits will be 
transferred (encrypted cvs file) by Deepsen to the CRO in charge of biometry at the end of the study 
The complete data management process (data capture, data entry, data validation, checks on plausibility, query 
handling, data editing after entry, coding, data base closure, etc.) will be defined in advance within a data 
handling plan/ data management plan together with a description of the personnel responsible for data entry. 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE – TAKEDA STUDY LEAD .............................................. 2 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR ........................................................... 3 
CONTACT INFORMATION ..................................................................................................... 4 
STUDY SYNOPSIS ................................................................................................................... 5 
AMENDMENTS AND UPDATES .......................................................................................... 11 
TABLE OF CONTENTS .......................................................................................................... 12 
LIST OF FIGURES .................................................................................................................. 15 
ADDITIONAL DOCUMENTS ................................................................................................ 15 
1 
ABBREVIATIONS ...................................................................................................... 16 
2 
BACKGROUND AND RATIONALE ......................................................................... 18 
2.1 
Epidemiology and Natural History of Haemophilia ..................................................... 18 
2.2 
Prophylaxis with Anti-Haemophilic Factors ................................................................ 18 
2.3 
Study Rationale ............................................................................................................. 19 
3 
RESEARCH QUESTION AND OBJECTIVES .......................................................... 21 
3.1 
Research Question ........................................................................................................ 21 
3.2 
Objectives ..................................................................................................................... 21 
3.2.1 Primary objective .......................................................................................................... 21 
3.2.2 Secondary objectives .................................................................................................... 21 
3.2.3 Exploratory objective .................................................................................................... 21 
4 
RESEARCH METHODS ............................................................................................. 22 
4.1 
Study Design ................................................................................................................. 22 
4.2 
Study Setting and Study Population ............................................................................. 24 
4.2.1 Number and Type of Participants ........................................................................... 24 
4.2.2 Sites, Regions and Countries .................................................................................. 24 
4.2.3 Participant Selection Criteria ................................................................................. 25 
4.2.3.1 
Inclusion Criteria ......................................................................................... 25 
4.2.3.2 
Exclusion Criteria ........................................................................................ 25 
4.2.4 Discontinuation of Participants .............................................................................. 26 
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4.3 
Data Source/Data Collection ........................................................................................ 26 
4.3.1 Test Phase .............................................................................................................. 26 
4.3.2 Clinical Study ......................................................................................................... 27 
4.3.3 Data Collection Procedures .................................................................................... 28 
4.3.4 Data Collection Instrument .................................................................................... 28 
4.4 
Variables (Exposures, Outcomes and/or Endpoints and Other Study Variables) ......... 28 
4.4.1 Exposures ............................................................................................................... 28 
4.4.2 Endpoints ............................................................................................................... 28 
4.4.2.1 
Endpoints Related to Primary Objective ..................................................... 28 
4.4.2.2 
Endpoints Related to the Secondary Objectives .......................................... 30 
4.4.2.3 
Endpoints Related to the Exploratory Objective ......................................... 30 
4.4.3 Other Study Variables ............................................................................................ 30 
4.5 
Sample Size .................................................................................................................. 31 
4.6 
Data Analysis ................................................................................................................ 31 
4.7 
Limitations of the Research Methods ........................................................................... 33 
5 
PROTECTION OF HUMAN SUBJECTS ................................................................... 34 
5.1 
Sponsor’s Responsibilities ............................................................................................ 34 
5.1.1 Compliance with Relevant Guidelines ................................................................... 34 
5.1.2 Insurance ................................................................................................................ 34 
5.1.3 Study Suspension, Termination and Completion ................................................... 34 
5.2 
Investigator’s Responsibility ........................................................................................ 34 
5.2.1 Compliance with Relevant Guidelines ................................................................... 34 
5.2.2 Protocol Adherence and Investigator Agreement .................................................. 35 
5.2.3 Documentation and Retention of Records ............................................................. 35 
5.2.3.1 
Case Report Forms ...................................................................................... 35 
5.2.3.2 
Recording, Access, and Retention of Sources of Data and Study 
Documents ................................................................................................... 36 
5.2.3.3 
Audit/Inspection ........................................................................................... 36 
5.3 
Ethical Considerations .................................................................................................. 36 
5.3.1 Informed Consent ................................................................................................... 36 
5.3.2 Institutional Review Board or Ethics Committee .................................................. 37 
5.3.3 Privacy and Confidentiality .................................................................................... 37 
6 
DATA MANAGEMENT AND QUALITY CONTROL ............................................. 39 
6.1 
Data Management ......................................................................................................... 39 
6.2 
Data Handling ............................................................................................................... 40 
6.3 
Database Archiving and Study Document Retention ................................................... 41 
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7 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ ADVERSE 
REACTIONS AND VR-BASED SOLUTION INCIDENTS ...................................... 42 
7.1 
Adverse Events/ Adverse Reactions ............................................................................. 42 
7.1.1 Adverse Events to be Collected .................................................................................... 42 
7.1.2 Definitions .................................................................................................................... 42 
7.1.2.1 
Adverse Events ............................................................................................ 42 
7.1.2.2 
Serious Adverse Event ................................................................................. 42 
7.1.2.3 
Adverse Drug Reactions .............................................................................. 43 
7.1.2.4 
Product Quality Issues ................................................................................. 43 
7.1.2.5 
Special Situation Reports ............................................................................. 43 
7.1.2.6 
Relationship of an Adverse Event to Studied Drug(s) ................................. 44 
7.1.3 Reporting ...................................................................................................................... 44 
7.1.3.1 
Collection and Recording of Adverse Events, Special Situation 
Reports (SSRs) and Product Quality Issues (PQIs) ..................................... 44 
7.1.3.2 
Reporting of Adverse Drug Reactions to Regulatory Agencies and 
IRB/EC ........................................................................................................ 45 
7.2 
VR-Based Solution Incidents ....................................................................................... 45 
7.2.1 Definition of Incidents ........................................................................................... 45 
7.2.2 Reporting of Incidents ............................................................................................ 45 
8 
PLAN FOR DISSEMINATION AND COMMUNICATION OF STUDY 
RESULTS ..................................................................................................................... 46 
8.1 
Public Posting and Disclosure of Study Information .................................................... 46 
8.2 
Study Results/Publications ............................................................................................ 46 
8.3 
Submission of Summary of Final Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees ...................................................... 46 
9 
REFERENCES ............................................................................................................. 47 
10 
APPENDICES .............................................................................................................. 49 
10.1 
Studied VR-Based Solution .......................................................................................... 49 
10.1.1 Game Module ......................................................................................................... 49 
10.1.2 Relaxation Module ................................................................................................. 49 
10.1.3 Learning Module .................................................................................................... 49 
10.2 
Participating Centres ..................................................................................................... 51 
10.3 
Questionnaires/Scales Used for Assessments ............................................................... 53 
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LIST OF FIGURES 
Figure 1: 
Study Design Flow Chart ....................................................................................... 23 
 
 
ADDITIONAL DOCUMENTS 
• 
Detailed description of the VR-based solution 
• 
Simplified user guide regarding the VR-based solution (to be provided to patients at 
inclusion) 
• 
Instructions regarding the most current problems potentially encountered when using 
the VR-based solution (to be provided to patients at inclusion) 
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1 ABBREVIATIONS 
3D 
Three-dimensional 
AE 
Adverse event 
ANSM 
Agence Nationale de Sécurité du Médicament et des produits de santé 
A-VAS 
Visual analogue scale for anxiety 
CRF/eCRF 
Case report form/electronic case report form 
CRO 
Clinical research Organization 
EDC 
Electronic data capture 
EQ-5D-3L 
European Quality of Life 5 dimensions 3 levels 
EQ-5D-Y 
European Quality of Life 5 dimensions four youth 
HLGT 
High-level group term 
HLT 
High-level term 
ICH 
International Conference on Harmonisation 
IRBs/ECs 
Institutional Review Boards/Ethics Committees 
IV 
Intravenous 
LLT 
Low-level term 
LSMeans 
Least-Squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAS-4 
4-item Morisky Medication Adherence Scale 
MR 
Reference method 
NSAID 
Non-steroidal anti-inflammatory drug 
PGIC 
Patient’s Global Impression of Change 
PHQ-9 
Patient Health Questionnaire (module 9 for depression) 
PRO/ePRO Patient reported outcome/electronic patient reported outcome 
PT 
Preferred term 
PV 
Pharmacovigilance 
P-VAS 
Visual analogue scale for pain 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
STAI-S 
State Anxiety Inventory 
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STAI-Y 
State-Trait Anxiety Inventory 
VAS 
Visual analogue scale 
VR 
Virtual reality 
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2 BACKGROUND AND RATIONALE 
2.1 
Epidemiology and Natural History of Haemophilia 
Haemophilia is a rare X-linked bleeding recessive disorder caused by a deficiency of 
coagulation Factor VIII (in haemophilia A) or Factor IX (in haemophilia B). It is commonly 
observed in males, but may be rarely seen in females as a consequence of homozygosity, double 
heterozygous mutation or unbalanced lyonization (Manucci 2001). On the basis of clotting 
factor concentrations, the disease can be severe (factor deficiency <1%), moderate (1-5%), or 
mild (between 6% and 40%) (PNDS Hémophilie 2019). Patients with severe haemophilia 
represent approximately half of the diagnosed cases (Srivastava 2015). 
Based on recent data, the prevalence of haemophilia appears to be higher than previously 
estimated (Stonebraker 2020). A recent study showed that the expected number of patients with 
haemophilia worldwide is 1 125 000, of whom 418 000 should have severe disease (Iorio 2019). 
Haemophilia A accounts for 80-85% of all haemophilia cases (World Federation of Hemophilia 
2018). The prevalence of haemophilia A (per 100 000 males) is 17.1 cases for all severities of 
the disease, and 6.0 cases for severe haemophilia A. In addition, incidence at birth (per 100 000 
males) is 24.6 cases for all severities of haemophilia A, and 9.5 cases for severe haemophilia 
A. In France, a total or approximately 7 000 haemophilia patients are estimated (World 
Federation of Hemophilia 2018). 
Depending on the level of coagulation factor activity, patients with haemophilia may present 
with easy bruising, inadequate clotting of traumatic or even mild injury, or, in the case of severe 
haemophilia, spontaneous haemorrhage (PNDS Hémophilie 2019). The frequency of bleeding 
depends on the site: joints (70-80%), muscle (10-20%), other sites (major bleeds; 5-10%), and 
central nervous system (< 5%) (Srivastava 2015). Severe and/or repeated bleeds may lead to 
chronic synovitis, resulting in chronic, painful, arthropathy and disability. 
Diagnosis of haemophilia is commonly made in the case of bleeding symptoms or family 
history in patients with severe disease, and frequently on the basis of haemostasis tests for 
patients with a mild or moderate form of haemophilia (Réseau FranceCoag 2005, PNDS 
Hémophilie 2019). 
2.2 
Prophylaxis with Anti-Haemophilic Factors 
The standard of care, which is to offer primary prophylactic infusions with anti-haemophilic 
factors to patients with severe haemophilia, has led to dramatic increase in the quality of life 
for these patients (Coppola 2010). Regular infusion of factor concentrates (primary 
prophylaxis) significantly contributed to prevent bleeding and subsequent joint damage. 
Current recommendations promote early treatment of children with haemophilia (Manco- 
Johnson 2007, Fisher 2016, Feldman 2018, Manco-Johnson 2018). Primary prophylaxis should 
start before the age of 3 and even before reports of joint bleeds, secondary prophylaxis included 
all other situations (World Federation of Hemophilia 2020). 
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In France, since the recommendations of the CoMETH (Coordination médicale pour l’étude et 
le traitement des maladies hémorragiques constitutionnelles), progressively intensive 
prophylaxis is favoured, according to the Canadian model (Meunier 2009). This regimen aims 
to increase adherence to treatment by children and parents, initially and for long-time, and to 
limit venous access problems (Feldman 2006, Meunier 2009). 
Primary long-term prophylaxis consists of starting - at the latest at the 2nd hemarthrosis (whether 
spontaneous or post-traumatic) or before the age of 3 years - intravenous preventive therapy 
with anti-haemophilic factor in severe or moderate haemophilia patients meeting these criteria. 
Implementation of secondary prophylaxis (after more than 2 hemarthroses or beyond 3 years) 
or tertiary (after arthropathy occurrence) (Manco-Johnson 2007) concerns all persons with 
severe haemophilia who did not receive primary prophylaxis. 
Long-term prophylaxis therapy of haemophilia required several infusions of anti-haemophilic 
factor per week that may lead to a real treatment burden for patients (pain, anxiety, decrease in 
quality of life…) and relatives. Despite the medical advantages of such a continuous therapy, 
this treatment burden could lead to treatment avoidance and poor adherence and then contribute 
to poor medical outcomes. 
2.3 
Study Rationale 
Virtual reality (VR) technology enables people to become immersed in a computer-simulated, 
three-dimensional (3D) environment. The potential use of VR in the medical field has recently 
been explored. 
Based on pain-rating (visual analogue or graphic scales), VR distraction was notably shown to 
be effective for reducing pain during medical procedures (Hoffman 2001, Malloy 2010, 
Hoffman 2011, Arane 2017, Le Du 2021). It was also shown that immersive VR reduced pain 
ratings and pain-related brain activity assessed by functional magnetic resonance imaging 
(Hoffman 2011). 
Overall, VR’s immersive, entertaining effects are useful for redirecting the patient’s attention 
away from painful treatment experiences and reducing anxiety, discomfort, or unpleasantness 
(Wiederhold 2007, Dascal 2017). 
If distraction is a common non-pharmacologic technique used by health care professionals to 
manage and attenuate anxiety, and possibly pain, during painful procedures in paediatric 
patients (Koller 2012), VR might offer even more distraction, as it completely immerses the 
patient in another world and involves multiple senses (Malloy 2010). A recent interventional 
study showed that a VR environment could be developed and safely used during paediatric 
haemophilia care for distraction during IV interventions, with the potential to improve patient 
experience during medical procedures (Dun 2019). 
In this context, it is of interest to explore the concrete interest and potential of a VR-based 
solution specifically developed and adapted to haemophilia patients. To answer to this question, 
a proof-of-concept (POC) study appears to be the best design (see some examples of POC 
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studies 
provided 
by 
the 
National 
Institute 
of 
Health 
Research, 
https://www.nihr.ac.uk/documents/proof-of-concept/19909). 
Deepsen, a French company specialized in e-health solutions to reduce pain, has developed a 
medical device CE marked, VR-based solution specifically adapted to haemophilia patients 
receiving frequent anti-haemophilic factor infusions. 
This VR-based solution comprises: 
• A mobile phone application including explanation on the different steps to be followed 
to perform infusions in satisfactory conditions, notably as regards safety, as well as VAS 
for pain and anxiety to be completed at each Factor VIII or Factor IX infusion between 
inclusion and the Week 4 visit 
• A 3D mask (to be used before or during infusions) including 
o Simulation of the infusions themselves (before infusion) 
o A relaxing and distracting content (during and after infusions). 
More details on this VR-based solution are provided in section 10.1 and in additional 
documents. 
Takeda is fully involved in the prophylactic treatment of haemophilia, notably through 
providing a recombinant Factor VIII (Advate®, octocog alfa) or Factor IX (Rixubis®, nonacog 
gamma). 
In this context, Takeda proposes to conduct a proof-of-concept study designed to assess the 
ability of this VR-based solution aiming to reduce the treatment burden in patients and relatives. 
The studied population will be haemophilia patients receiving prophylactic Factor VIII or 
Factor IX infusions. Patients with haemophilia A or B will be enrolled. 
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3 RESEARCH QUESTION AND OBJECTIVES 
3.1 
Research Question 
Haemophilia patients with long-term prophylaxis therapy experience a real burden related to 
repetitive intravenous perfusions which could lead to treatment avoidance and poor adherence 
and then contribute to poor medical outcomes. 
In this context, this proof-of-concept 4-week study mainly aim to assess the impact of a specific 
VR-based solution to be used in infusions ‘environment on the different aspects of the treatment 
burden (pain, anxiety, depression, quality of life). Adherence and satisfaction to the VR-based 
solution will be also assessed, and the evolution of drug therapies used by patients for pain and 
anxiety. Adverse events (AEs) related to the VR-based solution will be collected. 
3.2 
Objectives 
3.2.1 Primary objective 
• To describe the evolution of the treatment burden in haemophilia patients receiving 
prophylactic Factor VIII or Factor IX infusions, under a virtual-reality based solution, 
as well as for patient relatives and health care professionals 
3.2.2 Secondary objectives 
• To describe the satisfaction of patients, relatives, and health care professionals with the 
virtual-reality based solution 
• To describe the tolerance of the virtual-reality based solution 
3.2.3 Exploratory objective 
• To describe the evolution of drug therapies used by patients for pain and anxiety, under 
the virtual-reality based solution. 
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4 RESEARCH METHODS 
4.1 
Study Design 
This is an interventional (with minimal risks and constraints), prospective, national, and 
multicentre proof-of-concept study designed to describe, in France, the evolution of the 
treatment burden of haemophilia patients receiving prophylactic Factor VIII or Factor IX 
infusions, using a VR-based solution, as well as for patient relatives and health care 
professionals. 
The VR-based solution to be studied is a medical device CE marked (class I) and specifically 
developed by Deepsen, a French company specialized in e-health solutions to reduce pain. It 
includes both a mobile phone application (for explanation on infusions) and a 3D mask to be 
used during infusions. 
Whatever the step of the study is, nurses and investigators will be specifically trained to the 
VR-based solution at the time of study implementation, during an on-site visit. In addition, 
enrolled patients will be trained by the nurses at inclusion, and a specific user guide will be 
provided to them. 
The content of the different parts of the studied solution is adapted to the person who will be in 
charge of the infusions when not performed by the healthcare professional (patient or family). 
More details on this VR-based solution are provided in section 10.1. 
This study will be conducted in two successive steps: 
• A preliminary test phase will be conducted in a limited number of patients (n=8) to 
validate the proper functioning of the hardware and software solution, and its 
appropriation by patients and caregivers (learning agility, understanding of modules and 
objectives, and actions to be taken if technical problems). This phase will be conducted 
at the National Reference Centre for Haemophilia and other rare inherited bleeding 
disorders (Lyon) that will be also involved in the study itself. This test phase will consist 
of a single visit for patients. These patients will be allowed to participate in the clinical 
study itself, after a period of 4 months minimum with no use of the virtual-reality based 
solution. These patients will be selected to present different characteristics in terms of 
age and autonomy with Factor VIII infusions (2 patients for each of the 4 following 
subgroups: autonomous children, autonomous adults, non-autonomous children, and 
non-autonomous adults) 
• The 4-week clinical study itself will be conducted as follows for eligible patients: 
o At the inclusion visit, the Factor VIII or Factor IX infusion will be firstly 
performed at hospital as usual, with no use of the VR-based solution. After 
collection of baseline data collected from investigators, patients and relatives, 
patients (and/or relatives) will be trained with the VR-based solution by the 
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Data to be collected at each study time-point are detailed in section 0. 
Study duration 
The total length of the study, from screening of the first patient for the test phase of the study 
to the end of the clinical study itself, is expected to be approximately 15 months: 
• Test phase of the study (to validate the proper functioning of the hardware and software 
solution, and its appropriation by patients and caregivers): 6 months 
• Clinical study itself: 7 months (inclusions: 6 months; follow-up: 4 weeks) 
Reference method 
The VR-based solution to be studied could lead clinicians to change the current management 
of haemophilia patients (e.g.: potential decrease in analgesics or anxiolytics). This study is 
therefore qualified as an interventional study with minimal risks and constraints as the 
intervention performed on the subjects are listed in the decree of April 12th, 2018; NOR: 
SSAP1810239A (JORF No 0089, dated on 2018, April 17). 
In addition, this study is in accordance with the reference MR-001 method. 
4.2 
Study Setting and Study Population 
4.2.1 Number and Type of Participants 
For this French proof-of-concept study, no sampling method will be applied. 
4.2.2 Sites, Regions and Countries 
This study will be conducted in France in the following haemophilia treatment centres: 
• For the test phase of the study, aiming to validate the proper functioning of the hardware 
and software solution, and its appropriation by patients and caregivers, patients will be 
enrolled by the National Reference Centre for Haemophilia and other rare inherited 
bleeding disorders (Lyon) 
• For the clinical study itself, six haemophilia treatment centres will be involved (Lyon 
Reference Centre, Clermont Ferrand, Bordeaux, Toulouse, Nantes, and Strasbourg). 
Details on participating centres are provided in Section 0. 
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4.2.3 Participant Selection Criteria 
To validate the proper functioning of the hardware and software solution, and its appropriation 
by patients and caregivers (learning agility, understanding of modules and objectives, and 
actions to be taken if technical problems), patients enrolled in the test-phase should have similar 
characteristics than those included in the second phase. 
For the test phase of the study, different patient profiles are required in order to fully validate 
the proper functioning of the hardware and software solution, and its appropriation by patients 
and caregivers. Consequently, these 8 patients will be selected to present different 
characteristics in terms of age and autonomy with Factor VIII infusions (2 patients for each of 
the 4 following subgroups: autonomous children, autonomous adults, non-autonomous 
children, non-autonomous adults). 
For the clinical study itself, investigators will be asked to include patients in rank order from 
the study implementation. In addition, two groups of patients will be defined according to their 
autonomy with Factor VIII or Factor IX infusions according to physician opinion: autonomy 
acquired or in the process of being acquired; non-autonomy. In each participant centre, 
investigators will be asked to include half of their patients in each group, in a consecutive way. 
Whatever the step of the study is, only patients over the age of 6 years will be eligible as they 
are able to understand and fulfil (with parents’ aid if useful) the scales to be used to assess their 
treatment burden over the study period. 
Inclusion and exclusion criteria are detailed below. 
4.2.3.1 Inclusion Criteria 
The subject will not be considered eligible for the study without meeting all of the criteria 
below. 
• Male patient over the age of 6 years, with diagnosed Congenital Haemophilia A or B, 
whatever the severity is 
• Patient under long-term prophylaxis with intravenous Factor VIII or Factor IX infusions 
• Patient (or the legal guardians if patient age <18 years) able and willing to give written 
informed consent and to comply with the requirements of the study protocol 
• Patient affiliated to the national social security or beneficiary to such insurance 
4.2.3.2 Exclusion Criteria 
The subject will be excluded from the study if any of the following exclusion criteria are met: 
• Patient with known or suspected hypersensitivity to virtual-reality based tools 
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• Patient with central venous line for the administration of Factor VIII or Factor IX 
• Patient (and the legal guardians if patient age <18 years) with history of unreliability or 
non-cooperation (including for completion of self-reported questionnaires) 
• Patient (and the legal guardians if patient age <18 years) with insufficient 
comprehension of French language 
• Patient participating in another clinical trial 
• Patient deprived of his liberty by judicial or administrative order. 
NB: patients with haemophilia A having participated in the test phase of the study could be 
included in the clinical study itself after a period of 4 months minimum with no use of the 
virtual-reality based solution. 
4.2.4 Discontinuation of Participants 
Patients have the right to voluntarily withdraw from the study at any time for any reason. In 
addition, the investigator has the right to withdraw a patient from the study at any time. 
Every effort should be made to obtain information on patients who withdraw from the study. 
The primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. However, patients will not be followed for any reason after consent has been withdrawn. 
Patients who withdraw from the study will not be replaced. 
4.3 
Data Source/Data Collection 
Before any study procedures, subjects have to be informed about the study objectives and 
content, how their data will be processed, and they should consent in written to take part in the 
test phase or in the clinical study itself. 
No directly identifiable patient data will be collected in the CRF completed by investigators 
and the VR-based solution completed by patients (anxiety and pain VAS). 
4.3.1 Test Phase 
At the end of the single visit conducted at the Lyon centre (National Reference Centre for 
Bleeding disorders), patients (or relatives) will complete a paper qualitative questionnaire on 
learning agility, understanding of modules and objectives, and actions to be taken if technical 
problems. The eight completed questionnaires will be sent to Deepsen in order to perform 
adaptations if required. 
In addition, in the event of adverse events related to the infusions of Factor VIII or VR-based 
solution, or incidents related to the medical device, they are to be reported to the Sponsor or 
Deepsen respectively, as specified in section 7. 
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4.3.2 Clinical Study 
Data will be collected by investigators (or nurses involved in the study) at the inclusion and 
Week 4 visits, on the basis of patient medical files. 
Patient reported outcomes will be collected by patients (and/or relatives) on self-reported 
questionnaires at the time of each Factor VIII or Factor IX infusion (at the inclusion visit with 
no use of the VR-based solution and at each of the following infusions with the use of the VR- 
based solution). 
Data to be collected during the 4-week clinical study are detailed in the following table. 
Table 1. Data Collection Schedule 
Enrolment 
Visit 
At each Factor 
VIII or Factor IX 
infusion 
Week 4 visit 
(or premature 
study 
withdrawal) 
Data to be collected by investigators 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Patient and disease characteristics1 
X 
Drugs taken by patients for pain and anxiety2 
X 
X 
Incidents with the VR-based solution, adverse 
events related to the infusions of Factor VIII or 
Factor IX, and VR-based solution, serious 
adverse events 
 
Reasons for premature study withdrawal3 
X 
Data to be collected by patients 
VAS for pain and anxiety4 
X 
X 
X 
Adherence to Factor VIII or Factor IX infusions 
(MMAS-4)5 
X 
X 
Adherence to VR-based solution (MMAS-4)5 
X 
Data to be collected by patients and relatives 
Quality of life, using the EQ‐ 5D‐ 3L (or EQ‐ 
5D‐ Y for youth) 
X 
X 
Anxiety, using the STAI-Y 
X 
X 
Depression, using the PHQ-9 
X 
X 
Data to be collected by patients, relatives, and investigators or nurses 
Global Impression of Change (GIC) 
X 
Satisfaction and preference with the VR-based 
solution 
X 
1. Type of haemophilia (A or B), patient age at diagnosis and inclusion, haemophilia severity according to the 
residual level of Factor VIII or Factor IX, disease complications over the last 12 months (haemorrhagic events, 
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synovitis, chronic arthritis), Factor VIII or Factor IX infusions [age at first infusion, inhibitors’ history, 
immune tolerance (yes/no, success or failure), current number of weekly infusions, place of Factor VIII or 
Factor IX infusion (at hospital, at home, at both places), autonomy with Factor VIII or Factor IX infusions 
(autonomy acquired or in the process of being acquired, non-autonomy, person in charge of infusions if non 
autonomy)], socio-professional activity and education level of patients (or parents). 
2. Daily use of analgesics / NSAIDs and anxiolytics for at least 3 months (inclusion visit) and over the last week 
(Week 4 visit); drugs taken at the infusion of Factor VIII or Factor IX (at inclusion and Week 4 visits) 
3. Patient no longer wants to participate in the study, moved home/changed medical team, patient’s death, other 
4. Pain VAS completed after each infusion of Factor VIII or Factor IX; Anxiety VAS completed before and after 
each infusion (without the VR-based solution at inclusion and using the VR-based solution for the following 
infusions) 
5. Relatives will be asked to assess adherence to Factor VIII or Factor IX infusions and VR-based solution for 
non-autonomous patients 
 
4.3.3 Data Collection Procedures 
See above for data to be collected at each study visit (inclusion and Week 4) and by patients 
and/or relatives at each infusion of Factor VIII or Factor IX in the meantime (section 4.3). 
4.3.4 Data Collection Instrument 
Data collection by investigators (or nurses involved in the study) will be performed using a 
dedicated electronic case report form (eCRF). 
Data collection by patients and relatives will be performed using: 
• Paper self-reported questionnaires at the inclusion and Week 4 visits 
• Dedicated electronic self-reported questionnaires (ePRO) at each factor VIII or Factor 
IX injection between inclusion and Week 4. These VAS for pain and anxiety will be 
implemented into the VR-based solution provided to patients at the inclusion visit. 
4.4 
Variables (Exposures, Outcomes and/or Endpoints and Other Study Variables) 
4.4.1 Exposures 
Not Applicable – No study treatment in this study. 
4.4.2 Endpoints 
4.4.2.1 Endpoints Related to Primary Objective 
• Before each Factor VIII or Factor IX infusion 
o Anxiety (patients and relatives) using an Anxiety VAS (A-VAS). 
 Absolute and relative variation 
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 Decrease of 2 points out of 10 in the A-VAS. 
• After each Factor VIII or Factor IX infusion 
o Pain (patients) using a Pain Visual Analogue Scale (P-VAS) 
 Absolute and relative variation 
 Decrease of 2 points out of 10 in the P-VAS 
o Anxiety (patients and relatives) using an Anxiety VAS (A-VAS). 
 Absolute and relative variation 
 Decrease of 2 points out of 10 in the A-VAS. 
• At inclusion and at end of follow-up (week 4) 
o Quality of life measured with the European Quality of Life 5 Dimensions 3‐ 
levels (EQ‐ 5D‐ 3L questionnaire (patients and relatives) - one scale for adults 
and one scale for children (EQ-5D-Y) 
 Absolute and relative variation 
 Decrease of 2 points out of 10 in the VAS 
o Anxiety using the State-Trait Anxiety Inventory STAI-Y (patients and relatives) 
including 2 types of anxiety: State and Trait. 20 items for each type of anxiety 
(score from 20 to 80) 
 Absolute and relative variation 
 Decrease of at least one level of anxiety state (STAI-S) severity. Severity 
is defined as a score on STAI-S 20-35 (very low) 36-45 (low) 46-55 
(moderate) 56-65 (high) 66-80 (very high) 
o Depression using PHQ-9 Depression Severity (patients and relatives): 9 items 
(score from 0 to 27). 
 Absolute and relative variation 
 Decrease of at least one level of depression severity. Severity is defined 
as a score on PHQ-9: 0-5 (none) 5-10 (mild) 10-15 (moderate) 15-20 
(moderately severe) 20-27 (severe). 
o Adherence to infusions using MMAS-4 
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 Absolute variation and changes in classes (0-1: low adherence; 2-3: 
medium adherence; 4: high adherence) 
 Score at 4 (high adherence) at the end of follow-up 
• At the end of follow-up 
o Adherence to virtual-reality based solution at the end of follow-up using 
MMAS-4 
 Score at 3 or 4 in classes (0-1: low adherence; 2-3: medium adherence; 
4: high adherence) 
o Patients’ Global Impression of Change (PGIC) Scale at the end of follow-up 
(patients, relatives and caregivers) 
 Value at 3 or more 
4.4.2.2 Endpoints Related to the Secondary Objectives 
• At the end of follow-up (week 4) 
o Satisfaction, Willingness to Continue the virtual-reality based solution: patient, 
caregiver and relatives using a 4-point Likert scale 
 Score at 3 or 4 (satisfied or very satisfied) 
o Preference for the virtual-reality based solution: patient, caregiver and relatives 
using a binary question 
 Preference for the virtual-reality based solution versus no virtual-reality 
based solution 
o Incidents with the VR-based solution, adverse events related to the infusions of 
Factor VIII or Factor IX, or VR-based solution, serious adverse events 
4.4.2.3 Endpoints Related to the Exploratory Objective 
Drug therapies used by patients for pain and anxiety at inclusion and end of follow-up. 
4.4.3 Other Study Variables 
Not applicable 
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4.5 
Sample Size 
This clinical study requires 34 subjects to detect an absolute difference (evolution between 
before and after the virtual-reality based solution) with an effect size of 0.5 (ratio 
difference/standard deviation) which is considered to be a medium effect size. Power is set at 
80% and the significance level at 5% two-sided. 
As an example, the study has a sufficient power to detect a difference of 2±4 points on the 
anxiety or pain scales. With 17 patients in the acquired autonomy or without autonomy 
subgroups and the same hypotheses, the effect size is expected to increase from 0.5 to 0.7. 
4.6 
Data Analysis 
The statistical considerations and analysis plan are summarized below. A more detailed 
description of analyses will be provided in a Statistical Analysis Plan (SAP) that will be 
finalized and approved by the Scientific Committee before the database lock. 
Statistical analysis will be performed by eXYSTAT under the supervision of the sponsor and 
the Scientific Committee. All statistical analyses will be performed in accordance with the SAP 
using SAS® release 9.4 or higher. All computer programs and macros will be developed and 
validated according to eXYSTAT standard operating procedures. Internal review by the lead 
statistician in charge of the project will be performed, including SAS® codes and programming, 
SAS® logs and outputs and edition of the TFL. Then, an external review of the TFL will be 
performed by another statistician and the medical writer. 
Quantitative data will be summarized by the following descriptive statistics: number of data 
available, number of missing data, mean, standard deviation, first quartile (Q1), median, third 
quartile (Q3), minimum and maximum. When relevant, the associated 95%confidence interval 
will be also presented. 
Qualitative data will be summarized by the following descriptive statistics: number of data 
available, number of missing data, frequency and percentage for each modality. The 
percentages will be based on the number of data available. When relevant, the associated 95% 
confidence interval will be also presented. 
No interim analysis is planned for this study. 
All the analyses will be presented in 3 columns according to subgroups: autonomy, without 
autonomy, and total. 
Missing data will not be replaced and only observed data will be analysed. 
The risk 1 error (α) will be set to 5% (two-sided). 
Study populations 
Included set (IS) 
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The full analysis set will include all included patients with or without assessment at the of the 
week 4 visit. 
Full Analysis set (FAS) – Primary population 
The full analysis set will include all included patients for whom at least one assessment at the 
of the week 4 visit is available. 
Number and percentage of patients included in the FAS will be described with the reason for 
non-inclusion in the FAS. Number and percentage of patients prematurely discontinued with 
the reason for premature discontinuation will be also provided. 
Patient and disease characteristics 
Patient and disease characteristics will be described at inclusion overall and per subgroup in the 
IS and FAS: patient age at diagnosis and inclusion, haemophilia severity according to the 
residual level of Factor VIII or Factor IX, disease complications over the last 12 months 
(haemorrhagic events, synovitis, chronic arthritis), factor VIII or Factor IX perfusions [age at 
first perfusion, inhibitors’ history, immune tolerance (yes/no, success or failure), current 
number of weekly perfusions], daily use of analgesics NSAIDs, and/or anxiolytics for at least 
3 months, socio-professional activity and education level of patients (or parents). 
Drug therapies used by patients for pain and anxiety 
Drug therapies used by patients for pain and anxiety will be coded using the WHO Drug 
dictionary. Results will be presented on FAS overall and by subgroup 
Drug therapies used by patients for pain and anxiety will be described as follows: 
• Number and percentage of patients with at least one drug therapy for pain and anxiety 
• For each indication, number, and percentage of patients with at least one drug therapy for 
pain and anxiety 
• Drug therapy for pain and anxiety will also be tabulated by the 4th level of the Anatomic 
Therapeutic Class (ATC4) and Preferred-Term (PT) 
Study analysis 
All analyses will be performed in the FAS population. 
Quantitative paired variables will be compared to assess the change from baseline significance 
using the Wilcoxon signed rank test. Changes will be associated with their exact 95% two sided 
Clopper-Person confidence interval. 
Then means absolute variation before and after the virtual-reality based solution will be 
described using an analysis of covariance adjusted on baseline value and group (acquired 
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autonomy or without autonomy). This model will estimate the LSMeans with the associated 
two-sided 95% confidence interval and p value. 
The percentage of responder patients for each scale (pain, anxiety, depression, quality of life, 
adherence to treatment, satisfaction, willingness to continue and preference) will be presented 
with the associated 95% two-sided exact confidence interval. 
If the p value is significant for at least one endpoint among pain, anxiety, depression or quality 
of life, this proof-of-concept study will be considered as positive. 
Adverse Events 
AE term will be assigned to the lowest level term (LLT), and a preferred term (PT) will be 
classified by a high-level term (HLT), a high-level group term (HLGT) and a system organ 
class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA) 
thesaurus. The last available version at the time of database lock of MedDRA will be used. 
A listing of adverse events sorted by SOC will be provided with the overall information 
including relation to a drug or to the medical device. 
4.7 
Limitations of the Research Methods 
For this proof-of-concept study, no representativeness of the studied population is required. 
After the test phase conducted in 8 patients, only a limited number of 34 eligible patients will 
be included (17 patients with acquired autonomy and 17 patients without autonomy). No 
handling for multiplicity is considered for the analysis of the different endpoints. 
However, 
• The six participating centres, fully involved in the management of haemophilia patients 
and prophylactic Factor VIII or Factor IX infusions, will be located in different French 
areas (Lyon Reference Centre; Clermont Ferrand, Bordeaux, Toulouse, Nantes, and 
Strasbourg) 
• Physicians will be asked to include consecutive eligible patients from the study 
implementation. 
Patients with haemophilia having participated in the test phase of the study in the coordinator 
centre will be solicited to participate in the clinical study itself. To limit the bias related to their 
prior exposure to the VR-based solution during a single visit, a period of at least four months 
will be requested between the two phases of the study, with no use of the VR-based solution. 
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5 PROTECTION OF HUMAN SUBJECTS 
5.1 
Sponsor’s Responsibilities 
5.1.1 Compliance with Relevant Guidelines 
The study will be conducted in full conformance with all relevant French, European and 
international regulations applicable to interventional researches including the International 
Conference on Harmonisation (ICH) guideline for Good Clinical Practice. 
The VR-based solution to be studied is a class I medical device and it is compliant with the 
Regulation (EU) 2017/745 applicable since 26 May 2021. 
This VR-based solution could lead clinicians to changes in the current management of 
haemophilia patients (e.g.: potential decrease in analgesics or anxiolytics). In addition, the last 
study visit at Week 4 is required to assess the overall evolution of treatment burden, including 
for the hospital team. This study is therefore in accordance with the reference MR-001 method 
defined in France for interventional studies with minimal risks and constraints (This category 
of studies id defined in the decree of April 12th, 2018; NOR: SSAP1810239A; JORF No 0089, 
dated on 2018, April 17). 
The sponsor will ensure that local regulatory authority requirements are met before the start of 
the study. 
5.1.2 Insurance 
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start 
of the study. 
5.1.3 Study Suspension, Termination and Completion 
The sponsor may decide to suspend or prematurely terminate the study at any time for whatever 
reason; such a decision will be communicated to investigator(s)/sites(s), regulatory agencies, 
Ministries of Health (if required) and Institutional Review Boards/Ethics Committees 
(IRBs/ECs) in writing as applicable. Conversely, should the investigator/site decide to 
withdraw from execution of the study, they will communicate their intention immediately in 
writing to the sponsor. Additionally, the discontinuation of a registered study which has been 
posted to a designated public website will be updated accordingly. 
5.2 
Investigator’s Responsibility 
5.2.1 Compliance with Relevant Guidelines 
The investigator must undertake to perform the study in accordance with applicable regulatory 
requirements and guidelines. 
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It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable participants within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licences and certifications necessary to demonstrate such 
qualification. Curriculum vitae for these individuals as well as the investigator are provided to 
the study sponsor (or designee) before starting the study. 
5.2.2 Protocol Adherence and Investigator Agreement 
The investigator must adhere to the protocol as detailed in this document. The investigator is 
responsible for enrolling only those participants who have met protocol eligibility criteria. The 
investigator is required to sign the protocol signature page to confirm acceptance and 
willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at the site, the investigator will promptly 
inform the sponsor and the IRBs/ECs and provide them with a detailed written explanation. 
Upon study completion, the sponsor will provide the investigator, IRB/EC, and Regulatory 
Agency with final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable contract research 
organization (CRO), investigator, or, for multicentre studies, the coordinating investigator 
according to national provisions, and will be documented in the investigator agreement. 
5.2.3 Documentation and Retention of Records 
5.2.3.1 Case Report Forms 
eCRFs are to be completed through use of a Sponsor-designated EDC system. Centres will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with instructions 
from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be reviewed 
and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a readable 
format (PDF/A) that must be kept with the study records. 
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5.2.3.2 Recording, Access, and Retention of Sources of Data and Study Documents 
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records kept at 
pharmacies, laboratories, and medico-technical departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the Trial Monitoring Plan. This includes any protocol data to be entered directly into 
the eCRFs (i.e., no prior written or electronic record of the data) and considered source data. 
Source documents that are required to verify the validity and completeness of data entered into 
the eCRFs must not be obliterated or destroyed and must be retained per the policy for retention 
of records. 
Records and documents pertaining to the conduct of this study including eCRFs, electronic 
PRO data, Informed Consent Form, and medication inventory records, must be retained by the 
Principal Investigator for 2 years after the last publication of the study results or until the 
signature of the final study report. After that period of time, the documents may be destroyed, 
subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor. Written notification 
should be provided to the Sponsor prior to transferring any records to another party or moving 
them to another location, according to national regulations. 
5.2.3.3 Audit/Inspection 
Site visits may be conducted by the Sponsor or an authorized representative for inspection of 
study data, subjects’ medical records, and eCRFs. The investigator will permit national and 
local health authorities; Sponsor monitors, representatives, and collaborators; and the IRBs/ECs 
to inspect facilities and records relevant to this study. 
5.3 
Ethical Considerations 
5.3.1 Informed Consent 
The Sponsor’s sample Informed Consent Form will be provided to each centre. 
The investigator or authorized designee will explain to each patient the objectives, methods, 
and potential risks associated with each procedure. Patients will be told that they are free to 
refuse to participate and may withdraw their consent at any time for any reason. 
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The Consent Form must be signed and dated by the patient (or his legal guardians if <18 years) 
before his/her participation in the study. Consent Forms are adapted according to the age of 
patients: 
• For the test phase, two Consent Form are available: for children between 6 and 18 years, 
and for adults (≥18 years) 
• For the clinical study itself, three Consent Forms are available: for children between 6 
and 12 years, for children between 12 and 18 years, and for adults (≥18 years). 
The case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained prior to participation in the study. 
The Consent Form should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the patient to participate. 
The final revised IRB/EC-approved Consent Form must be provided to the Sponsor for health 
authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised Consent 
Forms, the case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained using the updated/revised Consent 
Form for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient his legal guardians if <18 
years. All signed and dated Consent Forms must remain in each patient’s study file or in the 
site file and must be available for verification by study monitors at any time. 
5.3.2 Institutional Review Board or Ethics Committee 
This protocol, the Informed Consent Form, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Sponsor and reviewed 
and approved by the IRB/EC before the study is initiated. In addition, any patient recruitment 
materials must be approved by the IRB/EC. Approval by the IRB/EC will be provided to the 
ANSM with the study synopsis. 
The Sponsor is responsible for providing written summaries of the status of the study to the 
IRB/EC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. The Sponsor is also responsible for promptly informing 
the IRB/EC of any protocol amendments. 
5.3.3 Privacy and Confidentiality 
The privacy rights of individuals and the confidentiality of medical records will be protected in 
accordance with all applicable laws, regulations and guidelines. 
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Sites and laboratories or entities providing support for this study, which process personal data 
relating to EU-based subjects, must comply with the EU General Data Protection Regulation 
and with the French law called “Loi Informatique et Libertés” in performing all their processing 
activities in connection with this study. 
After subjects have been informed about how their data will be processed and have consented 
in written to take part in the study, the sponsor and/or its representatives reviews their medical 
records and data collected during the study. These records and data may, in addition, be 
reviewed by others including the following: independent auditors who validate the data on 
behalf of the sponsor; third parties with whom the sponsor may develop, national or local 
regulatory authorities; and the IRB/EC which gave approval for the study to proceed. The 
sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations and guidelines to maintain the 
confidentiality of subjects’ identities. 
No directly identifiable patient data will be collected in the CRF completed by investigators 
and the VR-based solution (VAS for pain an anxiety completed by patients or relatives). 
Subjects are assigned a unique identifying number and the number of the virtual-reality based 
solution provided to patients at the inclusion visit. However, their year of birth will also be 
collected. Investigators will keep a list of codes to identify enrolled patients and their medical 
files. This list will never be conveyed to the Sponsor. 
The results of studies – containing subjects’ unique identifying numbers, relevant medical 
records and year of birth – will be recorded. 
The sponsor may transfer data collected in this study to its affiliates, collaborators, licensees 
and other companies and organizations working with or for the sponsor in connection with these 
purposes. No data will be conveyed outside the European Union. 
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6 DATA MANAGEMENT AND QUALITY CONTROL 
6.1 
Data Management 
Data management of this study will be performed by the contract research organization (CRO) 
eXYSTAT, under the supervision of the Sponsor. Data management notably includes quality 
checking of the data. Data entered manually will be collected via EDC through use of eCRFs. 
Centres will be responsible for data entry into the EDC system. In the event of discrepant data, 
eXYSTAT will request data clarification from the centres, which the centres will resolve 
electronically in the EDC system. 
In addition, an ePRO will be developed as a specific module of the VR-based solution to collect 
subject’s data. At the end of the data collection, patient data on the virtual-reality based solution 
during the study will be transferred (encrypted cvs file) by Deepsen to the CRO in charge of 
biometry. 
The complete data management process (data capture, data entry, data validation, checks on 
plausibility, query handling, data editing after entry, coding, data base closure, etc.) will be 
defined in advance within a data management plan/data validation plan together with a 
description of the personnel responsible for data entry. 
The Sponsor will perform oversight of the data management of this study, including approval 
of eXYSTAT’s data management plans and specifications. Collection of patient indirect 
personal data between the inclusion and Week 4 visits will be transferred (encrypted cvs files) 
by Deepsen to the CRO in charge of biometry at the end of the study, and then from eXYSTAT 
to the Sponsor at the final locked version of the database. eXYSTAT standard procedures will 
be used to handle and process the electronic transfer of these data. 
A validated, electronic database will be employed from the EDC system. An audit trail of all 
changes to this database, including the date, reason for the data change and who made the 
change, will be maintained within the same database. The audit trail will be part of the archived 
data at the end of the study. 
System backups for data and records retention for the study data will be consistent with the 
eXYSTAT’s standard procedures. Electronic Case Report Forms (eCRF)/ Electronic Patient 
Reported Outcomes (e-PRO) 
eCRFs are to be completed through use of the EDC system. Centres will receive training and 
have access to a manual for appropriate eCRF completion. eCRFs will be submitted 
electronically to the Sponsor and should be handled in accordance with instructions from the 
Sponsor. 
ePROs are to be completed through use of the dedicated part of the VR-based solution by 
subjects. To ensure confidentiality and security of the data, personal logins will be used by 
patients on the virtual-reality based solution. 
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To ensure confidentiality, security of the data personal logins and passwords will be used. This 
process allows the restriction of system access to authorized personnel only. The list of 
authorized personnel for centres and study team will be documented. The system will ensure a 
traceability of any data modified, the date of modification, the reason for modification and 
identification of the corresponding user via the audit-trail. Each confirmation or correction of 
data must be performed by authorized site staff on the eCRF with the reason of correction. 
After completion and cleaning process of data and before database lock, each eCRF will be 
signed by the investigator using electronic signature function available on the eCRF (entering 
login and password). This action will ensure that the investigator confirms the accuracy, 
completeness, and legibility of the data collected on the eCRF. 
At the end of the study, the investigator will receive patient data for his or her site in a readable 
format (PDF/A) on a compact disc that must be kept with the study records. Acknowledgement 
of receipt of the compact disc is required. 
6.2 
Data Handling 
The final data will be transferred to the SAS-system for data analyses in accordance with the 
SAP. The MedDRA dictionary will be used for coding of AEs. Concomitant medication will 
be coded using the World Health Organization Drug Dictionary Anatomical Therapeutic 
Chemical code. 
6.2.1 Deviations from the Protocol 
Deviations from the protocol will be judged during the study and/or during the Data review will 
classify protocol deviations (major/minor) for statistical analysis. 
6.2.2 Data Quality Assurance 
Throughout the study, remote monitoring will be performed by eXYSTAT (regular contacts 
with the investigators/nurses) to ensure an ongoing quality control (adherence to the protocol, 
completeness, consistency, and accuracy of the data being entered on the eCRF). Remote 
monitoring will not include access to nominative data on patients. Investigators agree to 
cooperate to ensure that any problems detected in the course of these remote activities are 
resolved. 
A study monitor may visit centres in accordance with the monitoring plan and review the 
CRF/eCRF data against the source data for completeness and accuracy. Discrepancies between 
source data and data entered on the CRF/eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is enrolled, it is expected that site personnel 
will complete the CRF/eCRF entry within approximately 3 business days of the subject’s 
routine consultation/observation. 
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6.3 
Database Archiving and Study Document Retention 
All research documents, including all source data, and analytical data sets, all protocol versions, 
correspondence pertaining to the study (i.e. between sponsor, investigators, suppliers, 
regulators and scientific community), standard operating procedures, quality control, 
monitoring or audit reports, informed consent releases, copies of signed IRB/EC and other 
external reviewer reports, data analysis plan, computer programs, statistical outputs and study 
report and/or publications, shall be securely stored and archived after completion of the study. 
The archival material should be sufficiently detailed to permit re-editing and re-analysis. 
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7 MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ 
ADVERSE REACTIONS AND VR-BASED SOLUTION INCIDENTS 
7.1 
Adverse Events/ Adverse Reactions 
7.1.1 Adverse Events to be Collected 
Only AEs related to the Factor VIII or Factor IX perfusions and to the VR-based solution, and 
all SAEs must be reported in this study. Consequently, non-serious AEs not related to the Factor 
VIII or Factor IX perfusions and to the VR-based solution will be not reported. Indeed, no drugs 
are to be studied in this interventional study. 
The healthcare professional or patient shall be informed of the possibility to report direct to the 
relevant Takeda Pharmacovigilance department or national pharmacovigilance reporting 
system any adverse reactions not being collected as part of the study. These will be treated as 
spontaneous reports and independent of the study. 
7.1.2 Definitions 
7.1.2.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, a new disease or worsening in severity or frequency 
of a concomitant disease, temporally associated with the use of a medicinal product, whether 
or not the event is considered causally related to the use of the product. 
Although abnormal laboratory values are typically not considered AEs, the following 
considerations may result in an abnormal laboratory value being considered an AE: 
• a laboratory test result that meets the criteria for a serious adverse event (SAE) 
• a laboratory test result that requires the subject/patient to receive specific corrective 
therapy 
• a laboratory abnormality that leads to discontinuation of therapy 
• a laboratory abnormality that the healthcare provider considers to be clinically 
significant. 
7.1.2.2 Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
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• results in death. Note that death is an outcome of an event. The event(s) causing death 
should be recorded 
• in the view of the healthcare provider, places the subject/patient at immediate risk of 
death (a life-threatening event); however, this does not include an event that, had it 
occurred in a more severe form, might have caused death 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• results in a congenital anomaly/birth defect 
• any other medically important event that, in the opinion of the healthcare provider, may 
jeopardize the subject/patient or may require intervention to prevent one of the other 
outcomes listed in the definition above. (Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or 
convulsions occurring at home that do not require an inpatient hospitalization.) 
7.1.2.3 Adverse Drug Reactions 
An adverse drug reaction (ADR) is an AE for which there is at least a reasonable suspicion of 
a causal relationship between an AE and a suspected medicinal product. 
7.1.2.4 Product Quality Issues 
A Product Quality Issue (PQI) refers to defects related to the safety, identity, strength, quality, 
or purity of the product or with the physical characteristics, packaging, labelling, or design of 
the product. 
7.1.2.5 Special Situation Reports 
A Special Situation Report (SSR) includes any of the following events: 
• pregnancy: any case in which a pregnant patient is exposed to a Takeda Product or in 
which a female patient or female partner of a male patient becomes pregnant following 
treatment with Takeda Product. Exposure is considered either through maternal 
exposure or via semen following paternal exposure 
• breastfeeding: infant exposure from breast milk 
• overdose: all information of any accidental or intentional overdose 
• drug abuse, misuse or medication error: all information on medicinal product abuse, 
misuse or medication error (potential or actual) 
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• suspected transmission of an infectious agent: suspected (in the sense of confirmed or 
potential) transmission of an infectious agent by a medicinal product 
• lack of efficacy of Takeda Product 
• accidental/occupational exposure 
• use outside the terms of the marketing authorization, also known as “off-label” 
• use of falsified medicinal product 
• use of counterfeit medicinal product 
• drug–drug interactions and drug–food interactions 
• inadvertent or accidental exposure with or without an AE 
• unintended benefit. 
A SSR should be reported even if there is no associated AE. 
7.1.2.6 Relationship of an Adverse Event to Studied Drug(s) 
The assessment of the relationship of an AE to the drug(s) and VR-based solution is based on 
the consideration of all available information about the event, including temporal relationship 
to drug administration, recognized association with drug product/class, pharmacological 
plausibility and alternative aetiology (e.g., underlying illness, concurrent conditions, 
concomitant treatments). 
• Related (yes): an AE that follows a reasonable temporal sequence from administration of 
the medication, vaccine or device (including the course after withdrawal of the medication), 
and for which a causal relationship is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out, although factors other than the medication, vaccine or device, such as 
underlying diseases, complications, concomitant drugs and concurrent treatments, may also 
have contributed. 
• Not related (no): an AE that does not follow a reasonable temporal sequence from 
administration of the medication, vaccine or device and/or that can reasonably be explained 
by other factors, such as underlying disease, complications, concomitant drugs and 
concurrent treatments. 
7.1.3 Reporting 
7.1.3.1 Collection and Recording of Adverse Events, Special Situation Reports (SSRs) and 
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Product Quality Issues (PQIs) 
Collection and recording of SAEs, AEs, SSRs and PQIs will commence once the study 
participant has provided informed consent. 
The investigator should notify Takeda within 1 working day of becoming aware of a fatal or 
life-threatening SAE, and other SAEs, and within 7 calendar days for all other events/issues. 
This is typically achieved by the investigator completing the AE report pages of an eCRF or by 
submitting an AE Report Form to Takeda. 
The investigator may be contacted by Takeda to obtain additional information on the event or 
for data clarification. The investigator shall make best effort to obtain the requested additional 
information and will notify Takeda within 1 working day of obtaining the additional 
information for a fatal or life-threatening SAE, and other SAEs, and within 7 calendar days for 
all other events/issues. 
7.1.3.2 Reporting of Adverse Drug Reactions to Regulatory Agencies and IRB/EC 
Takeda is responsible for reporting serious and non-serious ADRs suspected of being related to 
Takeda products to regulatory authorities. The investigator is responsible for reporting ADRs 
to the IRB/EC, if required by national law or regulation. The investigator shall maintain records 
of all such submissions. 
7.2 
VR-Based Solution Incidents 
7.2.1 Definition of Incidents 
An incident is a minor hardware and/or software event that prevents the correct use of the 
solution in its context. The incidents are mainly associated with misuse by the user of the 
solution or with a software and/or hardware failure. 
7.2.2 Reporting of Incidents 
A specific document with solutions for the most current problems potentially encountered when 
using the VR-based solution will be provided by investigators to patients at inclusion (see 
additional documents). 
For other incidents, patients will be asked to inform as soon as possible the investigator in order 
to receive another material. 
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8 PLAN FOR DISSEMINATION AND COMMUNICATION OF STUDY 
RESULTS 
8.1 
Public Posting and Disclosure of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites as 
required by regional regulatory requirement(s). 
8.2 
Study Results/Publications 
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral or other form. 
After the research data are finalized and become available, the scope, planning and development 
of the publication(s), and how such publication(s) will be reviewed and amended is all in 
accordance with The International Society for Medical Publication Professionals (ISMPP) 
Good Publications Practice (GPP3). Unless otherwise required by the scientific journal to which 
the publication is submitted, or the forum in which it is presented, authorship will comply with 
the International Committee of Medical Journal Editors (ICMJE) Recommendation for the 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals. 
8.3 
Submission of Summary of Final Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees 
The sponsor will provide a summary of the final study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s), as appropriate. The 
sponsor will provide the ECs with a copy of the same summary. 
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9 REFERENCES 
Arane K, Behboudi A, Goldman RD. Virtual reality for pain and anxiety management in 
children. Can Fam Physician 2017;63(12):932-4 
Coppola A, Di Capua M, Di Minno MN, et al. Treatment of hemophilia: a review of current 
advances and ongoing issues. J Blood Med 2010;1:183-95. 
Dascal J, Reid M, IsHak WW, et al. Virtual reality and medical inpatients: A systematic review 
of randomized, controlled trials. Innov Clin Neurosci 2017;14(1-2):14-21 
Dunn A, Patterson J, Biega CF, et al. A novel clinician-orchestrated virtual reality platform for 
distraction during pediatric intravenous procedures in children with hemophilia: randomized 
controlled trial. JMIR Serious Games 2019;7(1):e10902 
Feldman BM, Pai M, Rivard GE, et al. Tailored prophylaxis in severe hemophilia A: interim 
results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study. J Thromb 
Haemost 2006;4(6):1228-36 
Feldman BM, Rivard GE, Babyn P, et al. Tailored frequency-escalated primary prophylaxis for 
severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study 
longitudinal cohort. Lancet Haematol 2018;5(6):e252-e260 
Fischer K, Collins PW, Ozelo MC, et al. When and how to start prophylaxis in boys with severe 
hemophilia without inhibitors: communication from the SSC of the ISTH. J Thromb Haemost 
2016;14(5):1105-9. 
Hoffman HG, Patterson DR, Carrougher GJ, et al. Effectiveness of virtual reality-based pain 
control with multiple treatments. Clin J Pain. 2001;17(3):229-35 
Hoffman HG, Chambers GT, Meyer WJ 3rd, et al. Virtual reality as an adjunctive non- 
pharmacologic analgesic for acute burn pain during medical procedures. Ann Behav Med 
2011;41(2):183-91 
Iorio A, Stonebraker JS, Chambost H, et al. Establishing the prevalence and prevalence at birth 
of hemophilia in males: A meta-analytic approach using national registries. Ann Intern Med 
2019;171(8):540-6 
Koller D, Goldman RD. Distraction techniques for children undergoing procedures: a critical 
review of pediatric research. J Pediatr Nurs 2012;27(6):652-81 
Le Du K, Septans AL, Maloisel F, et al. A new option in pain prevention with bliss, a therapeutic 
virtual reality solution in bone marrow biopsy context: Results of a French open-label 
multicenter randomized phase II/III study (REVEH Trial). Journal of Clinical Oncology 
2021;39(15 Suppl):6573 
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Malloy KM, Milling LS. The effectiveness of virtual reality distraction for pain reduction: A 
systematic review. Clin Psychol Rev 2010;30(8):1011-8 
Manco-Johnson M. Comparing prophylaxis with episodic treatment in haemophilia A: 
implications for clinical practice. Haemophilia 2007;13 Suppl 2:4-9 
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to 
prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357(6):535-44 
Manco-Johnson MJ, Lundin B, Funk S, et al. Effect of late prophylaxis in hemophilia on joint 
status: a randomized trial. J Thromb Haemost 2017;15(11):2115-2124 
Manucci PM, Tuddenham EG. The hemophilias-from royal genes to gene therapy. N Engl J 
Med 2001;344(23):1773-9 
Meunier S, Trossaert M, Berger C, et al. French guidelines. Long-term prophylaxis for severe 
haemophilia A and B children to prevent haemophiliac arthropathy. Arch Pediatr 
2009;16(12):1571-8 
PNDS Hémophilie. Centre de Référence Hémophilie et autres déficits constitutionnels en 
protéines 
de 
la 
oagulation. 
2019, 
version 
3. 
https://www.has- 
sante.fr/upload/docs/application/pdf/2019-10/pnds_hemophilie_argumentaire_10.10.19.pdf. 
Accessed 27 July 2021 
Réseau FranceCoag. Cohorte française des patients atteints de maladies hémorragiques par 
déficits héréditaires en protéines de la coagulation. Données descriptives 2005. 
https://www.vie-publique.fr/sites/default/files/rapport/pdf/064000522.pdf. Accessed 27 July 
2021 
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of 
hemophilia. Haemophilia 2013;19(1):e1–47. 
Stonebraker JS, Bolton-Maggs PHB, Brooker M, et al. The World Federation of Hemophilia 
Annual Global Survey 1999-2018. Haemophilia 2020;26(4):591-600 
Wiederhold MD, Wiederhold BK. Virtual reality and interactive simulation for pain distraction. 
Pain Med.2007;8:182-8 
World Federation of Hemophilia. Report of the Annual Global Survey. 2018. 
http://www1.wfh.org/publications/files/pdf-1731.pdf. Accessed 27 July 2021 
World Federation of Hemophilia. WFH Guidelines for the Management of Hemophilia, 3rd 
edition. https://onlinelibrary.wiley.com/doi/10.1111/hae.14046. Accessed 27 July 2021 
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10 APPENDICES 
10.1 Studied VR-Based Solution 
The VR-based solution has been designed to provide haemophilia patients and accompanying 
persons (caregivers / family) with a digital tool able to help them reduce the burden of disease 
and treatment. With the use of a VR headset or a smartphone, patients and accompanying 
persons have access to 3 therapeutic modules, each designed to respond to a specific use in the 
care protocol: 
10.1.1 Game Module 
This module is a therapeutic game designed to distract and relax patients, during their regular 
medical cares related to their haemophilia problems. Busy playing, patients feel less pain related 
to this procedure. The game is based on a hypnotherapeutic speech, inviting the player to 
transform / make disappear his stress and/or pain. This speech, transposed into the game 
mechanics, is carried by a voice-over. We distinguish the following 4 phases of play: 
• 
Observation game (tutorial): the player is asked to identify the objects to be transformed. 
• 
Shooting game: the player transforms / makes disappear objects. 
• 
Painting game: the player repopulates the environment. 
• 
Shooting game: the player shoots bubbles, haemoglobin cells that he loads with clotting 
factor. 
This module is started by the accompanying person. It has an indefinite duration, allowing to 
manage the time of the session. An end-of-game button, on the tablet, allows the caregiver to 
activate it once the injection is over. 
10.1.2 Relaxation Module 
This module consists of reducing the stress and the anxiety of parents and/or children in the 
moments preceding the prophylaxis cares. Parents in the phase of learning to inject the clotting 
factor to their child, go through great phases of anxiety. We offer 20-minutes sessions for 
parents to reduce their stress and anxiety, with a 360 audio-visual immersive bubble to drive 
them out of their stress zone. These sessions are structured as follows: 7 minutes of guided 
cardiac coherence type respiratory exercise (10-second cycle). 13 minutes of hypnotic 
relaxation 
10.1.3 Learning Module 
The objective of this module is to serve as a reassurance support for patients or parents in the 
learning phase of intravenous injection of clotting factor. Whether to inject or self-inject the 
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clotting factor, VR simulation allows Patient or parents to relive at their own tempo, and as 
many times as necessary, the different stages of the care protocol to make it a routine. 
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10.3 Questionnaires/Scales Used for Assessments 
The following scales/assessments will be utilized in this study: 
 
Full Title of Scale/Assessment 
Version 
Number 
Date Issued 
MMAS-4 
Final 
2021/09/20 
EQ‐ 5D‐ 3L (or EQ‐ 5D‐ Y for youth) 
1.2 
2012 
STAI-Y 
NA 
1977 
PHQ-9 
NA 
PGIC 
1.0 
2004/03/19 
A separate master file containing each scale/assessment listed above will be provided to the 
centre. 
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