An 18-month Low-interventional Prospective, Multicentre Study to Assess Joint Outcomes in Patients With Haemophilia A or B on Prophylaxis With Efmoroctocog Alfa or Eftrenonacog Alfa
Phase: PHASE4
Conditions: Hemophilia A, Hemophilia B
Sponsor: Swedish Orphan Biovitrum



Sobi 
 
Eftrenonacog alfa/Alprolix® - Efmoroctocog alfa/Elocta® 
Clinical Study No: Sobi.HAEM89-007 
Confidential 
 
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Table of contents 
1 
Synopsis ............................................................................................................................ 6 
2 
Abbreviations and definition of terms............................................................................. 10 
2.1 
List of Abbreviations and definitions ......................................................................... 10 
3 
Ethics ............................................................................................................................... 12 
3.1 
Independent ethics committee .................................................................................... 12 
3.2 
Ethical consideration of the study .............................................................................. 12 
3.3 
Patient information and consent ................................................................................. 12 
4 
Introduction ..................................................................................................................... 13 
4.1 
Background ................................................................................................................ 13 
4.2 
Study rationale ............................................................................................................ 15 
4.3 
Potential risks and benefits ......................................................................................... 16 
5 
Study objectives and endpoints ....................................................................................... 16 
5.1 
Primary objective ....................................................................................................... 16 
5.1.1 
Primary endpoint ................................................................................................... 16 
5.2 
Secondary objectives .................................................................................................. 16 
5.2.1 
Secondary endpoints supporting the secondary objective(s) ................................. 17 
5.3 
Exploratory objectives – florio HAEMO sub-study ................................................... 17 
5.3.1 
Exploratory endpoints ............................................................................................ 17 
6 
Investigational plan ......................................................................................................... 18 
6.1 
Overall study design and plan .................................................................................... 18 
6.2 
Discussion of study design, including the choice of control groups .......................... 19 
6.2.1 
Patient input into design ........................................................................................ 19 
6.3 
Selection of study population ..................................................................................... 20 
6.3.1 
Inclusion criteria .................................................................................................... 20 
6.3.1.1 florio HAEMO sub-study ................................................................................. 20 
6.3.2 
Exclusion criteria ................................................................................................... 20 
6.3.3 
Withdrawal of patients from study ........................................................................ 21 
6.3.3.1 Withdrawal from study ..................................................................................... 21 
6.3.4 
Replacement of withdrawn patients....................................................................... 21 
6.4 
Study treatment(s) and concomitant therapy .............................................................. 21 
6.4.1 
Prior and concomitant therapy ............................................................................... 22 
6.4.2 
Treatment compliance ........................................................................................... 22 
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Eftrenonacog alfa/Alprolix® - Efmoroctocog alfa/Elocta® 
Clinical Study No: Sobi.HAEM89-007 
Confidential 
 
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6.5 
Effectiveness and safety assessments ......................................................................... 23 
6.5.1 
Study schedule ....................................................................................................... 23 
6.5.1.1 Schedule of events ............................................................................................ 23 
6.5.1.2 Visit 0/1 – Enrolment/Baseline ......................................................................... 27 
6.5.1.3 Visit 2 – Month 6 .............................................................................................. 27 
6.5.1.4 Visit 3 – Month 12 ............................................................................................ 27 
6.5.1.5 Visit 4 – Month 18/End of study ....................................................................... 27 
6.5.2 
Demography .......................................................................................................... 27 
6.5.3 
Haemophilia history............................................................................................... 28 
6.5.4 
Medical and surgical history .................................................................................. 28 
6.5.5 
Surgical and other interventions ............................................................................ 28 
6.5.6 
Target and impaired joints ..................................................................................... 29 
6.5.7 
Concomitant therapy .............................................................................................. 29 
6.5.8 
Bleeding episodes .................................................................................................. 29 
6.5.9 
Haemophilia treatment........................................................................................... 29 
6.5.10 
Effectiveness assessments ..................................................................................... 30 
6.5.10.1 Ultrasound joint examination – HEAD-US ...................................................... 30 
6.5.10.2 Functional joint examination – HJHS ............................................................... 30 
6.5.10.3 Patient-Reported Outcomes .............................................................................. 31 
6.5.11 
Exploratory endpoints - florio HAEMO sub-study ............................................... 33 
6.5.11.1 florio HAEMO patient questionnaire ................................................................ 33 
6.5.12 
Safety assessments ................................................................................................. 34 
6.5.12.1 Adverse events .................................................................................................. 35 
6.5.12.2 Abnormal test findings, pre-existing conditions, procedures ........................... 35 
6.5.12.3 Lack of efficacy ................................................................................................ 36 
6.5.12.4 Serious adverse event ........................................................................................ 36 
6.5.12.5 Hospitalization .................................................................................................. 36 
6.5.12.6 Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................... 36 
6.5.12.7 Adverse event reporting period ......................................................................... 37 
6.5.12.8 Obtaining and recording adverse event information ......................................... 37 
6.5.12.9 Severity assessment .......................................................................................... 37 
6.5.12.10 Causality assessment .................................................................................... 37 
6.5.12.11 Adverse events of special interest ................................................................ 38 
6.5.12.12 Serious adverse event reporting.................................................................... 38 
6.5.12.13 Follow-up of unresolved adverse events ...................................................... 38 
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Eftrenonacog alfa/Alprolix® - Efmoroctocog alfa/Elocta® 
Clinical Study No: Sobi.HAEM89-007 
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6.5.12.14 Exposure during pregnancy and breastfeeding ............................................. 39 
6.5.12.15 Appropriateness of safety measurements ..................................................... 39 
7 
Quality control and quality assurance ............................................................................. 39 
8 
Statistical plan ................................................................................................................. 40 
8.1 
Determination of sample size ..................................................................................... 40 
8.2 
Definition of study populations .................................................................................. 40 
8.3 
Overall statistical and analytical plan ......................................................................... 41 
8.3.1 
General statistical issues ........................................................................................ 41 
8.3.2 
Demographics and baseline characteristics ........................................................... 41 
8.3.3 
Analysis related to primary objective .................................................................... 41 
8.3.4 
Analysis related to secondary objective ................................................................ 43 
8.3.5 
Analysis related to exploratory objectives ............................................................. 44 
8.3.6 
Analysis of safety and tolerability data ................................................................. 44 
8.3.6.1 Adverse events .................................................................................................. 44 
8.3.7 
Interim analysis ...................................................................................................... 44 
8.3.8 
Handling of missing data ....................................................................................... 44 
9 
Data collection, handling and record keeping ................................................................. 45 
9.1 
Data standards ............................................................................................................ 45 
9.2 
Case report form ......................................................................................................... 45 
9.3 
Source data ................................................................................................................. 46 
9.4 
Protocol deviations ..................................................................................................... 46 
9.5 
Database closure ......................................................................................................... 47 
9.6 
Record retention ......................................................................................................... 47 
9.7 
Data protection ........................................................................................................... 48 
10 
End of study .................................................................................................................... 48 
11 
Sponsor’s discontinuation criteria ................................................................................... 48 
12 
Dissemination and publication of results ........................................................................ 48 
13 
Reference list ................................................................................................................... 49 
Appendix 1 
Study Administrative Structure ............................................................................. 52 
Appendix 2 
florio HAEMO Patient Questionnaire ................................................................... 53 
Appendix 3 
florio HAEMO Caregiver Questionnaire............................................................... 55 
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Eftrenonacog alfa/Alprolix® - Efmoroctocog alfa/Elocta® 
Clinical Study No: Sobi.HAEM89-007 
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Table of tables 
Table 1 
PRO questionnaires ................................................................................. 32 
Table 2 
florio HAEMO patient questionnaire ...................................................... 34 
Table 3  
Determination of sample size .................................................................. 40 
Table 4 
HEAD-US scoring method ...................................................................... 43 
 
Table of figures 
Figure 1 
Study Design ........................................................................................... 19 
 
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Eftrenonacog alfa/Alprolix® - Efmoroctocog alfa/Elocta® 
Clinical Study No: Sobi.HAEM89-007 
Confidential 
 
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1 
Synopsis 
STUDY 
IDENTIFIERS 
 
Title of study: 
An 18-month low-interventional prospective, multicentre study to assess joint outcomes 
in patients with haemophilia A or B on prophylaxis with efmoroctocog alfa or 
eftrenonacog alfa 
Clinical study number: 
Sobi.HAEM89-007 
Type of study: 
Therapeutic use 
STUDY 
OBJECTIVES 
 
Primary objective: 
To evaluate the overall joint status as detected by ultrasound (US) in haemophilia A and 
B patients treated with efmoroctocog alfa (rFVIIIFc) or eftrenonacog alfa (rFIXFc) 
prophylaxis over the 18-month study period. 
Secondary objectives: 
 
To evaluate the joint status as detected by US in the Haemophilia Early 
Arthropathy Detection with Ultrasound (HEAD-US) specific items of hypertrophic 
synovium, cartilage and bone damage in haemophilia A and B patients treated with 
rFVIIIFc or rFIXFc prophylaxis over the 18-month study period 
 
To evaluate the clinical joint status as detected by Hemophilia Joint Health Score 
(HJHS) in haemophilia A and B patients treated with rFVIIIFc or rFIXFc 
prophylaxis over the 18-month study period 
 
To evaluate the presence, resolution, recurrence and new development of target 
joints in haemophilia A and B patients treated with rFVIIIFc or rFIXFc prophylaxis 
over 18 months 
 
To describe the bleeding episodes in haemophilia A and B patients treated with 
rFVIIIFc or rFIXFc prophylaxis over the 18-month study period 
 
To evaluate the quality of life in haemophilia A and B patients treated with 
rFVIIIFc or rFIXFc prophylaxis over the 18-month study period 
Exploratory objectives 
– florio® HAEMO 
sub-study: 
 
Impact of florio HAEMO on patients’ sense of protection and their physical 
activity level in haemophilia A and B patients treated with rFVIIIFc or rFIXFc 
prophylaxis 
 
Explore adherence to prescribed treatment regimen in haemophilia A and B 
patients treated with rFVIIIFc or rFIXFc prophylaxis 
 
Explore relationship between estimated FVIII and FIX levels and physical activity 
in haemophilia A and B patients treated with rFVIIIFc or rFIXFc prophylaxis 
 
Explore timing of bleeding episodes in relation to estimated FVIII and FIX levels 
and physical activity in haemophilia A and B patients treated with rFVIIIFc or 
rFIXFc prophylaxis 
 
Explore the use of florio HAEMO to characterise pain and well-being in 
haemophilia A and B patients treated with rFVIIIFc or rFIXFc prophylaxis 
STUDY 
ENDPOINTS 
 
Primary endpoint: 
 
Change from baseline in total HEAD-US score up to month 18 (end of study -
EOS). 
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Eftrenonacog alfa/Alprolix® - Efmoroctocog alfa/Elocta® 
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Secondary endpoints: 
 
Change from baseline in HEAD-US score for hypertrophic synovium at 6, 12 and 
18 months 
 
Change from baseline in HEAD-US score for cartilage at 6, 12 and 18 months 
 
Change from baseline in HEAD-US score for bone at 6, 12 and 18 months 
 
Change from baseline in total HJHS at month 18 (EOS) 
 
Number and location of target joints at baseline, 6, 12 and 18 months 
 
Total Annualized bleeding rate (ABR), joint ABR, target joint ABR, 
traumatic/spontaneous ABR 
 
Patient-Reported Outcomes Measurement Information System (PROMIS) physical 
function/activity scores at baseline and 18 months 
 
PROMIS pain intensity and interference scores at baseline and 18 months 
 
IPAQ-SF scores at baseline and 18 months 
Exploratory endpoints 
– florio HAEMO sub-
study: 
 
Results from questionnaire on impact of florio HAEMO tools on patients’ sense of 
protection and their physical activity level 
 
florio HAEMO captured treatment adherence scores  
 
florio HAEMO captured estimated FVIII and FIX levels 
 
florio HAEMO captured physical activity type, duration and intensity  
 
florio HAEMO captured bleed data (timing, location, cause, treated/untreated) 
 
florio HAEMO captured FVIII/FIX administration data (time, dose) 
 
florio HAEMO captured pain data (time, location, cause, intensity) 
 
florio HAEMO captured well-being data 
STUDY DESIGN 
AND METHODS 
 
Study design: 
This is a prospective, low-interventional, single-arm, multicentre study to describe the 
joint health over an 18-month period of prophylactic treatment with rFVIIIFc or rFIXFc 
in patients with haemophilia A or haemophilia B in a real-world setting. Approximately 
250 patients will be enrolled in the study. Around 80% of the patients are expected to 
have haemophila A and around 20% haemophila B.  
Retrospective data from patient medical records will be collected for at least 6 months 
before enrolment in the study. From enrolment and throughout the study, patients will 
perform on-site study visits at 6-month intervals. Each patient is expected to actively 
participate in the study for 18 months (from baseline to EOS visit). 
Joint health will be assessed with HEAD-US and HJHS scoring. Quality of life and 
physical activity will be assessed with Patient-reported outcomes (PROs). Patients will 
be on prophylactic treatment with rFVIIIFc or rFIXFc according to usual clinical 
practice and the dosing guide in the respective Summary of Product Characteristics 
(SmPC). Choice of treatment will not be dictated by the study protocol. 
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Eftrenonacog alfa/Alprolix® - Efmoroctocog alfa/Elocta® 
Clinical Study No: Sobi.HAEM89-007 
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Number of patients 
planned: 
Approximately 250. Around 80% of the patients are expected to have Haemophila A 
and around 20% Haemophila B. 
Diagnosis and main 
criteria for inclusion: 
A patient must fulfill the following criteria in order to be included in the study: 
1. Age ≥ 6 years 
2. Diagnosis of haemophilia A or B 
3. Having at least 6 months documented pre-study treatment data regarding 
treatment prescriptions and bleeding episodes prior to the baseline visit 
4. Previous treatment for haemophilia A or B with any marketed recombinant 
and/or plasma-derived FVIII or FIX concentrate for at least 6 months 
5. Start of prophylactic treatment with rFVIIIFc or rFIXFc prior to study enrolment 
or latest at the baseline visit, in accordance with local regulations 
6. Signed and dated informed consent provided by the patient, or the patient’s 
legally authorized representative for patients under the legal age. Assent should 
be obtained from paediatric patients in accordance with local regulations 
 
florio HAEMO sub-study 
To be eligible for the florio HAEMO sub-study a patient should have used florio 
HAEMO (a CE marked medical device used in routine clinical practice) for at least 3 
months and must agree to have data collected from the florio HAEMO app by 
providing a separate informed consent or assent. 
Assessments: 
 
At each visit HEAD-US assessments will be performed. Information on pain, anti-
inflammatory and anti-depressant medications will be recorded 
 
At enrolment/baseline and EOS, PROs will be completed 
 
At enrolment/baseline and EOS, HJHS will be assessed 
 
For patients participating in the florio HAEMO sub-study a questionnaire on the 
impact of florio HAEMO on patients’ sense of protection and their physical 
activity level will be administered when they enter the sub-study. Data from the 
florio HAEMO app will be collected 
 
Safety Assessments: 
The following safety events should be collected: 
 
Serious Adverse Events (SAEs) 
 
Non-serious Adverse Events (AEs) assessed as causally related to treatment with 
rFVIIIFc or rFIXFc and considered unexpected 
 
AEs of special interest: inhibitor development, thrombotic events and serious 
hypersensitivity reaction including anaphylactic reactions 
 
AEs leading to premature discontinuation of rFVIIIFc or rFIXFc 
 
Exposure during pregnancy, medication errors, misuse or abuse in relation to 
rFVIIIFc or rFIXFc 
 
Any AE suspected to be causally related to a medicinal product other than the studied 
Sobi product, and which does not result from a possible interaction with it, should be 
reported by the Investigator to the concerned authority via the national reporting 
system, or to the Marketing Authorization Holder of the suspected medicinal product. 
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Eftrenonacog alfa/Alprolix® - Efmoroctocog alfa/Elocta® 
Clinical Study No: Sobi.HAEM89-007 
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2 
Abbreviations and definition of terms 
2.1 
List of Abbreviations and definitions 
Term 
Definition 
ABR 
Annualized bleeding rate 
AE 
Adverse event 
Bleeding episode 
A bleeding episode starts from the first sign/symptom of bleeding 
as reported by the patient and ends no more than 72 hours after the 
last injection to treat the bleeding episode (1). Any subsequent 
bleeding at the same location and injections administered 
≤72 hours from the previous injection will be considered as the 
same bleeding episode. Multiple bleeding locations treated with a 
single injection will also be considered a single bleeding episode. 
Any injection to treat the bleeding episode that is administered 
>72 hours after the preceding one will be considered the first 
injection to treat a new bleeding episode in the same location. Any 
injection used to treat subsequent bleeding at a different location 
will be considered a separate bleeding episode, regardless of the 
time from the last injection to treat a bleeding episode. 
BU 
Bethesda unit 
CDISC 
Clinical data interchange standards consortium 
CRO 
Contract research organization 
(e)CRF 
(electronic) Case report form 
EOS 
End of study 
EDC 
Electronic data capture 
EU 
European Union 
FAS 
Full analysis set 
FIX 
Factor IX 
FVIII 
Factor VIII 
GCP 
Good clinical practice 
GPV 
Global pharmacovigilance & patient safety 
Haemophilia severity 
Mild haemophilia: >5 IU/dL to <40 IU/dL endogenous factor 
VIII/IX 
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Term 
Definition 
Moderate haemophilia: 1 to 5 IU/dL endogenous factor VIII/IX 
Severe haemophilia: <1 IU/dL endogenous factor VIII/IX 
HEAD-US 
Haemophilia Early Arthropathy Detection with Ultrasound 
HRQoL 
Health-related quality of life 
HJHS 
Hemophilia Joint Health Score 
ICH 
International council for harmonisation 
IEC 
Independent ethics committee 
IPAQ-SF 
International Physical Activity Questionnaire - Short Form 
Impaired joint 
Any joint that has persistent functional or structural abnormalities, 
considered clinically relevant by the Investigator, with or without 
bleeding episodes. 
Index joint 
Ankle, knee, elbow (left and right) 
Major surgery 
Any surgical procedure (elective or emergent) that usually, but not 
always, involves general anesthesia and/or respiratory assistance, 
in which a major body cavity is penetrated and exposed, or a 
substantial impairment of physical or physiological functions is 
produced (e.g., laparotomy, thoracotomy, craniotomy, operation in 
joint, or dental extraction of any molar teeth or ≥3 nonmolar teeth). 
Minor surgery 
Any surgery that do not fall under the definition of Major surgery 
MRI 
Magnetic resonance imaging 
NIH 
National Institute of Health 
PP 
Per Protocol 
PRO 
Patient-reported outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
(PROMIS®) 
rFVIIIFc  
Efmoroctocog alfa (a recombinant FVIII Fc fusion protein, 
Elocta®) 
rFIXFc  
Eftrenonacog alfa (a recombinant FIX Fc fusion protein, Alprolix®)
ROM 
Range of motion 
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Eftrenonacog alfa/Alprolix® - Efmoroctocog alfa/Elocta® 
Clinical Study No: Sobi.HAEM89-007 
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Term 
Definition 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SmPC 
Summary of Product Characteristics 
Sobi 
Swedish Orphan Biovitrum AB (publ) 
SUSAR 
Suspected unexpected serious adverse reaction 
Target joint 
Three or more spontaneous bleeds into a single joint within a 
consecutive 6-month period. Where there have been ≤2 bleeds into 
the joint within a consecutive 12-month period the joint is no 
longer considered a target joint (1) 
Recurrence is defined as ≥3 spontaneous bleeds in a single joint 
within any consecutive 6-month period after target joint resolution. 
US 
Ultrasound 
3 
Ethics 
3.1 
Independent ethics committee 
It is the responsibility of the investigator to ensure approval of the study protocol, possible 
amendments and the written patient information and informed consent form from the 
Independent ethics committee (IEC) before commencing the study. The investigator should file 
all correspondence with the IEC as applicable. Copies of IEC correspondence and approvals 
should be forwarded to the Contract research organization (CRO). 
3.2 
Ethical consideration of the study 
This study will be conducted in compliance with this protocol, the International council for 
harmonisation Good clinical practice (ICH GCP) (2), European regulation 536/2014 (3) for 
clinical studies, other applicable regulatory requirements, and in accordance with the ethical 
principles that have their origin in the 2013 version of the Declaration of Helsinki) (4). 
3.3 
Patient information and consent 
It is the responsibility of the investigator or designee to give each patient (or the patient’s 
acceptable representative) prior to any study-related activities, full and adequate verbal and 
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written information regarding the objective and procedures of the study and the possible risks 
involved. The patients must be informed about their right to withdraw from the study at any 
time. 
The written patient information and/or informed consent/assent form must not be changed 
without prior discussion with Swedish Orphan Biovitrum AB (publ) (Sobi). Before any revisions 
are implemented, the revised written patient information and/or informed consent form must be 
approved by the IEC. 
It is the responsibility of the investigator or designee to obtain signed informed consent (or 
witnessed verbal consent according to applicable regulations) from all patients prior to any 
study-related activities. The patients should receive a copy of the written information, the signed 
informed consent form and assent form for patients not being able to provide full consent (i.e. 
minors). Patients who become adults during the study duration will be re-consented as applicable 
in accordance with local regulations. 
For patients willing to participate in the florio® HAEMO sub-study (see section 6.5.11), a 
separate consent will be obtained. 
4 
Introduction 
4.1 
Background 
Haemophilia is a rare genetic disorder characterized by a deficiency in coagulation factor VIII 
(FVIII; haemophilia A) or factor IX (FIX; haemophilia B) causing impaired haemostasis and 
prolonged bleeding episodes. Severe haemophilia, defined as <1% of normal Factor VIII/FIX 
activity in haemophilia A and haemophilia B respectively, occurs in approximately 45% of 
haemophilia A and approximately 35% of haemophilia B patients, and results in frequent and 
spontaneous bleeds into muscles and joints, commonly the elbows, knees, and ankles (5, 6, 7). 
Bleeding into joints can cause acute pain and swelling and can result in reduced joint range of 
motion (ROM), long-term cartilage damage and haemophilic arthropathy (5). As a result of 
bleeding episodes and resulting progressive joint damage, haemophilia patients experience 
decreased physical functioning, pain, and poor health-related quality of life (HRQoL) (8). 
The cornerstone of haemophilia treatment in patients with haemophilia A and B is FVIII or FIX 
prophylaxis, respectively, to prevent and control bleeding episodes and, consequently, prevent or 
slow down the development of arthropathy. In fact, joint damage and progressive chronic 
arthropathy are the hallmarks of haemophilia because a single or few repeated joint bleeds can 
lead to structural joint damage due to synovial inflammation caused by haemosiderin deposition 
(9). Synovial iron deposition and inflammatory cell proliferation provokes degeneration of joint 
surfaces and eventually loss of normal joint function (9, 10) and may lead to disabling 
arthropathy. In addition to its efficacy for arthropathy prevention, FVIII or FIX prophylaxis has 
been associated with improvements in HRQoL and opportunities for a more physically active life 
(11, 12). 
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Extended half-life products used for replacement factor therapy have been developed utilizing Fc 
or albumin fusion technology, or pegylation, to prolong their half-life (13). Efmoroctocog alfa [a 
recombinant FVIII Fc fusion protein, Elocta®] (rFVIIIFc) and Eftrenonacog alfa [a recombinant 
FIX Fc fusion protein, Alprolix®] (rFIXFc) are recombinant coagulation factor concentrates with 
extended half-life. In contrast to standard half-life factor replacement products, the addition of 
the Fc region of human immunoglobulin G1 (IgG1) to the recombinant factor allows rFVIIIFc 
and rFIXFc to bypass lysosomal degradation and remain circulating in the bloodstream longer 
than standard half-life factor replacement products, thus prolonging the plasma terminal half-life. 
rFVIIIFc first received market authorization in June 2014 in the US, for the treatment of 
haemophilia A. Thereafter, in November 2015, it received market authorization in the European 
Union (EU) under the tradename Elocta®. rFIXFc first received market authorization in the US 
March 2014 and then in Europe in May 2016 for the treatment of haemophilia B under the 
tradename Alprolix®. 
Despite the use of prophylaxis many patients still experience joint bleeds which may lead to joint 
deterioration over time (14, 15). Furthermore, not all bleeds may be clinically evident, as there 
are indications of subclinical bleeds in patients receiving treatment for their haemophilia (16). It 
is therefore important to gather additional information on the joint health of haemophilia patients 
using currently available examination methods. 
Thorough examination of the joints and follow-up of patients is a crucial part of patient 
management and helps to identify when there is a need to adjust the treatment regimen. There are 
currently several examination methods to identify joint damage early on, including clinical joint 
examination and different imaging techniques. The functional Hemophilia Joint Health Score 
(HJHS) (17, 18, 19) for clinical joint assessment and more recently the Haemophilia Early 
Arthropathy Detection with UltraSound (HEAD-US) protocol for joint imaging are two 
established examinations. 
The HEAD-US protocol has been developed for non-radiologists to assess synovial hypertrophy 
and cartilage defects using point-of-care ultrasound (US) examination, enabling direct 
assessment of joint health in conjunction with medical history and physical examination (20). 
The HEAD-US scoring method is based on an additive scale with assessment of ankles, knees 
and elbows. It includes indicators of disease activity (synovitis; hypertrophic synovium) and 
structural osteochondral damage (articular cartilage and subchondral bone). 
Strengthening muscles can help improve joint health by reducing impacts on joints, and 
participation in sporting activities may help individuals compensate for motor skill deficits that 
arise because of complications of haemophilia, such as arthropathy (21). Among adults with 
haemophilia, regular physical activity helps prevent obesity and other chronic conditions; in 
children and adolescents with haemophilia, physical exercise supports joint, bone, and muscle 
health; weight control; and anxiety reduction (22). 
However, patients may limit their physical activities due to fear of bleeding if they are unaware 
of their current FVIII or FIX level. Patient apps and wearables are now available which allow 
patients to view their estimated FVIII or FIX levels, and capture health-related data (such as 
bleeding episodes, pain, well-being, physical activity levels etc.). 
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These data can be shared with the treating physician supporting the planning to individualize the 
patient’s factor treatment based on current lifestyle, health status and physical activity levels. 
florio HAEMO, a CE marked medical device used as part of routine clinical practice, consists of 
the florio HAEMO app (for patients with haemophilia and/or their caregivers) and the florio 
HAEMO dashboard (for healthcare professionals). 
Synovitis is currently considered a marker of haemophilia activity and can be unnoticed on 
physical examination, especially in patients on prophylaxis. Performing point-of-care US 
examination is considered as the most practical option for regular monitoring of joints to detect 
soft tissue and osteochondral changes, and physical examination provide complementary 
information on the joint disease. 
Favourable joint outcomes are expected with modern haemophilia A and haemophilia B 
management. However, evaluation of long-term treatment outcomes is hampered by the delay 
between bleeding episodes during childhood and resulting joint outcomes in adulthood. Future 
research with combined US and/or Magnetic resonance imaging (MRI) is needed to better 
understand joint outcomes. Ultrasound paired with physical examination increases the sensitivity 
for detection of joint damage (23). Accordingly, the expected joint health outcomes, based on 
HEAD-US scoring, in patients receiving adequate prophylactic treatment is at least the 
maintenance of a stable joint status or the improvement in reversible lesions for the patients with 
already established joint damage. 
4.2 
Study rationale 
The efficacy and safety of rFVIIIFc and rFIXFc have been established in clinical trials as 
required for regulatory approvals. In addition, several completed and ongoing non-interventional 
studies describe the effectiveness and usage of rFVIIIFc and rFIXFc in the real-world setting 
(24, 25). However, there are still limited real-world data on joint health outcomes, assessed with 
objective measures, in patients receiving rFVIIIFc or rFIXFc prophylaxis. 
The main purpose of this study is to prospectively describe the joint health over an 18-month 
period of prophylactic treatment with rFVIIIFc or rFIXFc in patients with haemophilia A or 
haemophilia B in a real-world setting in Europe. This is a low-interventional, multicentre study 
using point-of-care US examination for regular monitoring of soft tissue and osteochondral 
changes in the joints, as well as physical examination as a complementary assessment of joint 
disease. 
Data output from florio HAEMO, and patient feedback via a patient questionnaire on physical 
activity levels and sense of protection while using florio HAEMO, will be analyzed as 
exploratory objectives in a sub-study. This sub-study will explore possible correlations between 
the levels of physical activity, the estimated FVIII/FIX levels and bleeding occurrence. 
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4.3 
Potential risks and benefits 
This is a low-interventional study. While joint assessments with HEAD-US and HJHS may be 
part of the patient’s usual routine clinical care, the study specific requirement to complete these 
assessments according to the study’s schedule of events is considered a low intervention. The 
completion of Patient-reported outcomes (PROs) is also considered a low intervention. These 
interventions are not assessed to pose more than minimal risk to the patients. 
rFVIIIFc and rFIXFc have marketing authorization and will be used per approved indication. 
They will be prescribed independently from the decision to enrol a patient in the study, and 
choice of treatment is hence not dictated by the study protocol. 
Participation is not expected to have any particular benefit for the enrolled patients, other than a 
potentially more intensive follow-up by their physician. The results from the study may help in 
improving the knowledge of joint disease and US assessment in patients with haemophilia, and 
potentially in improving the management of haemophilic arthropathy in the future. 
5 
Study objectives and endpoints 
5.1 
Primary objective 
To evaluate the overall joint status as detected by ultrasound in haemophilia A and B patients 
treated with rFVIIIFc or rFIXFc prophylaxis over the 18-month study period. 
5.1.1 
Primary endpoint 
Change from baseline in total HEAD-US score up to month 18 (EOS). 
5.2 
Secondary objectives 
 To evaluate the joint status as detected by ultrasound in the HEAD-US specific items of 
hypertrophic synovium, cartilage and bone damage in haemophilia A and B patients 
treated with rFVIIIFc or rFIXFc prophylaxis over the 18-month study period 
 To evaluate the clinical joint status as detected by HJHS in haemophilia A and B patients 
treated with rFVIIIFc or rFIXFc prophylaxis over the 18-month study period 
 To evaluate the presence, resolution, recurrence and new development of target joints in 
haemophilia A and B patients treated with rFVIIIFc or rFIXFc prophylaxis over 18 
months 
 To describe the bleeding episodes in haemophilia A and B patients treated with rFVIIIFc 
or rFIXFc prophylaxis over the 18-month study period 
 To evaluate the QoL in haemophilia A and B patients treated with rFVIIIFc or rFIXFc 
prophylaxis over the 18-month study period 
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5.2.1 
Secondary endpoints supporting the secondary objective(s) 
 Change from baseline in HEAD-US score for hypertrophic synovium at 6, 12 and 18 
months 
 Change from baseline in HEAD-US score for cartilage at 6, 12 and 18 months 
 Change from baseline in HEAD-US score for bone at 6, 12 and 18 months 
 Change from baseline in total HJHS at month 18 (EOS) 
 Number and location of target joints at baseline, 6, 12 and 18 months 
 Total Annualized bleeding rate (ABR), joint ABR, target joint ABR, 
traumatic/spontaneous ABR 
 Patient-Reported Outcomes Measurement Information System (PROMIS) physical 
function/activity scores at baseline and 18 months 
 PROMIS pain intensity and interference scores at baseline and 18 months 
 International Physical Activity Questionnaire - Short Form (IPAQ-SF) scores at baseline 
and 18 months 
5.3 
Exploratory objectives – florio HAEMO sub-study 
 Impact of florio HAEMO on patients’ sense of protection and their physical activity level 
in haemophilia A and B patients treated with rFVIIIFc or rFIXFc prophylaxis 
 Explore adherence to prescribed treatment regimen in haemophilia A and B patients 
treated with rFVIIIFc or rFIXFc prophylaxis 
 Explore relationship between estimated FVIII and FIX levels and physical activity in 
haemophilia A and B patients treated with rFVIIIFc or rFIXFc prophylaxis 
 Explore timing of bleeding episodes in relation to estimated FVIII and FIX levels and 
physical activity in haemophilia A and B patients treated with rFVIIIFc or rFIXFc 
prophylaxis 
 Explore the use of florio HAEMO to characterise pain and well-being in haemophilia A 
and B patients treated with rFVIIIFc or rFIXFc prophylaxis 
5.3.1 
Exploratory endpoints 
 Results from questionnaire on impact of florio HAEMO tools on patients’ sense of 
protection and their physical activity level 
 florio HAEMO captured treatment adherence scores 
 florio HAEMO captured estimated FVIII and FIX levels 
 florio HAEMO captured physical activity type, duration and intensity 
 florio HAEMO captured bleed data (timing, location, cause, treated/untreated) 
 florio HAEMO captured FVIII/FIX administration data (time, dose) 
 florio HAEMO captured pain data (time, location, cause, intensity) 
 florio HAEMO captured well-being data 
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6 
Investigational plan 
6.1 
Overall study design and plan 
This is a prospective, low-interventional, single-arm, multicentre study to describe the joint 
health over an 18-month period of prophylactic treatment with rFVIIIFc or rFIXFc in patients 
with haemophilia A or haemophilia B in a real-world setting. Approximately 250 patients will be 
enrolled in the study. Around 80% of the patients are expected to have haemophila A and around 
20% haemophila B. 
Retrospective data from patient medical records will be collected for at least 6 months before 
enrolment in the study. From enrolment and throughout the study, patients will perform on-site 
study visits at 6-month intervals. Each patient is expected to actively participate in the study for 
18 months (from baseline to end of study [EOS] visit). 
Joint health will be assessed with HEAD-US and HJHS scoring. Quality of life and physical 
activity will be assessed with PROs. Patients will be on prophylactic treatment with rFVIIIFc or 
rFIXFc according to usual clinical practice and the dosing guide in the respective Summary of 
Product Characteristics (SmPC). Choice of treatment will not be dictated by the study protocol. 
The recruitment period is planned to be approximately 12 months from the timepoint when the 
first patient is enrolled in the study. Around 60 sites in approximately 11 European countries are 
expected to participate in the study. 
No specific evaluation committees will be utilized for this study, since it is a low-interventional 
study having no interventions posing more than minimal risk to the patients. 
Interim analyses are planned to be performed during the study. The first interim analysis is to be 
performed once recruitment is completed. The purpose of the first interim analysis is to assess 
the baseline variability of HEAD-US score results and to share baseline characteristics with the 
haemophilia community. The second interim analysis is planned to be performed once at least 
50% of the patients have completed their 12-month visit and will evaluate the joint health status 
at that time. 
In an optional, exploratory sub-study, data will be collected via the florio HAEMO app. All 
exploratory endpoints and objectives in the study are related to the exploratory sub-study. 
The overall study design is described in Figure 1. 
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Figure 1 
Study Design 
 
6.2 
Discussion of study design, including the choice of control groups 
This prospective, low-interventional, multicentre study is being conducted to describe the joint 
health over an 18-month period in patients on prophylactic treatment with rFVIIIFc or rFIXFc 
with haemophilia A or haemophilia B in a real-world setting. The 18-month follow-up period is 
considered to be long enough to see changes and/or show medium/long-term stabilization of 
joint status. Patients treated on demand are not included in the study, as this would lead to a too 
high variability in the patient population. 
Joint outcomes will be described over time and reported in a quantitative/objective manner with 
HEAD-US and HJHS scores. These assessments are not always fully incorporated in routine 
clinical practice and are therefore intended to be investigated in the low-interventional setting of 
this study. Both examinations have been chosen due to their complimentary features – HJHS is a 
clinical assessment focused on functionality and HEAD-US is a more sensitiveUS assessment 
with the ability to detect structural joint damage and synovitis earlier on in the joint 
deterioration. 
This study will not have a control group. The reason for this is that it is not considered needed to 
be able to evaluate the primary objective of the study. 
Patients excluded from participation in this study (section 6.3.2) will have been assessed as not 
being suitable for the study. 
6.2.1 
Patient input into design 
Representatives from patient organizations in six countries – Czech Republic, France, Germany, 
Italy, Spain and Sweden, joined Patient Council meetings and provided input on the study design 
which included objectives and endpoints, PRO scales, visit schedule and study assessments. 
Their feedback resulted in the decision on the PROs to be used in the study and their format, and 
also influenced the decision on study duration. The group appreciated a study with focus on both 
joint health and pain. 
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6.3 
Selection of study population 
Children from the age of six are allowed to be enrolled in the study. To enrol children in this 
type of study is considered justified since the study is not posing more than minimal risk to the 
participating patients and signs of joint damage due to haemophilia are known to develop from 
an early age. It is judged that children from the age of six are able to comply with study 
procedures without any major impact on their daily life. 
Prospective approval of a protocol deviation to recruitment and enrolment criteria, also known as 
protocol waiver or exemption, is not permitted. 
6.3.1 
Inclusion criteria 
A patient must fulfill the following criteria in order to be included in the study: 
1. Age ≥ 6 years 
2. Diagnosis of haemophilia A or B 
3. Having at least 6 months documented pre-study treatment data regarding treatment 
prescriptions and bleeding episodes prior to the baseline visit 
4. Previous treatment for haemophilia A or B with any marketed recombinant and/or 
plasma-derived FVIII or FIX concentrate for at least 6 months 
5. Start of prophylactic treatment with rFVIIIFc or rFIXFc prior to study enrolment or latest 
at the baseline visit, in accordance with local regulations 
6. Signed and dated informed consent provided by the patient, or the patient’s legally 
authorized representative for patients under the legal age. Assent should be obtained from 
paediatric patients in accordance with local regulations 
6.3.1.1 
florio HAEMO sub-study 
To be eligible for the florio HAEMO sub-study a patient should have used florio HAEMO (a CE 
marked medical device used in routine clinical practice) for at least 3 months and must agree to 
have data collected from the florio HAEMO app by providing a separate informed consent or 
assent. 
6.3.2 
Exclusion criteria 
The presence of any of the following will exclude a patient from inclusion in the study: 
1. Any medical condition which in the opinion of the investigator makes the patient 
unsuitable for inclusion 
2. Prophylactic treatment with non-factor therapy during the 6 months prior to enrolment 
3. Presence of factor VIII or FIX inhibitory antibodies (inhibitors) (≥0.60 Bethesda Units 
[BU]/mL) at the latest available inhibitor test 
4. Enrolment in a concurrent clinical interventional study, or intake of an Investigational 
medicinal product, within 3 months prior to inclusion in this study 
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5. Foreseeable inability to cooperate with given instructions or study procedures 
6.3.3 
Withdrawal of patients from study 
6.3.3.1 
Withdrawal from study 
Whenever possible and irrespective of the reason for withdrawal, the patient should be examined 
as soon as possible. All relevant assessments should be completed, preferably according to the 
schedule of events (see section 6.5.1.1). The Case report form (CRF) should be completed as far 
as possible. Date and reason for the study withdrawal should be clearly described in the CRF. 
A patient should be withdrawn from the study for any one of the following reasons: 
 The patient develops factor VIII or FIX inhibitory antibodies (inhibitor titre ≥0.60 
BU/mL) 
 The patient or his legally authorized representative(s) withdraws consent 
 The patient enrols into an interventional clinical study in which an investigational 
treatment or approved therapy for investigational use is administered 
 The patient enrols into a low-interventional clinical study where the assessments 
performed are of such nature that the patient cannot be considered treated per usual 
routine practice 
 The patient discontinues prophylactic treatment with rFVIIIFc or rFIXFc 
 The patient is no longer willing to undergo the mandatory US examination 
If any Adverse Event (AE) is associated with the withdrawal this should be recorded in the CRF. 
If the patient withdraws consent for disclosure of future information (data, samples), the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
Patients will not be withdrawn if they miss a study visit. 
If a patient withdraws from the study and more than 3 months since the last study visit have 
passed, all assessments should be performed to the extent possible. If a patient withdraws from 
the study less than 3 months since the last visit, PRO collection and HJHS assessment should be 
performed to the extent possible. 
6.3.4 
Replacement of withdrawn patients 
Withdrawn patients will not be replaced. 
6.4 
Study treatment(s) and concomitant therapy 
Study treatments/interventions are all pre-specified interventions (e.g., clinical assessments and 
behavioral) intended to be administered to the study participants during the study conduct. 
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Both rFVIIIFc and rFIXFc will be used as per clinical routine for each patient and their use will 
not be dictated by the protocol. 
6.4.1 
Prior and concomitant therapy 
Therapies considered necessary for the patient’s welfare may be given at the discretion of the 
investigator. Pain, anti-inflammatory and anti-depressant therapies used in the month preceding 
baseline/every follow-up visit must be recorded in the CRF. No medicinal product under 
investigation may be used in this study. 
6.4.2 
Treatment compliance 
Treatment compliance, as assessed by the investigator, will be recorded in the CRF.
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6. Patients participating in the florio HAEMO sub-study will be asked to complete a questionnaire once. It can occur at baseline or any time during the main study, if 
they enrol in the sub-study after the baseline visit. 
7. Refer to section “safety assessments” for the safety events to be captured. 
8. All SAEs (including medically important AEs) from the Enrolment visit to the patient’s last study visit.
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6.5.1.2 
Visit 0/1 – Enrolment/Baseline 
In this study, assessments related to enrolment and baseline may be performed either on the same 
day or divided over more than one day, depending on the availability of the patient and the site 
personnel. A time window of +28 days from the enrolment visit is allowed, if it is not possible to 
perform all assessments at the same time. No assessments may be performed prior to obtaining 
signed informed consent. The date when the HEAD-US assessment is performed will be 
considered as the baseline visit date and will be used to calculate the timepoints for the follow-up 
visits. 
At the enrolment visit and prior to any study-related activities the patient/the patient’s legally 
authorized representative have to sign and date the informed consent form. 
The inclusion and exclusion criteria will be reviewed and recorded (see sections 6.3.1 and 6.3.2). 
Data will be collected in accordance with the schedule of events (see section 6.5.1.1). 
6.5.1.3 
Visit 2 – Month 6 
Data will be collected in accordance with the schedule of events (see section 6.5.1.1). 
All study assessments should be performed within a ±28 days time window. 
6.5.1.4 
Visit 3 – Month 12 
Data will be collected in accordance with the schedule of events (see section 6.5.1.1). 
All study assessments should be performed within a ±28 days time window. 
6.5.1.5 
Visit 4 – Month 18/End of study  
Data will be collected in accordance with the schedule of events (see section 6.5.1.1). 
All study assessments should be performed within a -28 and +56 days time window. The date of 
the last assessment should be considered as the EOS date. 
If a patient prematurely withdraws from the study and more than 3 months since the last study 
visit have passed, all assessments should be performed to the extent possible. If a patient 
withdraws from the study less than 3 months since the last visit, PRO collection and HJHS 
assessment should be performed to the extent possible. 
6.5.2 
Demography 
Demographics includes age at screening (year of birth), sex, weight and height. The body weight 
recordings will be repeated at each visit. Height will be measured at the baseline visit for all 
patients, thereafter only for patients <18 years old. Body mass index will be calculated based on 
the weight and height measurements. 
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6.5.3 
Haemophilia history 
Haemophilia history will be collected at the baseline/enrolment visit including the following: 
 severity of disease 
 type of haemophilia 
 age at diagnosis 
 inhibitor history 
 type of prophylactic treatment (primary, secondary or tertiary prophylaxis) 
 age at prophylaxis initiation 
 haemophilia prescription information (product, regimen, and dosing) from the 6 months 
period prior to enrolment 
 haemophilia prescription information (product, regimen, and dosing) at time of enrolment 
 previous non-factor therapy (product, start and stop date) 
 bleeding episodes (location, spontaneous/traumatic) from the 6 months prior to enrolment 
 date of first injection with rFVIIIFc or rFIXFc 
6.5.4 
Medical and surgical history 
Significant medical and surgical history during at least the previous 6 months before enrolment 
will be collected. 
Medical history includes any significant medical condition, including the following: 
 history of allergy/anaphylactic shock 
 HIV 
 hepatitis B and C infection status 
 clinically significant liver, renal, cardiovascular diseases 
 clinical depression 
 non-haemophilic acute or chronic medical conditions causing mobility/joint problems 
 other coagulation disorder(s) in addition to haemophilia A or B 
For surgical history, orthopaedic or musculoskeletal surgical or other interventions are of special 
interest. Information on date and type of intervention will be collected; for surgical interventions 
also classification in major/minor. 
Data on surgical and other interventions related to joints will be collected for all joints and for 
anytime in the past. 
6.5.5 
Surgical and other interventions 
Information on joint related surgeries and other interventions (including, but not limited to 
orthopaedic interventions, synoviorthesis (radio- and chemical)) will be collected. Moreover, any 
additional joint assessments including MRI, X-ray, and ROM will be documented. Information 
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on non-joint related surgeries, including tooth extractions, (type, date, classification 
(major/minor), related bleeding episodes) will be separately collected. 
6.5.6 
Target and impaired joints 
At baseline, information on target joints (presence and location) will be recorded as per the 
assessment of the investigator. For the follow-up visits, resolution/reccurence/development of 
target joints will be calculated based on the investigator reported bleeds, as per the target joint 
definitions for resolution, recurrence and development (1). 
Information on the presence, location and related assessments of impaired joints will be recorded 
as per the assessment of the investigator. A joint can simultaneously be a target joint and an 
impaired joint. The status of an impaired joint will be assessed at the baseline visit, and details 
on clinical/functional investigations performed as well as any changes in e.g. pain will be 
collected. 
6.5.7 
Concomitant therapy 
Pain, anti-inflammatory and anti-depressant therapies used in the month preceeding baseline/ 
every follow-up visit will be collected. 
6.5.8 
Bleeding episodes 
For any bleeding episode, the following will be collected: 
 bleeding episode circumstance (e.g. spontaneous, traumatic) 
 bleeding episode location (e.g. muscle, joint, other) 
 date of bleeding episode 
 dose (IU) and number of injections used to treat the bleed 
6.5.9 
Haemophilia treatment 
The prescribed rFVIIIFc or rFIXFc dose (IU) and injection frequency will be collected at each 
follow-up visit. 
Any change in haemophilia treatment (dose, injection frequency or any other change in 
management, for example physiotherapy) will be collected at each visit. 
FVIII or FIX plasma activity levels, including dose administered (IU) and time since last dose 
(h) will be collected if available. 
Physician judgement of patient’s treatment adherence to rFVIIIFc or rFIXFc will be collected at 
each visit. 
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6.5.10 
Effectiveness assessments 
6.5.10.1 
Ultrasound joint examination – HEAD-US 
At the baseline, month 6, 12 and 18 (EOS) visits, the six index joints (elbows, knees and ankles) 
will be examined and scored by the investigator or delegate using the HEAD-US protocol (26). 
The person who performs the assessment should be properly trained and for consistency it is 
recommended that the same person performs the assessment at each study visit. 
The HEAD-US protocol describes that a linear array 12-5 MHz US transducer is used to perform 
the joint examination. Elbows are examined with sweeps E1-E3 shifting the probe as described 
in the protocol. Knee joints planes K1-K4, and ankle joints A1-A3. There is a minor variation in 
the HEAD-US scoring method based on age, i.e. knee imaging scanning plane K4 is not 
performed in children. 
One joint is scored at a time. The disease activity (synovitis) score rates the status of the 
hypertrophic synovium. Hypertrophic synovium is graded in three steps (0: absent/minimal; 1: 
mild/moderate [score=1], 2: severe [score=2]) based on the comprehensive evaluation of the 
joint recesses and the mean amount of synovial tissue contained in them. 
The disease damage score of articular surfaces rates the structural osteochondral damage. 
Concerning the articular cartilage, the damage is graded in five steps (0: normal; 1: echotexture 
abnormalities and focal loss involving <25% of the target surface [score=1]; 2: partial/full-
thickness loss of the cartilage involving at least 50% of the target surface [score=2]; 3: 
partial/full-thickness loss of the cartilage involving >50% of the target surface [score=3]; 4: 
complete cartilage destruction or absent visualization of the articular cartilage on the target 
surface [score=4]). 
Damage of subchondral bone is scored using a three-grade scale (0: normal; 1: mild irregularities 
of the subchondral bone with/without initial osteophytes around the joint [score=1]; 2: deranged 
subchondral bone with/without erosions and presence of prominent osteophytes around the joint 
[score=2]). 
The HEAD-US total score represents the sum of item scores for abnormalities detected and 
ranges from 0 up to 48. 
6.5.10.2 
Functional joint examination – HJHS 
At the baseline and month18 (EOS) visits, the investigator or delegate will assess joint 
structure/function using the HJHS scoring system version 2.1 (27, 28). The person who performs 
the assessment should be properly trained and for consistency it is recommended that the same 
person performs the assessment at each study visit. The six index joints (elbows, knees and 
ankles) will be examined and scored. The score for each joint is the sum of the individual item 
scores for the 8 dimensions. Global gait is assessed separately. 
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The minimum score per joint is 0, the maximum score is 20. 
The total joint score (range 0-120) is the sum of the 6 joint scores. The HJHS total score is total 
joint score + global gait (range 0-4); minimum score 0, maximum 124. 
6.5.10.3 
Patient-Reported Outcomes 
Patient questionnaires will be administered at the baseline and 18 months (EOS), to evaluate and 
compare changes in patients’ perceptions of pain and physical activity/function. PRO 
questionnaires will be completed by patients or caregivers depending on age, see Table 1 for 
additional details. When possible, caregivers of paediatric patients less than 8 years old will 
complete the PRO instruments verbatim based on the patient’s responses. Patients and/or 
caregivers will be encouraged to complete the PROs based on the patient’s age at enrolment. It is 
expected that it will take approximately 8-10 minutes per visit to complete all questionnaires. 
The PROs are expected to be completed on paper and the paper forms will be considered as the 
source document for the PRO data. Due to language availability, not all patients may be required 
to complete all PROs. 
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6.5.10.3.1.2 
PROMIS Pain interference (pain interference - short form 6a, paediatric pain 
interference short form 8a, parent proxy pain interference) 
Measures consequences of pain on relevant aspects of one’s life. This includes the extent to 
which pain hinders engagement with social, cognitive, emotional, physical, and recreational 
activities There are 6 questions for adults and 8/13 questions for children/parents. It takes 1-2 
minutes to complete. 
6.5.10.3.1.3 
PROMIS Physical function / activity (physical function - short form 6b, 
paediatric physical activity -short form 8a, parent proxy physical activity short 
form 8a) 
Includes the functioning of one’s upper extremities (dexterity), lower extremities (walking or 
mobility), and central regions (neck, back), as well as instrumental activities of daily living. 
There are 6 questions for adults and 8/8 questions for children/parents. It takes 1-2 minutes to 
complete. 
6.5.10.3.2 
IPAQ-SF 
The IPAQ-SF is a validated, 7-day recall questionnaire suitable for people between 15-69 years 
of age to measure current levels of physical activity (30). IPAQ-SF assesses physical activity 
across domains; leisure-time physical activity, domestic and gardening activities, work-related 
physical activity and transport-related physical activity. The items are structured to provide 
separate domain specific scores for walking, moderate-intensity and vigorous-intensity activity 
within each of the work, transportation, domestic chores and gardening (yard) and leisure-time 
domains. Scoring of the IPAQ-SF results in a continuous variable in the form of total MET-
minutes per week, as well as categorization into high, moderate or low physical activity level. 
The IPAQ-SF will be administered at baseline and at the yearly visits. It is expected to take 
approximately 5 minutes to complete. 
6.5.11 
Exploratory endpoints - florio HAEMO sub-study 
If a patient has used florio HAEMO (a certified medical device used in routine clinical practice) 
for at least 3 months and agrees to have data collected from it by providing informed consent, the 
patient can participate in the florio HAEMO exploratory sub-study. 
A questionnaire on the impact of florio HAEMO on patients’ sense of protection and their 
physical activity level will be administered, and data from florio HAEMO on estimated FVIII 
levels, physical activity levels, bleeds, pain, well-being and rFVIIIFc/rFIXFc dosing will be 
collected. Data will be retrospectively collected from the 6-month period prior to enrolment, and 
until EOS. 
6.5.11.1 
florio HAEMO patient questionnaire 
All patients who use florio HAEMO to monitor their haemophilia, or their caregivers for patients 
<12 years of age (Table 2), and who consent to the use of florio HAEMO data in the study, will 
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6.5.12.1 
Adverse events 
6.5.12.1.1 
Definitions 
An AE is any untoward medical occurrence in a study patient to whom a medicinal product is 
administered and which does not necessarily have a causal relationship with this treatment. 
AEs include the following: 
 Abnormal test findings, as specified below 
 Clinically significant signs and symptoms 
 Changes in physical examination findings 
 Progression/worsening of underlying disease 
In addition, signs and symptoms resulting from the following should also be handled according 
to the same principles as AEs: 
 Overdose 
 Withdrawal of treatment 
 Interactions 
In order to qualify for reporting as an AE in this study, at least one of the above-mentioned 
criteria must be met, and be in accordance with the listed safety data to be collected as defined at 
the beginning of this section. 
For pregnancies and breastfeeding, see section 6.5.12.14. 
6.5.12.2 
Abnormal test findings, pre-existing conditions, procedures 
Any abnormal test finding or pre-existing condition, which worsens or increases in frequency or 
any unplanned medical procedures should be recorded, if any of the following criteria apply: 
 SAEs 
 Non-serious AEs assessed as causally related to treatment with rFVIIIFc or rFIXFc and 
considered unexpected 
 AEs of special interest: Inhibitor development, thrombotic events and serious 
hypersensitivity reaction including anaphylactic reactions 
 AEs leading to premature discontinuation of rFVIIIFc or rFIXFc 
 Exposure during pregnancy, medication errors, misuse or abuse in relation to rFVIIIFc or 
rFIXFc 
Diagnostic and therapeutic non-invasive and planned invasive procedures, such as planned 
surgery, should not be reported as AEs. 
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6.5.12.3 
Lack of efficacy 
Failure of pharmacologic action or therapeutic benefit shall be recorded only when assessed as 
an SAE. 
6.5.12.4 
Serious adverse event  
An AE that meets one or more of the following criteria/outcomes is classified as serious: 
 Results in death. 
 Is life threatening (i.e., at immediate risk of death). 
 Requires in-patient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect (i.e., in an offspring to the study patient). 
 Is a medically important AE. 
Medically important AEs are events that may not result in death, be life threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical judgement, 
may jeopardize the patient or may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization or development of dependency or abuse. 
Serious also includes any other event that the investigator or company judges to be serious. Any 
suspected transmission via a medicinal product of an infectious agent is also considered serious. 
6.5.12.5 
Hospitalization 
Hospitalization includes transfers within a hospital (e.g. from the psychiatric unit to the intensive 
care unit) and also includes admissions less than 24 hours. The following situations are not 
considered hospitalizations (although other SAE criteria may still apply): 
 Outpatient procedures/ambulatory care 
 Emergency department visits 
Hospitalization in the absence of an AE occurring during the study should not be considered an 
SAE. This includes: 
 Hospitalization due to a pre-existing condition not associated with a worsening of the 
pre-existing condition 
 Protocol-specified admission 
 Elective admission, e.g. due to cosmetic surgery 
 Pre-planned admission for a condition specified at baseline for the patient 
6.5.12.6 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is an adverse reaction which is not consistent with the EU SmPC. 
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6.5.12.7 
Adverse event reporting period 
The period for recording all AEs in the eCRF begins upon signature of the informed consent 
form and collection of non-serious AEs ends at the last study visit. 
All SAEs should be reported to Sobi from the time the patient has signed the informed consent 
until the EOS visit. Subsequently only SAEs assessed by the investigator as related, and fatal 
SAEs, should be reported during the follow-up period, until EOS visit. 
6.5.12.8 
Obtaining and recording adverse event information 
The investigator is to record all observed AEs (directly observed, spontaneously reported by the 
patient or solicited), in the eCRF using concise medical terminology. 
Each patient will be questioned about AEs at each clinic visit following initiation of treatment. 
The question asked will be “Since your last clinic visit, have you had any health problems?”. 
When possible and appropriate, a diagnosis rather than individual signs and symptoms shall be 
recorded. The investigator is responsible for obtaining sufficient information to determine 
seriousness, causality and outcome of each AE. 
6.5.12.9 
Severity assessment 
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum severity of the AE. For the purpose of consistency, these severity grades are defined 
as follows: 
MILD 
Does not interfere with patient's usual function 
MODERATE  
Interferes to some extent with patient's usual function 
SEVERE 
 
Interferes significantly with patient's usual function 
6.5.12.9.1 
Severity versus seriousness 
A mild, moderate, or severe AE may or may not be serious, see section 6.5.12.4. These terms are 
used to describe the intensity of a specific event. Medical judgement should be used on a case-
by-case basis. 
For example, a headache may be severe in intensity, but would not be classified as serious unless 
it met one of the criteria for serious events listed above. 
6.5.12.10 
Causality assessment 
For each AE, the investigator must make a causality assessment to determine if there is a 
reasonable possibility that the study treatment caused the AE. The AE is assessed as related or 
not related to the study treatment. 
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6.5.12.11 
Adverse events of special interest 
The following are considered adverse events of special interest: 
 inhibitor development 
 thrombotic events 
 serious hypersensitivity reaction including anaphylactic reactions  
6.5.12.12 
Serious adverse event reporting 
Both serious and non-serious AEs are to be reported on the AE page of the eCRF as specified in 
the eCRF instructions. 
If an SAEs occurs, Sobi Good Pharmacovigilence Practice (GVP) will be notified by e-mail to 
adverseevent@sobi.com by the investigator entering the required information about the SAE into 
the appropriate module of the eCRF using the designated SAE form within 24 hours of 
awareness of the event by the investigator. This is also applicable for SAE follow-up 
information. 
All SAEs must be recorded on the eCRF SAE form, irrespective of the study treatment received 
by the patient, and whether or not this event is considered by the investigator to be related to 
study treatment. The investigator must complete the eCRF SAE form in English and must assess 
the causal relationship of the event to study treatment. 
The eCRF SAE collection form is not the same as the AE eCRF form. The forms must be 
completed in a consistent manner. For example, the same AE term should be used on both forms. 
If the eCRF is not functioning, the SAE can be reported by emailing a completed paper SAE 
report form, using the e-mail address adverseevent@sobi.com. The event must be updated 
electronically in the eCRF by the clinical site once eCRF function resumes. 
All new information obtained, relevant to an SAE report, should be forwarded to Sobi GVP by e-
mail to adverseevent@sobi.com within the same timeframe as the initial information. 
The investigator shall provide Sobi GVP with sufficient information to enable a complete 
medical assessment of the reported event. Best efforts shall be made by the investigator to 
provide Sobi with additional information related to any SAE as requested. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from Sobi/CRO, will review it and will 
notify the IECs, if appropriate according to local requirements. 
Sobi Global pharmacovigilance & patient safety (GPV)will report SUSARs to the relevant 
Health Authorities in all concerned countries according to local regulations. Sobi/CRO will 
notify central IECs according to local requirements, and investigators. 
6.5.12.13 
Follow-up of unresolved adverse events 
All reported AEs should be followed up until they are resolved or the investigator assesses them 
as chronic or stable, or the patient’s participation in the study ends, i.e., until the last scheduled 
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visit. How to report changes in an ongoing AE during a patient's participation in the study is 
described in the eCRF instructions. 
In addition, all serious and non-serious AEs assessed by the investigator as related to the study 
treatment should continue to be followed up until they resolve or until the investigator assesses 
them as “chronic” or “stable”, even after the patient's participation in the study is over, but 
without further recordings into the eCRF. 
6.5.12.14 
Exposure during pregnancy and breastfeeding 
All events of exposure to the study treatment during pregnancy (female patient or male patient’s 
partner) or breastfeeding, shall be reported to Sobi GPV by e-mail to adverseevent@sobi.com 
within 24 hours of awareness by any study personnel using the Pregnancy Notification Form, 
whether the exposure is associated with an AE or not. This includes all situations where a female 
is or has been found to be pregnant after being exposed to study treatment; directly, indirectly or 
via her partner (paternal exposure). 
In all reported situations of exposure during pregnancy, Sobi will provide the investigator with a 
Pregnancy Report Form which shall be completed and returned by the investigator. The 
investigator is responsible for monitoring the outcome of the pregnancy and to inform Sobi of 
relevant information and any information requested related to the outcome of the pregnancy. 
Before collecting any details on the pregnancy, its outcome, the birth, and health of the baby, a 
separate consent form should be collected from the mother and/or the father of the child, as 
required by local regulations. 
Any AEs and SAEs observed during and in relation to pregnancy, delivery or breastfeeding 
should be recorded in the eCRF and, as applicable, be reported to Sobi as described previously in 
this section. 
6.5.12.15 
Appropriateness of safety measurements 
The safety measurements in this study is in line with the scope and type of the clinical study, the 
level of knowledge on the safety profile of the study drugs, the disease profile of the study 
patients, and supported by EU regulatory requirements. 
7 
Quality control and quality assurance 
This study will be conducted in compliance with this protocol, study specific procedures, Sobi 
and/or CRO SOPs, the ICH GCP Guideline (2), and applicable regulatory requirements. 
The sponsor will systematically review the study quality management to identify, evaluate and 
control risks to study critical processes and data which would affect patient safety and reliability 
of study data. 
The Sponsor will establish a systematic, prioritized, risk-based approach to monitoring and has 
chosen a combination of on-site and centralized monitoring. 
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Monitoring visits to the study site will be performed periodically during the study, to help ensure 
compliance with the protocol, study specific procedures and applicable regulatory requirements. 
Source documents will be reviewed for verification of agreement with data in CRFs. All patient 
informed consent forms will be reviewed. The investigator or institution guarantees access to 
source documents by Sobi, its representatives, and appropriate regulatory agencies. 
The study site may be patient to a quality assurance audit by Sobi or its representatives, as well 
as inspection by appropriate regulatory agencies. 
It is important that the investigator(s) and the(ir) relevant personnel are available during the 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
8 
Statistical plan 
8.1 
Determination of sample size 
With a sample size of 250 patients (200 with haemophilia A and 50 with haemophilia B) 
assuming a standard deviation of 13, the mean change from baseline in Total HEAD-US score 
will be estimated with a level of accuracy that is lower than a clinically meaningful worsening of 
2, e.g. a half width of 1.61 (Table 3). The standard deviation is based on the expected variability 
among the patients with regards to prior treatment before enrolment and the diversity of joint 
status. 
Table 3  
Determination of sample size 
Confidence level 
Standard deviation 
n 
Half width 
95% 
7 
250 
0.87 
95% 
10 
250 
1.25 
95% 
13 
250 
1.61 
95% 
13 
200 
1.80 
8.2 
Definition of study populations 
Full analysis set (FAS): All patients enrolled in the study. 
Per protocol (PP) analysis set: All patients enrolled in the study who completed the study without 
any major protocol violations. 
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8.3 
Overall statistical and analytical plan 
8.3.1 
General statistical issues 
A detailed Statistical Analysis Plan (SAP) describing further details of the statistical analyses to 
be used will be prepared prior to first patient in. 
All continuous variables will be summarized with descriptive statistics including number of 
observations, mean, standard deviation, median, quartiles, minimum and maximum values. 
Categorical variables will be summarized in frequency tables including number of observed 
responses in each category as well as percentages. Number of missing observations will also be 
displayed. No formal statistical hypothesis testing is planned. 
Baseline is defined as the measurements taken on Visit 1. 
Historical data (6-months before enrolment) will be tabulated by type of haemophilia, total and 
listed. 
8.3.2 
Demographics and baseline characteristics 
All demographics and baseline characteristics will be summarized with descriptive statistics by 
type of haemophilia and in total. Individual patient data will be listed. 
Disposition: Patient disposition will be listed with any withdrawals flagged. Frequencies 
(number and %) of the total number of patients enrolled, completed, prematurely withdrawn 
(including reason for withdrawal) from the study, number of sites with at least one patient 
enrolled, number of patients in the FAS and number of patients in the PP set will be summarized.  
Demographics: Demographic data (age, weight, height, severity of haemophilia and type of 
haemophilia (A or B)) at baseline visit will be summarized and listed by descriptive statistics. 
Number and location of impaired joints at baseline will be presented by descriptive statistics. 
8.3.3 
Analysis related to primary objective 
The primary objective is to evaluate the overall joint status as detected by US in haemophilia A 
and B patients treated with rFVIIIFc or rFIXFc prophylaxis over the 18-month study period. 
The primary endpoint is change from baseline in total HEAD-US score up to month 18 (EOS) 
and will be based on both the FAS and PP set. 
The primary endpoint, change from baseline, will be calculated from baseline (Visit 1) to month 
18 (EOS). The change in HEAD-US score will also be calculated from baseline to month 6 and 
month 12. Mean change from baseline for the primary endpoint, will be estimated using a 
generalized linear mixed model for repeated measures, adjusted for clinically important 
covariates (for example, age, severity of haemophilia, type of haemophilia, presence of joint 
disease at inclusion, prophylactic regimen and dose intensity) as applicable. The estimated mean 
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change from baseline in Total HEAD-US score will be presented with 95% confidence interval. 
In general, patients with events that could affect the interpretation of the Total HEAD-US score 
but not leading to discontinuation of treatment will be included in the primary analysis. Patients 
with events leading to discontinuation of treatment will be included in the primary analysis 
including all data collected up to discontinuation. To assess the robustness of these results, 
sensitivity analyses will be performed including one based on the PP analysis set. Further details 
will be specified in the SAP. 
Examples of subgroups that will be created if applicable, to further explore the endpoint are age 
(6-<12, 12-<18, ≥18 years), severity of haemophilia (mild/moderate/severe), type of haemophilia 
(A/B), presence of joint disease at inclusion (synovial hypertrophy and/or osteochondral 
changes), prophylactic regimen (primary/secondary/tertiary), dose intensity cross tabulated by 
change vs. no change in HEAD-US score, treatment (on demand vs. prophylaxis) prior to 
enrolment into the study and compliance (if e.g. 20% of the patients have < 80% compliance). 
If there are few mild and moderate patients then these two severities will be pooled. 
The HEAD-US score represents the sum of item scores for abnormalities detected. Its values 
range from 0 (minimum) to 8 (maximum), see Table 4. 
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Table 4 
HEAD-US scoring method 
Disease activity (synovitis) 
Scale 
Hypertrophic synovium 
 
Absent/Minimal 
0 
Mild/Moderate 
1 
Severe 
2 
Disease damage (articular surfaces) 
 
Normal 
0 
Echotexture abnormalities, focal partial/full-thickness loss of the articular cartilage involving <25% 
of the target surface 
1 
Partial/full-thickness loss of the articular cartilage involving at least ≤50% of the target surface* 
2 
Partial/full-thickness loss of the articular cartilage involving >50% of the target surface 
3 
Complete cartilage destruction or absent visualization of the articular cartilage on the target bony 
surface 
4 
Bone 
 
Normal 
0 
Mild irregularities of the subchondral bone with/without initial osteophytes around the joint 
1 
Deranged subcondral bone with/without erosions and presence of prominent osteophytes around the 
joint 
2 
Note: Elbow: anterior aspect of the distal humeral epiphysis, Knee: femoral trochlea; Ankle: 
anterior aspect of the talar dome. 
 
8.3.4 
Analysis related to secondary objectives 
A detailed description of the secondary objectives and endpoints are found in section 5.2 of the 
protocol. The secondary endpoints will be based on both the FAS and the PP set. 
HEAD-US scores (hypertrophic synovium, cartilage, bone) and HJHS scores (Sum of joint 
totals, Global Gait Score, HJHS total score) will be presented using descriptive statistics at each 
visit. In addition, the change from baseline to each post-baseline visit will also be presented with 
descriptive statistics and the estimated average change from baseline together with 95% CI. 
The number and proportion of patients with target joints as well as the total number of target 
joints will be analyzed by summary statistics as well as frequency tables for each visit. Target 
joint locations will be given for each visit in frequency tables. 
The ABR for treated bleeds and ABR for all (treated and untreated bleeds) will be derived for the 
period between baseline and month 6 visit, for the period between month 6 and month 12 visit, 
for the period between month 12 and month 18, and as well as for the entire 18-month study 
period. The ABR will also be presented for the retrospective 6 month period. ABR will be 
presented using summary statistics for all periods and also be presented by type 
(spontaneous/traumatic/unknown) and location (joint/muscle/unknown). The number and 
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percentage of patients who had a at least one bleeding episode (overall, circumstance, locations 
and target joint) over the 18-month prospective period will also be presented as well as the 
corresponding total number of episodes. The number and proportion of patients with 0 joint 
bleeds will be presented, as well as the number and proportions with 1, 2 etc. joint bleeds. To 
justify an estimation of the ABR and to reduce potential misclassification, a patient had to be 
documented for at least 3 months. 
PROMIS and IPAQ-SF scores will be presented at baseline and 18 months graphically and in 
tabular form with descriptive statistics (mean IPAQ-SF score measured as MET-minutes/week) 
and change. 
8.3.5 
Analysis related to exploratory objectives 
All patients who use florio HAEMO or their caregivers for patients <12 years of age and who 
consent to the use of florio HAEMO data in the study, will, once they have used florio HAEMO 
for at least 3 months, be asked to complete a questionnaire with questions about their use of 
florio HAEMO, how it affects their haemophilia management, and if it has an impact on their 
sense of protection and activity level. The results from the questionnaire will be summarized 
using descriptive statistics as appropriate. Data generated from florio HAEMO (treatment 
adherence scores, estimated FVIII or FIX levels, physical activity levels, dosing, bleeds, pain, 
well-being) will be analyzed and described in the SAP. 
8.3.6 
Analysis of safety and tolerability data 
8.3.6.1 
Adverse events 
Reported AEs during the study will be coded using the Medical Dictionary for Regulatory 
Activities. The incidence of AEs will be summarized in frequency tables by treatment, system 
organ class, preferred term and maximum severity. Separate tabulations will performed for 
serious and non-serious AEs. 
8.3.7 
Interim analysis 
Interim analyses are planned to be performed during the study. The first interim analysis is to be 
performed once recruitment is completed. The purpose of the first interim analysis is to assess 
the baseline variability of HEAD-US results and to share baseline characteristics with the 
haemophilia community. The second interim analysis is planned to be performed once at least 
50% of the patients have completed their 12-month visit and will evaluate the joint health status 
at that time. 
8.3.8 
Handling of missing data 
Methods for handling missing data will be described in the SAP. 
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9 
Data collection, handling and record keeping 
9.1 
Data standards 
Collection of data should be performed in the Clinical data acquisition standards harmonization 
format, according to the Clinical data interchange standards consortium (CDISC). The standards 
should be used to the extent possible and/or required for the specific study/project. The minimum 
requirement of the CDISC standard is to collect all core variables specified as ‘Required’ in the 
Study Data Tabulation Model format. 
9.2 
Case report form 
A CRF is required and should be completed for each enrolled patient. In this study a web based, 
validated electronic data capture (EDC) software tool will be used to collect and process the 
study data. The management of the EDC system will be based on the model of outsourcing. 
The data should be entered by site users into the EDC system on an ongoing basis. In principle, it 
is recommended to perform data entry within 5 working days from the visit date unless otherwise 
specified by the site Clinical Trial Agreement. To ensure data quality within EDC, automated 
edit checks will be built into the EDC system and triggered to correct or verify the input data. 
Any data changes or modifications within EDC will be automatically tracked by an audit trail 
detailing date, time and name of the user performing corrections. 
Clinical data management will be conducted in accordance with regulatory standards. This 
applies to data recorded directly in eCRF and to data from other sources stored at secure servers 
(e.g. IXRS, Laboratory). Additional details regarding data collection and validation procedures 
will be detailed in a Data Management Plan. 
Access to the EDC system is granted and revoked in accordance with regulatory requirements. 
Only authorized personnel will have access to the EDC system upon completion of the user 
training. 
The investigator will review and approve the eCRF entries for each patient with an electronic 
signature. The signatures serve to attest that the information contained on the eCRFs is correct. 
At all times, the investigator has final responsibility for the accuracy and authenticity of all data 
entered in the eCRF. 
The completed original eCRFs are the sole property of Sobi and should not be made available in 
any form to third parties, except for authorized representatives of appropriate regulatory 
authorities, without written permission from Sobi. 
At the end of the study, a final copy of the database will be stored at the Sponsor. Sobi will 
ensure that an eCRF copy of trial’s final and locked data is provided to the Investigator in a form 
of a write protected PDF files and that the eCRF copies are an exact copy of the data maintained 
in the database. 
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9.3 
Source data 
Patient source documents are the physician’s patient records maintained at the study site. In most 
cases, the source documents will be the hospital’s or the physician’s chart. In those cases, the 
information collected in the eCRFs must match those charts. In some cases, a portion of the 
source documents for a given patient may be the eCRF. 
The florio HAEMO database will be considered as the source for the florio HAEMO data. 
A separate source document location agreement will be completed and signed by the principal 
investigator and the monitor before study start. 
Source data should be attributable, legible, contemporaneous, original, accurate, and complete. 
Changes to source data should be traceable, should not obscure the original entry, and should be 
explained if necessary (e.g. via an audit trial). 
9.4 
Protocol deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of patients. The investigator should not 
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to study patients. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited. 
For the purpose of this protocol, deviations requiring notification to CRO are defined as any 
patients who: 
 Entered into the study even though they did not satisfy entry criteria; 
 Developed withdrawal criteria during the study and were not withdrawn; 
When a deviation from the protocol is identified, the investigator or designee must ensure the 
CRO is notified. The CRO will follow up with the investigator, as applicable, to assess the 
deviation and the possible impact to the safety and / or effectiveness of the patient to determine 
patient continuation in the study. 
The investigator and CRO must contact Sobi immediately if a deviation is discovered that 
significantly affects or has the potential to significantly affect human patient protection or the 
reliability of study results. 
The investigator will also assure that deviations are reported and documented in accordance with 
IEC and applicable regulatory requirements. 
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9.5 
Database closure 
Prior to database closure, all tasks or criteria defined in the data management plan must be 
completed and documented. The study database must be locked before breaking of the blind and 
before generation of any results. The database lock will be approved by relevant study personnel 
and all edit accesses will be removed. 
Prior to database closure, all tasks or criteria defined in the data management plan must be 
completed and documented. The study database must be locked before generation of any results. 
The database lock will be approved by relevant study personnel and all edit accesses will be 
removed. 
If data errors are detected after database lock which either: 
a) Have a significant impact on the statistical outcome of the analysis 
b) Affects the safety profile of the investigational product 
c) Affects the benefit-risk of the investigational product  
the database may be unlocked if approved. 
9.6 
Record retention 
The investigator should maintain a record of the location(s) of investigator’s essential documents 
as defined in the ICH GCP Guideline (2) including source documents and should have control of 
and continuous access to all essential documents and records generated by the 
investigator/institution before, during, and after the study. 
All documents and data relating to the study will be kept securely by the investigator in a 
secure file and/or electronically. The storage system used during the study and for archiving 
(irrespective of the type of media used) should provide for document identification, version 
history, search and retrieval. The data will be available for evaluation and/or audits from Health 
Authorities, Sobi or Sobi’s representatives. 
When a copy is used to replace an original document (e.g. source documents, CRF), the copy 
should fulfill the requirements for certified copy as defined in ICH GCP Guideline (2). 
The records of the clinical trial should be retained by the Investigator for at least 25 years after 
the end of the clinical trial. However the medical files of patients shall be archived in accordance 
with national law. Further details around archiving is specified in the Clinical Trial Agreement. 
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator or another 
institution. 
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9.7 
Data protection 
Study patients will be assigned a unique identifier by the sponsor. Any patient records or datasets 
that are transferred to the sponsor will contain the identifier only; patient names or any 
information which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient who will be required to give consent for their data to be used as described in the 
informed consent. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IECmembers, and by inspectors from regulatory authorities. 
The contract between sponsor and study sites specifies responsibilities of the parties related data 
protection, including handling of data security breaches and respective communication and 
cooperation of the parties. 
Information technology systems used to collect, process, and store study-related data are secured 
by technical and organizational security measures designed to protect such data against 
accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
10 
End of study 
The end of this study is defined as the date of last patient out, i.e., the last patient’s last visit. 
11 
Sponsor’s discontinuation criteria 
Sobi reserves the right to discontinue the study prior to inclusion of the intended number of 
patients but intends only to exercise this right for valid scientific or administrative reasons. After 
such a decision, the investigator must contact all participating patients before the next scheduled 
site visit. All study materials must be collected and all the CRFs completed to the greatest extent 
possible. 
12 
Dissemination and publication of results 
Sobi will register the study by posting study information and post study results regardless of 
outcome on a publicly accessible website in accordance with applicable laws and regulations, 
e.g., on www.clinicaltrials.gov and EudraCT. The results of this study will be published within 6 
months of the EOS. 
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Sobi is committed to publishing study results in a complete, accurate, balanced, transparent and 
Stimely manner. Sobi follows the principles of the International Committee of Medical Journal 
Editors recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals including criteria for authorship (31). 
The data from this study will be considered for reporting at a scientific meeting or for 
publication in a scientific journal. The sponsor will be responsible for these activities and will 
work with the investigators to determine how the publication is written, the number and order of 
authors, the journal or scientific meeting to which it will be submitted, and other related issues. 
The results of the study, or any part thereof, shall not be published without the prior written 
consent and approval of Sobi, such consent and approval not to be unreasonably withheld. 
13 
Reference list 
1 
Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. 
Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb 
Haemost. 2014;12(11):1935-9 
2 
ICH Harmonised Guideline: Integrated addendum to ICH E6 (R1), Guideline for Good 
Clinical Practice E6(R2) Current Step 4 version dated 9 November 2016. Available from: 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html 
3 
Clinical Trials Regulation (Regulation (EU) No 536/2014) EUR-Lex - 32014R0536 - EN 
- EUR-Lex (europa.eu) 
4 
World Medical Association Declaration of Helsinki; Ethical Principles for Medical 
Research Involving Human Subjects. Amended version dated October 2013. Available 
from: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-
for-medical-research-involving-human-subjects/ 
5 
Roosendaal G, Lafeber FP. Blood-induced joint damage in hemophilia. Semin Thromb 
Hemost. 2003;29(1):37-42 
6 
WFH. About Bleeding Disorders: Severity of hemophilia [Internet]. World Federation of 
Hemophilia Web site Website. http://www.wfh.org/en/page.aspx?pid=643. Published 
2013. Updated May 2012. Accessed Oct. 2015. 
7 
G Dolan et al, Blood Reviews 2018 
8 
van Genderen FR, Westers P, Heijnen L, et al. Measuring patients' perceptions on their 
functional abilities: validation of the Haemophilia Activities List. Haemophilia. 
2006;12(1):36-46 
9 
Pulles AE, Mastbergen SC et al. Pathophysiology of hemophilic arthropathy and 
potential targets for therapy. Pharmacological Research 115. 2017:192-199 
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10 
Valentino LA, Walsh CE, et al. Patient- and caregiver-reported bleeding symptoms and 
reason for starting and stopping treatment with rFVIIa: analysis of the Dosing 
Observational study in Haemophilia (DOSE). Haemophilia. 2012 
11 
Berntorp E, Astermark J, et al. Consensus perspectives on prophylactic therapy for 
haemophilia: Summary statement. Haemophilia. 2003 
12 
Konkle BA, Shapiro AD, et al. BIVV001 Fusion Protein as Factor VIII Replacement 
Therapy for Hemophilia A. N Engl J Med. 2020;383:1018-27 
13 
MASAC Document #226 (Replaces #169). MASAC Recommendation Regarding the 
Use of Recombinant Clotting Factor Products with Respect to Pathogen Transmission. 
May 2014. New York, NY: National Hemophilia Foundation (NHF). 
http://www.hemophilia.org/sites/default 
14 
Berntorp E, Dolan G, Hay C, Linari S, Santagostino E, Tosetto A, et al. European 
retrospective study of real-life haemophilia treatment. Haemophilia: the official journal 
of the World Federation of Hemophilia. 2017;23(1):105-14 
15 
Lofqvist T, Nilsson IM, Berntorp E, Pettersson H. Haemophilia prophylaxis in young 
patients--a long-term follow-up. Journal of internal medicine. 1997;241(5):395-400 
16 
Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. 
Prophylaxis versus episodic treatment to prevent joint disease in boys with severe 
hemophilia. N Engl J Med. 2007;357(6):535-44 
17 
Hilliard P, Funk S, Zourikian N, Bergstrom BM, Bradley CS, McLimont M, et al. 
Hemophilia joint health score reliability study. Haemophilia: the official journal of the 
World Federation of Hemophilia. 2006;12(5):518-25 
18 
Feldman BM FS, Hilliard P, Van Der Net J, Zourikian N, Berstrom B-M, Engelbert 
RHH, Abad A, Petrini P, Manco-Johnson M, and the International Prophylaxis Study 
Group. Hemophilia Joint Health Score (HJHS) 2.1 
19 
The XXVIII World Federation of Hemophillia Congress June 1-5, 2008; Istanbul, Turkey 
20 
Martinoli C, Della Casa Alberighi O, Di Minno G, Graziano E, Molinari AC, Pasta G, et 
al. Development and definition of a simplified scanning procedure and scoring method 
for Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US). Thrombosis 
and haemostasis. 2013;109(6):1170-9 
21 
Fischer K, Konkle B, Broderick C, Kessler CM. Prophylaxis in real life scenarios. 
Haemophilia : the official journal of the World Federation of Hemophilia. 2014;20 Suppl 
4:106-13 
22 
Niu X, Poon JL, Riske B, Zhou ZY, Ullman M, Lou M, et al. Physical activity and health 
outcomes in persons with haemophilia B. Haemophilia: the official journal of the World 
Federation of Hemophilia. 2014;20(6):814-21 
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23 
Schmidt DE, Michalopoulou A, Fischer K, et al. Long-term joint outcomes in adolescents 
with moderate or severe haemophilia A. Haemophilia. 2022;28(6):1054-1061. 
24 
24-month Prospective, Multicentre, Non-interventional Study to Evaluate the 
Effectiveness of Elocta Compared to Conventional Factor Products in the Prophylactic 
Treatment of Patients With Haemophilia A (A-SURE) (NCT02976753)  
25 
A 24-month Prospective, Non-interventional, Multicentre Study to Evaluate the Real-
World Usage and Effectiveness of Elocta and Alprolix in Patients With Haemophilia A 
or B (PREVENT) (NCT03055611) 
26 
Martinoli C, Alberighi ODC, Di Minno G, et al. Development and definition of a 
simplified scanning procedure and scoring method for Haemophilia Early Arthropathy 
Detection with Ultrasound (HEAD-US). Thromb Haemost. 2013;109:1170–1179 
27 
Feldman BM, Funk SM, Bergstrom BM, et al. Validation of a new pediatric joint scoring 
system from the International Hemophilia Prophylaxis Study Group: validity of the 
hemophilia joint health score. Arthritis Care Res. 2011;63:223-230. 
28 
St-Louis J, Abad A, Funk S, et al. The Hemophilia Joint Health Score version 2.1 
Validation in Adult Patients Study: A multicenter international study. Res Pract Thromb 
Haemost. 2022;6(2):e12690 
29 
Cella D, Yount S, et al. The Patient-Reported Outcomes Measurement Information 
System (PROMIS): Progress of an NIH Roadmap Cooperative Group During Its First 
Two Years. Medical Care, 45(5 suppl 1). 2007;S3-S11 
30 
Craig CL, Marshall AL, Sjostrom M, et al. International physical activity questionnaire: 
12-country reliability and validity. Med Sci Sports Exerc. 2003;35:1381‐1395 
31 
International Committee of Medical Journal Editors. Recommendations for the conduct, 
reporting, editing, and publication of scholarly work in medical journals: updated 
December 2016 [Internet]. International Committee of Medical Journal Editors (ICMJE); 
2016. [cited 2017 Jan 12]. Available from: http://www.icmje.org/recommendations/  
 
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Appendix 1 
Study Administrative Structure 
Monitoring: IQVIA Ltd., Reading, United Kingdom 
SAE reporting: Shared responsibility between IQVIA Ltd., Reading, United Kingdom and 
Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden 
Data management: IQVIA Ltd., Reading, United Kingdom 
Statistics: IQVIA Ltd., Reading, United Kingdom 
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Appendix 2 
florio HAEMO Patient Questionnaire 
florio HAEMO Effect on Sense of Protection & Activity Level 
Have you used any other haemophilia management tool before? 
o Yes 
o No 
If yes; enter the one(s) you have you used: _________________________________________ 
How often did you use florio HAEMO to monitor your estimated FVIII or FIX levels in the last 
month? 
o Daily 
o A few times per week 
o Once weekly 
o A few times per month 
o Never 
Since you started using florio HAEMO, do you feel more in control of your haemophilia? 
o In much better control 
o In better control 
o No difference 
o In worse control 
o In much worse control 
Since you started using florio HAEMO, do you feel more protected against bleeds? 
o  Much more protected 
o More protected 
o No difference 
o Less protected 
o Much less protected 
Has florio HAEMO helped you in choosing the timing of your physical activities? 
o Yes 
o No 
Has florio HAEMO helped you to facilitate care planning and potential treatment adjustment 
discussions with your health care provider? 
o Yes 
o No 
Would you recommend the use of florio HAEMO to other haemophilia patients? 
o Yes 
o No 
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If you answered no, can you comment on the reason(s)? 
______________________________________________________________ 
Patient Study ID: ________________________ 
 
Date of completion: ______________________ 
 
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Appendix 3 
florio HAEMO Caregiver Questionnaire 
florio HAEMO Effect on Sense of Protection & Activity Level 
 
Has your child used any other haemophilia management tool before? 
o Yes 
o No 
If yes; enter the one(s) you have you used: _________________________________________ 
How often did your child use florio HAEMO to monitor his/her estimated FVIII or FIX levels in 
the last month? 
o Daily 
o A few times per week 
o Once weekly 
o A few times per month 
o Never 
Since your child started using florio HAEMO, do you feel more in control of your child’s 
haemophilia? 
o In much better control 
o In better control 
o No difference 
o In worse control 
o In much worse control 
Since your child started using florio HAEMO, do you feel that your child is more protected 
against bleeds? 
o Much more protected 
o More protected 
o No difference 
o Less protected 
o Much less protected 
Has florio HAEMO helped your child in choosing the timing of his/her physical activities? 
o Yes 
o No 
Has florio HAEMO helped you and your child to facilitate care planning and potential treatment 
adjustment discussions with his/her health care provider? 
o Yes 
o No 
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Would you recommend the use of florio HAEMO to other haemophilia patients? 
o Yes 
o No 
If you answered no, can you comment on the reason(s)? 
______________________________________________________________ 
 
Patient Study ID: ________________________ 
 
Date of completion: ______________________ 
 
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