An 18-month Low-interventional Study to Assess Joint Health in Haemophilia A and B Patients on Prophylaxis With Efmoroctocog Alfa or Eftrenonacog Alfa

Study Overview
=================
Brief Summary
-----------------
The goal of this low-interventional study is to describe the overall joint health in patients with haemophilia A or haemophilia B prophylactically treated with rFVIIIFc or rFIXFc. The main question it aims to answer is the: • Evaluation of 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. Participants will come to 6-monthly visits during the 18-month long study period and will perform an ultrasound with the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) protocol at each visit. At baseline and end of study visits, the patients will be assessed with the clinical scoring system Haemophilia Joint Health Score (HJHS) and complete patient questionnaires. Retrospective data from patient medical records will also be collected for at least 6 months before enrolment in the study.

Detailed Description
-----------------
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 joint health and detection of hypertrophic synovium, cartilage and bone damage. At the same time, clinical joint status will also be examined by HJHS. This study will evaluate the presence, resolution, recurrence, and new development of target joints. It will also describe bleeding episodes and evaluate the quality of life and physical activity with PROs. If patients are using the CE marked Florio HAEMO app in their routine clinical practice, they will be offered to participate in an optional sub-study that aims to explore possible correlations between the levels of physical activity, the estimated FVIII/FIX levels and bleeding occurrence.

Official Title
-----------------
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

Conditions
-----------------
Hemophilia A, Hemophilia B

Intervention / Treatment
-----------------
* Procedure: Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US)
* Other: Haemophilia Joint Health Score (HJHS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 6 years Diagnosis of haemophilia A or B Having at least 6 months documented pre-study treatment data regarding treatment prescriptions and bleeding episodes prior to the baseline visit Previous treatment for haemophilia A or B with any marketed recombinant and/or plasma-derived FVIII or FIX concentrate for at least 6 months Start of prophylactic treatment with rFVIIIFc or rFIXFc prior to study enrollment or latest at the baseline visit, in accordance with local regulations 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 Exclusion Criteria: Any medical condition which in the opinion of the investigator makes the subject patient unsuitable for inclusion Prophylactic treatment with non-factor therapy during the 6 months prior to enrolment Presence of factor VIII or FIX inhibitory antibodies (inhibitors) (≥0.60 Bethesda Units [BU]/mL) at the latest available inhibitor test Enrolment in a concurrent clinical interventional study, or intake of an IMP, within three months prior to inclusion in this study Foreseeable inability to cooperate with given instructions or study procedures

Ages Eligible for Study
-----------------
Minimum Age: 6 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: This is a low-interventional study, with the drugs being prescribed and used according to clinical practice. The interventions in the study are the addition of the mandatory joint examinations HEAD-US (ultrasound) and HJHS (functional joint assessment).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Efmoroctocog alfa or eftrenonacog alfa<br>Efmoroctocog alfa or eftrenonacog alfa is prescribed and used according to usual clinical practice. | Procedure: Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US)<br>* Ultrasound examination<br>Other: Haemophilia Joint Health Score (HJHS)<br>* Functional joint examination<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in total HEAD-US score up to month 18 (end of study - EOS) | HEAD-US is a standardized, fast, repeatable, and simple ultrasound scoring protocol for hemophiliac joints. The HEAD-US joint score will be calculated for the six index joints (elbows, knees, and ankles). The specific joint score is made up of three item scores: disease activity (synovitis), disease damage of articular surfaces, and disease damage of subchondral bone. The specific joint score is the sum of the three item scores for each specific joint. Its values range from 0 (minimum) to 8 (maximum). The total score represents the sum of item scores for abnormalities detected. | Baseline and month 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in HEAD-US score for hypertrophic synovium | HEAD-US is a standardized, fast, repeatable, and simple ultrasound scoring protocol for hemophiliac joints. The HEAD-US joint score will be calculated for the six index joints (elbows, knees, and ankles). 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. | Baseline, month 6, 12 and 18 | 
| Change from baseline in HEAD-US score for cartilage | HEAD-US is a standardized, fast, repeatable, and simple ultrasound scoring protocol for hemophiliac joints. The HEAD-US joint score will be calculated for the six index joints (elbows, knees, and ankles). 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]). | Baseline, month 6, 12 and 18 | 
| Change from baseline in HEAD-US score for bone | HEAD-US is a standardized, fast, repeatable, and simple ultrasound scoring protocol for hemophiliac joints. The HEAD-US joint score will be calculated for the six index joints (elbows, knees, and ankles). 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]). | Baseline, month 6, 12 and 18 | 
| Change from baseline in total Hemophilia Joint Health Score (HJHS) at month 18 (EOS) | The HJHS measures joint health, in the domain of body structure and function (i.e., impairment). The six index joints (elbows, knees, and ankles) will be examined and scored. The minimum score per joint is 0, the maximum score is 20. In addition, Gait is scored on a scale from 0 to 4 based on the number of skills that are not within the normal limits. The total score will be the sum of scores across all six joints plus the gait score (range from 0 to 124, with 0 being normal and 124 being the most severe disease). | Baseline and month 18 | 
| Number of target joints | A target joint is defined as a joint with three or more spontaneous bleeds into the joint within a consecutive 6-month period. The study will evaluate the presence, resolution, recurrence, and new development of target joints. | Baseline, month 6, 12 and 18 | 
| Location of target joints | A target joint is defined as a joint with three or more spontaneous bleeds into the joint within a consecutive 6-month period. The study will evaluate the presence, resolution, recurrence, and new development of target joints. | Baseline, month 6, 12 and 18 | 
| Total annualized bleeding rate (ABR) | 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 months retrospective period to baseline, baseline to 6 months, 6-12 months, 12-18 months and entire study period | 
| Joint ABR | For any bleeding episode, the following will be collected: bleeding episode circumstance (e.g., spontaneous, traumatic), bleeding episode location, date of bleeding episode, dose (IU) and number of injections used to treat the bleed. | 6 months retrospective period to baseline, baseline to 6 months, 6-12 months, 12-18 months and entire study period | 
| Target joint ABR | For any bleeding episode, the following will be collected: bleeding episode circumstance (e.g., spontaneous, traumatic), bleeding episode location, date of bleeding episode, dose (IU) and number of injections used to treat the bleed. | 6 months retrospective period to baseline, baseline to 6 months, 6-12 months, 12-18 months and entire study period | 
| Traumatic/spontaneous ABR | 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 months retrospective period to baseline, baseline to 6 months, 6-12 months, 12-18 months and entire study period | 
| PROMIS physical function/activity short form 6b and 8a scores | Patient-Reported Outcomes Measurement Information System (PROMIS) is a validated system of reliable and precise measures of patient-reported health status. PROMIS measures cover physical, mental, and social health, use a 5-point Likert response scale and a recall period of the past 7 days. The Numeric Rating Scale measures for adults (6b) consist of a single item rating physical function on average over the past 7 days, ranging from 5 (without any difficulty) to 1 (unable to do). Lower scores mean a worse outcome. The Numeric Rating Scale measures for pediatric and parent proxy (8a) each consist of a single item rating physical activity on average over the past 7 days, ranging from 1 (no days) to 5 (6-7 days). Lower scores mean a worse outcome. | Baseline and 18 months | 
| PROMIS pain intensity 3a and 1a scores | Patient-Reported Outcomes Measurement Information System (PROMIS) is a validated system of reliable and precise measures of patient-reported health status. PROMIS measures cover physical, mental, and social health, use a 5-point Likert response scale and a recall period of the past 7 days. The Numeric Rating Scale measures for adults (3a) consist of a single item rating pain over the past 7 days from 1 (had no pain) to 5 (very severe). Higher scores mean a worse outcome. The Numeric Rating Scale measures for pediatric and parent proxy (1a) each consist of a single item rating pain over the past 7 days, ranging from 0 (no pain) to 10 (worst pain you can think of). Higher scores mean a worse outcome. | Baseline and month 18 | 
| PROMIS pain interference short form 6a and 8a scores | Patient-Reported Outcomes Measurement Information System (PROMIS) is a validated system of reliable and precise measures of patient-reported health status. PROMIS measures cover physical, mental, and social health, use a 5-point Likert response scale and a recall period of the past 7 days. The Numeric Rating Scale measures (adult, pediatric, parent proxy) each consist of a single item rating pain interference with different activities over the past 7 days, ranging from 1 (not at all/never) to 5 (very much/almost always). Higher scores mean a worse outcome. | Baseline and month 18 | 
| IPAQ-SF scores | International Physical Activity Questionnaire - Short Form (IPAQ-SF). The IPAQ-SF is a validated, 7-day recall questionnaire measuring current levels of physical activity. Scoring of the IPAQ 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. Higher scores mean higher physical activity level (better outcome). | Baseline and month 18 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Blood coagulation disorder, Coagulation protein disorder, Haemophilia, FVIII, FIX, Efmoroctocog alfa, Eftrenonacog alfa