A Study Evaluating Physical Activity and Joint Health in Severe Haemophilia A Patients ≥12 Years Treated Once Weekly With Efanesoctocog Alfa

Study Overview
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Brief Summary
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FREEDOM is a multicentre, open-label, single-arm, phase 3b study in Europe that aims to enrol approximately 90 previously treated severe haemophilia A patients aged ≥12 years, currently on prophylaxis. After a run-in period of 30-45 days, patients will receive efanesoctocog alfa prophylaxis, 50 IU/kg once-weekly for 24 months (additional preventive dose not permitted). An activity tracker and an electronic patient diary will be used to collect data on physical activity, bleeds, factor dosing, pain, and injuries from screening throughout the study. The primary objective is to describe changes in physical activities over 24 months on efanesoctocog alfa prophylaxis, with a primary endpoint of change from baseline in International Physical Activity Questionnaire (IPAQ) at month 24. Secondary objectives include relationship between physical activity and other variables (bleeds, joint status, pain, injuries, and quality of life); changes in joint status as assessed by HEAD-US, HJHS and MRI; occurrence of bleeds, injuries, pain. Safety and tolerability of efanesoctocog alfa will also be evaluated.

Official Title
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A Phase 3b Open-label Study Evaluating Physical Activity and Joint Health in Previously Treated Patients ≥12 Years With Severe Haemophilia A Treated With Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein (Efanesoctocog Alfa) for 24 Months

Conditions
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Hemophilia A, Severe

Intervention / Treatment
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* Drug: Efanesoctocog alfa


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Previous treatment for haemophilia A with any marketed recombinant and/or plasma-derived FVIII for at least 150 EDs. Having received prophylactic treatment with any marketed recombinant and/or plasma FVIII or emicizumab per local label for at least 12 months preceding enrolment. Having 12 months documented pre-study treatment data regarding prophylactic treatment prescriptions and 6 months data on bleeding episodes prior to baseline visit. Willingness and ability to complete training in the use of the study ePD and to use the ePD in their own smartphone throughout the study. Willingness and ability to use the activity tracker provided by the sponsor to measure physical activity and heart rate. Be able and willing to administer efanesoctocog alfa intravenously at home. Key Exclusion Criteria: Serious musculoskeletal and/or neurological impairment limiting the mobility and the physical ability to a degree that makes the patient unsuitable for the study as judged by the investigator. Other known coagulation disorder(s) in addition to haemophilia A. History and/or current positive inhibitor test defined as ≥0.6 BU/mL. Treatment with NSAIDs above the maximum dose specified in the prescribing information within 2 weeks prior to screening. Systematic treatment within 12 weeks prior to screening with chemotherapy and/or other immunosuppressive drugs. Treatment with an investigational product within 30 days or 5.5 half-lives prior to screening, whichever is longer. Major surgery within 12 weeks prior to screening or planned major orthopaedic surgery to occur during the study. At baseline visit, patients who have not been compliant in using the activity tracker.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Efanesoctocog alfa<br>All patients will be treated intravenously once weekly with 50 IU/kg efanesoctocog alfa | Drug: Efanesoctocog alfa<br>* Recombinant coagulation factor VIII Fc-von Willebrand Factor-XTEN fusion protein (rFVIIIFc-VWF-XTEN)<br>* Other names: BIVV001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in International Physical Activity Questionnaire (IPAQ) scoring | The IPAQ 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. Higher scores means higher physical activity level. | Baseline and month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in International Physical Activity Questionnaire (IPAQ) scoring | The IPAQ 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. Higher scores means higher physical activity level. | Baseline and month 12 | 
| International Physical Activity Questionnaire (IPAQ) score | The IPAQ 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. Higher scores means higher physical activity level. | Baseline, month 6, 12, 18 and 24 | 
| Change in mean daily minutes in physical activity | Tracker-recorded | Run-in month, month 12 and 24 | 
| Mean daily minutes of physical activity | Tracker-recorded | Per 6-month period | 
| Change in type of workouts | Patient and tracker reported | Run-in month, month 12 and 24 | 
| Change in frequency of workouts | Patient and tracker reported | Run-in month, month 12 and 24 | 
| Change in duration of workouts | Patient and tracker reported | Run-in month, month 12 and 24 | 
| Change in patient reported intensity of workouts | The patient will report workouts in a patient diary and rate the intensity on a 5 level scale. The levels are: 1 = easy, 2 = moderate, 3 = slightly challenging, 4 = exhausting, 5 = very exhausting. The changes will be calculated on a intra-patient basis | Run-in month, month 12 and 24 | 
| Change in tracker recorded intensity of workouts | The patient will be provided with an activity tracker that will automatically record workouts when the patient is wearing the tracker. The intensity levels will be based on the heart rate and will be presented on a 4 level scale. The levels are: 1 = out of range, 2 = fat burn, 3 = cardio, 4 = peak | Run-in month, month 12 and 24 | 
| Mean value of patient and tracker reported type of workouts | Type of workout will be transcribed into a risk level of participating in a given activity for a haemophilia patient. Risk levels are based on a rating of 1-3 where level 1 represents a low risk of causing a bleeding episode and level 3 represents a high risk. The mean value will be calculated per 6-month period | Per 6-month period | 
| Mean value of frequency of workouts | Patient and tracker reported | Per 6-month period | 
| Mean value of duration of workouts | Patient and tracker reported | Per 6-month period | 
| Mean value of patient reported intensity of workouts | The patient will report workouts in a patient diary and rate the intensity on a 5 level scale. The levels are: 1 = easy, 2 = moderate, 3 = slightly challenging, 4 = exhausting, 5 = very exhausting. The mean value will be calculated per 6-month period | Per 6-month period | 
| Mean value of tracker recorded intensity of workouts | The patient will be provided with an activity tracker that will automatically record workouts when the patient is wearing the tracker. The intensity levels will be based on the heart rate and will be presented on a 4 level scale. The levels are: 1 = out of range, 2 = fat burn, 3 = cardio, 4 = peak The mean value will be calculated per 6-month period | Per 6-month period | 
| Change in mean daily number of steps | Tracker-recorded | Run-in month, month 12 and 24 | 
| Mean daily number of steps | Tracker-recorded | Per 6-month period | 
| Achieving WHO-recommended levels of MVPA | Tracker-recorded | Run-in month, month 12 and 24 | 
| Occurrence of bleeds in relation to workouts |  | Baseline to month 24 | 
| Occurrence of pain in relation to workouts |  | Baseline to month 24 | 
| Occurrence of injuries in relation to workouts |  | Baseline to month 24 | 
| Occurrence of bleeding episodes impacting daily activity |  | Baseline to month 24 | 
| Change from baseline in Haemophilia Joint Health Score (HJHS) score | 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, month 6, 12, 18, 24 | 
| Change from baseline in Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) | The HEAD-US joint score will be calculated for six joints, the right and left ankle, knee, and elbow joints. 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. 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, month 12 and 24 | 
| Change from baseline in haemophilic arthropathy assessed by the International Prophylaxis Study Group (IPSG) Magnetic Resonance Imaging (MRI) scale | The IPSG scale is made up of two subscores, one for soft-tissue changes and one for osteochondral changes. MRI joint score is the sum of the soft tissue and osteochondral subscores for each joint, ranging from 0-17 where 0 is absence of damage. MRI total score is the sum of joint scores across all joints. | Baseline, month 24 | 
| Target joint development (three or more spontaneous bleeds into a single joint within a consecutive 6-month period) | The number and proportion of patients with target joint development and the total number of target joint developed will be assessed. | Month 6, 12, 18, 24 | 
| Target joint resolution ( ≤2 bleeds into the joint within a consecutive 12-month period the joint is no longer considered a target joint) | The number and proportion of patients with target joint resolution and the total number of target joint resolutions will be assessed | Month 6, 12, 18, 24 | 
| Target joint recurrence (≥3 spontaneous bleeds in a single joint within any consecutive 6-month period after target joint resolution) | The number and proportion of patients with target joint recurrence and the total number of target joint recurrence will be assessed | Month 6, 12, 18, 24 | 
| Number of bleeding episodes |  | Per 6-month period and cumulative | 
| Annualized bleeding rate (ABR) |  | Baseline to month 24 | 
| Total annualized efanesoctocog alfa consumption |  | Baseline to month 24 | 
| Number of injections and dose to treat a bleeding episode |  | Baseline to month 24 | 
| Pain reported via electronic patient diary | The patient will report pain (cause of pain, location and intensity. The intensity will reported as mild, moderately low, moderately high, severe and worst possible. | Baseline to month 24 | 
| Pain intensity reported in the Patient-Reported Outcomes Measurement Information System (PROMIS) Scale - Pain Intensity 3a | The PROMIS Pain Intensity instrument assesses pain intensity on a 5-point Likert scale, ranging from 1 (had no pain) to 5 (very severe) | Baseline, month 6, 12, 18, 24 | 
| Pain interference reported in the Patient-Reported Outcomes Measurement Information System (PROMIS) scale - Pain interference 6a | The PROMIS Pain Interference 6a is a patient-assessed instrument and is to measure pain interference on a 5-point Likert scale, ranging from 1 (not at all) to 5 (very much) | Baseline, month 6, 12, 18, 24 | 
| Quality of life assessed by EuroQoL 5-dimension 5-level (EQ-5D-5L) | EQ-5D-5L assess 5 dimensions of health outcome (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each of the dimensions in the EQ-5D-5L questionnaire is divided into 5 levels: Level 1: indicating no problem Level 2: indicating slight problems Level 3: indicating moderate problems Level 4: indicating severe problems Level 5: indicating unable to/extreme problems Patients will select a level for each dimension that best describes their health status for that dimension. A 5 digit code will be obtained, made up of the response for each dimension. This code will then be converted to an index score.The EQ-5D-5L VAS is an overall assessment of health on a scale from 1-100 that the patient provides at the end of the EQ-5D-5L questionnaire. 100 represents the best health you can imagine and 0 represents the worst health you can imagine. | Baseline, month 6, 12, 18, 24 | 
| Assessment of treatment preference | This will be assessed with the Treatment Preference Survey that consists of 2 questions on perceived impact of treatment. | 24 months | 
| The occurrence of adverse events and serious adverse events |  | From screening to month 24 | 
| The occurrence of clinically significant changes | Assessed by physical examination, vital signs and laboratory tests | Baseline, month 6, 12, 18, 24 | 
| Development of inhibitors (neutralizing antibodies directed against FVIII) | Determined via the Nijmegen modified Bethesda assay | Baseline, month 6, 12, 18, 24 | 
| The occurrence of thrombotic and embolic events |  | From screening to month 24 | 
| Number of non-study medical care encounters | The number and proportion of patients having non-study medical care encounter visits will be described, as well as the corresponding total number of visits. | From baseline to month 24 | 
| Duration of non-study medical care encounters | The duration of non-study medical care encounter visits will be described. | From baseline to month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood coagulation disorder, Coagulation protein disorder, Haemophilia, FVIII, Efanesoctocog alfa