The Hemophilia Ultrasound Project

Study Overview
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Brief Summary
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To evaluate the prevalence of subclinical arthropathy in children with severe hemophilia undergoing a prophylaxis regimen and without evidence of target joints, using a validated ultrasound scoring method.

Detailed Description
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Persons with Hemophilia (A or B) often experience recurrent joint bleeds, most commonly affecting the ankles, knees and elbows. These bleeds can lead to significant pain and disability over time. If recurrent joint bleeds are not managed with prompt and adequate infusions of factor concentrate, the damage caused by the presence of blood in the joint space will eventually result in a condition called debilitating chronic hemophilic arthropathy. The initiation of and adherence to a prophylactic infusion regimen, starting with the first or second joint bleed, is essential for prevention of progression to arthropathy. Studies have demonstrated that prophylaxis with recombinant or plasma-derived factor VIII or IX concentrates is effective in preventing clinical joint bleeds and the progression to debilitating joint disease in patients with severe hemophilia A or B respectively. However, for patients on prophylaxis, the absence of symptomatic joint bleeds and/or structural and functional abnormalities of joints on physical examination and plain radiographic images can lead to the erroneous assumption that the prophylaxis is completely effective. It has been established that patients with severe hemophilia are still at risk for subclinical bleeding (microbleeds) despite seemingly adequate prophylaxis. Young adults, despite a lifetime on prophylaxis and apparently normal joints are developing arthropathy in their 20's and 30's. Prophylaxis as currently practiced may only be delaying the onset of clinical joint disease. The recent advancements in ultrasound imaging (US) have been proven to be effective in confirming a joint bleed, monitoring the evolution of a joint bleed and assessing the resolution or recurrence of a bleed. Previous studies have evaluated the prevalence of subclinical arthropathy in young hemophilic adults using both US and MRI techniques and concluded that US is as effective and sensitive as MRI identifying these subclinical joint abnormalities. However, to the investigators' knowledge, no prior studies have used US technique over an extended period of time to monitor the natural evolution of joint arthropathy in children with hemophilia who are adherent to an established prophylaxis regimen and have no evidence of clinical joint compromise. The seminal Joint Outcome Study, which confirmed the role of prophylaxis in preventing overt clinical joint disease, mandated a trough residual factor VIII level of 1%. While this trough level significantly decreased overt hemarthroses and joint damage, the evidence suggestive of microbleeds raised a question as to the protection afforded by such a low trough level. Intuitively it would seem as if a higher trough level should confer greater protection against microbleeds, and result in more sustainable joint health. The ideal protective trough, has not been established. The investigators' hypothesis is that US is a valuable imaging technique to monitor the natural evolution of hemophilic arthropathy in children with severe hemophilia A or B who are undergoing prophylaxis regimen and do not manifest clinical evidence of hemophilic arthropathy. Through this observational study, the investigators will provide valuable information in regards the prevalence, progression and severity of joint abnormalities. The use of US to detect microbleeds before the cumulative damaging effects demonstrable by MRI, will also allow tailoring of treatment and the implementation of new prophylaxis strategies.

Official Title
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Evaluation of Joint Arthropathy Using Ultrasound Technique in Children With Severe Hemophilia Undergoing Prophylaxis Regimen

Conditions
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Hemophilia A, Hemophilia B

Intervention / Treatment
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* Other: Ankle and Knee Ultrasound Joint Assessment
* Other: Ankle and Knee Magnetic Resonance Imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe Hemophilia Cohort:Patients from 0 up to 30 months of age with diagnosis of severe hemophilia A or B defined as a factor VIII:C/IX:C of <1% undergoing prophylaxis regimen with any factor VIII or IX concentrate and without evidence (clinical or by history) of target joint disease. Mild/moderate Hemophilia Cohort:Patients from 0 up to 30 months of age with diagnosis of mild hemophilia A or B defined as a factor VIII:C/IX:C of 5-50% and those with diagnosis of moderate hemophilia A or B defined a s a factor VIII:C/IX:C of 1-5% without evidence (clinical or by history) of target joint disease and no history of spontaneous joint bleeds. Exclusion Criteria: Patients with concomitant Hepatitis B, Hepatitis C and HIV viral infections (because of a recognized arthritogen effect). Present or prior history of anti FVIII or IX inhibitors. Known inflammatory joint disease. Established target joint.

Ages Eligible for Study
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Maximum Age: 30 Months

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Severe Hemophilia A or B<br>Medical history, physical exam, vital signs,physical therapist targeted exam and ultrasound joint assessment (ankles and knees) every 6 months. MRI joint assessment (knees and ankles) at End of Trial Visit (Month 60). | Other: Ankle and Knee Ultrasound Joint Assessment<br>* Ultrasound Examination of the ankles and knees<br>Other: Ankle and Knee Magnetic Resonance Imaging<br>* Ankle and Knee Magnetic Resonance Imaging<br>|
| Mild/Moderate Hemophilia A or B<br>Medical history, physical exam, vital signs,physical therapist targeted exam and ultrasound joint assessment (ankles and knees) every year. MRI joint assessment (knees and ankles) at End of Trial Visit (Month 60). | Other: Ankle and Knee Ultrasound Joint Assessment<br>* Ultrasound Examination of the ankles and knees<br>Other: Ankle and Knee Magnetic Resonance Imaging<br>* Ankle and Knee Magnetic Resonance Imaging<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence and natural progression of subclinical arthropathy (joint changes) in children with severe hemophilia undergoing prophylaxis using a validated ultrasound (HEAD-US) protocol. | Two independent readers will describe all the ultrasonography positive joint findings and/or changes on a standardized spreadsheet; they will also rate and score these changes based on the HEAD-US scale providing a final score for each of the evaluated joints (ankles and knees). | 5 years | 
| Prevalence and natural progression of subclinical arthropathy (joint changes) in children with mild and/or moderate hemophilia using a validated ultrasound (HEAD-US) protocol. | Two independent readers will describe all the ultrasonography positive joint findings and/or changes on a standardized spreadsheet; they will also rate and score these changes based on the HEAD-US scale providing a final score for each of the evaluated joints (ankles and knees). | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characteristics of subclinical joint changes (time of presentation, natural evolution, etc.) between patients with severe hemophilia and those with mild/moderate hemophilia. | The investigators will describe and compare all the ultrasonography joint findings and/or changes on a standardized spreadsheet in between the two cohort of patients. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophilia, Arthropathy, Pediatric