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There is cumulating evidence for the presence of non-observed or subclinical joint bleeding in patients with haemophilia. Early detection of active subclinical synovial proliferation would allow early intervention in order to prevent deterioration of joint health. Patients with subclinical (=non-observed) signs of synovial proliferation in knee(s), ankle(s) and/or elbow(s) will be invited to participate in this study to further characterize the synovial proliferation status (active or inactive) by means of physical examination, MRI, ultrasound and elastography. Synovial proliferation status will be monitored for a maximum period of 12 weeks, during which participants will also receive standard-of-care treatment, i.e. administration of optimized coagulation factor replacement therapy and prescription of the NSAID celecoxib (optional).
To be completed
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ultrasound imaging | Other | Ultrasound, MRI and elastography to screen for and follow subclinical synovial changes in ankle, elbow and knee. |
|
| Measure | Description | Time Frame |
|---|---|---|
| - The primary objective of this study is to evaluate the diagnostic accuracy of physical examination and ultrasound to identify active synovial proliferation in haemophilia patients with subclinical synovial hypertrophy. | As no gold standard to identify active subclinical proliferation is available, "change in synovial proliferation over time" will be used as surrogate endpoint. This is measured by ultrasound assessment according HEAD-US protocol . Possible outcomes are: no change (baseline HEAD-US score = 12-week follow-up HEAD-US score) or changed (baseline HEAD-US score < or > 12-week follow-up HEAD-US score). Fully recovered synovial proliferation will also be categorized as changed. The diagnostic accuracy will be derived comparing 'change in synovial proliferation' with the 'presumed' definition at baseline (active or inactive). Definition of active synovial proliferation at baseline: synovial proliferation on ultrasound and the presence of at least one of the following criteria:
| 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| - To identify predictors for (changes in) synovial proliferation status within participant characteristics (age, baseline treatment, joint bleeding history) and joint characteristics (extent of arthropathy (Pettersson score on X-rays)). | Baseline participant characteristics (age, baseline treatment, joint bleeding history) and joint characteristics (extent of arthropathy (Pettersson score on X-rays)) will be extracted from medical files. |
| Measure | Description | Time Frame |
|---|---|---|
| - To describe elastographic differences between active clinical synovitis, active subclinical synovial hypertrophy and inactive subclinical hypertrophy. | For the side objective a group of patients with active clinical synovitis will only undergo elastography and be used as positive control in elastography-analysis, no other measurement nor analysis will be performed. | At baseline (week 0) without follow-up |
Inclusion Criteria:
Exclusion Criteria:
A major bleed ≤ 3 months or a minor bleed ≤ 1 month prior to inclusion in the joint of interest.
On demand therapy.
Currently treated with any type of haemophilia prophylaxis medication.
Joints with prosthesis or treated with arthrodesis will not be included for physical examination and ultrasound analysis. However, participants may still be included in the study with their other joints.
Confirmed inflammatory joint diseases such as rheumatoid arthritis or psoriatic arthritis.
History of inhibitor development (≥ 5 Bethesda Units* (BU) at any time or 1-5 BU for
Contra-indication for treatment with NSAIDs, (allergy, severe liver failure, renal failure (GFR <30ml/min), congestive heart failure (NYHA II-IV), peripheral arterial disease and/or cerebrovascular disease.
Haemophilia is an X-linked disease.
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The study population consists of male participants ≥ 12 years of age, with severe haemophilia A or B treated with prophylaxis, who were diagnosed with asymptomatic synovial proliferation in ≥1 joint (ankle, knee and/or elbow) by means of ultrasound imaging during routine screening at the outpatient clinic of the Van Creveldkliniek, UMC Utrecht, the Netherlands.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Lize van Vulpen, MD, PhD | Contact | +31887558450 | l.f.d.vanvulpen-2@umcutrecht.nl | |
| Merel Timmer, PhD | Contact | m.a.timmer@umcutrecht.nl |
| Name | Affiliation | Role |
|---|---|---|
| Lize van Vulpen, MD, PhD | University Medical Center Utrecht - Van Creveldkliniek | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Medical Center Utrecht | Recruiting | Utrecht | 3584CX | Netherlands |
Pseudonimyzed data may be shared with other (international) researchers upon request at the principal investigator.
On group level, data will be presented at congresses and in peer-reviewed articles.
15 years after study closure.
Please contact the principal investigator, Dr. L.F.D. van Vulpen.
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| ID | Term |
|---|---|
| D006467 | Hemophilia A |
| D002836 | Hemophilia B |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| D019220 | High-Energy Shock Waves |
| ID | Term |
|---|---|
| D000069453 | Ultrasonic Waves |
| D013016 | Sound |
| D011840 | Radiation, Nonionizing |
| D011827 | Radiation |
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| 12 weeks |
| - To evaluate the diagnostic accuracy of the presence of synovial hemosiderin, as measured by MRI, to identify active synovial proliferation in haemophilia patients with subclinical synovial hypertrophy. | Clinical and ultrasound definition of active synovial proliferation: synovial proliferation on ultrasound (HEAD-US synovium score >0) and the presence of at least one of the following criteria: - Hemosiderin on MRI: IPSG score Hemosiderin Deposit > 0 at baseline | 12 weeks |
| - To evaluate the diagnostic accuracy of synovial elastography to identify active synovial proliferation in hemophilia patients with subclinical synovial hypertrophy | Clinical and ultrasound definition of active synovial proliferation: synovial proliferation on ultrasound (HEAD-US synovium score >0) and the presence of at least one of the following criteria: - Elastography: | 12 weeks |
| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D040181 | Genetic Diseases, X-Linked |
| D055585 |
| Physical Phenomena |