Synovial Proliferation on Routine Ultrasound: Active or Inactive? (2BEGIN)

Synovial Proliferation on Routine Ultrasound: Active or Inactive? A Prospective Study

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).

Study Overview

• Status: Recruiting
• Conditions: Hemophilia A; Hemophilia B; Haemophilia
• Intervention / Treatment: Other: Ultrasound imaging

Detailed Description

To be completed

• Study Type: Observational
• Enrollment (Estimated): 46

Contacts and Locations

• Study Contact: Name: Lize van Vulpen, MD, PhD; Phone Number: +31887558450; Email: l.f.d.vanvulpen-2@umcutrecht.nl
• Study Contact Backup: Name: Merel Timmer, PhD; Email: m.a.timmer@umcutrecht.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584CX
    • Recruiting
    • University Medical Center Utrecht
    • Contact: Lize van, MD, PhD; Phone Number: +31887558450; Email: l.f.d.vanvulpen-2@umcutrecht.nl
    • Sub-Investigator: Merel Timmer, PhD
    • Sub-Investigator: Wouter Foppen, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

Inclusion Criteria:

• Gender: male
• Patients with severe haemophilia A or B
• Treated with registered prophylaxis medication including coagulation factors and by- passing agents.
• Age ≥ 12 years
• Subclinical synovial proliferation in ≥1 joint (ankle, knee and/or elbow), defined as the presence of hypertrophic synovium, score >0 according to the HEAD-US protocol, as confirmed during routine ultrasound screening.
• Able to give written informed consent.

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

  • 1 year prior to inclusion.
• 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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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: HJHS swelling >0; Warmth palpation absent/present at baseline; JADE Synovial Hyperaemia >0; No history of synovial proliferation (yes/no); Hemosiderin on MRI (IPSG>0); Elastography	12 weeks

Secondary Outcome Measures

Outcome Measure	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.	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

Other Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Van Creveldkliniek
• Investigators: Principal Investigator: Lize van Vulpen, MD, PhD, University Medical Center Utrecht - Van Creveldkliniek

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: October 30, 2024
• First Submitted That Met QC Criteria: January 30, 2025
• First Posted (Actual): February 5, 2025

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: MRI; Ultrasound; Elastography; Subclinical synovial proliferation
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Genetic Diseases, X-Linked; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Hemophilia A; Hemophilia B; Physical Phenomena; Radiation; Radiation, Nonionizing; Ultrasonic Waves; Sound; High-Energy Shock Waves
• Other Study ID Numbers: 2BEGIN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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.

• IPD Sharing Time Frame: 15 years after study closure.
• IPD Sharing Access Criteria: Please contact the principal investigator, Dr. L.F.D. van Vulpen.
• IPD Sharing Supporting Information Type: ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No