Intra-Articular Bevacizumab for Preventing Recurrent Hemarthrosis in Hemophilia With Chronic Synovitis

Khyber Medical University Peshawar25 enrolled

Overview

Hemophilia is an inherited bleeding disorder characterized by deficiency of clotting factors, leading to increased bleeding tendencies. The most common complications are joint bleeds (hemarthroses), which cause chronic changes in joints and ultimately disability. Recurrent hemarthroses often result from chronic synovitis in target joints of patients with hemophilia, a process driven by Vascular Endothelial Growth Factor (VEGF) mediated pathological angiogenesis. Intra-articular administration of Bevacizumab, a VEGF neutralizing monoclonal antibody, may block this process and reduce the frequency of recurrent joint bleeds. This study evaluates the efficacy and safety of intra-articular Bevacizumab for preventing recurrent hemarthrosis in patients with hemophilia and chronic synovitis.

Hemophilia A is the most prevalent inherited bleeding disorder in Pakistan, accounting for approximately 69% of all hemophilia cases. A major complication is recurrent joint bleeding (hemarthrosis), which leads to chronic synovitis and progressive hemophilic arthropathy. This joint deterioration significantly impairs mobility and quality of life. The underlying pathophysiology is driven by repeated hemarthroses, which cause increased local expression of Vascular Endothelial Growth Factor (VEGF). VEGF promotes abnormal angiogenesis and synovial proliferation, perpetuating a cycle of inflammation and bleeding, even when symptoms are not overt. Bevacizumab is a recombinant humanized monoclonal antibody that specifically inhibits VEGF. Local intra-articular administration offers a targeted therapeutic approach to disrupt this pathogenic cycle directly at the site of pathology. By neutralizing VEGF, Bevacizumab may mitigate synovitis, reduce bleeding frequency, and slow progression of hemophilic arthropathy, while minimizing systemic exposure and associated adverse effects. To investigate this therapeutic strategy, a two-year, open-label, single-arm clinical trial will be conducted at the Institute of Pathology and Diagnostic Medicine (IPDM), Khyber Medical University (KMU), and Hayatabad Medical Complex, Peshawar, Pakistan. A total of 25 participants with Hemophilia A and chronic synovitis in one or more target joints (knee, elbow, or ankle) will be enrolled. All participants will receive intra-articular Bevacizumab injections following prophylactic factor replacement therapy to prevent procedure-related bleeding. The first four participants will receive 20 mg/0.8 mL per injection. If well tolerated without major toxicities, the remaining participants will receive 40 mg/1.6 mL per injection. Each injection will be administered into the target joint once every 28 days for a total of four doses. The primary efficacy outcome will be the change in the Annualized Bleeding Rate (ABR) of the target joint, calculated from 3-month pre- and post-treatment data. Secondary outcomes will include changes in joint health assessed using the Hemophilia Joint Health Score (HJHS, Version 2.1; range 0-124, where higher scores indicate worse joint health) and synovial inflammation measured by Magnetic Resonance Imaging (MRI) with the International Prophylaxis Study Group (IPSG)-compatible scoring system. This study may provide critical insight into a novel, VEGF-targeted strategy for managing chronic synovitis in hemophilia patients and preserving long-term joint health.

Interventions

Intra-articular BevacizumabDRUG

This clinical trial investigates the intra-articular injection of Bevacizumab, a recombinant humanized monoclonal antibody that inhibits Vascular Endothelial Growth Factor (VEGF). The intervention functions by binding to and neutralizing VEGF-A, thereby blocking the pathogenic angiogenesis and vascular permeability that characterizes chronic hemophilic synovitis. For administration, the first four patients will receive a dose of 20 mg in 0.8 mL per injection, and if this is well-tolerated without major toxicities, the dose for all subsequent patients will be increased to 40 mg in 1.6 mL. Each injection will be administered directly into the target joint (knee, elbow, or ankle) once every 28 days for a total of four doses. Crucially, all injections will be performed only after appropriate prophylactic factor replacement to mitigate any procedure-related bleeding risk.

Eligibility

Sex: ALL

Medical Language ↔ Plain English

Inclusion Criteria: * Confirmed diagnosis of Hemophilia A. * Presence of one or more target joints (knee, elbow, ankle) with chronic synovitis and a history of \>2 hemarthrosis episodes in the past 6 months. * Target joint World Federation of Hemophilia (WFH) joint score of 2-3. * Adequate hematological, renal, and liver function (as specified by protocol lab values). * Ability and willingness to provide informed consent and comply with the study protocol. Exclusion Criteria: * HIV positive diagnosis. * Severely damaged joints or anatomical limitations preventing safe injection. * Contraindications to MRI. * Uncontrolled hypertension. * Recent major surgery/trauma (\<28 days). * Serious non-healing wound, active cardiovascular disease, or other significant comorbidities that could increase risk or interfere with the study.

Outcomes

Primary Outcomes

Annualized Bleeding Rate (ABR) of the Target Joint

The efficacy of the intervention will be assessed by the change in the number of recurrent hemarthrosis episodes specifically in the treated target joint. The rate will be annualized from data collected over a 3-month period. Response will be categorized as: 'Excellent' (0 bleeds), 'Good' (75-99% reduction), 'Fair' (50-74% reduction), or 'Poor' (\<50% reduction).

Time frame: Baseline (3 months pre-treatment) compared to the 3-month period following the completion of the treatment protocol (i.e., 3 months after the 4th injection).

Clinical Joint Health Score

Change in joint health and function as measured by the Hemophilia Joint Health Score (HJHS 2.1), a standardized physical examination tool that assesses pain, swelling, muscle atrophy, crepitus on motion, range of motion (flexion/extension loss), strength, and gait. Scale Range: 0 to 124 (higher scores indicate worse joint health and function). Interpretation: 0 = best outcome (no joint damage or impairment) 124 = worst outcome (severe joint involvement and functional limitation)

Time frame: Baseline scores compared to scores at 1, 3, 6, and 12 months after initiation of therapy

Synovial Hypertrophy

Change in synovial membrane thickness in the target joint as assessed by MRI, scored according to the IPSG MRI scale for synovial hypertrophy (0-3; 0 = none, 3 = \>5 mm).

Time frame: Baseline MRI (before starting therapy) compared to MRI performed 6 months after completion of therapy.

Joint Effusion/Hemarthrosis

Change in effusion or hemarthrosis volume in the target joint, assessed using the IPSG MRI scale (0-3; 0 = none, 3 = severe joint distention).

Time frame: Baseline vs. 6 months after completion of therapy.

Synovial Inflammation Composite (Soft Tissue Subtotal)

Change in the combined soft tissue inflammation score, calculated as the sum of effusion/hemarthrosis, synovial hypertrophy, and hemosiderin deposition (range 0-9)..