Ultrasonography in Hemophilic Joint Disease and Serum Markers

NCT02634918 | Completed

• 1 other identifier: #15-145
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Hemophilia is a bleeding disorder (deficiency of a blood clotting factor/ protein) resulting in bleeding in joints and muscles. As patients continue to bleed into their joints they develop progressive joint damage leading to joint contractures, disability and days missed from work and school resulting in chronic debilitating pain and compromised quality of life. Current therapy is the administration of the missing protein or factor concentrate on a scheduled basis to prevent bleeding into the joints referred to as prophylaxis. This factor concentrate is expensive \~ $ 3,000 - 6,000 per infusion/ week in a child weighing 20 kg translating into $ 77,000 /yr for life. This regimen has been shown to be effective to prevent joint bleeds but the timing is unclear and not based on adequate evidence. Currently joint damage is diagnosed using MRI which is expensive and requires sedation in children \< 6 yrs of age. Therefore there is a need for a user friendly tool such as a ultrasound to monitor for the development of joint disease and tailor treatment based on an individual child's needs. This would also enable differentiating a joint bleed from a soft tissue bleed which present similarly and duration of treatment tends to be longer for a joint bleed. Acharya et al have previously shown that ultrasound is comparable to MRI for the diagnosis of hemophilic joint disease in hemophilia patients over the age of 6 years. However, the diagnostic findings in children \< 18 years with hemophilia on ultrasound is not well defined(1). The hemophilic synovium after repeated joint bleeds reveals the development of new vessels which are fragile and contribute to recurrent joint bleeds. Acharya et al have previously shown that angiogenesis, a process of new vessel formation is active in hemophilic synovium and angiogenic markers were significantly elevated in hemophilic patients with joint disease when compared to those without (2). Since ultrasound can detect these new vessel changes in the hemophilic synovium in hemophilia patients with joint disease and hemophilia patients with joint disease demonstrate elevated markers of new vessel formation these investigators would now like to determine whether radiological findings of hemophilic joint disease correlate with serological angiogenic markers. This may enable the development of biomarkers for hemophilic joint disease. Findings from this study will enable the development of ultrasound as a user friendly tool in the hemophilia clinic in order to understand whether every pain and swelling in a joint is actually a joint bleed or soft tissue bleed and to monitor for joint changes to institute or augment scheduled factor infusions ( prophylaxis). This will also result in significant improvement in quality of life with tailored prophylaxis .

Conditions

Hemophilia A; Hemophilia B; Hemarthroses

Keywords

ultrasound,; ultrasonography; hemophilic joint; Doppler

Outcome Measures

Primary Outcomes (1)

• To determine the prevalence rates of synovial and cartilage changes using USG-PDS:

  Synovial changes on USG- PDS: Scoring system for synovitis which has 2 components - joint effusion and synovial thickening: Joint effusion will be defined as a compressible anechoic intracapsular area and the amount of fluid will be semiquantitatively scored usinga previosuly described scoring system by Martinoli et al. Quantitative assessment of the power Doppler signal: Power Doppler signal will be assessed subjectively for degree of vascularity -Table 2, Table 2 Degree of Vascularity PDS Signal Score Normal or minimal No signal or local dark red 1 Mild hyperemia Dark red to red 2 Moderate hyperemia Red to orange 3 Marked hyperemia Orange to yellow 4

  12 months

Secondary Outcomes (1)

• To determine whether the presence/absence of synovial and cartilage changes measured using USG-PDS are associated with any changes in biological surrogate marker levels.

  15 months

Study Arms (3)

Ultrasound

3 groups of hemophilia patients - Those with \> 20 bleeds into a joint, those with \< 2 bleeds into a joint and those with no bleeds into a joint will be enrolled into the study

Other: ultrasound

those with < 2 bleeds into a joint and

3 groups of hemophilia patients Group I - Those with \> 20 bleeds into a joint, Group II - those with \< 2 bleeds into a joint and Group III - those with no bleeds into a joint will be enrolled into the study

Other: ultrasound

those with no bleeds into a joint will be enrolled into the st

3 groups of hemophilia patients Group I - Those with \> 20 bleeds into a joint, Group II - those with \< 2 bleeds into a joint and Group III - those with no bleeds into a joint will be enrolled into the study

Other: ultrasound

Interventions

ultrasound OTHER

ultrasound will be performed in hemophilia boys with a history of 20 joint bleeds- Group I, less than 2 joint bleeds into a joint -Group II and no joint bleeds- Group III

Ultrasound; those with < 2 bleeds into a joint and; those with no bleeds into a joint will be enrolled into the st

Eligibility Criteria

• Age: 6 Months - 18 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Boys with hemophilia and inherited bleeding disorders with and without a history of hemarthroses

You may qualify if:

• All children ages 6 months - 18 years with hemophilia A or B
• Hemophilia subjects with and without a history of hemarthroses including target joints ( joint of interest) and joints without documented bleeds( control joints)
• Hemophilia subjects with a history of inhibitor to FVIII or FIX and documented hemarthroses
• History of hemarthroses more than 4 weeks prior to study enrolment to allow for resolution of hemarthroses which could affect detection of synovial and cartilage changes

You may not qualify if:

• Bleeding disorder subjects without a diagnosis of hemophilia
• Hemophilia subjects with any underlying illness such as liver or renal disease or any systemic illness such as diabetes or any other chronic illness apart from the hemophilia
• Hemophilia subjects on medications which could increase bleeding risk such as non steroidal anti inflammatory agents, anti seizure medications apart from factor concentrates
• History of hemarthroses within the 4 weeks prior to study enrolment

Sponsors & Collaborators

• Northwell Health: lead
• National Cancer Institute (NCI): collaborator
• University of California, San Diego: collaborator

Study Sites (1)

Feinstein Institute of Medical Research Northwell Health

New Hyde Park, New York, 11040, United States

Location

Related Publications (18)

• Acharya SS, Schloss R, Dyke JP, Mintz DN, Christos P, DiMichele DM, Adler RS. Power Doppler sonography in the diagnosis of hemophilic synovitis--a promising tool. J Thromb Haemost. 2008 Dec;6(12):2055-61. doi: 10.1111/j.1538-7836.2008.03160.x. Epub 2008 Sep 23.

  PMID: 18823337 RESULT

• Acharya SS, Kaplan RN, Macdonald D, Fabiyi OT, DiMichele D, Lyden D. Neoangiogenesis contributes to the development of hemophilic synovitis. Blood. 2011 Feb 24;117(8):2484-93. doi: 10.1182/blood-2010-05-284653. Epub 2010 Dec 16.

  PMID: 21163925 RESULT

• Jansen NW, Roosendaal G, Lundin B, Heijnen L, Mauser-Bunschoten E, Bijlsma JW, Theobald M, Lafeber FP. The combination of the biomarkers urinary C-terminal telopeptide of type II collagen, serum cartilage oligomeric matrix protein, and serum chondroitin sulfate 846 reflects cartilage damage in hemophilic arthropathy. Arthritis Rheum. 2009 Jan;60(1):290-8. doi: 10.1002/art.24184.

  PMID: 19116938 RESULT

• Manco-Johnson MJ, Riske B, Kasper CK. Advances in care of children with hemophilia. Semin Thromb Hemost. 2003 Dec;29(6):585-94. doi: 10.1055/s-2004-815626.

  PMID: 14719175 RESULT

• Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med. 1994 Oct;236(4):391-9. doi: 10.1111/j.1365-2796.1994.tb00815.x.

  PMID: 7931042 RESULT

• Madhok R, Bennett D, Sturrock RD, Forbes CD. Mechanisms of joint damage in an experimental model of hemophilic arthritis. Arthritis Rheum. 1988 Sep;31(9):1148-55. doi: 10.1002/art.1780310910.

  PMID: 3048275 RESULT

• Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Gungor T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet. 1992 Mar 7;339(8793):594-8. doi: 10.1016/0140-6736(92)90874-3.

  PMID: 1347102 RESULT

• Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003 Jul;9(4):418-35. doi: 10.1046/j.1365-2516.2003.00780.x.

  PMID: 12828678 RESULT

• Lusher JM. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol. 1991 Jul;28(3 Suppl 6):3-5. No abstract available.

  PMID: 1780767 RESULT

• Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P, Matsunaga A, Medeiros D, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, Evatt BL. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007 Aug 9;357(6):535-44. doi: 10.1056/NEJMoa067659.

  PMID: 17687129 RESULT

• Blanchette VS, Al-Musa A, Stain AM, Ingram J, Fille RM. Central venous access devices in children with hemophilia: an update. Blood Coagul Fibrinolysis. 1997 Aug;8 Suppl 1:S11-4.

  PMID: 9351530 RESULT

• Manco-Johnson MJ, Nuss R, Geraghty S, Funk S, Kilcoyne R. Results of secondary prophylaxis in children with severe hemophilia. Am J Hematol. 1994 Oct;47(2):113-7. doi: 10.1002/ajh.2830470209.

  PMID: 8092125 RESULT

• Valentino LA, Hakobyan N, Enockson C, Simpson ML, Kakodkar NC, Cong L, Song X. Exploring the biological basis of haemophilic joint disease: experimental studies. Haemophilia. 2012 May;18(3):310-8. doi: 10.1111/j.1365-2516.2011.02669.x. Epub 2011 Nov 2.

  PMID: 22044636 RESULT

• Nuss R, Kilcoyne RF, Geraghty S, Shroyer AL, Rosky JW, Mawhinney S, Wiedel J, Manco-Johnson M. MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage. Haemophilia. 2000 May;6(3):162-9. doi: 10.1046/j.1365-2516.2000.00383.x.

  PMID: 10792474 RESULT

• Lundin B, Manco-Johnson ML, Ignas DM, Moineddin R, Blanchette VS, Dunn AL, Gibikote SV, Keshava SN, Ljung R, Manco-Johnson MJ, Miller SF, Rivard GE, Doria AS; International Prophylaxis Study Group. An MRI scale for assessment of haemophilic arthropathy from the International Prophylaxis Study Group. Haemophilia. 2012 Nov;18(6):962-70. doi: 10.1111/j.1365-2516.2012.02883.x. Epub 2012 Jul 5.

  PMID: 22765835 RESULT

• Joseph-Silverstein J, Rifkin DB. Endothelial cell growth factors and the vessel wall. Semin Thromb Hemost. 1987 Oct;13(4):504-13. doi: 10.1055/s-2007-1003526.

  PMID: 3321439 RESULT

• Ortega N, Jonca F, Vincent S, Favard C, Ruchoux MM, Plouet J. Systemic activation of the vascular endothelial growth factor receptor KDR/flk-1 selectively triggers endothelial cells with an angiogenic phenotype. Am J Pathol. 1997 Nov;151(5):1215-24.

  PMID: 9358746 RESULT

• Maeno N, Takei S, Imanaka H, Takasaki I, Kitajima I, Maruyama I, Matsuo K, Miyata K. Increased circulating vascular endothelial growth factor is correlated with disease activity in polyarticular juvenile rheumatoid arthritis. J Rheumatol. 1999 Oct;26(10):2244-8.

  PMID: 10529148 RESULT

Biospecimen

Retention: SAMPLES WITHOUT DNA

plasma samples for angiogenic and cartilage degradation markers

MeSH Terms

Conditions

Hemophilia A; Hemophilia B; Hemarthrosis

Interventions

High-Energy Shock Waves

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, X-Linked; Joint Diseases; Musculoskeletal Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ultrasonic Waves; Sound; Radiation, Nonionizing; Radiation; Physical Phenomena

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Study Record Dates

• First Submitted: October 8, 2015
• First Posted: December 18, 2015
• Study Start: January 1, 2016
• Primary Completion: August 1, 2019
• Study Completion: December 1, 2019
• Last Updated: February 13, 2020

Record last verified: 2020-02

Locations

US (1)