A Prospective Assessment of Bone Health in Patients With Severe Hemophilia A on Factor VIII vs Factor Mimetic Prophylaxis (Efa Emi Bone Health Study)

Официальное название

A Multi-institution Prospective Assessment of Bone Health in Patients With Severe Hemophilia A on Factor VIII vs Factor Mimetic Prophylaxis (Efa Emi Bone Health Study)

Обзор

This study will compare bone mineral density in patients with severe hemophilia A receiving prophylaxis with emicizumab or efanesoctocog alfa. Participants will undergo assessments of bone mineral density, bone remodeling biomarkers, thrombin generation, plasmin generation, and joint health over a five-year period. The study aims to evaluate whether differences in prophylactic therapy are associated with differences in bone health outcomes.

Подробное описание

Reduced bone mineral density, osteoporosis, and fractures are increasingly recognized in persons with severe hemophilia A. The mechanisms underlying impaired bone health in hemophilia are multifactorial and may include reduced physical activity, chronic joint disease, inflammation, and abnormalities in coagulation-related pathways involved in bone remodeling.

Thrombin has been shown to play an important role in bone metabolism through activation of protease-activated receptor-1 (PAR-1) signaling pathways that influence osteoblast and osteoclast activity. Reduced thrombin generation in severe hemophilia A may contribute to decreased bone formation and increased bone resorption.

Efanesoctocog alfa is an extended half-life factor VIII replacement therapy that maintains higher circulating factor VIII levels and supports thrombin generation. Emicizumab is a non-factor prophylactic therapy that effectively prevents bleeding but does not replace factor VIII. The comparative effects of these therapies on long term bone health have not been well established.

This prospective observational study will compare longitudinal changes in bone mineral density among patients with severe hemophilia A receiving prophylaxis with emicizumab or efanesoctocog alfa over 5 years. Participants will undergo serial dual-energy X-ray absorptiometry (DXA) assessments and evaluation of bone remodeling biomarkers, inflammatory cytokines, thrombin generation, plasmin generation, and joint health over a five-year period.

Первичные конечные точки

• Longitudinal change in femoral neck bone mineral density (g/cm²) [Срок оценки: Baseline and annually through 5 years.]

Вторичные конечные точки (4)

• Longitudinal change in Lumbar spine (L1-L4) bone mineral density (g/cm²) [Срок оценки: Baseline and annually through 5 years.]
• Longitudinal change in total hip bone mineral density (g/cm²) [Срок оценки: Baseline and annually through 5 years.]
• Longitudinal Change in Bone Remodeling Biomarkers and Cytokines [Срок оценки: Baseline and annually through 5 years.]
• Change in Thrombin Generation and Plasmin Generation Parameters [Срок оценки: Baseline and annually through 5 years]

Критерии участия

Критерии включения

• The participant or legally authorized representative is willing and able to provide written informed consent.
• Diagnosis of severe hemophilia A (factor VIII activity < 1%).
• Male sex.
• Age between 30 and 50 years (inclusive).
• BMI between 18.5 and 40 kg/m2
• The participant must have been on prophylaxis with Efanesoctocog alfa or Emicizumab for at least 3 months prior to enrollment and intend to remain on the current regimen for the next 5 years.
• Willingness to undergo all research procedures, including DEXA scans and the collection of blood samples.
• Willingness to complete all standard-of-care bleeding and treatment logs.

Критерии исключения

• Unwillingness of the participant, parent, or legally authorized representative to provide informed consent.
• Diagnosis of a bleeding disorder other than or in addition to severe hemophilia A.
• Active Factor VIII inhibitors at the time of enrollment
• History of a disease known to influence bone metabolism unrelated to a bleeding disorder. (Examples: Paget's disease, osteogenesis imperfecta, Ehlers Danlos syndrome, Hyperparathyroidism)
• Past or present treatment with any anti-osteoporotic medication, excluding oral vitamin D or oral calcium supplements.
• Documented HIV infection or HCV infection (whether in progress or cured) at the cirrhotic stage.
• Presence of a non-removable metal device that would interfere with research procedures.
• Inability to tolerate a DEXA scan due to limited range of motion or body habitus.
• History of bone fractures or surgical repair within 8 weeks prior to enrollment.
• Participants with weight >300 pounds, due to limitations of DEXA scanner

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Только случаи

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• Sivagurunathan S, Pagel CN, Loh LH, Wijeyewickrema LC, Pike RN, Mackie EJ. Thrombin inhibits osteoclast differentiation through a non-proteolytic mechanism. J Mol Endocrinol. 2013 Apr 23;50(3):347-59. doi: 10.1530/JME-12-0177. Print 2013 Jun. PMID 23419317
• Song SJ, Pagel CN, Campbell TM, Pike RN, Mackie EJ. The role of protease-activated receptor-1 in bone healing. Am J Pathol. 2005 Mar;166(3):857-68. doi: 10.1016/S0002-9440(10)62306-1. PMID 15743797
• Pagel CN, Song SJ, Loh LH, Tudor EM, Murray-Rust TA, Pike RN, Mackie EJ. Thrombin-stimulated growth factor and cytokine expression in osteoblasts is mediated by protease-activated receptor-1 and prostanoids. Bone. 2009 May;44(5):813-21. doi: 10.1016/j.bone.2008.12.031. Epub 2009 Jan 15. PMID 19442625
• Pagel CN, de Niese MR, Abraham LA, Chinni C, Song SJ, Pike RN, Mackie EJ. Inhibition of osteoblast apoptosis by thrombin. Bone. 2003 Oct;33(4):733-43. doi: 10.1016/s8756-3282(03)00209-6. PMID 14555279
• Al Dieri R, de Laat B, Hemker HC. Thrombin generation: what have we learned? Blood Rev. 2012 Sep;26(5):197-203. doi: 10.1016/j.blre.2012.06.001. Epub 2012 Jul 2. PMID 22762893
• Goldscheitter G, Recht M, Sochacki P, Manco-Johnson M, Taylor JA. Biomarkers of bone disease in persons with haemophilia. Haemophilia. 2021 Jan;27(1):149-155. doi: 10.1111/hae.13986. Epub 2020 Aug 27. PMID 32856388
• Gerstner G, Damiano ML, Tom A, Worman C, Schultz W, Recht M, Stopeck AT. Prevalence and risk factors associated with decreased bone mineral density in patients with haemophilia. Haemophilia. 2009 Mar;15(2):559-65. doi: 10.1111/j.1365-2516.2008.01963.x. Epub 2009 Feb 1. PMID 19187193
• Wallny TA, Scholz DT, Oldenburg J, Nicolay C, Ezziddin S, Pennekamp PH, Stoffel-Wagner B, Kraft CN. Osteoporosis in haemophilia - an underestimated comorbidity? Haemophilia. 2007 Jan;13(1):79-84. doi: 10.1111/j.1365-2516.2006.01405.x. PMID 17212729

Идентификаторы

NCT: NCT07582276 · 300130

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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