Prospective Biomarkers of Bone Metabolism in Hemophilia A

NCT02306694 | Completed Phase 3 Results

• 1 other identifier: e11104
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

One of the major shortcomings in studying bone disease in hemophilia is the lack of fracture outcome data demonstrating the clinical significance of decreased BMD and altered bone biomarkers in the hemophilia population. This study demonstrates that PwH have an increased risk of fracture compared to the general population and that the issue of bone health will increase in importance as the PwH population ages.

Conditions

Hemophilia; Bone Disease

Keywords

hemophilia; bone disease; clinical study; biomarkers

Outcome Measures

Primary Outcomes (4)

• Bone Biomarker Density (BMD)

  BMD was measured as Z-scores/T-scores using Dual-Energy X-ray Absorptiometry (DEXA) scanning; specifically looking at Spine, Hip/Neck, and Hip total scores. BMD Z-scores compare what would be expected in someone your age and body size. A Z-score, is a unit of standard deviation, where above 0 would indicate the bones are more dense than expected, while a Z-score below 0 would indicate the bones were less dense.

  5 days

• Joint Health

  Hemophilia Joint Health Score (HJHS); with a higher score representing worst outcomes, scores could range from 0 (no problems) to a max score of 120 (severe problems).

  5 days

• Quality of Life Using the VAS and EQ-5D-3L

  Visual Analog Scale (VAS) via the EQ-5D-3L was used to report participants self-rated health. EQ-5D-3L total score ranges from 5 (no problems) to 15 (significant problems). VAS scores could range from 0 (worst health ever) to 100 (best health ever).

  5 days

• Plasma Cytokine Concentration Differences From 0-hour to 24-hour

  cytokines were measured using ELISA/magnetic bead multiplex kits. We calculated concentration change from hour 0 to hour 24. Cytokines: FGF, C-Terminal telopeptide (CTX-1), Dickkopf WNT signaling pathway inhibitor 1(DKK1), Eotaxin, fibroblast growth factor 23(FGF23), interferon gamma, interleukin 13, interleukin 1 beta, interleukin receptor 1 antagonist, interleukin 2, interleukin 4, interleukin 6, interleukin 17, interleukin 8, interleukin 9 Insulin, interferon gamma induced protein 10 (IP10), Leptin, monocyte chemoattractant protein1, monocyte chemoattractant protein1, macrophage inflammatory protein 1a (MIP1a), osteoclasts, Osteoprotegerin, osteopontin, platelet derived growth factors, parathyroid horomone, Recepter activator of nuclear factor kappa-B ligand (RANKL), chemokine ligand 5, sclerostin, transforming growth factor-beta 1, transforming growth factor beta 2, transforming growth factor beta 3, tumor necrosis factor alpha, vascular endothelial growth factor, MIP1b.

  24 hours

Other Outcomes (3)

• Medication Adherence

  5 days

• Hemophilia Activities List (HAL) and the International Society of Thrombosis and Hemostasis- Bleeding Assessment Tool (ISTH-BAT)

  5 days

• Participant Quality of Life

  5 days

Study Arms (1)

Open label

EXPERIMENTAL

Everyone receives Advate (antihemophilic factor) on Day 1 and 3.

Drug: Advate

Interventions

Advate DRUG

Patients who are currently taking Advate as their factor replacement will be eligible for the 5-day study.

Also known as: Antihemophilic Factor (Recombinant)

Open label

Eligibility Criteria

• Age: 16 Years - 85 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Males with a diagnosis of hemophilia A with a historic baseline FVIII level ≤ 2%.
• Age \> 16 years old
• Currently using ADVATE as FVIII replacement therapy

You may not qualify if:

• Subject or guardian is unwilling or unable to give written informed consent and/or assent
• Joint or muscle bleeding within 2 weeks of Study Day 1
• Presence of a current factor inhibitor (\>0.6 BU/mL via Nijmegan-modified Bethesda assay)
• Known collagen vascular bone disease.

Sponsors & Collaborators

• Oregon Health and Science University: lead
• Baxter Healthcare Corporation: collaborator

Study Sites (1)

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Related Publications (14)

• Plug I, Van Der Bom JG, Peters M, Mauser-Bunschoten EP, De Goede-Bolder A, Heijnen L, Smit C, Willemse J, Rosendaal FR. Mortality and causes of death in patients with hemophilia, 1992-2001: a prospective cohort study. J Thromb Haemost. 2006 Mar;4(3):510-6. doi: 10.1111/j.1538-7836.2006.01808.x.

  PMID: 16460432 BACKGROUND

• Siboni SM, Mannucci PM, Gringeri A, Franchini M, Tagliaferri A, Ferretti M, Tradati FC, Santagostino E, von Mackensen S; Italian Association of Haemophilia Centres (AICE). Health status and quality of life of elderly persons with severe hemophilia born before the advent of modern replacement therapy. J Thromb Haemost. 2009 May;7(5):780-6. doi: 10.1111/j.1538-7836.2009.03318.x. Epub 2009 Feb 12.

  PMID: 19220727 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Barnes C, Wong P, Egan B, Speller T, Cameron F, Jones G, Ekert H, Monagle P. Reduced bone density among children with severe hemophilia. Pediatrics. 2004 Aug;114(2):e177-81. doi: 10.1542/peds.114.2.e177.

  PMID: 15286254 BACKGROUND

• Gallacher SJ, Deighan C, Wallace AM, Cowan RA, Fraser WD, Fenner JA, Lowe GD, Boyle IT. Association of severe haemophilia A with osteoporosis: a densitometric and biochemical study. Q J Med. 1994 Mar;87(3):181-6.

  PMID: 8208906 BACKGROUND

• Tlacuilo-Parra A, Morales-Zambrano R, Tostado-Rabago N, Esparza-Flores MA, Lopez-Guido B, Orozco-Alcala J. Inactivity is a risk factor for low bone mineral density among haemophilic children. Br J Haematol. 2008 Mar;140(5):562-7. doi: 10.1111/j.1365-2141.2007.06972.x.

  PMID: 18275434 BACKGROUND

• Amorosa V, Tebas P. Bone disease and HIV infection. Clin Infect Dis. 2006 Jan 1;42(1):108-14. doi: 10.1086/498511. Epub 2005 Nov 30.

  PMID: 16323100 BACKGROUND

• Anagnostis P, Vakalopoulou S, Vyzantiadis TA, Charizopoulou M, Karras S, Goulis DG, Karagiannis A, Gerou S, Garipidou V. The clinical utility of bone turnover markers in the evaluation of bone disease in patients with haemophilia A and B. Haemophilia. 2014 Mar;20(2):268-75. doi: 10.1111/hae.12271. Epub 2013 Oct 7.

  PMID: 24118364 BACKGROUND

• Liel MS, Greenberg DL, Recht M, Vanek C, Klein RF, Taylor JA. Decreased bone density and bone strength in a mouse model of severe factor VIII deficiency. Br J Haematol. 2012 Jul;158(1):140-3. doi: 10.1111/j.1365-2141.2012.09101.x. Epub 2012 Apr 2. No abstract available.

  PMID: 22469061 BACKGROUND

• Kempton CL, Antun A, Antoniucci DM, Carpenter W, Ribeiro M, Stein S, Slovensky L, Elon L. Bone density in haemophilia: a single institutional cross-sectional study. Haemophilia. 2014 Jan;20(1):121-8. doi: 10.1111/hae.12240. Epub 2013 Aug 1.

  PMID: 23902277 BACKGROUND

• Lee SK, Lorenzo J. Cytokines regulating osteoclast formation and function. Curr Opin Rheumatol. 2006 Jul;18(4):411-8. doi: 10.1097/01.bor.0000231911.42666.78.

  PMID: 16763463 BACKGROUND

• Brinker MR, O'Connor DP. The incidence of fractures and dislocations referred for orthopaedic services in a capitated population. J Bone Joint Surg Am. 2004 Feb;86(2):290-7.

  PMID: 14960673 BACKGROUND

• Roche AF, Roberts J, Hamill PV. Skeletal maturity of youths 12--17 years racial, geographic area, and socioeconomic differentials. United States, 1966-1970. Vital Health Stat 11. 1978 Oct;(167):1-98. No abstract available.

  PMID: 214960 BACKGROUND

MeSH Terms

Conditions

Hemophilia A; Bone Diseases

Interventions

Factor VIII

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; Musculoskeletal Diseases

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Results Point of Contact

• Title: Dr. Jayson Taylor
• Organization: Oregon Health & Science University

taylojas@ohsu.edu

503-494-8716

Study Officials

• Jason Taylor, MD, PhD

  Oregon Health and Science

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2014
• First Posted: December 3, 2014
• Study Start: December 1, 2014
• Primary Completion: April 16, 2018
• Study Completion: April 16, 2018
• Last Updated: April 1, 2020
• Results First Posted: March 24, 2020

Record last verified: 2020-03

Locations

US (1)