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| Name | Class |
|---|---|
| Baxter Healthcare Corporation | INDUSTRY |
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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.
This is a pilot study to determine the impact of factor replacement on bone biomarkers in up to 20 hemophilia A subjects. Subjects will be recruited over 1 year for the 5-day protocol.
Following a 72-hour washout period, factor levels and bone biomarkers will be followed before and after 50 units/kg replacement on Day 1 and 20 units/kg replacement on Day 3. Each subject can serve as their Figure 4. Fracture rates in PwH compared to historic controls.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Open label | Experimental | Everyone receives Advate (antihemophilic factor) on Day 1 and 3. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Advate | Drug | Patients who are currently taking Advate as their factor replacement will be eligible for the 5-day study. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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| Measure | Description | Time Frame |
|---|---|---|
| Medication Adherence | VERITAS instrument self-reported compliance with factor replacement regimen. The VERITAS is composed of 6 subsections, where scores range from 1 (best adherence) to 5 (worst adherence). A total score was calculated with the minimum score of 24 (most adherent) and a maximum score of 120 (least adherent) | 5 days |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jason Taylor, MD, PhD | Oregon Health and Science | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Oregon Health and Science University | Portland | Oregon | 97239 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16460432 | Background | 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. | |
| 19220727 | Background |
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Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Open Label | Everyone receives Advate (antihemophilic factor) on Day 1 and 3. Advate: Patients who are currently taking Advate as their factor replacement will be eligible for the 5-day study. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Open Label | Everyone receives Advate (antihemophilic factor) on Day 1 and 3. Advate: Patients who are currently taking Advate as their factor replacement will be eligible for the 5-day study. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | Z-Score | 5 days |
|
1 month
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Open Label | Everyone receives Advate (antihemophilic factor) on Day 1 and 3. Advate: Patients who are currently taking Advate as their factor replacement will be eligible for the 5-day study. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jayson Taylor | Oregon Health & Science University | 503-494-8716 | taylojas@ohsu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 28, 2017 | May 7, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006467 | Hemophilia A |
| D001847 | Bone Diseases |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| D005169 | Factor VIII |
| ID | Term |
|---|---|
| D001779 | Blood Coagulation Factors |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
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| 24 hours |
| Hemophilia Activities List (HAL) and the International Society of Thrombosis and Hemostasis- Bleeding Assessment Tool (ISTH-BAT) |
The HAL is used to assess physical activity; scores range from 42 (severe problems) to 252 (no problems). The ISTH-BAT was used to evaluate bleeding phenotype. Each section was scored using a 0 to 4 scale for each of the 12 subsections. A total score was calculated by taking the sum of each section, resulting in a range of scores from 0 (no bleeding history) to 48 (most extensive clinical intervention for bleeding) |
| 5 days |
| Participant Quality of Life | Haem-A-QoL was used to assess various components indicating participants quality of life. Haem-A-QoL is composed of 10 subsections with 3-8 questions in each. Questions are rated from 1 to 5, with 5 being the most negative influence on quality of life. Some questions are worded in the inverse, such that the 1 corresponds to the greatest negative impact on quality of life. In this case, the score is inverted to match the remainder of questions for statistical analysis. A Transformed scores is calculated for each subsection and for the total of all the subjections. The scores range from 0 (best quality of life) to 225 (worst quality of life). | 5 days |
| 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. |
| 19187193 | 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. |
| 17212729 | 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. |
| 15286254 | 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. |
| 8208906 | 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. |
| 18275434 | 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. |
| 16323100 | 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. |
| 24118364 | 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. |
| 22469061 | 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. |
| 23902277 | 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. |
| 16763463 | 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. |
| 14960673 | 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. |
| 214960 | 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. |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Weight | Mean | Standard Deviation | lb |
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
| Primary | 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). | Posted | Mean | Standard Deviation | score on a scale | 5 days |
|
|
|
| Primary | 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). | Posted | Mean | Standard Deviation | score on a scale | 5 days |
|
|
|
| Primary | 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. | Some participant samples were unable to be analyzed at all time points due to poor sample quality or other factors. | Posted | Mean | Standard Deviation | pg/mL | 24 hours |
|
|
|
| Other Pre-specified | Medication Adherence | VERITAS instrument self-reported compliance with factor replacement regimen. The VERITAS is composed of 6 subsections, where scores range from 1 (best adherence) to 5 (worst adherence). A total score was calculated with the minimum score of 24 (most adherent) and a maximum score of 120 (least adherent) | Posted | Mean | Standard Deviation | score on a scale | 5 days |
|
|
|
| Other Pre-specified | Hemophilia Activities List (HAL) and the International Society of Thrombosis and Hemostasis- Bleeding Assessment Tool (ISTH-BAT) | The HAL is used to assess physical activity; scores range from 42 (severe problems) to 252 (no problems). The ISTH-BAT was used to evaluate bleeding phenotype. Each section was scored using a 0 to 4 scale for each of the 12 subsections. A total score was calculated by taking the sum of each section, resulting in a range of scores from 0 (no bleeding history) to 48 (most extensive clinical intervention for bleeding) | Posted | Mean | Standard Deviation | score on a scale | 5 days |
|
|
|
| Other Pre-specified | Participant Quality of Life | Haem-A-QoL was used to assess various components indicating participants quality of life. Haem-A-QoL is composed of 10 subsections with 3-8 questions in each. Questions are rated from 1 to 5, with 5 being the most negative influence on quality of life. Some questions are worded in the inverse, such that the 1 corresponds to the greatest negative impact on quality of life. In this case, the score is inverted to match the remainder of questions for statistical analysis. A Transformed scores is calculated for each subsection and for the total of all the subjections. The scores range from 0 (best quality of life) to 225 (worst quality of life). | Posted | Mean | Standard Deviation | score on a scale | 5 days |
|
|
|
| 0 |
| 16 |
| 0 |
| 16 |
| 0 |
| 16 |
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| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D009140 | Musculoskeletal Diseases |
| D011498 |
| Protein Precursors |
| D001685 | Biological Factors |
|
| DKK1 |
|
|
| Eotaxin |
|
|
| fibroblast growth factor 23 |
|
|
| interferon gamma |
|
|
| interleukin 13 |
|
|
| Interleukin 1 beta |
|
|
| interleukin receptor 1 antagonist |
|
|
| interleukin 2 |
|
|
| interleukin 4 |
|
|
| interleukin 6 |
|
|
| interleukin 17 |
|
|
| interleukin 8 |
|
|
| interleukin 9 |
|
|
| Insulin |
|
|
| IP10 |
|
|
| Leptin |
|
|
| MCP1 |
|
|
| MIP1a |
|
|
| osteoclasts |
|
|
| osteoprotegerin |
|
|
| osteopontin |
|
|
| platelet derived growth factors |
|
|
| parathyroid horomone |
|
|
| RANKL |
|
|
| chemokine ligand 5 |
|
|
| sclerostin |
|
|
| transforming growth factor-beta 1 |
|
|
| transforming growth factor beta - 2 |
|
|
| transforming growth factor beta - 3 |
|
|
| tumor necrosis factor alpha |
|
|
| VEGF |
|
|
| MIP1b |
|
|