Bone Disease, Hemophilia
Conditions
Keywords
hemophilia, bone disease, clinical study, biomarkers
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.
Detailed description
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.
Interventions
DRUGAdvate
Patients who are currently taking Advate as their factor replacement will be eligible for the 5-day study.
Sponsors
Baxter Healthcare Corporation
Oregon Health and Science University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
16 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Males with a diagnosis of hemophilia A with a historic baseline FVIII level ≤ 2%. 2. Age \> 16 years old 3. Currently using ADVATE as FVIII replacement therapy
Exclusion criteria
1. Subject or guardian is unwilling or unable to give written informed consent and/or assent 2. Joint or muscle bleeding within 2 weeks of Study Day 1 3. Presence of a current factor inhibitor (\>0.6 BU/mL via Nijmegan-modified Bethesda assay) 4. Known collagen vascular bone disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bone Biomarker Density (BMD) | 5 days | 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. |
| Joint Health | 5 days | 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). |
| Quality of Life Using the VAS and EQ-5D-3L | 5 days | 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). |
| Plasma Cytokine Concentration Differences From 0-hour to 24-hour | 24 hours | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Hemophilia Activities List (HAL) and the International Society of Thrombosis and Hemostasis- Bleeding Assessment Tool (ISTH-BAT) | 5 days | 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) |
| Participant Quality of Life | 5 days | 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). |
| Medication Adherence | 5 days | 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) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Open Label |
|---|---|
| Age, Categorical <=18 years | 3 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants |
| Race/Ethnicity, Customized White | 16 Participants |
| Region of Enrollment United States | 16 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 16 Participants |
| Weight | 149.3 lb STANDARD_DEVIATION 192.9 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
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.
Time frame: 5 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label | Bone Biomarker Density (BMD) | Spine BMD (Spine L1-L4 Z-score) | -0.74 Z-Score | Standard Deviation 1.22 |
| Open Label | Bone Biomarker Density (BMD) | Hip Total BMD | -0.16 Z-Score | Standard Deviation 1.12 |
| Open Label | Bone Biomarker Density (BMD) | Hip Neck BMD | -0.16 Z-Score | Standard Deviation 1.23 |
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).
Time frame: 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label | Joint Health | 19.91 score on a scale | Standard Deviation 16.26 |
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.
Time frame: 24 hours
Population: Some participant samples were unable to be analyzed at all time points due to poor sample quality or other factors.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | Basic FGF | 2.04 pg/mL | Standard Deviation 1.78 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | C-Terminal telopeptide | 0.03 pg/mL | Standard Deviation 0.12 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | DKK1 | -7.73 pg/mL | Standard Deviation 15.63 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | Eotaxin | -2.84 pg/mL | Standard Deviation 14.09 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | fibroblast growth factor 23 | -6.72 pg/mL | Standard Deviation 9.95 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | interferon gamma | 0.12 pg/mL | Standard Deviation 0.52 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | interleukin 13 | -0.76 pg/mL | Standard Deviation 1.52 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | Interleukin 1 beta | -0.12 pg/mL | Standard Deviation 0.19 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | interleukin receptor 1 antagonist | -131.72 pg/mL | Standard Deviation 429.93 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | interleukin 2 | 0.71 pg/mL | Standard Deviation 1.16 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | interleukin 4 | -0.28 pg/mL | Standard Deviation 0.39 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | interleukin 6 | 0.22 pg/mL | Standard Deviation 0.38 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | interleukin 17 | -0.13 pg/mL | Standard Deviation 0.8 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | interleukin 8 | -0.56 pg/mL | Standard Deviation 0.99 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | interleukin 9 | -14.83 pg/mL | Standard Deviation 14.03 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | Insulin | -279.39 pg/mL | Standard Deviation 1518.67 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | IP10 | -10.06 pg/mL | Standard Deviation 36.49 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | Leptin | -208.39 pg/mL | Standard Deviation 6728.25 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | MCP1 | -6.42 pg/mL | Standard Deviation 7.53 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | MIP1a | -0.23 pg/mL | Standard Deviation 0.4 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | osteoclasts | -2146.62 pg/mL | Standard Deviation 5921.06 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | osteoprotegerin | 113.70 pg/mL | Standard Deviation 328.53 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | osteopontin | -493.87 pg/mL | Standard Deviation 6795.35 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | platelet derived growth factors | -103.83 pg/mL | Standard Deviation 156.52 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | parathyroid horomone | -6.72 pg/mL | Standard Deviation 25.7 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | RANKL | 228.10 pg/mL | Standard Deviation 277.99 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | chemokine ligand 5 | -414.77 pg/mL | Standard Deviation 681.82 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | sclerostin | -398.13 pg/mL | Standard Deviation 838.83 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | transforming growth factor-beta 1 | -519.05 pg/mL | Standard Deviation 772.15 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | transforming growth factor beta - 2 | -10.08 pg/mL | Standard Deviation 16.43 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | transforming growth factor beta - 3 | -0.74 pg/mL | Standard Deviation 1.49 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | tumor necrosis factor alpha | -1.09 pg/mL | Standard Deviation 2.76 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | VEGF | -4.03 pg/mL | Standard Deviation 12.17 |
| Open Label | Plasma Cytokine Concentration Differences From 0-hour to 24-hour | MIP1b | -7.19 pg/mL | Standard Deviation 9.36 |
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).
Time frame: 5 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label | Quality of Life Using the VAS and EQ-5D-3L | EQ-5D-3L | 6.92 score on a scale | Standard Deviation 1.83 |
| Open Label | Quality of Life Using the VAS and EQ-5D-3L | VAS | 82.42 score on a scale | Standard Deviation 15.08 |
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)
Time frame: 5 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label | Hemophilia Activities List (HAL) and the International Society of Thrombosis and Hemostasis- Bleeding Assessment Tool (ISTH-BAT) | HAL | 226 score on a scale | Standard Deviation 41.78 |
| Open Label | Hemophilia Activities List (HAL) and the International Society of Thrombosis and Hemostasis- Bleeding Assessment Tool (ISTH-BAT) | ISTH-BAT | 16.92 score on a scale | Standard Deviation 6.56 |
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)
Time frame: 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label | Medication Adherence | 56.25 score on a scale | Standard Deviation 5.29 |
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).
Time frame: 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label | Participant Quality of Life | 113.83 score on a scale | Standard Deviation 58.19 |