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Prospective Biomarkers of Bone Metabolism in Hemophilia A

Primary Purpose

Hemophilia, Bone Disease

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Advate
Sponsored by
Oregon Health and Science University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia focused on measuring hemophilia, bone disease, clinical study, biomarkers

Eligibility Criteria

16 Years - 85 Years (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

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.

Sites / Locations

  • Oregon Health and Science University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Open label

Arm Description

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

Outcomes

Primary Outcome Measures

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.
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).
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).
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.

Secondary Outcome Measures

Full Information

First Posted
November 25, 2014
Last Updated
March 23, 2020
Sponsor
Oregon Health and Science University
Collaborators
Baxter Healthcare Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT02306694
Brief Title
Prospective Biomarkers of Bone Metabolism in Hemophilia A
Official Title
Prospective Biomarkers of Bone Metabolism in Hemophilia A
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
December 2014 (Actual)
Primary Completion Date
April 16, 2018 (Actual)
Study Completion Date
April 16, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Oregon Health and Science University
Collaborators
Baxter Healthcare Corporation

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia, Bone Disease
Keywords
hemophilia, bone disease, clinical study, biomarkers

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Open label
Arm Type
Experimental
Arm Description
Everyone receives Advate (antihemophilic factor) on Day 1 and 3.
Intervention Type
Drug
Intervention Name(s)
Advate
Other Intervention Name(s)
Antihemophilic Factor (Recombinant)
Intervention Description
Patients who are currently taking Advate as their factor replacement will be eligible for the 5-day study.
Primary Outcome Measure Information:
Title
Bone Biomarker Density (BMD)
Description
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
Title
Joint Health
Description
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
Title
Quality of Life Using the VAS and EQ-5D-3L
Description
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
Title
Plasma Cytokine Concentration Differences From 0-hour to 24-hour
Description
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
Other Pre-specified Outcome Measures:
Title
Medication Adherence
Description
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
Title
Hemophilia Activities List (HAL) and the International Society of Thrombosis and Hemostasis- Bleeding Assessment Tool (ISTH-BAT)
Description
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
Title
Participant Quality of Life
Description
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

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Exclusion Criteria: 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jason Taylor, MD, PhD
Organizational Affiliation
Oregon Health and Science
Official's Role
Principal Investigator
Facility Information:
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States

12. IPD Sharing Statement

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Prospective Biomarkers of Bone Metabolism in Hemophilia A

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