HemophiliaPhase 3NCT02306694
Prospective Biomarkers of Bone Metabolism in Hemophilia A
A Phase 3 study testing Advate in people with Hemophilia and Bone Disease, run by Oregon Health and Science University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 16 to 85 years, men only
- Conditions the study is for
- Hemophilia, Bone Disease
- What is being tested?
- Advate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2014to 16 Apr 2018
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 85 years
- Men only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Oregon Health and Science University
Portland, Oregon, 97239
About this study
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.
Read the 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.
- Conditions
- Hemophilia, Bone Disease
- Being tested
- Advate
- Keywords
- hemophilia, bone disease, clinical study, biomarkers
- Medical subject headings
- Hemophilia A, Bone Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AdvateDrug
Also called Antihemophilic Factor (Recombinant)
Patients who are currently taking Advate as their factor replacement will be eligible for the 5-day study.
| Study group | Role | What they receive |
|---|---|---|
| Open label | Experimental | Everyone receives Advate (antihemophilic factor) on Day 1 and 3. Receives: Drug: Advate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Dec 2014 (estimated)
- Study startDec 2014
- Primary completion16 Apr 2018
- Study completion16 Apr 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for HemophiliaStudies of the same condition, open and under way.
- More trials run by Oregon Health and Science UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oregon Health and Science University
- Sponsor type
- University, hospital or other
- Collaborators
- Baxter Healthcare Corporation
- Responsible party
- Sponsor
- Investigators
- Jason Taylor, MD, PhD, Principal investigator, Oregon Health and Science
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02306694
- Sponsor's protocol ID
- e11104
- Status last verified
- Mar 2020
- First submitted
- 25 Nov 2014
- Last updated
- 1 Apr 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 16460432Siboni 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.
PubMed 19220727Gerstner 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.
PubMed 19187193Wallny 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.
PubMed 17212729Barnes 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.
PubMed 15286254Gallacher 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.
PubMed 8208906Tlacuilo-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.
PubMed 18275434Amorosa 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.
PubMed 16323100Anagnostis 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.
PubMed 24118364Liel 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.
PubMed 22469061Kempton 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.
PubMed 23902277Lee 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.
PubMed 16763463Brinker 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.
PubMed 14960673Roche 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.
PubMed 214960
Study at a glance
From the registry record, last updated by the sponsor on 1 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Biomarkers of Bone Metabolism in Hemophilia A
- ClinicalTrials.gov ID
- NCT02306694
- Acronym / sponsor ID
- e11104
- Conditions
- Hemophilia, Bone Disease
- Keywords
- hemophilia, bone disease, clinical study, biomarkers
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- Oregon Health and Science UniversityUniversity, hospital or other
- Collaborators
- Baxter Healthcare Corporation
- Study start
- Dec 2014 (actual)
- Primary completion
- 16 Apr 2018 (actual)
- Study completion
- 16 Apr 2018 (actual)
- First posted
- 3 Dec 2014 (estimated)
- Results
- Posted 24 Mar 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Open label | Experimental | Drug: AdvateEveryone receives Advate (antihemophilic factor) on Day 1 and 3. |
Who may qualify
- Ages
- 16 to 85 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AdvateAlso: Antihemophilic Factor (Recombinant)Patients who are currently taking Advate as their factor replacement will be eligible for the 5-day study. | Drug | Open label |
Primary outcome
Bone Biomarker Density (BMD)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Apr 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 16460432Plug 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.
- Background: PubMed 19220727Siboni 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.
- Background: PubMed 19187193Gerstner 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.
- Background: PubMed 17212729Wallny 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.
- Background: PubMed 15286254Barnes 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.
- Background: PubMed 8208906Gallacher 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.
- Background: PubMed 18275434Tlacuilo-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.
- Background: PubMed 16323100Amorosa 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.
- Background: PubMed 24118364Anagnostis 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.
- Background: PubMed 22469061Liel 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.
- Background: PubMed 23902277Kempton 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.
- Background: PubMed 16763463Lee 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jason Taylor, MD, PhD principal investigator
Oregon Health and Science
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Advate in people with Hemophilia and Bone Disease, run by Oregon Health and Science University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Mar 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Bone Biomarker Density (BMD) (time frame: 5 days). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02306694, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2020.