Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001397808
Ethics application status
Approved
Date submitted
3/09/2021
Date registered
15/10/2021
Date last updated
16/09/2022
Date data sharing statement initially provided
15/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The Haemophilia Osteoporosis Registry (THOR): Identifying Mechanisms of Bone Loss in Haemophilia
Scientific title
The Haemophilia Osteoporosis Registry (THOR): Identifying Mechanisms of Bone Loss in Haemophilia
Secondary ID [1] 305213 0
nil
Universal Trial Number (UTN)
U1111-1269-1868
Trial acronym
THOR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Haemophilia A 323483 0
Osteoporosis 323484 0
Sarcopenia 323485 0
Osteoarthritis 323486 0
Condition category
Condition code
Blood 321052 321052 0 0
Clotting disorders
Musculoskeletal 321053 321053 0 0
Osteoporosis
Musculoskeletal 321054 321054 0 0
Osteoarthritis

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This is a prospective longitudinal observational study, recruiting men with haemophilia A and age-matched controls residing in Victoria, Australia, with a total of 176 participants. Stratified sampling by age will be used to ensure equal distribution across the four age-bands, namely 18-30, 31-40, 41-50, 51+ years.

Recruitment will include: patients with haemophilia A will be approached during clinical consultations (in person or via telehealth) at Alfred Health. Each patient who is approached to join the study will be recorded in the Log Book. If patients consent to passing on their contact details, the consultant will refer the patients to the team at Monash Medical Centre to discuss the study in further detail. Potential participants will undergo screening against criteria to determine their eligibility for participation.
The age-matched controls will be recruited through:
- Posters displayed throughout Monash Medical Centre and Monash University Clayton Campus, and;
- Email lists, newsletters, social media, recruitment registry, community organisations, local social and sports clubs will also be employed to advertise recruitment

Participants will come into Monash Medical Centre for a study visit at baseline and follow-up 1, with an interval of 12 months between study visits.

Data collected will include:
- Questionnaires: general demographics, medical history, including medication use and co-morbidities at baseline (General Questionnaire); health changes during the study will be collected at follow-up (General Medical Hx Update); Patient Reported Outcomes Burdens and Experiences (PROBE) questionnaire (containing the EQ-5D-5L and VAS); Bone-specific Physical Activity Questionnaire (BPAQ or BSPA in REDCap); International Physical Activity Questionnaire (IPAQ); Gilbert Joint Health Score questionnaire (Gilbert Score).
- Anthropometry: height, weight and sidedness
- Bloods: fasting blood samples will be collected to measure procollagen type 1 N propeptide (P1NP), C-terminal telopeptide of type 1 collagen (CTX), calcium, phosphate, vitamin D, and liver function tests (bilirubin, albumin, GGT, ALP, AST, ALT).
- Bone health: dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR-pQCT)
- Joint health: HR-pQCT will scan the ankle and knee joints
- Body composition: DXA
- Muscle strength: hand grip strength and jumping mechanography

These will all be collected at both study visits by the research team (including research assistant, Research Fellow, Students (ie PhD, Honours, Medical students). The anticipated duration of each study visit is 1.5hrs.
Intervention code [1] 321612 0
Early Detection / Screening
Comparator / control treatment
Healthy (non-haemophilia) age-matched male controls will be recruited for comparison.
Control group
Active

Outcomes
Primary outcome [1] 328828 0
Determine the change in total bone mineral density (BMD) from HR-pQCT, between controls and haemophilia A patients
Timepoint [1] 328828 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Primary outcome [2] 328829 0
Determine the change in aBMD (DXA) between controls and haemophilia A patients
Timepoint [2] 328829 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Primary outcome [3] 328830 0
Determine the difference in bone turnover markers between controls and haemophilia A patients. Plasma EDTA will be collected to measure procollagen type 1 N propeptide (P1NP) for bone formation and C-terminal telopeptide of type 1 collagen (CTX) for bone resorption, using the automated Roche Cobas system. This is a composite primary outcome
Timepoint [3] 328830 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [1] 400543 0
Whole body fat mass assessed by Hologic Horizon A dual energy x-ray absorptiometry (DXA)
Timepoint [1] 400543 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [2] 400544 0
Peak muscle force in the legs assessed by the Leonardo ground reaction force platform
Timepoint [2] 400544 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [3] 400545 0
Hand grip strength (kg) in the dominant hand will be tested via a hand dynamometer. Participants will be seated on a chair without an armrest, while gripping the dynamometer facing the floor. Participants will be given three attempts, with the highest reading taken as the “peak grip strength”.
Timepoint [3] 400545 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [4] 400546 0
Differences in physical activity will be determined using the International Physical Activity Questionnaire (IPAQ)
Timepoint [4] 400546 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [5] 400547 0
Differences in Patient Reported Outcomes Burdens and Experiences (PROBE) questionnaire
Timepoint [5] 400547 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [6] 400548 0
Differences in Bone-specific Physical Activity Questionnaire (BPAQ)
Timepoint [6] 400548 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [7] 400553 0
differences in blood biochemistry: calcium
Timepoint [7] 400553 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [8] 400554 0
knee joint health using HR-pQCT
Timepoint [8] 400554 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [9] 401283 0
ankle joint health using HR-pQCT
Timepoint [9] 401283 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [10] 401284 0
Physical function will be assessed with the Chair rise test. This test will be conducted on the Leonardo ground reaction force plate. The participant is instructed to attempt to stand straight from a seated position, five times as quickly as possible without stopping in between. The participant keeps their arms folded across their chest. The exercise is timed, and audible count is made each time the participant rises and stops timing when the participant has completed their fifth repetition. The time taken to complete the test, and/or the number of stands completed. The test is aborted if not completed within 1 minute, or if the participant is unable to not use their arms as an aid. This test will be performed 3 times and all 3 measurements will be recorded. The test with the shortest duration will be taken as the measurement for analyses.
Timepoint [10] 401284 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [11] 401285 0
Peak muscle power in the legs assessed by the Leonardo ground reaction force platform
Timepoint [11] 401285 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [12] 401286 0
Whole body lean mass assessed by Hologic Horizon A dual energy x-ray absorptiometry (DXA)
Timepoint [12] 401286 0
Baseline (enrolment and 12 months post-enrolment follow-up
Secondary outcome [13] 401287 0
differences in blood biochemistry: phosphate
Timepoint [13] 401287 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [14] 401288 0
differences in blood biochemistry: vitamin D levels
Timepoint [14] 401288 0
Baseline (enrolment) and 12 months post-enrolment follow-up
Secondary outcome [15] 401289 0
differences in blood biochemistry: liver function tests as a composite outcome (bilirubin, albumin, GGT, ALP, AST, ALT)
Timepoint [15] 401289 0
Baseline (enrolment) and 12 months post-enrolment follow-up

Eligibility
Key inclusion criteria
Eligibility for inclusion as a participant in this study will require a potential participant to satisfy all of the following eligibility criteria:
- Aged 18 years or older
- Male
- Body weight less than 160 kg (maximum rating of imaging machines).
- At least one side of the body must be free from any metal, or other material in limbs or surrounding locations, that could interfere with imaging.
- Fluent in written and spoken English, has capacity to provide informed consent and can communicate effectively with researchers. A legally acceptable representative and/or impartial witness fluent in written and spoken English and the participant’s first/fluent language acting as translator will also be acceptable, providing they are able to attend all scheduled sessions with the participant.


Patients with haemophilia recruited for the study should also satisfy the additional criterion below:
- Previously diagnosed with moderate to severe haemophilia A

Participants in the control group should also satisfy the additional criteria below:
- Be in good health without any major medical co-morbidities (diabetes, chronic kidney disease and recent cardiovascular events – stroke, myocardial infarction or heart attack)
- No other medical condition that in the opinion of the investigators may deem inclusion unsafe or inappropriate (e.g., recent exposure to nuclear medicine; conditions that may reduce ability to remain supine during DXA (e.g., vertigo); conditions that may reduce ability to remain still during scans (e.g. Parkinson’s disease, motor-neuron disease).
- Not be on medications that targets bone health e.g., Alendronate (Fosamax), Risedronate (Actonel), Ibandronate (Boniva), Zoledronate (Aclasta), Denosumab (Prolia), Teriparatide (Forteo) and Romosozumab (Evenity).
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
For all participants:
- Have other medical condition that in the opinion of the investigators may deem inclusion unsafe or inappropriate (e.g., recent exposure to nuclear medicine; conditions that may reduce ability to remain supine during DXA (e.g., vertigo); conditions that may reduce ability to remain still during scans (e.g. Parkinson’s disease, motor-neuron disease).

Control participants:
- On medications that targets bone health e.g., Alendronate (Fosamax), Risedronate (Actonel), Ibandronate (Boniva), Zoledronate (Aclasta), Denosumab (Prolia), Teriparatide (Forteo) and Romosozumab (Evenity).


Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample Size
Power calculations were based on mean total BMD HR-pQCT data from a previous study, to achieve 90% power with a significance level of 5%, with age-matched to controls (1:1). Recruitment will include 88 patients with haemophilia A and 88 age-matched controls (44 per group: 22 controls and 22 patients with haemophilia A), with a total of 176 participants.

Statistical Analysis
Each variable will be inspected for data errors. In the case of missing or spurious data, original files will be consulted to identify the correct values. When correct values cannot be confirmed, the data point will be classified as missing. Non-normal data will be transformed to meet normality assumptions of parametric methods, or non-parametric methods will be used where appropriate. Initially, repeated measures ANOVA will compare change in bone and muscle parameters. Multivariable regression analyses will be performed to determine whether these associations are independent of potential confounders such as age, body weight, co-morbidities, physical activity and social demographics. For all analyses, a p-value of <0.05 or 95% confidence interval not including the null point will be considered statistically significant. All data will be analysed using STATA.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/12/2021
Actual
9/06/2022
Date of last participant enrolment
Anticipated
30/06/2023
Actual
Date of last data collection
Anticipated
1/09/2024
Actual
Sample size
Target
176
Accrual to date
21
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 20460 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 20461 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 35229 0
3168 - Clayton
Recruitment postcode(s) [2] 35230 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 309593 0
Commercial sector/Industry
Name [1] 309593 0
Bayer Hemophilia Awards Program (BHAP)
Country [1] 309593 0
Switzerland
Primary sponsor type
University
Name
Monash University
Address
Department of Medicine
School of Clinical Sciences at Monash Health
MHTP Translational Research Facility

Monash Medical Centre
246 Clayton Road
Clayton VIC 3168, Australia
Country
Australia
Secondary sponsor category [1] 310603 0
None
Name [1] 310603 0
Address [1] 310603 0
Country [1] 310603 0
Other collaborator category [1] 281973 0
Hospital
Name [1] 281973 0
Alfred Health
Address [1] 281973 0
Haemophilia Treatment Centre,
The Alfred Hospital,
55 Commercial Rd,
Melbourne, Victoria,
Australia 3004
Country [1] 281973 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309369 0
Monash Health HREC
Ethics committee address [1] 309369 0
Ethics committee country [1] 309369 0
Australia
Date submitted for ethics approval [1] 309369 0
16/06/2021
Approval date [1] 309369 0
17/09/2021
Ethics approval number [1] 309369 0
RES-21-0000387A

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113910 0
Dr Ayse Zengin
Address 113910 0
Department of Medicine
School of Clinical Sciences at Monash Health
Monash University
Level 5/Block E
Monash Medical Centre
246 Clayton Road
Clayton VIC 3168
Country 113910 0
Australia
Phone 113910 0
+61 3 8572 2918
Fax 113910 0
Email 113910 0
[email protected]
Contact person for public queries
Name 113911 0
Ayse Zengin
Address 113911 0
Department of Medicine
School of Clinical Sciences at Monash Health
Monash University
Level 5/Block E
Monash Medical Centre
246 Clayton Road
Clayton VIC 3168
Country 113911 0
Australia
Phone 113911 0
+61 3 8572 2918
Fax 113911 0
Email 113911 0
[email protected]
Contact person for scientific queries
Name 113912 0
Ayse Zengin
Address 113912 0
Department of Medicine
School of Clinical Sciences at Monash Health
Monash University
Level 5/Block E
Monash Medical Centre
246 Clayton Road
Clayton VIC 3168
Country 113912 0
Australia
Phone 113912 0
+61 3 8572 2918
Fax 113912 0
Email 113912 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual patient data will not be available to share.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
13093Informed consent form    382713-(Uploaded-03-09-2021-14-22-56)-Study-related document.pdf
13337Ethical approval    382713-(Uploaded-23-09-2021-11-45-58)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.