Primary objectivesPart 1:• To establish a corrected standardized gradient of fracture risk using the POROUS R3C ultrasound device based on prevalent fractures.Part 2:• To establish a corrected standardized gradient of fracture risk using the POROUS…
ID
Source
Brief title
Acronym: POROUS-preFX
Condition
- Bone, calcium, magnesium and phosphorus metabolism disorders
- Fractures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Clinical endpoints
Part 1:
Prevalent fractures are the focus of the analysis in Part 1, i.e., fractures
that occurred prior to the Baseline visit. This is reflected in establishing
corrected standardized odds ratio (sOR) for the POROUS R3C ultrasound
device-derived POROUS-ScorePrev. Statistically significant discriminative power
of the sOR will be achieved if the lower limit of the 95% confidence interval
of the sOR is greater than 1. The POROUS-ScorePrev will be evaluated to
demonstrate the discriminative performance of the POROUS R3C ultrasound device
for prevalent fractures.
Part 2:
Incident fractures are the focus of the analysis in Part 2, i.e., fractures
that occur after the Baseline visit until the EoS. This is reflected in
establishing corrected standardized relative risk (sRR) for the POROUS R3C
ultrasound device-derived POROUS-Score. Statistically significant prediction
power of the sRR will be achieved if the lower limit of the 95% confidence
interval of the sRR is greater than 1. The POROUS-Score will be evaluated to
demonstrate the predictive performance of the POROUS R3C ultrasound device for
incident fractures.
The following fractures, which are associated with cortical bone and/or
increasing age, will be considered for collecting information on both prevalent
and incident fractures. Any incident fractures caused by high-energy external
forces will be excluded (censored) from the analysis.
Proximal humerus, Shaft of humerus, Distal humerus , Proximal ulna, Shaft of
ulna, Proximal radius, Shaft of radius, Distal radius, Thoracic spine , Lumbar
spine, Rib, Multiple ribs, Pelvic ring, Acetabulum, Femur subtrochanteric,
Femur femoral neck, Femur pertrochanteric, Shaft of femur, Distal femur,
Proximal tibia, Shaft of tibia, Distal tibia, Fibula/lateral malleolus
Fracture risk prediction model
The diagnostic value of physical biomarkers, which are derived from Baseline
measurements with the POROUS R3C ultrasound device, will be assessed, and
selected physical biomarkers will be integrated into a model, resulting in a
composite POROUS-Score, for fracture risk prediction. In Part 1, the model will
be developed using data on prevalent fractures, while in Part 2, the model will
be developed using data on incident fractures. The resulting POROUS-Scores are,
therefore, different in Part 1 and Part 2. In Part 1, it is termed
POROUS-ScorePrev, whereas in Part 2, it is termed POROUS-Score. Additionally,
anthropometric data (age, sex, and BMI) will be evaluated and selected for
adding predictive strength to the prediction model.
Part 1:
Prevalent fractures will be recorded, and all relevant variables, including
ultrasound parameter values and anthropometric information, will be used to
perform partial least squares - discriminant analysis (PLS-DA) followed by
subwindow permutation analysis using a Monte-Carlo approach. Only variables
that have statistically significant discriminative power will be used in the
next step, where a new fracture discrimination model will be created using
PLS-DA analysis. Thereafter, the performance of the model will be investigated
using receiver operating characteristics (ROC) analysis.
The PLS-DA yields the final composite POROUS-ScorePrev (generated from the
internally validated model). Then, standardized odds ratios (sOR) will be
calculated, for the final composite POROUS-ScorePrev (generated from the
internally validated model), i.e., the fold-increase of the relative fracture
risk per standard deviation decrease of the respective score. Similarly, the
sOR will be calculated for the DXA T-scores. Since the comparative data are not
from randomized groups, confounders will be analyzed (e.g. clinical risk
factors, age, sex, and anthropometric data) in the association between the DXA
T-score and prevalent fractures. The model shall be adjusted if the
confounders* effect is different from the effects reported in the literature.
Finally, the POROUS sOR will be corrected based on a formula for the assessment
of peripheral bone densitometry devices, officially published by The
International Society for Clinical Densitometry (ISCD):
ln(sORcor) = ln(sORstudy(POROUS)) x ln(sORref (DXA)) /
ln(sORstudy (DXA))
The sORs in this study are sORstudy(POROUS) and sORstudy(DXA); sORref(DXA) is
obtained from published meta-analyses. The sORcor correction is needed to (i)
normalize the sOR against the gold standard DXA and (ii) account for the
potential effects on sOR caused by the study population. The discriminative
ability of the POROUS model for prevalent fractures is demonstrated if the
lower limit of the 95% confidence interval of the corrected sOR is higher than
1.
Part 2:
Incident fractures will be recorded, and all relevant variables, including
ultrasoundparameter values and anthropometric information, will be used to
perform PLSDA followed by sub-window permutation analysis using a Monte-Carlo
approach.Only variables that have statistically significant predictive power
will be used in the next step, where a multivariate Cox-proportional Hazard
model will be performed to calculate the hazard ratio (HR). Then, the model
performance will be investigated using ROC analysis. Internal validation of the
model will be done by running cross-validation followed by Bootstrap analysis.
The sRR will be calculated, i.e., the fold-increase of the relative fracture
risk per standard deviation
decrease of the respective score. Similarly, the sRR will be calculated for the
DXA T-scores. Since the comparative data are not from randomized groups,
confounders (e.g. clinical risk factors, age, sex, and anthropometric data)
will be analyzed in the association between the DXA T-score and incident
fractures. The model shall be adjusted if confounders* effect is different from
the effects reported
in the literature. Finally, the POROUS sRR will also be corrected based on a
formula for the assessment of bone peripheral densitometry devices, officially
published by the ISCD:
ln(sRRcor) = ln(sRRstudy(POROUS)) x ln(sRRref (DXA)) /
ln(sRRstudy (DXA))
The sRRs in this study are sRRstudy(POROUS) and sRRstudy(DXA); sRRref(DXA) is
obtained from published meta-analyses. The sRRcor correction is needed to (i)
normalize the sRR against the gold standard DXA and (ii) account for the
potential effects on sRR caused by the study population. The predictive ability
of the POROUS model for incident fractures is demonstrated if the lower limit
of the 95% confidence interval of the corrected sRR is higher than 1.
Secondary outcome
Safety endpoints
In order to establish that the POROUS R3C ultrasound device is safe with a
minimal number of adverse events affecting the participants or the healthcare
professionals using the device, the following safety endpoints are investigated:
• Incidence of procedural/device-related adverse events, caused by the
o Absorbed energy
o Probe/transducer heating
o Irritation by ultrasound gel
o Release of substances
o Inappropriate hygiene measures.
• Other (serious) adverse events.
Performance endpoints
The discriminative and predictive performance of the POROUS R3C ultrasound
device will be analysed for prevalent and incident fractures, respectively.
Part 1:
Establish discriminative performance of the POROUS R3C ultrasound device in
comparison with DXA based on prevalent fractures. sOR values for both
POROUS-ScorePrev and DXA T-Score will be compared by applying ROC analysis.
Part 2:
Establish predictive performance of the POROUS R3C ultrasound device in
comparison with DXA based on incident fractures. Standardized hazard ratio
(sHR) values for both POROUS-Score and DXA T-Score will be compared by applying
Cox-proportional hazard modelling.
Exploratory endpoints
Performance endpoints
Part 1:
• Establish associations of various ultrasound parameters measured by the
POROUS R3C ultrasound device with specific clinical risk factors/indicators for
vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex,
BMI, and prevalent fractures.
• Establish corrected sOR for prevalent fractures (e.g. hip, vertebral, and
major osteoporotic fractures) and demonstrate significant performance.
• Establish reference data for developing age-matched POROUS Z-scores using the
POROUS R3C ultrasound device based on prevalent fractures.
Part 2:
• Establish associations of various ultrasound parameters measured by the
POROUS R3C ultrasound device with specific clinical risk factors/indicators for
vertebral and hip fractures (as outlined by the DVO), including BMD, age, sex,
BMI, and incident fractures.
• Establish corrected sRR for incident fractures (e.g. hip, vertebral, and
major osteoporotic fractures) and demonstrate significant performance.
• Establish reference data for developing age-matched POROUS Z-scores using the
POROUS R3C ultrasound device based on incident fractures.
Treatment effect endpoints
• Treatment effect of anti-osteoporotic (anti-resorptive/anabolic) medication
on DXA T-Scores and POROUS-Scores with respect to fracture incidence.
• Treatment effect of drugs known to influence bone metabolism on DXA T-Scores
and POROUS-Scores (oral glucocorticoid of >= 2.5 mg/day prednisone equivalent
for > 3 months, proton pump inhibitors, aromatase inhibitors, hormone ablation
therapy/antiandrogens in male participants).
Background summary
Brief description of the investigational device
The POROUS R3C is an ultrasound device for measuring and quantifying
microstructural, acoustic, and viscoelastic properties in cortical bone (e.g.,
in the tibia of the lower limb). The purpose of the device is to analyse the
microstructural, acoustic, and viscoelastic properties of human cortical bone,
to discriminate prevalent fractures, and to predict fracture risk in an aging
population. The accompanying software generates B-mode images for guidance and
stores pre-beamformed data for further analysis. These performance abilities
are based on data obtained by ultrasound imaging and measurement of cortical
bone properties. The output parameter values can be used to assess bone state
and quality and determine physical biomarkers in cortical bone. The
standardized risk ratios are obtained from measurements at the midshaft tibia
and estimate the risk for fractures at various bone sites (e.g., spine and hip)
in an aging population.
Clinical investigation purpose and background
Currently, osteoporosis and fracture risk are indirectly evaluated via the
assessment of risk factors and bone mineral density (BMD) measurement.
Although BMD is currently the most important indicator for osteoporosis
associated bone fractures, most of those fractures occur in persons who do not
show pathologically reduced BMD value. Therefore, osteoporosis is one of the
most frequently underdiagnosed common diseases. Established guidelines for the
diagnosis of osteoporosis recommend the assessment of fracture risk factors and
the T-Score, which is derived from the measurement of areal bone mineral
density (aBMD) by means of DXA at major fracture sites, i.e. spine and proximal
femur. DXA is regarded as the *gold standard* well-established methodology to
determine aBMD for diagnostic purpose.
Epidemiological data emphasise the urgency of developing diagnostic tools that
can improve fracture risk prediction so that patients can be treated with the
appropriate anti-osteoporotic therapies. Current guidelines for diagnosis and
treatment lead to treatment gaps. It is estimated that at least 80% of males
and 77% of females who would benefit from osteoporosis treatment are neither
diagnosed nor treated in Germany. The POROUS R3C ultrasound device enables a
non-invasive, non-ionising quantitative detection of microstructural bone
changes. As opposed to diagnosis based on a combination of clinical risk
factors and a relative decrease of BMD, the novel device enables detecting
pathological changes of bone microstructure at an earlier timepoint as well as
monitoring such changes in a longitudinal manner. In the course of this
clinical investigation, data will be collected to establish relevant
ultrasound-based physical biomarkers for the prediction of fracture risk.
Study objective
Primary objectives
Part 1:
• To establish a corrected standardized gradient of fracture risk using the
POROUS R3C ultrasound device based on prevalent fractures.
Part 2:
• To establish a corrected standardized gradient of fracture risk using the
POROUS R3C ultrasound device based on incident fractures and to
demonstrate the predictive performance of the derived fracture risk,
Secondary objectives
Part 1:
• To compare the discriminative performance of the POROUS R3C ultrasound device
and standard-of-care DXA based on prevalent fractures.
Part 2:
• To assess the safety of the POROUS R3C ultrasound device by monitoring
adverse events affecting participants or the healthcare professionals using the
device.
• To compare the predictive performance of the POROUS R3C ultrasound device and
standard-of-care DXA based on incident fractures.
Exploratory objectives
Part 1:
• To assess the association of various ultrasound parameters measured by the
POROUS R3C ultrasound device with specific clinical risk factors/indicators for
vertebral and hip fractures (as outlined by the DVO) and prevalent fractures.
• To demonstrate the discriminative performance of the POROUS R3C ultrasound
device based on subgroups of prevalent fractures, e.g., hip,
vertebral, and major osteoporotic fractures.
• To establish reference data for developing age-matched POROUS Z-scores using
the POROUS R3C ultrasound device based on prevalent fractures.
Part 2:
• To assess the association of various ultrasound parameters measured by the
POROUS R3C ultrasound device with specific clinical risk factors/indicators for
vertebral and hip fractures (as outlined by the DVO) and incident fractures.
• To demonstrate the predictive performance of the POROUS R3C ultrasound device
based on subgroups of incident fractures, e.g., hip, vertebral, and major
osteoporotic fractures.
• To establish reference data for developing age-matched POROUS Z-scores using
the POROUS R3C ultrasound device based on incident fractures.
• To explore the treatment effect of anti-osteoporotic medication
• To explore the treatment effect of drugs known to influence bone metabolism.
Study design
This is a single-cohort, multicentre, prospective, age- and sex-stratified
study in participants > 55 years of age. In this study, Baseline data will be
collected to establish a corrected standardized gradient of fracture risk using
the POROUS R3C ultrasound device and test its performance in predicting
fracture risk. Further, the performance of the POROUS R3C ultrasound device in
the analysis of cortical bone properties and discrimination of prevalent
fractures will be assessed. Participants will be enrolled into different groups
based on their age (consisting of
five-year bands), sex (males and females), and risk status for hip and
vertebral fractures (i.e., high risk of >= 2-fold and low risk of < 2-fold
increased risk compared to the general population of the same age and sex).
Two measurements with each device: investigational device (POROUS R3C
ultrasound device at the midshaft tibia), and comparator (DXA of the lumbar
spine and proximal femur), are scheduled per participant:
• Measurement 1: At Baseline
• Measurement 2: At the End-of-Study (EoS) visit.
Part 1:
In Part 1, information on prevalent fractures will be used to establish a
corrected standardized gradient of fracture risk using the POROUS R3C
ultrasound device. In other words, Part 1 aims to establish the discriminative
performance and a standardized gradient of fracture risk based on prevalent
fractures. In addition, the discriminative performance of the POROUS R3C
ultrasound device and standardof-care DXA will be compared based on prevalent
fractures.
Part 2:
In Part 2, information on incident fractures will be used to establish a
corrected standardized gradient of fracture risk using the POROUS R3C
ultrasound device. It will be developed to demonstrate the predictive
performance of the derived fracture risk. In other words, Part 2 aims to
establish a standardized gradient of fracture risk based on incident fractures.
In addition, the predictive performance of the POROUS R3C ultrasound device and
standard-of-care DXA will be compared based on incident fractures. The
collection of data obtained by DXA and the POROUS R3C device at the EoS visit
is used to monitor changes in the bone state in comparison to the respective
data obtained at Baseline. However, only measurement data obtained by the
POROUS R3C device at Baseline is used to develop the POROUS-Score model and the
standardized gradient of fracture risk (for Part 1 and Part 2).
Intervention
Intervention 1
Measurement with POROUS R3C ultrasound device at midshaft tibia
Measurements are to be performed at the central antero-medial tibia region. The
tibia length is assessed as the distance between the medial knee joint cleft
and the medial malleolus. The ultrasound transducer is coupled to the skin at
this position using an ultrasound coupling pad. Then transducer must be
positioned about 1cm above the surface of the skin using a gel pad.
Conventional B-mode images are used to position the probe. The probe has then
to be manually tilted until the bone surface is approximately normal to the
sound beam direction and the focus position is adjusted to be approximately
aligned with the periosteal bone surface. Scans of the bone using the CortBS
(x2) and Multifocus (x2) methods must be performed. The 3D acquisition
minimises the operator dependence of the measurement. This is done manually
using the probe applicator and sweep module. Beamsteering sequences must be
used to send focused beams at multiple inclination angles to the cortical bone
surface.
Intervention 2
Radiation:DXA measurement , lumbar spine and prox. femur
The aBMD of the lumbar spine and the proximal femur at Baseline and at the
EndofStudy visit after 36 months are assessed via DXA. The following DXA
measurements are to be performed:
Spine L1-4
Hip left (alternatively Hip right, if a valid measurement of the left hip is
not possible)
Intervention 3
Radiation: DXA-based VFA. Alternatively, VFA may be replaced by projectional
radiography
DXA-based Vertebral Fracture Assessment (VFA) of thoracic and lumbar spine from
T4 to L5 (Alternatively, VFA may be replaced by projectional radiography of
thoracic spine T4-T12 and lumbar spine L1-L5 if DXA-based VFA is not available.
Intervention 4
Radiation: Projectional radiography of thoracic spine (alternatively to DXA
based VFA, if it is not available).
Projectional radiography of thoracic spine T4-T12 and lumbar spine L1-L5
Study burden and risks
Risks of the clinical trial
POROUS R3C is a device which applies ultrasound energy into the human body
where it is resorbed. Like other ultrasound devices, it does not emit ionising
radiation. Risks related to the output of acoustic levels are reduced by
fulfilment of the applicable standard ISO 60601-2-37. Appliance of ultrasound
energy is performed and experienced for a long time, risks arising from this
kind of energy can be assumed to be under control.
Safety incidents or adverse effects might be caused by the emitted non-ionising
radiation, probe/transducer overheating, the release of substances, and
inappropriate hygiene measures.
A too-high output level of the device might cause thermal stress in the
measured participant*s body, which can lead to serious injury. Temporary, mild
skin irritation as a result of a reaction to the ultrasound gel is not common
but possible.
The safety of the gold standard and comparator DXA is well-known. DXA scanning
involves exposure to low-dose ionising radiation. In this clinical
investigation, a single DXA scan for assessing BMD values and T-Score reaches a
maximum radiation dose of ~0.08 mSv. Even if the Vertebral Fracture Assessment
is done with conventional X-Ray (alternativly to DXA) a maximum radiation dose
of ~0.22 mS. For comparison, the total worldwide average effective dose from
naturally occurring background radiation is approximately 2.4 mSv per year.
The overall risks for the study participants associated with the use of the
investigational device and the use of other techniques in the clinical
investigation are acceptable from the sponsor's point of view.
Benefits of the clinical trial
Participation in the clinical trial may result in an indirect benefit for
participants if a diagnosis of osteoporosis is made as a result of the DXA
examination and early treatment can be initiated (independently of the
investigation).
The aim of the study is to evaluate the performance of the POROUS R3C device
for fracture risk prediction. This increase in knowledge can form the basis for
further studies on the further development of refined models for fracture risk
prediction and the diagnosis of osteoporosis. If the POROUS method becomes
established, it would have advantages over the current gold standard DXA: The
method is based on ultrasound technology, which does not involve the use of
ionising radiation. The operating costs are low and the availability of the
mobile device could be higher than that of DXA. In addition, the direct
measurement of physical parameters makes it possible to derive microstructural,
macrostructural and viscoelastic properties of the cortical bone that are
associated with the pathogenesis of osteoporosis. This promises an increased
gain in knowledge compared to the DXA BMD. By reconstructing a 3D image of the
cortical bone, the microarchitecture of the bone, including osteoporotic pores,
can be analysed. Patients benefit from the improved ability to predict fracture
risk and, if necessary, to initiate therapeutic measures at an early stage.
Conclusion of the risk analysis
By analysing the risks the Sponsor comes to the conclusion that the probability
that participants in the clinical investigation will experience a benefit (due
to the incidental finding of osteoporosis with DXA) or will not be harmed by
the examinations outweighs the probability of harm due to a residual risk of
the procedures used. All residual risks are considered acceptable mostly
because of low occurrence probability. In addition, there is the great general
benefit of the POROUS application, provided that the method whose benefits are
to be demonstrated here becomes established. The benefit/risk profile is,
therefore, determined as acceptable for the clinical investigation.
Am Mühlenberg 11
Potsdam Golm 14476
NL
Am Mühlenberg 11
Potsdam Golm 14476
NL
Listed location countries
Age
Inclusion criteria
• Female or male individuals aged 56 to and including 85 years.
• Written informed consent has been obtained.
[Let op: Klinische risicofactoren die nodig zijn voor het berekenen van het
risico op heup- en wervelfracturen (op basis van het risicoberekeningsschema
van de DVO-richtlijn osteoporose) worden tijdens de screening verzameld. Dit
gebeurt om over- of ondervertegenwoordiging te voorkomen met betrekking tot de
vereiste steekproefgrootte van deelnemers met een >= 2-voudig verhoogd
leeftijds- en geslachtsgecorrigeerd risico op heup- en wervelfracturen en
deelnemers met een < 2-voudig verhoogd leeftijds- en geslachtsgecorrigeerd
risico.]
Exclusion criteria
• Presence of diseases that rule out valid measurements with the DXA and/or
POROUS R3C devices (e.g., fractures or metal implants in the examined bones,
paralysis of the lower extremities, severe bone abnormalities).
• Inability to undergo the investigations required by the Clinical
Investigation Plan (CIP) or cognitive limitations that preclude understanding
of the Participant Information Sheet and the Informed Consent Document.
• Previous medical procedures involving exposure to a cumulative dose of
ionising radiation deemed by the Investigator to exceed usual limits within
standard of care.
• Enrolment in any other interventional clinical study (current or during the
last three months)
• Close affiliation with an investigational site, e.g. employed at
investigational site, close relative of an investigator, dependent person (e.g.
student of the investigational site).
Further, individuals who are being or have been treated within the indicated
period prior to the beginning of the study with any of the following
antiresorptive therapies are excluded from the clinical investigation:
• Bisphosphonates (due to residual effects of bisphosphonates after
discontinuation):
o Intravenous (IV) zoledronate within the last 3 years.
o Oral alendronate within the last year, if (continuous) treatment duration
before was > 1 year.
o Oral risedronate within the last year, if (continuous) treatment duration
before was > 1 year.
o Ibandronate (IV or oral) within the last year, if (continuous) treatment
duration before was > 1 year.
• Denosumab within the last 3 years
• Hormone replacement therapy (HRT) including combination therapy or oestrogen
alone in postmenopausal women within the last 6 months.
• Raloxifene within the last 6 months.
Individuals who are being or have ever been treated with any of the following
anabolic therapies are excluded from the clinical investigation:
• Teriparatide
• Romosozumab
• Abaloparatide.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | NCT06567054 |
| CCMO | NL86252.000.24 |