Ignite Creation Date:
2024-10-25 @ 7:52 PM
Last Modification Date:
2024-10-26 @ 3:38 PM
Study NCT ID:
NCT06567054
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-06-28
Brief Title:
Clinical Study to Predict the Risk of Bone Fractures With the POROUS Ultrasound Device
Sponsor:
None
Organization:
None
Study Overview
Official Title:
A Prospective Single-cohort Multicentre Clinical Investigation to Evaluate the Performance of POROUS R3C Ultrasound Device for Fracture Risk Prediction in Middle-aged and Elderly Men and Women
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
POROUS-preFX
Brief Summary:
Osteoporosis is a widespread medical condition among older people It causes the bones to weaken and become more likely to break Osteoporosis and bone fracture risk are currently evaluated by looking at clinical risk factors and measuring bone mineral density BMD The lower the BMD is the higher the risk of osteoporotic fractures in the future However most bone fractures occur in people who do not have very low BMD values This means that osteoporosis and fracture risk are often not diagnosed Many of these non-diagnosed patients would benefit from treatment to reduce the probability of bone fractures
An X-ray device called DXA is the main tool used to diagnose osteoporosis and fracture risk clinically DXA measures two-dimensional BMD in the hip and spine The POROUS ultrasound device measures various properties of the outer layer of the bone in the lower leg It has several advantages over DXA 1 its image resolution is higher and three-dimensional 2 it can detect bone changes without radiation 3 it can detect these bone changes early and how they change over time
For this clinical study we will recruit men and women over 55 years old Most will have clinical risk factors such as background diseases for developing osteoporosis The study is anticipated to last 4 years
Our major research questions are
Can the POROUS ultrasound device predict fracture risk
How does its performance compare to DXA
What is the safety of the new device
The participants will
answer questions about their medical history
be measured for height and weight and take a physical test
be examined for the presence of silent fractures in the spine
be examined at the beginning and end of the study with the two devices DXA and POROUS
be called by telephone every six months and asked if they suffer from new bone fractures take any medication that might affect their bones or if their health status has changed
The participants will be monitored for 3 years
An X-ray device called DXA is the main tool used to diagnose osteoporosis and fracture risk clinically DXA measures two-dimensional BMD in the hip and spine The POROUS ultrasound device measures various properties of the outer layer of the bone in the lower leg It has several advantages over DXA 1 its image resolution is higher and three-dimensional 2 it can detect bone changes without radiation 3 it can detect these bone changes early and how they change over time
For this clinical study we will recruit men and women over 55 years old Most will have clinical risk factors such as background diseases for developing osteoporosis The study is anticipated to last 4 years
Our major research questions are
Can the POROUS ultrasound device predict fracture risk
How does its performance compare to DXA
What is the safety of the new device
The participants will
answer questions about their medical history
be measured for height and weight and take a physical test
be examined for the presence of silent fractures in the spine
be examined at the beginning and end of the study with the two devices DXA and POROUS
be called by telephone every six months and asked if they suffer from new bone fractures take any medication that might affect their bones or if their health status has changed
The participants will be monitored for 3 years
Detailed Description:
Background and purpose
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 ie spine and proximal femur DXA is regarded as the gold standard well-established methodology to determine aBMD for diagnostic purposes Epidemiological data emphasize 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
Device description
The POROUS R3C ultrasound device enables a non-invasive non-ionizing 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 design
This is a single-cohort multicenter 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 ie 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
Study 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 standard-of-care DXA will be compared based on prevalent fractures
Study 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
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
Part 2 - 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 factorsindicators for vertebral and hip fractures as outlined by the DVO and prevalent fractures
Part 1 - To demonstrate the discriminative performance of the POROUS R3C ultrasound device based on subgroups of prevalent fractures eg hip vertebral and major osteoporotic fractures
Part 1 - To establish reference data for developing age-adjusted 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 factorsindicators for vertebral and hip fractures as outlined by the DVO and incident fractures
Part 2 - To demonstrate the predictive performance of the POROUS R3C ultrasound device based on subgroups of incident fractures eg hip vertebral and major osteoporotic fractures
Part 2 - To establish reference data for developing age-adjusted POROUS Z-scores using the POROUS R3C ultrasound device based on incident fractures
Part 2 - To explore the treatment effect of anti-osteoporotic medication
Part 2 - To explore the treatment effect of drugs known to influence bone metabolism
Participants
A total of 1600 female and male participants 55 years of age will be included in the investigation This population is planned to include 1120 participants with 2-fold increased age- and sex-adjusted risk for hip and vertebral fractures and 480 participants with a 2-fold increased age- and sex-adjusted risk for hip and vertebral fractures
Stratification of participants fracture risk 2-fold increased risk
Age group 56-60 malesfemales 40 per group total 80
Age group 61-65 malesfemales 40 per group total 80
Age group 66-70 malesfemales 40 per group total 80
Age group 71-75 malesfemales 40 per group total 80
Age group 76-80 malesfemales 40 per group total 80
Age group 81-85 malesfemales 40 per group total 80
Stratification of participants fracture risk 2-fold increased risk
Age group 66-70 females 100 per group
Age group 71-75 males 100 per group females 160 per group total 260
Age group 76-80 malesfemales 180 per group total 360
Age group 81-85 malesfemales 200 per group total 400
The expected number of incident fractures 140 at 24 months 210 at 36 months
The assumed number of fractures per analysis group DXA and POROUS R3C at Month 24 and Month 36 respectively is based on age- and sex-matched incidence rates for fractures Rupp et al Deutsches Ärzteblatt International 2021 further updated by data on the incidence of vertebral fractures Fink et al JBMR 2005
Risk calculation for hip and vertebral fractures
At Screening assessment of clinical risk factors and application of risk calculating scheme as outlined in the Dachverband Osteologie DVO tri-national umbrella association of German Austrian and Swiss medical and scientific professional societies in the field of bone diseases osteoporosis guideline will determine whether a participant is at increased risk 2-fold compared to the general population of the same age and sex for hip and vertebral fractures Please note that the calculation of the pertinent risk as performed in this study does not include any DXA-based BMD measurements and T-Scores No DXA BMD measurement or DXA-based vertebral fracture assessment VFA will be conducted at Screening Noteworthy DXA-based BMD measurement results and T-Scores will be included in the different analyses of the study endpoints but not for the risk calculation at Screening as described above Screened and eligible individuals will be enrolled in the investigation until the necessary sample size for hisher corresponding group based on age sex and risk status has been reached see Table below To avoid over-recruiting once the necessary sample size for one group has been reached no further individuals with matching age band sex and risk status will be enrolled in the study
Duration of the study
The planned overall clinical investigation is expected to take 48 months including an enrolment period of approximately 12 months and a clinical investigation period of 36 months Per participant the total time of participation in the investigation will take 36 months 20 months -1 month after the first participant has been included in the investigation a checkpoint assessment of the number of fracture events so far recorded is planned The aim is to assess whether the number of fractures projected to be reached after each participant will have been followed-up for 24 months would be sufficient for a test of the primary endpoint with sufficient statistical power If this is the case the clinical investigation period will be shortened to 24 months correspondingly the overall duration will be shortened to 36 months If at the checkpoint assessment the number of fractures is insufficient the follow-up period will remain as planned and the EoS visit will take place at 36 months amounting to the originally planned overall duration of 48 months
Duration of participation
The total time of participation in the investigation will take 36 months per participant with the option to be shortened to an investigational period of 24 months based on the results of a checkpoint assessment of reported fractures scheduled at Month 20 -1 month
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 More precisely logistic discriminant analysis will be performed Area under the curve AUC values and their confidence intervals will be computed from ROC curves for each model Internal validation of the model will be performed by using cross-validation followed by bootstrap analysis Odds ratios will be determined for both the final composite POROUS-ScorePrev generated from the internally validated model and DXA T-Score Standardized odds ratios sOR will be calculated ie the fold-increase of the relative fracture risk per standard deviation decrease of the respective score The discriminative ability of the POROUS model for prevalent fractures is demonstrated if the lower limit of the 90 confidence interval of the corrected sOR is higher than 1
Part 2
Incident fractures will be recorded and all relevant variables including ultrasound parameter 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 standardized relative risk sRR will be calculated ie the fold-increase of the relative fracture risk per standard deviation decrease of the respective score The sRR will be determined for both the final composite POROUS-Score generated from the internally validated model and DXA T-Score The predictive ability of the POROUS model for incident fractures is demonstrated if the lower limit of the 90 confidence interval of the corrected sRR is higher than 1
Clinical procedures
The following clinical procedures are performed during the investigation
Screening
Informed consent
Inclusionexclusion criteria
Calculation of individual risk for hip and vertebral fractures as per modified version of the DVO risk calculation scheme excluding DXA-based BMD measurement and T-Score
Enrolment into corresponding age-sex-risk group
Baseline Visit 2 0-14 days after Screening
Scanning with the POROUS R3C ultrasound device at the central anteromedial tibia region
Scanning with DXA aBMD of the lumbar spine and proximal femur
Fracture anamnesis including DXA-based VFA Alternatively VFA may be replaced by projectional radiography if VFA is not available
Assessment of clinical risk indicators as per DVO guideline
Assessment of concomitant medication initiation of anti-osteoporotic medication as well as oral glucocorticoids proton pump inhibitors aromatase inhibitors hormone ablation therapyantiandrogens in males
Recording of adverse events
Follow-up period Interim visits phone survey - Visits 3-7 at Month 6 12 18 24 30 14 days
Assessment of incident fractures to be validated by requesting medical documents - X-ray images physicians findings
Concomitant medication assessment
Recording of adverse events
Early-termination ET visitphone survey Participants who withdraw early ie before undergoing the EoS visit will be offered an ET clinical visit including
VFA or projectional radiography of the spine respectively if VFA is not available
Anamnesis of incident fractures since the last visitphone survey
Concomitant medication assessment see above
Recording of adverse events Alternatively the visit can be conducted as a phone survey if the time gap since the last DXAVFA is 6 months or the participant is not available for a clinical visit
EoS visit - Visit 8 at Month 36 14 days
Scanning with the POROUS R3C ultrasound device at the central anteromedial tibia region
Scanning with DXA aBMD of the lumbar spine and proximal femur
Assessment of incident fractures including VFA or projectional radiography of the spine
Re-assessment of fracture risk factorsindicators as per DVO guideline and recalculation of risk for hip and vertebral fractures
Concomitant medication assessment
Recording of adverse events
Subgroup analysis
General subgroups for analyses are defined based on age sex and risk for hip and vertebral fractures Stratification groups are presented in the table on Number of participants to be included in the investigation included above In addition subgroup analyses are done to monitor treatment effects as described in the exploratory endpoint of Part 2
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 ie spine and proximal femur DXA is regarded as the gold standard well-established methodology to determine aBMD for diagnostic purposes Epidemiological data emphasize 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
Device description
The POROUS R3C ultrasound device enables a non-invasive non-ionizing 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 design
This is a single-cohort multicenter 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 ie 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
Study 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 standard-of-care DXA will be compared based on prevalent fractures
Study 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
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
Part 2 - 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 factorsindicators for vertebral and hip fractures as outlined by the DVO and prevalent fractures
Part 1 - To demonstrate the discriminative performance of the POROUS R3C ultrasound device based on subgroups of prevalent fractures eg hip vertebral and major osteoporotic fractures
Part 1 - To establish reference data for developing age-adjusted 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 factorsindicators for vertebral and hip fractures as outlined by the DVO and incident fractures
Part 2 - To demonstrate the predictive performance of the POROUS R3C ultrasound device based on subgroups of incident fractures eg hip vertebral and major osteoporotic fractures
Part 2 - To establish reference data for developing age-adjusted POROUS Z-scores using the POROUS R3C ultrasound device based on incident fractures
Part 2 - To explore the treatment effect of anti-osteoporotic medication
Part 2 - To explore the treatment effect of drugs known to influence bone metabolism
Participants
A total of 1600 female and male participants 55 years of age will be included in the investigation This population is planned to include 1120 participants with 2-fold increased age- and sex-adjusted risk for hip and vertebral fractures and 480 participants with a 2-fold increased age- and sex-adjusted risk for hip and vertebral fractures
Stratification of participants fracture risk 2-fold increased risk
Age group 56-60 malesfemales 40 per group total 80
Age group 61-65 malesfemales 40 per group total 80
Age group 66-70 malesfemales 40 per group total 80
Age group 71-75 malesfemales 40 per group total 80
Age group 76-80 malesfemales 40 per group total 80
Age group 81-85 malesfemales 40 per group total 80
Stratification of participants fracture risk 2-fold increased risk
Age group 66-70 females 100 per group
Age group 71-75 males 100 per group females 160 per group total 260
Age group 76-80 malesfemales 180 per group total 360
Age group 81-85 malesfemales 200 per group total 400
The expected number of incident fractures 140 at 24 months 210 at 36 months
The assumed number of fractures per analysis group DXA and POROUS R3C at Month 24 and Month 36 respectively is based on age- and sex-matched incidence rates for fractures Rupp et al Deutsches Ärzteblatt International 2021 further updated by data on the incidence of vertebral fractures Fink et al JBMR 2005
Risk calculation for hip and vertebral fractures
At Screening assessment of clinical risk factors and application of risk calculating scheme as outlined in the Dachverband Osteologie DVO tri-national umbrella association of German Austrian and Swiss medical and scientific professional societies in the field of bone diseases osteoporosis guideline will determine whether a participant is at increased risk 2-fold compared to the general population of the same age and sex for hip and vertebral fractures Please note that the calculation of the pertinent risk as performed in this study does not include any DXA-based BMD measurements and T-Scores No DXA BMD measurement or DXA-based vertebral fracture assessment VFA will be conducted at Screening Noteworthy DXA-based BMD measurement results and T-Scores will be included in the different analyses of the study endpoints but not for the risk calculation at Screening as described above Screened and eligible individuals will be enrolled in the investigation until the necessary sample size for hisher corresponding group based on age sex and risk status has been reached see Table below To avoid over-recruiting once the necessary sample size for one group has been reached no further individuals with matching age band sex and risk status will be enrolled in the study
Duration of the study
The planned overall clinical investigation is expected to take 48 months including an enrolment period of approximately 12 months and a clinical investigation period of 36 months Per participant the total time of participation in the investigation will take 36 months 20 months -1 month after the first participant has been included in the investigation a checkpoint assessment of the number of fracture events so far recorded is planned The aim is to assess whether the number of fractures projected to be reached after each participant will have been followed-up for 24 months would be sufficient for a test of the primary endpoint with sufficient statistical power If this is the case the clinical investigation period will be shortened to 24 months correspondingly the overall duration will be shortened to 36 months If at the checkpoint assessment the number of fractures is insufficient the follow-up period will remain as planned and the EoS visit will take place at 36 months amounting to the originally planned overall duration of 48 months
Duration of participation
The total time of participation in the investigation will take 36 months per participant with the option to be shortened to an investigational period of 24 months based on the results of a checkpoint assessment of reported fractures scheduled at Month 20 -1 month
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 More precisely logistic discriminant analysis will be performed Area under the curve AUC values and their confidence intervals will be computed from ROC curves for each model Internal validation of the model will be performed by using cross-validation followed by bootstrap analysis Odds ratios will be determined for both the final composite POROUS-ScorePrev generated from the internally validated model and DXA T-Score Standardized odds ratios sOR will be calculated ie the fold-increase of the relative fracture risk per standard deviation decrease of the respective score The discriminative ability of the POROUS model for prevalent fractures is demonstrated if the lower limit of the 90 confidence interval of the corrected sOR is higher than 1
Part 2
Incident fractures will be recorded and all relevant variables including ultrasound parameter 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 standardized relative risk sRR will be calculated ie the fold-increase of the relative fracture risk per standard deviation decrease of the respective score The sRR will be determined for both the final composite POROUS-Score generated from the internally validated model and DXA T-Score The predictive ability of the POROUS model for incident fractures is demonstrated if the lower limit of the 90 confidence interval of the corrected sRR is higher than 1
Clinical procedures
The following clinical procedures are performed during the investigation
Screening
Informed consent
Inclusionexclusion criteria
Calculation of individual risk for hip and vertebral fractures as per modified version of the DVO risk calculation scheme excluding DXA-based BMD measurement and T-Score
Enrolment into corresponding age-sex-risk group
Baseline Visit 2 0-14 days after Screening
Scanning with the POROUS R3C ultrasound device at the central anteromedial tibia region
Scanning with DXA aBMD of the lumbar spine and proximal femur
Fracture anamnesis including DXA-based VFA Alternatively VFA may be replaced by projectional radiography if VFA is not available
Assessment of clinical risk indicators as per DVO guideline
Assessment of concomitant medication initiation of anti-osteoporotic medication as well as oral glucocorticoids proton pump inhibitors aromatase inhibitors hormone ablation therapyantiandrogens in males
Recording of adverse events
Follow-up period Interim visits phone survey - Visits 3-7 at Month 6 12 18 24 30 14 days
Assessment of incident fractures to be validated by requesting medical documents - X-ray images physicians findings
Concomitant medication assessment
Recording of adverse events
Early-termination ET visitphone survey Participants who withdraw early ie before undergoing the EoS visit will be offered an ET clinical visit including
VFA or projectional radiography of the spine respectively if VFA is not available
Anamnesis of incident fractures since the last visitphone survey
Concomitant medication assessment see above
Recording of adverse events Alternatively the visit can be conducted as a phone survey if the time gap since the last DXAVFA is 6 months or the participant is not available for a clinical visit
EoS visit - Visit 8 at Month 36 14 days
Scanning with the POROUS R3C ultrasound device at the central anteromedial tibia region
Scanning with DXA aBMD of the lumbar spine and proximal femur
Assessment of incident fractures including VFA or projectional radiography of the spine
Re-assessment of fracture risk factorsindicators as per DVO guideline and recalculation of risk for hip and vertebral fractures
Concomitant medication assessment
Recording of adverse events
Subgroup analysis
General subgroups for analyses are defined based on age sex and risk for hip and vertebral fractures Stratification groups are presented in the table on Number of participants to be included in the investigation included above In addition subgroup analyses are done to monitor treatment effects as described in the exploratory endpoint of Part 2
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None