Ignite Creation Date:
2024-05-06 @ 3:39 PM
Last Modification Date:
2024-10-26 @ 1:53 PM
Study NCT ID:
NCT04705194
Status:
UNKNOWN
Last Update Posted:
2021-01-22
First Post:
2021-01-08
Brief Title:
Hepatectomy Risk Assessment With Functional Magnetic Resonance Imaging
Sponsor:
University of Leeds
Organization:
University of Leeds
Study Overview
Official Title:
Hepatectomy Risk Assessment With Functional Magnetic Resonance Imaging
Status:
UNKNOWN
Status Verified Date:
2021-01
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HEPARIM
Brief Summary:
Liver resection remains the only curative option for primary or metastatic liver cancer but a more accurate prediction of post-hepatectomy liver failure PHLF is needed to further reduce morbidity and mortality and to extend the indication to a wider patient population Magnetic resonance Imaging MRI is a promising new source of liver function tests as it can provide segmental function alongside measurements of perfusion tissue structure and standard morphological assessment
The primary aim of HEPARIM is to determine if quantitative MRI biomarkers of liver function and perfusion can improve predictions of post-hepatectomy liver function as measured by an indocyanine green ICG liver function test Secondary aims is to validate the MRI measurements of liver function against ICG
HEPARIM is an observational cohort study recruiting patients referred locally for a one- or two-stage liver resection of 2 segments or more Before surgery all participants will undergo an ICG liver function test and a Dynamic Gadoxetate-enhanced DGE MRI scan of the liver The ICG test will be repeated at one day after surgery The Gadoxetate Clearance GC of the future liver remnant FLR-GC will be determined from the DGE-MRI data and correlated to the post-operative ICG R15 as primary outcome measure Preoperative ICG R15 will be correlated against GC of the whole liver WL-GC to address the secondary objective In patients that undergo a staged hepatectomy an additional MRI and ICG test will be performed before the first stage to assess its effect on volumetric and functional growth of the FLR
Additional pre- and postoperative data will be collected from medical records including demographics and medical histories biochemistry pathology and radiology reports and any long-term outcome data collected in the 90-day follow-up visit These data will be used in a multi-variate analysis to determine which preoperative biomarkers are most predictive of immediate and long-term outcomes to identify the added value of functional MRI over routine clinical markers and to derive a multi-variate prediction model that can be validated in future studies
The primary aim of HEPARIM is to determine if quantitative MRI biomarkers of liver function and perfusion can improve predictions of post-hepatectomy liver function as measured by an indocyanine green ICG liver function test Secondary aims is to validate the MRI measurements of liver function against ICG
HEPARIM is an observational cohort study recruiting patients referred locally for a one- or two-stage liver resection of 2 segments or more Before surgery all participants will undergo an ICG liver function test and a Dynamic Gadoxetate-enhanced DGE MRI scan of the liver The ICG test will be repeated at one day after surgery The Gadoxetate Clearance GC of the future liver remnant FLR-GC will be determined from the DGE-MRI data and correlated to the post-operative ICG R15 as primary outcome measure Preoperative ICG R15 will be correlated against GC of the whole liver WL-GC to address the secondary objective In patients that undergo a staged hepatectomy an additional MRI and ICG test will be performed before the first stage to assess its effect on volumetric and functional growth of the FLR
Additional pre- and postoperative data will be collected from medical records including demographics and medical histories biochemistry pathology and radiology reports and any long-term outcome data collected in the 90-day follow-up visit These data will be used in a multi-variate analysis to determine which preoperative biomarkers are most predictive of immediate and long-term outcomes to identify the added value of functional MRI over routine clinical markers and to derive a multi-variate prediction model that can be validated in future studies
Detailed Description:
OBJECTIVES
1 To determine if DGE-MRI can improve predictions of post-hepatectomy liver function 2 To validate DGE-MRI based measurements of liver function against gold-standard liver function tests 3a to determine if preoperative DGE-MRI can improve predictions of post-operative PHLF 3b to develop a multi-parametric prediction model for 90-day post-operative outcome combining MRI clinical chemistry and patient history 3c To determine the relationship between volumetric and functional liver growth after portal vein embolisation
RECRUITMENT
Patients considered for major liver resection will be identified at the Hepatobiliary multi-disciplinary team MDT meeting at St James University Hospital Leeds and contacted by phone Patients will have at least 3 days to consider this information and after that they will be contacted by the member of their clinical care team to schedule the baseline visit Formal written consent will be obtained on the day of the visit If they dont consent to participation then only the MRI scans will be collected and stored in their medical records
BASELINE VISIT
An initial dataset will be captured incorporating the patients medical history and up-to-date investigations This will be obtained through a combination of patient interview review of paper notes and review of the patients electronic medical record An MRI safety screening form will be administered If a contraindication to MRI is found at this point the visit will be cancelled and the patient will be excluded from the study An ICG safety questionnaire will be used to exclude patients with contraindications to ICG use Patients excluded from ICG testing at this point will not be excluded from the study as other measures of liver function will still be available for analysis of tertiary outcomes
Patients will be cannulated and ICG will be administered intravenously as a bolus dose of 05 mgkg through the cannula The ICG will be reconstituted with 5 ml of water for injection for every 25 mg of ICG leading to a dilution of 5mg ICG per 1 ml Serial percutaneous ICG measurements will then be taken using an ICG clearance meter using a finger clip device LiMON Maquet Germany Patients will lie in the supine position and calibration will be performed before testing starts
In order to derive absolute ICG concentrations two separate blood samples of 25mL each will be taken both after ICG injection pre-operative The samples will be processed and stored in a dedicated facility in the Leeds Institute for Cardiovascular and Metabolic Medicine LICAMM and analyzed as a batch at the end of the study The remaining samples will be stored for a maximum of 5 years to measure metabolomics data for secondary research After 5 years any remaining samples will be destroyed according to standard LICAMM procedure for sample disposal
The MRI will be performed straight after ICG measurement in the 3 T MRI by radiographers of the department The scan will last max 15hrs and will include the injection of a standard dose of MRI contrast agent Gadoxetate Primovist Bayer AG The same cannula will be used to administer the MRI contrast as for the ICG test Other scans that will be taken in the same session include T1- and T2-weighted anatomical imaging T2-mapping T1-mapping proton-density fat fraction
SURGERY AND FOLLOW-UP
After the baseline visit some patients will require re-discussion in the MDT and all patients will attend for a preoperative clinic appointment A proportion of patients will not progress to surgery due to clinician or patient choice these patients will not be followed up further The data that has already been collected will be used for addressing the secondary objective
Intraoperative measurements of the resected liver segments will be taken including weight and volume measured using fluid displacement After surgery data obtained as part of the patients standard intra and post-operative care will be collected from their medical records This includes any blood tests during admission the characteristics of the operation complications and length of stay Pathology results will be collected The ICG test with the finger-clip device will be repeated postoperatively at bedside to determine a reference value for postoperative liver function This will be performed on day 1 post-surgery if feasible A PHLF score will be determined according the International Study Group of Liver Surgery ISGLS definition
All patients who underwent surgery will attend the hospital for a routine post-operative clinic appointment after 90 days Data from this appointment will be collected by the clinical research fellow including complications readmissions and mortality At the end of the study patients who have requested to do so will be sent a summary of the studys findings and implications
PVEALPPS ARM
Patients requiring portal vein embolisation PVE or Associating Liver Partition and Portal vein Ligation for Staged hepatectomy ALPPS will be recruited in the same way as participants in the resection arm They will attend the same baseline visit and the routine clinic visit Patients may decline the PVEALPPS at this point or the clinician may decide it is inappropriate at the clinic appointment If this occurs and the patient proceeds to surgery they will remain in the study If they do not proceed to surgery their data will be used to address the secondary objectives
A patient who does proceed to PVEALPPS will attend the hospital for a routine computed tomography CT scan after the first stage and a second research visit will be scheduled at that point This visit will proceed in the same manner as the baseline visit They will be re-discussed in the MDT and come for a preoperative clinic appointment Patients may be deemed ineligible for surgery or make the decision not to proceed with surgery in which case their data already collected can feed into the secondary objectives If they do proceed to surgery the same intra-operative and post-operative data will be taken as for the resection arm
SAMPLE SIZE
The aim is to recruit 134 participants into the study which will include an estimated 122 in the primary surgery arm and 12 in the PVE arm Of the 134 recruited participants an estimated 112 will feed into the primary objective
The power calculation assessed the impact of study size by simulating a hypothetical population of 1 million patients and evaluating model robustness to estimate the model beta coefficient of FLR-GC in relation to ICG clearance Modelling was informed by pilot data in 29 cases 10k samples of 122 patients are drawn with replacement generating empirical distributions of the parameters Results demonstrated that even at the poorest precision simulated the fixed sample of 122 is sufficient to obtain reliable beta coefficients
DATA ANALYSIS
Statistical analysis shall be performed by Professor Gilthorpe at the University of Leeds using the anonymized data sheet and the RStudio software package RStudio Boston USA A univariable analysis will be performed comparing FLR-GC against post-operative ICG-R15 primary objective and WL-GC against preoperative ICG-R15 secondary objective Second the correlations will be investigated in a multivariable analysis to determine if the MRI adds value to existing preoperative biomarkers which MRI biomarkers are most predictive and to derive a model for predicting PHLF It will then be tested whether this combined score is significantly worse when DGE-MRI is removed from the prediction In the PVEALPPS group changes in volume will be correlated to changes in function of the FLR between pre PVEpre-ALPPS and post-PVEpost-ALPPS
DATA MANAGEMENT
Identifiable data will not be accessed by researchers outside of the clinical care team and are only retained for quality control backup and to follow-up on any incidental findings Anonymised research data will be recorded using the participants study ID Paper forms used for data capture will be stored in a secure location in St James University Hospital Electronic research data will be stored in a participant study record in a secure database in St James University Hospital and in password protected network drives set up and maintained by University IT Additional databases will be set up to retain the source data for further processing including MRI in DICOM Digital Imaging and Communications in Medicine format raw ICG data and digitized histopathology slides
MRI data will be recorded using the patient ID in the secure Picture Archiving and Communication System PACS of the radiology department Routine radiology reports will be retrieved and included in the participants anonymous study file The MRI images will be transferred anonymously from the scanner to the universitys DICOM database where they will be analyzed by a research fellow to extract the relevant imaging biomarkers
All excel sheets with anonymised study data will be transferred to a long-term data repository where they will be maintained for a minimum of 25 years Source data for MRI and ICG will be retained indefinitely in a dedicated imaging data management system hosted by the University to enable secondary research educational use and data sharing
INCIDENTAL FINDINGS AND BLINDING
All data collected for the study except calculated MRI biomarkers and ICG measurements are acquired as part of the routine workup and will therefore be available to the clinical care team through the patients medical records All ICG liver function measurements from finger clip device will be reviewed separately by the hepatology consultant Any unusual findings will be flagged up to the clinical care team as incidental findings and dealt with according to usual practices For those patients that have an extra MRI scan as part of their participation in the study these MRIs will be reviewed by a radiologist Any unusual findings will be flagged up to the clinical care team as incidental findings and dealt with according to usual practices Unvalidated MRI biomarkers will not be reviewed for incidental findings or otherwise communicated to the clinical care team The non-clinical research fellows working on analysis of MRI and ICG data will be blinded to the clinical history of the patient and other function tests
WITHDRAWAL OF PARTICIPANTS
If a patient decides to withdraw their consent to inclusion in the study at any point then no further data regarding their care will be collected Should the patient wish data collected up until withdrawal of consent will be destroyed using the hospitals confidential waste bins Patients who lose their capacity to consent after initial inclusion in the study for reasons that are not related to their surgery will be treated in the same manner as if they had withdrawn consent Previously collected data will not be destroyed If a patient is unable to complete their MRI study for any reason they will automatically be withdrawn from the study Data collected until the point of withdrawal will be retained
1 To determine if DGE-MRI can improve predictions of post-hepatectomy liver function 2 To validate DGE-MRI based measurements of liver function against gold-standard liver function tests 3a to determine if preoperative DGE-MRI can improve predictions of post-operative PHLF 3b to develop a multi-parametric prediction model for 90-day post-operative outcome combining MRI clinical chemistry and patient history 3c To determine the relationship between volumetric and functional liver growth after portal vein embolisation
RECRUITMENT
Patients considered for major liver resection will be identified at the Hepatobiliary multi-disciplinary team MDT meeting at St James University Hospital Leeds and contacted by phone Patients will have at least 3 days to consider this information and after that they will be contacted by the member of their clinical care team to schedule the baseline visit Formal written consent will be obtained on the day of the visit If they dont consent to participation then only the MRI scans will be collected and stored in their medical records
BASELINE VISIT
An initial dataset will be captured incorporating the patients medical history and up-to-date investigations This will be obtained through a combination of patient interview review of paper notes and review of the patients electronic medical record An MRI safety screening form will be administered If a contraindication to MRI is found at this point the visit will be cancelled and the patient will be excluded from the study An ICG safety questionnaire will be used to exclude patients with contraindications to ICG use Patients excluded from ICG testing at this point will not be excluded from the study as other measures of liver function will still be available for analysis of tertiary outcomes
Patients will be cannulated and ICG will be administered intravenously as a bolus dose of 05 mgkg through the cannula The ICG will be reconstituted with 5 ml of water for injection for every 25 mg of ICG leading to a dilution of 5mg ICG per 1 ml Serial percutaneous ICG measurements will then be taken using an ICG clearance meter using a finger clip device LiMON Maquet Germany Patients will lie in the supine position and calibration will be performed before testing starts
In order to derive absolute ICG concentrations two separate blood samples of 25mL each will be taken both after ICG injection pre-operative The samples will be processed and stored in a dedicated facility in the Leeds Institute for Cardiovascular and Metabolic Medicine LICAMM and analyzed as a batch at the end of the study The remaining samples will be stored for a maximum of 5 years to measure metabolomics data for secondary research After 5 years any remaining samples will be destroyed according to standard LICAMM procedure for sample disposal
The MRI will be performed straight after ICG measurement in the 3 T MRI by radiographers of the department The scan will last max 15hrs and will include the injection of a standard dose of MRI contrast agent Gadoxetate Primovist Bayer AG The same cannula will be used to administer the MRI contrast as for the ICG test Other scans that will be taken in the same session include T1- and T2-weighted anatomical imaging T2-mapping T1-mapping proton-density fat fraction
SURGERY AND FOLLOW-UP
After the baseline visit some patients will require re-discussion in the MDT and all patients will attend for a preoperative clinic appointment A proportion of patients will not progress to surgery due to clinician or patient choice these patients will not be followed up further The data that has already been collected will be used for addressing the secondary objective
Intraoperative measurements of the resected liver segments will be taken including weight and volume measured using fluid displacement After surgery data obtained as part of the patients standard intra and post-operative care will be collected from their medical records This includes any blood tests during admission the characteristics of the operation complications and length of stay Pathology results will be collected The ICG test with the finger-clip device will be repeated postoperatively at bedside to determine a reference value for postoperative liver function This will be performed on day 1 post-surgery if feasible A PHLF score will be determined according the International Study Group of Liver Surgery ISGLS definition
All patients who underwent surgery will attend the hospital for a routine post-operative clinic appointment after 90 days Data from this appointment will be collected by the clinical research fellow including complications readmissions and mortality At the end of the study patients who have requested to do so will be sent a summary of the studys findings and implications
PVEALPPS ARM
Patients requiring portal vein embolisation PVE or Associating Liver Partition and Portal vein Ligation for Staged hepatectomy ALPPS will be recruited in the same way as participants in the resection arm They will attend the same baseline visit and the routine clinic visit Patients may decline the PVEALPPS at this point or the clinician may decide it is inappropriate at the clinic appointment If this occurs and the patient proceeds to surgery they will remain in the study If they do not proceed to surgery their data will be used to address the secondary objectives
A patient who does proceed to PVEALPPS will attend the hospital for a routine computed tomography CT scan after the first stage and a second research visit will be scheduled at that point This visit will proceed in the same manner as the baseline visit They will be re-discussed in the MDT and come for a preoperative clinic appointment Patients may be deemed ineligible for surgery or make the decision not to proceed with surgery in which case their data already collected can feed into the secondary objectives If they do proceed to surgery the same intra-operative and post-operative data will be taken as for the resection arm
SAMPLE SIZE
The aim is to recruit 134 participants into the study which will include an estimated 122 in the primary surgery arm and 12 in the PVE arm Of the 134 recruited participants an estimated 112 will feed into the primary objective
The power calculation assessed the impact of study size by simulating a hypothetical population of 1 million patients and evaluating model robustness to estimate the model beta coefficient of FLR-GC in relation to ICG clearance Modelling was informed by pilot data in 29 cases 10k samples of 122 patients are drawn with replacement generating empirical distributions of the parameters Results demonstrated that even at the poorest precision simulated the fixed sample of 122 is sufficient to obtain reliable beta coefficients
DATA ANALYSIS
Statistical analysis shall be performed by Professor Gilthorpe at the University of Leeds using the anonymized data sheet and the RStudio software package RStudio Boston USA A univariable analysis will be performed comparing FLR-GC against post-operative ICG-R15 primary objective and WL-GC against preoperative ICG-R15 secondary objective Second the correlations will be investigated in a multivariable analysis to determine if the MRI adds value to existing preoperative biomarkers which MRI biomarkers are most predictive and to derive a model for predicting PHLF It will then be tested whether this combined score is significantly worse when DGE-MRI is removed from the prediction In the PVEALPPS group changes in volume will be correlated to changes in function of the FLR between pre PVEpre-ALPPS and post-PVEpost-ALPPS
DATA MANAGEMENT
Identifiable data will not be accessed by researchers outside of the clinical care team and are only retained for quality control backup and to follow-up on any incidental findings Anonymised research data will be recorded using the participants study ID Paper forms used for data capture will be stored in a secure location in St James University Hospital Electronic research data will be stored in a participant study record in a secure database in St James University Hospital and in password protected network drives set up and maintained by University IT Additional databases will be set up to retain the source data for further processing including MRI in DICOM Digital Imaging and Communications in Medicine format raw ICG data and digitized histopathology slides
MRI data will be recorded using the patient ID in the secure Picture Archiving and Communication System PACS of the radiology department Routine radiology reports will be retrieved and included in the participants anonymous study file The MRI images will be transferred anonymously from the scanner to the universitys DICOM database where they will be analyzed by a research fellow to extract the relevant imaging biomarkers
All excel sheets with anonymised study data will be transferred to a long-term data repository where they will be maintained for a minimum of 25 years Source data for MRI and ICG will be retained indefinitely in a dedicated imaging data management system hosted by the University to enable secondary research educational use and data sharing
INCIDENTAL FINDINGS AND BLINDING
All data collected for the study except calculated MRI biomarkers and ICG measurements are acquired as part of the routine workup and will therefore be available to the clinical care team through the patients medical records All ICG liver function measurements from finger clip device will be reviewed separately by the hepatology consultant Any unusual findings will be flagged up to the clinical care team as incidental findings and dealt with according to usual practices For those patients that have an extra MRI scan as part of their participation in the study these MRIs will be reviewed by a radiologist Any unusual findings will be flagged up to the clinical care team as incidental findings and dealt with according to usual practices Unvalidated MRI biomarkers will not be reviewed for incidental findings or otherwise communicated to the clinical care team The non-clinical research fellows working on analysis of MRI and ICG data will be blinded to the clinical history of the patient and other function tests
WITHDRAWAL OF PARTICIPANTS
If a patient decides to withdraw their consent to inclusion in the study at any point then no further data regarding their care will be collected Should the patient wish data collected up until withdrawal of consent will be destroyed using the hospitals confidential waste bins Patients who lose their capacity to consent after initial inclusion in the study for reasons that are not related to their surgery will be treated in the same manner as if they had withdrawn consent Previously collected data will not be destroyed If a patient is unable to complete their MRI study for any reason they will automatically be withdrawn from the study Data collected until the point of withdrawal will be retained
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 19NW0139 | OTHER | Research Ethics Committee | None |
| MRP0233981 | OTHER_GRANT | None | None |