Ignite Creation Date:
2024-10-26 @ 3:36 PM
Last Modification Date:
2024-10-26 @ 3:36 PM
Study NCT ID:
NCT06528834
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-07-26
Brief Title:
Coronary Artery Disease in Hearts Donated for Transplantation
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Coronary Angiographic Assessment of Hearts Donated for Transplantation Declined on the Grounds of VisiblePalpable Coronary Artery Disease at the Time of Retrieval
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-07
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:
None
Brief Summary:
In spite of recent initiatives in particular the introduction into clinical practice of donation after circulatory death DCD there is a persistent mismatch between the demand for donor hearts for transplantation and their supply 1 This mismatch is accentuated by the relatively low rate of utilisation of hearts donated for transplantation ie the proportion of organs transplanted divided by the number of donations In the UK between 2016 and 2018 this ranged from 257 to 308 2 For the year 202223 a total of 207 heart transplants DBD and DCD were performed out of 1429 donations giving a utilisation rate of 145 3
The rigorous assessment of donor heart quality prior to and during donor organ retrieval which is a crucial determinant of recipient outcome accounts for the low utilisation rate In both the donation after brainstem death DBD and DCD settings pre-retrieval echocardiography is the principal method of anatomical and functional assessment In the DCD setting where normothermic organ perfusion either in situ or ex situ is mandatory to restore myocardial function additional functional and biochemical assessments are available
In addition to recipient risk factors donor age and comorbidity burden continue to limit the applicability and effectiveness of heart transplantation Older donors are both associated with an increased comorbidity burden and prevalence of coronary artery disease CAD Donor-transmitted CAD is of particular concern due to the significant association with early graft dysfunction when multi-vessel disease is present 45 Guidelines recommend that donor hearts with obstructive CAD in any major coronary artery be declined for transplantation 4 However there is evidence that single vessel CAD neither alters short- nor long term recipient prognosis 6 The short and long term risks to the recipient of donor heart CAD needs to be carefully evaluated in relation to the risk of a transplant candidate remaining on the waiting list 78
None of the methods currently available in the UK for the assessment of potential heart donors allows adequate characterisation of coronary artery disease CAD Instead retrieval surgeons place a heavy reliance on an indirect assessment of CAD ie direct visualisation and palpation of the large epicardial coronary arteries with the aim of identifying occlusive lesions The discovery of such lesions is the justification for declining a donor organ otherwise deemed to be suitable for transplantation
In other countries access to coronary artery imaging prior to heart donation is an established option where indicated Indeed the Association of Organ Procurement Organizations Consensus Statement supported by the Society of Critical Care Medicine and the American College of Chest Physicians recommends coronary angiography in all older donors 40 years and in younger patients with risk factors for CAD
In the proposed study we seek to perform coronary angiography at Harefield Hospital on donated hearts where our retrieval team has declined the organ solely on the grounds of visiblepalpable CAD In so doing we aim to better understand the diagnostic utility of the assessment method An internal audit of heart retrieval has revealed that of the donated hearts offered to Harefield since 2020 between 8 to 13 are declined per annum on the grounds of visiblepalpable coronary artery disease ie approx 10 per annum Assuming a study enrolment rate of 13 of donated hearts with CAD identified at the time of retrieval we therefore anticipate that this study will take 36 months to complete This investigation forms part of a broader researchservice improvement initiative which aims to not only enhance the assessment of CAD in potential donors but also to better understand the pathogenesis of CAD in heart transplant recipients The ultimate goals are to reduce the risks associated with transplantation and increasing donor organ availability We propose to initiate this investigation as a single centre study but would welcome the participation of other UK centres who would like to collaborate
We believe this research initiative is well aligned with the strategic objectives of the NHS BT Business Plan 2022-23 9
1 Hsich E Circ Heart Fail 2016 Apr 94 e002679
2 Rushton and Hogg March 2019 NHSBTCAG CHARH1925
3 NHS-BT Annual Activity ReportSection 7 Cardiothoracic activity 2022-23
4 Ivanes F et al Int J Cardiol 2019 27771-8
5 Kotloff RM et al Crit Care med 2015431291-325
6 Dorent et al Arch Cardiovasc Dis 2018111126-39
7 Kilic A et al J Thorac Dis 201461097-104
8 Estevz-Loureiro R et al Transplant Proc 2010422987-91
9 NHS BT Business Plan 2022-23 July 2022
The rigorous assessment of donor heart quality prior to and during donor organ retrieval which is a crucial determinant of recipient outcome accounts for the low utilisation rate In both the donation after brainstem death DBD and DCD settings pre-retrieval echocardiography is the principal method of anatomical and functional assessment In the DCD setting where normothermic organ perfusion either in situ or ex situ is mandatory to restore myocardial function additional functional and biochemical assessments are available
In addition to recipient risk factors donor age and comorbidity burden continue to limit the applicability and effectiveness of heart transplantation Older donors are both associated with an increased comorbidity burden and prevalence of coronary artery disease CAD Donor-transmitted CAD is of particular concern due to the significant association with early graft dysfunction when multi-vessel disease is present 45 Guidelines recommend that donor hearts with obstructive CAD in any major coronary artery be declined for transplantation 4 However there is evidence that single vessel CAD neither alters short- nor long term recipient prognosis 6 The short and long term risks to the recipient of donor heart CAD needs to be carefully evaluated in relation to the risk of a transplant candidate remaining on the waiting list 78
None of the methods currently available in the UK for the assessment of potential heart donors allows adequate characterisation of coronary artery disease CAD Instead retrieval surgeons place a heavy reliance on an indirect assessment of CAD ie direct visualisation and palpation of the large epicardial coronary arteries with the aim of identifying occlusive lesions The discovery of such lesions is the justification for declining a donor organ otherwise deemed to be suitable for transplantation
In other countries access to coronary artery imaging prior to heart donation is an established option where indicated Indeed the Association of Organ Procurement Organizations Consensus Statement supported by the Society of Critical Care Medicine and the American College of Chest Physicians recommends coronary angiography in all older donors 40 years and in younger patients with risk factors for CAD
In the proposed study we seek to perform coronary angiography at Harefield Hospital on donated hearts where our retrieval team has declined the organ solely on the grounds of visiblepalpable CAD In so doing we aim to better understand the diagnostic utility of the assessment method An internal audit of heart retrieval has revealed that of the donated hearts offered to Harefield since 2020 between 8 to 13 are declined per annum on the grounds of visiblepalpable coronary artery disease ie approx 10 per annum Assuming a study enrolment rate of 13 of donated hearts with CAD identified at the time of retrieval we therefore anticipate that this study will take 36 months to complete This investigation forms part of a broader researchservice improvement initiative which aims to not only enhance the assessment of CAD in potential donors but also to better understand the pathogenesis of CAD in heart transplant recipients The ultimate goals are to reduce the risks associated with transplantation and increasing donor organ availability We propose to initiate this investigation as a single centre study but would welcome the participation of other UK centres who would like to collaborate
We believe this research initiative is well aligned with the strategic objectives of the NHS BT Business Plan 2022-23 9
1 Hsich E Circ Heart Fail 2016 Apr 94 e002679
2 Rushton and Hogg March 2019 NHSBTCAG CHARH1925
3 NHS-BT Annual Activity ReportSection 7 Cardiothoracic activity 2022-23
4 Ivanes F et al Int J Cardiol 2019 27771-8
5 Kotloff RM et al Crit Care med 2015431291-325
6 Dorent et al Arch Cardiovasc Dis 2018111126-39
7 Kilic A et al J Thorac Dis 201461097-104
8 Estevz-Loureiro R et al Transplant Proc 2010422987-91
9 NHS BT Business Plan 2022-23 July 2022
Detailed Description:
STUDY RATIONALE AND RISKBENEFIT ANALYSIS This investigation forms part of a broader researchservice improvement initiative which aims to not only improve the assessment of CAD in potential donors but also to better understand the pathogenesis of CAD in heart transplant recipients The ultimate goals are to reduce the risks associated with transplantation and increase donor organ availability We propose to initiate this investigation as a single centre study but would welcome the participation of other UK centres who would like to collaborate
We believe this research initiative is well aligned with the strategic objectives of the NHS BT Business Plan 2022-23 in particular i reducing harm to patients recipients and ii achieving the 4-5 year target of higher deceased donor transplant activity by 419 9
MANAGEMENT OF POTENTIAL STUDY RISKS We have not identified any incremental risks associated with the retrieval and transport of the donated heart beyond those associated with a conventional donor heart retrieval procedure We are satisfied that suitable arrangements have been made for the appropriate labelling and secure storage of the heart donated for research prior to angiography We believe the risk of disclosure of donor or recipient identify will be minimised by pseudoanonymisation and the application standard Trust research procedures Angiography will be performed by an experienced interventional cardiologist Radiation exposure to clinical personnel during the angiography procedure will be controlled using standard measures
STUDY OBJECTIVES PRIMARY OBJECTIVE Determination of whether there is discordance between visualisationpalpation and coronary artery angiography for the diagnosis of coronary artery disease
SECONDARY OBJECTIVES Na
Prerequisites for commencement of the study include approvals from
The Research Innovation and Novel Technologies Advisory Committee NHSBT A Research Ethics Committee Both of these requirements have been fulfilled
Prerequisites for study enrolment are that
the donation centre should be within scope ie holding a suitable HTA licence compatible with organ retrieval for research purposes within the INOAR scheme
the donors family have provided generic consent for the use of untransplantable organs for research purposes
the heart is deemed untransplantable on the grounds of the visualisationpalpation of coronary heart disease at the time of retrieval
the untransplantable heart is not deemed suitable for valve homograftpatch retrieval
the untransplanable heart is not allocated to alternative research studies through the INOAR scheme
If all these criteria are fulfilled and confirmed enrolment may commence The cardiothoracic retrieval team will give priority to the retrieval of any organs destined for transplantation The donated heart will be retrieved using the conventional Donation after Brainstem Death DBD method irrespective of whether the heart was initially offered through the DBD or Donor Circulatory Death DCD pathways The packaging will be labelled using a pseudoanonymised code The donated heart will be transported to Harefield Hospital by the retrieval team and will be placed within a designated organ storage fridge within the operating theatre facility Within 24 hours the interventional cardiologist will perform contrast coronary angiography After the study procedure the heart will be made available for further research studies if appropriate Alternatively it will be submitted to disposal using an approved method
TREATMENT AND RATIONALE Treatment does not feature in the study design The only proposed intervention is coronary angiography of hearts deemed untransplantable at the time of retrieval on the grounds of visiblepalpable coronary artery disease
ELIGIBILITY CRITERIA INCLUSION CRITERIA Adult hearts donated for transplantation in UK centres attended by the Harefield Retrieval Team yet deemed untransplantable because of visiblepalpable coronary artery disease
Donation centre holds HTA research licence making the donation of organs for research possible under the INOAR scheme
EXCLUSION CRITERIA Donation centre does not hold appropriate research licence Donors family decline to offer generic consent to the use of donated organs for research purposes
Logistic issues preventing study enrolment
DISCONTINUATIONWITHDRAWAL OF PARTICIPANTS AND STOPPING RULES Na SUBJECTPATIENT RECRUITMENT PROCESS This will occur through establish transplantation procedures as detailed in 61
STUDY PROCEDURES Left and right coronary artery angiography using standard catheters radio-opaque dye in a catheter laboratory at Harefield Hospital
We recognise there will be no dye wash-out as occurs during a conventional procedure in a beating heart If necessary crystalloid solution will be used to achieve a similar effect
INFORMED CONSENT Generic consent for the use of untransplantable organs for research purposes is currently sought from the donors family by the Specialist Nurse in Organ Donation see attached form
RANDOMISATION PROCEDURE Na single arm study
EMERGENCY UN-BLINDING Na STUDY ASSESSMENTS SCREENING ASSESSMENTS No screening assessments are planned
BASELINE ASSESSMENTS The only relevant baseline assessment is direct visualisationpalpation of the coronary arteries at the time of retrieval of the donated heart
TREATMENT PROCEDURE Not applicable
SUBSEQUENT ASSESSMENTS Within 24 hours of retrieval the donated heart will undergo left and right coronary artery angiography This procedure will be performed in the catheter laboratory by an experienced Interventional Cardiologist
SUMMARY CHART OF STUDY ASSESSMENTS Only one procedure will be performed per enrolment within 24 hours of retrieval of the heart donated for research purposes
METHODS Laboratory Procedures Na Radiology or any other procedures The study does not entail ionising radiation exposure to a patient Radiation exposure to clinical staff will be controlled using standard IRMER recommendations
Is ARSAC licence required No Techniques and Interventions Coronary angiography
Tools Standard left and right heart coronary artery catheters radio-opaque dye within a catheter laboratory
Study Drugs Na
DEFINITION OF THE END OF STUDY Completion of angiography procedure on the 10th donated heart enrolled in the study followed by data analysis by the designated statistician
SAFETY REPORTING DEFINITION Na RECORDING ADVERSE EVENTS AES
Na REPORTING OF SAES TO THE SPONSOR AND THE REC THE TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECT AFTER AES
Na
PREGNANCY Na
ANNUAL PROGRESS REPORTS APRS The Chief Investigator will prepare the APR for the study It will be reviewed by the RO and sent to the REC by the CI within 30 days of the anniversary date on which the favourable opinion was given by the REC and annually until the study is declared ended A copy of the report will be provided to regulatory stakeholders
REPORTING URGENT SAFETY MEASURES Na
DATA MANAGEMENT AND QUALITY ASSURANCE CONFIDENTIALITY All data will be handled in accordance with the Data Protection Act 2018 NHS Caldecott Principles The UK Policy Framework for Health and Social Care Research and the condition of the REC approval
The Case Report Forms CRFs will not bear the subjects name or other personal identifiable data The subjects study Identification Number ID will be used for identification
DATA COLLECTION TOOL Case Report Forms CRF will be designed by the CI and the final version will be reviewed and discussed with the study Sponsor All data will be entered legibly in black ink with a ball-point pen If the Investigator makes an error it will be crossed through with a single line in such a way to ensure that the original entry can still be read The correct entry will then be clearly inserted The amendment will be initialled and dated by the person making the correction immediately Overwriting or use of correction fluid will not be permitted
It is the Investigators responsibility to ensure the accuracy of all data entered and recorded in the CRFs The Delegation of Responsibilities Log will identify all study personnel responsible for data collection entry handling and managing the database
The research data will take the form of a pseudoanonymised angiography report bearing the ID reference number provided by the Interventional Cardiologist of standardised format with the inclusion of selected angiographic imagesvideos where appropriate This information will be compared with the summary report provided by the retrieval surgeon The custodianship of the research data will be the responsibility of the research nurse
DATA HANDLING AND ANALYSIS Software standard coronary angiographic software will be employed for analysis and static and videographic image generation Reports will be written using Microsoft Word on a Trust computer
Data quality will be assured by cross referencing to the date of the retrieval procedure
Research data will be stored on a secure Trust computer with an automated data back-up facility to ensure data security
Data analysis will be performed by Rachel Hogg Senior Statistician NHS BT
134 ARCHIVING ARRANGEMENTS The study documents including the Study Master File SMF Case Report Forms CRFs Informed Consent Forms along with the study database will be kept for a minimum of five years They will be stored in locked offices within the Royal Brompton and Harefield Hospitals The CI is responsible for the secure archiving of study documents The study database will also be kept electronically on the RBHFT computer network for a minimum of five years
The approved repository for longer retention of local materials for studies that involve RBH patients is Box-It Storage UK The study documentation will be prepared for archiving by the research team in line with the Research Office Archiving SOP and the transfer will be arranged by the Research Office
STATISTICAL DESIGN
SAMPLE SIZE AND RECRUITMENT
Ideally we would have liked to increase the number of donated hearts enrolled in this study However there are logistic challenges associated with recruitment and there is competition for such organs for the purposes of homograft valve retrieval and for other research studies
An internal audit of heart retrieval has revealed that of the donated hearts offered to Harefield since 2020 between 8 to 13 are declined per annum on the grounds of visiblepalpable coronary artery disease ie approx 10 per annum Assuming a study enrolment rate of 13 of donated hearts with CAD identified at the time of retrieval we therefore anticipate that this study will take 36 months to complete
Consequently the endpoints of the proposed study and sample size are not intended to be powered for statistical inference Instead the intention is to support or refute a reasonable assurance of the validity of direct visualisationpalpation for the detection of CAD
Discordance between the diagnosis of coronary artery disease at the time of retrieval and the angiography data false positive would be a cause of concern that would provide real-world evidence of the need for coronary artery imaging in organ donors prior to retrieval where indicated Rachel Hogg Senior Statistician BHS BT has kindly provided advice concerning study design and has agreed to assist with the data analysis
ENDPOINTS Primary endpoints The goal of this study is perform coronary angiography on hearts which were retrieved by our transplant team and were declined for transplantation solely on the grounds of visiblepalpable ie manual examination coronary artery disease In so doing we aim to better understand whether the current assessment method is reliable Thus the primary endpoint is discordance between the two diagnostic methods
Secondary endpoints Na
STATISTICAL ANALYSIS PLAN See above
Primary endpoint analysis As the study is not powered for detailed statistical inference data analysis will be of a descriptive nature
Secondary endpoint analysis Na
RANDOMISATION Na INTERIM ANALYSIS IF APPLICABLE Na OTHER STATISTICAL CONSIDERATIONS Na 15 COMMITTEES INVOLVED IN THE STUDY NHS Organ Donation and Transplantation Research Innovation and Novel Technologies Advisory Group RINTAG have reviewed the proposed application and given a favourable opinion
The Lead Clinician for Organ Donation for the UK Dr Dale Gardiner has also been informed of our intention to submit this research proposal and is supportive of it in principle
Favourable IRB approval was also obtained as detailed above
MONITORING AND AUDITING The requirement for study monitoring or audit will be based on the internal Research Office risk assessment procedure and applicable Standard Operating Procedures SOPs It is the responsibility of the RO to determine the monitoring risk assessment and explain the rationale to the study research team
Study monitoring andor audit will be discussed with the CI before arrangements are made to conduct the visit
DIRECT ACCESS TO SOURCE DATA The Investigatorsinstitutions will permit study-related monitoring audits REC review and regulatory inspections providing direct access to source datadocuments
ETHICS AND REGULATORY REQUIREMENTS The Sponsor will ensure that the study protocol Patient Information Sheet PIS Informed Consent Form ICF GP letter and submitted supporting documents have been approved by the Health Research Authority HRA which includes Research Ethics Committee REC approval if applicable prior to any patient recruitment taking place The protocol and all agreed substantial protocol amendments will be documented and submitted for HRA approval prior to implementation
Before sites can enrol patients into the study confirmation of capacity and capability must be issued by the institution hosting the trial unless HRA specifically has confirmed in the HRA approval letter that this is not required It is the responsibility of the PI at each site to ensure that all subsequent amendments gain the necessary approvals by the participating site This does not affect the individual clinicians responsibility to take immediate action if thought necessary to protect the health and interest of individual patients
Within 90 days after the end of the study the CI will ensure that the REC is notified that the study has finished If the study is terminated prematurely those reports will be made within 15 days after the end of the study
The CI will supply a final summary report of the clinical study to the REC and the Sponsor in parallel within one year after the end of the study
FINANCE
8300 has been allocated from an internal Trust research account for the proposed study This is sufficient to cover
1500 RINTAG application fee which covers the first 12 months of the study
600 2 x 300 annual renewal fee for the above to enable the study to run for 36 months
6000 10 x 600 per angiography investigation - fully funded angiography - costs kindly provided by the Divisional Interventional Lead Cardiology
On this basis sufficient funds are available for the enrolment of 10 donated hearts with a contingency of 200
There will be no incremental transport costs as our Transplant Retrieval Team will be attending the donation centre in the course of their normal duties
INSURANCE AND INDEMNITY Na PUBLICATION POLICY Data ownership rights will reside with the host institution STATEMENT OF COMPLIANCE The trial will be conducted in compliance with the protocol Sponsors Standard Operating Procedures SOPs GCP and the applicable regulatory requirements
The study conduct shall comply with all relevant laws of the UK country in which the study site is located including but not limited to the Human Rights Act 1998 the Data Protection Act 2018 and with all relevant guidance relating to medicines and clinical studies from time to time in force including but not limited to the ICH GCP the World Medical Association Declaration of Helsinki entitled Ethical Principles for Medical Research Involving Human Subjects 2008 Version the UK Policy Framework for Health and Social Care Research
This study will be conducted in compliance with the protocol approved by HRA and according to RGF standards No deviation from the protocol will be implemented without the prior review and approval of the Sponsor and HRA except where it may be necessary to eliminate an immediate hazard to a research subject In such case the deviation will be reported to the Sponsor and the REC as soon as possible
We believe this research initiative is well aligned with the strategic objectives of the NHS BT Business Plan 2022-23 in particular i reducing harm to patients recipients and ii achieving the 4-5 year target of higher deceased donor transplant activity by 419 9
MANAGEMENT OF POTENTIAL STUDY RISKS We have not identified any incremental risks associated with the retrieval and transport of the donated heart beyond those associated with a conventional donor heart retrieval procedure We are satisfied that suitable arrangements have been made for the appropriate labelling and secure storage of the heart donated for research prior to angiography We believe the risk of disclosure of donor or recipient identify will be minimised by pseudoanonymisation and the application standard Trust research procedures Angiography will be performed by an experienced interventional cardiologist Radiation exposure to clinical personnel during the angiography procedure will be controlled using standard measures
STUDY OBJECTIVES PRIMARY OBJECTIVE Determination of whether there is discordance between visualisationpalpation and coronary artery angiography for the diagnosis of coronary artery disease
SECONDARY OBJECTIVES Na
Prerequisites for commencement of the study include approvals from
The Research Innovation and Novel Technologies Advisory Committee NHSBT A Research Ethics Committee Both of these requirements have been fulfilled
Prerequisites for study enrolment are that
the donation centre should be within scope ie holding a suitable HTA licence compatible with organ retrieval for research purposes within the INOAR scheme
the donors family have provided generic consent for the use of untransplantable organs for research purposes
the heart is deemed untransplantable on the grounds of the visualisationpalpation of coronary heart disease at the time of retrieval
the untransplantable heart is not deemed suitable for valve homograftpatch retrieval
the untransplanable heart is not allocated to alternative research studies through the INOAR scheme
If all these criteria are fulfilled and confirmed enrolment may commence The cardiothoracic retrieval team will give priority to the retrieval of any organs destined for transplantation The donated heart will be retrieved using the conventional Donation after Brainstem Death DBD method irrespective of whether the heart was initially offered through the DBD or Donor Circulatory Death DCD pathways The packaging will be labelled using a pseudoanonymised code The donated heart will be transported to Harefield Hospital by the retrieval team and will be placed within a designated organ storage fridge within the operating theatre facility Within 24 hours the interventional cardiologist will perform contrast coronary angiography After the study procedure the heart will be made available for further research studies if appropriate Alternatively it will be submitted to disposal using an approved method
TREATMENT AND RATIONALE Treatment does not feature in the study design The only proposed intervention is coronary angiography of hearts deemed untransplantable at the time of retrieval on the grounds of visiblepalpable coronary artery disease
ELIGIBILITY CRITERIA INCLUSION CRITERIA Adult hearts donated for transplantation in UK centres attended by the Harefield Retrieval Team yet deemed untransplantable because of visiblepalpable coronary artery disease
Donation centre holds HTA research licence making the donation of organs for research possible under the INOAR scheme
EXCLUSION CRITERIA Donation centre does not hold appropriate research licence Donors family decline to offer generic consent to the use of donated organs for research purposes
Logistic issues preventing study enrolment
DISCONTINUATIONWITHDRAWAL OF PARTICIPANTS AND STOPPING RULES Na SUBJECTPATIENT RECRUITMENT PROCESS This will occur through establish transplantation procedures as detailed in 61
STUDY PROCEDURES Left and right coronary artery angiography using standard catheters radio-opaque dye in a catheter laboratory at Harefield Hospital
We recognise there will be no dye wash-out as occurs during a conventional procedure in a beating heart If necessary crystalloid solution will be used to achieve a similar effect
INFORMED CONSENT Generic consent for the use of untransplantable organs for research purposes is currently sought from the donors family by the Specialist Nurse in Organ Donation see attached form
RANDOMISATION PROCEDURE Na single arm study
EMERGENCY UN-BLINDING Na STUDY ASSESSMENTS SCREENING ASSESSMENTS No screening assessments are planned
BASELINE ASSESSMENTS The only relevant baseline assessment is direct visualisationpalpation of the coronary arteries at the time of retrieval of the donated heart
TREATMENT PROCEDURE Not applicable
SUBSEQUENT ASSESSMENTS Within 24 hours of retrieval the donated heart will undergo left and right coronary artery angiography This procedure will be performed in the catheter laboratory by an experienced Interventional Cardiologist
SUMMARY CHART OF STUDY ASSESSMENTS Only one procedure will be performed per enrolment within 24 hours of retrieval of the heart donated for research purposes
METHODS Laboratory Procedures Na Radiology or any other procedures The study does not entail ionising radiation exposure to a patient Radiation exposure to clinical staff will be controlled using standard IRMER recommendations
Is ARSAC licence required No Techniques and Interventions Coronary angiography
Tools Standard left and right heart coronary artery catheters radio-opaque dye within a catheter laboratory
Study Drugs Na
DEFINITION OF THE END OF STUDY Completion of angiography procedure on the 10th donated heart enrolled in the study followed by data analysis by the designated statistician
SAFETY REPORTING DEFINITION Na RECORDING ADVERSE EVENTS AES
Na REPORTING OF SAES TO THE SPONSOR AND THE REC THE TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECT AFTER AES
Na
PREGNANCY Na
ANNUAL PROGRESS REPORTS APRS The Chief Investigator will prepare the APR for the study It will be reviewed by the RO and sent to the REC by the CI within 30 days of the anniversary date on which the favourable opinion was given by the REC and annually until the study is declared ended A copy of the report will be provided to regulatory stakeholders
REPORTING URGENT SAFETY MEASURES Na
DATA MANAGEMENT AND QUALITY ASSURANCE CONFIDENTIALITY All data will be handled in accordance with the Data Protection Act 2018 NHS Caldecott Principles The UK Policy Framework for Health and Social Care Research and the condition of the REC approval
The Case Report Forms CRFs will not bear the subjects name or other personal identifiable data The subjects study Identification Number ID will be used for identification
DATA COLLECTION TOOL Case Report Forms CRF will be designed by the CI and the final version will be reviewed and discussed with the study Sponsor All data will be entered legibly in black ink with a ball-point pen If the Investigator makes an error it will be crossed through with a single line in such a way to ensure that the original entry can still be read The correct entry will then be clearly inserted The amendment will be initialled and dated by the person making the correction immediately Overwriting or use of correction fluid will not be permitted
It is the Investigators responsibility to ensure the accuracy of all data entered and recorded in the CRFs The Delegation of Responsibilities Log will identify all study personnel responsible for data collection entry handling and managing the database
The research data will take the form of a pseudoanonymised angiography report bearing the ID reference number provided by the Interventional Cardiologist of standardised format with the inclusion of selected angiographic imagesvideos where appropriate This information will be compared with the summary report provided by the retrieval surgeon The custodianship of the research data will be the responsibility of the research nurse
DATA HANDLING AND ANALYSIS Software standard coronary angiographic software will be employed for analysis and static and videographic image generation Reports will be written using Microsoft Word on a Trust computer
Data quality will be assured by cross referencing to the date of the retrieval procedure
Research data will be stored on a secure Trust computer with an automated data back-up facility to ensure data security
Data analysis will be performed by Rachel Hogg Senior Statistician NHS BT
134 ARCHIVING ARRANGEMENTS The study documents including the Study Master File SMF Case Report Forms CRFs Informed Consent Forms along with the study database will be kept for a minimum of five years They will be stored in locked offices within the Royal Brompton and Harefield Hospitals The CI is responsible for the secure archiving of study documents The study database will also be kept electronically on the RBHFT computer network for a minimum of five years
The approved repository for longer retention of local materials for studies that involve RBH patients is Box-It Storage UK The study documentation will be prepared for archiving by the research team in line with the Research Office Archiving SOP and the transfer will be arranged by the Research Office
STATISTICAL DESIGN
SAMPLE SIZE AND RECRUITMENT
Ideally we would have liked to increase the number of donated hearts enrolled in this study However there are logistic challenges associated with recruitment and there is competition for such organs for the purposes of homograft valve retrieval and for other research studies
An internal audit of heart retrieval has revealed that of the donated hearts offered to Harefield since 2020 between 8 to 13 are declined per annum on the grounds of visiblepalpable coronary artery disease ie approx 10 per annum Assuming a study enrolment rate of 13 of donated hearts with CAD identified at the time of retrieval we therefore anticipate that this study will take 36 months to complete
Consequently the endpoints of the proposed study and sample size are not intended to be powered for statistical inference Instead the intention is to support or refute a reasonable assurance of the validity of direct visualisationpalpation for the detection of CAD
Discordance between the diagnosis of coronary artery disease at the time of retrieval and the angiography data false positive would be a cause of concern that would provide real-world evidence of the need for coronary artery imaging in organ donors prior to retrieval where indicated Rachel Hogg Senior Statistician BHS BT has kindly provided advice concerning study design and has agreed to assist with the data analysis
ENDPOINTS Primary endpoints The goal of this study is perform coronary angiography on hearts which were retrieved by our transplant team and were declined for transplantation solely on the grounds of visiblepalpable ie manual examination coronary artery disease In so doing we aim to better understand whether the current assessment method is reliable Thus the primary endpoint is discordance between the two diagnostic methods
Secondary endpoints Na
STATISTICAL ANALYSIS PLAN See above
Primary endpoint analysis As the study is not powered for detailed statistical inference data analysis will be of a descriptive nature
Secondary endpoint analysis Na
RANDOMISATION Na INTERIM ANALYSIS IF APPLICABLE Na OTHER STATISTICAL CONSIDERATIONS Na 15 COMMITTEES INVOLVED IN THE STUDY NHS Organ Donation and Transplantation Research Innovation and Novel Technologies Advisory Group RINTAG have reviewed the proposed application and given a favourable opinion
The Lead Clinician for Organ Donation for the UK Dr Dale Gardiner has also been informed of our intention to submit this research proposal and is supportive of it in principle
Favourable IRB approval was also obtained as detailed above
MONITORING AND AUDITING The requirement for study monitoring or audit will be based on the internal Research Office risk assessment procedure and applicable Standard Operating Procedures SOPs It is the responsibility of the RO to determine the monitoring risk assessment and explain the rationale to the study research team
Study monitoring andor audit will be discussed with the CI before arrangements are made to conduct the visit
DIRECT ACCESS TO SOURCE DATA The Investigatorsinstitutions will permit study-related monitoring audits REC review and regulatory inspections providing direct access to source datadocuments
ETHICS AND REGULATORY REQUIREMENTS The Sponsor will ensure that the study protocol Patient Information Sheet PIS Informed Consent Form ICF GP letter and submitted supporting documents have been approved by the Health Research Authority HRA which includes Research Ethics Committee REC approval if applicable prior to any patient recruitment taking place The protocol and all agreed substantial protocol amendments will be documented and submitted for HRA approval prior to implementation
Before sites can enrol patients into the study confirmation of capacity and capability must be issued by the institution hosting the trial unless HRA specifically has confirmed in the HRA approval letter that this is not required It is the responsibility of the PI at each site to ensure that all subsequent amendments gain the necessary approvals by the participating site This does not affect the individual clinicians responsibility to take immediate action if thought necessary to protect the health and interest of individual patients
Within 90 days after the end of the study the CI will ensure that the REC is notified that the study has finished If the study is terminated prematurely those reports will be made within 15 days after the end of the study
The CI will supply a final summary report of the clinical study to the REC and the Sponsor in parallel within one year after the end of the study
FINANCE
8300 has been allocated from an internal Trust research account for the proposed study This is sufficient to cover
1500 RINTAG application fee which covers the first 12 months of the study
600 2 x 300 annual renewal fee for the above to enable the study to run for 36 months
6000 10 x 600 per angiography investigation - fully funded angiography - costs kindly provided by the Divisional Interventional Lead Cardiology
On this basis sufficient funds are available for the enrolment of 10 donated hearts with a contingency of 200
There will be no incremental transport costs as our Transplant Retrieval Team will be attending the donation centre in the course of their normal duties
INSURANCE AND INDEMNITY Na PUBLICATION POLICY Data ownership rights will reside with the host institution STATEMENT OF COMPLIANCE The trial will be conducted in compliance with the protocol Sponsors Standard Operating Procedures SOPs GCP and the applicable regulatory requirements
The study conduct shall comply with all relevant laws of the UK country in which the study site is located including but not limited to the Human Rights Act 1998 the Data Protection Act 2018 and with all relevant guidance relating to medicines and clinical studies from time to time in force including but not limited to the ICH GCP the World Medical Association Declaration of Helsinki entitled Ethical Principles for Medical Research Involving Human Subjects 2008 Version the UK Policy Framework for Health and Social Care Research
This study will be conducted in compliance with the protocol approved by HRA and according to RGF standards No deviation from the protocol will be implemented without the prior review and approval of the Sponsor and HRA except where it may be necessary to eliminate an immediate hazard to a research subject In such case the deviation will be reported to the Sponsor and the REC as soon as possible
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