Coronary Artery Disease in Hearts Donated for Transplantation

STUDY RATIONALE AND RISK/BENEFIT ANALYSIS This investigation forms part of a broader research/service 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 41.9% \[9\].

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 visualisation/palpation and coronary artery angiography for the diagnosis of coronary artery disease.

SECONDARY OBJECTIVES N/a

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' (i.e. holding a suitable HTA licence compatible with organ retrieval for research purposes within the INOAR scheme). * the donor's family have provided generic consent for the use of untransplantable organs for research purposes. * the heart is deemed untransplantable on the grounds of the visualisation/palpation of coronary heart disease at the time of retrieval. * the untransplantable heart is not deemed suitable for valve homograft/patch 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 Brain(stem) 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 visible/palpable 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 visible/palpable 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 Donor's family decline to offer generic consent to the use of donated organs for research purposes.

Logistic issues preventing study enrolment.

DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS AND STOPPING RULES N/a. SUBJECT/PATIENT RECRUITMENT PROCESS This will occur through establish transplantation procedures as detailed in 6.1.

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 donor's family by the Specialist Nurse in Organ Donation (see attached form).

RANDOMISATION PROCEDURE N/a, single arm study.

EMERGENCY UN-BLINDING N/a STUDY ASSESSMENTS SCREENING ASSESSMENTS No screening assessments are planned.

BASELINE ASSESSMENTS The only relevant baseline assessment is direct visualisation/palpation 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 N/a Radiology or any other procedure(s) 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 N/a.

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 N/a RECORDING ADVERSE EVENTS (AES)

N/a REPORTING OF SAES TO THE SPONSOR AND THE REC THE TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECT AFTER AES

N/a

PREGNANCY N/a

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 N/a

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 subject's name or other personal identifiable data. The subject's 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 Investigator's 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.