Improving Transplant Opportunities for Patients who are Sensitized (ITOPS): Protocol for a Feasibility, Randomized, Controlled, Phase III Clinical Trial

• Background: Kidney transplantation offers a better quality of life and a clear survival advantage compared to long-term dialysis. However, rates of transplantation are low for highly sensitized patients (HSP) who have a broad specicity of human leucocyte antigen (HLA) specic antibodies. This is because the presence of pre-formed HLA Donor Specic Antibodies can result in hyperacute rejection and is an immunological veto to transplantation. The proportion of eligible donors therefore decreases with increasing sensitization, resulting in increased waiting time prior to transplantation. This study aims to assess the ecacy of a combination of B cell depletion and proteasome inhibition, together with antibody removal and steroids, to reduce HLA antibodies in HSP, predicted to improve rates of transplantation, and to determine the feasibility of conducting a future denitive trial. • Methods: ITOPS is a multi-center, randomized parallel, non-blinded, controlled phase III feasibility trial. The participants will be allocated in a 1:1 ratio to either the trial intervention (rituximab followed by 1-2 cycles of plasmapheresis, bortezomib and dexamethasone) or control group (no intervention). • to the Secondary outcomes include recruitment and transplantation rates, durability of change and absolute percentage change in cRF, and acceptability of the intervention. to of larger trial at least 50% of the participants in the intervention arm an absolute reduction in cRF of a minimum of 10% at 12 weeks following their last intervention. proportion is <50% in the intervention arm but 50% is included within the 95% condence interval, then consideration to proceed to a larger randomized trial will be given alongside other aspects of feasibility.


Background and rationale {6a}
Despite the advantages of kidney transplantation compared to long term dialysis, rates of transplantation are low for sensitized patients with high levels and breadth of human leucocyte antigen (HLA) speci c antibodies (1). The production of these antibodies is stimulated by exposure or sensitization to non-self HLA, and frequently occurs following pregnancy, blood transfusion and previous transplantation (2). In terms of their risk to the graft, pre-formed HLA Donor Speci c Antibodies are heterogeneous (3)(4)(5)(6)(7)(8). The Luminex Single Antigen Bead assay allows semi-quanti cation of antibody concentration (expressed as Mean Fluorescence Intensity, MFI) and serial monitoring of antibodies of individual HLA speci cities. An MFI < 2000 is generally associated with a negative ow cytometric cross match and is a safe threshold for transplantation.
Highly Sensitized (HS) patients (those with a calculated Reaction Frequency (cRF) ≥ 85%) are di cult to match to a compatible donor. Compared to recipients with a lower degree of sensitization, HS patients tend to be younger, are more likely to be female and their waiting time before receiving an offer of a deceased donor transplant is longer (Table 1).   Table 2). This demonstrates that for those patients who have already accrued at least 3 years waiting time, a relatively modest decrease in cRF can substantially increase the chance of being offered a transplant. For those with a living donor, the UK Living Kidney Sharing Scheme (UKLKSS) offers the chance of receiving a compatible transplant. However, for those with a cRF ≥ 95% the chance of being offered a match through the UKLKSS is relatively small.
We analyzed the likelihood of a match (ever) in the UKLKSS based on all patients included between 2012-2015, which also con rmed the impact of reduction in cRF (Table 3). In addition to the personal, social and economic impact, long term dialysis is associated with an accumulation of related morbidity and mortality (9). UKTR data from 2018-19 suggests 10% of HS patients will die within ve years of joining the transplant waiting list, and a further 12% will be removed from the transplant waiting list due to deteriorating health, so that transplantation is no longer an option (Annual activity report 2018-19, NHSBT, UK). This has provided the impetus for the development of protocols for modi cation of HLA antibody pro le prior to transplantation, referred to as desensitization.
The published case reports and trials that have used a combination desensitization protocol with both rituximab and bortezomib have shown the greatest reduction in HLA antibodies and increase in rates of transplantation with good posttransplant outcomes (17)(18)(19)32). The success of these trials has informed the design of this trial, with the aim of optimizing response rates without unacceptable toxicity. The overall aim of our study is hence to test e cacy and durability of reduction in antibodies using a combination of desensitization treatments in a prospective controlled approach against the current standard of care (SOC).

Objectives {7}
The primary objective is to assess the e cacy of a combination of B cell depletion and proteasome inhibition, together with antibody removal and steroids, to reduce HLA antibodies in HS patients.
The secondary objectives are: 1. To con rm that the expected number of patients can be recruited in the time frame of the trial. 2. To con rm that the intervention is su cient to result in a durable fall in cRF.
3. To con rm that B cell depletion persists at 12 weeks following intervention. 4. To determine whether the intervention impacts on Quality of Life.
5. To con rm whether any transplants arise as a consequence of the intervention.
6. To con rm incidence of peripheral neuropathy (any grade).

Trial Design {8}
The ITOPS design is a parallel two arm feasibility trial, with participants being allocated in a 1:1 ratio to the trial intervention versus control group. The is no blinding in the study.

Eligibility criteria {10}
Highly sensitized patients who have completed the standard medical and surgical assessments prior to being considered eligible for kidney transplantation will be included according to criteria detailed below.
Inclusion criteria: 1. Male or female, aged 18 years or older.
2. Able to give informed consent and willing to ful l trial requirements.
3. Have completed the necessary assessments to receive a renal transplant.
4. In stable health as determined by the Investigator based on medical history and laboratory tests during the screening period.
5. Negative serological test for hepatitis B (surface antigen and core antibody) and hepatitis C within the last 6 months, and Human Immunode ciency Virus (HIV) within the last 12 months.
7. Female participant of childbearing potential must be willing to use a highly effective method of contraception for one year following rituximab (this period will also include the recommended three-month period for avoidance of pregnancy following bortezomib). Male participants must be willing to use a highly effective form of contraception for 3 months post last dose of bortezomib. Exclusion criteria: 1. Pregnancy, planned pregnancy during the trial period, or current breast feeding.

Who will take informed consent? {26a}
It is the responsibility of the Principle Investigator (PI) at each site to give adequate oral and written information about the purposes and procedures of the study, information about data protection, the possible advantages and disadvantages of participation, and option to withdraw from the study at any time and without any given reason. Written informed consent must be obtained for all participants prior to any trial-related procedures. The right of the patient to refuse to participate without giving a reason will be respected.
All staff involved in trial-related activities will be authorized, trained and competent to do so according to the ethically approved protocol, principles of International Conference on Harmonization Good Clinical Practice (ICH GCP) and Declaration of Helsinki as detailed in the Medicines for Human Use (Clinical Trials) Regulations and associated amendments.
Additional consent provisions for collection and use of participant data and biological specimens {26b} Separate, speci c, optional consent will be sought for collection of biological samples for exploratory analyses. A separate explanatory section is included in the Patient Information Sheet.

Interventions
Explanation for the choice of comparators {6b} There are no approved interventions for this group of patients, and the comparator is therefore current SOC, which is regular monitoring of HLA antibody levels.

Intervention description {11a}
Intervention arm: Day 0: Rituximab intravenously as a single dose of 1 g. A reduced dose of 500 mg will be administered to participants weighing less than 50 kg.
If the fall in cRF is less than 10% 12 weeks after the rst treatment cycle of plasmapheresis, bortezomib and dexamethasone, a second cycle of treatment will be offered.

Criteria for discontinuing or modifying allocated interventions {11b}
The dose of bortezomib may be modi ed based on the result of the full blood count (FBC) done prior to administration. A neutrophil count of ≥ 2 × 10 9 /L and platelet count ≥ 100 × 10 9 /L are prerequisites for inclusion in the trial. On subsequent days of treatment, if the neutrophil count is ≥ 0.5 × 10 9 /L and platelet count ≥ 30 × 10 9 /L, that day's dose will be given. If the neutrophil count is < 0.5 × 10 9 /L and/or the platelet count is < 30 × 10 9 /L, no further treatment will be given for that cycle. If a second cycle is considered, bortezomib will be given at half the original dose.

Strategies to improve adherence to interventions {11c}
The intervention is carried out in hospital under nursing supervision and hence non-adherence should be limited. Participants will receive prophylaxis against infection. The importance of this will be emphasized, together with ensuring supply of regular prescriptions. The trial and data managers will also monitor adherence through site visits and the data which is inputted onto the trial database. Any issues will be reported to and discussed at the trial management group meetings.

Relevant concomitant care permitted or prohibited during the trial {11d}
Paracetamol (1 g, oral), chlorpheniramine (10 mg, intravenous) and hydrocortisone (100 mg, intravenous) are given prior to the infusion of rituximab.
Prophylaxis against infection is required for all patients in the intervention group as per local practice.
Prophylaxis against pneumocystis jiroveci pneumonia for 6 months after rituximab:

Provisions for post-trial care {30}
Once the trial is over, all participants will receive all standard care whilst on the waiting list and following transplantation.
This is an NHS-sponsored research trial, and the NHS indemnity scheme therefore applies. If there is negligent harm during the clinical trial when the NHS body owes a duty of care to the person harmed, NHS indemnity covers NHS staff, medical academic staff with honorary contracts, and those conducting the trial. The NHS indemnity scheme does not cover nonnegligent harm. The liability of the manufacturers of rituximab and bortezomib is strictly limited to those claims arising from faulty manufacturing of the commercial product and not to any aspects of the conduct of the trial.

Outcomes {12}
Primary Outcome The proportion of patients achieving an absolute reduction in cRF of at least 10% at 12 weeks following their last intervention, compared to control group who have received no intervention.
For the purposes of calculating reaction frequency in the ITOPS trial, all HLA A, B and DR antibodies with an MFI ≥ 2000 when tested in the local H&I laboratory will be classi ed as positive. HLA Cw, DP and DQ antibodies will be classi ed as positive according to local practice. HLA A, B and DR antibodies with an MFI < 2000 at 12 weeks (and other time-points for the purpose of other relevant secondary outcomes) will be removed from unacceptable antigen listing.
If the MFI of an HLA A, B or DR antibody rises above an MFI of 2500 following previous de-listing, they will be listed again. A cut off of 2500 is used for re-listing as there is greater variability in antibody level at these relatively low concentrations.
Secondary Outcomes: 1. The proportion of eligible participants who consent to the trial.
2. Con rmation that at 12 weeks post-nal intervention there has been an absolute fall in cRF of least 10% in at least 50% of the participants treated, compared to cRF at enrolment.
3. The proportion of patients in the intervention and control groups achieving an absolute reduction in cRF of at least 10% at 24 weeks following their last intervention or on routine monitoring, as compared to cRF at enrolment.

The proportion of patients in the intervention and control groups achieving an absolute reduction in cRF of at least 10%
at 48 weeks following their last intervention or on routine monitoring, as compared to cRF at enrolment.
5. Compared to cRF at enrolment, the percentage decrease in cRF at 12, 24, 36 and 48 weeks following nal treatment in intervention group or on routine monitoring.
6. The percentage of participants in the intervention group with B cell depletion at 12 weeks after the rst cycle of B cell depletion is de ned as an absolute reduction in B cell count to equal to or less than 5% the B cell count at enrolment for that individual participant.
7. Patient acceptability -quality of life questionnaires (European Quality of Life -5 dimensions, EQ-5D and Kidney Disease Quality of Life -Short Form, KDQoL-will be completed at recruitment and 18 months after enrolment for both intervention and control groups (or 90 days after transplantation, whichever is either face to face or by post. 8. The number of participants receiving a transplant during the study period from either a deceased or a living donor (with con rmation that any increase in offer rate was as a result of change in cRF as per ITOPS protocol).
9. The number of participants developing any grade neuropathy following each cycle of treatment.

Sample size {14}
As this is a small-scale feasibility study, a formal sample size calculation was not performed. Based on the expected pool of potentially eligible participants (64 patients when the protocol was written: 15 at the University Hospital of Wales in Cardiff, 23 at Southmead Hospital in Bristol and 26 at St James' Hospital in Leeds), expected rates of potential participants who are con rmed to be ineligible (20%), a sample size of 38 participants was proposed to be recruited over a 12 months period.
This will allow the trial to determine whether 50% of participants in the intervention group achieve an absolute reduction in cRF of at least 10% after 12 weeks of their last intervention as compared to cRF at enrolment, which would be a clinically important outcome. Speci cally, taking n = 19, an exact 95% con dence interval for the true proportion of participants who achieve an absolute reduction in cRF of at least 10% in intervention arm is [27%, 73%].

Recruitment {15}
All potentially eligible participants will be identi ed by pre-screening the inclusion and exclusion criteria against the active transplant waiting list at each centre. The initial approach will be by a member of the clinical team responsible for the patients' care, followed by a more detailed discussion with the trial team. The intervention will be scheduled according to the participants convenience.

Assignment Of Interventions: Allocation
Sequence generation {16a} The allocation sequence will be produced by the trial statistician using SAS statistical software. The allocation sequence will have a varying undisclosed block size and will be strati ed by site. Participants will be allocated to a 1:1 ratio to the trial intervention (rituximab, plasmapheresis, bortezomib and dexamethasone) versus control (standard care) group.

Concealment mechanism {16b}
Participants will be randomized using Sealed Envelope (www.sealedenvelope.com), which is an interactive web-based randomization service, and the allocation sequence will be uploaded into it by the trial statistician. Allocation concealment will be ensured as the list will be held securely by the statistician and within the randomization system only. The participant's screening log number and initials will need to be provided to Sealed Envelope to obtain randomization code and treatment group. The trial manager will be noti ed of new randomizations by Sealed Envelope.

Implementation {16c}
Participant allocation will be made using Sealed Envelope, which will allocate the next randomization code and treatment group in sequence at each center. The PI at each site will enroll the patient into the trial. Randomization may be done by any member of the research team.

Assignment Of Interventions: Blinding
Who will be blinded {17a} No-one within the trial is blinded to the intervention.

Procedure for unblinding if needed {17b}
Not applicable.

Data Collection And Management
Plans for assessment and collection of outcomes {18a} Plans to promote participant retention and complete follow-up {18b} As trial participants will be attending for regular dialysis retention of participants in the trial is expected to be high.

Data management {19}
Individual patient data for the ITOPS trial will be captured on an electronic Case Report Form (eCRF). Only the data required by the protocol will be captured in the eCRF. Each PI and trial site will keep a record of all participating patients with su cient information to link records, including eCRFs, hospital notes and samples, and all original signed informed consent forms.
The PI has overall responsibility for data collection at their site. Participant data will be entered electronically onto the trial database designed and administered by the NHSBT CTU data management team using MACRO-v4.4.0.6647, a commercially available FDA 21 CRF Part 11 compliant clinical trial database system produced by Elsevier. The MACRO database will have in-built validation rules and conditions, to help optimize the quality of the data. In addition, the designated H&I scientist at each site will be responsible for completion of a standardized and anonymized spreadsheet detailing the MFI of all HLA antibodies at each time point, which will be sent electronically (using password protected spreadsheet) to the NHSBT CTU at the end of the study for analysis.
The NHSBT CTU staff will be in regular contact with local site personnel to check on progress and to help with any queries that may arise. Incoming electronic forms will be checked for completeness, consistency, timelines, and compliance with the protocol.

Con dentiality {27}
All investigators and trial site staff must comply with the requirements of the UK Data Protection regulations with regards to the collection, storage, processing, and disclosure of personal information and will uphold the regulations' core principles. The con dentiality standards will be maintained by coding each patient enrolled in the trial through assignment of a unique patient identi cation number.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Several recent studies have demonstrated that the cytokine pro le, lymphocyte immunophenotype or detailed antibody characteristics of an individual may be predictive of response to desensitization and subsequent outcome (32-37). There will therefore be a parallel collection of clinical samples for mechanistic studies, at time points from randomization until one year following the nal intervention. These will include blood samples and the plasmapheresis e uent obtained from the rst exchange of each cycle. A separate funding application will be made for the assays to be performed. Any results from the parallel studies will be correlated with clinical outcomes, with the aim of increasing understanding of the response of HLA sensitized patients to proteasome inhibition, enabling future risk strati cation and prediction of those more likely to respond to this intervention.
These samples will be stored locally for the duration of the study, before shipping to Cardiff, or the center performing the speci c assays of interest. In the longer term, any remaining samples will be shipped and stored in the Wales Kidney Research Tissue Bank in the Institute of Nephrology, University Hospital of Wales, Cardiff University, Cardiff. The necessary HTA approvals are in place for sample storage.
Analyses of these will form a separate future study and will not in uence decision making in the current trial. Participation in this sub-trial is optional and speci c consent will be sought. Participants who decline will remain eligible for inclusion in the ITOPS trial.

Statistical methods for primary and secondary outcomes {20a}
Full details of the statistical analyses will be speci ed in the Statistical Analysis Plan. This section summarizes the main points.
The analysis will be performed on intention to treat basis and will include all randomized participants on whom values of a response variable have been obtained. The data will be analyzed according to the treatment arm to which the participant was randomized.
Participants who did not meet all the inclusion criteria and/or met at least one of the exclusion criteria will be considered as randomized in error. Participants who were randomized to the intervention group but did not receive any trial treatment and participants who were randomized to the control group but received the trial treatment will be considered as protocol deviations. Participants randomized in error and participants where the protocol was not followed as speci ed will also be considered as protocol deviations. Participants randomized in error, participants with protocol deviation, and those withdrawn will be included in intention to treat analysis.
As this is a small-scale feasibility trial and all centers will follow the same protocol, no adjustment will be made for any center differences. Equally this trial has not been powered to detect differences between arms of the trial. Hence no statistical testing will be performed.

Analysis of Primary and Secondary outcomes
The proportion (and exact Binomial 95% con dence interval) of participants achieving an absolute reduction in cRF of at least 10% at 12 weeks following their last intervention or on routine monitoring, as compared to cRF at enrolment. This will be calculated for each trial arm and overall. We will consider this study feasible and worthy of further development into a larger randomized trial if the point estimate for achieving a 10% reduction is ≥ 50% in the intervention arm. If the estimate is < 50% in the intervention arm but 50% is included within the 95% con dence interval, then consideration to proceed to a larger randomized trial will be given alongside other aspects of feasibility.
Recruitment and dropout rates will be presented by center. Serious infectious episodes and serious adverse events will be summarized. The number of participants in the intervention group developing any grade neuropathy following each cycle of treatment will be reported.
The method used for the analysis of the proportion of participants achieving an absolute reduction in cRF of at least 10% at 24 weeks and at 48 weeks following their last intervention or on routine monitoring, as compared to cRF at enrolment, will be similar to that described for the primary outcome. As compared to cRF at enrolment, mean change in cRF at 12, 24, 36and 48 weeks following the last treatment in intervention group or on routine monitoring in control group will be presented with the standard deviation. The difference in mean change between arms will be presented for 12, 24, 36 and 48 weeks separately, along with a 95% con dence interval.
The number, proportion and exact Binomial 95% con dence interval will be presented for participants receiving transplant and for those participants in the intervention group with B cell depletion at 12 weeks after completing the rst cycle of treatment. Quality of Life will be assessed using EQ-5D-5L and KDQoL-SF questionnaires. The proportional change from enrolment in Quality of Life at 18 months following enrolment (or 90 days after transplantation, whichever is earlier) will be calculated for each participant and from which the median and interquartile range will be presented.

Other analyses
The analysis with MFI cut off point of 2000 will be the primary analysis. However, this is a relatively stringent cut-off, and if any change in cRF is relatively modest the analysis will be rerun using an MFI cut off value of 3000. This data will be available as part of the luminex SAB measurement performed throughout the trial. This secondary analysis will be for exploratory purposes only and it will not in uence the conclusions of the trial.

Interim analyses {21b}
No interim analyses are planned.

Methods for additional analyses (e.g. subgroup analyses) {20b}
No subgroup analyses are planned.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Please see 20a and further details to be speci ed in the statistical analysis plan. All missing data will be assumed to be missing at random and missing data will not be imputed.
Plans to give access to the full protocol, participant level-data and statistical code {31c} The Trial Steering Committee (TSC), which has representation from all participating sites, will have access to the nal trial dataset. Custody of the nal data set will reside with the CI and NHSBT CTU (for audit purposes). Access to the nal data set for additional analyses will be permitted under the agreement of the TSC, and according to the trial publication policy.

Oversight And Monitoring
Composition of the coordinating centre and trial steering committee 5d The Trial Management Group (TMG) has been set up by the CI and will include the lead investigators from the other participating sites (Bristol and Leeds), members of the NHSBT CTU (trial manager, operations manager, data manager and statistician) and the Sponsor representative. The TMG convenes regularly, either face-to-face or by teleconference to discuss recruitment and other practical aspects of the trial. The day-to-day management of the trial is coordinated through the NHSBT CTU and the CI.
A TSC with an independent Chair, statistician, clinician, and patient representatives and will be responsible for overseeing the progress of the trial. The TSC will convene biannually either in person or by teleconference. The TSC will focus on progress of the trial, patient safety, and the consideration of new information relevant to the research question. The TSC will provide advice, through its Chair, to the CI, the Trial Sponsor, the Trial funder, and the Host Institution. The ultimate decision on continuation of the trial lies with the TSC. The TSC Charter includes details of membership as well as roles and responsibilities of the committees' members.
Composition of the data monitoring committee, its role and reporting structure {21a} The NHSBT CTU has a core Independent Data Monitoring Committee (DMC) for its transplantation-related trials. The group will act as DMC to this trial, with the primary role of overseeing safety int the trial. They will periodically review trial data by arm and overall, to determine patterns and trend of events, or to identify safety issues. They will provide recommendations to the Chair of the TSC on whether the trial should continue and can recommend premature closure of the trial. The DMC Charter includes details of membership as well as roles and responsibilities of the committees' members.    Events which do not require reporting as an SAE The following events will not be considered as SAEs and therefore will not need expedited reporting: Hospitalization for routine treatment or monitoring, or general care, not associated with any deterioration in condition, Hospitalization due to any elective surgical procedure that was planned and scheduled prior to trial entry, Hospitalization, either elective or emergency, related to vascular access (excluding complications relating to vascath insertion, which will constitute a SAE), Any change of condition or other follow-up information should be updated within the electronic SAE Form in the ITOPS database as soon as it is available or at least within 24 hours of the information becoming available. Events will be followed up until the event has resolved or a nal outcome has been reached.
All SAEs assigned by the PI or delegate (or following central review) as both suspected to be related to IMP-treatment and unexpected will be classi ed as SUSARs and will be subject to expedited reporting to the Medicines and Healthcare Products Regulatory Agency (MHRA). The NHBT CTU will inform the Sponsor, the MHRA, and the Research Ethics Committee (REC) of SUSARs within the required expedited reporting timelines.

Frequency and plans for auditing trial conduct {23}
The Trial Monitoring Plan has been developed and agreed by the Trial Management Group (TMG), TSC and CI based on the trial risk assessment.
Monitoring procedures, including regular visits to the trial sites, will be carried out by a trial monitor centrally and at sites (at least twice a year excluding initiation and close out visits) and are detailed in the trial speci c monitoring plan.
A risk assessment has been conducted which acknowledges the potential risks to the trial. This section provides an overview of the Quality Assurance (QA) and Quality Control (QC) measures that have been put in place to ensure the trial is performed and data generated and recorded in accordance with the principles of ICH GCP.
The NHSBT CTU data managers will review all data received for errors and missing data points.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} The Trial Management Group will consider protocol amendments, decide with the NHSBT CTU whether this is nonsubstantial or substantial, and communicate this to the sponsor. If the sponsor wishes to make a substantial amendment to the Clinical Trial Authorisation (CTA) or the documents that supported the original application for the CTA, the sponsor will submit a valid notice of amendment to the licensing authority (MHRA) for consideration. If the sponsor wishes to make a substantial amendment to the REC application or supporting documents, the sponsor will submit a valid notice of amendment to the REC for consideration. The MHRA and/or the REC will provide a response regarding the amendment within 35 days of receipt of the notice. Amendments will also be noti ed to the Health and Care Research Wales Permissions Service and communicated to the participating organisations (Research and Development o ce and local research team), and departments of participating sites.

Dissemination Plans {31a}
Within one year of the end of the trial, the CI will submit a nal report with the results, including any publications or abstracts, to the REC. The report will include analysis and tabulation of the data.
The nal report's abstract and reference will be accessible on the NHSBT CTU website.
Participants who indicated their interest to know the outcome will be informed by sending them a copy of the trial ndings by post through their local investigators. In addition, results will be presented at national meetings and submitted for publication in specialty journals.
Reporting will according to CONSORT recommendations. Publication of the results will be based on outcomes at 12 months following the last recruited patient. No interim publication of results is planned.
The CI and TSC will approve any publications arising from this trial, including those proposed by participating investigators.
No data may be made public before publication and never without agreement from the CI and Sponsor.

Discussion
The policy for deceased donor kidney allocation in the UK changed in September 2019. The new offering scheme was introduced to re ect the changing donor pool and to address some of the inequities observed in the previous scheme (introduced in 2006). Of particular relevance to the ITOPS study, the 2019 scheme gives preferential offering to patients with a matchability score of 10, a cRF of 100% or an accrued waiting time of at least 7 years. If a recipient meeting these criteria (tier A) is not identi ed, the allocation algorithm then considers all other potential recipients (tier B). Kidneys in tier B are allocated according to a points-based system, including matchability. As a consequence, patients previously considered for enrolment in ITOPS are now much more likely to receive an offer through the national scheme compared to the 2006 scheme in place when the trial was conceived and opened to recruitment.
The DMC met in March to consider the impact of both the Covid 19 pandemic on the safety of continuing recruitment and the new allocation scheme. They recommended that recruitment be halted, but data collection from existing participants continue. The TSC reviewed and agreed to proceed with the recommendation.

Trial Status
The trial opened on 24/9/18 and the rst patient was recruited on 7/12/18. Recruitment was halted on the recommendation of the DMC on 20/3/20.