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

Improving Transplant Opportunities for Patients who are Sensitized (ITOPS): Protocol for a Feasibility, Randomized, Controlled, Phase III Clinical Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study Protocol Improving Transplant Opportunities for Patients who are Sensitized (ITOPS): Protocol for a Feasibility, Randomized, Controlled, Phase III Clinical Trial Sian Griffin, Tracey Rees, Samaher Sweity, Helen Williams, Laura Pankhurst, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-122212/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract • 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 specificity of human leucocyte antigen (HLA) specific antibodies. This is because the presence of pre-formed HLA Donor Specific 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 efficacy 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 definitive 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). • Discussion: The primary outcome is the proportion of patients achieving an absolute reduction in sensitization (calculated reaction frequency, cRF) of at least 10% at 12 weeks following their last intervention, compared to the control group. Secondary outcomes include recruitment and transplantation rates, durability of change and absolute percentage change in cRF, and acceptability of the intervention. We will proceed to development of a larger trial if at least 50% of the participants in the intervention arm achieve an absolute reduction in cRF of a minimum of 10% at 12 weeks following their last intervention. If the proportion is <50% in the intervention arm but 50% is included within the 95% confidence interval, then consideration to proceed to a larger randomized trial will be given alongside other aspects of feasibility. • Trial Registration: International Standard Randomized Controlled Trial Number ISRCTN66441193 https://doi.org/10.1186/ISRCTN66441193 Hepatobiliary & Transplant Surgery Health Economics & Outcomes Research Kidney transplant HLA antibodies Highly Sensitised Rituximab Bortezomib Plasmapheresis Figures Figure 1 Introduction 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) specific 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 Specific Antibodies are heterogeneous ( 3 – 8 ). The Luminex Single Antigen Bead assay allows semi-quantification of antibody concentration (expressed as Mean Fluorescence Intensity, MFI) and serial monitoring of antibodies of individual HLA specificities. An MFI < 2000 is generally associated with a negative flow cytometric cross match and is a safe threshold for transplantation. Highly Sensitized (HS) patients (those with a calculated Reaction Frequency (cRF) ≥ 85%) are difficult 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 1 Sensitized patients on the UK renal transplant waiting list, 31/12/16. Number of patients Median Age (years) Female (%) Median waiting time to transplant* (days) cRF < 85% • 74% of waiting list 3851 54 35 843 85 ≤ cRF < 94% • 6% of waiting list 289 51 67 1331 cRF ≥ 95% • 20% of waiting list 1049 49 56 2074 *Adult patients joining the UK kidney transplant waiting list from 1/4/09–31/3/14. To define those participants most likely to benefit from a reduction in cRF (in terms of subsequent likelihood of receiving the offer of a transplant), we data from the UK Transplant Registry (UKTR), held National Health Service Blood and Transplant (NHSBT), to analyze transplants performed in the United Kingdom (UK) between 01/01/2012 and 31/12/2015 by waiting time and sensitization (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. Table 2 Chance of a deceased donor transplant in the following year, stratified by waiting time and sensitization, including patients in the waiting list between 01/01/2012 and 31/12/2015. Deceased Donor cRF Waiting time Chance of a transplant in the next year ≥ 95% 3 years 9% 90–94% 9% 85–89% 11% 80–84% 21% ≥ 95% 5 years 9% 90–94% 19% 85–89% 26% 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 confirmed the impact of reduction in cRF (Table 3 ). Table 3 Chance of a match in the UK Living Kidney Sharing Scheme by sensitization. UK Living Kidney Sharing Scheme cRF Chance of a transplant 100% 4% 95–99% 21% 85–94% 42% 10–84% 47% 0–9% 37% 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 five 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 modification of HLA antibody profile prior to transplantation, referred to as desensitization. Desensitization strategies have used combinations of antibody removal by plasma exchange or immunoadsorption, antibody modulation by intravenous immunoglobulin (IVIg), depletion of B cells by CD20 blockade (by rituximab) and targeting plasma cells by proteasome inhibition (bortezomib and more recently carfilzomib) ( 10 – 14 ) ( 15 – 20 ). The Cedars-Sinai group has the greatest experience of transplanting patients following desensitization with protocols using Rituximab and IVIg ( 11 , 13 , 14 , 21 ). However, the suppression of HLA antibodies using this approach is relatively short lived, and rates of antibody mediated rejection following transplantation are relatively high ( 10 , 22 – 25 ). As might be expected, treatment with Rituximab and IVIg has no effect on splenic memory B cells and plasma cells ( 26 ). Bortezomib has been used both to treat antibody mediated rejection ( 27 – 30 ), and as part of a desensitization regimen to lower HLA antibody levels prior to transplantation ( 15 , 17 – 19 , 27 , 31 , 32 ). 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 post-transplant outcomes ( 17 – 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 efficacy 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 efficacy 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: To confirm that the expected number of patients can be recruited in the time frame of the trial. To confirm that the intervention is sufficient to result in a durable fall in cRF. To confirm that B cell depletion persists at 12 weeks following intervention. To determine whether the intervention impacts on Quality of Life. To confirm whether any transplants arise as a consequence of the intervention. To confirm 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. Methods: Participants, Interventions And Outcomes Study setting {9} The study will be conducted in the renal departments of three UK transplant centres: University Hospital of Wales, Cardiff (Cardiff and Vale University Health Board); St James’s Hospital, Leeds (Leeds Teaching Hospital NHS Trust) and Southmead Hospital, Bristol (North Bristol NHS Trust). 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 : Male or female, aged 18 years or older. Able to give informed consent and willing to fulfil trial requirements. Have completed the necessary assessments to receive a renal transplant. In stable health as determined by the Investigator based on medical history and laboratory tests during the screening period. Negative serological test for hepatitis B (surface antigen and core antibody) and hepatitis C within the last 6 months, and Human Immunodeficiency Virus (HIV) within the last 12 months. Documented immune status to varicella zoster virus (VZV) (at any time). 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. Persistent (for at least one year) and stable (tested on at least three occasions over the preceding 18 months) circulating HLA antibodies defined by Luminex Single Antigen Bead analysis at the time of recruitment. Recipients awaiting deceased donor transplantation: cRF ≥ 85% and at least 3 years on the transplant waiting list. Recipients with an HLA incompatible living donor who have been considered for enrolment in the UK Living Kidney Sharing Scheme: cRF is ≥ 95% or, cRF is ≥ 85% and they have received no offers after three runs in the UKLKSS. Exclusion criteria : Pregnancy, planned pregnancy during the trial period, or current breast feeding. Active viral, bacterial or fungal infection precluding immunosuppression. Active malignant disease. Patients listed for transplantation of any organ other than kidney alone. History of, or active, clinically significant, respiratory, gastrointestinal (including pancreatitis), hepatic, cardiac, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other disorder that, in the Investigator’s opinion, could affect the conduct of the trial. History of non-adherence, alcohol or substance abuse that, in the judgment of the Investigator, may impair or risk the subject’s full participation in the trial. Positive serological test for hepatitis B, C or HIV. Negative serological test for VZV. Previous graft loss to recurrent primary disease within 2 years of transplantation. Documented intolerance of bortezomib, rituximab or their excipients, or dexamethasone. Persistent thrombocytopaenia, platelet count < 100 × 10 9 /L for the past three consecutive months. Persistent neutropaenia, absolute neutrophil count < 2 × 10 9 /L for the past three consecutive months. Hypogammaglobulinaemia, serum immunoglobulin G (IgG) less than local laboratory lower limit of normal at screening. Peripheral neuropathy of any grade (reported by symptoms or on clinical examination). Currently involved in any other clinical trial of an investigational medicinal product (IMP) or have taken an IMP within 30 days prior to trial entry except the SIMPLIFIED trial (ISRCTN15087616 https://doi.org/10.1186/ISRCTN15087616 . Natural vitamin D (cholecalciferol) versus standard care in patients receiving dialysis). 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, specific, 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. Days 21, 24, 28, 31: Plasmapheresis (1.5 plasma volumes) followed by bortezomib 1.3 mg/m2 subcutaneously and dexamethasone 20 mg orally. If the fall in cRF is less than 10% 12 weeks after the first 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 modified 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: First line agent – cotrimoxazole- dose as per local practice Prophylaxis against herpes simplex infection for three weeks beginning with the first dose of bortezomib for each cycle of the treatment: First line agent – acyclovir, 200 mg daily Regular prescriptions including anti-hypertensive drugs, phosphate binders, vitamin D and erythropoiesis stimulating agents should continue. 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 non-negligent 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 classified as positive. HLA Cw, DP and DQ antibodies will be classified 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 : The proportion of eligible participants who consent to the trial. Confirmation that at 12 weeks post-final 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. 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. Compared to cRF at enrolment, the percentage decrease in cRF at 12, 24, 36 and 48 weeks following final treatment in intervention group or on routine monitoring. The percentage of participants in the intervention group with B cell depletion at 12 weeks after the first cycle of B cell depletion is defined 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. 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. The number of participants receiving a transplant during the study period from either a deceased or a living donor (with confirmation that any increase in offer rate was as a result of change in cRF as per ITOPS protocol). The number of participants developing any grade neuropathy following each cycle of treatment. Participant timeline {13} Figure 1 . Participant timeline. 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 confirmed 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. Specifically, taking n = 19, an exact 95% confidence 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 identified 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 stratified 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 notified 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 sufficient 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. Confidentiality {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 confidentiality standards will be maintained by coding each patient enrolled in the trial through assignment of a unique patient identification 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 profile, 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 final intervention. These will include blood samples and the plasmapheresis effluent obtained from the first 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 stratification 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 specific 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 influence decision making in the current trial. Participation in this sub-trial is optional and specific consent will be sought. Participants who decline will remain eligible for inclusion in the ITOPS trial. Statistical Methods Statistical methods for primary and secondary outcomes {20a} Full details of the statistical analyses will be specified 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 specified 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% confidence 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% confidence 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% confidence interval. The number, proportion and exact Binomial 95% confidence 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 first 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 influence 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 specified 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 final trial dataset. Custody of the final data set will reside with the CI and NHSBT CTU (for audit purposes). Access to the final 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. Table 4. Schedule of study events Table 4a. Treatment period schedule 1 TIMEPOINT Pre-screening Baseline 1 Treatment (D = day, Wk=Week, V=visit) V1 V2 1 V3 2 V4 V5 V6 D0 D21 3 D24 4 D28 4 D31 4 Confirmation of Sensitization and Waiting Time on Transplant List X Informed Consent 5 X History and physical examination/ Concomitant medication X X X X X X Eligibility Screening with review of SOC tests: FBC, clotting screen, bone profile, LFTs, magnesium, HBV (HBsAg is SOC, HBcAb is not (and required before treatment with rituximab), HCV, HIV, and VZV X X Serum pregnancy test X 6 ECG, Total immunoglobulins (IgG) and B cell count (for IG only) (all not SOC) X EQ-5D 7 and KDQoL-SF 8 questionnaires X FACT/GOG-Ntx4 9 questionnaire X X 10 Randomization X Interventions Administration of Rituximab X Plasmapheresis followed by bortezomib with dexamethasone X X X X FBC, clotting screen, bone profile (before each treatment) X X X X 1 - Visit 2 – If not within 4 weeks of visit 1, blood and pregnancy tests (if applicable) to be repeated.2 - Insertion of vascath if required. 3 –This visit can be performed between 21 to 28 days post rituximab administration (i.e. day 0). Please adjust the subsequent visits accordingly if this visit has occurred between day 22-28 as per trial schedule. 4- Treatment given on days 24, 28 and 31 can be given within +3 days if required, and same applies if a second cycle is needed. 6 - If V1 delayed beyond 4 weeks, pregnancy test to be repeated (if applicable). 7 - EQ-5D - European Quality of Life - 5 Dimensions. 8 - KDQOL-SF- Kidney Disease Quality of Life Short Form. 9 - FACT/GOG-Ntx4- Functional Assessment of Cancer Therapy/Gynaecologic Oncology Group/Neurotoxicity. 10 - FACT/GOG-Ntx4 questionnaire to be completed at the end of cycle 1 (and end of cycle 2 if applicable) for the IG only. 5- Informed consent before any trial related activities. Non SOC tests can be done on V1 after consent. If required another visit/s can be scheduled to perform and/or review these. Table 4b. Treatment period schedule 2 TIMEPOINT Pre-screening Baseline Treatment (D = day, Wk=Week, V=visit) +/- 3 days for visits 7 - 10, other subsequent visits +/- one Wk Treatment Post Treatment 1 V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 D0 D21 D24 D28 D31 Wk 1 Wk 2 Wk 3 Wk 4 Wk 8 Wk 12 2 Concomitant medication X X X X X X X X X X X X Total immunoglobulins (IgG) and B cell count X 3 Assessment of HLA Antibodies And cRF Intervention Group (IG) X 4 X X X X X Control Group (CG) X 4 X X Sub-Study SAMPLES 5 Blood Samples for IG X X 6 X 6 X 6 X 6 X X X X X X First bag (or 100ml) of PEx 7 fluid for IG X 8 Blood Samples for CG X X AE Assessment (see Section 9) 9 X X X X X X X X X X X X 1- Number of week(s) post treatment (i.e. post day 31) for intervention group and post randomization (i.e. post visit 1) for control group. 2- Assessment at 12 weeks to determine whether a second cycle is needed. If no– monitoring every 4 weeks to one year. If yes– return to day 21 (V3) with same monitoring schedule thereafter. 3- Total immunoglobulins and B cell count are required only for the IG. B cell count is not required to determine eligibility. 4- Standard of Care (SOC) tests 5- Please refer to the sub-study Lab Manual for details 6- A blood sample before and after each plasmapheresis 7- PEx- Plasma Exchange 8- To be obtained again if a second cycle is needed 9- AEs of special interest will be collected from consent and ARs from the first dose of IMP administration until 28 days after the last intervention, and for similar duration and time-points for participants in the control group (can be conducted by phone if participants have no clinic visits). SAEs to be collected from consent until 18-month follow-up visit for both groups. Table 4b. Follow-up period schedule TIMEPOINT Follow-Up post treatment for Intervention Group, and post randomization for Control Group +/- one Wk (Wk=week) for samples and visits at each time-point. V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 (End of Study) Wk 16 Wk 20 Wk 24 Wk 28 Wk 32 Wk 36 Wk 40 Wk 44 Wk 48 18 month Concomitant medication X X X X X X X X X Total immunoglobulins (IgG) (IG only) X X X EQ-5D, KDQoL-SF and FACT/GOG-Ntx4 questionnaires X Assessment of HLA Antibodies And cRF Intervention Group (IG) X X X X X X X X X Control Group (CG) X X X Sub-Study SAMPLES Blood Samples for IG X X X Blood Samples for CG X X X AE Assessment (see Section 9) 9 X X X X X X X X X X 9- AEs of special interest will be collected from consent and ARs from the first dose of IMP administration until 28 days after the last intervention, and for similar duration and time-points for participants in the control group (can be conducted by phone if participants have no clinic visits). SAEs to be collected from consent until 18-month follow-up visit for both groups. Adverse event reporting and harms {22} Adverse events (AEs) of special interest (outlined in Table 5 ) will be collected from the time of consent until 28 days after the last intervention, and for a similar duration for participants in the control group. Adverse reactions (ARs) will be collected from the first dose of IMP administration and continue to be collected until 28 days after the last intervention, and for a similar duration for participants in the control group. Those AEs/ARs meeting the definition of a Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) will also be reported to the NHSBT CTU within 24 hours of observing or learning of the event using the trial specific electronic SAE Form. Table 5 Adverse events of special interest Adverse event Grade 1 2 3 4 Haemoglobin (g/L) <LLN to 100 80–100 < 80 Life threatening consequences, urgent intervention indicated Neutrophils (X 10 9 /L) <LLN to 1.5 1.0–1.5 0.5–1.0 < 0.5 Platelets (X 10 9 /L) <LLN to 75 50–75 25–50 < 25 Nausea Loss of appetite without alteration in eating habits Oral intake decreased without significant weight loss; dehydration or malnutrition Inadequate oral caloric or fluid intake; iv fluids, NG feeding or TPN indicated Vomiting One or two episodes (separated by 5 minutes) in 24 hours 3–5 episodes (separated by 5 minutes) in 24 hours > 6 episodes (separated by 5 minutes) in 24 hours; iv fluids or TPN indicated Life threatening consequences; urgent intervention indicated Diarrhoea Increase of 7 stools per day over baseline; incontinence; limiting self-care activities of daily living (ADL) Life-threatening consequences; urgent intervention indicated Peripheral motor neuropathy Asymptomatic, clinical or diagnostic observations only, intervention not indicated Moderate symptoms, limiting instrumental ADL Severe symptoms, limiting self-care ADL, assistive device indicated Life threatening consequences, urgent intervention indicated Peripheral sensory neuropathy Asymptomatic, loss of deep tendon reflexes or paraesthesia Moderate symptoms, limiting instrumental ADL Severe symptoms, limiting self-care ADL Life threatening consequences, urgent intervention indicated Infection Asymptomatic or requiring local intervention (depending on site) Requiring local or oral treatment (depending on site) Requiring parenteral treatment Life-threatening Abbreviations: ADL, activities of daily living; iv, intravenous; LLN, lower limit normal; TPN, total parenteral nutrition Instrumental ADLs include meal preparation, shopping, using the telephone, managing money. Self-care ADLs include bathing, dressing, using the toilet, taking medication. 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), Transplantation, Events occurring at the time of dialysis and judged to be related to the dialysis. For each SAE/SAR and Suspected Unexpected Serious Adverse Event (SUSAR) the following information will be collected: Full details in medical terms and case description Event duration (start and end dates, if applicable) Action taken Outcome Seriousness criteria Causality Expectedness (Expectedness assessment will only be undertaken if an event is deemed to be related) 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 final 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 classified 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 specific 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 non-substantial 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 notified to the Health and Care Research Wales Permissions Service and communicated to the participating organisations (Research and Development office 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 final report with the results, including any publications or abstracts, to the REC. The report will include analysis and tabulation of the data. The final 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 findings 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 reflect 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 identified, 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 first patient was recruited on 7/12/18. Recruitment was halted on the recommendation of the DMC on 20/3/20. Abbreviations ADL Activities of Daily Living AEs Adverse events ARs Adverse reactions CG Control Group cRF Calculated Reaction Frequency CTA Clinical Trials Authorisation CTU Clinical Trials Unit DMC Data Monitoring Committee DSA Donor Specific Antibody cRF Calculated Reaction Frequency eCRF electronic Case Record Form EQ-5D European Quality of Life-5 Dimensions FACT/GOG-Ntx Functional Assessment of Cancer Therapy/Gynecologic Oncology Group/Neurotoxicity FBC Full Blood Count ICH GCP International Conference on Harmonization Good Clinical Practice H&I Histocompatibility and Immunogenetics HBV Hepatitis B virus HCV Hepatitis C virus HIV Human Immunodeficiency Virus HLA Human Leucocyte Antigen HR Hazard Ratio HS Highly Sensitized HSP Highly Sensitized Patient IgG Immunoglobulin G IG Intervention Group IMP Investigational Medicinal Product ISF Investigator Site File ISRCTN International standard randomised controlled trial number IVIg Intravenous Immunoglobulin KDQOL-SF Kidney Disease Quality of Life Short Form LFTs Liver Function Tests MHRA Medicines and Healthcare Products Agency MFI Mean Fluorescence Intensity NHS National Health Service NHSBT NHS Blood and Transplant PEx Plasma Exchange PI Principal Investigator QA Quality Assurance QC Quality Control REC Research and Ethics Committee SAE Serious Adverse Event SAR Serious Adverse Reaction SOC Standard of Care SUSAR Suspected Unexpected Serious Adverse Reaction TMG Trial Management Group TSC Trial Steering Committee UK United Kingdom UKLKSS UK Living Kidney Sharing Scheme UKTR UK Transplant Registry VZV Varicella Zoster Virus Declarations Acknowledgements All patients who participated in the study. Data manager: Rupa Sharma Alison Deary, Head of Operations, NHSBT Additional statistical advice: Matthew Robb, Cara Hudson, Dianne Bautista Additional H&I advice: Frances Edwards (Cardiff), Amy De’Ath (Cardiff), Surinder Day (Bristol) Lead research nurses: Maria Coleman (Cardiff), Amanda Scott (Bristol), Sadie Smith (Leeds) Sponsor guidance: Maureen Edgar (Cardiff) Pharmacist advice: Dr Kathryn Murray (Cardiff) Authors’ contributions {31b} SVG, RR, SD, TR, BC, DC and HW contributed to the trial design. SVG, RR, SD, TR and HW contributed to the funding acquisition. SVG, RR, SD, TR, LP, HW and SS contributed to the trial steering. SVG, RR, SD, TR, BC, and SS contributed to the data collection. SVG, RR, DI, SD, TR, SS and LP contributed to the drafting of the manuscript. SVG, RR, SD, TR, SS and LP contributed to the critical review of the manuscript. All authors read and approved the final manuscript. Funding {4} The ITOPS study is funded by a grant from the Garfield Weston Foundation to Kidney Research UK. Availability of data and materials {29} Custody of the final data set will reside with the CI and NHSBT CTU. Access to the final data set for analyses will be permitted by agreement of the TSC. Ethics approval and consent to participate {24} Ethical approval for the study was provided by the Wales REC 1, reference number 17/WA/0313. Written, informed consent to participate will be obtained from all participants. Consent for publication {32} Informed consent forms are available from the corresponding author on request. Competing interests {28} The Chief Investigator, Principle Investigators and all members of the trial committees declare they have no competing interests that might influence trial design, conduct or reporting. Authors ’ information (optional) SVG. Consultant Nephrologist, Cardiff and Vale University Health Board (Chief Investigator) TR. Consultant Clinical Scientist. Head of the Welsh Transplantation and Immunogenetics Laboratory SS. Clinical Trial Manager, NHSBT HW. Patient advisor LP. Senior Statistician, NHSBT BC. Consultant Clinical Scientist, Leeds Teaching Hospital NHS Trust DC. Medical Statistician. Associate Director Statistics and Clinical Studies, NHSBT ME. Research Governance Coordinator, Cardiff and Vale University Health Board KM. Clinical Trials Pharmacist CD. Clinical Operations Manager, NHSBT SD. Consultant Nephrologist, Leeds Teaching Hospital NHS Trust RR. Consultant Nephrologist, Southmead Hospital, Bristol References Montgomery RL, B.E.; King, K.E.; Kraus E.S.; Kucirka, L.M.; Locke, J.E.; Warren, D.S.; Simpkins, C.E.; Daghal, N.N.; Singer, A.L.; Zachary, A.A.; Segev, D.L. Desensitisation in HLA incompatible kidney recipients and survival. New England Journal Medicine. 2011;365:9. Higgins R, Lowe D, Daga S, Hathaway M, Williams C, Lam FT, et al. 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Leeds","correspondingAuthor":false,"prefix":"","firstName":"Sunil","middleName":"","lastName":"Daga","suffix":""},{"id":5898454,"identity":"6b8e5ca2-ed8b-4a87-9d4e-2c7e1dbfec30","order_by":11,"name":"Rommel Ravanan","email":"","orcid":"","institution":"Southmead Hospital, Bristol","correspondingAuthor":false,"prefix":"","firstName":"Rommel","middleName":"","lastName":"Ravanan","suffix":""}],"badges":[],"createdAt":"2020-12-04 23:35:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-122212/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-122212/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":4212101,"identity":"1725878d-9535-4fbf-94ea-fa5fd212606b","added_by":"auto","created_at":"2020-12-12 00:07:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":179905,"visible":true,"origin":"","legend":"Participant timeline.","description":"","filename":"Onlinefloatimage1.Png","url":"https://assets-eu.researchsquare.com/files/rs-122212/v1/49cf4025b26e8ef97a951eb7.Png"},{"id":13631586,"identity":"1e3856ec-fd18-40a2-9642-e107b0d08888","added_by":"auto","created_at":"2021-09-17 08:17:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1366420,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-122212/v1/2f95e5ad-2429-4f98-bc1e-acf66cf0ba31.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eImproving Transplant Opportunities for Patients who are Sensitized (ITOPS): Protocol for a Feasibility, Randomized, Controlled, Phase III Clinical Trial\u003c/p\u003e","fulltext":[{"header":"Introduction","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eBackground and rationale {6a}\u003c/h2\u003e \u003cp\u003eDespite 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) specific antibodies(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). 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 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In terms of their risk to the graft, pre-formed HLA Donor Specific Antibodies are heterogeneous (\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The Luminex Single Antigen Bead assay allows semi-quantification of antibody concentration (expressed as Mean Fluorescence Intensity, MFI) and serial monitoring of antibodies of individual HLA specificities. An MFI\u0026thinsp;\u0026lt;\u0026thinsp;2000 is generally associated with a negative flow cytometric cross match and is a safe threshold for transplantation.\u003c/p\u003e \u003cp\u003eHighly Sensitized (HS) patients (those with a calculated Reaction Frequency (cRF)\u0026thinsp;\u0026ge;\u0026thinsp;85%) are difficult 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\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSensitized patients on the UK renal transplant waiting list, 31/12/16.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian Age\u003c/p\u003e \u003cp\u003e(years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMedian waiting time to transplant* (days)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecRF\u0026thinsp;\u0026lt;\u0026thinsp;85%\u003c/p\u003e \u003cp\u003e\u0026bull; 74% of waiting list\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3851\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e843\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e85\u0026thinsp;\u0026le;\u0026thinsp;cRF\u0026thinsp;\u0026lt;\u0026thinsp;94%\u003c/p\u003e \u003cp\u003e\u0026bull; 6% of waiting list\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1331\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecRF\u0026thinsp;\u0026ge;\u0026thinsp;95%\u003c/p\u003e \u003cp\u003e\u0026bull; 20% of waiting list\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2074\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003e*Adult patients joining the UK kidney transplant waiting list from 1/4/09\u0026ndash;31/3/14.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo define those participants most likely to benefit from a reduction in cRF (in terms of subsequent likelihood of receiving the offer of a transplant), we data from the UK Transplant Registry (UKTR), held National Health Service Blood and Transplant (NHSBT), to analyze transplants performed in the United Kingdom (UK) between 01/01/2012 and 31/12/2015 by waiting time and sensitization (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This demonstrates that for those patients who have already accrued at least 3\u0026nbsp;years waiting time, a relatively modest decrease in cRF can substantially increase the chance of being offered a transplant.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChance of a deceased donor transplant in the following year, stratified by waiting time and sensitization, including patients in the waiting list between 01/01/2012 and 31/12/2015.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDeceased Donor\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ecRF\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eWaiting time\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eChance of a transplant in the next year\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;95%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e3\u0026nbsp;years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e90\u0026ndash;94%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e85\u0026ndash;89%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e80\u0026ndash;84%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;95%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e5\u0026nbsp;years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e90\u0026ndash;94%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e85\u0026ndash;89%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFor 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\u0026thinsp;\u0026ge;\u0026thinsp;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\u0026ndash;2015, which also confirmed the impact of reduction in cRF (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChance of a match in the UK Living Kidney Sharing Scheme by sensitization.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eUK Living Kidney Sharing Scheme\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ecRF\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eChance of a transplant\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e95\u0026ndash;99%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e85\u0026ndash;94%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u0026ndash;84%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn addition to the personal, social and economic impact, long term dialysis is associated with an accumulation of related morbidity and mortality (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). UKTR data from 2018-19 suggests 10% of HS patients will die within five 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 modification of HLA antibody profile prior to transplantation, referred to as desensitization.\u003c/p\u003e \u003cp\u003eDesensitization strategies have used combinations of antibody removal by plasma exchange or immunoadsorption, antibody modulation by intravenous immunoglobulin (IVIg), depletion of B cells by CD20 blockade (by rituximab) and targeting plasma cells by proteasome inhibition (bortezomib and more recently carfilzomib) (\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) (\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The Cedars-Sinai group has the greatest experience of transplanting patients following desensitization with protocols using Rituximab and IVIg (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). However, the suppression of HLA antibodies using this approach is relatively short lived, and rates of antibody mediated rejection following transplantation are relatively high (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). As might be expected, treatment with Rituximab and IVIg has no effect on splenic memory B cells and plasma cells (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Bortezomib has been used both to treat antibody mediated rejection (\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), and as part of a desensitization regimen to lower HLA antibody levels prior to transplantation (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe 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 post-transplant outcomes (\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). 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 efficacy and durability of reduction in antibodies using a combination of desensitization treatments in a prospective controlled approach against the current standard of care (SOC).\u003c/p\u003e \u003c/div\u003e \n\u003ch2\u003eObjectives {7}\u003c/h2\u003e\n \u003cp\u003eThe primary objective is to assess the efficacy of a combination of B cell depletion and proteasome inhibition, together with antibody removal and steroids, to reduce HLA antibodies in HS patients.\u003c/p\u003e \u003cp\u003eThe secondary objectives are:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo confirm that the expected number of patients can be recruited in the time frame of the trial.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo confirm that the intervention is sufficient to result in a durable fall in cRF.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo confirm that B cell depletion persists at 12 weeks following intervention.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo determine whether the intervention impacts on Quality of Life.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo confirm whether any transplants arise as a consequence of the intervention.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo confirm incidence of peripheral neuropathy (any grade).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \n\u003ch2\u003eTrial Design {8}\u003c/h2\u003e\n \u003cp\u003eThe 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.\u003c/p\u003e "},{"header":"Methods: Participants, Interventions And Outcomes","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy setting {9}\u003c/h2\u003e\n\u003cp\u003eThe study will be conducted in the renal departments of three UK transplant centres: University Hospital of Wales, Cardiff (Cardiff and Vale University Health Board); St James\u0026rsquo;s Hospital, Leeds (Leeds Teaching Hospital NHS Trust) and Southmead Hospital, Bristol (North Bristol NHS Trust).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eEligibility criteria {10}\u003c/h2\u003e\n\u003cp\u003eHighly 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eMale or female, aged 18\u0026nbsp;years or older.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eAble to give informed consent and willing to fulfil trial requirements.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eHave completed the necessary assessments to receive a renal transplant.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eIn stable health as determined by the Investigator based on medical history and laboratory tests during the screening period.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eNegative serological test for hepatitis B (surface antigen and core antibody) and hepatitis C within the last 6 months, and Human Immunodeficiency Virus (HIV) within the last 12 months.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eDocumented immune status to varicella zoster virus (VZV) (at any time).\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eFemale 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\u0026nbsp;months post last dose of bortezomib.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePersistent (for at least one year) and stable (tested on at least three occasions over the preceding 18\u0026nbsp;months) circulating HLA antibodies defined by Luminex Single Antigen Bead analysis at the time of recruitment.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eRecipients awaiting deceased donor transplantation:\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003ecRF\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;85% and at least 3\u0026nbsp;years on the transplant waiting list.\u003c/p\u003e\n\u003cdiv class=\"ItemContent\"\u003e\n\u003cdiv id=\"Par57\" class=\"OListPara\"\u003e\n\u003cdiv class=\"OrderedList\"\u003e\n\u003cdiv class=\"ListItem\"\u003e\n\u003cdiv class=\"ItemContent\"\u003e\n\u003cdiv id=\"Par58\" class=\"OListPara\"\u003eRecipients with an HLA incompatible living donor who have been considered for enrolment in the UK Living Kidney Sharing Scheme:\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ecRF is \u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;95% or,\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ecRF is \u0026ge;\u0026thinsp;85% and they have received no offers after three runs in the UKLKSS.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003ePregnancy, planned pregnancy during the trial period, or current breast feeding.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eActive viral, bacterial or fungal infection precluding immunosuppression.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eActive malignant disease.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients listed for transplantation of any organ other than kidney alone.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eHistory of, or active, clinically significant, respiratory, gastrointestinal (including pancreatitis), hepatic, cardiac, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other disorder that, in the Investigator\u0026rsquo;s opinion, could affect the conduct of the trial.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eHistory of non-adherence, alcohol or substance abuse that, in the judgment of the Investigator, may impair or risk the subject\u0026rsquo;s full participation in the trial.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePositive serological test for hepatitis B, C or HIV.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eNegative serological test for VZV.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePrevious graft loss to recurrent primary disease within 2\u0026nbsp;years of transplantation.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eDocumented intolerance of bortezomib, rituximab or their excipients, or dexamethasone.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePersistent thrombocytopaenia, platelet count\u0026thinsp;\u0026lt;\u0026thinsp;100\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L for the past three consecutive months.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePersistent neutropaenia, absolute neutrophil count\u0026thinsp;\u0026lt;\u0026thinsp;2\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L for the past three consecutive months.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eHypogammaglobulinaemia, serum immunoglobulin G (IgG) less than local laboratory lower limit of normal at screening.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePeripheral neuropathy of any grade (reported by symptoms or on clinical examination).\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eCurrently involved in any other clinical trial of an investigational medicinal product (IMP) or have taken an IMP within 30 days prior to trial entry except the SIMPLIFIED trial (ISRCTN15087616 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/ISRCTN15087616\u003c/span\u003e\u003c/span\u003e. Natural vitamin D (cholecalciferol) versus standard care in patients receiving dialysis).\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eWho will take informed consent? {26a}\u003c/h2\u003e\n\u003cp\u003eIt 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.\u003c/p\u003e\n\u003cp\u003eAll 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/h2\u003e\n\u003cp\u003eSeparate, specific, optional consent will be sought for collection of biological samples for exploratory analyses. A separate explanatory section is included in the Patient Information Sheet.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eInterventions\u003c/h2\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eExplanation for the choice of comparators {6b}\u003c/h2\u003e\n\u003cp\u003eThere are no approved interventions for this group of patients, and the comparator is therefore current SOC, which is regular monitoring of HLA antibody levels.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eIntervention description {11a}\u003c/h2\u003e\n\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\n\u003ch2\u003eIntervention arm:\u003c/h2\u003e\n\u003cp\u003eDay 0: Rituximab intravenously as a single dose of 1\u0026nbsp;g. A reduced dose of 500\u0026nbsp;mg will be administered to participants weighing less than 50\u0026nbsp;kg.\u003c/p\u003e\n\u003cp\u003eDays 21, 24, 28, 31: Plasmapheresis (1.5 plasma volumes) followed by bortezomib 1.3\u0026nbsp;mg/m2 subcutaneously and dexamethasone 20\u0026nbsp;mg orally.\u003c/p\u003e\n\u003cp\u003eIf the fall in cRF is less than 10% 12 weeks after the first treatment cycle of plasmapheresis, bortezomib and dexamethasone, a second cycle of treatment will be offered.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/h2\u003e\n\u003cp\u003eThe dose of bortezomib may be modified based on the result of the full blood count (FBC) done prior to administration. A neutrophil count of \u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L and platelet count\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;100\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L are prerequisites for inclusion in the trial. On subsequent days of treatment, if the neutrophil count is \u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;0.5\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L and platelet count\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;30\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L, that day\u0026rsquo;s dose will be given. If the neutrophil count is \u0026lt;\u0026thinsp;0.5\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L and/or the platelet count is \u0026lt;\u0026thinsp;30\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n\u003ch2\u003eStrategies to improve adherence to interventions {11c}\u003c/h2\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n\u003ch2\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/h2\u003e\n\u003cp\u003eParacetamol (1\u0026nbsp;g, oral), chlorpheniramine (10\u0026nbsp;mg, intravenous) and hydrocortisone (100\u0026nbsp;mg, intravenous) are given prior to the infusion of rituximab.\u003c/p\u003e\n\u003cp\u003eProphylaxis against infection is required for all patients in the intervention group as per local practice.\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eProphylaxis against \u003cem\u003epneumocystis jiroveci\u003c/em\u003e pneumonia for 6 months after rituximab:\u003c/p\u003e\n\u003cdiv class=\"UnorderedList\"\u003e\n\u003cdiv class=\"ItemContent\"\u003e\n\u003cdiv id=\"Par92\" class=\"OListPara\"\u003eFirst line agent \u0026ndash; cotrimoxazole- dose as per local practice\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eProphylaxis against herpes simplex infection for three weeks beginning with the first dose of bortezomib for each cycle of the treatment:\u003c/p\u003e\n\u003cdiv class=\"UnorderedList\"\u003e\n\u003cdiv class=\"ItemContent\"\u003e\n\u003cdiv id=\"Par95\" class=\"OListPara\"\u003eFirst line agent \u0026ndash; acyclovir, 200\u0026nbsp;mg daily\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eRegular prescriptions including anti-hypertensive drugs, phosphate binders, vitamin D and erythropoiesis stimulating agents should continue.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n\u003ch2\u003eProvisions for post-trial care {30}\u003c/h2\u003e\n\u003cp\u003eOnce 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 non-negligent 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n\u003ch2\u003eOutcomes {12}\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003cp\u003eFor the purposes of calculating reaction frequency in the ITOPS trial, all HLA A, B and DR antibodies with an MFI\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2000 when tested in the local H\u0026amp;I laboratory will be classified as positive. HLA Cw, DP and DQ antibodies will be classified as positive according to local practice. HLA A, B and DR antibodies with an MFI\u0026thinsp;\u0026lt;\u0026thinsp;2000\u0026nbsp;at 12 weeks (and other time-points for the purpose of other relevant secondary outcomes) will be removed from unacceptable antigen listing.\u003c/p\u003e\n\u003cp\u003eIf 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary Outcomes\u003c/strong\u003e:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eThe proportion of eligible participants who consent to the trial.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eConfirmation that at 12 weeks post-final 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.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eCompared to cRF at enrolment, the percentage decrease in cRF at 12, 24, 36 and 48 weeks following final treatment in intervention group or on routine monitoring.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe percentage of participants in the intervention group with B cell depletion at 12 weeks after the first cycle of B cell depletion is defined 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.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatient acceptability \u0026ndash; quality of life questionnaires (European Quality of Life \u0026ndash; 5 dimensions, EQ-5D and Kidney Disease Quality of Life \u0026ndash; 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.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe number of participants receiving a transplant during the study period from either a deceased or a living donor (with confirmation that any increase in offer rate was as a result of change in cRF as per ITOPS protocol).\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe number of participants developing any grade neuropathy following each cycle of treatment.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n\u003ch2\u003eParticipant timeline {13}\u003c/h2\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Participant timeline.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n\u003ch2\u003eSample size {14}\u003c/h2\u003e\n\u003cp\u003eAs 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\u0026nbsp;at the University Hospital of Wales in Cardiff, 23\u0026nbsp;at Southmead Hospital in Bristol and 26\u0026nbsp;at St James\u0026rsquo; Hospital in Leeds), expected rates of potential participants who are confirmed to be ineligible (20%), a sample size of 38 participants was proposed to be recruited over a 12 months period.\u003c/p\u003e\n\u003cp\u003eThis 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. Specifically, taking n\u0026thinsp;=\u0026thinsp;19, an exact 95% confidence interval for the true proportion of participants who achieve an absolute reduction in cRF of at least 10% in intervention arm is [27%, 73%].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n\u003ch2\u003eRecruitment {15}\u003c/h2\u003e\n\u003cp\u003eAll potentially eligible participants will be identified 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\u0026rsquo; care, followed by a more detailed discussion with the trial team. The intervention will be scheduled according to the participants convenience.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Assignment Of Interventions: Allocation","content":"\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n\u003ch2\u003eSequence generation {16a}\u003c/h2\u003e\n\u003cp\u003eThe 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 stratified 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\n\u003ch2\u003eConcealment mechanism {16b}\u003c/h2\u003e\n\u003cp\u003eParticipants will be randomized using Sealed Envelope (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"10.1186/ISRCTN66441193\" target=\"_blank\"\u003ewww.sealedenvelope.com\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e), 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\u0026rsquo;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 notified of new randomizations by Sealed Envelope.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec26\" class=\"Section2\"\u003e\n\u003ch2\u003eImplementation {16c}\u003c/h2\u003e\n\u003cp\u003eParticipant 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eAssignment Of Interventions: Blinding\u003c/h2\u003e\n\u003cdiv id=\"Sec28\" class=\"Section2\"\u003e\n\u003ch2\u003eWho will be blinded {17a}\u003c/h2\u003e\n\u003cp\u003eNo-one within the trial is blinded to the intervention.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec29\" class=\"Section2\"\u003e\n\u003ch2\u003eProcedure for unblinding if needed {17b}\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eData Collection And Management\u003c/h2\u003e\n\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e\n\u003ch2\u003ePlans for assessment and collection of outcomes {18a}\u003c/h2\u003e\n\u003cp\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec32\" class=\"Section2\"\u003e\n\u003cp\u003eAs trial participants will be attending for regular dialysis retention of participants in the trial is expected to be high.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec33\" class=\"Section2\"\u003e\n\u003ch2\u003eData management {19}\u003c/h2\u003e\n\u003cp\u003eIndividual 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 sufficient information to link records, including eCRFs, hospital notes and samples, and all original signed informed consent forms.\u003c/p\u003e\n\u003cp\u003eThe 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\u0026nbsp;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\u0026amp;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.\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec34\" class=\"Section2\"\u003e\n\u003ch2\u003eConfidentiality {27}\u003c/h2\u003e\n\u003cp\u003eAll 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\u0026rsquo; core principles. The confidentiality standards will be maintained by coding each patient enrolled in the trial through assignment of a unique patient identification number.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeveral recent studies have demonstrated that the cytokine profile, lymphocyte immunophenotype or detailed antibody characteristics of an individual may be predictive of response to desensitization and subsequent outcome (\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e). There will therefore be a parallel collection of clinical samples for mechanistic studies, at time points from randomization until one year following the final intervention. These will include blood samples and the plasmapheresis effluent obtained from the first 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 stratification and prediction of those more likely to respond to this intervention.\u003c/p\u003e\n\u003cp\u003eThese samples will be stored locally for the duration of the study, before shipping to Cardiff, or the center performing the specific 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.\u003c/p\u003e\n\u003cp\u003eAnalyses of these will form a separate future study and will not influence decision making in the current trial. Participation in this sub-trial is optional and specific consent will be sought. Participants who decline will remain eligible for inclusion in the ITOPS trial.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eStatistical Methods\u003c/h2\u003e\n\u003cdiv id=\"Sec36\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/h2\u003e\n\u003cp\u003eFull details of the statistical analyses will be specified in the Statistical Analysis Plan. This section summarizes the main points.\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003cp\u003eParticipants 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 specified 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.\u003c/p\u003e\n\u003cp\u003eAs 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.\u003c/p\u003e\n\u003cdiv id=\"Sec37\" class=\"Section3\"\u003e\n\u003ch2\u003eAnalysis of Primary and Secondary outcomes\u003c/h2\u003e\n\u003cp\u003eThe proportion (and exact Binomial 95% confidence 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 \u0026ge;\u0026thinsp;50% in the intervention arm. If the estimate is \u0026lt;\u0026thinsp;50% in the intervention arm but 50% is included within the 95% confidence interval, then consideration to proceed to a larger randomized trial will be given alongside other aspects of feasibility.\u003c/p\u003e\n\u003cp\u003eRecruitment 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.\u003c/p\u003e\n\u003cp\u003eThe 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% confidence interval.\u003c/p\u003e\n\u003cp\u003eThe number, proportion and exact Binomial 95% confidence 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 first 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec38\" class=\"Section3\"\u003e\n\u003ch2\u003eOther analyses\u003c/h2\u003e\n\u003cp\u003eThe 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 influence the conclusions of the trial.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec39\" class=\"Section2\"\u003e\n\u003ch2\u003eInterim analyses {21b}\u003c/h2\u003e\n\u003cp\u003eNo interim analyses are planned.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec40\" class=\"Section2\"\u003e\n\u003ch2\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/h2\u003e\n\u003cp\u003eNo subgroup analyses are planned.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlease see 20a and further details to be specified in the statistical analysis plan. All missing data will be assumed to be missing at random and missing data will not be imputed.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec41\" class=\"Section2\"\u003e\n\u003ch2\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/h2\u003e\n\u003cp\u003eThe Trial Steering Committee (TSC), which has representation from all participating sites, will have access to the final trial dataset. Custody of the final data set will reside with the CI and NHSBT CTU (for audit purposes). Access to the final data set for additional analyses will be permitted under the agreement of the TSC, and according to the trial publication policy.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eOversight And Monitoring\u003c/h2\u003e\n\u003cdiv id=\"Sec43\" class=\"Section2\"\u003e\n\u003ch2\u003eComposition of the coordinating centre and trial steering committee 5d\u003c/h2\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003cp\u003eA 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\u0026rsquo; members.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec44\" class=\"Section2\"\u003e\n\u003ch2\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/h2\u003e\n\u003cp\u003eThe 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\u0026rsquo; members.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Schedule of study events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4a. Treatment period schedule\u003c/strong\u003e\u003cstrong\u003e 1\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003e\u003cstrong\u003eTIMEPOINT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003ePre-screening\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003csup\u003e1\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" width=\"36%\"\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment (D = day, Wk=Week, V=visit)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV2\u003csup\u003e1\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV3\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV5\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD0\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD21\u003c/strong\u003e\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD24\u003c/strong\u003e\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD28\u003c/strong\u003e\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD31\u003c/strong\u003e\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003e\u003cstrong\u003eConfirmation of Sensitization and Waiting Time on Transplant List\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eInformed Consent\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eHistory and physical examination/ Concomitant medication\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eEligibility Screening with review of SOC tests: FBC, clotting screen, bone profile, LFTs, magnesium, HBV (HBsAg is SOC, HBcAb is not (and required before treatment with rituximab), HCV, HIV, and VZV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eSerum pregnancy test\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e6\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eECG, Total immunoglobulins (IgG) and B cell count (for IG only) (all not SOC)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eEQ-5D\u003csup\u003e7\u003c/sup\u003e and KDQoL-SF\u003csup\u003e8 \u003c/sup\u003equestionnaires\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eFACT/GOG-Ntx4\u003csup\u003e9 \u003c/sup\u003equestionnaire\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e10\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eRandomization\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eAdministration of Rituximab\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003ePlasmapheresis followed by bortezomib with dexamethasone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"46%\"\u003e\n\u003cp\u003eFBC, clotting screen, bone profile (before each treatment)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"49%\"\u003e\n\u003cp\u003e1 - Visit 2 \u0026ndash; If not within 4 weeks of visit 1, blood and pregnancy tests (if applicable) to be repeated.2 - Insertion of vascath if required.\u003c/p\u003e\n\u003cp\u003e3 \u0026ndash;This visit can be performed between 21 to 28 days post rituximab administration (i.e. day 0). Please adjust the subsequent visits accordingly if this visit has occurred between day 22-28 as per trial schedule.\u003c/p\u003e\n\u003cp\u003e4- Treatment given on days 24, 28 and 31 can be given within +3 days if required, and same applies if a second cycle is needed.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50%\"\u003e\n\u003cp\u003e6 - If V1 delayed beyond 4 weeks, pregnancy test to be repeated (if applicable).\u003c/p\u003e\n\u003cp\u003e7 - EQ-5D - European Quality of Life - 5 Dimensions.\u003c/p\u003e\n\u003cp\u003e8 - KDQOL-SF- Kidney Disease Quality of Life Short Form.\u003c/p\u003e\n\u003cp\u003e9 - FACT/GOG-Ntx4- Functional Assessment of Cancer Therapy/Gynaecologic Oncology Group/Neurotoxicity.\u003c/p\u003e\n\u003cp\u003e10 - FACT/GOG-Ntx4 questionnaire to be completed at the end of cycle 1 (and end of cycle 2 if applicable) for the IG only.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"100%\"\u003e\n\u003cp\u003e5- Informed consent before any trial related activities. Non SOC tests can be done on V1 after consent. If required another visit/s can be scheduled to perform and/or review these.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4b. Treatment period schedule\u003c/strong\u003e\u003cstrong\u003e 2\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003e\u003cstrong\u003eTIMEPOINT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003ePre-screening\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"11\" width=\"59%\"\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(D = day, Wk=Week, V=visit) +/- 3 days for visits 7 - 10, other subsequent visits +/- one Wk\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"5\" width=\"24%\"\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"6\" width=\"35%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePost Treatment\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV2\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV3\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV5\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV7\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV8\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV9\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV10\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV11\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV12\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD0\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD21\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD24\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD28\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eD31\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 1 \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 2\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 3\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 8\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 12\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003eConcomitant medication\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003eTotal immunoglobulins (IgG) and B cell count\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e3\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment of HLA Antibodies And cRF\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003eIntervention Group (IG)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e4\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003eControl Group (CG)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e4\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003e\u003cstrong\u003eSub-Study SAMPLES\u003csup\u003e5\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003eBlood Samples for IG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e6\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e6\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e6\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e6\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003eFirst bag (or 100ml) of PEx\u003csup\u003e7\u003c/sup\u003e fluid for IG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003csup\u003e8\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003eBlood Samples for CG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"26%\"\u003e\n\u003cp\u003e\u003cstrong\u003eAE Assessment (see Section 9)\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e9\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"67%\"\u003e\n\u003cp\u003e1- Number of week(s) post treatment (i.e. post day 31) for intervention group and post randomization (i.e. post visit 1) for control group.\u003c/p\u003e\n\u003cp\u003e2- Assessment at 12 weeks to determine whether a second cycle is needed. If no\u0026ndash; monitoring every 4 weeks to one year. If yes\u0026ndash; return to day 21 (V3) with same monitoring schedule thereafter.\u003c/p\u003e\n\u003cp\u003e3- Total immunoglobulins and B cell count are required only for the IG. B cell count is not required to determine eligibility.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32%\"\u003e\n\u003cp\u003e4- Standard of Care (SOC) tests\u003c/p\u003e\n\u003cp\u003e5- Please refer to the sub-study Lab Manual for details\u003c/p\u003e\n\u003cp\u003e6- A blood sample before and after each plasmapheresis\u003c/p\u003e\n\u003cp\u003e7- PEx- Plasma Exchange\u003c/p\u003e\n\u003cp\u003e8- To be obtained again if a second cycle is needed\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"100%\"\u003e\n\u003cp\u003e9- AEs of special interest will be collected from consent and ARs from the first dose of IMP administration until 28 days after the last intervention, and for similar duration and time-points for participants in the control group (can be conducted by phone if participants have no clinic visits). SAEs to be collected from consent until 18-month follow-up visit for both groups.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4b. Follow-up period schedule\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e\u003cstrong\u003eTIMEPOINT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"11\" width=\"78%\"\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-Up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003epost treatment for Intervention Group, and post randomization for Control Group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e+/- one Wk (Wk=week) for samples and visits at each time-point.\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV13\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV14\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV15\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV16\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV17\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV18\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV19\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV20\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV21\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e\u003cstrong\u003eV22\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(End of Study)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 16\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 20\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 24\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 28\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 32\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 36\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 40\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 44\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWk 48\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e\u003cstrong\u003e18 month\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003eConcomitant medication\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003eTotal immunoglobulins (IgG) (IG only)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003eEQ-5D, KDQoL-SF and FACT/GOG-Ntx4 questionnaires\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment of HLA Antibodies And cRF\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003eIntervention Group (IG)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003eControl Group (CG)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e\u003cstrong\u003eSub-Study SAMPLES\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003eBlood Samples for IG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003eBlood Samples for CG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e\u003cstrong\u003eAE Assessment (see Section 9)\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e9\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"100%\"\u003e\n\u003cp\u003e9- AEs of special interest will be collected from consent and ARs from the first dose of IMP administration until 28 days after the last intervention, and for similar duration and time-points for participants in the control group (can be conducted by phone if participants have no clinic visits). SAEs to be collected from consent until 18-month follow-up visit for both groups.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec45\" class=\"Section2\"\u003e\n\u003ch2\u003eAdverse event reporting and harms {22}\u003c/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eAdverse events (AEs) of special interest (outlined in Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e) will be collected from the time of consent until 28 days after the last intervention, and for a similar duration for participants in the control group.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eAdverse reactions (ARs) will be collected from the first dose of IMP administration and continue to be collected until 28 days after the last intervention, and for a similar duration for participants in the control group.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThose AEs/ARs meeting the definition of a Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) will also be reported to the NHSBT CTU within 24 hours of observing or learning of the event using the trial specific electronic SAE Form.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab7\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAdverse events of special interest\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAdverse event\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eGrade\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHaemoglobin (g/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;LLN to 100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80\u0026ndash;100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLife threatening consequences, urgent intervention indicated\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNeutrophils (X 10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;LLN to 1.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0\u0026ndash;1.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u0026ndash;1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlatelets (X 10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;LLN to 75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u0026ndash;75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u0026ndash;50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;25\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNausea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLoss of appetite without alteration in eating habits\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOral intake decreased without significant weight loss; dehydration or malnutrition\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInadequate oral caloric or fluid intake; iv fluids, NG feeding or TPN indicated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVomiting\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOne or two episodes (separated by 5 minutes) in 24 hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u0026ndash;5 episodes (separated by 5 minutes) in 24 hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;6 episodes (separated by 5 minutes) in 24 hours; iv fluids or TPN indicated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLife threatening consequences; urgent intervention indicated\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiarrhoea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIncrease of \u0026lt;\u0026thinsp;4 stools per day over baseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIncrease of 4\u0026ndash;6 stools per day over baseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIncrease of \u0026gt;\u0026thinsp;7 stools per day over baseline; incontinence; limiting self-care activities of daily living (ADL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLife-threatening consequences; urgent intervention indicated\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePeripheral motor neuropathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAsymptomatic, clinical or diagnostic observations only, intervention not indicated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate symptoms, limiting instrumental ADL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere symptoms, limiting self-care ADL, assistive device indicated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLife threatening consequences, urgent intervention indicated\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePeripheral sensory neuropathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAsymptomatic, loss of deep tendon reflexes or paraesthesia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate symptoms, limiting instrumental ADL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere symptoms, limiting self-care ADL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLife threatening consequences, urgent intervention indicated\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAsymptomatic or requiring local intervention (depending on site)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRequiring local or oral treatment (depending on site)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRequiring parenteral treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLife-threatening\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: ADL, activities of daily living; iv, intravenous; LLN, lower limit normal; TPN, total parenteral nutrition\u003c/p\u003e\n\u003cp\u003eInstrumental ADLs include meal preparation, shopping, using the telephone, managing money. Self-care ADLs include bathing, dressing, using the toilet, taking medication.\u003c/p\u003e\n\u003cdiv id=\"Sec46\" class=\"Section3\"\u003e\n\u003ch2\u003eEvents which do not require reporting as an SAE\u003c/h2\u003e\n\u003cp\u003eThe following events will not be considered as SAEs and therefore will not need expedited reporting:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eHospitalization for routine treatment or monitoring, or general care, not associated with any deterioration in condition,\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eHospitalization due to any elective surgical procedure that was planned and scheduled prior to trial entry,\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eHospitalization, either elective or emergency, related to vascular access (excluding complications relating to vascath insertion, which will constitute a SAE),\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eTransplantation,\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eEvents occurring at the time of dialysis and judged to be related to the dialysis.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eFor each SAE/SAR and Suspected Unexpected Serious Adverse Event (SUSAR) the following information will be collected:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eFull details in medical terms and case description\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eEvent duration (start and end dates, if applicable)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eAction taken\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eOutcome\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eSeriousness criteria\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eCausality\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eExpectedness (Expectedness assessment will only be undertaken if an event is deemed to be related)\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAny 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 final outcome has been reached.\u003c/p\u003e\n\u003cp\u003eAll SAEs assigned by the PI or delegate (or following central review) as both suspected to be related to IMP-treatment and unexpected will be classified 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec47\" class=\"Section2\"\u003e\n\u003ch2\u003eFrequency and plans for auditing trial conduct {23}\u003c/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eThe Trial Monitoring Plan has been developed and agreed by the Trial Management Group (TMG), TSC and CI based on the trial risk assessment.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eMonitoring 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 specific monitoring plan.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eA 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.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe NHSBT CTU data managers will review all data received for errors and missing data points.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec48\" class=\"Section2\"\u003e\n\u003ch2\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/h2\u003e\n\u003cp\u003eThe Trial Management Group will consider protocol amendments, decide with the NHSBT CTU whether this is non-substantial 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 notified to the Health and Care Research Wales Permissions Service and communicated to the participating organisations (Research and Development office and local research team), and departments of participating sites.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eDissemination Plans {31a}\u003c/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eWithin one year of the end of the trial, the CI will submit a final report with the results, including any publications or abstracts, to the REC. The report will include analysis and tabulation of the data.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe final report\u0026rsquo;s abstract and reference will be accessible on the NHSBT CTU website.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eParticipants who indicated their interest to know the outcome will be informed by sending them a copy of the trial findings by post through their local investigators. In addition, results will be presented at national meetings and submitted for publication in specialty journals.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eReporting 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.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe CI and TSC will approve any publications arising from this trial, including those proposed by participating investigators.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eNo data may be made public before publication and never without agreement from the CI and Sponsor.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Discussion","content":" \u003cp\u003eThe policy for deceased donor kidney allocation in the UK changed in September 2019. The new offering scheme was introduced to reflect 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\u0026nbsp;years. If a recipient meeting these criteria (tier A) is not identified, 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.\u003c/p\u003e \u003cp\u003eThe 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.\u003c/p\u003e \n\u003ch2\u003eTrial Status\u003c/h2\u003e\n \u003cp\u003eThe trial opened on 24/9/18 and the first patient was recruited on 7/12/18. Recruitment was halted on the recommendation of the DMC on 20/3/20.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"2\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eActivities of Daily Living\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdverse reactions\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl Group\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecRF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCalculated Reaction Frequency\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCTA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClinical Trials Authorisation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCTU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClinical Trials Unit\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDMC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eData Monitoring Committee\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDonor Specific Antibody\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecRF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCalculated Reaction Frequency\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeCRF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eelectronic Case Record Form\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEQ-5D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEuropean Quality of Life-5 Dimensions\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFACT/GOG-Ntx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFunctional Assessment of Cancer Therapy/Gynecologic Oncology Group/Neurotoxicity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFull Blood Count\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICH GCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInternational Conference on Harmonization Good Clinical Practice\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH\u0026amp;I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHistocompatibility and Immunogenetics\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatitis B virus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatitis C virus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHuman Immunodeficiency Virus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHLA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHuman Leucocyte Antigen\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard Ratio\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHighly Sensitized\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHSP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHighly Sensitized Patient\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImmunoglobulin G\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntervention Group\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigational Medicinal Product\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eISF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigator Site File\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eISRCTN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInternational standard randomised controlled trial number\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVIg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntravenous Immunoglobulin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKDQOL-SF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKidney Disease Quality of Life Short Form\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLFTs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver Function Tests\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMHRA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedicines and Healthcare Products Agency\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMFI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean Fluorescence Intensity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNHS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNational Health Service\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNHSBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNHS Blood and Transplant\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePEx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlasma Exchange\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrincipal Investigator\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQuality Assurance\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQuality Control\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eREC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResearch and Ethics Committee\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSerious Adverse Event\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSerious Adverse Reaction\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStandard of Care\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSUSAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSuspected Unexpected Serious Adverse Reaction\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrial Management Group\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrial Steering Committee\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnited Kingdom\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUKLKSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUK Living Kidney Sharing Scheme\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUKTR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUK Transplant Registry\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVZV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVaricella Zoster Virus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients who participated in the study.\u003c/p\u003e\n\u003cp\u003eData manager: Rupa Sharma\u003c/p\u003e\n\u003cp\u003eAlison Deary, Head of Operations, NHSBT\u003c/p\u003e\n\u003cp\u003eAdditional statistical advice: Matthew Robb, Cara Hudson, Dianne Bautista\u003c/p\u003e\n\u003cp\u003eAdditional H\u0026amp;I advice: Frances Edwards (Cardiff), Amy De\u0026rsquo;Ath (Cardiff), Surinder Day (Bristol)\u003c/p\u003e\n\u003cp\u003eLead research nurses: Maria Coleman (Cardiff), Amanda Scott (Bristol), Sadie Smith (Leeds)\u003c/p\u003e\n\u003cp\u003eSponsor guidance: Maureen Edgar (Cardiff)\u003c/p\u003e\n\u003cp\u003ePharmacist advice: Dr Kathryn Murray (Cardiff)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSVG, RR, SD, TR, BC, DC and HW contributed to the trial design. SVG, RR, SD, TR and HW contributed to the funding acquisition. SVG, RR, SD, TR, LP, HW and SS contributed to the trial steering. SVG, RR, SD, TR, BC, and SS contributed to the data collection. SVG, RR, DI, SD, TR, SS and LP contributed to the drafting of the manuscript. SVG, RR, SD, TR, SS and LP contributed to the critical review of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ITOPS study is funded by a grant from the Garfield Weston Foundation to Kidney Research UK.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCustody of the final data set will reside with the CI and NHSBT CTU. Access to the final data set for analyses will be permitted by agreement of the TSC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for the study was provided by the Wales REC 1, reference number 17/WA/0313. Written, informed consent to participate will be obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent forms are available from the corresponding author on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Chief Investigator, Principle Investigators and all members of the trial committees declare they have no competing interests that might influence trial design, conduct or reporting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo; \u003c/strong\u003e\u003cstrong\u003einformation (optional)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSVG. Consultant Nephrologist, Cardiff and Vale University Health Board (Chief Investigator)\u003cbr /\u003eTR. Consultant Clinical Scientist. Head of the Welsh Transplantation and Immunogenetics Laboratory\u003cbr /\u003eSS. Clinical Trial Manager, NHSBT\u003cbr /\u003eHW. Patient advisor\u003cbr /\u003eLP. Senior Statistician, NHSBT\u003cbr /\u003eBC. Consultant Clinical Scientist, Leeds Teaching Hospital NHS Trust\u003cbr /\u003eDC. Medical Statistician. Associate Director Statistics and Clinical Studies, NHSBT\u003cbr /\u003eME. Research Governance Coordinator, Cardiff and Vale University Health Board\u003cbr /\u003eKM. Clinical Trials Pharmacist\u003cbr /\u003eCD. Clinical Operations Manager, NHSBT\u003cbr /\u003eSD. Consultant Nephrologist, Leeds Teaching Hospital NHS Trust\u003cbr /\u003eRR. Consultant Nephrologist, Southmead Hospital, Bristol\u003cstrong\u003e\u003cbr /\u003e\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMontgomery RL, B.E.; King, K.E.; Kraus E.S.; Kucirka, L.M.; Locke, J.E.; Warren, D.S.; Simpkins, C.E.; Daghal, N.N.; Singer, A.L.; Zachary, A.A.; Segev, D.L. Desensitisation in HLA incompatible kidney recipients and survival. New England Journal Medicine. 2011;365:9.\u003c/li\u003e\n\u003cli\u003eHiggins R, Lowe D, Daga S, Hathaway M, Williams C, Lam FT, et al. Pregnancy-induced HLA antibodies respond more vigorously after renal transplantation than antibodies induced by prior transplantation. Hum Immunol. 2015;76(8):546-52.\u003c/li\u003e\n\u003cli\u003ePatel RT, P.I. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med. 1969;280(14):735-9.\u003c/li\u003e\n\u003cli\u003ePollinger HS, Stegall MD, Gloor JM, Moore SB, Degoey SR, Ploeger NA, et al. 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Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369(13):1215-26.\u003c/li\u003e\n\u003cli\u003eManook M KL, Ahmed Z, Robb M, Johnson R, Shaw O, Kessaris N, Dorling A, Mamode, N Post-listing survival for highly sensitised patients on the UK kidney transplant waiting list: a matched cohort anaylsis. Lancet. 2017;389(10070):727-734\u003c/li\u003e\n\u003cli\u003eStegall MD, Gloor J, Winters JL, Moore SB, Degoey S. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant. 2006;6(2):346-51.\u003c/li\u003e\n\u003cli\u003eJordan SC, Vo AA, Peng A, Toyoda M, Tyan D. Intravenous gammaglobulin (IVIG): a novel approach to improve transplant rates and outcomes in highly HLA-sensitized patients. Am J Transplant. 2006;6(3):459-66.\u003c/li\u003e\n\u003cli\u003eVo AA, Wechsler EA, Wang J, Peng A, Toyoda M, Lukovsky M, et al. Analysis of subcutaneous (SQ) alemtuzumab induction therapy in highly sensitized patients desensitized with IVIG and rituximab. Am J Transplant. 2008;8(1):144-9.\u003c/li\u003e\n\u003cli\u003eVo A, Lukovsky M, Toyoda M, Wang J, Reinsmoen N, Lai CH, et al. Rituximab and intravenous immunoglobulin for desensitisation during renal transplantation\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eNew England Journal Medicine. 2008;359(3):242-251\u003c/p\u003e\n\u003col start=\"14\"\u003e\n\u003cli\u003eVo AA, Petrozzino J, Yeung K, Sinha A, Kahwaji J, Peng A, et al. Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab. Transplantation. 2013;95(6):852-8.\u003c/li\u003e\n\u003cli\u003eEjaz NS, Shields AR, Alloway RR, Sadaka B, Girnita AL, Mogilishetty G, et al. Randomized controlled pilot study of B cell-targeted induction therapy in HLA sensitized kidney transplant recipients. Am J Transplant. 2013;13(12):3142-54.\u003c/li\u003e\n\u003cli\u003eCicora F, Paz M, Mos F, Roberti J. Use of bortezomib to treat anti-HLA antibodies in renal transplant patients: a single centre experience. Transpl Immunol. 2013;29:71-10.\u003c/li\u003e\n\u003cli\u003eAubert O, Suberbielle C, Gauthe R, Francois H, Obada EN, Durrbach A. Effect of a proteasome inhibitor plus steroids on HLA antibodies in sensitized patients awaiting a renal transplant. Transplantation. 2014;97(9):946-52.\u003c/li\u003e\n\u003cli\u003eWoodle ES, Shields AR, Ejaz NS, Sadaka B, Girnita A, Walsh RC, et al. Prospective iterative trial of proteasome inhibitor-based desensitization. Am J Transplant. 2015;15(1):101-18.\u003c/li\u003e\n\u003cli\u003eJeong JC, Jambaldorj E, Kwon HY, Kim MG, Im HJ, Jeon HJ, et al. Desensitization Using Bortezomib and High-dose Immunoglobulin Increases Rate of Deceased Donor Kidney Transplantation. Medicine (Baltimore). 2016;95(5):1-10.\u003c/li\u003e\n\u003cli\u003eTremblay S, Driscoll JJ, Rike-Shields A, Hildeman DA, Alloway RR, Girnita AL, et al. A prospective, iterative, adaptive trial of carfilzomib-based desensitization. Am J Transplant. 2020;20(2):411-421.\u003c/li\u003e\n\u003cli\u003eVo AA, Choi J, Cisneros K, Reinsmoen N, Haas M, Ge S, et al. Benefits of rituximab combined with intravenous immunoglobulin for desensitization in kidney transplant recipients. Transplantation. 2014;98(3):312-9.\u003c/li\u003e\n\u003cli\u003eAlachkar N, Lonze BE, Zachary AA, Holechek MJ, Schillinger K, Cameron AM, et al. Infusion of high-dose intravenous immunoglobulin fails to lower the strength of human leukocyte antigen antibodies in highly sensitized patients. Transplantation. 2012;94(2):165-71.\u003c/li\u003e\n\u003cli\u003eMarfo K, Ling M, Bao Y, Calder B, Ye B, Hayde N, et al. Lack of effect in desensitization with intravenous immunoglobulin and rituximab in highly sensitized patients. Transplantation. 2012;94(4):345-51.\u003c/li\u003e\n\u003cli\u003eLobashevsky AL, Higgins NG, Rosner KM, Mujtaba MA, Goggins WC, Taber TE. Analysis of anti-HLA antibodies in sensitized kidney transplant candidates subjected to desensitization with intravenous immunoglobulin and rituximab. Transplantation. 2013;96(2):182-90.\u003c/li\u003e\n\u003cli\u003eMacklin PS, Morris PJ, Knight SR. A systematic review of the use of rituximab for desensitization in renal transplantation. Transplantation. 2014;98(8):794-805.\u003c/li\u003e\n\u003cli\u003eRamos EJ, Pollinger HS, Stegall MD, Gloor JM, Dogan A, Grande JP. The effect of desensitization protocols on human splenic B-cell populations in vivo. Am J Transplant. 2007;7(2):402-7.\u003c/li\u003e\n\u003cli\u003eLemy A, Toungouz M, Abramowicz D. Bortezomib: a new player in pre- and post-transplant desensitization? Nephrol Dial Transplant. 2010;25(11):3480-9.\u003c/li\u003e\n\u003cli\u003eWalsh RC, Brailey P, Girnita A, Alloway RR, Shields AR, Wall GE, et al. Early and late acute antibody-mediated rejection differ immunologically and in response to proteasome inhibition. Transplantation. 2011;91(11):1218-26.\u003c/li\u003e\n\u003cli\u003eWalsh RC, Alloway RR, Girnita AL, Woodle ES. Proteasome inhibitor-based therapy for antibody-mediated rejection. Kidney Int. 2012;81(11):1067-74.\u003c/li\u003e\n\u003cli\u003eTouzot M, Couvrat-Desvergnes G, Castagnet S, Cesbron A, Renaudin K, Cantarovich D, et al. Differential modulation of donor-specific antibodies after B-cell depleting therapies to cure chronic antibody mediated rejection. Transplantation. 2015;99(1):63-8.\u003c/li\u003e\n\u003cli\u003eBudde K, Lehner LJ. Bortezomib-based antibody reduction therapy: the first step to \"true\" desensitization? Am J Transplant. 2015;15(1):10-12.\u003c/li\u003e\n\u003cli\u003eYabu JM, Siebert JC, Maecker HT. Immune Profiles to Predict Response to Desensitization Therapy in Highly HLA-Sensitized Kidney Transplant Candidates. PLoS One. 2016;11(4):1-16.\u003c/li\u003e\n\u003cli\u003eRajakariar R, Jivanji N, Varagunam M, Rafiq M, Gupta A, Sheaff M, et al. High pre-transplant soluble CD30 levels are predictive of the grade of rejection. Am J Transplant. 2005;5(8):1922-5.\u003c/li\u003e\n\u003cli\u003eBanham G, Prezzi D, Harford S, Taylor CJ, Hamer R, Higgins R, et al. Elevated pretransplantation soluble BAFF is associated with an increased risk of acute antibody-mediated rejection. Transplantation. 2013;96(4):413-20.\u003c/li\u003e\n\u003cli\u003eKhovanova N, Daga S, Shaikhina T, Krishnan N, Jones J, Zehnder D, et al. Subclass analysis of donor HLA-specific IgG in antibody-incompatible renal transplantation reveals a significant association of IgG4 with rejection and graft failure. Transpl Int. 2015;28(12):1405-15.\u003c/li\u003e\n\u003cli\u003eSchaefer SM, Susal C, Opelz G, Dohler B, Becker LE, Klein K, et al. Pre-transplant soluble CD30 in combination with total DSA but not pre-transplant C1q-DSA predictes antibody-mediated graft loss in presensitized high-risk kidney transplant recipients. HLA. 2016;87(2):89-100.\u003c/li\u003e\n\u003cli\u003eZhang Y, Briggs D, Lowe D, Mitchell D, Daga S, Krishnan N, et al. A new data-driven model for post-transplant antibody dynamics in high risk kidney transplantation. Math Biosci. 2017;284:3-11.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pilot-and-feasibility-studies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pafs","sideBox":"Learn more about [Pilot and Feasibility Studies](http://pilotfeasibilitystudies.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/PAFS/default.aspx","title":"Pilot and Feasibility Studies","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Kidney transplant, HLA antibodies, Highly Sensitised, Rituximab, Bortezomib, Plasmapheresis","lastPublishedDoi":"10.21203/rs.3.rs-122212/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-122212/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e• \u0026nbsp;\u003cstrong\u003eBackground:\u003c/strong\u003e 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 specificity of human leucocyte antigen (HLA) specific antibodies. This is because the presence of pre-formed HLA Donor Specific 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. \u0026nbsp;This study aims to assess the efficacy 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 definitive trial. \u003c/p\u003e\u003cp\u003e•\u0026nbsp; \u003cstrong\u003eMethods:\u003c/strong\u003e 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). \u003c/p\u003e\u003cp\u003e•\u0026nbsp; \u003cstrong\u003eDiscussion:\u003c/strong\u003e The primary outcome is the proportion of patients achieving an absolute reduction in sensitization (calculated reaction frequency, cRF) of at least 10% at 12 weeks following their last intervention, compared to the control group. Secondary outcomes include recruitment and transplantation rates, durability of change and absolute percentage change in cRF, and acceptability of the intervention. We will proceed to development of a larger trial if at least 50% of the participants in the intervention arm achieve an absolute reduction in cRF of a minimum of 10% at 12 weeks following their last intervention. If the proportion is \u0026lt;50% in the intervention arm but 50% is included within the 95% confidence interval, then consideration to proceed to a larger randomized trial will be given alongside other aspects of feasibility.\u003c/p\u003e\u003cp\u003e• \u003cstrong\u003eTrial Registration: \u003c/strong\u003eInternational Standard Randomized Controlled Trial Number\u003cstrong\u003e \u003c/strong\u003eISRCTN66441193 https://doi.org/10.1186/ISRCTN66441193\t\u003c/p\u003e","manuscriptTitle":"Improving Transplant Opportunities for Patients who are Sensitized (ITOPS): Protocol for a Feasibility, Randomized, Controlled, Phase III Clinical Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-12 00:07:11","doi":"10.21203/rs.3.rs-122212/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2021-12-12T11:37:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-09-14T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"editorInvitedReview","content":"","date":"2021-08-30T22:44:59+00:00","index":0,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-08-30T00:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-01-02T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-12-13T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-12-02T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-12-02T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-12-01T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-12-01T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pilot-and-feasibility-studies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pafs","sideBox":"Learn more about [Pilot and Feasibility Studies](http://pilotfeasibilitystudies.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/PAFS/default.aspx","title":"Pilot and Feasibility Studies","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"12e1aae7-f9d2-48f5-ab2a-45fc09dadc48","owner":[],"postedDate":"December 12th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":1428738,"name":"Hepatobiliary \u0026 Transplant Surgery"},{"id":1428739,"name":"Health Economics \u0026 Outcomes Research"}],"tags":[],"updatedAt":"2022-09-22T10:53:29+00:00","versionOfRecord":[],"versionCreatedAt":"2020-12-12 00:07:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-122212","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-122212","identity":"rs-122212","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}