Search

Design Investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Background Allografts in 3% of kidney transplant patients fail annually. Development of antibodies against human leucocyte antigens is a validated predictive biomarker of allograft failure. Under immunosuppression is recognised to contribute, but whether increasing immunosuppression can prevent allograft failure in human leucocyte antigen Ab+ patients is unclear. Participants Renal transplant recipients > 1 year post-transplantation attending 13 United Kingdom transplant clinics, without specific exclusion criteria. Interventions Regular screening for human leucocyte antigen antibodies followed, in positive patients by interview and tailored optimisation of immunosuppression to tacrolimus, mycophenolate mofetil and prednisolone. Objective To determine if optimisation of immunosuppression in human leucocyte antigen Ab+ patients can cost-effectively prevent kidney allograft failure. Outcome Time to graft failure after 43 months follow-up in patients receiving the intervention, compared to controls, managed by standard of care. Costs and quality-adjusted life-years were used in the cost-effectiveness analysis. Randomisation and blinding Random allocation (1 : 1) to unblinded biomarker-led care or double-blinded standard of care stratified by human leucocyte antigen antibodies status (positive/negative) and in positives, presence of donor-specific antibodies (human leucocyte antigen antibodies against donor human leucocyte antigen) or not (human leucocyte antigen antibodies against non-donor human leucocyte antigen), baseline immunosuppression and transplant centre. Biomaker-led care human leucocyte antigen Ab+ patients received intervention. Human leucocyte antigen Ab-negative patients were screened every 8 months. Recruitment Began September 2013 and for 37 months. The primary endpoint, scheduled for June 2020, was moved to March 2020 because of COVID-19. Numbers randomised From 5519 screened, 2037 were randomised (1028 biomaker-led care, 1009 to standard of care) including 198 with human leucocyte antigen antibodies against donor human leucocyte antigen (106 biomaker-led care, 92 standard of care) and 818 with human leucocyte antigens antibodies against non-donor human leucocyte antigen (427 biomaker-led care, 391 standard of care). Numbers analysed Two patients were randomised in error so 2035 were included in the intention-to-treat analysis. Outcome The trial had 80% power to detect a hazard ratio of 0.49 in biomarker-led care DSA+ group, > 90% power to detect hazard ratio of 0.35 in biomarker-led care non-DSA+ group (with 5% type 1 error). Actual hazard ratios for graft failure in these biomarker-led care groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54 to 1.74), respectively. There was 90% power to demonstrate non-inferiority of overall biomarker-led care group with assumed hazard ratio of 1.4: This was not demonstrated as the upper confidence limit for graft failure exceeded 1.4: (1.02, 95% CI 0.72 to 1.44). The hazard ratio for biopsy-proven rejection in the overall biomarker-led care group was 0.5 [95% CI: 0.27 to 0.94: p = 0.03]. The screening approach was not cost-effective in terms of cost per quality-adjusted life-year. Harms No significant differences in other secondary endpoints or adverse events. Limitations Tailored interventions meant optimisation was not possible in some patients. We did not study pathology on protocol transplant biopsies in DSA+ patients. Conclusions No evidence that optimised immunosuppression in human leucocyte antigen Ab+ patients delays renal transplant failure. Informing patients of their human leucocyte antigen antibodies status appears to reduce graft rejection. Future work We need a better understanding of the pathophysiology of transplant failure to allow rational development of effective therapies. Trial registration This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information. Plain language summary Although kidney transplantation is the gold-standard treatment for kidney failure, thousands of transplants fail each year due to damage by the immune system. Finding circulating antibodies against the transplant can identify patients at high risk of failure. Under-treatment with immunosuppressive drugs plays a part in promoting the damage and increasing immunosuppression can slow progression in some but not all patients. In the Optimized TacrolimuS and MMF for HLA Antibodies after Renal Transplantation OuTSMART trial, we screened kidney transplant patients for circulating antibodies then, in the intervention arm, counselled everyone on the importance of taking immunosuppression, before optimising treatments to ‘best available’. We recruited > 2000 patients and split them into two groups randomly; in the first we revealed antibody results, encouraged adherence and tailored treatment to a combination of three drugs called tacrolimus, mycophenolate, and prednisolone, in a regimen that was judged optimal for each. In the second group, we did not release the antibody test results to patients or their doctors, and all treatment decision were based on local standard of care. At the end, we compared the numbers of transplant failures in each group. We confirmed that patients with antibodies were at higher risk of transplant failure, but found no differences in failures between those in whom we had intervened compared to those treated by standard of care. Although more developed rejection after standard care, there were no differences in the other things we measured, including the numbers who died, developed diabetes, infections or cancer and no differences in the number who developed new side effects. We therefore conclude that there is no basis for optimising drug treatment in those with antibodies at risk of transplant failure. Instead, novel treatments are needed. This trial will influence current practice around the world and hopefully incentivise research into new strategies to prevent transplant failure. Scientific summary Background Kidney transplants do not last for the natural lifespan of most recipients, and many patients eventually suffer progressive decline in transplant function leading to graft failure and need to return to dialysis. Around the world, this problem is significant, as 3% of kidney transplant patients return to dialysis each year. The single biggest cause of allograft dysfunction leading to transplant failure is immune-mediated damage and a prevalent hypothesis in the field is that inappropriately low levels of immunosuppression, either physician-led or due to patient non-adherence, is an important contributor to the initiation and progression of this immune-mediated damage. There are still no effective treatments for allograft dysfunction that is proven to be due to immune-mediated damage. Enhancing baseline immunosuppression appears to stabilise graft function in some patients. Two recent randomised trials of the anti-CD20 monoclonal antibody rituximab showed no impact, although both were stopped prematurely as they were underpowered. More recent reports indicate that anti-IL-6 monoclonals show promise at stabilising estimated Glomerular Filtration Rate (eGFR), but these have yet to be tested in large randomised trials. Since the development of circulating antibodies (Ab) against human leucocyte antigens (HLA) has been validated as a strong prognostic biomarker of kidney transplant failure, and there is genuine equipoise about whether increasing or optimising immunosuppression can benefit patients at risk of transplant failure, in the OuTSMART trial we tested the hypothesis that screening for these Ab followed by optimising oral immunosuppression treatment, could prevent allograft failure. Objectives Primary Determine the time to graft failure in patients testing positive for HLA Ab at baseline or within 32 months of randomisation who receive an optimised anti-rejection medication intervention with prednisolone, tacrolimus (Tac) and mycophenolate mofetil (MMF) (‘treatment’), compared to a control group who test positive for HLA Ab at baseline or within 32 months post-randomisation who remain on their established immunotherapy and whose clinicians are not aware of their Ab status. The primary endpoint was to be assessed remotely when 43 months post-randomisation was achieved by all. Secondary Determine the time to graft failure in patients randomised to ‘unblinded’ HLA Ab screening, compared to a control group randomised to ‘blinded’ HLA Ab screening. Determine whether treatment influences patient survival. Determine whether ‘treatment’ influences the development of graft dysfunction as assessed by presence of proteinuria (protein:creatinine ratio > 50 or albumin:creatinine ratio > 35) and change in eGFR. Determine whether ‘treatment’ influences the rates of acute rejection in these groups. Determine the adverse effect profiles of ‘treatment’ in this group, in particular whether they are associated with increased risk of infection, malignancy or diabetes mellitus. Determine the cost-effectiveness of routine screening for HLA Ab and prolonging transplant survival using this screening/treatment protocol. Determine the impact of biomarker screening and ‘treatment’ on the patients’ adherence to drug therapy and their perceptions of risk to the health of the transplant. Methods OuTSMART was an investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Eligible patients were recipients of cross-match negative transplants aged 18–75, more than 1 year post-transplant with an eGFR ≥30 ml/min willing to consent to the screening/treatment process. Patients were excluded if they were recipients of cross-match positive transplant requiring HLA desensitisation to remove Ab, recipients of additional solid organ transplants (e.g. pancreas, heart, etc.), had a history of malignancy (except non-melanomatous lesions restricted to the skin), had recent acute rejection, had a history of hepatitis B, C or human immunodeficiency virus (HIV), were known to have HLA Ab and received specific treatment for that Ab, had known hypersensitivity to any of the investigational medicinal products (IMPs), had known hereditary disorders of carbohydrate metabolism, were pregnant at the time of consent, or were females who refused to consent to using suitable contraception through the trial. Additionally, patients enrolled in any other studies involving administration of another IMP at time of recruitment were excluded. Stratified randomisation was 1 : 1 to two arms, blinded standard care (SC) or unblinded biomarker-led care (BLC). Randomisation was stratified first by the result from blood test screening for HLA Ab. The HLA Ab+ patients were further screened with single antigen beads to determine whether donor-specific Ab (DSA) were present or whether the only Ab detected was non-DSA. Thus, biomarker stratification led to three groups within each arm (DSA+, non-DSA+ and HLA Ab-neg). The second stratification was based on current immunosuppression, to ensure balanced numbers already on Tac or MMF in each group. The final stratification was by site. Patients in the SC arm were blinded to their biomarker status, as were their physicians, and remained on baseline immunotherapy, whereas patients in the BLC arm were told their HLA Ab status and were offered intervention. HLA Ab-negative patients in either arm remained on their existing immunotherapy and were rescreened for new HLA Abs every 8 months. Those patients who become positive during subsequent screening rounds were moved to the appropriate HLA Ab positive groups (DSA+ or non-DSA+) for final data analysis. All patients in the unblinded arm found to be positive on second or subsequent rounds were offered the same intervention as those patients who were positive in the first screening round, and these were intensively followed up for an additional 32 months from the time they become positive. Thus the maximum amount of time any single patient remained in intensive follow-up was 64 months. New patients were recruited to the study at each successive screening round. Intervention in the unblinded HLA Ab + patients consisted of informing patients of their HLA Ab status, followed by, in those with DSA or non-DSA, an interview to encourage medication adherence followed by medication changes to optimised doses of Tac, MMF and Prednisolone. Medication changes were tailored to each individual and failure to change, or to tolerate changes was not regarded as treatment failure, so some patients stayed on the same drug regimen. Patients with DSA and non-DSA were offered the same intervention. The primary outcome was originally transplant failure rates over 3 years, but this was changed to time to graft failure after an audit revealed that the prevalence and incidence rates of HLA Ab + patients were less than expected when planning the trial. With a planned minimum follow-up period of 43 months, the trial had 80% power to detect a hazard ratio (HR) of 0.49 in donor-specific antibody+ patients. Secondary endpoints were collected at 32 months and included patient death/survival, rates of biopsy-proven acute rejection, diabetes, infection and cancer, a health economic analysis and formal assessment of adherence. Results Recruitment started in September 2013. Over 37 months, 5519 patients were screened for eligibility and 2037 were randomised (1028 to unblinded BLC and 1009 to double-blinded SC). We identified 198 with DSA and 818 with non-DSA, and at the end of screening, there were 1021 in the Ab-neg groups. Baseline variables were well-matched between groups at the end of Ab-screening. Forty-five per cent of the DSA detected were directed against HLA-DQB antigens. Although the majority of patients were taking Tac (73%), MMF (67%) or prednisolone (55%), only 22% with DSA and 27% with non-DSA were taking all three drugs. Baseline immunosuppression use was balanced across arms and did not change during the trial in the SC arm. Ninety-seven per cent of HLA Ab+ recruits in the BLC arm had the formal interview, and the proportion taking all three drugs in the BLC arm increased to 54% (DSA) and 44% (non-DSA). There were 34 graft failures in HLA Ab+ recruits in the SC arm over the course of the study compared to 42 in the BLC arm. The HRs for graft failure in BLC DSA+ and non-DSA+ groups were 1.54 [95% confidence interval (CI) 0.72 to 3.30] and 0.97 (0.54 to 1.74), respectively, providing no evidence of a difference. The data for DSA+ groups confirmed that the presence of DSA was associated with an increased risk of graft failure, but non-DSA were not associated with graft failure compared to patients without Ab. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 : (1.02, 95% CI 0.72 to 1.44). The HR for the secondary endpoint biopsy-proven rejection in the overall unblinded BLC group was 0.5 (95% CI 0.27 to 0.94; p = 0.03), but there were no significant differences in patient survival, biopsy-proven rejection, proven infections, malignancies, diabetes, development of proteinuria or mean eGFRs at the end of the trial. After adjusting for baseline quality of life, there was no significant gain of quality-adjusted life-year (QALY) in the BLC arm, but an incremental cost-effectiveness ratio per QALY that was significantly higher than the threshold set by the National Institute for Health and Care Excellence. Our analysis of adherence revealed significantly improved adherences for all three drugs in the BLC DSA+ group. Conclusions Thus, we conclude that the development of DSA (but not non-DSA) is associated with an increased risk of graft failure, but there is no evidence to support the primary hypothesis, that optimisation of immunosuppression in DSA+ patients can prevent this from happening. Trial registration This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information.

Background: To provide precision cognitive remediation therapy (CR) for schizophrenia, we need to understand whether the mechanism for improved functioning is via cognition improvements. This mechanism has not been rigorously tested for potential moderator effects., Study Design: We used data (n = 377) from a randomized controlled trial using CIRCuiTS, a therapist-supported CR, with participants from first-episode psychosis services. We applied structured equation modeling to test whether: (1) CR hours explain the goal attainment functional outcome (GAS) at posttreatment, (2) global cognitive improvement mediates GAS, and if (3) total symptoms moderate the CR hours to cognitive improvement pathway, and/or negative symptoms moderate the cognition to functioning pathway, testing moderator effects via the mediator or directly on CR hours to functioning path., Study Results: CR produced significant functioning benefit for each therapy hour (Coeff = 0.203, 95% CI 0.101-0.304, P < .001). The mediated path from CR hours to cognition and cognition to functioning was small and nonsignificant (Coeff = 0.014, 95% CI = -0.010, 0.037, P = .256). Total symptoms did not moderate the path to cognition (P = .211) or the direct path to outcome (P = .896). However, negative symptoms significantly moderated the effect of cognitive improvements on functioning (P = .015) with high negative symptoms reducing the functional gains of improved cognition., Conclusions: Although cognitive improvements were correlated with functioning benefit, they did not fully explain the positive effect of increased therapy hours on functioning, suggesting additional CR factors also contribute to therapy benefit. Negative symptoms interfere with the translation of cognitive improvements into functional gains so need consideration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Objective: Cognitive remediation (CR) improves cognition and aids recovery in people with psychosis. An active therapist provides increased benefit, but CR training for therapists is not routinely available, so CR has limited scalability. This study describes the development and evaluation of the first online CR therapist training programme., Methods: An online CR training, based on expert and novice therapist consultations, was developed, and then pilot tested with novice trainees and changes made to produce the evaluation version. Feasibility, acceptability, and training benefits were assessed in a group of naïve UK NHS mental health professionals. Training engagement with a group of clinicians who accessed the programme for professional development was compared to those who paid fees., Results: Most mental health professionals finished training and passed the knowledge test, indicating that training enhanced clinicians' knowledge. Fee-paying trainees had significantly faster completion times and a higher proportion finished in the recommended time. Those who were successful at passing the knowledge questionnaire had significantly fewer years in practice. The majority were satisfied with the programme, felt they had made considerable progress and that training would allow them to begin practicing CR, and would recommend the training to colleagues., Conclusions: This online CR training programme was feasible, acceptable to participants and showed benefits for clinicians. It improved knowledge even in the most junior of staff who have had less time to develop clinical know-how., (© 2023 The Authors. Psychology and Psychotherapy: Theory, Research and Practice published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

Background: Exposure-based cognitive-behaviour therapies (CBT) are effective but their acceptability in pregnancy is untested. Time-intensive delivery of CBT (INT-CBT) may accelerate treatment response. This feasibility trial aimed to explore this., Methods: This multi-centre parallel-group trial recruited pregnant women with anxiety-related disorders via maternity and mental health settings and randomised (1:1) to INT-CBT (8-10 treatment hours over two weeks) or standard weekly one-hour CBT sessions (WCBT). Both groups also received late pregnancy and postpartum follow-ups. Participants received 10-12 total hours of individual therapy using remote delivery (95 %). Outcomes were assessed: at baseline; after two weeks of treatment, late pregnancy, at 1 and 3 months postpartum (by blinded assessors), alongside a qualitative interview. Pre-specified primary feasibility outcomes regarding acceptability, recruitment and retention were evaluated. The secondary outcome of adjusted mean difference was estimated for the proposed primary outcome., Results: All feasibility outcomes were met. Of 135 screened, 59 women were randomised into the trial (29 INT-CBT:30 WCBT). 93 % completed treatment and 81 % provided data at 3 m postpartum. No adverse effects were attributable to treatment. Women receiving INT-CBT showed a reduction in anxiety (GAD-7) after two weeks of treatment compared to WCBT (aMD = -4.17, 95%CI -6.03 to -2.31) with narrower difference at 3-month postpartum aMD = -0.11 (95%CI -3.23, 3.00). Women described the momentum of INT-CBT as helpful to drive change., Conclusions: Exposure-based therapies are acceptable to pregnant women. INT-CBT may reduce anxiety quickly and should be tested in a confirmatory trial examining longer term outcomes. There may be limitations to generalisability from sampling and COVID., Trial Registration: doi:https://doi.org/10.1186/ISRCTN81203286 prospectively registered 27/6/2019., Competing Interests: Declaration of competing interest None. The work was carried out in the UK., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Approximately 15% of pregnant women experience anxiety disorders. Effective treatments exist but their acceptability during pregnancy, particularly exposure therapy, is not known., Aims: To understand patient and therapist experiences of time-intensive and weekly exposure-based therapy for anxiety disorders delivered during pregnancy. Trial registration: ISRCTN81203286., Method: In-depth interviews were conducted with patients and therapists who had taken part in a feasibility trial of predominantly online time-intensive versus weekly cognitive-behavioural therapy in pregnancy in a primary care setting in the UK. Data were analysed using reflexive thematic analysis., Results: In total, 45 women participating in the trial and 6 therapists who had delivered the treatments were interviewed. Five themes were developed from the data that showed convergence from therapist and patient perspectives: 'Acquiring tools to navigate the perinatal period'; 'Motivated yet constrained by pregnancy'; 'Having the confidence to face fears and tolerate uncertainty'; 'Momentum with the need for flexibility'; 'Being removed from the face-to-face world'., Conclusions: Exposure therapy is acceptable and helpful in pregnancy and can lead to lasting gains. Exposure is a key element of treatment and needs to be confidently conducted by therapists with perinatal knowledge and expertise. Treatments need to consider the unfolding context of pregnancy. The momentum of intensive therapy can lead to rapid improvements, but is demanding for both patients and therapists, especially fitting round other commitments. Online treatments can work well and are a good fit for perinatal women, but this needs to be balanced with the need for social connection, suggesting a hybrid model is the ideal.

Cognitive Remediation (CR) improves cognition and functioning but is implemented in a variety of ways (independent, group and one-to-one). There is no information on whether service users find these implementation methods acceptable or if their satisfaction influences CR outcomes. We used mixed participatory methods, including focus groups, to co-develop a CR satisfaction scale. This was refined using three psychometric criteria (Cronbach's alpha, item discrimination, test-retest agreement) to select items. Factor analysis explored potential substructures. The refined measure was used in structural equation joint modelling to evaluate whether satisfaction with CR is affected by implementation method and treatment engagement or influences recovery outcome, using data from a randomised controlled trial. Four themes (therapy hours, therapist, treatment effects, computer use) generated a 31-item Cognitive Remediation Satisfaction scale (CRS) that reduced to 18 Likert items, 2 binary and 2 open-ended questions following psychometric assessment. CRS had good internal consistency (Alpha = 0.814), test-retest reliability (r= 0.763), and concurrent validity using the Working Alliance Inventory (r = 0.56). A 2-factor solution divided items into therapy engagement and therapy effects. Satisfaction was not related to implementation method but was significantly associated with CR engagement. Therapy hours were significantly associated with recovery, but there was no direct effect of satisfaction on outcome. Although satisfaction is important to therapy engagement, it has no direct effect on outcome. CR therapy hours directly affect outcome irrespective of which implementation model is used, so measuring satisfaction early might help to identify those who are likely to disengage. The study has mixed methods design., (© 2023. Springer Nature Limited.)

Background and Hypothesis: Cognitive remediation (CR) benefits cognition and functioning in psychosis but we do not know the optimal level of therapist contact, so we evaluated the potential benefits of different CR modes., Study Design: A multi-arm, multi-center, single-blinded, adaptive trial of therapist-supported CR. Participants from 11 NHS early intervention psychosis services were independently randomized to Independent, Group, One-to-One, or Treatment-as-usual (TAU). The primary outcome was functional recovery (Goal Attainment Scale [GAS]) at 15-weeks post randomization. Independent and TAU arms were closed after an interim analysis, and three informative contrasts tested (Group vs One-to-One, Independent vs TAU, Group + One-to-One vs TAU). Health economic analyses considered the cost per Quality Adjusted Life Year (QALY). All analyses used intention-to-treat principles., Study Results: We analyzed 377 participants (65 Independent, 134 Group, 112 One-to-One, 66 TAU). GAS did not differ for Group vs One-to-One: Cohen's d: 0.07, -0.25 to 0.40 95% CI, P = .655; Independent vs TAU: Cohen's d: 0.07, -0.41 to 0.55 95% CI, P = .777. GAS and the cognitive score improved for Group + One-to-One vs TAU favoring CR (GAS: Cohen's d: 0.57, 0.19-0.96 95% CI, P = .003; Cognitive score: Cohens d: 0.28, 0.07-0.48 95% CI, P = .008). The QALY costs were £4306 for Group vs TAU and £3170 for One-to-One vs TAU. Adverse events did not differ between treatment methods and no serious adverse events were related to treatment., Conclusions: Both active therapist methods provided cost-effective treatment benefiting functional recovery in early psychosis and should be adopted within services. Some individuals benefited more than others so needs further investigation., Trial Registration: ISRCTN14678860 https://doi.org/10.1186/ISRCTN14678860Now closed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Healthcare workers (HCWs) have faced considerable pressures during the COVID-19 pandemic. For some, this has resulted in mental health distress and disorder. Although interventions have sought to support HCWs, few have been evaluated., Aims: We aimed to determine the effectiveness of the 'Foundations' application (app) on general (non-psychotic) psychiatric morbidity., Method: We conducted a multicentre randomised controlled trial of HCWs at 16 NHS trusts (trial registration number: EudraCT: 2021-001279-18). Participants were randomly assigned to the app or wait-list control group. Measures were assessed at baseline, after 4 and 8 weeks. The primary outcome was general psychiatric morbidity (using the General Health Questionnaire). Secondary outcomes included: well-being; presenteeism; anxiety; depression and insomnia. The primary analysis used mixed-effects multivariable regression, presented as adjusted mean differences (aMD)., Results: Between 22 March and 3 June 2021, 1002 participants were randomised (500:502), and 894 (89.2%) followed-up. The sample was predominately women (754/894, 84.3%), with a mean age of 44⋅3 years (interquartile range (IQR) 34-53). Participants randomised to the app had a reduction in psychiatric morbidity symptoms (aMD = -1.39, 95% CI -2.05 to -0.74), improvement in well-being (aMD = 0⋅54, 95% CI 0⋅20 to 0⋅89) and reduction in insomnia (adjusted odds ratio (aOR) = 0⋅36, 95% CI 0⋅21 to 0⋅60). No other significant findings were found, or adverse events reported., Conclusions: The app had an effect in reducing psychiatric morbidity symptoms in a sample of HCWs. Given it is scalable with no adverse effects, the app may be used as part of an organisation's tiered staff support package. Further evidence is needed on long-term effectiveness and cost-effectiveness.

Background: 3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure., Methods: Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients., Findings: From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54-1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection., Interpretation: Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy., Funding: The National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34)., Competing Interests: DB declares consulting fees and speaker honoraria from Hansa Biopharma. RT declares membership of ESOT Education Committee (2018–2021) (expenses reimbursed). PM declares research funding from NIHR. AD declares research funding from the 10.13039/501100007155Medical Research Council, consulting fees (paid to KCL) from Hansa Biopharma, Verici Diagnostics, UCB Pharma and Quell Therapeutics, Membership of the Herperis Faculty 2019, 2021 and 2022 (expenses reimbursed), Membership of the UK Organ donation and transplantation research network executive since 2020 (unpaid), Membership of the EME funding Committee (2014–2019) and the EME funding committee subgroup (2018–2019) (both unpaid). The remaining authors declare no conflicts of interest., (© 2023 The Authors.)