Study Design: Human Leukocyte Antigen Class I Molecule A∗02-Chimeric Antigen Receptor Regulatory T Cells in Renal Transplantation.

Introduction: Cell therapy with regulatory T cells (Tregs) in solid organ transplantation is a promising approach for the prevention of graft rejection and induction of immunologic tolerance. Previous clinical studies have demonstrated the safety of Tregs in renal transplant recipients. Antigen-specific Tregs, such as chimeric antigen receptor (CAR)-Tregs, are expected to be more efficacious than polyclonal Tregs in homing to the target antigen. We have developed an autologous cell therapy (TX200-TR101) where a human leukocyte antigen (HLA) class I molecule A∗02 (HLA-A∗02)-CAR is introduced into autologous naive Tregs from a patient with HLA-A∗02-negative end-stage renal disease (ESRD) awaiting an HLA-A∗02-positive donor kidney. Methods: This article describes the design of the STEADFAST study, a first-in-human, phase I/IIa, multicenter, open-label, single-ascending dose, dose-ranging study to assess TX200-TR101 in living-donor renal transplant recipients. Up to 15 transplant recipients will receive TX200-TR101 and will be followed up for a total of 84 weeks post-transplant, alongside a control cohort of up to 6 transplant recipients. All transplant recipients will receive a standard of care immunosuppressive regimen, with the intent of intensified tapering of the regimen in the TX200-TR101 cohort. Results: The primary end point is the incidence and severity of treatment-emergent adverse events (AEs) within 28 days post-TX200-TR101 infusion. Other end points include additional safety parameters, clinical and renal outcome parameters, and the evaluation of biomarkers. Conclusion: The STEADFAST study represents the next frontier in adoptive cell therapies. TX200-TR101 holds great potential to prevent immune-mediated graft rejection and induce immunologic tolerance after HLA-A∗02-mismatched renal transplantation.

Evolving landscape of stroke prevention in atrial fibrillation within the UK between 2012 and 2016: a cross-sectional analysis study using CPRD.

OBJECTIVE: To describe the changes in prescribing of oral anticoagulant (AC) and antiplatelet (AP) agents in patients with non-valvular atrial fibrillation (NVAF) in the UK and to identify the characteristics associated with deviation from guideline-based recommendations. DESIGN: Five cross-sectional analyses in a large retrospective population-based cohort study. SETTING: General practices contributing data to the UK Clinical Practice Research Datalink. PARTICIPANTS: The study included patients with a diagnosis of NVAF and eligible for anticoagulation (CHA2DS2-VASc score ≥2) on 1 April of 2012, 2013, 2014, 2015 and 1st January 2016. RESULTS: The proportion of patients being treated with AC increased at each index date, showing an absolute rise of 16.7% over the study period. At the same time, the proportion of patients treated with an AP alone was reduced by half, showing an absolute decrease of 16.8%. The proportion of patients not receiving any antithrombotic (AT) treatment remained the same across the study period. A number of predictors were identified for AP alone or no treatment compared with AC treatment. CONCLUSION: Major improvements in the AT management of patients with NVAF for stroke prevention in the UK were observed between April 2012 and January 2016. Despite this, nearly 20% of at-risk patients still received AP alone and over 15% were on no AT agents in January 2016.

Early real-world evidence of persistence on oral anticoagulants for stroke prevention in non-valvular atrial fibrillation: a cohort study in UK primary care.

OBJECTIVES: To examine the characteristics and persistence in patients newly initiated with oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF). DESIGN: Cohort study in Clinical Practice Research Datalink. SETTING: UK primary care. PARTICIPANTS: 15 242 patients with NVAF newly prescribed apixaban, rivaroxaban, dabigatran or vitamin K antagonists (VKAs) between 1 December 2012 and 31 October 2014. 13 089 patients were OAC naïve. OUTCOME MEASURES: Patient characteristics and risk of non-persistence compared to apixaban using Cox regression models over the entire follow-up and using a time-partitioned approach to handle non-proportional hazards. RESULTS: Among the OAC naïve patients, VKAs were most common (78.1%, n=10 218), followed by rivaroxaban (12.1%, n=1589), dabigatran (5.7%, n=741) and apixaban (4.1%, n=541). High baseline stroke risk (CHA2DS2VASc ≥2) ranged from 80.2% (dabigatran) to 88.4% (apixaban and rivaroxaban). History of stroke and bleeding was the highest among apixaban (23.7% and 31.6%) and lowest among VKA patients (15.9% and 27.5%). Across the entire follow-up period, adjusting for differences in characteristics, there was no evidence of a difference in non-persistence between VKA and apixaban (HR 0.92 (95% CI 0.68 to 1.23)). Non-persistence was higher with dabigatran (HR 1.67 (1.20 to 2.32)) and rivaroxaban (HR 1.41 (1.02 to 1.93)) than apixaban. Using the partitioned approach, non-persistence was lower with VKA (HR 0.33 (0.22 to 0.48)), and higher with dabigatran (HR 1.65 (1.08 to 2.52)) compared to apixaban in the first 2 months of follow-up. After 2 months, non-persistence was higher with VKA (HR 1.70 (1.08 to 2.66)) and dabigatran (HR 2.10 (1.30 to 3.41)). Pooling OAC naïve and experienced patients, non-persistence was also higher with rivaroxaban compared to apixaban after 2 months of follow-up (HR 1.69 (1.19 to 2.39)). CONCLUSIONS: Observed differential prescribing of OACs can result in channelling bias in comparative effectiveness research. Persistence patterns changed over follow-up time, but there are indications of improved persistence rates with apixaban over other OACs in the UK. A larger study with longer follow-up is needed to corroborate findings. This study is registered on ClinicalTrials.gov (NCT02488421).