Explore the vast range of titles available.

Standard practice for immunosuppressive therapy after renal transplantation is quadruple therapy using antibody induction, low-dose tacrolimus, mycophenolate mofetil, and corticosteroids. Long-term steroid intake significantly increases cardiovascular risk factors with negative effects on the outcome, especially post-transplantation diabetes associated with morbidity and mortality. In this trial, we examined the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation. In this open-label, multicentre, randomised controlled trial, we randomly assigned renal transplant recipients in a 1:1:1 ratio to receive either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C). The study was done in 21 centres across Germany. Only participants aged between 18 and 75 years with a low immunological risk who were scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor were considered for enrolment. Patients receiving a second renal transplant were eligible, provided that the first allograft was not lost due to acute rejection within the first year after transplantation. Donor and recipient had to be ABO compatible. Grafts with pre-transplant existing donor-specific human leukocyte antigen (HLA) antibodies were not eligible and the recipients had to have a panel-reactive antibody concentration of 30% or less. Pregnant women and nursing mothers were excluded from the study. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 12 months. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00724022. Between Aug 7, 2008, and Nov 30, 2013, 615 patients were randomly assigned to arm A (206), arm B (189), and arm C (192). BPAR rates were not reduced by rabbit ATG (9·9%) compared with either treatment arm A (11·2%) or B (10·6%; A versus C: p=0·75, B versus C p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p=0·0004). Patient survival (94·7% in arm A, 97·4% in arm B, and 96·9% in arm C) and censored graft survival (96·1% in arm A, 96·8% in arm B, and 95·8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms. Rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunological risk profile can be achieved without loss of efficacy and is advantageous in regard to post-transplantation diabetes incidence. Investigator Initiated Trial; financial support by Astellas Pharma GmbH, Sanofi, and Roche Pharma AG.

This study demonstrates that switching from calcineurin inhibitors to sirolimus had an antitumoral effect in kidney-transplant recipients with cutaneous squamous-cell carcinomas and may have implications concerning immunosuppressive treatment of such patients. Skin cancers affect more than half of organ-transplant recipients during their long-term course. 1 Several studies have shown that after a first cutaneous squamous-cell carcinoma, multiple subsequent skin cancers develop in 60 to 80% of kidney-transplant recipients within 3 years. 2 , 3 Transplant recipients share common risk factors with the nonimmunosuppressed population, 4 but the specific tumor burden of such patients is linked to the immunosuppressive medications used. 5 , 6 A decrease in cutaneous carcinogenesis after the reduction of immunosuppression has been reported. 7 Consequently, changes in immunosuppression are frequently made in patients with skin cancer, although there is currently no consensus on the level . . .

ObjectiveTo compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN).Study designThis is an open randomised controlled parallel group study.MethodsAdult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06–0.1 mg/kg/day) or MMF (2–3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time.Results150 patients (92% women; aged 35.5±12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (−12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8±26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by ≥30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35).ConclusionsTAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen.Trial registration numberHospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319).

Tacrolimus is the most commonly used immunosuppression drug after solid organ transplantation; however, its dosing is challenging due to substantial inter-individual variability, often resulting in blood levels that deviate from the target therapeutic range. We explored whether a dynamically customized, phenotypic-outcome-guided drug dosing method could improve maintenance of drug trough levels within pre-determined target ranges, focusing on tacrolimus immediately after liver transplantation. This single-center, partially blinded, completed clinical trial involved 62 adults undergoing liver transplantation, block randomized into parallel groups: standard-of-care (SOC) clinician-determined or Phenotypic Personalized Medicine (PPM)-guided tacrolimus dosing. The primary outcome was percentage of post-transplant days with large (>2 ng/mL) deviations from the target range. At trial completion, analysis found statistically significant improvement in the PPM group ( n  = 27): 24.2% of days showing large deviations compared to 38.4% in the SOC group ( n  = 29) (difference −14.2%, 95% CI: −26.7 to −1.5 %, P  = 0.029) with no increase in adverse events. These results demonstrate that PPM-guided tacrolimus dosing more effectively maintains drug levels within the target range compared to SOC, suggesting a promising approach to improving drug dosing. The trial was registered at ClinicalTrials.gov with the identifier NCT03527238. Tacrolimus is a critical immunosuppressant for liver transplant recipients, but its dosing is challenging due to individual variability. Here, the authors show that a phenotypic personalized medicine approach improves tacrolimus dosing precision, reducing large deviations from target levels and shortening hospital stays in a Phase 2 randomized trial.

ObjectivesTo report the 10-year outcome of lupus nephritis (LN) treated with mycophenolate mofetil (MMF) or tacrolimus (TAC) induction in a randomised controlled trial.MethodsPatients with active LN were treated with MMF or TAC combined with high-dose prednisolone. Responders were switched to azathioprine (AZA) at month 6. Clinical outcomes at 10 years (renal flares, renal function decline and mortality) were assessed. Factors affecting prognosis were studied by Cox regression. Urine protein-to-creatinine ratio (uPCr) and estimated glomerular filtration rate (eGFR) at different time points were evaluated for their prediction of a poor prognosis by receiver operating characteristic (ROC) analysis.Results150 patients were studied (age 35.5±12.8 years). Complete renal response rate was similar between MMF (59%) and TAC-treated patients (62%; p=0.71). AZA maintenance was given to 79% patients. After 118.2±42 months, proteinuric and nephritic renal flares occurred in 34% and 37% of the MMF, and 53% and 30% of the TAC groups of patients, respectively (p=0.49). The cumulative incidence of a composite outcome of ↓eGFR ≥30%, chronic kidney disease stage 4/5 or death at 10 years was 33% in both groups (p=0.90). Factors independently associated with a poor renal prognosis were first-time LN (HR 0.12 (0.031 to 0.39); p=0.01), eGFR (HR 0.98 (0.96 to 0.99); p=0.008) and no response at month 6 (HR 5.18 (1.40 to 19.1); p=0.01). ROC analysis revealed an uPCr >0.75 and eGFR of <80 mL/min at month 18 best predicted a poor renal prognosis.ConclusionsLong-term data confirmed non-inferiority of TAC to MMF as induction therapy of LN. An uPCr≤0.75 and eGFR of ≥80 mL/min at month 18 best predicted a favourable 10-year outcome and may be suitable targets for induction/consolidation therapy.Trial registration number NCT00371319.

Tacrolimus is metabolized in the liver with the participation of cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5). Omeprazole, unlike famotidine, is a substrate and inhibitor of CYP2C19, CYP3A4, CYP3A5 enzymes. The aim of the study is to compare the effect of omeprazole and famotidine on the tacrolimus concentration and the kidney transplant function. A randomized study was conducted in 24 adult patients with stable kidney transplant function who received a standard triple immunosuppression regimen. Patients were assigned to the group I (n = 12) additionally receiving omeprazole (20 mg) or the group II (n = 12) receiving famotidine (20 mg). At the time of qualification and during follow-up visits, tacrolimus blood concentration and selected laboratory tests were performed. Statistical analysis was performed using the MedCalc system. The value of tacrolimus concentration in the blood increased after a year in the group I (7.27 ± 2.33 vs 9.20 ± 2.46 ng/mL, p = 0.0478). A reduction in tacrolimus dosage was observed after three years in the group I (3.56 ± 1.75 vs 2.78 ± 1.00 mg, p = 0.0440) and in the group II (2.72 ± 0.84 vs 2.10 ± 0.48 mg, p = 0.0051). There was significant difference in the percentage changes of glomerular filtration rate between the groups after 3 years of the study (− 5.56% vs 9.13%, p = 0.0343). Omeprazole significantly change the concentration of tacrolimus in the blood when administered together with tacrolimus after one year of observation. There was no effect of famotidine or omeprazole on the function of the kidney transplant. ClinicalTrials.gov identifier: NCT05061303.

The risk of relapse after successful repigmentation in vitiligo is estimated to 40% within the first year. It has been shown in atopic dermatitis that continuous low-level use of topical corticosteroids and calcineurin inhibitors in previously affected skin can prevent new flares. We hypothesized that a twice-weekly application of 0.1% tacrolimus ointment might be effective for maintaining repigmentation in therapeutically repigmented lesions of vitiligo patients. After randomization, sixteen patients with 31 patches were assigned to the placebo group and 19 patients with 41 patches were assigned to the tacrolimus group. In the intention-to-treat analysis, 48.4% of lesions showed depigmentation in the placebo group, whereas 26.8% did in the tacrolimus group (P=0.059). The intention-to-treat results did not remain significant after adjustment for within-patient clustering, odds ratio (OR) 2.55; 95% confidence interval (CI; 0.65–9.97); P=0.1765. The per-protocol analysis (n=56) showed that 40% of lesions had some depigmentation in the placebo group, whereas only 9.7% did in the tacrolimus group (P=0.0075). The per-protocol results remained significant after adjustment for within-patient clustering: OR 6.22; 95% CI (1.48–26.12); P=0.0299. Our study shows that twice-weekly application of 0.1% tacrolimus ointment is effective in preventing the depigmentation of vitiligo patches that have been previously successfully repigmented.

Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the 2 regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research. The TEAMMATE trial (IND 127980) is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the safety and efficacy of EVL and low-dose TAC (LD-TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). Children aged <21 years at HT were randomized (1:1 ratio) at 6 months post-HT to either regimen, and followed for 30 months. Children with recurrent rejection, multi-organ transplant recipients, and those with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 were excluded. The primary efficacy hypothesis is that, compared to TAC/MMF, EVL/LD-TAC is more effective in preventing 3 MATEs: acute cellular rejection (ACR), CKD and CAV. The primary safety hypothesis is that EVL/LD-TAC does not have a higher cumulative burden of 6 MATEs (antibody mediated rejection [AMR], infection, and post-transplant lymphoproliferative disorder [PTLD] in addition to the 3 above). The primary endpoint is the MATE score, a composite, ordinal surrogate endpoint reflecting the frequency and severity of MATEs that is validated against graft loss. The study had a target sample size of 210 patients across 25 sites and is powered to demonstrate superior efficacy of EVL/LD-TAC. Trial enrollment is complete and participant follow-up will be completed in 2023. The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT

Lupus nephritis (LN) is typically treated with intravenous cyclophosphamide (IVCY), which is associated with serious adverse effects. Tacrolimus may be an alternative for initial treatment of LN; however, large-scale, randomized clinical studies of tacrolimus are lacking. To assess efficacy and safety of tacrolimus vs IVCY as an initial therapy for LN in China. This randomized (1:1), open-label, parallel-controlled, phase 3, noninferiority clinical trial recruited patients aged 18 to 60 years with systemic lupus erythematosus and LN class III, IV, V, III+V, or IV+V primarily from outpatient settings at 35 centers in China. Inclusion criteria included body mass index of 18.5 or greater to less than 27, 24-hour urine protein of 1.5 g or greater, and serum creatinine of less than 260 μmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons). Overall, 314 were randomized. The first patient was enrolled March 10, 2015, and the study finished September 13, 2018. The follow-up period was 24 weeks. Data were analyzed from December 2019 to March 2020. Oral tacrolimus (target trough level, 4-10 ng/mL) or IVCY for 24 weeks plus prednisone. Complete or partial response rate at week 24 (prespecified). A total of 314 patients were randomized (158 [50.3%] to tacrolimus and 156 [49.7%] to IVCY). Overall, 299 patients (95.2%) were treated (tacrolimus group, 157 [52.5%]; IVCY group, 142 [47.5%]). Baseline demographic and clinical characteristics were generally similar between groups (mean [SD] age, 34.2 [9.5] years; 262 [87.6%] female). Tacrolimus was found to be noninferior to IVCY for LN response at week 24. There was a complete or partial response rate of 83.0% (117 of 141 patients) in the tacrolimus group and 75.0% (93 of 124 patients) in the IVCY group (difference, 7.1%; 2-sided 95% CI, -2.7% to 16.9%; lower limit of 95% CI greater than -15%). At week 24, least-square mean change in Systemic Lupus Erythematosus Disease Activity Index score was -8.6 with tacrolimus and -6.4 with IVCY (difference, -2.2; 95% CI, -3.1 to -1.3). Changes in other immune parameters and kidney function were generally similar between groups. Serious treatment-emergent adverse events (TEAEs) were reported in 29 patients in the tacrolimus group (18.5%) and 35 patients in the IVCY group (24.6%). Most common serious study drug-related TEAEs were infections (14 [8.9%] and 23 [16.2%], respectively). Seven patients in each group withdrew due to AEs. In this study, oral tacrolimus appeared noninferior to IVCY for initial therapy of active LN, with a more favorable safety profile than IVCY. Tacrolimus may be an alternative to IVCY as initial therapy for LN. ClinicalTrials.gov Identifier: NCT02457221.