A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.</p> <p>Methods/Design</p> <p>The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 2^1/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.</p> <p>Discussion</p> <p>If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.</p> <p>Trial Register</p> <p>Trial registered at <url>http://www.clinicaltrials.gov</url>: NCT00355862</p> <p>(EudraCT Number: 2005-005362-36)</p

EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus Advagraf™ in liver transplant recipients

Background Graft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagraf™, was developed (vs 2x/day Prograf®). Benefits of Advagraf™ are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs Advagraf™ in de novo liver transplant (LTx) recipients. Methods The EnGraft compares bioavailability and tests superiority of Envarsus® (test arm) versus Advagraf™ (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period. Discussion C/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function but also linked to reduced neurotoxic side effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022

HCC recurrence in HCV-infected patients after liver transplantation: SiLVER Study reveals benefits of sirolimus in combination with CNIs - a post-hoc analysis

Factors affecting outcomes in liver transplant (LTx) recipients with hepatocellular carcinoma (HCC) and hepatitis C viral (HCV) infection include the choice of immunosuppression. Here, we analyzed the HCV+ subgroup of patients from the randomized controlled, international SiLVER Study. We performed a post hoc analysis of 166 HCV+ SiLVER Study patients regarding HCC outcome after LTx. Control patients (group A: n&nbsp;=&nbsp;88) received mTOR inhibitor (mTORi)-free, calcineurin inhibitor (CNI)-based versus sirolimus-based immunosuppression (group B: n&nbsp;=&nbsp;78). We found no significant difference regarding HCV-RNA titers between group A and B. Since no effect in group B could be due to variable sirolimus dosing, we split group B into patients receiving sirolimus-based immunosuppression&nbsp;+&nbsp;CNIs for &gt;50% (B1; n&nbsp;=&nbsp;44) or &lt;50% (B2; n&nbsp;=&nbsp;34) of the time. While there remained no difference in HCV-RNA titer between groups, HCC recurrence-free survival in group B1 (81.8%) was markedly better versus both group A (62.7%; P&nbsp;=&nbsp;0.0136) and group B2 (64.7%; P&nbsp;=&nbsp;0.0326); Interestingly, further subgroup analysis revealed an increase (P&nbsp;=&nbsp;0.0012) in liver enzyme values in group B2. Taken together, in HCV-infected patients with HCC and LTx, mTORi immunosuppression&nbsp;+&nbsp;CNIs yields excellent outcomes. Unexpectedly, higher levels of liver inflammation and poorer outcomes occur with mTORi monotherapy in the HCV+ subgroup

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

Peer reviewe

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma : A Randomized, Multicenter, Open-Label Phase 3 Trial

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age 60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.Peer reviewe

Efficacy of ibuprofen versus lornoxicam after third molar surgery: a randomized, double-blind, crossover pilot study

PURPOSE: The aim of this study is to compare the analgesic efficacy and tolerability of a pre-emptive/post-surgery 4-day regimen of oral ibuprofen 400 mg with that of lornoxicam 8 mg. METHODS: Sixteen patients received ibuprofen or lornoxicam, respectively, before and after surgery of impacted third molars in two separate appointments, in a double-blind, randomized, and crossover design. The postoperative analgesic and rescue medication consumption was recorded and pain scores were evaluated with a visual analogue scale at 2, 6, 24, 48, and 72 h, postoperatively. RESULTS: No statistically significant differences were found between ibuprofen 400 mg and lornoxicam 8 mg with respect to study medication (p = 0.34) or rescue analgesic consumption (p = 0.5) (SUMstudy and SUMrescue). Ibuprofen: SUMstudy median 7.5 interquartile range IQR (4.25-8), 95% CI (4.6-7.7); SUMrescue median and IQR 0, 95% CI (-0.6-4.6). Lornoxicam: SUMstudy median 7 IQR (3.75-9), 95% CI (7.7-4.9); SUMrescue median and IQR 0, 95% CI (-0.7-2.7). The area under the pain intensity curve (AUC(2-72) PI) over the 4 days of investigation did not reveal significant differences between the two medications (p = 0.32). AUC(2-72) PI ibuprofen: median 1,509.7 IQR (712.36-2,444.65); 95% CI (1,078.7-2,156.5). AUC(2-72) PI lornoxicam: median 1,166.9 IQR (783.4-2,221.2), 95% CI (1,032-2,130.6). Moreover, patient satisfaction and incidence of adverse events did not reveal any significant differences between treatment groups. CONCLUSION: Ibuprofen 400 mg and lornoxicam 8 mg were rated as equal and effective pain treatment medication after wisdom tooth surgery. In comparison, neither of the drugs provided clinical advantages nor did side effects occur more frequently after one of the analgesics

Comparison of different flow-reducing bag-valve ventilation devices regarding respiratory mechanics and gastric inflation in an unprotected airway model

OBJECTIVE: Gastric inflation (GI) is a significant issue when ventilation is performed on unprotected airways. DESIGN: Experimental analysis on the respiratory effects of hose extended bag-valve ventilation devices designed to reduce inspiratory pressure and flow. SETTING: Laboratory with lung/oesophageal sphincter simulator and pressure-flow-volume analyser. Lung compliance: 300ml/kPa, airway resistance: 0.5kPa/l/s. Lower oesophageal sphincter pressure (LOSP): 0.5kPa. INTERVENTIONS: Bag-valve ventilation of lung simulator. Twelve academic dental staff members used four devices: Ambu Mark III attached to either a reservoir bag (R) or a pressure relief valve (SV), SMART BAG (SB), and Easy Grip (EG) as control. RESULTS: After Bonferroni correction (p-level of significance 0.0083) for multiple comparisons, no evidence of difference between inspiratory tidal volumes (TVIN) administered by use of R (median 137ml) and SB (149ml) was found. Differences in TVIN were only detected between R and SV (188ml) (p=0.002). Only a trend towards TVIN differences between SB and R in comparison to EG (195ml) was found (p=0.009). Distributions of peak pressures differed when R (median 0.7kPa) and SV (1.0kPa) (p=0.006) or SB (0.7kPa) and SV (p=0.002) were compared. Peak inspiratory flow rates differed between EG (median 59l/min) and R (32l/min) as well as SB (42l/min) and between SB and SV (50l/min) (all with p=0.001). GI was lowest by use of R (median 103ml) compared to all other devices (EG: 518ml, SV: 394ml, SB: 271ml) (p=0.001). The areas under the pressure/flow over time curves were larger during SB compared to R ventilation. Mean airway pressures were significantly lower by use of R (0.1kPa) compared to SB (0.3kPa) (p<0.008). CONCLUSION: Lowering GI by pressure-flow reduction may result in lower TV depending on the device used. Lowest GI resulted from R ventilation. This may be explained by the specific pressure/time or flow/time patterns achieved by use of this device