Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
coTrial Associates, Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
Trials. 2023 May 11;24(1):325. doi: 10.1186/s13063-023-07344-7.
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.
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.
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.
This trial has been registered (4 May 2020) in the EU Clinical Trials Register, EudraCT-Nummer: 2020-000796-20. Additionally, this trial has been registered (22 January 2021) at ClinicalTrials.gov: NCT04720326. The trial received a favourable opinion from the concerned lead ethics committee at the University of Regensburg, under the reference 20-1842-112.
移植物排斥和慢性 CNI 毒性仍然是器官移植成功的障碍。他克莫司目前的制剂，如 Prograf®和 Advagraf™，在药代动力学和耐受性方面存在局限性，部分原因是生物利用度不理想。由于剂量不依从可能导致移植物排斥，因此开发了他克莫司的每日一次制剂 Advagraf™（与每天两次的 Prograf®相比）。Advagraf™的益处被治疗谷浓度的延迟实现以及需要高达 50%更高的剂量来维持 Prograf®等效谷浓度所抵消。Envarsus®也是一种延长释放的每日一次他克莫司制剂，使用 MeltDose™药物输送技术开发，以提高药物生物利用度；提高生物利用度导致患者药物吸收变异性降低，峰谷波动不明显。在三期从头肾移植研究中，Envarsus®被证明与每日两次的他克莫司不劣效；然而，在从头肝移植（LTx）受者中，没有 IV 期研究显示 Envarsus®优于 Advagraf™。
EnGraft 比较了生物利用度，并测试了从头 LTx 受者中 Envarsus®（试验组）与 Advagraf™（对照组）的优势。来自德国 15 个移植中心的 268 名患者将在 LTx 后 14 天内按 1:1 随机分组。主要终点是随机分组后 12 周时测定的剂量归一化谷浓度（C/D 比值）。次要终点包括剂量调整次数、达到首次定义的谷浓度的时间和移植物排斥的发生率。此外，将在 3 年期间评估临床和实验室参数。
C/D 比值是他克莫司生物利用度的估计值。使用 Envarsus 提高生物利用度和增加 C/D 比值可能会降低肾功能不全和其他他克莫司相关毒性；先前的试验表明，较高的 C/D 比值（即他克莫司代谢较慢）不仅与改善肾功能相关，还与减少神经毒性副作用相关。较高的 C/D 比值可能会改善 LTx 受者的临床结局；EnGraft 已经开始，到 2022 年 1 月已招募了三分之一的患者。
该试验已于 2020 年 5 月 4 日在欧盟临床试验注册处注册，EudraCT-Nummer：2020-000796-20。此外，该试验已于 2021 年 1 月 22 日在 ClinicalTrials.gov 上注册：NCT04720326。该试验得到了雷根斯堡大学相关主要伦理委员会的有利意见，参考号为 20-1842-112。
