A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT

Armin D Goralczyk, Andreas Schnitzbauer, Tung Y Tsui, Giuliano Ramadori, Thomas Lorf, Aiman Obed, Armin D Goralczyk, Andreas Schnitzbauer, Tung Y Tsui, Giuliano Ramadori, Thomas Lorf, Aiman Obed

Abstract

Background: Immunosuppression with calcineurin inhibitors (CNI) increases the risk of renal dysfunction after orthotopic liver transplantation (OLT). Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation.

Methods/design: A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate), liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT), treatment failure, (i. e., re-introduction of CNI), incidence of adverse events, and mortality up to one year after OLT.

Discussion: This prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation) of this phase III trial.

Trial registration number: NCT00890253 (clinicaltrials.gov).

Figures

Figure 1
Figure 1
Scheme of proposed reno-protective immunosuppressive regimen without CNI. Abbr.: EC-MPS, enteric-coated mycophenolate sodium; POD, post-operative day; BW, body weight; q12h and q24h, every 12 or 24 hours.
Figure 2
Figure 2
Flow chart of the CILT study. Derived from an optimal two-stage design for a phase II clinical trial with the following parameters: p0 = 0.8, p1 = 0.95, error probability α = 0.05, and error probability β = 0.2. Abbr.: n, number of patients; r, maximum number of responders at which H0 will not be rejected; H1, alternative hypothesis.

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