A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT

Abstract

Background: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression.

Methods: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025.

Discussion: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents.

Trial registration: EU CT-Number: 2022-500024-30-00.

Keywords: Graft rejection; Immunological monitoring; Immunosuppression; Infection; Kidney transplantation; Personalised medicine; Tacrolimus; Torque teno virus.

Fig. 1

Tacrolimus (TAC) dosing during the interventional phase of the TTVguideIT study: In the active/interventional group, the tacrolimus trough level range will be adapted by torque teno virus (TTV) load. The target TTV load ranges from 4.6 log₁₀ copies per millilitre (c/mL) to 6.2 log₁₀ c/mL as the optimal range. If TTV is not within the optimal range, the TAC trough level target has to be adapted by one step up (only if the patient is adherent to TAC intake) or down compared to the current TAC trough level. One TAC trough level adaption step is defined as 2±1 ng/mL. Additional rules are detailed in the trial protocol. In the control group, TAC will be dosed according to TAC trough levels defined by the local centre standard

Fig. 2

Study flow of the TTVguideIT study: Informed consent will be obtained from all consecutive adult recipients of a kidney allograft within the first 2 weeks after transplantation at the inpatient ward, and patients will be enrolled in the screening phase of the study (V−3). Subsequent screening visits will be in months 2 (V−2) and 3 (V−1) after transplantation. If all inclusion criteria are met and no exclusion criteria are present, participants will be enrolled in the clinical trial and randomised in month 4 after transplantation (V1). The TAC dose will be adjusted according to the TTV-guided TAC trough level target or the routine centre TAC trough level target. Participants will visit the outpatient clinic every 6 weeks, following the same procedure up to and including month 12 after transplantation (V2–V6). Follow-up will be performed until month 13 post-transplantation (V7)

Fig. 3

Trial design of the TTVguideIT study: Screening will start within the first 2 weeks after transplantation (V−3). Subsequent screening visits will be in months 2 (V−2) and 3 (V−1) after transplantation. Enrolment and randomisation will be in month 4 after transplantation (V1). During the interventional phase, visits will be every 6 weeks (V2–V6). Follow-up will be performed until month 13 post-transplantation (V7)