Fixed low dose versus concentration-controlled initial tacrolimus dosing with reduced target levels in the course after kidney transplantation: results from a prospective randomized controlled non-inferiority trial (Slow & Low study).
Stumpf, J., et al.EClinicalMedicine 2024; 67: 102381.
Aims
To assess if a slow & low tacrolimus regimen is non-inferior to classical dose of tacrolimus with regards biopsy proven acute rejection (BPAR) in an adult kidney transplant population.
Interventions
Participants were randomised to receive standard of care which was basiliximab induction, MMF, steroids and tacrolimus with trough levels 7-9mg/ml or ‘slow & low’ regimen of basiliximab induction, MMF, steroids and tacrolimus with 5 mg/day fixed for 7 days when to a trough level of 5-7ng/ml.
Participants
432 adult kidney transplant recipients receiving ABO-compatible organs with low immunological risk scores, from living or deceased donors.
Outcomes
Primary efficacy outcome was the combined endpoint of BPAR, graft failure and death within 6 months. Secondary endpoints were renal function, delayed graft function. Chronic ABMR, DSAs, PTDM, infective incidence
Follow-up
6 months post-transplantation
CET Conclusions
This large multi-centre European open-label RCT demonstrated non-inferiority of a slow & low tacrolimus regimen with regards their composite end-point of BPAR, graft failure and death over a period of 6 months. However, one should be cautious in the interpretation. It is important to note that the study was conducted in immunologically low risk recipients, clearly recipients with a negative CDC cross-match, but also no history of rejection in previous allografts, no DSAs, PRA <20% and no DCD organs, which in a wider context does limit the impact of the regimen’s presented non-inferiority. When scrutinising the results more closely, the combined primary end-point occurred in 20.3% of slow & low and 18.8% of the standard care, risk difference and two-sided 90% confidence interval 1.5% (−6.0%; 9.0%; one-sided test of equivalence with a non-inferiority margin of 12.5% p = 0.008), but in this context a non-inferiority margin of 12.5% could be considered too large, but if reduced to margins closer to 5%, which one might consider more appropriate in this context, significance would likely not be reached. This combined with the finding that there was a statistically higher percentage of BANFF IA-III, i.e above borderline, in the slow and low regimen compared with standard (11.6% vs 5.2%, p=0.027) could be a concern. The assessment on the impact of these is limited by the duration of follow-up being only 6 months, given these subtle event changes are impactful on the ultimate lifespan of a graft rather than necessarily acute losses. We must then consider conceptually the overall reason for interest in a slow & low regimen, which is the effects of early high trough levels. Slow & low avoided concerningly high trough levels within the first week, and by week 4 the levels in standard and slow & low are equilibrated, with acceptable therapeutic levels for nearly all patients throughout. However, despite this no difference was observed in secondary outcome parameter such as AE, SAE, kidney function, neurotoxicity, PTDM, or DGF (the study duration being too limited to consider implication to cardiovascular risk factors). While standardising early tacrolimus use is attractive for its clinical ease and its potential non-inferiority to standard care, the fact remains that variations in tacrolimus metabolism exist, and the present study is insufficient to confidently demonstrate the non-inferiority or reasoning behind a slow & low regimen.
Data analysis
Modified intention-to-treat analysis
Trial registration
EudraCT - 2013-001770-19