A randomized trial of everolimus-based quadruple therapy versus standard triple therapy early after lung transplantation.
Gottlieb, J., Neurohr, C. et al. (2019).American Journal of Transplantation [record in progress].
Aims
The aim of the current study was to demonstrate that everolimus with low CNI exposure in a quadruple immunosuppression regimen is superior to a standard triple CNI regimen in terms of renal function, as assessed by eGFR, in patients with impaired kidney function early after lung transplantation.
Interventions
Patients were randomised to either a quadruple low CNI regimen or to a standard triple CNI regimen.
Participants
The study population comprised 232 adults (>18 years) who had received a lung transplant from a deceased donor 3â€18 months prior to study entry.
Outcomes
The primary endpoint was renal function at 12 months, as assessed by estimated GFR. Secondary endpoints included: renal function at months 1, 3, 6, 9 and 12, incidence of acute rejection, incidence and time to progression of bronchiolitis obliterans syndrome (BOS), incidence of graft loss/retransplantation, incidence of death, exercise capacity (as assessed by the six-minute walk test) and quality of life, all at months 6 and 12 post-randomisation.
Follow-up
12 months
CET Conclusions
This is an interesting and well conducted study in lung transplantation. The primary aim was to see if the addition of everolimus to the immunosuppression regimen would permit reduction of CNI doses and hence improve eGFR at one year after randomisation. Reduced eGFR is also a surrogate marker, or predictor, for future cardiovascular events and mortality. The study was only conducted in patients at least 3 months after transplantation and with only mild to moderate renal impairment. The method of randomisation was adequate and allocation concealment was maintained, although the study had to be open-label to permit clinicians to monitor and adjust drug doses. The power calculation is presented and seems reasonable. Both intention to treat and per-protocol results are presented. At the end of the study 70% of the everolimus group were still on allocated treatment, compared to 90% in the standard treatment group. In both the ITT and per protocol analysis, patients in the everolimus arm had an improved eGFR at 12 months (65ml/min versus 55ml/min ITT). Patients in the standard treatment arm had on average a gradual fall in eGFR over the 12 months, whilst patients in the everolimus arm had on average a small increase. There was no significant difference in BPAR rates, which were equally low. Acne and peripheral oedema were significantly more common in the everolimus arm (18% versus 1% and 33% versus 16%). There was no significant difference in infectious complications. Despite being underpowered, this study demonstrated that a quadruple immunosuppression regimen including everolimus could improve eGFR in lung transplant recipients compared to standard triple immunosuppression. A significant proportion of patients will not tolerate this study regimen, but it did not result in an increase in serious adverse events.
Data analysis
Strict intention-to-treat analysis
Trial registration
ClinicalTrials.gov - NCT01404325