MedicalResearch.com Interview with:
Prof. Dr. med. Christian Hugo
Head, Division of Nephrology
Medical Clinic III
Universitätsklinikum Carl Gustav Carus
an der Technischen Universität Dresden
MedicalResearch.com: What is the background for this study?
Response: At the end of 2007, the harmony trial was designed predominantly based on the one year results of the ELITE-Symphony trial, demonstrating that low dose tacrolimus, mycophenolate mofetile, and steroids together with monoclonal interleukin-2-receptor (CD 25 antigen) antibody induction therapy has superior efficacy in renal transplant patients compared to all other regimens (low or normal dose cyclosporine or sirolimus) tested. While these advantages of the low dose tacrolimus protocol were so convincing to become the new gold standard of immunosuppressive therapy within the next few years (see KDIGO guide lines for renal transplantation in 2009), the low dose tacrolimus treatment arm also demonstrated increased incidence rates regarding post-transplantation diabetes mellitus (PTDM, at that time called new onset of diabetes after transplantation – NODAT) compared to the low cyclosporine treatment arm. Previous studies had also demonstrated a detrimental association between NODAT and cardiovascular events and mortality, the leading cause of death in renal transplant recipients. Corticosteroid-free or rapid withdrawal regimens were relatively encouraging regarding influencing NODAT rates but only at the price of an increased rate of T cell mediated acute rejections.
Unfortunately at the time of study planning, the lack of PTDM incidence data in the literature as prospectively assessed by predefined (ADA) criteria did not allow to calculate case numbers for the Harmony trial. In contrast, sufficient evidence on biopsy proven acute rejection (BPAR) rates with/without rapid steroid withdrawal (RSW) enabled us to choose BPAR as the primary endpoint, which was for many years the number one goal / primary end point in transplant studies. In general, rabbit ATG therapy was considered to be superior compared to interleukin-2-receptor antagonistic induction therapy in the prevention of BPAR, but this comparison had not been tested in the situation of RSW in an immunological low risk transplant population.
Thus our randomized, multicentre Harmony Study was performed to evaluate which of the two induction therapies (Basiliximab versus rabbit ATG) was most efficacious at permitting rapid steroid withdrawal in a tacrolimus and MMF based immunosuppressive therapy within the first year after kidney transplantation. Efficacy of steroid withdrawal was evaluated against the currently accepted gold standard immunosuppressive regimen (low tacrolimus plus MMF plus corticosteroid regimen from the ELITE-Symphony trial).
MedicalResearch.com: What are the main findings?
Response: Biopsy proven acute rejection rates were not reduced by rabbit ATG (9·9%) compared to both other treatment arms A (11·2%) or B (10·6%) (A versus C: p=0·75; B versus C: p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes mellitus in arm B to 23·9% and in arm C to 22·7% compared to standard arm A with 39·2% (A versus B and C: P = 0·0004). Patient and censored graft survival after 12 months were excellent and equivalent in all arms with 94·7%, 97·4%, 96·9% and 96·1%, 96·8%, 95·8% respectively. Safety parameters like infections or the incidence of post-transplantation malignancies did not differ between the study arms.
While rabbit ATG did not show superiority over basiliximab induction for the prevention of biopsy proven acute rejections after rapid steroid withdrawal within one year after renal transplantation, this is the first multicentre, randomized study to demonstrate that rapid steroid withdrawal can be safely performed without compromising efficacy with a tacrolimus/MMF based regimen thus potentially improving safety profile in particular, reducing the incidence of the important cardiovascular risk factor PTDM.
Furthermore, our finding suggests that, in this low immunological risk population both induction agents, ATG or basiliximab are equipotent.
MedicalResearch.com:What should readers take away from your report?
Response: To our knowledge, the investigator initiated randomized, multicentre Harmony Study is the first study to provide evidence regarding the most efficacious and safe protocol for rapid steroid withdrawal and optimized choice of induction therapy (basiliximab versus rabbit ATG) within the first year after kidney transplantation. Our findings imply that rabbit ATG induction combined with RSW is not able to further lower the rate of biopsy proven acute rejections in an immunological low-risk patient population compared to basiliximab induction either with or without RSW based on the current gold standard therapy of low tacrolimus / MMF maintenance immunosuppression. On the other hand, the data of the Harmony trial demonstrate for the first time that RSW together with low dose tacrolimus and mycophenolate mofetil immunosuppression can be achieved with either induction therapies in more than 80% of renal transplant recipients without any negative impact on efficacy (rejections, survival etc.) but with a marked decrease of the cardiovascular risk factor PTDM within the first year after transplantation.
With all restrictions/limitations (long term follow up investigation etc.) as discussed in the article, we view these one year results as a major step towards the justification and stratification of RSW after renal transplantation. The Harmony study provides novel evidence for a new standard immunosuppressive strategy including RSW in an immunologically low-risk recipient population.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: The long term followup of this study (3 and 5y) is ongoing and important to see in regard to the incidence of cardiovascular events, mortality and allograft survival and function.
In addition, it may be important to find out whether renal transplant recipients with higher immunological risk can similarly successfully ( according to efficacy and safety) being treated with rapid steroid withdrawal.
In addition, we already started a trial (Slow&Low study), in which we hope to see beneficial results in regard to incidence of post-transplantation diabetes mellitus, kidney function or other safety parameters by achieving really low tacrolimus levels from the beginning after renal transplantation in an bottom up approach.
MedicalResearch.com: Is there anything else you would like to add?
Response: For a low immunological risk recipient population after renal transplantation, “Harmony may be better than Symphony”!
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial
Thomusch, Oliver et al.
The Lancet , Volume 0 , Issue 0 ,
Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.
More Medical Research Interviews on MedicalResearch.com