TEAMMATE Trial: Everolimus with Low-Dose Tacrolimus to Prevent Rejection in Children after Cardiac Transplantation

By Lucas Marinacci on

Key Points

  • This was the first randomized trial to evaluate the safety and efficacy of everolimus and low-dose tacrolimus in pediatric heart transplant recipients.
  • The open-label trial demonstrated that this combination is safe compared to standard dose tacrolimus and mycophenolate mofetil but was not associated with a lower burden of coronary allograft vasculopathy, rejection, and chronic kidney disease.
  • TEAMMATE was limited by lower event rates than expected and challenges related to protocol adherence due to the COVID19 pandemic.

There are no FDA-approved immunosuppression regimens to prevent rejection after heart transplantation (HT) in children.  While everolimus (EVL) may reduce the risk of cardiac allograft vasculopathy, chronic kidney disease, and cytomegalovirus (CMV) infection compared to tacrolimus (TAC), there are no randomized trials comparing them head -to-head.

On November 11, 2023 the results of The TEAMMATE Trial: Everolimus to Prevent Rejection in Children After Cardiac Transplantation were presented at AHA Scientific Sessions 2023.   This was the first randomized multicenter trial in pediatric HT that compared EVL and low dose TAC with standard dose TAC and mycophenolate mofetil (MMF) among patients aged less than 21 years 6 month post-HT.  It was open-label and conducted at 25 US sites.  Children were excluded if they had recurrent rejection, a received multi-organ transplant, nonadherence, severe hyperlipidemia or proteinuria, active infection, or an estimated glomerular filtration rate of <30ml/min/1.73m2.  The primary outcomes used the major adverse transplant event (MATE) score,  a composite which reflects the frequency and severity of MATEs that is validated against graft loss.1   The primary efficacy endpoint was the MATE-3 which included CAV, CKD, and acute cellular rejection (ACR).  The primary safety endpoint was the MATE-6, which included the components of the MATE-3 in addition to antibody-mediated rejection, infection, and port-transplant lymphoproliferative disorder (PTLD).  

The trial randomized 211 patients, 107 to the EVL group and 104 to the MMF group.  Three patients in the MMF group were lost to follow-up.   The main age in the EVL group was 7.2 years, while it was 9 years in the MMF group.  About 80% were white.   At 30 months post randomization, the mean MATE-3 score was 0.93 +/- 2.18 for the EVL group and 1.25+/- 2.46 for the MMF group, with a zero-inflated Wilcoxon p-vale of 0.15, indicating no difference in the primary efficacy endpoint.  EVL had a lower numerical MATE score for CAV and CKD and a numerically higher MATE score for cellular rejection.  

The mean MATE-6 score in the EVL group was 1.96 +/- 4.67  and in the MMF group it was 2.18 +/- 4.80, for an adjusted mean difference of -0.22 (95% CI -1.51-1.10); therefore there was no significant difference between the groups in terms of the primary safety endpoint.  The EVL group met the pre-specified safety goal of <3 for success. EVL had a numerically lower MATE score for CAV, CKD, and all types of rejection, but a numerically higher MATE score for infection and PTLD.    The EVL group also had a significantly lower cumulative burden of CAV, CKD, ACR, and CMV infection, significantly higher GFR, and significantly lower proportion of patients with anti-HLA antibodies, all pre-specified secondary endpoints.  They did not find any significant difference in treatment effect across pre-specified subgroups, which included transplant center volume, gender, race, and history of treated rejection.  In terms of adverse events, aphthous stomatitis was significantly higher in the EVL group, as were levels of cholesterol and liver enzymes.  Overall, 21% patients in each arm were withdrawn from the assigned study treatment.

Christopher S Almond, MD, of Stanford University, concluded: “Everolimus combined with low-dose tacrolimus is safe in children and young adults when initiated at 6 months after transplant and was not associated with a lower burden of CAV, rejection, and CKD, but was associated with a lower burden of MATE-3 events with CMV infection was included in the MATE score.  Subjects receiving everolimus tended to have a higher GFR, lower rate of anti-HLA antibody development, and less CMV infection but more hyperlipidemia and higher liver transaminases.”



1. Almond CS, Sleeper LA, Rossano JW, et al. The teammate trial: Study design and rationale tacrolimus and everolimus against tacrolimus and MMF in pediatric heart transplantation using the major adverse transplant event (MATE) score. Am Heart J. 2023;260:100–112.