TEAMMATE trial: A collaborative effort to improve the care of pediatric heart transplant recipients
Today, children survive an average of 15 years after a heart transplant, which means that many who receive a heart transplant during childhood fail to survive into adulthood. This is primarily due to infection, rejection, and renal and coronary complications. Unlike pediatric renal and liver transplant, where a number of randomized clinical trials have been performed as early as the 1990s, there has never been a multicenter randomized clinical trial of anti-rejection therapy in pediatric heart transplant. That is, until now.
Kevin P. Daly, MD, cardiologist at Boston Children’s Hospital and Christopher Almond, MD, MPH, cardiologist at Stanford Children’s Hospital, were inspired to action after a conversation about this lack of research while attending the International Society for Heart and Lung Transplantation (ISHLT) Annual Meeting in 2014.
In September of 2017, the results of their labor came to fruition with a grant award of $9.4 million to execute a novel randomized trial at 25 centers, with leadership at Boston Children’s (Data Coordinating Center) and Stanford University (Clinical Coordinating Center). The trial is supported by a grant from the United States Department of Defense. Lynn Sleeper, ScD, scientific director for cardiology and cardiac surgery clinical research at Boston Children’s is the principal investigator for the study.
First study of its kind
This FDA-regulated study is the first multicenter randomized trial of maintenance immunosuppression and will study 210 children at six months following their heart transplant and beyond. It aims to examine whether a new anti-rejection regimen — everolimus in combination with low-dose tacrolimus (EVL/TAC) — can reduce or prevent some of the common complications of transplant that limit survival, such as rejection, coronary artery disease and kidney disease, compared to the current standard of care, tacrolimus and mycophenolate mofetil (TAC/MMF).
Preliminary studies suggest that EVL/TAC may prevent rejection, coronary artery disease and kidney failure more effectively than TAC/MMF. However, these studies are limited by single-center design, inconsistent endpoint definitions and use of historical controls. In this new trial, the primary endpoint will be a recently-validated surrogate endpoint — the major adverse transplant event (MATE) score, which efficiently predicts long-term graft survival, and for which the study has obtained FDA approval. The FDA, NIH and other organizations have been behind an innovation push in surrogate endpoint development to improve the quality and efficiency of rare disease research.
“It’s been difficult to execute randomized medication trials in children for a variety of reasons, one being you don’t often have an adequate number of patients to achieve proper statistical power,” says Daly. “One of the real innovations of this trial is using the MATE score to reduce the required sample size.”
The study began enrollment in January of 2018 and will recruit patients over a period of 15 months. There will be 2.5 years of follow-up per subject (eight serial measurements) providing 90 percent power for the primary endpoint, the MATE score at 2.5 years. The endpoint will be centrally adjudicated and angiograms will be reviewed by a core laboratory at the University of Colorado-Anschutz Medical Campus.
The ultimate goals of this study are to:
- improve the long-term safety and survival of children after heart transplant
- obtain FDA approval of the first anti-rejection medicine for pediatric heart transplant
- catalyze collaboration between pediatric centers to support clinical trials in pediatric heart transplantation in the future
Utilizing a single IRB
Another innovation of this trial is using a single, central Institutional Review Board (IRB) through Boston Children’s. “We’re hoping this process will be a lot more efficient than using separate IRBs for each center,” says Sleeper. “It’s our understanding that this is the largest, most complex study that Boston Children’s has taken on in this way. Susan Kornetsky, the director of clinical research compliance for the IRB at Boston Children’s, has been a national leader in trying to drive this new approach.”
Providing regulators with rigorous data
While it remains to be seen whether one regimen is found to be superior over the other, the collection of high-quality safety and efficacy data as part of the present study should provide regulators with data that are sufficiently rigorous to generate pediatric-specific heart transplant labeling for one or more of the immunosuppressant regimens.
Find more information about the trial at https://clinicaltrials.gov/show/NCT03386539
A sample of recently-published research by Heart Center faculty.
Balasubramanya S, Zurakowski D, Borisuk M, Kaza AK, Emani SM, del Nido PJ, Baird CW. Right ventricular outflow tract reintervention after primary tetralogy of Fallot repair in neonates and young infants. The Journal of Thoracic and Cardiovascular Surgery.
Bergersen L, Benson LN, Gillespie MJ, Cheatham SL, Crean AM, Hor KN, Horlick EM, Lung TH, McHenry BT, Osten MD, Powell AJ, Cheatham JP. Harmony Feasibility Trial: Acute and Short-Term Outcomes With a Self-Expanding Transcatheter Pulmonary Valve. Cardiovascular Interventions. 2017; 10:1763-1773.
Chandler SF, Fynn-Thompson F, Mah DY. Role of cardiac pacing in congenital complete heart block. Expert Review of Cardiovascular Therapy. 2017; 15:853-861.
Chen J, Fu Y, Day DS, Sun Y, Wang S, Liang X, Gu F, Zhang F, Stevens SM, Zhou P, Li K, Zhang Y, Lin RZ, Smith LEH, Zhang J, Sun K., Melero-Martin JM, Han Z, Park PJ, Zhang B, Pu WT. VEGF amplifies transcription through ETS1 acetylation to enable angiogenesis. Nature Communications. 2017; 8:383.
Emani SM, Zurakowski D, Mulone M, DiNardo JA, Trenor CC, 3rd. Platelet testing to guide aspirin dose adjustment in pediatric patients after cardiac surgery. The Journal of Thoracic and Cardiovascular Surgery. 2017; 154:1723-1730.
Martin E, del Nido PJ, Nathan M. Technical performance scores are predictors of midterm mortality and reinterventions following congenital mitral valve repair. European Journal of Cardio-Thoracic Surgery.
Masoumi N, Copper D, Chen P, Cubberley A, Guo K, Lin RZ, Ahmed B, Martin D, Aikawa E, Melero-Martin J, Mayer, J. Elastomeric Fibrous Hybrid Scaffold Supports In Vitro and In Vivo Tissue Formation. Advanced Functional Materials. 2017; 27:11.
Merlocco A, Lacro RV, Gauvreau K, Rabideau N, Singh MN, Prakash A. Longitudinal Changes in Segmental Aortic Stiffness Determined by Cardiac Magnetic Resonance in Children and Young Adults With Connective Tissue Disorders (the Marfan, Loeys-Dietz, and Ehlers-Danlos Syndromes, and Nonspecific Connective Tissue Disorders). The American Journal of Cardiology. 2017; 120:1214-9.
Nasr VG, Faraoni D, Valente AM, DiNardo JA. Outcomes and Costs of Cardiac Surgery in Adults with Congenital Heart Disease. Pediatric Cardiology.
Nathan M, Beroukhim R, Gauvreau K, Demeritt A, Marcus E, Geva T, Baird C, del Nido PJ. Aortic Valve Repair in the Pediatric Population: Midterm Outcomes Comparing Leaflet Repair Using Autologous Pericardium Versus Porcine Intestinal Submucosa (Cormatrix ®). Journal of the American College of Cardiology. 2017; 69:557.
Prosnitz AR, Leopold J, Irons M, Jenkins K, Roberts AE. Pulmonary vein stenosis in patients with Smith-Lemli-Opitz syndrome. Congenital Heart Disease. 2017; 12:475-83.
Rajpal S, Alshawabkeh L, Opotowsky AR. Current Role of Blood and Urine Biomarkers in the Clinical Care of Adults with Congenital Heart Disease. Current Cardiology Reports. 2017; 19:50.
Rathod RH, Jurgen B, Hamershock RA, Friedman KG, Marshall AC, Samnaliev M, Graham DA, Jenkins K, Lock JE, Powell AJ. Impact of standardized clinical assessment and management plans on resource utilization and costs in children after the arterial switch operation. Congenital Heart Disease.
Rescoe E, Tang X, Perry DA, Sleeper LA, DiNardo JA, Kussman BD, Kheir, JN. Cerebral near-infrared spectroscopy insensitively detects low cerebral venous oxygen saturations after stage 1 palliation. The Journal of Thoracic and Cardiovascular Surgery. 2017; 154(3):1056-62.
Rollins CK, Newburger JW, Roberts AE. Genetic contribution to neurodevelopmental outcomes in congenital heart disease: are some patients predetermined to have developmental delay? Current Opinion in Pediatrics.
Shin B, Cowan DB, Emani SM, del Nido PJ, McCully JD. Mitochondrial Transplantation in Myocardial Ischemia and Reperfusion Injury. Advances in Experimental Medicine and Biology. 2017; 982:595-619.
Son MBF, Gauvreau K, Kim S, Tang A, Dedeoglu F, Fulton DR, Lo MS, Baker AL, Sundel RP, Newburger JW. Predicting Coronary Artery Aneurysms in Kawasaki Disease at a North American Center: An Assessment of Baseline z Scores. Journal of the American Heart Association. 2017; 6(6).
Tannous P, Ghelani SJ, Marshall AC, Porras D. Angiographically detectable Thebesian veins are a dynamic and reversible finding in the setting of congenital heart disease. Congenital Heart Disease. 2017; 12:467-74.
VanderPluym CJ, Cedars A, Eghtesady P, Maxwell BG, Gelow JM, Burchill LJ, Maltais S, Koehl DA, Cantor R., Blume ED. Outcomes following implantation of mechanical circulatory support in adults with congenital heart disease: An analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). The Journal of Heart and Lung Transplantation. 2017.
Gellis L, Baird CW, Emani S, Borisuk M, Gauvreau K, Padera RF, Jr., Sanders, SP. Morphologic and histologic findings in bioprosthetic valves explanted from the mitral position in children younger than 5 years of age. The Journal of thoracic and cardiovascular surgery.
Perry DA, Salvin JW, Romfh P, Chen P, Krishnamurthy K, Thomson LM, Polizzotti, BD, McGowan, FX, Vakhshoori, D, Kheir, JN. Responsive monitoring of mitochondrial redox states in heart muscle predicts impending cardiac arrest. Sci Transl Med. 2017;9(408):11.
Saleeb SF, McLaughlin SR, Graham DA, Friedman KG, Fulton DR. Resource reduction in pediatric chest pain: Standardized clinical assessment and management plan. Congenital heart disease. 2017.
Sykes MC, Nathan M, Sanders SP, Gauvreau K, Pigula FA, Rhodes J. Pseudoaneurysm complicating right ventricle-to-pulmonary artery conduit surgery: Incidence and risk factors. The Journal of thoracic and cardiovascular surgery. 2017;154(6):2046-9.
VanDusen NJ, Guo Y, Gu W, Pu WT. CASAAV: A CRISPR-Based Platform for Rapid Dissection of Gene Function In Vivo. Current protocols in molecular biology. 2017;120:31 11 1-31 11 4.
Bokma JP, Geva T, Sleeper LA, Babu Narayan SV, Wald R, Hickey K, Jansen, K, Wassall, R, Lu, M, Gatzoulis, MA, Mulder, BJ, Valente, AM. A propensity score-adjusted analysis of clinical outcomes after pulmonary valve replacement in tetralogy of Fallot. Heart British Cardiac Society. 2017.
Gellis L, Baird CW, Emani S, Borisuk M, Gauvreau K, Padera RF, Sanders SP. Morphologic and histologic findings in bioprosthetic valves explanted from the mitral position in children younger than 5 years of age. The Journal of Thoracic and Cardiovascular Surgery.
Perry DA, Salvin JW, Romfh P, Chen P, Krishnamurthy K, Thomson LM, Polizzotti BD, McGowan FX, Vakhshoori D, Kheir JN. Responsive monitoring of mitochondrial redox states in heart muscle predicts impending cardiac arrest. Science Translational Medicine. 2017; 9 (408):11.
Saleeb SF, McLaughlin SR, Graham DA, Friedman KG, Fulton DR. Resource reduction in pediatric chest pain: Standardized clinical assessment and management plan. Congenital Heart Disease. 2017.
Sykes MC, Nathan M, Sanders SP, Gauvreau K, Pigula FA, Rhodes J. Pseudoaneurysm complicating right ventricle-to-pulmonary artery conduit surgery: Incidence and risk factors. The Journal of Thoracic and Cardiovascular Surgery. 2017; 154(6): 2046-9.
VanDusen NJ, Guo Y, Gu W, Pu WT. CASAAV: A CRISPR-Based Platform for Rapid Dissection of Gene Function In Vivo. Current Protocols in Molecular Biology. 2017; 120:31 11 1-31 11 4.
Bokma JP, Geva T, Sleeper LA, Babu Narayan SV, Wald R, Hickey K, Jansen, K, Wassall, R, Lu M, Gatzoulis MA, Mulder BJ, Valente AM. A propensity score-adjusted analysis of clinical outcomes after pulmonary valve replacement in tetralogy of Fallot. Heart (British Cardiac Society). 2017.