Clinical trial design and rationale of the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) investigational device exemption clinical study protocol

The HeartMate 3 left ventricular assist system (LVAS; St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA) was recently introduced into clinical trials for durable circulatory support in patients with medically refractory advanced-stage heart failure. This centrifugal, fully magnetically levitated, continuous-flow pump is engineered with the intent to enhance hemocompatibility and reduce shear stress on blood elements, while also possessing intrinsic pulsatility. Although bridge-to-transplant (BTT) and destination therapy (DT) are established dichotomous indications for durable left ventricular assist device (LVAD) support, clinical practice has challenged the appropriateness of these designations. The introduction of novel LVAD technology allows for the development of clinical trial designs to keep pace with current practices. The prospective, randomized Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) clinical trial aims to evaluate the safety and effectiveness of the HeartMate 3 LVAS by demonstrating non-inferiority to the HeartMate II LVAS (also St. Jude Medical, Inc.). The innovative trial design includes patients enrolled under a single inclusion and exclusion criteria , regardless of the intended use of the device, with outcomes ascertained in the short term (ST, at 6 months) and long term (LT, at 2 years). This adaptive trial design includes a pre-specified safety phase (n = 30) analysis. The ST cohort includes the first 294 patients and the LT cohort includes the first 366 patients for evaluation of the composite primary end-point of survival to transplant, recovery or LVAD support free of debilitating stroke (modified Rankin score >3), or re-operation to replace the pump. As part of the adaptive design, an analysis by an independent statistician will determine whether sample size adjustment is required at pre-specified times during the study. A further 662 patients will be enrolled to reach a total of 1,028 patients for evaluation of the secondary end-point of pump replacement at 2 years. The HeartMate 3 left ventricular assist system (LVAS; St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA) was recently introduced into clinical trials for durable circulatory support in patients with medically refractory advanced-stage heart failure. This centrifugal, fully magnetically levitated, continuous-flow pump is engineered with the intent to enhance hemocompatibility and reduce shear stress on blood elements, while also possessing intrinsic pulsatility. Although bridge-to-transplant (BTT) and destination therapy (DT) are established dichotomous indications for durable left ventricular assist device (LVAD) support, clinical practice has challenged the appropriateness of these designations. The introduction of novel LVAD technology allows for the development of clinical trial designs to keep pace with current practices. The prospective, randomized Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) clinical trial aims to evaluate the safety and effectiveness of the HeartMate 3 LVAS by demonstrating non-inferiority to the HeartMate II LVAS (also St. Jude Medical, Inc.). The innovative trial design includes patients enrolled under a single inclusion and exclusion criteria , regardless of the intended use of the device, with outcomes ascertained in the short term (ST, at 6 months) and long term (LT, at 2 years). This adaptive trial design includes a pre-specified safety phase (n = 30) analysis. The ST cohort includes the first 294 patients and the LT cohort includes the first 366 patients for evaluation of the composite primary end-point of survival to transplant, recovery or LVAD support free of debilitating stroke (modified Rankin score >3), or re-operation to replace the pump. As part of the adaptive design, an analysis by an independent statistician will determine whether sample size adjustment is required at pre-specified times during the study. A further 662 patients will be enrolled to reach a total of 1,028 patients for evaluation of the secondary end-point of pump replacement at 2 years. Early clinical trials of durable left ventricular assist device (LVAD) support prospectively included bridge-to-transplant (BTT) candidates and compared them to historical or parallel control patients who did not undergo device implantation.1Frazier O.H. Rose E.A. McCarthy P. et al.Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system.Ann Surg. 1995; 222: 327-336Crossref PubMed Scopus (309) Google Scholar, 2Frazier O.H. Rose E.A. Macmanus Q. et al.Multicenter clinical evaluation of the HeartMate 1000 IP left ventricular assist device.Ann Thorac Surg. 1992; 53: 1080-1090Abstract Full Text PDF PubMed Scopus (361) Google Scholar, 3Frazier O.H. Rose E.A. Oz M.C. et al.Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation.J Thorac Cardiovasc Surg. 2001; 122: 1186-1195Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar After nearly a decade of successful BTT experience, the Thoratec paracorporeal VAD system and the HeartMate I devices (IP-LVAD and VE-LVAD; Thoratec Corporation, Pleasanton, CA) were commercially approved by the United States Food and Drug Administration (FDA) for this indication.1Frazier O.H. Rose E.A. McCarthy P. et al.Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system.Ann Surg. 1995; 222: 327-336Crossref PubMed Scopus (309) Google Scholar, 3Frazier O.H. Rose E.A. Oz M.C. et al.Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation.J Thorac Cardiovasc Surg. 2001; 122: 1186-1195Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar, 4Farrar D.J. Hill J.D. Pennington D.G. et al.Preoperative and postoperative comparison of patients with univentricular and biventricular support with the Thoratec ventricular assist device as a bridge to cardiac transplantation.J Thorac Cardiovasc Surg. 1997; 113: 202-209Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar The limited donor supply and consequent strict transplant candidacy criteria generated a need for such therapy in transplant-ineligible candidates with advanced heart failure who could potentially benefit from permanent, lifetime LVAD support. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, the first randomized, controlled trial with an LVAD, was thus conceived and led to FDA approval for the indication of “destination therapy” (DT).5Rose E.A. Gelijns A.C. Moskowitz A.J. et al.Long-term mechanical left ventricular assistance for end-stage heart failure.N Engl J Med. 2001; 345: 1435-1443Crossref PubMed Scopus (3375) Google Scholar, 6Rose E.A. Moskowitz A.J. Packer M. et al.The REMATCH trial: rationale, design, and end points.Ann Thorac Surg. 1999; 67: 723-730Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar On the basis of these approved indications, the Centers for Medicare and Medicaid Services in the USA established criteria for reimbursement, and the regulatory agencies used similar criteria for center accreditation. Accordingly, all successive clinical trials with new LVADs targeted these distinct BTT and DT indications. Thus, the ADVANCE trial of the HeartWare HVAD (HeartWare, Inc., Framingham, MA) enrolled a BTT population and compared outcomes with registry-derived patients implanted contemporaneously with commercially available devices.7Aaronson K.D. Slaughter M.S. Miller L.W. et al.Use of an intrapericardial, continuous flow, centrifugal pump in patients awaiting heart transplantation.Circulation. 2012; 125: 3191-3200Crossref PubMed Scopus (516) Google Scholar The HeartMate II LVAS (St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA) is currently approved for BTT and DT, whereas the HVAD remains indicated for BTT alone and trials examining the use of an HVAD in DT populations await completion. Despite improved survival and quality of life, long-term success with current devices remains partially limited by adverse effects, including infections, neurologic complications and pump thromboses.8Goldstein D.J. Naftel D. Holman W. et al.Continuous-flow devices and percutaneous site infections: clinical outcomes.J Heart Lung Transplant. 2012; 31: 1151-1157Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 9Coffin S.T. Haglund N.A. Davis M.E. et al.Adverse neurologic events in patients bridged with long-term mechanical circulatory support: a device-specific comparative analysis.J Heart Lung Transplant. 2015; 34: 1578-1585Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 10Stewart G.C. Givertz M.M. Mehra M. Pump thrombosis redux.J Heart Lung Transplant. 2015; 34: 1511-1514Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 11Stulak J.M. Davis M.E. Haglund N. et al.Adverse events in contemporary continuous-flow left ventricular assist devices: a multi-institutional comparison shows significant differences.J Thorac Cardiovasc Surg. 2016; 151: 177-189Abstract Full Text Full Text PDF Scopus (98) Google Scholar The HeartMate 3 LVAS is a centrifugal-flow pump engineered to optimize fluid dynamics and developed with wider blood-flow passages with the intent to avert thrombogenesis. The HeartMate 3 was first evaluated in humans in 50 patients in a single-arm, prospective, non-randomized clinical study outside of the USA to meet the Conformité Européenne (CE) mark requirements.12Schmitto J.D. Hanke J.S. Rojas S.V. et al.First implantation in man of a new magnetically levitated left ventricular assist device (HeartMate III).J Heart Lung Transplant. 2015; 34: 858-860Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 13Netuka I. Sood P. Pya Y. et al.Fully magnetically levitated left ventricular assist system for the treatment of advanced HF: a multicenter study.J Am Coll Cardiol. 2015; 66: 2579-2589Crossref PubMed Scopus (175) Google Scholar Figure 1 presents the competing outcomes analysis, and Table 1 presents the adverse event data from this first-in-humans experience through 6 months of follow-up.13Netuka I. Sood P. Pya Y. et al.Fully magnetically levitated left ventricular assist system for the treatment of advanced HF: a multicenter study.J Am Coll Cardiol. 2015; 66: 2579-2589Crossref PubMed Scopus (175) Google ScholarTable 1All Adverse Events Through 6 Months for the 50 Patients Enrolled in the HeartMate 3 CE Mark Clinical Trial13Netuka I. Sood P. Pya Y. et al.Fully magnetically levitated left ventricular assist system for the treatment of advanced HF: a multicenter study.J Am Coll Cardiol. 2015; 66: 2579-2589Crossref PubMed Scopus (175) Google ScholarDays 0 to 30 (n = 50)Days >30 (n = 49)All (n = 50)Adverse eventPatients (n)Patients (%)Number of eventsPatients (n)Patients (%)Number of eventsPatients (n)Patients (%)Number of eventsBleeding15301981616193835Requiring surgery61262427148GI bleeding242364486Cardiac arrhythmias142814363173417Infection102014122414183628Sepsis4844848168Drive-line1214845105StrokeaIncludes 3 procedural-related events: 1 implant issue (difficulty engaging inflow conduit); 1 after anaphylactic shock from contrast media; and 1 after transcatheter aortic valve implantation procedure.2424846126Ischemic242242484Hemorrhagic000242242Neurologic dysfunction otherbSeizure (n = 2) and transient ischemic attack (n = 2).242242484Device thrombosis000000000Device malfunction000000000Hemolysis000000000Psychiatric episode121242363Renal dysfunction51050005105Hepatic dysfunction121000121Respiratory failure71471218168Right heart failure4841215105Requiring RVAD242000242Wound dehiscence242242363Other eventcOther adverse events include pleural effusion (n = 1), volume status (n = 5), and high/low INR (n = 7) and various (n = 10).183635193925275460GI, gastrointestinal; INR, international normalized ratio; RVAD, right ventricular assist device.a Includes 3 procedural-related events: 1 implant issue (difficulty engaging inflow conduit); 1 after anaphylactic shock from contrast media; and 1 after transcatheter aortic valve implantation procedure.b Seizure (n = 2) and transient ischemic attack (n = 2).c Other adverse events include pleural effusion (n = 1), volume status (n = 5), and high/low INR (n = 7) and various (n = 10). Open table in a new tab GI, gastrointestinal; INR, international normalized ratio; RVAD, right ventricular assist device. The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing MCS Therapy With HeartMate 3) investigational device exemption (IDE) randomized, pivotal clinical trial aims to evaluate the safety and effectiveness of the HeartMate 3 LVAS by demonstrating non-inferiority to the HeartMate II LVAS when used for the treatment of advanced, refractory left ventricular heart failure, irrespective of the primary implant strategic intent. The HeartMate 3 LVAS includes an implanted blood pump, a modular drive-line and external power and control components (Figure 2). With the exception of the system controller, all external components are identical for both the HeartMate II (HMII) and HeartMate 3 (HM3). The design strategy for the HM3 involved adopting successful elements of the HMII while pursuing a different technological path to address hemocompatibility factors associated with most clinically significant adverse events with mechanical circulatory support. Comparisons of the fundamental characteristics of the HMII and HM3 are provided in Table 2 and Figure 3. A description of the HMII has been provided elsewhere.14Miller L.W. Pagani F.D. Russell S.D. et al.Use of a continuous-flow device in patients awaiting heart transplantation.N Engl J Med. 2007; 357: 885-896Crossref PubMed Scopus (1414) Google ScholarTable 2Comparison of HeartMate II and HeartMate 3 DevicesCharacteristicHeartMate IIHeartMate 3Pump (flow)AxialCentrifugalBearingMechanical (blood washed)MagneticHydraulic capacityUp to 10.0 liters/minUp to 10.0 liters/minImplantation locationExtrathoracicIntrathoracicTypical clinical speed range8,000 to 10,000 rpm5,000 to 6,000 rpmTextured surfaces (sintered titanium)YesYesInflow graft14-mm sealed VascutekNoneOutflow graft14-mm sealed Vascutek14-mm sealed VascutekQuick pump in in of HMII Open table in a new tab Figure of the HeartMate blood from the left into the pump through the inflow blood is by the inflow the controlled by the to the for blood to through the through the of the HeartMate 3. The is magnetically levitated and The levitated passages and A the is in this are into the implantable Figure The technology in the HM3 a magnetically levitated and blood-flow passages are with the intent to reduce blood shear stress the blood-flow passages speed for the introduction of an The is intended to of the pump and to a of in of pulsatility. also the and in the HM3 as compared with the HMII pump. devices the the the pump and through the pump, and the the of this is for the HMII for the centrifugal HM3 (Figure a the design the Thus, the of clinical a in the pump in a in for the HMII for the The clinical of these and technological characteristics in the HM3 will be in the MOMENTUM 3 study and The MOMENTUM 3 clinical trial is an prospective, randomized, pivotal the HM3 LVAS with the HMII LVAS in advanced-stage heart failure patients (Figure The study will 1,028 patients in to the The MOMENTUM 3 trial a for regulatory on the basis of clinical from clinical and has an innovative trial design with the is an with patients enrolled in the trial under a single inclusion and exclusion regardless of the intended use of the device such as and long-term such as is a pre-specified safety phase = 30) in of a study while 3. is an ST cohort of the first 294 patients for evaluation of outcomes to 6 months of support, to the non-inferiority of the HM3 compared with the is an LT cohort of the first 366 patients for evaluation of outcomes to 2 of support, to the non-inferiority of the HM3 compared with the is of a further 662 patients a sample size of for evaluation of a secondary end-point of pump replacement at 2 to the of the HM3 the The study has an adaptive design, with an pre-specified analysis by an independent statistician to determine power and sample size The primary of the MOMENTUM 3 study is to evaluate the safety and effectiveness of the HM3 LVAS by demonstrating non-inferiority to the HMII when used for the treatment of advanced, refractory heart failure. of adverse quality of as by the and status as by the and Heart of device and of need for or The study will also be to evaluate a secondary end-point to determine whether the of pump replacement at months is different treatment The primary end-point is a composite of survival free of debilitating stroke (modified Rankin score or the need for a pump The ST end-point will be at 6 months and the LT end-point at Patients who are to a device a pre-specified end-point will be study or device to recovery a pre-specified end-point will be study patients the study criteria will be enrolled regardless of the use of the device or Patients with advanced heart failure as with or who are refractory to advanced heart failure are candidates for the study. A of the study inclusion and exclusion criteria is in Table and or has with or while not on and also meet of the on current practice for at of the and are to heart failure for at and on for of to use of to or associated with or an in the of the of MCS of of mechanical aortic cardiac valve will not be to a or at the of LVAD of dysfunction or to with the study and LVAS of in 6 months of of an to or or therapy the will the of of the factors for indications of dysfunction or INR not to shock or of by and with a most of is to of stroke to or a of with significant or the need for replacement by or has to aortic for during pump or and both support to has or such as and in clinical is to study or the could survival to aortic biventricular assist cardiac volume in 1 heart INR, international normalized ratio; left ventricular mechanical circulatory Heart Open table in a new tab aortic biventricular assist cardiac volume in 1 heart INR, international normalized ratio; left ventricular mechanical circulatory Heart study candidates will be randomized the HMII and the The will be by study center and to the will be through the data system Study will be a of 50 randomized Patients will be enrolled in the study all randomized patients will be included in the analysis. The will be as a pivotal study includes a pre-specified for safety is with the new for a approval of and Food and Drug for and for Evaluation and for and Food and Drug Administration adaptive designs for device clinical Scholar The study was limited to study during the safety data were when the first to 30 of support. included the status of a of adverse and a description of device The data were to an independent data safety and the with a to the trial to to a total of study The first study to and to a total of 30 patients during the FDA of the safety This phase in after of the the FDA to the Thus, the phase of in and is A total of 1,028 patients will be enrolled in the study. patients will be enrolled and randomized to evaluate the primary end-point for of the first 294 patients will be evaluated at 6 months for the primary 662 patients will be randomized to the total of 1,028 for the secondary end-point analysis. On the basis of a of data from the for Circulatory Support and is the HMII population will a composite success of at 6 Naftel Pagani F.D. et patients and Heart Lung Transplant. 2015; 34: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. et left ventricular assist device outcomes in use compared with the clinical Thorac Surg. Full Text Full Text PDF PubMed Scopus Google Scholar is also the HM3 population will a composite success of to pump at 6 months by or drive-line patients in will be required to power to the HM3 is to HMII at a of non-inferiority of in the and the to non-inferiority with a = data were from to in the study. patients were implanted with an HMII in at these and a transplant or to recovery 6 on and to data to evaluate the success an patients will be randomized of to for these This patients to be randomized in total for the ST cohort analysis. On the basis of the from the HMII destination therapy is of the HMII patients will the composite primary M.S. et heart failure treated with continuous-flow left ventricular assist Engl J Med. PubMed Scopus Google Scholar is also the HM3 patients will a composite success of to pump at months by or will HM3 and HMII patients total to power to the HM3 is to the HMII when the of non-inferiority in the and is the to non-inferiority with a = The patients treatment for the ST indication will in a total of patients randomized in total Thus, the LT indication will include the 294 patients from the ST indication a of patients available to the LT at patients randomized to HeartMate 3 to months free of debilitating stroke on device data be for the LT non-inferiority by will be for the primary end-point to primary the study will be to whether the HM3 pump is to the HMII by the of pump the HMII pump replacement at months will be by with the 1,028 patients treatment will power = the 366 patients for the LT indication are the study will to 662 patients for the secondary analysis. include blood and cardiac current and quality of will be at at the of and at and adverse to the and device will be as data will be as the of with and data will be as and Adverse events will be as events Adverse events with and after the implant will be data will be the will be the as all randomized will be to in the event of data will also be for analysis and for safety analysis and all secondary primary will be A of or a of will be used to The LT indication will be the ST indication has been will not be non-inferiority is the data will be for the of with the to the analysis will be A analysis will be when the first patients enrolled in the study an or of support, independent statistician will this analysis and the will be to the The of the analysis is to the power for on the with to ST and on the non-inferiority of on the of the analysis, an adjustment to the sample size The analysis will not be used to the trial for and thus adjustment of the significant for the analysis is will be for and intended use of the device at the of are secondary and a analysis to and as a of center volume and of experience will be Centers will data into a system is with of and will be and by St. Jude Medical, Inc., for all study will be data to use the system and after has been independent clinical events to the will all will also the and device of these adverse independent will of the clinical safety data and study or as in this study will approval from will the of will be for all patients enrolled in the study. new available a will be required to and the as and all patients will be by the to the be approved by the of the MOMENTUM 3 study on at were in the safety to of the safety data in the first patients by the the FDA provided approval to to all study on The study is currently as is the randomized comparison will into the of the novel HM3 when compared with an established The size of the study will for into pre-specified and thus an for for LVAS the trial to the use of LVAS therapy in advanced-stage heart failure irrespective of primary intent or in an to contemporary clinical G.C. M. et and from the for circulatory J Am Coll Full Text Full Text PDF Scopus Google Scholar and are of St. Jude Medical, D.G. with St. Jude Medical, Inc., and with St. Jude Medical, Inc., and support from St. Jude Medical, Inc., and with Jude Medical, Inc., and and The for of the and for the of the HeartMate 3. The MOMENTUM 3 Study and St. and Givertz and and and and and and of the of and and Mark Slaughter of and and of Heart and of (St. and St. (St. Heart of of of Pagani of and of and of of of of and and of and and and