Medical Device Daily Associate

In what could be seen as a coup, ventricular assist device maker Thoratec (Pleasanton, California) reported that the FDA granted it a virtually condition-free approval of its investigational device exemption (IDE) for the company to begin a Phase II pivotal clinical trial for its next generation HeartMate II LVAS (Left Ventricular Assist System). The system is designed to provide long-term cardiac support for patients who are in end-stage heart failure.

The study incorporates a number of unique elements, including the use of the device for both bridge-to-transplantation (BTT) and destination therapy (DT), the first time the FDA has approved a clinical trial with both indications in one protocol, Thoratec said.

The company is in the process of identifying prospective centers beyond those 10 that participated in the Phase I study. Initial patient enrollment could begin within 30 days, pending appropriate approvals within the hospitals, the company said.

A unique aspect of the BTT study design is that the control group will be comprised of data from previous clinical trials and concurrent data from the company's voluntary VAD implant registry, enabling a non-randomized trial design in which all subjects will receive the HeartMate II. The BTT arm of the study will involve 133 patients at up to 25 centers with the primary endpoint being the rate of survival to transplantation, or 180 days.

Secondary endpoints include adverse events, device reliability, quality of life and functional status. The company noted that it has already enrolled 25 patients in the Phase I portion of the BTT trial, leaving 108 patients to be accrued in the Phase II pivotal study.

The DT arm of the study will involve 200 total patients, randomizing the HeartMate II to the currently approved system, the HeartMate XVE on a 2-1 basis, respectively. The study provides for a composite two-year endpoint, which includes patient survival, rate of neurological events and device reliability.

Secondary endpoints in the DT arm of the trial include adverse events, clinical reliability, assessment of neuro-cognitive function and patient quality of life.

Importantly, the company said it believes the inclusion and exclusion criteria of the trial will also allow the DT arm to enroll patients who are not yet as ill as those in the company's original Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, even providing for inclusion of some late New York Heart Association (NYHA) Class III congestive heart failure patients (REMATCH enrolled only NYHA Class IV patients).

While acknowledging that there aren't “night and day“ differences between the NYHA Class III and IV patients, Keith Grossman, president and CEO of Thoratec, told Medical Device Daily that the company was really pleased to be able to get Class III patients into the trial protocol. “It is a difference, and it's moving in the right way directionally. Not only was FDA willing to go along with it [but] they were actually a strong proponent of moving things in this direction,“ he said, adding that the FDA does want to see ventricular assist device (VAD) technology advance and enable companies to get “out of the box“ of only treating patients who are close to death.

Grossman also attributed the FDA's willingness to work with the company on trial protocols to the success of the company's positive Phase I trial results for the HeartMate II. “Results matter,“ he said.

Both the BTT and DT arms allow for home discharge, based on the patient's condition. The DT protocol also includes a separate cohort of small patients who, because of their body size, could not be randomized to the larger HeartMate XVE. Cross-over patients will also be allowed in the trial, enabling those DT patients currently being supported by Thoratec's HeartMate XVE to be implanted with the HeartMate II on an elective basis in the event of the need for device replacement.

The only condition of the FDA approval is that the company establish an independent, blinded clinical endpoint committee to review adverse events occurring in the study.

The Phase I bridge-to-transplantation study, which began in November 2003 (Medical Device Daily, Nov. 24, 2003), included 25 patients at 10 centers, with approximately six years of cumulative patient support. Of these, 12 continue to be supported by the device, with 11 of them discharged to their homes. Another six have been transplanted and seven have died for reasons unrelated to the device. In addition, 10 patients have been implanted with the device in Europe.

The company said it hopes to file for European marketing approval this year. All told 41 patients have received the device to date, including those implanted under compassionate or emergency use provisions of the IDE regulations for both bridge-to-transplantation and destination therapy.

Grossman said he believes enrollment in the smaller BTT arm will be completed first since it is a more “well-defined indication.“ He estimated enrollment completion in that arm sometime before the end of this year or early in 2006. The DT arm enrollment, he said, is tougher to predict but he estimates a 2006 time frame is pretty safe.

If approved, the HeartMate II would be the third generation of the company's VAD to be cleared for use as a destination therapy. In November 2002, the HeartMate VE became the first VAD to receive U.S. approval for a DT indication (MDD, Nov. 8, 2002). That was followed by the HeartMate XVE in April 2003 (MDD, April 8, 2003).

Because it operates with a rotary pump, the HeartMate II is significantly smaller than its pulsatile forebears, and so can be used in smaller individuals. It weighs about 12 ounces and is about 1.5 inches in diameter and 2.5 inches in length. It has only one moving part and thus can be made to be simpler and quieter than pulsatile systems.

The company also has in development a second non-pulsatile pump, the HeartMate III, which instead of using axial flow employs a “centrifugal flow“ non-pulsatile approach. That pump is in preclinical evaluation.

Jason Mills, a medical technology analyst for First Albany Capital (San Francisco), wrote in a research report that he expects an additional 10 centers to receive IRB approval in the study “imminently,“ with another five to 10 added within coming months. He noted that “while our analysis clearly suggests DT offers the largest ultimate market opportunity, we think [HeartMate II] use in BTT offers a more 'near-term' catalyst for investors, as it could expand the transplant list, thus, potentially driving accelerating VAD-BTT growth above our estimates over the next few years.“

Mills said First Albany models DT approval for HeartMate II in the 2008-2009 time frame, and said it continues to believe that the current generation of the device (HeartMate XVE) will continue to ramp, possibly augmented by a beta referral sales force recently initiated by the company or by a larger cardiology company vis- -vis an acquisition of the company or a marketing alliance.