Edwards Lifesciences has reached a verbal agreement with FDA on an amended design for the PARTNER trial of its Sapien transcatheter aortic valve, the company announced during its Dec. 7 2007 investor conference.

The modified PARTNER design includes 1,040 patients, instead of the original enrollment goal of 600, and will also incorporate a separate evaluation of the transapical implant approach with the Ascendra delivery system.

"We've gone through extensive discussions with FDA and we have reached a verbal consensus that this [amended plan] will be the trial design and these will be the sample sizes going forward," explained Larry Wood, corporate VP-transcatheter valve replacement.

Sapien is designed as an alternative to open heart aortic valve replacement in patients with symptomatic, crucial calcific aortic stenosis.

The company projects FDA will approve Sapien in 2011, although some analysts believe this is overly optimistic and that a 2012 approval is more likely. At its investor conference in December 2006, the company predicted Sapien could earn FDA approval by the end of 2009 (¹ Also see "U.S. Approval Of Edwards Sapien Transcatheter Heart Valve Possible In 2009" - Medtech Insight, 18 December, 2006., p. 11).

Incorporating "Key Learnings" Into Trial Design

In both the original and revised PARTNER designs, patients enrolled in the trial will first be evaluated for their surgical operability. Those deemed to be too high risk for surgery will be put in a medical management cohort and then randomized to receive either medical management only or medical management plus a Sapien valve. Patients who can withstand surgery will be randomized to either surgical aortic valve replacement or Sapien.

The trial is designed to show that Sapien is noninferior to open-heart valve surgery and superior to medical management, as measured by one-year mortality. Secondary endpoints include quality of life and various valve performance measures.

Edwards predicts the study will take 12 to 18 months to enroll. However, the company has so far enrolled only 91 patients at eight sites in the United States and Europe. Seven more sites have been trained and will be ready to enroll patients soon.

The sample sizes for the original design were derived by estimating one-year mortality rates based on early feasibility data and the scientific literature. In the one year the study has run so far, Edwards has discovered that it underestimated the patient comorbidities and overestimated patient survival rates when it originally designed the trial.

Wood also noted that patients assigned to medical management are being treated more aggressively than the trial investigators had anticipated. Because of the follow-up office visits required by the study protocol, patients in the study are seeing their doctor more often than if they were not in the trial. This gives the doctor more opportunities to adjust and optimize the patient's therapy.

"This is a very sick patient population. The average age of patients in the trial is 82 years old and they have a lot of comorbidities. This is a patient population that's really never been actively studied before, so trying to derive those [mortality rates] from the literature was difficult because there's not a lot that exists on it," Wood explained.

Based on the revised estimates of patient mortality, investigators determined that PARTNER will need more patients in order to meet the primary mortality endpoint. Under the new protocol, Cohort A will enroll 690 patients instead of 350 and Cohort B will enroll 350 patients instead of 250.

New PARTNER Will Include Transapical Approach

The original PARTNER protocol approved by FDA allowed the Sapien to be delivered only with the RetroFlex transfemoral system. The transfemoral route goes through an incision in the leg and the femoral artery.

At the TCT conference in Washington, D.C., in October, PARTNER Primary Investigator Martin Leon, M.D., Columbia University, said one reason the trial was enrolling slowly was because many of the patients are not good candidates for the transfemoral procedure and surgeons are therefore reluctant to allow them to be randomized in the trial.

Surgeons would be more amenable to participation in PARTNER if the transapical approach - the valve is inserted through a small incision in the rib cage - was part of the protocol, Leon said (² Also see "Edwards Hits Snags With Trial Of Catheter-Delivered Heart Valve" - Medtech Insight, 29 October, 2007., p. 11).

"We've always said that we think it's critically important that we include transapical patients in the trial," Wood said. "It's one of the things that drives the partnership [with surgeons] and it's also one of the ways that we can ensure that we can treat the widest range of patients with severe aortic stenosis."

In the revised PARTNER trial, patients assigned to the surgical arm will be evaluated for their suitability for the femoral access approach. Patients deemed suitable for the femoral approach will be randomized to either transfemoral implant of a Sapien or surgical valve replacement. Patients not suitable for the femoral approach will be randomized to either surgery or the transapical Sapien procedure.

The company had originally planned to begin including transapical patients in PARTNER in late 2007. The investigators originally assumed that the outcomes for the transapical and transfemoral approaches would be similar enough to pool together.

The primary analysis of the surgical cohort will still pool the data from the transapical and transfemoral arms, as proposed in the original PARTNER design.

However, FDA recommended that the PARTNER surgical cohort include separate randomized transfemoral and transapical arms because the patients best suited to the transfemoral approach have different comorbidities than those assigned to the transapical approach.

"They wanted to make sure that they could compare patients to what would be their appropriate control group," Wood explained. "But that also means that they have to have enough patients in each of those subgroups to perform that analysis, and that's one of the things that drove the sample size up."

"This is really a critical part of designing this trial and it was one of the things that took some time to work out with FDA," Wood said.

- Reed Miller (re.miller@elsevier.com)

Edwards Redesigns PARTNER Trial, Pushes Back Sapien Approval Timeline

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