The FDA has dropped a yellow flag on plans for a confirmatory clinical trial by Vasogen (Mississauga, Ontario) for its heart failure treatment.

The agency on Friday raised concerns about how the company plans to recruit patients for its Advanced Chronic Heart Failure CLinical Assessment of Immune Modulation Therapy (ACCLAIM II) trial, intended to support an application for U.S. market approval of the company’s device technology, called the Celacade System.

Chris Waddick, president/CEO of Vasogen, told Medical Device Daily that the FDA’s latest communication came as a surprise, specifically in that the agency would not allow use of data from the first ACCLAIM trial.

“ACCLAIM missed its primary endpoint for the group as a whole, but in 700 patients we saw a significant impact,” Waddick said.

The FDA’s Center for Devices and Radiological Health said it is concerned with Vasogen’s use of the Bayesian approach for analysis of its data that approach allowing researchers to combine data from prior studies with current information in both the design and analysis stages of a trial. That approach allows researchers to recruit a heterogeneous study population between ACCLAIM and ACCLAIM II, the issue that is now being questioned by the agency.

According to CDRH, when good prior information on clinical use of a device exists, the Bayesian approach may enable the agency to reach the same decision on a device with an enrollment of smaller size or shorter-duration.

The FDA apparently rescinded earlier communications with the company in which it agreed to the trial design (a horse-changing in mid-stream that both device and drug companies often complain of).

Celacade technology targets the inflammation underlying chronic heart failure. During a brief outpatient procedure, a small sample of a patient’s blood is drawn into the Celacade single-use disposable cartridge and exposed to controlled oxidative stress using the Celacade, the company’s proprietary medical device technology. The treated blood is then administered to the same patient intramuscularly.

An initial course of treatment comprising three consecutive outpatient procedures is administered over a two-week period, and treatments are continued once a month thereafter.

Oxidative stress is a factor known to initiate apoptosis (programmed cell death), a physiologic process that is inherently anti-inflammatory. The ACCLAIM trial studied 2,408 subjects with chronic heart failure at 175 clinical centers in seven countries.

ACCLAIM II was designed to assess the ability of Celacade to reduce the risk of death or first cardiovascular hospitalization.

The difference in time-to-death or first cardiovascular hospitalization (the primary endpoint) for the intent-to-treat study population was not statistically significant; however, the risk reduction directionally favored the Celacade group.

Vasogen said that its immediate focus will be to clarify the FDA’s position on the proposed ACCLAIM II study protocol and statistical analysis plan and to work with members of the ACCLAIM II Steering Committee to address the FDA’s concerns.

“The FDA had concerns that we will not be able to recruit a similar patient population,” Waddick said.

The agency indicated there has been an evolution in heart failure care since the ACCLAIM trial was initiated that may result in a differently treated patient group.

“We don’t see where there’s been a material change in heart failure care,” Waddick said, “because in ACCLAIM, [patients] were on standard therapy, and it would be the same approach for ACCLAIM II.”

The company received approval to proceed with the ACCLAIM trial in 2002.

Vasogen said that to help sort out this problem and make a revised approach to the agency, it has retained Berry Consultants and Donald Berry, MD, head of the Division of Quantitative Sciences and chairman of the Department of Biostatistics at The University of Texas M.D. Anderson Cancer Center (Houston), a recognized authority in the area of Bayesian and adaptive trial design.

In North America and Europe, chronic heart failure affects about 12 million people.

Last May, Vasogen reported closing on $16 million in financing through the sale of common shares at $3.25 a share. Net proceeds were about $14.6 million (Medical Device Daily, May 29, 2007).

Vasogen in 2004 was granted CE mark approval for its lead product, Celacade therapy (MDD, Feb. 11, 2004).

In 2003 it raised $37.5 million in a private placement, selling 9.375 million shares at $4 each (MDD, July 8, 2003).