ADAPT Naproxen Signal “Not Sufficiently Compelling” To Halt Trial – Speaker

The halting of the NIH-sponsored ADAPT trial, which suggested that naproxen may be linked to an elevated cardiovascular risk, was due more to external factors and safety concerns surrounding the COX-2 class than the study data themselves.

ADAPT was cut short Dec. 20 after researchers found naproxen users to be 1.5 times more likely to experience a cardiovascular event than placebo subjects (¹ (Also see "Naproxen Heart Concerns Surface In Halted NIH Alzheimer’s Trial" - Pink Sheet, 3 Jan, 2005.), p. 3).

During the Feb. 16-18 meeting of FDA's Arthritis Drugs and Drug Safety & Risk Management advisory committees on the safety of COX-2 inhibitors, public testimony from Constantine Lyketsos, MD, Johns Hopkins Hospital, shed more light on the stoppage of the trial.

Presenting a statement on behalf of the ADAPT Steering Committee, Lyketsos said an analysis of the 2,463 ADAPT participants who were randomized before October 2004 was submitted to the study's monitoring committee Dec. 10.

"Those analyses [showed] a weak signal suggesting increased risks of cardiovascular and cerebrovascular events with naproxen," Lyketsos said. "Reviewing the data, however, we understood well the monitoring committee's evident conclusion that this signal was not sufficiently compelling or definitive to warrant a recommendation to suspend the treatment or to otherwise alter the protocol," he said.

Lyketsos noted the findings soon were followed by preliminary results from the APC trial, which showed patients taking Pfizer's Celebrex 800 mg daily were 3.4 times more likely to experience a CV event than placebo users, and those taking celecoxib 400 mg daily were 2.5 times more likely.

After learning about the APC results, "we took seriously the possibility of harm over time to ADAPT participants receiving celecoxib," Lyketsos said. "Especially in a prevention trial with no strong prospects of immediate benefit, we had strong misgivings about continuing celecoxib treatments."

The Independent Review Boards that oversaw ADAPT immediately began to question the steering committee about the implications of the APC results, "and seemed likely to question a decision to continue" with the study, Lyketsos observed. In addition, had the study not been halted, the steering committee would have been "unable to offer much explanation to our participants, thereby endangering the relationship of trust that is vital to the success of long-term trials," he noted.

Lyketsos also commented on the effect that the news surrounding the COX-2 class was having on the trials. "ADAPT was experiencing some difficulty with adherence to treatments," he said. "This difficulty grew following the withdrawal of rofecoxib [Merck's Vioxx ], and we expected the announcement of the APC results to exaggerate the problem further with scores of participants stopping treatment, in effect 'voting with their feet.' This would erode statistical power and increase the potential for bias in ADAPT."

"Thus, even though the ADAPT safety data did not themselves warrant suspension of celecoxib treatments, there seemed little practical choice but to do so," Lyketsos said.

Patient concerns surrounding continued use of naproxen following the end of the ADAPT trial also were addressed by voting consultant Steven Nissen, MD, medical director of the Cleveland Clinic.

"The problem that occurred here is that a warning was issued on naproxen, which has the effect of being the medical equivalent of screaming 'Fire!' in a crowded auditorium," he said. "All over the country, many of us got calls from patients saying, 'I want to stop my naproxen because it causes cardiovascular risk.'"

"It would have been far better to have announced that the trial was suspended for futility rather than for hazard when there was a non-significant statistical pattern," Nissen concluded.

Voting consultant John Farrar, MD, University of Pennsylvania, added that halting ADAPT appeared to be motivated by external concerns. "It wasn't that there were, at this point, emerging trends that happened to be in the unfavorable direction of naproxen. Rather, it was the external data of the APC trial for Celebrex that was the driving issue" behind the decision, he opined.

The ADAPT steering committee expects to submit a scientific paper for peer review and publication "within a few weeks" which will focus on the "process and rationale underlying the decision to suspend treatments and enrollment in ADAPT."

"Because those decisions did rely in some measure on the ADAPT safety data as of [Dec. 10, 2004], the paper will also disclose some of those data," the committee said.