VISTA-16 at Last: Investigators Allege Misconduct by Sponsor

November 18, 2013

DALLAS, TX (updated) — Results of the Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks Study (VISTA-16) were presented during a late-breaking clinical-trials session here today at the American Heart Association (AHA) 2013 Scientific Sessions .

The phase-3 trial of varespladib (Anthera Pharmaceuticals), a novel inhibitor of secretory phospholipase A2 (sPLA2) hypothesized to be a potential treatment for ACS, was unexpectedly halted in March 2012 after the data safety monitoring board (DSMB) found no evidence that the drug was effective and recommended the study's premature termination , as reported by heartwire .

Dr Stephen Nicholls

Lead investigator Dr Stephen Nicholls (South Australian Health and Medical Research Institute, Adelaide) presented the results, which have also been published online today in the Journal of the American Medical Association [1].

In an announcement that eclipsed the actual trial results, Nicholls explained that the reason behind the 18-month delay lay largely with the sponsor, Anthera, which refused to turn the database over to investigators.

"This trial was appropriately conducted and a logical extension of the phase 2 program, and the sponsor did the right thing and accepted immediately the recommendation by the DSMB to terminate the study," Nicholls said. "However, despite multiple requests and what was a contractual obligation, the sponsor did not provide the academic steering committee with the database for this study. In fact, more than a year after the cessation of this study, it was only at that point that we received the database, when the sponsor's license of the compound expired and the license actually returned to the original developer of the compound. We were very grateful that the second company saw it appropriate that these data be put in the public domain."

What's more, the VISTA-16 trial protocol specified that investigators would follow up with all patients at six months, even if the study was stopped. "The sponsor, despite receiving a letter of insistence by the academic steering committee that they should continue to do that . . . only collected [six-month] data in one-third of the patients."

In the trial, the primary end point—a composite of cardiovascular mortality, nonfatal MI, nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization—occurred in 136 patients (6.1%) with ACS compared with 109 patients (5.1%) treated with placebo.

There was a nonsignificant 25% increase in risk of the primary end point in varespladib-treated patients. More important, varespladib was associated with a significant 66% higher risk of MI (3.4% in the varespladib arm vs 2.2% in the placebo arm; p=0.005) and cardiovascular mortality, MI, and stroke (4.6% in varespladib arm vs 3.8% in the placebo arm; p=0.04).

Importantly, there was a numerically higher risk of mortality at six months in the active-treatment group, Nicholls noted. "This did not meet statistical significance, but keep in mind that in two-thirds of patients that data were not collected," he said.

"Despite experimental and observation clinical data suggesting that pan-inhibition of sPLA2 would exert beneficial cardiovascular effect, the VISTA-16 trial provides evidence to the contrary," conclude the investigators.

Dr Gabriel Steg

Discussing the results here today, Dr Gabriel Steg (Univerity of Paris, France) made the point that the incomplete ascertainment of the VISTA-16 data "failed our obligations not only to the scientific community but also to patients."

He also noted that two trials are ongoing with a similar, though not identical drug, darapladib (GlaxoSmithKline). "We learned a week ago that the primary end point on the first of these trials was not met and more information will be forthcoming, and we'll see what the full results will be." That said, Steg continued, the VISTA-16 results "certainly do not rule out the inflammation hypothesis. There are a host of trials addressing inflammation and targeting inflammation as a method of reducing recurrent events after ACS and AMI."

Nicholls reported research support from Anthera Pharmaceuticals, AstraZeneca, Cerenis Therapeutics, Lilly, InfraReDx, Roche, Resverlogix, Novartis, Amgen, and LipoScience; and consulting fees from AstraZeneca, Abbott, AtheroNova, Esperion, Merck, Takeda, Roche, Amgen, LipoScience, Novartis, Omthera, CSL Behring, Boehringer-Ingelheim, and Pfizer. Disclosures for the coauthors are listed in the paper.


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