February 16, 2001

Drug tested at VUMC first to treat sepsis

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Linda Norman is traveling to the University of Ulster in Northern Ireland to study bioterrorism. (photo by Dana Johnson)

Drug tested at VUMC first to treat sepsis

After six years of research here, Vanderbilt University Medical Center stands poised as the international clinical coordinating center for the first drug proven to reduce deaths due to sepsis, an infection process that claims more than 250,000 lives a year in the U.S. alone.

As reported in this week’s issue of The New England Journal of Medicine, in clinical trials that concluded in June 2000, the drug, Zovant TM, (recombinant human activated protein C), was shown to reduce overall mortality by almost 20 percent. The study, sponsored by APC manufacturer Ely Lilly, was conducted at Vanderbilt and 163 other medical centers in 11 countries.

“This is really a breakthrough. There are no other drugs of this type that show such a decrease in mortality,” said Dr. Gordon Bernard, professor of Medicine and associate director of Allergy and Pulmonary Critical Care Medicine. Bernard, who presented the findings of the study at a Feb. 11 meeting of the Society of Critical Care Medicine, lists the introduction of APC with the practice of sterile techniques and the discovery of antibiotics as a milestone in infection management.

“Now we’ve gone from just treating an infection to treating the severe organ and other tissue damage that occurs during the severe sepsis process,” he said. “This is the first drug that deals directly with this huge clinical problem.”

Bernard led phase II trials of the drug at Vanderbilt beginning in 1994 when Lilly approached him with the potentially lifesaving drug. In 1998 trials expanded, with VUMC continuing to be the international coordinating center. “The phase III trial was halted because of the profound effect on the decrease in mortality,” Bernard said.

Protein C is naturally converted to activated protein C (APC) during severe bleeding and sepsis to prevent excess thrombosis, enhance fibrinolysis and decrease inflammation. “It’s an anticoagulant with anti-inflammatory properties,” Bernard said.

But when pneumonia, appendicitis or other infections lead to sepsis, APC is depleted. The body’s response to the infection – to wall off the area with clots and produce inflammation – goes awry. Clots form indiscriminately and can choke otherwise uninfected and healthy tissue to death and leads to multi-organ failure.

Intensive care patients, those severely compromised, are constantly at risk of sepsis and medical efforts focus on preventing the disorder. In the double-blind, placebo-controlled trial, 31 percent of patients on placebo who acquired sepsis died; with Zovant TM, mortality fell by 20 percent to 25 percent.

“That may not sound like much, but of 250,000 deaths a year, that amounts to 50,000 lives saved a year in the U.S. alone,” Bernard said. “That’s roughly the number of people who die in motor vehicle accidents.”

At Vanderbilt, an estimated 700 lives would be saved.

As the clinical coordinating center, VUMC will field questions from physicians in North America, Europe and Australia to qualify patients for the drug. And, Bernard said, Vanderbilt and Lily will continue to look for other clinical applications of Zovant, including cases of acute respiratory distress and veno-occlusive disease in bone marrow transplant patients.

“This is an exciting new compound,” he said.