BERLIN - June 10, 2004 - Early findings of a study comparing the investigative agent lumiracoxib show that patients who receive this medication for arthritis symptoms are 50 percent less likely to experience adverse gastrointestinal (GI) effects than those who are treated with conventional non-steroidal anti-inflammatory drugs (NSAIDs), according to Christopher J. Hawkey, MD.

Dr. Hawkey, professor of gastroenterology at Nottingham University in Nottingham, United Kingdom, presented his and his co-investigators' findings here June 9th at the annual meeting of the European Congress of Rheumatology (EULAR). The study design was recently published in Alimentary Pharmacologic Therapy (2004;19:1-13). The investigation, Therapeutic Arthritis Research and Gastrointestinal Event Trial of lumiracoxib (TARGET), was funded by Novartis, the manufacturer of lumiracoxib.

Throughout their history, selective cyclo-oxygenase-2 (COX-2) inhibitors were originally developed as a way to address the adverse gastrointestinal events that have been linked to non-selective NSAIDs, Dr. Hawkey said. Because lumiracoxib has a different molecular structure from other COX-2 inhibitors, TARGET constituted "the first true test of the COX-2 hypothesis," Dr. Hawkey said.

Prior imaging studies had shown that patients treated with lumiracoxib had no upper gastrointestinal erosions at all, a rate that was even lower than placebo, he said. "Conventional NSAIDs are linked to a four-fold increase in the rate of gastric ulcers," Dr. Hawkey said. "Therefore, the TARGET study design stipulated that patients treated with lumiracoxib should be four times less likely than those treated with an NSAID to experience such events."

For the current research, the investigative team developed several principles that guided the study design and differentiated it from several other studies of COX-2 inhibitors' gastrointestinal safety. They identified ulcer complications as the primary endpoint, allowed for and stratified low-dose aspirin use, and mandated a retention level of at least 60 percent and a homogeneous population, consisting only of patients with osteoarthritis. Ulcer complications were defined primarily as signs of bleeding, such as vomiting bright red blood, a sudden drop in hemoglobin, and shock, or an ulcer visible by endoscope with or without stigmata.

In order to have sufficient power, the investigators determined that the initial recruitment must consist of at least 18,000 patients. "This is a representative, well balanced group of patients that is large enough to establish the GI safety of lumiracoxib in light of the controversies which have arisen with previous GI outcomes studies," Dr. Hawkey stated. These controversies consisted of dropout rates that at times exceeded 50%, inconsistent allowing of aspirin use, and multiple GI endpoints. In addition to studying GI safety, the size of the study will also allow the investigators to study cardiovascular safety, he said.

The investigators randomized 18,325 patients to either lumiracoxib or to one of the two comparator NSAIDs, naproxen or ibuprofen. Of these patients, 23.7 percent were on low-dose aspirin. Over a one-year period, 13,500 patients continued in the study, or 60.7 percent.

"The lumiracoxib patients were twice less likely to have ulcer complications compared to the NSAID-treated patients, when a four-fold drop would have been comparable to placebo," Dr. Hawkey said. "There are several reasons why. It may be that lumiracoxib is not equivalent to placebo. Also, nearly 24 percent of the patients were aspirin users." Therefore, the investigators will stratify for aspirin use to see if aspirin users treated with lumiracoxib are more likely than non-aspirin users to have ulcer complications.