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Positive Results Announced for Phase III Study of Alvimopan in Postoperative Ileus
"We are very excited to report today's positive results in both the 6 mg and 12 mg treatment groups, and believe they support our goal of submitting a New Drug Application for Entereg(TM) (alvimopan) to the U.S. Food and Drug Administration late in the first half of 2004," stated Bruce A. Peacock, president and chief executive officer of Adolor. "Successful completion of Study 313 is an important accomplishment in our clinical development program evaluating Entereg(TM) (alvimopan) in the management of postoperative ileus and builds on the top-line results from Study 302 announced in April of this year. We are now focused on completing Study 308 as our next important milestone. We believe our four phase 3 clinical studies represent a very substantial clinical development program which, when complete, will have enrolled approximately 2,000 patients."
In the primary endpoint of Study 313, time to recovery of gastrointestinal function, a statistically significant difference was achieved in both the Entereg(TM) (alvimopan) 6 mg and 12 mg treatment groups, each as compared to the placebo group (Cox proportional hazard model; for 6 mg group, hazard ratio = 1.28; P less than 0.05; for 12 mg group, hazard ratio = 1.54; P less than 0.01). Mean times of recovery were 120 hours, 105 hours, and 98 hours for the placebo, 6 mg, and 12 mg groups, respectively. This equates to mean times to recovery of gastrointestinal function that are approximately 15 hours and 22 hours sooner for the alvimopan 6 mg and 12 mg treatment groups, respectively, each as compared with placebo.
A difference in favor of Entereg(TM) (alvimopan) was observed for all of the secondary endpoints in both the 6 mg and 12 mg treatment groups, including a difference in time to hospital discharge order written in the 6 mg treatment group (Cox proportional hazard model; hazard ratio = 1.25) and a statistically significant difference in the 12 mg treatment group (Cox proportional hazard model; hazard ratio = 1.42). Mean times to hospital discharge order written were approximately 13 hours and 20 hours sooner for the 6 mg and 12 mg treatment groups, respectively, each as compared to placebo.
Entereg(TM) (alvimopan) was generally well tolerated in this study. The most frequently observed adverse events in both the 6 mg and 12 mg treatment groups and the placebo groups were nausea, vomiting, and hypotension.
"Postoperative ileus (POI) is a significant problem in many patients undergoing abdominal surgery, delaying recovery of their bowel function, prolonging their hospitalization, and potentially leading to other complications," said Conor P. Delaney, M.D., M.Ch., Ph.D., F.R.C.S.I. (Gen), Cleveland Clinic Foundation, and a principal investigator on the study. "At the current time, it is impossible to predict who will develop POI, and there are no approved drug treatments available. The positive results of this Phase III study of alvimopan, in patients undergoing colectomy or radical hysterectomy, are very encouraging. When compared to placebo, patients in the alvimopan treatment groups had an earlier recovery of bowel function and hospital discharge order written, which in my opinion suggests a clinically meaningful difference in recovery."
About Study 313 and the Entereg(TM) (alvimopan) Clinical Development Program
The clinical development program for the study of Entereg(TM) (alvimopan) in postoperative ileus includes four phase 3 clinical studies. Three of these studies (14CL302, 14CL313, and 14CL308) are double-blind, placebo controlled, multi-center studies each designed to enroll patients scheduled to undergo certain types of major abdominal surgery and receiving opioids for pain relief. Under these protocols, patients are randomized into three arms to receive placebo, 6 mg, or 12 mg doses of Entereg(TM) (alvimopan) at least two hours prior to surgery, and then twice a day beginning on the first postoperative day until hospital discharge or for a maximum of seven days. The primary endpoint in these three studies is a composite measure of the time to recovery of both the upper and lower gastrointestinal functions, whichever occurred last, as defined by time to tolerability of solid foods and time to first flatus or first bowel movement.
Top-line results from the first study, 14CL302, were announced in April 2003. Study 14CL302 enrolled 451 patients who were scheduled to undergo large bowel resections, simple or radical hysterectomies. A statistically significant difference was achieved in the primary endpoint of Study 14CL302, time to recovery of gastrointestinal function, in the Entereg(TM) (alvimopan) 6 mg treatment group compared to the placebo group. A positive trend was observed in the primary endpoint of the study for the Entereg(TM) (alvimopan) 12 mg treatment group; however, the difference from placebo was not statistically significant. The most frequently observed adverse events in both the placebo and treatment groups were nausea, vomiting, and hypotension.
The second study 14CL313, the subject of today's announcement, enrolled 510 patients who were scheduled to undergo small bowel resections, large bowel resections or radical hysterectomies.
Enrollment is continuing in the third study, 14CL308, for which we are targeting completion of enrollment early in the fourth quarter of 2003. Study 14CL308 includes patients scheduled to undergo small bowel resections, large bowel resections, and simple or radical hysterectomies.
The fourth POI clinical study, 14CL306, was designed as a safety study and is a double-blind, placebo-controlled multi-center study which enrolled patients scheduled to undergo total abdominal simple hysterectomy and receiving opioids for pain relief. Under this protocol, patients were randomized to receive either Entereg(TM) (alvimopan) 12 mg (approximately 400 patients) or placebo (approximately 100 patients), at least two hours prior to surgery, and then twice a day beginning on the first postoperative day on an inpatient or outpatient basis for seven days.
About Postoperative Ileus
Many patients undergoing open abdominal surgery experience temporary bowel impairment of variable duration. This phenomenon, known as postoperative ileus or POI, may be exacerbated and prolonged by multiple factors including the use of opioid analgesics for pain relief. POI is characterized by pain, abdominal distention or bloating, nausea and vomiting, accumulation of gas and fluids in the bowel, and delays in the passage of flatus or stool. There has been little advance in the treatment of POI since the introduction of nasogastric decompression, which has limited effectiveness and is uncomfortable for patients. There are no FDA-approved drugs for the management of POI currently available. There is a need for improved treatments because postoperative ileus can have a negative impact on patient recovery and health care costs.
Source: Adolor Corporation