Safety and Efficacy of IV Infusion of TZP-101 for POI After Major Open Abdominal Surgery

Multicenter, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Assess Efficacy and Safety of TZP-101 When Administered as 30 Minute i.v. Infusion for POI to Subjects Undergoing Major Open Abdominal Surgery

The purpose of this study is to determine whether TZP-101 is effective in the management of post operative ileus in subjects undergoing major open abdominal surgery (i.e. partial large bowel resection).

Subjects will be randomized according to an adaptive randomization procedure.

Inclusion Criteria:

Subjects who meet all of the following inclusion criteria may be enrolled in the study:

• Male or Female, 18 to 80 years of age, inclusive
• If female, post-menopausal for the past 12 months, surgically sterile (i.e. tubal ligation, hysterectomy), or using an adequate method of birth control (i.e., oral contraceptives, double barrier method, IUD cover or sterilized partner
• Subject is scheduled to undergo a partial large bowel resection with primary anastomosis - See Appendix II
• Subject's body weight is ≤100kg
• Subject is scheduled to receive postoperative pain management with i.v. opioids
• Subject is scheduled to have nasogastric tube removed at the end of surgery
• Subject is scheduled to be offered liquids on postoperative day 1
• Subject is scheduled to be encouraged for ambulation on postoperative day 1
• Subject is scheduled to be offered solid food on postoperative day 2

Exclusion Criteria:

Subjects who meet any of the following exclusion criteria may not be enrolled in the study:

• A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450(men)/ >470(women) milliseconds)
• Subject has history of additional risk factors for Torsades de Pointes (heart failure, hypokalemia, family history of Long QT Syndrome)
• Subject requires use of concomitant medication that prolongs the QT interval - List provided in Study Procedures Manual
• Subject requires use of concomitant medication that is a known to interact with isoenzyme CYP3A4
• Subject has complete bowel obstruction
• Subject is scheduled to receive a thoracic epidural
• Subject is scheduled to receive total colectomy, colostomy, or ileostomy
• Subject is scheduled to receive a lower anterior resection
• Subject is scheduled for laparoscopic procedure
• Subject is scheduled to receive prophylactic antiemetics post surgery; however subjects may receive intraoperatively as part of the anesthesia protocol and postoperative antiemetics for symptomatic treatment
• Subject has significant impairment of liver or renal function (ALT/AST 2 ½ times the upper limit of normal; creatinine clearance < 50mL/min.)
• Subject has a psychiatric disorder or cognitive impairment that would interfere with participation in the study
• Subject has severe cardiovascular, pulmonary, hematological diseases
• Subject has participated in an investigational study 30 days prior or received TZP-101 90 days prior to the study initiation
• Subject is pregnant (confirmed by quantitative serum pregnancy test) or is breast-feeding
• Subject has a known history of Hep B, Hep C or HIV
• Subject has a known history of drug or alcohol abuse
• Subject has a recent, adult history of clinically significant hypersensitivity reaction(s) to any drug