Lee Techner

Alvimopan, a novel, peripherally acting μ opioid antagonist: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus

Objective:To demonstrate that alvimopan (6 or 12 mg) accelerates recovery of gastrointestinal (GI) function in patients undergoing laparotomy for bowel resection or radical hysterectomy. Summary Background Data:Postoperative ileus (POI) following laparotomy may increase morbidity and extend hospitalization. Opioids can contribute to the duration of POI. Alvimopan is a novel opioid receptor antagonist in development for the management of POI. Methods:A total of 510 patients scheduled for bowel resection or radical hysterectomy were randomized (1:1:1) to receive alvimopan 6 mg, alvimopan 12 mg, or placebo orally ≥2 hours before surgery, then twice a day (b.i.d.) until hospital discharge or for up to 7 days. The primary efficacy end point was a composite of time to recovery of upper and lower GI function. An associated secondary end point was time to hospital discharge order written. Results:The modified intent-to-treat population included 469 patients (451 bowel resection and 18 radical hysterectomy patients). Time to recovery of GI function was accelerated for the alvimopan 6 mg (hazard ratio [HR] = 1.28; P < 0.05) and 12 mg (HR = 1.54; P < 0.001) groups with a mean difference of 15 and 22 hours, respectively, compared with placebo. The time to hospital discharge order written was also accelerated in the alvimopan 12 mg group (HR = 1.42; P = 0.003) with a mean difference of 20 hours compared with placebo. The incidence of adverse events was similar among treatment groups. Conclusions:Alvimopan accelerated GI recovery and time to hospital discharge order written compared with placebo in patients undergoing laparotomy and was well tolerated.

Phase III Trial of Alvimopan, a Novel, Peripherally Acting, Mu Opioid Antagonist, for Postoperative Ileus After Major Abdominal Surgery

PURPOSEPostoperative ileus presents significant clinical challenges that potentially prolong hospital stay, contribute to readmission, and increase morbidity. There is no approved treatment for postoperative ileus. Alvimopan is a novel, peripherally acting, mu opioid receptor antagonist currently in development for the management of postoperative ileus.METHODSPatients undergoing partial colectomy or simple or radical hysterectomy were randomized to receive alvimopan 6 mg (n = 152), alvimopan 12 mg (n = 146), or placebo (n = 153) orally 2 hours before surgery and twice daily thereafter until discharge or for up to seven days. The primary efficacy end point, time to return of gastrointestinal function, was a composite measure of passage of flatus or stool and tolerating solid food. Secondary end points included time to the hospital discharge order written. Adverse events were monitored throughout the study.RESULTSMean time to gastrointestinal recovery was significantly reduced in patients treated with alvimopan 6 mg vs. placebo (hazard ratio = 1.45; P = 0.003), with a smaller reduction seen with alvimopan 12 mg (hazard ratio = 1.28; P = 0.059). Mean time to the hospital discharge order written was significantly accelerated in patients treated with alvimopan 6 mg (hazard ratio = 1.50; P < 0.001). The most common treatment-emergent adverse events across all treatment groups were nausea, vomiting, and hypotension; the incidence of nausea and vomiting was reduced by 53 percent in the alvimopan 12-mg group.CONCLUSIONSIn patients undergoing major abdominal surgery, alvimopan accelerated gastrointestinal recovery and time to the hospital discharge order written compared with placebo and was well tolerated.

Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery Results of a randomized, double-blind, controlled study

BackgroundAlvimopan is a peripherally acting mu-opioid receptor (PAM-OR) antagonist for accelerating gastrointestinal recovery after surgery.MethodsPatients undergoing open laparotomy (bowel resection, n = 418; hysterectomy, n = 197) were randomized to receive alvimopan 6 or 12 mg or placebo orally ≥2 h before surgery and then b.i.d. until hospital discharge (up to 7 days). The primary efficacy endpoint was time to gastrointestinal (GI) recovery (measured by toleration of solid food and passage of flatus/stool; GI-3). Secondary endpoints included time to GI-2 recovery (toleration of solid food and passage of stool) and hospital discharge order written (DCO).ResultsAlvimopan did not significantly accelerate GI-3 compared with placebo [6 mg: hazard ratio (HR) = 1.20, p = 0.080; 12 mg: HR = 1.24, p = 0.038). However, after adjustment for significant covariates (sex/surgical duration), benefits were significant for both doses (6 mg: HR = 1.24, p = 0.037; 12 mg: HR = 1.26, p = 0.028). Alvimopan also significantly accelerated time to GI-2 (6 mg: HR = 1.37, p = 0.008; 12 mg: HR = 1.33, p = 0.018) and DCO (6 mg: HR = 1.31, p = 0.008; 12 mg: HR = 1.28, p = 0.015). Adverse events were similar between groups.ConclusionsAlvimopan (6 or 12 mg) accelerates GI recovery and is well tolerated in patients undergoing open laparotomy.

Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies.

Objective:To obtain further analysis regarding specific outcomes and alvimopan doses in bowel resection (BR) patients. Summary Background Data:Although postoperative ileus (POI) is common after BR, there is currently no recognized treatment or prevention available. Alvimopan, a novel, peripherally active mu-opioid receptor antagonist, accelerated GI recovery after BR or hysterectomy in 3 phase III trials. Methods:A pooled retrospective subset analysis of BR patients in alvimopan phase III trials was performed. Randomized BR patients received alvimopan 6 mg (n = 397), 12 mg (n = 413), or placebo (n = 402) ≥2 hours before surgery and twice daily until hospital discharge for ≤7 days. The primary endpoint of each trial was time to recovery of GI function. Hospital discharge order (DCO) written, readmission, and morbidities were also assessed. Cox proportional hazard models were used to analyze treatment effects on time-to-event endpoints. Results:Alvimopan (6 or 12 mg) significantly accelerated GI recovery (GI-3; hazard ratio = 1.28 and 1.38, respectively; P ≤ 0.001 for both). Alvimopan significantly accelerated time to DCO written by 16 hours for 6 mg and 18 hours for 12 mg (P < 0.001 for both) from a mean of 147 hours for placebo. Alvimopan-treated patients had reduced postoperative morbidity compared with placebo, and incidence of prolonged hospital stay or readmission was significantly reduced (P < 0.001). Tolerability profiles were similar among groups. Conclusions:Alvimopan significantly accelerated GI recovery in BR patients. A 12-mg dose provided more consistent benefits across both sexes and all ages. Postoperative morbidity rates, prolonged hospital stay, and rates of hospital readmission were significantly reduced. Alvimopan reduces the consequences of POI after BR.

Alvimopan Accelerates Gastrointestinal Recovery After Radical Cystectomy: A Multicenter Randomized Placebo-Controlled Trial

BACKGROUND Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS). OBJECTIVE To assess the efficacy of alvimopan to accelerate GI recovery after RC. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics. INTERVENTION Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed. RESULTS AND LIMITATIONS Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy. CONCLUSIONS Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo. PATIENT SUMMARY This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT00708201.

Gastrointestinal Tract Recovery in Patients Undergoing Bowel Resection Results of a Randomized Trial of Alvimopan and Placebo With a Standardized Accelerated Postoperative Care Pathway

OBJECTIVE To investigate the efficacy and safety of alvimopan, 12 mg, administered orally 30 to 90 minutes preoperatively and twice daily postoperatively in conjunction with a standardized accelerated postoperative care pathway for managing postoperative ileus after bowel resection. DESIGN, SETTING, AND PATIENTS This multicenter, randomized, placebo-controlled, double-blind, phase 3 trial enrolled adult patients undergoing partial bowel resection with primary anastomosis by laparotomy and scheduled to receive intravenous, opioid-based, patient-controlled analgesia. A standardized accelerated postoperative care pathway including early ambulation, oral feeding, and postoperative nasogastric tube removal was used to facilitate gastrointestinal (GI) tract recovery in all of the patients. MAIN OUTCOME MEASURES The primary end point was time to GI-2 recovery (toleration of solid food and first bowel movement). Secondary end points included time to GI-3 recovery (toleration of solid food and first flatus or bowel movement), hospital discharge order written, and actual hospital discharge. Postoperative length of hospital stay based on calendar day of hospital discharge order written, opioid consumption, and overall postoperative ileus-related morbidity were recorded. RESULTS Alvimopan, 12 mg, was well tolerated and significantly accelerated GI-2 recovery, GI-3 recovery, and actual hospital discharge compared with a standardized accelerated postoperative care pathway alone (hazard ratio = 1.5, 1.5, and 1.4, respectively; P < .001 for all). Time to hospital discharge order written as measured by hazard ratio (1.4) and by postoperative calendar days (mean for alvimopan, 5.2 days; mean for placebo, 6.2 days) was also accelerated. Opioid consumption was comparable between groups, and alvimopan was associated with reduced postoperative ileus-related morbidity compared with placebo. CONCLUSIONS Alvimopan, 12 mg, administered 30 to 90 minutes before and twice daily after bowel resection is well tolerated, accelerates GI tract recovery, and reduces postoperative ileus-related morbidity without compromising opioid analgesia.

Alvimopan, a peripherally acting μ-opioid receptor antagonist, is associated with reduced costs after radical cystectomy: economic analysis of a phase 4 randomized, controlled trial.

PURPOSE We evaluated the effect of alvimopan treatment vs placebo on health care utilization and costs related to gastrointestinal recovery in patients treated with radical cystectomy in a randomized, phase 4 clinical trial. MATERIALS AND METHODS Resource utilization data were prospectively collected and evaluated by cost consequence analysis. Hospital costs were estimated from 2012 Medicare reimbursement rates and medication wholesale acquisition costs. Differences in base case mean costs between the study cohorts for total postoperative ileus related costs (hospital days, study drug, nasogastric tubes, postoperative ileus related concomitant medication and postoperative ileus related readmissions) and total combined costs (postoperative ileus related, laboratory, electrocardiograms, nonpostoperative ileus related concomitant medication and nonpostoperative ileus related readmission) were evaluated by probabilistic sensitivity analysis using a bootstrap approach. RESULTS Mean hospital stay was 2.63 days shorter for alvimopan than placebo (mean±SD 8.44±3.05 vs 11.07±8.23 days, p=0.005). Use of medications or interventions likely intended to diagnose or manage postoperative ileus was lower for alvimopan than for placebo, eg total parenteral nutrition 10% vs 25% (p=0.001). Postoperative ileus related health care costs were

Economic analysis of alvimopan in North American Phase III efficacy trials

2,340 lower for alvimopan and mean total combined costs were decreased by

Evaluation of Clinical Outcomes With Alvimopan in Clinical Practice A National Matched-Cohort Study in Patients Undergoing Bowel Resection

2,640 per patient for alvimopan vs placebo. Analysis using a 10,000-iteration bootstrap approach showed that the mean difference in postoperative ileus related costs (p=0.04) but not total combined costs (p=0.068) was significantly lower for alvimopan than for placebo. CONCLUSIONS In patients treated with radical cystectomy alvimopan decreased hospitalization cost by reducing the health care services associated with postoperative ileus and decreasing the hospital stay.

Alvimopan for the Management of Postoperative Ileus After Bowel Resection: Characterization of Clinical Benefit by Pooled Responder Analysis

PURPOSE The economic effect of the use of alvimopan in four randomized, double-blind, placebo-controlled, Phase III, North American efficacy trials was analyzed. METHODS Patients were eligible for the study if they were 18 years or older, were undergoing laparotomy for partial small or large bowel resection with primary anastomosis, and were scheduled for postoperative pain management with opioid-based i.v. patient-controlled analgesia. Patients analyzed in the North American Phase III trials received placebo or alvimopan 12 mg orally before surgery. Doses were administered twice daily beginning the day after surgery until hospital discharge or for a maximum of 15 doses. RESULTS Compared with placebo, alvimopan was associated with a significantly shorter mean time to gastrointestinal (GI) recovery and a significantly shorter mean time to a written discharge order. Alvimopan was also associated with a mean hospital length of stay (LOS) of one full day less than placebo. The mean cost of alvimopan based on a mean of 8.9 12-mg doses was