Clinical trial NCT04405037
Conditions: Ileus Gastrointestinal Dysfunction
Sponsor: Scott Steele
Start date: 2020-08-01; Completion date: 2024-04-02
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to evaluate the cost effectiveness of Alvimopan as rescue therapy in patients undergoing colorectal or small bowel resection who develop POI, and its safety and effectiveness in reducing LOS and POI duration.

This will be a prospective randomized control trial with a total of 58 patients, 29 in each group. Patients who undergo laparoscopic or open colorectal resection, small bowel resection, or ileostomy reversal with small bowel resection that subsequently develop postoperative ileus will be eligible for enrollment. If they meet inclusion/exclusion criteria, they will be randomized at the time of diagnosis of postoperative ileus to receive Alvimopan as rescue therapy or to receive conservative standard care.

Patients randomized to the study group will be given a maximum of 3 doses of Alvimopan 12mg orally, 12 hours apart. Alvimopan will be given from the time of diagnosis of postoperative ileus to the time of return of bowel function or the maximum 3 doses. Subsequent Alvimopan doses will be given if there is no return of bowel function or if symptoms of distension and/or nausea persist despite some return of bowel function.

Detailed description:
This study aims to evaluate the cost effectiveness of Alvimopan as rescue therapy in patients undergoing colorectal or small bowel resection who develop POI, and its safety and effectiveness in reducing LOS and POI duration.

Hypothesis:

The investigators hypothesize that the use of alvimopan as rescue therapy in patients undergoing colorectal and small bowel resection surgery who develop POI can shorten their duration of POI and hospital length of stay.

Objectives:

To perform a prospective RCT to evaluate the effect of alvimopan as rescue therapy compared to standard of care in reducing the duration of post-operative ileus and post-operative LOS after colorectal and small bowel resection surgery.

Protocol:

This will be a prospective randomized control trial with a total of 58 patients, 29 in each group. Patients who undergo laparoscopic or open colorectal resection, small bowel resection, or ileostomy reversal with small bowel resection that subsequently develop postoperative ileus will be eligible for enrollment. If they meet inclusion/exclusion criteria, they will be randomized at the time of diagnosis of postoperative ileus to receive Alvimopan as rescue therapy or to receive conservative standard care.

At the time of diagnosis of postoperative ileus and after enrollment and randomization, all patients will be returned to NPO status. Nasogastric tubes (NGT) may be placed for gastric decompression at the discretion of the surgical team if clinically indicated. In the event that an NGT is placed, medications will be given orally or via the NGT, which will be clamped for 30 minutes after administration. Patients will continue on standard ERAS pathways with the exception of reduction of diet. Antiemetics will be given as clinically indicated; however, no prokinetic or promotility agents will be given as scheduled dosages.

Patients randomized to the study group will be given a maximum of 3 doses of Alvimopan 12mg orally, 12 hours apart. Alvimopan will be given from the time of diagnosis of postoperative ileus to the time of return of bowel function or the maximum 3 doses. Subsequent Alvimopan doses will be given if there is no return of bowel function or if symptoms of distension and/or nausea persist despite some return of bowel function.

All patients will follow a standard ERAS pathway after surgery, with early feeding and ambulation, along with opioid minimizing measures as is our standard postoperative protocol.

The patient and surgical team will be able to know which arm of the study the patient is in based on documentation in the medical record of the administration of Alvimopan.

Standard discharge criteria will be applied to all patients, including: Passage of stool, Ability to tolerate solid food and to drink comfortably, Adequate oral analgesia, Patient's willingness to be discharged.

Arms: arm 1: Patients randomized to the study group will be given a maximum of 3 doses of Alvimopan 12mg orally, 12 hours apart. Alvimopan will be given from the time of diagnosis of postoperative ileus to the time of return of bowel function or the maximum 3 doses. Subsequent Alvimopan doses will be given if there is no return of bowel function or if symptoms of distension and/or nausea persist despite some return of bowel function.

All patients will follow a standard ERAS pathway after surgery, with early feeding and ambulation, along with opioid minimizing measures as is our standard postoperative protocol. arm 2: Control patients will follow a standard ERAS pathway after surgery, including NPO status, IV fluid rehydration, and nasogastric decompression, early feeding and ambulation, along with opioid minimizing measures as is our standard postoperative protocol.
Interventions: intervention 1: Alvimopan
Intervention descriptions: intervention 1: Alvimopan will be given to patients who are diagnosed with postoperative ileus after surgery

Protocol documents:
Prot_SAP_000.pdf: 
A Prospective Randomized Control Trial of The Effectiveness of Alvimopan as a Rescue Treatment of 
Postoperative Ileus Following Colorectal Surgery 
 
 
Principal Investigators: 
 
Conor P. Delaney, MD 
 
Scott R. Steele, MD 
 
 
Co-investigator: 
 
Laurie Y. Hung, MD 
 
Hannah Horne, PA 
 
Biostatistician: 
 
Xue Jia, MSc  
 
Protocol Version: 10/25/21 
 
NCT04405037 
 
Background: 
 
Most patients who undergo colorectal or small bowel resection (about 350,000 patients/year in the 
United States) will experience postoperative ileus, a temporary impairment of gastrointestinal function 
(8). POI is associated with increased morbidity, increased hospital length of stay (LOS), and increased 
health care costs (13). In most patients, LOS is typically determined by timing of GI recovery and POI has 
been shown to increase LOS by an average of 6 days with an annual cost of $1.46 billion (8). Currently, 
there is no specific treatment for or prevention of POI (8,16). Alvimopan is an oral, peripherally acting 
selective mu-opioid receptor antagonist that has been studied in patients undergoing abdominal and 
pelvic surgery, and was FDA approved in 2008 for short-term use to accelerate upper and lower 
gastrointestinal recovery in inpatients following segmental large or small bowel resection with primary 
anastomosis (8,14,15,16). Studies have demonstrated the effectiveness of Alvimopan in reducing time 
to return of bowel function, LOS and cost in abdominal surgery, however there have also been 
conflicting findings that have not observed these benefits in laparoscopic colorectal surgeries, have 
found no reduction in readmission rates or an increase in readmission rates, or have not found a 
reduction in cost (14,13,16,17,18). It is possible that the use of Alvimopan may be more effective in 
some populations than in others (i.e. low risk vs. high risk for POI, open vs. laparoscopic surgery) (13). 
The high cost of Alvimopan (currently $142.32/capsule) is of significant concern, and given 
prophylactically to all patients undergoing colorectal or small bowel resection may not be economically 
prudent as not all patients will develop POI or require treatment for POI (mild cases). This study aims to 
evaluate the cost effectiveness of Alvimopan as rescue therapy in patients undergoing colorectal or 
small bowel resection who develop POI, and its safety and effectiveness in reducing LOS and POI 
duration. 


 
Hypothesis: 
 
We hypothesize that the use of alvimopan as rescue therapy in patients undergoing colorectal and small 
bowel resection surgery who develop POI can shorten their duration of POI and hospital length of stay. 
 
Objectives: 
 
To perform a prospective RCT to evaluate the effect of alvimopan as rescue therapy compared to 
standard of care in reducing the duration of post-operative ileus and post-operative LOS after colorectal 
and small bowel resection surgery. 
 
Protocol: 
 
This will be a prospective randomized control trial with a total of 58 patients, 29 in each group. Patients 
who undergo laparoscopic or open colorectal resection, small bowel resection, or ileostomy reversal 
with small bowel resection that subsequently develop postoperative ileus will be eligible for enrollment. 
If they meet inclusion/exclusion criteria, they will be randomized at the time of diagnosis of 
postoperative ileus to receive Alvimopan as rescue therapy or to receive conservative standard care. 
 
At the time of diagnosis of postoperative ileus and after enrollment and randomization, all patients will 
be returned to NPO status. Nasogastric tubes (NGT) may be placed for gastric decompression at the 
discretion of the surgical team if clinically indicated. In the event that an NGT is placed, medications will 
be given orally or via the NGT, which will be clamped for 30 minutes after administration. Patients will 
continue on standard ERAS pathways with the exception of reduction of diet. Antiemetics will be given 
as clinically indicated; however, no prokinetic or promotility agents will be given as scheduled dosages. 
 
Patients randomized to the study group will be given a maximum of 3 doses of Alvimopan 12mg orally, 
12 hours apart. Alvimopan will be given from the time of diagnosis of postoperative ileus to the time of 
return of bowel function or the maximum 3 doses.  Subsequent Alvimopan doses will be given if there is 
no return of bowel function or if symptoms of distension and/or nausea persist despite some return of 
bowel function.   
 
All patients will follow a standard ERAS pathway after surgery, with early feeding and ambulation, along 
with opioid minimizing measures as is our standard postoperative protocol. 
 
The patient and surgical team will be able to know which arm of the study the patient is in based on 
documentation in the medical record of the administration of Alvimopan. 
 
Standard discharge criteria will be applied to all patients, including: Passage of stool, Ability to tolerate 
solid food and to drink comfortably, Adequate oral analgesia, Patient's willingness to be discharged. 
 
Study Design: 
 
This will be a prospective randomized control trial. Patients who undergo laparoscopic or open 
colorectal resection, small bowel resection, or ileostomy reversal with small bowel resection that 
subsequently develop postoperative ileus will be eligible for enrollment. 
 


If they meet inclusion/exclusion criteria, they will be randomized at the time of diagnosis of 
postoperative ileus to receive Alvimopan as rescue therapy or to receive conservative standard care. 
 
Alvimopan will be prescribed as 1 dose PO with clamping of any NG tube if present for 30 minutes. A 
subsequent dose (up to a maximum of 3 doses) may be repeated 12 hours later if there has been no 
recovery of GI function. 
 
Outcome: The primary outcome measure will be hospital length of stay after the diagnosis of POI (date 
of diagnosis until actual discharge). The secondary outcome measures will be: time to return of bowel 
function (date and time ileus identified to date and time of passing flatus, stool and tolerating diet), 
complications (serious adverse events and adverse events of interest 30 days postoperatively),  number 
of re-operations (any reoperations within 30 days of surgery), number of readmissions (any 
readmissions within 30 days of surgery) 
 
Inclusion Criteria: 
 
1. Subjects who have benign or malignant colonic or rectal disease that have undergone laparoscopic or 
open colorectal resection, small bowel resection or ileostomy reversal with small bowel resection and 
subsequently developed postoperative ileus, defined as: 
 
a. Patients with symptoms of bloating with or without nausea and vomiting, who require either:  
 
i. Return to NPO status after initial diet attempts 
 
ii. Undergo placement of a nasogastric tube 
 
b. Patients with absence of passage of flatus or stool who are either 
 
i. More than 5 days after open surgery without recovery of GI function 
 
ii. More than 3 days after laparoscopic surgery or ileostomy closure without recovery of GI function 
 
2. Subjects who are 18 years of age and older 
 
3. Subjects of either gender 
 
4. Subjects who are willing and able to adhere to protocol requirements, agree to participate in the 
study program and provide written and informed consent. 
 
Exclusion Criteria: 
 
1. Subjects who received Alvimopan preoperatively. 
 
2. Subjects that have already received scheduled peripherally acting mu-opioid receptor antagonists 
postoperatively. 
 
3. Subjects that have taken therapeutic doses of opioids for more than 7 days immediately prior to 
surgery. 


 
4. Subjects with severe hepatic impairment. 
 
5. Subjects with end-stage renal disease. 
 
6. Subjects who are pregnant. 
 
7. Subjects who have undergone imaging suggesting a small bowel obstruction. 
 
7. Subjects with a medical condition that may interfere with the use of the study medication Alvimopan. 
 
8. Subjects who have a condition or general disability or infirmity that in the opinion of the investigator 
precludes further participation in the study 
 
Data to be collected: 
 
The medical/surgical information below will be collected as part of this research study and is all 
information already available as part of the patients medical chart. 
 
A) Preoperative variables: 
 
1. Patient name, medical record number 
 
2. Past Medical History 
 
3. Past Surgical history 
 
4. Preoperative Medications (including steroids, anticoagulation, opioid use) 
 
5. Pre-operative Diagnosis 
 
6. Patient Demographics (age, gender, BMI, ASA score) 
 
B) Intraoperative variables: 
 
1. Procedure performed 
 
1. Time of surgery 
 
2. Wound classification 
 
3. Estimated blood loss 
 
4. Intraoperative transfusion 
 
5. Intraoperative IV fluids given 
 
6. Conversion from laparoscopic to open procedure 


 
7. Stoma creation 
 
C) Postoperative variables: 
 
1. Time/day of diagnosis of ileus 
 
2. Abdominal imaging demonstrating ileus if present 
 
3. Time from surgery to medication given 
 
4. Time from ileus diagnosis to medication given 
 
5. Was there return of bowel function (flatus or stool, solid or liquid, stoma output) prior to ileus 
 
6. Intra-abdominal infection/anastomotic leak 
 
7. Time/day of return of bowel function post ileus (flatus and stool- solid or liquid, and stoma function) 
 
8. Time/day of ability to tolerate oral diet (liquid and solid food) 
 
9. Nasogastric tube placement and daily output 
 
10. Duration of nasogastric tube 
 
11. Use and type of anti-emetics given 
 
12. Total number of Alvimopan doses given 
 
13. Post operative complications including reoperation 
 
14. Length of stay in hospital, defined as time from surgery to discharge 
 
15. Length of POI, defined as time from diagnosis of POI until discharge 
 
16. 30-day readmissions 
 
Study Completion of participation in the study will be 30 days after the date of POI. Any readmission up 
to 30 days post-operatively to the hospital as a direct result of their surgery will be followed. The 
patients will follow-up with the surgeon in the office in approximately 3-6 weeks, which is considered 
standard of care for all patients undergoing colorectal surgery and is not considered part of the research 
study. Any patient for whom follow-up documentation is missing or incomplete shall be contacted via 
telephone. The purpose of the call will be to simply determine return to function and outcome. Only a 
co-investigator shall contact the subject and will identify themselves at the beginning of the call. Any 
subject can reserve the right not to participate in the phone call interview; they would remain in the 
study. 
 
 


Statistical Analysis 
 
Planned Data Analysis: 
 
Descriptive statistics will be computed for all variables including mean ± standard deviation or median 
[25th, 75th percentiles] for continuous factors and frequency (percent) for categorical variables. 
Univariate analyses will be conducted to compare the distribution of pre-op characteristics across 
treatment groups using t-test or Wilcoxon rank sum tests for continuous variables and Chi-square or 
Fisher’s exact test for categorical variables. 
 
The hospital length of stay after the diagnosis of POI and time to return of bowel function are defined as 
the interval between the day of POI diagnosis and day of actual discharge from the hospital, and the day 
of POI diagnosis and day of return of bowel function.   T-test will be used to assess differences in the 
hospital length of stay after diagnosis of POI or time to return of bowel function across treatment 
groups.  Multivariable linear regression will be conducted to adjust for baseline measurements as well as 
potential confounding variables such as gender, obesity, and operative time.  Backwards variable 
selection will be used with a removal criteria of alpha > 0.1.  When required, data will be transformed in 
order to meet normality assumptions.   
 
For purposes of statistical analysis, a subset analysis may be done based on history of POI, type of 
operation, BMI, patients’ gender, or other clinically significant co-factors. All data will be analyzed with 
the use of SAS (version 9.4, The SAS Institute, Cary, NC), SPSS statistical software (SPSS Inc., Chicago, IL), 
or R version 3.6.1 (www.R-project.org). A p-value <0.05 will be considered statistically significant.  
 
Sample Size Calculations: 
 
We conducted the sample size calculation using estimates of length of stay after the diagnosis of POI .  
We are assuming equal-sized treatment groups and alpha = 0.05. 
 
We assumed that the average length of stay after the diagnosis of POI in no alvimopan group would be 
4.25 days, and alvimopan group 2.75 days.  Assuming a log-normal distribution, and co-efficient of 
variation of 0.6 based on prior data, there will be 80% power to detect decreases of a least 35% in 
length of stay after the diagnosis of POI in the Alvimopan group relative to the control group with 27 
patients in each group, a total of 54 patients.  Accounting for a dropout rate of about 5%, our 
enrollment goal will be 58 patients (29 per group).   
  
 
Reporting of Results 
 
Aggregate and anonymous, in text and table format, for publication in a medical journal. 
 
Consent 
 
A study coordinator will obtain informed consent from participating patients prior to Alvimopan 
administration.  The coordinator will have HIPPA training, certification in human subject protection, and 
will be familiar with the research protocol. The study coordinator will explain to each participant the 
purpose of the study as well as give the patient the opportunity to opt out of participation. Consents will 
be kept in a room accessible only to qualified research personnel working in the CORS department. 


Consents will be obtained prior to alvimopan administration. Patients will be offered participation in the 
study in a private clinic room. Patients will be offered to participate in the study post-operatively at the 
time of their post operative ileus diagnosis. Alvimopan is not part of the standard of care. It will be 
administered free of charge without extra financial charges to the enrolled patients.  
 
References: 
 
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2. Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative ileus. Neurogastroenterol Motil. 2004 
Oct;16 Suppl 2:54-60. Review. 
 
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Review. 
 
4. Behm B, Stollman N. Postoperative ileus: etiologies and interventions. Clin Gastroenterol Hepatol. 
2003 Mar;1(2):71-80. Review. 
 
5. Luckey A, Livingston E, Taché Y. Mechanisms and treatment of postoperative ileus. Arch Surg. 2003 
Feb;138(2):206-14. Review. 
 
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ICF_001.pdf: