Conditions: Ventral Hernia
Keywords: GI Tract Recovery Hospital Discharge
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether Alvimopan (Entereg) in ventral hernia surgery patients is associated with accelerated gastrointestinal recovery and reduced length of hospital stay compared to placebo controls.

Detailed description:
Background: One of the most common occurrences following ventral incisional hernia repair is post-operative ileus. Post-operative ileus is a source of patient discomfort and morbidity that ultimately delays discharge from the hospital and is frequently a source of patient readmission. Prolonged length of hospital stay due to post-operative ileus increases direct health care costs, as well as the indirect costs of a delay in returning to the workforce. The cause of prolonged ileus is multifactorial, but some of the main culprits include intra-operative bowel manipulation, the release of endogenous opioids, the administration of exogenous opioid analgesics during surgery and for post-operative pain control, inflammation, and fluid shifts. A study by Lowe et al showed that following ventral hernia repair, 27% of their study patients had a prolonged ileus, defined as lasting more than 7 days postoperatively. Likewise, the mean hospital stay for these patients was 12.5 days, due most frequently, to a delayed return of bowel function.

Ventral incisional hernia repair is a common operation and post-operative ileus remains a frequent and costly post-operative occurrence for which we do not currently have an effective therapy. Alvimopan has proven to successfully decrease the duration of post-operative ileus and is FDA approved for such use in patients who have undergone bowel resection. Ultimately, decreasing the interlude between operation and return of bowel function results in shorter hospital stays, lower hospital costs, and faster rehabilitation. We propose to study the effectiveness of Alvimopan in decreasing postoperative ileus time in patients undergoing ventral hernia repair, a cohort that we feel may benefit from the use of Alvimopan but that to date has not been studied.

Recruitment and Sample Size: A total of 140 patients are expected to undergo research related treatments. The study will contain one open surgery arm. The open surgery arm will be a single-site prospective, randomized, double-blinded, placebo-controlled clinical trial with 1:1 randomization between the study drug and placebo with 70 patients in each group for a total of 140 patients in the study. An interim evaluation of efficacy will be conducted separately in the open surgery arm when half the patients have been recruited.

This study is expected to enroll up to 140 subjects from one academic medical center (Froedtert Hospital and the Medical College of Wisconsin) a site that performs state of the art hernia repairs and is a high volume hernia practices.

Treatment: Consented patients in the Treatment Group will receive 12 milligrams (mg) of Alvimopan per-oral (PO) 30 to 90 minutes prior to ventral hernia repair in the pre-operative area and continue 12 mg PO twice daily until hospital discharge or post-operative day (POD) 7 for a maximum of 15 in-hospital doses (Appendix II). The first post-operative dose will begin after Nasogastric Tube (NGT) removal.

Patients in the Control Group will receive 12 milligrams (mg) of Placebo orally (PO) 30 to 90 minutes prior to Ventral Hernia Repair (VHR) in the pre-operative area and continue 12 mg PO twice a day until hospital discharge or post-operative (POD) 7 for a maximum of 15 in-hospital doses. The first post-operative dose will begin after NGT removal.

Warnings and precautions as provided in the prescribing information packet and US PI include:

1. A higher number of myocardial infarctions was reported in patients treated with alvimopan 0.5 mg twice daily compared with placebo 12 in a 12-month study in patients treated with opioids for chronic pain, although a causal relationship has not been established
2. Patients recently exposed to opioids are expected to be more sensitive to the effects of ENTEREG and therefore may experience abdominal pain, nausea and vomiting, and diarrhea.
3. Not recommended in patients with severe hepatic impairment.
4. Not recommended in patients with end stage renal disease.
5. Most common adverse reaction (incidence \>=1.5%) occurring with a higher frequency than placebo among ENTEREG-treated patients undergoing surgeries that included a bowel resection was dyspepsia \[2013 PI\].
6. Not recommended in patients with complete GI obstruction or in patients who have surgery for correction of complete bowel obstruction.
7. Not recommended in pancreatic or gastric anastomosis.

Arms:
arm 1: Alvimopan, 12mg, capsule. One 30 to 90 minutes before the scheduled start of surgery on Day 0, and twice daily beginning on POD 1 after NGT removal until hospital discharge or for a maximum of 7 days (up to 15 doses) of postoperative treatment. First post-operative dose begins after NGT removal. arm 2: Placebo, 12mg capsule. One 30 to 90 minutes before the scheduled start of surgery on Day 0, and twice daily beginning on POD 1 until hospital discharge or for a maximum of 7 days (up to 15 doses) of postoperative treatment. First post-operative dose begins after NGT removal.

Interventions: intervention 1: Alvimopan intervention 2: Placebo
Intervention descriptions: intervention 1: Alvimopan, 12mg, capsule. One 30 to 90 minutes before the scheduled start of surgery on Day 0, and twice daily beginning on POD 1 after NGT removal until hospital discharge or for a maximum of 7 days (up to 15 doses) of postoperative treatment. First post-operative dose begins after NGT removal. intervention 2: Placebo (sugar pill-will be the same size and color as the Alvimopan capsule), 12mg capsule. One 30 to 90 minutes before the scheduled start of surgery on Day 0, and twice daily beginning on POD 1 until hospital discharge or for a maximum of 7 days (up to 15 doses) of postoperative treatment. First post-operative dose begins after NGT removal.

Protocol document:
Prot_SAP_000.pdf: 
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Study Title: 
Gastrointestinal Tract Recovery in Patients 
Undergoing Open Ventral Hernia Repair: A Single-
Center, Randomized, Double-Blind, Trial of 
Alvimopan and Placebo 
Date: 
15-Oct-2014  
Research Type: 
Clinical   
Study Type: 
Prospective  
Cubist Investigational Drug: 
Alvimopan     
Primary Investigator Name: 
Dr. Matthew I. Goldblatt 
Primary Investigator Address: 
9200 West Wisconsin Ave 
Milwaukee, WI 53226-9934 
Please read all section instructions before entering information.  Complete all required fields by replacing the blue text.  
Additional instructions/information will be presented throughout in red text.  
Please note: to create bullets within the template type “*” then hit the space bar. 
1 
STUDY RATIONALE/BACKGROUND 
Alvimopan (Entereg) is an orally administered peripherally acting µ-opioid receptor 
antagonist that has been shown to decrease the duration of postoperative ileus.2,5,8,9 
Multiple double-blinded, randomized, placebo-controlled trials, have shown Alvimopan 
to reduce both the time to gastrointestinal recovery and the time to hospital discharge 
following bowel resection. This benefit was achieved without compromising pain 
management.10 Alvimopan selectively and competitively inhibits the µ-opioid receptors 
in the GI tract, but is unable to cross the blood-brain barrier. This prevents Alvimopan 
from affecting the central nervous system pathway that controls analgesia, allowing it to 
decrease postoperative ileus time without compromising pain control.10 In addition to 
accelerated gastrointestinal recovery and reduced length of hospital stay, the use of 
Alvimopan also significantly decreased the number of adverse events (most notably 
nausea and vomiting), and decreased the need for postoperative nasogastric tube 
reinsertion. These improved clinical outcomes had further impact by leading to lower 
hospital costs and increased patient satisfaction.3,5,8,9 Alvimopan is FDA approved for 
patient use with the intent of accelerating upper and lower gastrointestinal recovery 
following bowel resections. To date, no studies have been conducted regarding the use 
of Alvimopan in patients undergoing ventral hernia repairs. 
 
Conservative estimates suggest that the incidence of ventral incisional hernia after 
abdominal surgery via midline laparotomy is 10-20%.1,4,7 The occurrence of a ventral 
incisional hernia is associated with significant patient discomfort, disability and 
subsequent morbidity. These factors lead most patients suffering from a ventral 
incisional hernia to pursue elective repair. In 2005, there were greater than 348,000 
ventral hernia repairs in the United States alone.14 If left unrepaired, these hernias can 


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increase in size causing pain, abdominal wall deformity, skin breakdown, intestinal 
obstruction and/or intestinal strangulation.4  
 
One of the most common occurrences following ventral incisional hernia repair is post-
operative ileus. Post-operative ileus is a source of patient discomfort and morbidity that 
ultimately delays discharge from the hospital and is frequently a source of patient 
readmission. Prolonged length of hospital stay due to post-operative ileus increases 
direct health care costs, as well as the indirect costs of a delay in returning to the 
workforce. The cause of prolonged ileus is multifactorial, but some of the main culprits 
include intra-operative bowel manipulation, the release of endogenous opioids, the 
administration of exogenous opioid analgesics during surgery and for post-operative 
pain control, inflammation, and fluid shifts.3,5,8  A study by Lowe et al showed that 
following ventral hernia repair, 27% of their study patients had a prolonged ileus, 
defined as lasting more than 7 days postoperatively.4 Likewise, the mean hospital stay 
for these patients was 12.5 days, due most frequently, to a delayed return of bowel 
function.4  
 
Ventral incisional hernia repair is a common operation and post-operative ileus remains 
a frequent and costly post-operative occurrence for which we do not currently have an 
effective therapy. Alvimopan has proven to successfully decrease the duration of post-
operative ileus and is FDA approved for such use in patients who have undergone bowel 
resection. Ultimately, decreasing the interlude between operation and return of bowel 
function results in shorter hospital stays, lower hospital costs, and faster rehabilitation. 
We propose to study the effectiveness of Alvimopan in decreasing postoperative ileus 
time in patients undergoing ventral hernia repair, a cohort that we feel may benefit 
from the use of Alvimopan but that to date has not been studied. 
 
2 
STUDY HYPOTHESIS 
In patients undergoing open ventral hernia repair, we hypothesize that Alvimopan 
(Entereg) is associated with accelerated gastrointestinal recovery and reduced length of 
hospital stay compared to placebo controls. 
 
2.1 
PRELIMINARY DATA  
Fitzgibbons et al, (Creighton University) employed a single-center, randomized, double-
blind trial, of Alvimopan in open and laparoscopic ventral hernia repair patients. 
Comparisons were made between the length of time (in post-operative days) until 
patient flatus, bowel movement, and discharge from hospital. The treatment group 
(Alvimopan) showed a trend toward first flatus, bowel movement, and hospital 
discharge compared to the placebo group. However, this was not significant due to the 
small sample number within the sample population. The study results reported by 
Fitzgibbon et al. warrant a larger sample size to determine the outcomes achieved with 
Alvimopan in ventral hernia patients.        


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3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
STUDY OBJECTIVES 
3.1.1 PRIMARY OBJECTIVES:   
Primary Objective: To investigate the efficacy and safety of Almimopan, 12mg, 
administered orally 30 to 90 minutes preoperatively and twice daily postoperatively for 
a maximum of 7 days (15 total doses) in conjunction with a standardization 
postoperative care pathway for managing postoperative ileus after ventral hernia 
repair. 
 
3.1.2 SECONDARY OBJECTIVES:   
Secondary Objective: To investigate the post-operative gastrointestinal recovery,  and 
treatment related morbidity after ventral hernia repair.  
 
3.2 
STUDY ENDPOINTS 
3.2.1 PRIMARY ENDPOINT:   
Length of time (hrs/days) to gastrointestinal tract recovery 
3.2.1.1 PRIMARY ENDPOINT DEFINITION:   
Time to gastrointestinal recovery will be measured by the following: Time to first flatus, 
time to toleration of a liquid diet, time to toleration of a solid diet, time to toleration or 
oral pain medications, time to first bowel movement, time to GI-2 recovery, time to GI-3 
recovery, incidence of nasogastric tube insertion, episodes of emesis, use of anti-nausea 
medication, nausea, bloating, incidence of diet reduction or restriction, and initiation of 
TPN. 
 
Time to first flatus and time to first bowel movement are patient reported endpoints 
that occur during the hospitalization. Patients will be asked about flatus twice daily by 
the physician or a qualified study or clinical staff member. Additionally, patients will be 
instructed to notify the nurse following first flatus and/or bowel movement so that the 
time can be recorded.  
 
Toleration of a diet and toleration of oral pain medication are defined as ingestion of 
diet or medications that occurs without vomiting or significant nausea for four hours 
following ingestion.  
 
GI-2 recovery is defined as both toleration of solid food and occurrence of first bowel 
movement. GI-3 recovery is defined as toleration of solid food and either occurrence of 
first flatus or occurrence of first bowel movement.  
 
Patients requiring nasogastric tube insertion, requiring reduction or restriction of diet, 
having episodes of emesis, and/or needing initiation of TPN will be recorded. VAS 


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nausea, bloating and pain scores will be recorded by nursing staff at least twice each 
day. The number of doses of anti-nausea medication administered during the 
hospitalization will also be recorded.  
3.2.2 SECONDARY ENDPOINT(S):   
Length of hospital stay, 30-day  treatment related morbidity and re-admission 
rates, and post-operative pain scores.   
 
3.2.2.1 SECONDARY ENDPOINT DEFINITION(S):   
Length of stay will be measured in hours from the time that surgery is completed until 
the hospital discharge order is written (hrs/days).  
 
Treatment related morbidity and re-admission rates will be assessed from the time 
surgery is completed to 30-days post-operatively. Treatment related morbidity and re-
admission rates include: POI, indigestion, and any event determined by the attending 
physician to be directly related to treatment.  
 
Post-operative pain scores will be obtained from patients daily until hospital discharge, 
2-weeks post-operatively, and 30-days post-operatively using the Visual Analog Pain 
Scale (scale, 1-10) and the Hernia-Related Quality-of-Life Survey (HerQLes).  
 
4 
STUDY DESIGN 
4.1 
SITES  
Medical College of Wisconsin, Milwaukee, WI  
4.2 
INCLUSION/EXCLUSION CRITERIA 
4.2.1 INCLUSION CRITERIA 
1. Subjects will be informed about the study, have read, understood, and signed the 
Informed Consent Form 
2. Subjects of either gender that are ≥18 years of age 
3. Subjects who can ambulate preoperatively 
4. Subjects will have a Body-Mass Index (BMI) of ≤ 40mg/m2 
5. Subjects with an ASA classification of 1, 2 or 3 
6. Subjects not receiving an epidural to control perioperative pain 
7. Subjects will be undergoing elective single-staged open ventral (incisional or midline) 
hernia repair 
8. Subjects in which intra-operatively their surgical field/wound is characterized as Type 1 
(Appendix II) 
9. Subjects with a hernia defect ≥9 cm2 large 
 


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4.2.2 EXCLUSION CRITERIA 
1. Subjects who are not able to comprehend or comply with study requirements 
2. Subjects who are pregnant 
3. Subjects with BMI > 40 
4. Subjects with autoimmune disorder requiring >10mg of a corticosteroid per day 
5. Subjects with pre-existing systemic infections 
6. Subjects with a wound-healing disorder 
7. Subjects who have taken therapeutic doses of opioids for more than 7 consecutive days 
immediately prior to taking Alvimopan 
8. Subjects who are immunocompromised such as HIV or transplant, or receiving chemo or 
radiation therapy 
9. Subjects with a hernia defect < 9cm2 large when measured intra-operatively 
10. Subjects in which intra-operatively their surgical wound field/wound is characterized as 
Type 2, 3, or 4 (Appendix II) 
11. Subjects in which the ventral incisional hernia repair requires more than one operation 
to reduce the hernia or to complete the hernia repair 
12. Subjects with a hernia repair requiring an emergent procedure 
13. Subjects in which untreated cancer was found intra-operatively 
14. Subjects with cirrhosis or are currently being treated with dialysis 
15. Subjects with severe hepatic impairment (Childs-Pugh class C) 
16. Subjects with end-stage renal disease 
17. Subjects scheduled for a concomitant procedure that involves the GI tract 
18. Subjects with unplanned procedures that involve the GI tract  
19. Subjects requiring post-operative NGT 
20. Subjects participating in another prospective interventional study that involves the use 
of a device, drug, or surgery that would compromise the current study 
21. Subjects with an epidural to control perioperative pain 
 
4.3 
SAMPLE SIZE 
4.3.1 NUMBER OF CHARTS TO BE REVIEWED 
 Not Applicable.  
4.3.2 NUMBER OF SUBJECTS TO BE ENROLLED 
140: 70 Alvimopan, 70 Placebo  
4.3.3 SAMPLE SIZE DETERMINATION 
A total of 140 patients are expected to undergo research related treatments. The study 
will contain one open surgery arm. The open surgery arm will be a single-site 
prospective, randomized, double-blinded, placebo-controlled clinical trial with 1:1 


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randomization between the study drug and placebo with 70 patients in each group for a 
total of 140 patients in the study. An interim evaluation of efficacy will be conducted 
separately in the open surgery arm when half the patients have been recruited. 
 
This study is expected to enroll up to 140 subjects from one academic medical center 
(Froedtert Hospital and the Medical College of Wisconsin) a site that performs state of 
the art hernia repairs and is a high volume hernia practices.  
 
The study has been designed to provide at least 80% power to detect a 24-hour 
decrease in the time to return of bowel function in the treatment group compared to 
the control group at a one-sided 2.5% significance level. This corresponds to a two-sided 
5% significance level, but acknowledges the one-sided nature of the study hypothesis. 
Based on data from studies of the experimental treatment in other contexts, as well as 
internal data, we expect a standard deviation of 48 hours. Adjusting for the increase in 
sample size to accommodate the planned interim analysis, 64 evaluable patients per 
group will provide the desired power. More details of the power characteristics are 
shown under the Interim Analysis section. We will recruit 70 patients in each arm to 
accommodate a 5-10% dropout rate. 
 
4.4 
SCREENING, RANDOMIZATION, BLINDING 
4.4.1 SCREENING PROCEDURE 
1. All subjects undergoing open ventral (incisional or midline) hernia repair will be 
approached by study staff prior to surgery to participate in the study. 
2. Patients who meet all inclusion/exclusion criteria will be approached for voluntary 
informed consent. 
3. Final determination on whether a subject will be included in the study will be made 
during surgery. If intra-operatively it is concluded that the subject does not meet the 
study criteria, the subject will be excluded and the reason will be documented. 
4. The study team will maintain a screening log for all patient approached for consent per 
institutional IRB guidelines.  
 
4.4.2 RANDOMIZATION 
Patients will be randomized after written informed consent has been obtained and 
eligibility has been verified. Operationally, the blinded randomization will be carried out 
using patient-specific study numbers. Before the initiation of the study a list linking 
study IDs to treatment and control group will be generated following the randomization 
plan, and provided to Froedtert Hospitals Investigational Drug Services (IDS).  The IDS 
will receive study drugs from Cubist Pharmaceuticals, Inc. and package and distribute 
study medications to each study patient. The patient will then receive medication 
dispensed from the bottle with the corresponding study ID. 


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4.4.3 BLINDING 
The study will be performed in a double-blind fashion. The investigator, study staff, 
subjects, and monitors, will remain blinded to the treatment assignment. Alvimopan and 
the placebo will be visually identical and will be similarly packaged and administered.  
 
The identity of the study drug may only be revealed if the subject experiences a medical 
emergency whose management would require knowledge of the blinded treatment 
assignment.  The master randomization code list will be maintained by the IDS. Prior to 
unblinding, the surgeon or other care provider must contact the study principle 
investigator, and every attempt must be made by the treating surgeon to discuss the 
intended unblinding with the principle investigator (or a designee from IDS).  All cases of 
unblinding, including justification for unblinding, must be fully documented by the principle 
investigator, site investigator, and IDS designee.  The principle investigator may obtain the 
identity of the study drug dispensed to a subject through IDS.  
 
If the subject becomes unblinded, the subject will continue to be followed for adverse 
events up to 30 days, or 14 days past discharge if the patient is an inpatient after 30 days, 
but the efficacy data from this point will be carried forward and analyzed in the intent-to-
treat analysis. 
 
4.5 
REGULATORY AND ETHICS 
4.5.1 INFORMED CONSENT 
Voluntary written informed consent must be obtained before any study-related procedures are 
performed in accordance with International Conference on Harmonization (ICH) guidelines and 
the requirements of informed consent (Title 21 Code of Federal Regulations (CFR) Parts 50.20 
and 50.25).  Consent must be documented by the use of a written consent form approved by Cubist 
and the Institutional Review Board (IRB) in accordance with Title 21 CFR Part 50.27.  In the case 
of non-interventional studies, a waiver of informed consent may be granted by your IRB and will 
need to be provided to Cubist.  A technical guide is available upon request to assist you in 
understanding informed consent requirements. 
 
All patients who meet inclusion criteria and voluntarily agree to participate in the study 
will sign an IRB approved informed consent. 
 
4.5.2 INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE 
The Medical College of Wisconsin IRB will oversee the proposed study.  
4.5.3 INVESTIGATIONAL NEW DRUG (IND) FILING  
As the Sponsor Investigator you are responsible for determining whether an IND is necessary in 
order to conduct your proposed clinical study.  Cubist Pharmaceuticals does not make this 
determination for Sponsor-Investigator studies.  We strongly encourage you to contact the Food 
and Drug Administration (FDA) for assistance in determining the necessity of an IND.  
Information on who to contact can be found by clicking the following link: IND Guidance.  Section 
312.2 of Title 21 of the Code of Federal Regulations details the applicability and exceptions of the 
IND regulations.  A technical guide is available upon request to assist you in understanding when 
an IND may be required. 


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The study team submitted an IND application to the FDA to support our study.  
5 
STUDY PROCEDURES  
5.1 
TREATMENT 
Consented patients in the Treatment Group will receive 12 milligrams (mg) of Alvimopan 
per-oral (PO) 30 minutes to 90 minutes prior to ventral hernia repair in the pre-
operative area and continue 12 mg PO twice daily until hospital discharge or post-
operative day (POD) 7 for a maximum of 15 in-hospital doses (Appendix II). 
 
Patients in the Control Group will receive 12 milligrams (mg) of Placebo orally (PO) 30 
minutes to 1 hour prior to VHR in the pre-operative area and continue 12 mg PO twice a 
day until hospital discharge or post-operative (POD) 7 for a maximum of 15 in-hospital 
doses. 
 
If the maximum allowed number of doses is not achieved in a seven day period (15 
doses) the remaining study medication is to be returned to FH IDS for proper disposal.  
Under no circumstances is study medication to be re-used or re-packaged for sale or 
distribution. 
5.2 
INTERVENTION 
Not applicable.  
5.3 
PROCEDURES 
Patients who meet all includion criteria will undergo the study related procedures stated below.  
 
During enrollment, FH IDS will assign medication to patients in order of enrollment and 
according to the randomization code list.  The patient will then receive medication 
dispensed from the bottle with the corresponding study ID. 
 
Patient treatment will follow (section 5.1). 
 
Following surgery, patients will be admitted to the hospital and a basic standardized 
treatment pathway will be initiated.  
 
1) Following surgery patients are admitted with NPO status, PRN IV opioid pain 
medication, and PRN IV anti-nausea medication.  
2) Epidural use is up to the discretions of the treating surgeon. 
a. Non-narcotic adjuncts can be used as determined by the physician 


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3) Nasogastric tubes are NOT routinely left in following surgery. However, nasogastric tube 
use is up to the discretion of the treating surgeon. Patients who require NGT will be 
excluded from the study. 
4) Patients remain NPO until the following criteria are met: reported flatus, absence of 
nausea and/or emesis and/or bloating, and absence of abdominal distention. 
Alternatively, clinical determination made by the physician can be utilized for diet 
advancement. If clinical determination outside of these parameters is used then the 
justification for the clinical decision making will be recorded for these patients. 
5) Transition to oral pain medication will occur at or after the time of transition to clear 
liquids.  
6) Diet advancement after clears will occur at physician discretion 
7) Minimum discharge criteria include: toleration of diet beyond clears, toleration of oral 
pain medication, and absence of nausea/vomiting/distention.  
a. Toleration of solid food is NOT required for discharge 
b. Production of a bowel movement is NOT required for discharge 
 
5.4 
ADVERSE EVENT REPORTING 
If your study collects patient specific safety data, provide timelines and a detailed description of 
procedures for collecting, assessing and reporting adverse events. A technical guide is available upon 
request to assist you in completing the following section. 
 
It is the responsibility of the investigator(s) to oversee the safety of the study. The safety 
monitoring will include careful assessment and appropriate reporting of complications/events as 
noted below. 
 
Adverse events will be reviewed for clinical relevance and cause relation and reported as the 
events occur.   
 
The ACS NSQIP Variables and Definitions guidance document will be used to ensure 
consistency of defining and reporting the complications or events in this study. 
 
5.4.1 
DEFINITONS 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.  
 


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Pregnancy is not an AE; however, if a female subject becomes pregnant during the 
conduct of the study, the Investigator should discontinue study medication immediately.  
Follow up information regarding the outcome of the pregnancy and any sequelae, 
including fetal or neonatal abnormalities should be obtained and documented. All 
information obtained about the pregnancy including information on the infant after birth 
should be forwarded to Cubist Pharmacovigilance as soon as possible.  
 
The identification of the presence of a non-susceptible microorganism during treatment 
is generally not considered an AE unless associated with other unintended 
consequences (e.g., worsening of the disease under treatment). 
5.4.2 
RELATIONSHIP TO STUDY MEDICATION 
Many terms and definitions can be used to describe the causal relationship 
between a drug product and an AE. Examples include: definitely, probably, 
possibly, unlikely related, or not related. Phrases such as “plausible relationship”, 
“suspected causality”, or “causal relationship cannot be ruled out” have also been 
used to describe a positive causal attribution between the product and the AE. 
There is currently no standardized nomenclature.  
1. Not Related: an AE with a temporal relationship to the drug 
administered that makes a causal relationship improbable, and/or for 
which other drugs or underlying or concurrent disease provide a 
plausible explanation 
2. Unlikely Related: an AE that has a plausible temporal relationship to 
the drug administered, but for which other causative factor(s) more 
likely account for the event and where dechallenge (withdrawal of 
drug treatment) or dose reduction was not felt clinically indicated or 
improvements on dechallenge or dose reduction have not been 
observed 
3. Possibly Related: an AE that has a plausible temporal relationship to 
the drug administered, but for which other causative factor(s) could 
account for the event and where improvements on dechallenge or 
dose reduction may or may not have been observed. 
5.4.3 
EXPECTEDNESS OF AE 
An AE is considered unexpected if the specificity or severity is not consistent with 
the applicable product information. In this case, where a study is being performed 
prospectively outside of the current labeled use (e.g., the investigator holds their 
own IND), the Investigator Brochure is considered the applicable product 
information. 
 
Warnings and precautions as provided in the prescribing information packet 
include: 
1. A higher number of myocardial infarctions was reported in patients treated 
with alvimopan 0.5 mg twice daily compared with placebo 12 in a 12-month 
study in patients treated with opioids for chronic pain, although a causal 
relationship has not been established 


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2. Patients recently exposed to opioids are expected to be more sensitive to the 
effects of ENTEREG and therefore may experience abdominal pain, nausea 
and vomiting, and diarrhea. 
3. Not recommended in patients with severe hepatic impairment. 
4. Not recommended in patients with end stage renal disease. 
5. Most common adverse reaction (incidence >1.5%) occurring with a higher 
frequency than placebo among ENTEREG-treated patients undergoing 
surgeries that included a bowel resection was dyspepsia.  
6. Not recommended in patients with complete GI obstruction or in patients who 
have surgery for correction of complete bowel obstruction. 
7. Not recommended in pancreatic or gastric anastomosis. 
5.4.4 
RECORDING AND REPORTING AN AE 
If AEs are collected, any AE, regardless of seriousness, severity, or causal relationship to a drug, 
should be recorded on the case report form or SAE form.  For retrospective studies, investigators 
should report all AEs identified during the study period defined in the protocol. 
 
Any AE, regardless of seriousness, severity, or causal relationship to the study 
medication, will be recorded on the case report form or SAE form.  The form 
contains fields that allow for complete evaluation of an AE. All AEs starting with 
the first intervention or dose of study medication and throughout the duration of 
the study (through last patient visit) will be monitored.  
 
5.4.5 
RECORDING AND REPORTING A SAE 
5.4.5.1 STUDIES NOT PERFORMED UNDER AN IND 
Please report all required safety data to your IRB in accordance with your IRB’s 
directions. Healthcare professionals are encouraged to report adverse events or side effects 
related to the use of these products to the FDA's MedWatch Safety Information and Adverse 
Event Reporting Program; online reporting is available via: 
www.fda.gov/MedWatch/report.htm.  On the same day that you notify the FDA or your 
IRB, please send a copy of the AE report that you have submitted to the FDA or your IRB to 
Cubist’s Pharmacovigilance department at pv@cubist.com.  You will also be expected to 
cooperate with Cubist regarding any safety related inquiries related to this report. 
Not Applicable. 
 
5.4.5.2 STUDIES PERFORMED UNDER YOUR OWN IND 
You are obligated to notify the FDA in a written IND Safety Report of any adverse 
experience that you assess as both serious and related to the drug and are unexpected no 
later than 15 calendar days after your initial receipt of the information. Please refer to 21 
CFR Part 312.32 for definitions and reporting timeframes and requirements.   
 
Please report all required safety data to your IRB in accordance with your IRB’s 
directions.  
 


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On the same day that you notify the FDA of any SAE you must send a copy of each IND 
Safety Report (Initial Written Report and any Follow-ups to a Written Report) to Cubist’s 
Pharmacovigilance department at pv@cubist.com.  You will also be required to cooperate 
with Cubist regarding any safety related inquiries. 
 
Recording of AEs 
Any AE, regardless of seriousness, severity, or causal relationship to a drug, will be recorded on 
the case report form or SAE form.  The form contains fields that allow for complete evaluation of 
an AE. All AEs starting with the first intervention or dose of study medication and throughout the 
duration of the study (through last patient visit) will be monitored.  
 
Reporting of SAEs 
The study team will notify the FDA in a written IND Safety Report of any adverse experience 
that is assessed as both serious and related to the drug and is unexpected (not previously 
described in the package insert or Investigator’s Brochure). Each notification shall be made no 
later than 15 calendar days after initial receipt of the information.  21 CFR Part 312.32 will be 
referenced for definitions and reporting timeframes and requirements.  
 
Written notification using a MedWatch form (Form FDA 3500A) will be submitted or in narrative 
format. The submission will be clearly marked with the studies assigned IND number and “IND 
Safety Report”.  In each written IND Safety Report, the study team will identify all safety reports 
(if any) previously filed with the IND concerning similar adverse experience, and will analyze the 
significance of the adverse experience in light of the previous, similar reports. 
 
The study team is obligated to notify the FDA by telephone or FAX of any unexpected fatal or 
life-threatening experiences assessed as related to the drug no later than 7 calendar days after 
initial receipt of the information. The telephone call or FAX will be made to the Regulatory 
Project Manager at the study teams FDA review division. The telephone/FAX notification will be 
followed by a written IND Safety Report within 15 days of your initial receipt.  
 
The study team is also, obligated to promptly investigate all safety information and submit 
follow-up information to an initial written report (IND Safety Report—Follow-up to a Written 
Report) as soon as relevant information is available.  
 
On the same day that you notify the FDA, the study team will send a copy of each IND Safety 
Report (Initial Written Report and Follow-up to a Written Report) to Cubist. Copies of the IND 
Safety Report will be sent to Cubist Pharmacovigilance via email or FAX.  Email: 
pv@cubist.com  FAX: 877-224-3324 
 
In the cover letter to Cubist, the study team will identify ourselves as a Sponsor-
Investigator, provide our assigned IND number, full contact information, protocol title, 
and when the report was sent to the FDA. 
6 
DATA COLLECTION AND ANALYSIS 
6.1 
DATA COLLECTION 
For each subject who meets inclusion criteria, a clinical report form (CRF) must be 
completed and signed by the investigator to certify that the data within each CRF are 
complete and correct according to data collection schedule (Appendix I). Every effort 


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should be made to respond to all questions on each CRF page, completion of the data is 
required by the protocol. The header section of each CRF page should be completed to 
identify the Investigators/surgeon and subject identification. 
 
Upon receipt of completed CRFs and prior to entering data into the aggregate data 
summary table, the site-coordinator will ensure the accuracy of data recorded by 
comparison to supporting source documents. Adherence to proper recording of 
information as well as assuring that corrections are being made will also be addressed. 
 
One interim analysis will be conducted when the first half of patients in each group (35 
treatment and 35 control) complete their 30-day follow-up visit. Specifically, the interim 
analysis will be blinded and conducted at a nominal 0.0031 one-sided level of 
significance, while the final analysis will be conducted at a nominal 0.0219 one-sided 
level of significance. These values were calculated using a third-degree Kim-DeMets 
power alpha-spending function evaluated at the halfway point. If the actual information 
fraction at the time of the analysis is different, or the DSMC requests additional 
unblinded analysis, the significance levels will be adjusted using the alpha-spending 
function. 
 
Results of the interim analysis will determine if it is futile to continue patient enrollment 
based on statistically significant differences (24 hour decrease in the time to return of 
bowel function in the treatment group compared to controls at a one-sided 2.5% 
significance level between the treatment and control groups). In addition, the MCW IRB 
in collaboration with the study investigators may terminate the study at any time to 
maintain patient safety. 
 
The following table shows the probability of early stopping and the overall power of the 
study for various hypothetical effect sizes.  If the design assumptions are correct, the 
study will stop early for efficacy with 23% probability, but if the actual effect is 50% 
larger (due to larger mean difference or smaller within-group standard deviation), then 
the trial will stop early 60% of the time. 
 
Relative 
effect size* 
Probability of concluding superiority of the intervention 
At interim analysis At final analysis 
Overall 
0 
0.31% 
2.19% 
2.5% 
0.5 
4.1% 
24.6% 
28.7% 
1 
22.9% 
57.1% 
80.0% 
1.5 
60.0% 
38.8% 
98.8% 
2 
89.4% 
10.1% 
99.9% 
* The relative effect size is the ratio of the actual effect size to the design 
effect size of 24 hour difference with 48-hour within-group standard 
deviation. 
 
 


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6.2 
DATA VALIDATION 
Data validation (verification of case report forms against source data documents) is required for both 
prospective and retrospective studies in which data is being entered on case report forms.  Validation 
should be completed by an independent, study monitor, internal or external to the investigator/sponsor 
institution, who is not involved in the conduct or oversight of the study.  For database studies you will be 
required to attest that you have entered into a data use agreement with the database owner and that the 
data in the database has undergone validation/verification by that owner.  A technical guide is available 
upon request to assist you in completing the following section. 
 
The study team’s certified clinical research professional (CCRP) will review all data fields on the 
data collections forms. Data validation will occur after patients complete their final assessment 
at 30-days. Charts will be reviewed in batches of five. A list of missing data or data fields that 
need to be updated will be created. All errors, if any, will be identified and corrected. When all 
variables are reviewed, the CCRP will review the action items with the study team. Corrected 
fields on the paper data collection form will be dated and initialed by the study team. 
 
6.3 
DATA / STATISTICAL ANALYSIS 
All efficacy analyses will be intent to treat. The time to bowel function recovery and hospital 
length of stay will be compared between the two groups using Student’s t-test. Due to the 
short-term nature of the outcome measures we expect no censoring.  
 
7 
PUBLICATION 
It is intended that the results from this study will be published jointly by the 
investigators and members directly involved with study design and completion. The 
study PI will maintain ownership of all study related data. The investigators will comply 
with the ICMJE’s Uniform Requirements for manuscripts submitted to biomedical 
journals. 
8 
TIMELINE 
Upon final review of the study protocol, the signed contract shall be completed within 1-2 
months.  Duration of IRB/ethics approval is estimated to occur between 2-3 months after initial 
submission. To reach the goal of 140 patients in each study arm, at an estimated rate of 40 
enrolled patients per year, the study will last at least three years. If the interim analysis indicates 
that 35 patients per arm is sufficient to detect a significant difference between groups, final 
enrollment may occur within two years after the first enrolled patient.  
9 
REFERENCES 
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incisional hernia repair: Incidence and treatment. Surgical Endoscopy 16: 1720-1723. 
 
2. Buchler M, Seiler C, et al. (2008) Clinical trial: Alvimopan for the management of post-
operative ileus after abdominal surgery: results of an international randomized, double-
blind, multicentre, placebo-controlled clinical study. Alimentary Pharmacology & 
Therapeutics 28: 312-325. 


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10. Machin, D., Campbell, M., Fayers, P., and Pinol, A. (1997) Sample Size Tables for Clinical 
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Cliffs, New Jersey. 
 
12. Al-Sunduqchi, Mahdi S (1990) Determining the Appropriate Sample Size for Inferences 
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Effective Date 6Mar2014 
 
13. Itawi E, Savoie L, Hanna A, Apostolides G (2011) Alvimopan Addition to Standard 
Perioperative Recovery Pathway. JSLS 15:492-498.  
 
14. Poulose BK, Shelton J, Phillips S, Moore D, Nealon W, Penson D, Beck W, 
Holzman MD. Epidemiology and cost of ventral hernia repair: making the case for 
hernia research. Hernia. 2012 Apr;16(2):179-83.