Gastrointestinal Tract Recovery in Patients Undergoing Open Ventral Hernia Repair

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.

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 American Society of Anesthesiologists (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

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