Clinical trial NCT02379858: Gastrointestinal Tract Recovery in Patients Undergoing Open Ventral Hernia Repair
Official title: Gastrointestinal Tract Recovery in Patients Undergoing Open Ventral Hernia Repair: A Multi-Center, Randomized, Double-Blind, Trial of Alvimopan and Placebo
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Ventral Hernia
Keywords: GI Tract Recovery
Hospital Discharge
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-03-05
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Length of Time (Hrs/Days) to Gastrointestinal Tract Recovery
timeFrame: Participants will be followed for the duration of hospital stay, an expected average of 1 week.
Secondary outcomes:
measure: Length of Hospital Stay
timeFrame: Participants will be followed for the duration of hospital stay, an expected average of 1 week
measure: 30-day Treatment Related Morbidity and Re-admission Rates
timeFrame: Participants will be followed for the duration of hospital stay to 30 days after surgery, an expected average of 6 weeks
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Froedtert & the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Medical College of Wisconsin
name: Matthew I Goldblatt, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Berger D, Bientzle M, Muller A. Postoperative complications after laparoscopic incisional hernia repair. Incidence and treatment. Surg Endosc. 2002 Dec;16(12):1720-3. doi: 10.1007/s00464-002-9036-y. Epub 2002 Sep 6.
citation: Buchler MW, Seiler CM, Monson JR, Flamant Y, Thompson-Fawcett MW, Byrne MM, Mortensen ER, Altman JF, Williamson R. 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. Aliment Pharmacol Ther. 2008 Aug 1;28(3):312-25. doi: 10.1111/j.1365-2036.2008.03696.x.
citation: Delaney CP, Wolff BG, Viscusi ER, Senagore AJ, Fort JG, Du W, Techner L, Wallin B. Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies. Ann Surg. 2007 Mar;245(3):355-63. doi: 10.1097/01.sla.0000232538.72458.93.
citation: Lowe JB 3rd, Lowe JB, Baty JD, Garza JR. Risks associated with "components separation" for closure of complex abdominal wall defects. Plast Reconstr Surg. 2003 Mar;111(3):1276-83; quiz 1284-5; discussion 1286-8. doi: 10.1097/01.PRS.0000047021.36879.FD.
citation: Ludwig K, Enker WE, Delaney CP, Wolff BG, Du W, Fort JG, Cherubini M, Cucinotta J, Techner L. Gastrointestinal tract recovery in patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway. Arch Surg. 2008 Nov;143(11):1098-105. doi: 10.1001/archsurg.143.11.1098.
citation: McGreevy JM, Goodney PP, Birkmeyer CM, Finlayson SR, Laycock WS, Birkmeyer JD. A prospective study comparing the complication rates between laparoscopic and open ventral hernia repairs. Surg Endosc. 2003 Nov;17(11):1778-80. doi: 10.1007/s00464-002-8851-5. Epub 2003 Sep 10.
citation: Vargo D. Component separation in the management of the difficult abdominal wall. Am J Surg. 2004 Dec;188(6):633-7. doi: 10.1016/j.amjsurg.2004.08.051.
citation: Wolff BG, Michelassi F, Gerkin TM, Techner L, Gabriel K, Du W, Wallin BA; Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004 Oct;240(4):728-34; discussion 734-5. doi: 10.1097/01.sla.0000141158.27977.66.
citation: Wolff BG, Weese JL, Ludwig KA, Delaney CP, Stamos MJ, Michelassi F, Du W, Techner L. Postoperative ileus-related morbidity profile in patients treated with alvimopan after bowel resection. J Am Coll Surg. 2007 Apr;204(4):609-16. doi: 10.1016/j.jamcollsurg.2007.01.041.
citation: Itawi EA, Savoie LM, Hanna AJ, Apostolides GY. Alvimopan addition to a standard perioperative recovery pathway. JSLS. 2011 Oct-Dec;15(4):492-8. doi: 10.4293/108680811X13176785204076.
citation: 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. doi: 10.1007/s10029-011-0879-9. Epub 2011 Sep 9.