Subcutaneous Methylnaltrexone Versus Placebo for Postoperative Ileus Prevention

Study Overview
=================
Brief Summary
-----------------
This randomized controlled trial will prospectively evaluate the clinical benefit for subcutaneous methylnaltrexone (MNTX) in counteracting the obstipatory (causing constipation) effects of spinal surgery without increasing narcotic usage or otherwise disrupting the recovery course of patients. Using a double-blind randomized design, either subcutaneous MNTX (0.15 mg/kg rounded to 8 mg or 12 mg) or placebo will be administered starting before surgery and then daily for three days. Information will be collected from medical records in IHIS up to 30 days prior to surgery and then for up to 30 days after surgery.

Detailed Description
-----------------
Postoperative Ileus refers to the transient interruption of propulsive motor activity of the gastrointestinal (GI) tract that prevents effective movement of its contents and tolerance of oral intake. Although POI is generally considered to significantly increase hospital stays and inpatient costs after spinal surgery, the incidence, associated risk factors, and effective preventative strategies remain poorly characterized. The proposed etiologies underlying POI are broad and remain incompletely characterized. They include post surgical sympathetic nervous system activation, inflammatory factors, and the effects of analgesics on GI tract motility. Treatment often consists of aggressive bowel regimens, nasogastric tube insertion for decompression, and the application of various laxatives, suppositories, and enemas. The widespread use of these measures is unfortunately not supported by high level evidence. The incidence of POI after spinal fusion is reported to range between 0.6 to 16.7%. This estimated range likely represents a gross underestimate of POI given the retrospective nature of studies undertaken to date. Fineberg and colleagues reported that the risk increases nearly 3-fold following anterior lumbar spinal fusions as compared to posterior surgeries. Furthermore, the only risk factors they identified to be correlated with POI is male gender, = 3 fusion levels, alcohol abuse, anemia, electrolyte abnormalities, and weight loss. Kiely and colleagues found that ileus was associated with the administration of certain intravenous solutions such as lactated ringers and sodium chloride. Interestingly, they found that albumin administration was associated with a reduced incidence of ileus postoperatively. Lee and colleagues evaluated POI following orthopedic surgery and reported an incidence of 2.1%. They found that patients who developed POI were more likely to be older, had higher blood loss during surgery, and also had higher rates of preoperative constipation. This study, however, included all types of orthopedic surgeries (not limited to spinal fusion). Early clinical studies evaluated the effectiveness of MNTX in treating opioid-induced constipation (OIC). Several clinical trials confirmed that MNTX was well tolerated and counteracted the GI effects of opioids, thereby enhancing gut motility without inhibiting their analgesic properties. Only two studies to date have evaluated the potential effectiveness of MNTX in reducing the incidence of POI following GI surgery. Both studies were unfortunately hampered by serious design flaws. Most importantly, neither study included pre-operative administration of MNTX. As such, MNTX remains at this time approved only for chronic OIC based on two double-blind, randomized, placebo-controlled trials conducted in patients with advanced illness wherein MNTX rapidly induced laxation as compared to placebo.

Official Title
-----------------
Double-Blind, Randomized Trial of Peri-operative Subcutaneous Methylnaltrexone Versus Placebo for Postoperative Ileus Prevention After Adult Spinal Arthrodesis

Conditions
-----------------
Postoperative Ileus

Intervention / Treatment
-----------------
* Drug: Methylnaltrexone
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is scheduled to undergo a 1 - 3 level lumbar spinal fusion for degenerative spinal conditions including neurogenic claudication and/or lumbar radiculopathy with stenosis and/or spondylolisthesis. Subject must be over the age of 18 years old. Subject has been unresponsive to conservative care for a minimum of 6 months. The subject must in the investigator's opinion, be psychosocially, mentally, and physically able to fully comply with this protocol and have the ability to understand and give written informed consent. Exclusion Criteria: Previous Treatment with MNTX History of mechanical gastrointestinal obstruction History of OIC refractory to outpatient medical management Presence of a peritoneal catheter for intraperitoneal chemotherapy or dialysis Clinically relevant active diverticular disease Recent history of bowel surgery within previous 12 months Use of vinca alkaloids within previous four months Renal failure defined as Estimated Glomerular Filtration Rate (eGFR) <30 ml/min per 1.73 m^2 or requires dialysis Known or suspected allergy to MNTX or similar compounds (e.g. naltrexone or naloxone) Participation in a study with investigational products within 30 days before first dose of MNTX Pregnant or nursing Clinically important abnormalities that may interfere with participation or compliance to the study, as determined by investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized in a 1:1 fashion to receive methylnaltrexone or placebo. Participants will remain in the group they are randomized to for the duration of the study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Arm<br>The study arm will receive subcutaneous methylnaltrexone (0.15mg/kg rounded to 8 or 12 mg) before surgery and then daily, for the following three days after surgery (four doses). | Drug: Methylnaltrexone<br>* Randomization of methylnaltrexone to placebo will be at a 1:1 ratio. Those receiving methylnaltrexone (study drug) will receive a subcutaneous dose pre-surgery and daily for three days following surgery.<br>|
| Placebo Comparator: Placebo Arm<br>The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses). | Other: Placebo<br>* Randomization of methylnaltrexone to placebo will be at a 1:1 ratio. Those receiving placebo will receive a subcutaneous dose pre-surgery and daily for three days following surgery.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Bowel Movement | The time it takes for the participant to have a bowel movement from the end of surgery. | 30 days post-operative | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Discharge | The number of hours it takes for the participant to meet all discharge criteria and be released from the hospital.(Time-to-discharge/discharge eligibility) | 30 Days post-operative | 
| Time to Discharge | The time it takes for the participant to discharge | 30 Days post-operative | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Spinal Arthrodesis, Ileus, Postoperative Ileus, Adult Spinal Deformity