Subcutaneous Methylnaltrexone Versus Placebo for Postoperative Ileus Prevention

• ClinicalTrials.gov Identifier: NCT03852524
• Recruitment Status: Completed
• First Posted: February 25, 2019
• Results First Posted: October 6, 2021
• Last Update Posted: October 27, 2021
• Sponsor: Ohio State University
• Information provided by (Responsible Party): H Francis Farhadi, MD, PhD, Ohio State University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Postoperative Ileus	Drug: Methylnaltrexone; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 82 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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 (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Double-Blind, Randomized Trial of Peri-operative Subcutaneous Methylnaltrexone Versus Placebo for Postoperative Ileus Prevention After Adult Spinal Arthrodesis
• Actual Study Start Date: February 21, 2019
• Actual Primary Completion Date: April 4, 2021
• Actual Study Completion Date: May 12, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Study Arm; 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; 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.
Placebo Comparator: Placebo Arm; The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses).	Other: Placebo; 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.

Outcome Measures

Primary Outcome Measures :

1. Time to First Bowel Movement [ Time Frame: 30 days post-operative ]
   The time it takes for the participant to have a bowel movement from the end of surgery.

Secondary Outcome Measures :

1. Time to Discharge [ Time Frame: 30 Days post-operative ]
   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)
2. Time to Discharge [ Time Frame: 30 Days post-operative ]
   The time it takes for the participant to discharge

Other Outcome Measures:

1. Daily Narcotics [ Time Frame: 30 days post-operative ]
   The amount of daily narcotics (in morphine milli-equivalents) given to a patient (average of post op day 1 - 3)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Ohio

Ohio State University

Columbus, Ohio, United States, 43210

Sponsors and Collaborators

Ohio State University

  Study Documents (Full-Text)

Documents provided by H Francis Farhadi, MD, PhD, Ohio State University:

Study Protocol and Statistical Analysis Plan  [PDF] November 20, 2020

Informed Consent Form  [PDF] November 20, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gifford CS, McGahan BG, Miracle SD, Minnema AJ, Murphy CV, Vazquez DE, Weaver TE, Farhadi HF. Design and feasibility of a double-blind, randomized trial of peri-operative methylnaltrexone for postoperative ileus prevention after adult spinal arthrodesis. Contemp Clin Trials. 2022 Jan;112:106623. doi: 10.1016/j.cct.2021.106623. Epub 2021 Nov 17.

• Responsible Party: H Francis Farhadi, MD, PhD, Assistant Professor, Ohio State University
• ClinicalTrials.gov Identifier: NCT03852524
• Other Study ID Numbers: 2018H0260
• First Posted: February 25, 2019
• Results First Posted: October 6, 2021
• Last Update Posted: October 27, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by H Francis Farhadi, MD, PhD, Ohio State University:

Spinal Arthrodesis; Ileus; Postoperative Ileus; Adult Spinal Deformity

Additional relevant MeSH terms:

Ileus; Intestinal Obstruction; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Methylnaltrexone; Narcotic Antagonists; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents