Subcutaneous Methylnaltrexone Versus Placebo for Postoperative Ileus Prevention

• Sponsor: Ohio State University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03852524
• Collaborator: (none)
• Enrollment: 82
• Location: 1
• Arms: 2
• Actual Duration (Months): 26.6
• Patients Per Site Per Month: 3.1

Study Details

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
• 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.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: Feb 21, 2019
• Actual Primary Completion Date: Apr 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 [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 [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 [30 Days post-operative]

   The time it takes for the participant to discharge

Other Outcome Measures

1. Daily Narcotics [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Ohio State University	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Ohio State University

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 20, 2020
• Informed Consent Form - Nov 20, 2020

More Information

Publications

None provided.

• Responsible Party: H Francis Farhadi, MD, PhD, Assistant Professor, Ohio State University
• ClinicalTrials.gov Identifier: NCT03852524
• Other Study ID Numbers: 2018H0260
• First Posted: Feb 25, 2019
• Last Update Posted: Oct 27, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• 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, Assistant Professor, Ohio State University: Spinal Arthrodesis; Ileus; Postoperative Ileus; Adult Spinal Deformity
• Additional relevant MeSH terms: Ileus; Methylnaltrexone

Study Results

Participant Flow

Arm/Group Title	Study Arm: Methylnaltrexone	Placebo Arm
Arm/Group Description	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). 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.	The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses). 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.
Period Title: Overall Study
STARTED	41	41
COMPLETED	41	41
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Study Arm: Methylnaltrexone	Placebo Arm	Total
Arm/Group Description	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). 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.	The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses). 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.	Total of all reporting groups
Overall Participants	41	41	82
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	29 70.7%	28 68.3%	57 69.5%
>=65 years	12 29.3%	13 31.7%	25 30.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.8 (10.2)	60.8 (10.0)	61.3 (10.0)
Sex: Female, Male (Count of Participants)
Female	21 51.2%	23 56.1%	44 53.7%
Male	20 48.8%	18 43.9%	38 46.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 2.4%	1 1.2%
Not Hispanic or Latino	40 97.6%	38 92.7%	78 95.1%
Unknown or Not Reported	1 2.4%	2 4.9%	3 3.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 2.4%	0 0%	1 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 4.9%	7 17.1%	9 11%
White	38 92.7%	34 82.9%	72 87.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	41 100%	41 100%	82 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Arm: Methylnaltrexone	Placebo Arm
Arm/Group Description	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). 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.	The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses). 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.
Measure Participants	41	41
Median (Full Range) [hours]	61.8	50.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Arm: Methylnaltrexone, Placebo Arm
	Comments	The sample size (41 patients per study group; 82 patients total) for this superiority trial was calculated with a power of 90% (alpha = 0.05) and based on the assumption that 50% of subjects in the placebo group would experience a bowel movement by postoperative day 3, as compared to 85% in the treatment group. Additionally, a 10% lost-to-follow up rate was assumed.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.81
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	11
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to Discharge
Description	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)
Time Frame	30 Days post-operative

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Arm: Methylnaltrexone	Placebo Arm
Arm/Group Description	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). 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.	The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses). 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.
Measure Participants	41	41
Median (Inter-Quartile Range) [Hours]	105.0	90.7

3. Secondary Outcome

Title	Time to Discharge
Description	The time it takes for the participant to discharge
Time Frame	30 Days post-operative

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Arm: Methylnaltrexone	Placebo Arm
Arm/Group Description	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). 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.	The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses). 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.
Measure Participants	41	41
Mean (Full Range) [Days]	4.29	4.19

4. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Arm: Methylnaltrexone	Placebo Arm
Arm/Group Description	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). 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.	The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses). 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.
Measure Participants	41	41
Median (Inter-Quartile Range) [MME]	136.8	148.5

Adverse Events

Time Frame	Immediately pre-operative to 30 Days post-operative
Arm/Group Title	Study Arm: Methylnaltrexone		Placebo Arm
Arm/Group Description	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). 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.		The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses). 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.
All Cause Mortality
	Study Arm: Methylnaltrexone		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		0/41 (0%)
Serious Adverse Events
	Study Arm: Methylnaltrexone		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/41 (14.6%)		7/41 (17.1%)
Blood and lymphatic system disorders
hypoxemia, loss of response	1/41 (2.4%)	1	0/41 (0%)	0
Cardiac disorders
Non-ST-elevation myocardial infarction (NSTEMI)	0/41 (0%)	0	1/41 (2.4%)	1
Atrial fibrillation (also called AFib or AF) with rapid ventricular rate or response (RVR).;	1/41 (2.4%)	1	0/41 (0%)	0
Gastrointestinal disorders
Abdominal Pain	0/41 (0%)	0	1/41 (2.4%)	1
Post-Operative Ileus	1/41 (2.4%)	1	0/41 (0%)	0
Immune system disorders
Migratory artheralgias/ gout flare up	0/41 (0%)	0	2/41 (4.9%)	2
Infections and infestations
Wound Dehiscence	0/41 (0%)	0	1/41 (2.4%)	1
Psychiatric disorders
Disorientation/ Hallucinations secondary to alcohol withdrawal	0/41 (0%)	0	1/41 (2.4%)	1
Altered mental status (AMS)	1/41 (2.4%)	1	1/41 (2.4%)	1
Renal and urinary disorders
urinary tract infection (UTI) and hyponatremia	1/41 (2.4%)	1	0/41 (0%)	0
Social circumstances
Syncope; dehydration; Fracture- Right foot	1/41 (2.4%)	1	0/41 (0%)	0
Vascular disorders
Stroke	0/41 (0%)	0	1/41 (2.4%)	1
Other (Not Including Serious) Adverse Events
	Study Arm: Methylnaltrexone		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/41 (26.8%)		7/41 (17.1%)
Blood and lymphatic system disorders
Hemoglobin drop	1/41 (2.4%)	1	0/41 (0%)	0
Cardiac disorders
Hypotension, syncope	0/41 (0%)	0	1/41 (2.4%)	1
Gastrointestinal disorders
> 3 bowel movements in 1 day	4/41 (9.8%)	4	1/41 (2.4%)	1
Post-operative illeus	1/41 (2.4%)	1	1/41 (2.4%)	1
Infections and infestations
Wound dehiscence / drainage from incision	2/41 (4.9%)	2	2/41 (4.9%)	2
Musculoskeletal and connective tissue disorders
increasing pain with concern for infection without drainage or dis	1/41 (2.4%)	1	0/41 (0%)	0
Psychiatric disorders
AMS and emesis during attempted bowel movement.	1/41 (2.4%)	1	0/41 (0%)	0
Renal and urinary disorders
Diagnosis of Acute Kidney Injury	1/41 (2.4%)	1	0/41 (0%)	0
Kidney Disease Improving Global Outcomes Stage III (kidney disease)	0/41 (0%)	0	1/41 (2.4%)	1
Respiratory, thoracic and mediastinal disorders
left airspace disease concerning for brewing aspiration pneumonia	0/41 (0%)	0	1/41 (2.4%)	1
Surgical and medical procedures
Intraoperatively, a Cerebrospinal Fluid (CSF) leak was noted.	1/41 (2.4%)	1	0/41 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.