Double-Blind, Randomized Trial of Peri-operative Subcutaneous Methylnaltrexone Versus Placebo for Postoperative Ileus Prevention After Adult Spinal Arthrodesis
Phase: PHASE2
Conditions: Postoperative Ileus
Sponsor: Ohio State University

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Version Date: 11/16/2020 
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Double-Blind, Randomized Trial of Peri-operative Subcutaneous Methylnaltrexone 
Versus Placebo for Postoperative Ileus Prevention after Adult Spinal Arthrodesis 
 
NCT03852524 
 
 
 
 
 
 
 
 
 
 
V2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SIGNATURE PAGE 
 
 
 
TITLE:  Double-Blind, Randomized Trial of Peri-operative Subcutaneous 
Methylnaltrexone Versus Placebo for Postoperative Ileus Prevention after Adult Spinal 
Arthrodesis 
 
Protocol Number:  
Date:  
 
The signatures of the investigator and representative of the sponsor below constitute their 
approval of this protocol and provide the necessary assurances that this Clinical Trial will 
be conducted according to Good Clinical Practices and to all stipulations, clinically and 
administratively, as stated in the protocol, including all statements as to confidentiality. 
It is agreed that the protocol contains all necessary information required to conduct the 
Clinical Trial as outlined in the protocol.  
It is agreed that all participants in this study will provide written informed consent and/or 
a HIPAA Authorization and agree to the Clinical Trial procedures as approved by the 
Institutional Review Board, as applicable. 
 
 
PRINCIPAL INVESTIGATOR: 
 
__________________________________ 
Print Name 
 
__________________________________ 
 
______________________ 
Signature 
 
 
 
 
 
Date 

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TABLE OF CONTENTS 
 
 
 
1  
INVESTIGATIONAL PLAN .................................................................................. 4 
1.1  
Purpose ................................................................................................... 4 
2  
INTRODUCTION .................................................................................................. 4 
2.1  
Background .............................................................................................. 4 
2.2  
Drug Background ..................................................................................... 5 
3  
TRIAL DESIGN .................................................................................................... 5 
3.1  
Design ..................................................................................................... 5 
3.2 
Primary / Secondary Outcomes ............................................................... 6 
3.3  
Inclusion Criteria ...................................................................................... 6 
3.4  
Exclusion Criteria ..................................................................................... 6 
4  
STUDY PROCEDURE ......................................................................................... 7 
4.1  
Screening Assessments ........................................................................... 7 
4.1.1  Informed Consent .................................................................................... 7 
4.1.2  Medical History and Demographic Data ................................................ 7 
4.2 
Recruitment and Randomization .............................................................. 8 
4.3 
Perioperative and Postoperative Management ......................................... 8 
4.4 
Schedule of Events .................................................................................. 9 
4.7  
Success Criteria ....................................................................................... 9 
4.7.1  Primary Measure of Effectiveness ......................................................... 9 
4.7.2 Secondary Measure of Effectiveness .................................................. 10 
4.7.3  Tertiary Measure of Effectiveness .......................................................... 10 
4.8  
Subject Withdrawal ................................................................................ 10 
5  
STATISTICAL ANALYSIS PLAN ...................................................................... 10 
6  
REFERENCES ................................................................................................... 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1  
INVESTIGATIONAL PLAN 
 
1.1  
Purpose 
The purpose of this randomized controlled trial is to assess and compare the effect 
of peri-operative administration of Methylnaltrexone (MNTX) versus placebo on 
post-operative ileus (POI) following lumbar spinal fusion procedures.  
 
2  
INTRODUCTION 
 
2.1  
Background 
 
POI 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.  
 
POI was recognized as a complication of abdominal and other major surgeries as 
early as the late 1800s. The proposed etiologies underlying POI are broad and 
remain incompletely characterized. They include postsurgical sympathetic nervous 
system activation, inflammatory factors, and the effects of analgesics on GI tract 
motility [1, 2].  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% 
[3]. 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 [4]. 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 [3] 
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% [5]. They found that patients who developed 
POI were more likely to be older, had higher blood loss during surgery, and also 

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had higher rates of preoperative constipation. This study, however, included all 
types of orthopedic surgeries (not limited to spinal fusion).  
 
2.2  
Drug Background 
 
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 [8-10]. Only two studies to date have 
evaluated the potential effectiveness of MNTX in reducing the incidence of POI 
following GI surgery [11, 12]. Both studies were unfortunately hampered by serious 
design flaws. Most importantly, neither study included pre-operative administration 
of MNTX, which was a characteristic of the alvimopan studies that showed clinical 
benefit [13-15]. 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 [16, 17]. 
 
In 2001, alvimopan, a related peripherally acting µ-opioid receptor (PAM-OR) 
antagonist that selectively targets GI µ-opioid receptors, was noted to significantly 
reduce the time to first flatus passage, time to first bowel movement (BM), and time 
to discharge in a cohort of 78 patients undergoing either partial colectomy or total 
hysterectomy [18]. Wolff and colleagues found similar results in a larger cohort of 
469 patients undergoing bowel resection or hysterectomy [19]. These results led 
to approval by the FDA in 2008 of alvimopan as the first (and still only) drug for 
POI treatment after partial small or large bowel surgery. Unfortunately, however, 
alvimopan is contraindicated in patients that have taken opioids the week prior to 
surgery, which significantly limits its application to spinal surgery patients who are 
often taking opioid analgesics at relatively large doses.  
 
As such, there is a glaring paucity of clinical evidence regarding the potential 
benefits of PAM-OR antagonists for POI prophylaxis. Specifically, no studies have 
been undertaken to date evaluating MNTX in relation to POI prophylaxis after 
spinal fusion. A critical clinical need therefore needs to be addressed for spinal 
surgery patients who suffer from POI and its associated complications and costs. 
 
3  
TRIAL DESIGN 
 
3.1  
Design 
 

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This randomized controlled trial will prospectively evaluate the clinical benefit for 
subcutaneous MNTX in counteracting the obstipatory effects of spinal surgery 
without increasing narcotic usage or otherwise disrupting the recover 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. 
3.2 
Primary / Secondary Outcomes 
 
The primary outcome will be the time from the end of surgery to the first bowel 
movement (BM; in hours). A sample size of 43 randomly assigned patients per 
study group (86 subjects in total) was calculated to detect a treatment effect of 
MNTX (90% power; alpha = 0.05). This calculation was performed with the 
assumption that subjects who experience their first BM by day three comprise 50% 
in the placebo group and 85% in the treatment group. A 10% lost-to-follow up rate 
was also included in the calculation. The secondary outcomes will be the time to 
discharge and the time to discharge eligibility (in hours). Finally, exploratory 
outcomes will include the amount of daily narcotics (in morphine milli-equivalents) 
administered during the first 4 days or up to hospital discharge. Administration of 
drug/placebo will be stopped should the patient experience frequent stools, defined 
as greater than 3 BMs per day. 
 
3.3  
Inclusion Criteria 
 
Subjects will be considered for inclusion in this trial if they satisfy the following 
criteria: 
1. 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. 
2. Subject must be over the age of 18 years old. 
3. Subject has been unresponsive to conservative care for a minimum of 6 
months. 
4. 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. 
 
3.4  
Exclusion Criteria 
 
Subjects will be excluded from this trial if they satisfy any of the following criteria: 
1. Previous treatment with MNTX 

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2. History of mechanical gastrointestinal obstruction 
3. History of OIC refractory to outpatient medical management 
4. Presence of a peritoneal catheter for intraperitoneal chemotherapy or dialysis 
5. Clinically relevant active diverticular disease 
6. Recent history of bowel surgery (past 1 year) 
7. Use of vinca alkaloids within previous 4 months 
8. Renal failure defined as EGFR <30 ml/min per 1.73 m2 or requires dialysis 
9. Known or suspected allergy to MNTX or similar compounds (e.g. naltrexone 
or naloxone) 
10. Participation in a study with investigational products within 30 days before 
first dose of MNTX 
11. Pregnant or nursing 
12. Clinically important abnormalities that may interfere with participation or 
compliance to the study, as determined by investigator 
 
4  
STUDY PROCEDURE 
 
4.1  
Screening Assessments 
4.1.1  Informed Consent 
Subjects will be provided with an informed consent and will be given ample 
opportunity to review the consent and ask questions. The signed informed consent 
will be obtained before any study specific procedures are initiated that are not part 
of the investigator’s standard of care. A copy of the informed consent will be given 
to the subject. All subjects who meet all of the entry criteria will be considered for 
inclusion in this trial. Any subject meeting any of the exclusion criteria will be 
excluded from the trial. 
All subjects who have agreed to participate in this study, have signed the informed 
consent and who meet the inclusion/exclusion criteria will be considered enrolled 
and assigned a subject ID number. Once a Subject ID number has been issued, it 
cannot be reassigned or used for another subject. 
4.1.2  Medical History and Demographic Data  
Within 30 days prior to the surgery date, the following information will be collected: 
• Demographic data 
• Medical history, including a complete history of spinal disorder(s) (non-
operative or operative treatments performed) 
• Physical examination (including height, weight) 
• Current pain medications and other drug therapies. 

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• Primary diagnosis and any associated assessments collected per standard 
of care 
 
 
4.2 
Recruitment and Randomization 
 
All subjects will be randomized in the trial to receive either subcutaneous MNTX 
(0.15 mg/kg rounded to 8 mg or 12 mg) or placebo to be administered starting 
before surgery and then daily for three days. Subjects and investigators alike will 
be blinded to their group status for the duration of the study assessments and 
procedures (1 month post-operatively).  
 
A sample size of 43 randomly assigned patients per study group (86 subjects in 
total) was calculated to detect a treatment effect of MNTX (90% power; alpha = 
0.05). This calculation was performed with the assumption that subjects who 
experience their first BM by day three comprise 50% in the placebo group and 85% 
in the treatment group. A 10% lost-to-follow up rate was also included in the 
calculation. 
 
Potential participants will be identified by the principal investigator (HFF), co-
investigators, and study personnel through the review of medical records during 
outpatient clinic visits at the Ohio State University Comprehensive Spine Center. 
A partial waiver of HIPAA authorization has been requested for this purpose. Given 
historical surgical numbers, a sufficient number of patients who are candidates for 
lumbar fusion procedures and potentially eligible for study enrollment are expected 
to be evaluated during the study period.  
 
4.3 
Perioperative and Postoperative Management 
 
Enrolled patients will be given MNTX (0.15 mg/kg rounded to 8 mg or 12 mg) or 
placebo prior to surgery in the pre-operative holding area and every 24 hours for 
3 days following surgery (a total of 4 doses). This dosing matches the FDA 
approved dosing for the use of MNTX in patients effected by opioid induced 
constipation.  
 
Following surgery patients’ BMs will be closely monitored and the time to first BM 
will be recorded in hours. Patients will receive routine post-operative orders 
including early mobilization with a physical therapist on the first post-operative 
morning, intravenous patient controlled anesthesia for 1-2 days transitioned 
thereafter to an oral opioid regimen, as well as a bowel routine comprising 
Docusate Sodium, Senna Glycoside, Polyethylene Glycol 3350, and Bisacodyl  

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suppositories (started on post-operative day 2, if needed). All patients are also 
routinely discharged on a tapering oral opioid regimen.  
 
Administration of drug/placebo will be stopped should the patient experience 
frequent stools, defined as greater than 3 BMs per day. If a treating physician 
choses to prescribe the off-label use of Methylnaltrexone for the management of 
post-operative ileus, the subject will be unenrolled from the study. Abdominal X-
rays and CT will be collected and analyzed only if performed as standard of care 
to evaluate the GI tract following surgery. Additional review of concomitant 
medications, patient-reported pain levels (NRS), and adverse/serious adverse 
events will be reviewed daily for up to 96 hours following surgery and at 30 days 
post-operatively. 
 
4.4 
Schedule of Events 
 
 
 
Screening/
Enrollment  
(-30 days of 
procedure) 
Immediate
ly Pre-
operative 
Post-
operative 
Day 1 
Post-
operative 
Day 2 
Post-
operative 
Day 3 
30 Days 
Post-
operative 
Informed consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Concomitant medications review 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
Clinical Safety Labs (Chem7, CBC) 
 
X 
X 
X 
X 
 
MNTX/Placebo administration 
 
X 
X 
X 
X 
 
Vital Signs 
 
X 
X 
X 
X 
 
Numeric Pain Rating Scale 
X 
X 
X 
X 
X 
X 
X-rays and CT Scan** 
 
 
X** 
X** 
X** 
 
AE/ SAE review 
 
X 
X 
X 
X 
X 
**X-rays and CT scans are only to be collected if done as standard of care as determined by subject’s clinical care team 
 
 
 
4.7  
Success Criteria 
4.7.1  Primary Measure of Effectiveness  
A subject will be considered a success if a BM is achieved within 3 days of 
surgery. The primary outcome measure of effectiveness will be determined by 
the comparative rate of patients achieving BM and evading POI in the MNTX 
group versus placebo. 

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4.7.2 Secondary Measure of Effectiveness 
Secondary measures of effectiveness will be determined by the comparative 
average time to discharge eligibility and/or discharge in hours for the MNTX group 
versus placebo.  
 
4.7.3  Tertiary Measure of Effectiveness 
 
Tertiary measures of effectiveness will include the effect of MNTX on the amount 
of daily narcotics administered (in milli-equivalents) during the first 4 post-
operative days or up to hospital discharge.  
 
4.8  
Subject Withdrawal 
 
It is recognized that the subject’s participation in this trial is entirely voluntary, and 
that she/he may refuse to participate and may withdraw from participation at any 
time without jeopardy to any future medical care.  It is also recognized that the 
investigator, at his/her discretion, may withdraw a subject from this study based 
upon his/her professional judgment. 
 
Other Conditions for Withdrawal: 
 
Any subject who develops a severe concurrent medical illness during the trial 
should be withdrawn.  This type of illness is defined as any illness that would hinder 
the subject’s ability to return for scheduled follow-up appointments.  Such a 
withdrawal will not be counted for the purposes of determining success or failure. 
 
 
5  
STATISTICAL ANALYSIS PLAN  
Efficacy analyses will be based on a modified intent-to-treat population including 
all subjects randomly assigned and having received at least one dose of study 
drug. The distribution of the primary efficacy end point time of first BM will be 
estimated via the Kaplan-Meier product-limit method and compared between 
treatment groups using the log-rank test. Secondary efficacy end points will be 
evaluated at the alpha = 0.05 level of significance without adjustment for multiple 
comparisons. 
 
This study will attempt to identify not just relevant demographic and clinical risk 
factors for POI following spinal fusion, but also will quantify peri-operative opioid 
use in this patient population in order to determine whether an increased use of 
opioids increases the risk of POI. 

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Finally, safety will be assessed by monitoring adverse events (AEs), concomitant 
medications, vital signs, physical examination findings, ECG findings, and 
laboratory test results. Withdrawals owing to AEs will be evaluated as a safety end 
point. Treatment-emergent AEs, potentially clinically important laboratory 
measurements, and premature study discontinuations will be compared between 
groups by use of the Fisher exact probability test. 
 
6  
REFERENCES 
 
1. 
Luckey A, Livingston E, Tache Y. Mechanisms and treatment of 
postoperative ileus. Arch Surg. 2003;138(2):206-14. 
2. 
Behm B, Stollman N. Postoperative ileus: etiologies and interventions. Clin 
Gastroenterol Hepatol. 2003;1(2):71-80. 
3. 
Kiely PD, Mount LE, Du JY, et al. The incidence and risk factors for post-
operative ileus after spinal fusion surgery: a multivariate analysis. Int Orthop. 
2016;40(6):1067-74. 
4. 
Fineberg SJ, Nandyala SV, Kurd MF, et al. Incidence and risk factors for 
postoperative ileus following anterior, posterior, and circumferential lumbar 
fusion. Spine J. 2014;14(8):1680-5. 
5. 
Lee TH, Lee JS, Hong SJ, et al. Risk factors for postoperative ileus 
following orthopedic surgery: the role of chronic constipation. J 
Neurogastroenterol Motil. 2015;21(1):121-5. 
6. 
Iyer S, Saunders WB, Stemkowski S. Economic burden of postoperative 
ileus associated with colectomy in the United States. J Manag Care Pharm. 
2009;15(6):485-94. 
7. 
Wainwright TW, Immins T, Middleton RG. Enhanced recovery after 
surgery (ERAS) and its applicability for major spine surgery. Best Pract Res Clin 
Anaesthesiol. 2016;30(1):91-102. 
8. 
Foss JF. A review of the potential role of methylnaltrexone in opioid bowel 
dysfunction. Am J Surg. 2001;182(5A Suppl):19S-26S. 
9. 
Yuan CS, Foss JF, O'Connor M, Toledano A, Roizen MF, Moss J. 
Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time 
without affecting analgesia: a double-blind randomized placebo-controlled trial. 
Clin Pharmacol Ther. 1996;59(4):469-75. 
10. 
Yuan CS, Wei G, Foss JF, O'Connor M, Karrison T, Osinski J. Effects of 
subcutaneous methylnaltrexone on morphine-induced peripherally mediated side 
effects: a double-blind randomized placebo-controlled trial. J Pharmacol Exp 
Ther. 2002;300(1):118-23. 
11. 
Viscusi ER, Rathmell JP, Fichera A, et al. Randomized placebo-controlled 
study of intravenous methylnaltrexone in postoperative ileus. J Drug Assess. 
2013;2(1):127-34. 
12. 
Yu CS, Chun HK, Stambler N, et al. Safety and efficacy of 
methylnaltrexone in shortening the duration of postoperative ileus following 

IRB Approval Date: 11/20/2020 
Version Date: 11/16/2020 
Page 12 of 12 
 
segmental colectomy: results of two randomized, placebo-controlled phase 3 
trials. Dis Colon Rectum. 2011;54(5):570-8. 
13. 
Buchler MW, Seiler CM, Monson JR, et al. 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;28(3):312-25. 
14. 
Herzog TJ, Coleman RL, Guerrieri JP, Jr., et al. A double-blind, 
randomized, placebo-controlled phase III study of the safety of alvimopan in 
patients who undergo simple total abdominal hysterectomy. Am J Obstet 
Gynecol. 2006;195(2):445-53. 
15. 
Ludwig K, Enker WE, Delaney CP, et al. 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;143(11):1098-105. 
16. 
Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of 
opioid-induced constipation in advanced illness patients. J Support Oncol. 
2009;7(1):39-46. 
17. 
Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-
induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332-43. 
18. 
Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition 
of gastrointestinal opioid receptors. N Engl J Med. 2001;345(13):935-40. 
19. 
Wolff BG, Michelassi F, Gerkin TM, et al. 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;240(4):728-34; discussion 34-5. 
20. 
Bungard TJ, Kale-Pradhan PB. Prokinetic agents for the treatment of 
postoperative ileus in adults: a review of the literature. Pharmacotherapy. 
1999;19(4):416-23.