Clinical trial NCT03852524
Conditions: Postoperative Ileus
Keywords: Spinal Arthrodesis Ileus Postoperative Ileus Adult Spinal Deformity
Sponsor: Ohio State University
Start date: 2019-02-21; Completion date: 2021-05-12
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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). arm 2: The placebo arm will receive subcutaneous placebo before surgery and then daily, for the following three days after surgery (four doses).
Interventions: intervention 1: Methylnaltrexone intervention 2: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
IRB Approval Date: 11/20/2020 
Version Date: 11/16/2020 
Page 1 of 12 
 
 
 
 
 
 
 
 
 
 
 
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 


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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. 
 

ICF_001.pdf: 
CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2018H0260 
IRB Approval date:  11/20/2020 
Version:  3.0 
 
 
Page 1 of 9 
Form date: 07/18/16  
 
 
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Double-Blind, Randomized Trial of Peri-operative Subcutaneous 
5 
Methylnaltrexone Versus Placebo for Postoperative Ileus 
6 
Prevention after Adult Spinal Arthrodesis 
7 
 
8 
The Ohio State University Combined Consent to Participate in Research 
9 
and HIPAA Research Authorization 
10 
 
11 
NCT03852524 
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CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2018H0260 
IRB Approval date:  11/20/2020 
Version:  3.0 
 
 
Page 2 of 9 
Form date: 07/18/16  
 
 
35 
 
36 
 
37 
The Ohio State University Combined Consent to Participate in 
38 
Research and HIPAA Research Authorization 
39 
 
40 
 
41 
Study Title: 
Double-Blind, Randomized Trial of Peri-operative Subcutaneous 
Methylnaltrexone Versus Placebo for Postoperative Ileus 
Prevention after Adult Spinal Arthrodesis 
Principal Investigator: 
H. Francis Farhadi, MD, PhD 
Sponsor:  
The Ohio State University 
 
42 
• This is a consent form for research participation.  It contains important information 
43 
about this study and what to expect if you decide to participate.  Please consider the 
44 
information carefully. Feel free to discuss the study with your friends and family and 
45 
to ask questions before making your decision whether or not to participate. 
46 
• Your participation is voluntary.  You may refuse to participate in this study.  If you 
47 
decide to take part in the study, you may leave the study at any time.  No matter what 
48 
decision you make, there will be no penalty to you and you will not lose any of your 
49 
usual benefits.  Your decision will not affect your future relationship with The Ohio 
50 
State University.  If you are a student or employee at Ohio State, your decision will 
51 
not affect your grades or employment status. 
52 
• You may or may not benefit as a result of participating in this study.  Also, as 
53 
explained below, your participation may result in unintended or harmful effects for 
54 
you that may be minor or may be serious depending on the nature of the research. 
55 
• You will be provided with any new information that develops during the study 
56 
that may affect your decision whether or not to continue to participate.  If you 
57 
decide to participate, you will be asked to sign this form and will receive a copy of the 
58 
form.  You are being asked to consider participating in this study for the reasons 
59 
explained below.   
60 
 
61 
1.   Why is this study being done? 
62 
 
63 
Lumbar spinal decompression and fusion is a surgery done to free pinched nerves that 
64 
cause pain down your leg(s) and to stabilize your spine. Patients undergoing this surgery 
65 
are at risk of experiencing a complication known as post-operative ileus (POI). This is an 
66 
obstruction in your normal gastrointestinal (GI) activity that may cause symptoms such 
67 
as stomach pain, bloating, nausea, vomiting, constipation, difficulty passing gas, and 
68 
difficulty tolerating a normal diet.   
69 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2018H0260 
IRB Approval date:  11/20/2020 
Version:  3.0 
 
 
Page 3 of 9 
Form date: 07/18/16  
 
 
70 
This study is being done to see how safe and effective a drug named methylnaltrexone 
71 
(given around the time of your surgery) is at preventing this common complication 
72 
following lumbar spinal fusion surgeries.  
73 
 
74 
You are being asked to participate in this study because you will be having a lumbar 
75 
fusion procedure and potentially are at risk for experiencing POI.  
76 
 
77 
2.   How many people will take part in this study? 
78 
 
79 
It is expected that about 86 patients will take part in this study.  
80 
 
81 
3.   What will happen if I take part in this study? 
82 
 
83 
If you agree to take part in this study, you will be randomly assigned (like flipping a coin) 
84 
to receive either the methylnaltrexone or a placebo (a substance with no effect) within 2 
85 
hours before your lumbar spinal fusion procedure and then daily for three days following 
86 
the procedure. You will receive methylnaltrexone or placebo as a subcutaneous (under 
87 
the skin) injection. You will not be able to choose which treatment you receive and you 
88 
will have a 1 in 2 (or 50%) chance of receiving the drug or placebo. Neither you nor your 
89 
doctor will know which treatment you are receiving until the study is completely 
90 
finished.  
91 
 
92 
The following procedures are considered standard of care, which means that they would 
93 
be done even if you were not participating in this study.  
94 
 
95 
Before your surgery, you will have an assessment of your pain. You will also complete a 
96 
urine pregnancy test if you are able to become pregnant.   
97 
 
98 
After your surgery, you will be watched closely while in the hospital. During this time 
99 
your ability to use the restroom and your pain levels will be monitored closely. Should 
100 
your doctor feel you need a computer tomography (CT) scan of your stomach, we will 
101 
analyze this for the study. You will be monitored for up to 30 days after your surgery for 
102 
any adverse reactions or complications. 
103 
 
104 
The study team will access your medical records while you are in the study to obtain 
105 
information about your medical history, demographic information, physical exams, 
106 
procedures, medications and treatments, and surgery.  
107 
 
108 
4.   How long will I be in the study? 
109 
 
110 
You will be in the study for 30 days after your surgery.  
111 
 
112 
5. Can I stop being in the study? 
113 
 
114 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2018H0260 
IRB Approval date:  11/20/2020 
Version:  3.0 
 
 
Page 4 of 9 
Form date: 07/18/16  
 
You may leave the study at any time.  If you decide to stop participating in the study, 
115 
there will be no penalty to you, and you will not lose any benefits to which you are 
116 
otherwise entitled.  Your decision will not affect your future relationship with The Ohio 
117 
State University.  
118 
 
119 
6.   What risks, side effects or discomforts can I expect from being in the study? 
120 
 
121 
Loss of confidentiality: 
122 
There is a potential risk to your privacy. Every effort will be made to maintain your 
123 
privacy, however this cannot be guaranteed.  
124 
 
125 
Risks of Study Drug/Placebo Injection 
126 
The risks associated with the injection of methylnaltrexone or placebo include bleeding, 
127 
pain at the injection site, skin irritation, bruising, fainting, lightheadedness, and infection. 
128 
 
129 
Risks related to the use of Methylnaltrexone:  
130 
During the study, you will be monitored for evidence of any side effects. If you develop 
131 
side effects, your study doctor will give you the care that your need.  
132 
1. Gastrointestinal (GI) perforation: cases of gastrointestinal perforation (a harmful 
133 
opening in your gastrointestinal tract) have been rarely reported in adult patients with 
134 
opioid induced constipation (constipation that is caused by the use of opioid 
135 
medications) and advanced illness. 
136 
2. Severe or persistent diarrhea: rare cases of severe or persistent diarrhea during 
137 
treatment have been reported. Your doctor will monitor this very carefully and 
138 
discontinue therapy with the study drug if you have more than 3 bowel movements per 
139 
day.  
140 
3. Opioid withdrawal: symptoms consistent with opioid withdrawal (side effects that can 
141 
occur when someone stops taking their opioid medication), including excessive 
142 
sweating, chills, diarrhea, abdominal pain, anxiety, and yawning have rarely occurred 
143 
in patients previously treated with Methylnaltrexone.  
144 
4. Unknown risks: there may be other risks or side effects that are unknown at this time.  
145 
 
146 
7.   What benefits can I expect from being in the study? 
147 
 
148 
You may or may not benefit from participating in this study.  
149 
 
150 
Your participation in this research may help other patients undergoing lumbar spinal 
151 
fusion procedures in the future.  
152 
 
153 
8.   What other choices do I have if I do not take part in the study? 
154 
 
155 
You may choose not to participate without penalty or loss of benefits to which you are 
156 
otherwise entitled. 
157 
 
158 
9. What are the costs of taking part in this study? 
159 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2018H0260 
IRB Approval date:  11/20/2020 
Version:  3.0 
 
 
Page 5 of 9 
Form date: 07/18/16  
 
 
160 
There will be no cost to you for participating in this study. The costs for your standard of 
161 
care procedures will be billed to you or your insurance.  
162 
 
163 
       The study drug/placebo will be paid for by the study.  
164 
 
165 
10. Will I be paid for taking part in this study? 
166 
 
167 
You will not be paid for participating in this study.  
168 
 
169 
 
170 
11. What happens if I am injured because I took part in this study? 
171 
 
172 
If you suffer an injury from participating in this study, you should notify the researcher or 
173 
study doctor immediately, who will determine if you should obtain medical treatment at 
174 
The Ohio State University Wexner Medical Center.   
175 
 
176 
The cost for this treatment will be billed to you or your medical or hospital insurance. The 
177 
Ohio State University has no funds set aside for the payment of health care expenses for 
178 
this study.  
179 
 
180 
12. What are my rights if I take part in this study? 
181 
 
182 
If you choose to participate in the study, you may discontinue participation at any time 
183 
without penalty or loss of benefits.  By signing this form, you do not give up any personal 
184 
legal rights you may have as a participant in this study. 
185 
 
186 
You will be provided with any new information that develops during the course of the 
187 
research that may affect your decision whether or not to continue participation in the 
188 
study. 
189 
 
190 
You may refuse to participate in this study without penalty or loss of benefits to which 
191 
you are otherwise entitled. 
192 
 
193 
An Institutional Review Board responsible for human subjects research at The Ohio State 
194 
University reviewed this research project and found it to be acceptable, according to 
195 
applicable state and federal regulations and University policies designed to protect the 
196 
rights and welfare of participants in research. 
197 
 
198 
13. Will my study-related information be kept confidential? 
199 
 
200 
Efforts will be made to keep your study-related information confidential.  However, there 
201 
may be circumstances where this information must be released.  For example, personal 
202 
information regarding your participation in this study may be disclosed if required by state 
203 
law.   
204 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2018H0260 
IRB Approval date:  11/20/2020 
Version:  3.0 
 
 
Page 6 of 9 
Form date: 07/18/16  
 
 
205 
Also, your records may be reviewed by the following groups (as applicable to the 
206 
research): 
207 
• 
Office for Human Research Protections or other federal, state, or international 
208 
regulatory agencies; 
209 
• 
U.S. Food and Drug Administration; 
210 
• 
The Ohio State University Institutional Review Board or Office of Responsible 
211 
Research Practices; 
212 
• 
The sponsor supporting the study, their agents or study monitors; and 
213 
• 
Your insurance company (if charges are billed to insurance). 
214 
 
215 
 
216 
14. HIPAA AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
217 
      RESEARCH PURPOSES  
218 
 
219 
I. 
What information may be used and given to others? 
220 
 
221 
• Past and present medical records; 
222 
• Research records; 
223 
• Records about phone calls made as part of this research; 
224 
• Records about your study visits; 
225 
• Information that includes personal identifiers, such as your name, or a number 
226 
associated with you as an individual; 
227 
• Information gathered for this research about: 
228 
Physical exams 
229 
Laboratory, x-ray, and other test results; and  
230 
• Records about the study device 
231 
 
232 
II. 
Who may use and give out information about you? 
233 
 
234 
Researchers and study staff.   
235 
 
236 
III. Who might get this information? 
237 
 
238 
• The sponsor of this research.  “Sponsor” means any persons or companies that are: 
239 
• working for or with the sponsor; or  
240 
• owned by the sponsor. 
241 
• Authorized Ohio State University staff not involved in the study may be aware that 
242 
you are participating in a research study and have access to your information; 
243 
• If this study is related to your medical care, your study-related information may be 
244 
placed in your permanent hospital, clinic or physician’s office record. 
245 
 
246 
IV. 
 Your information may be given to: 
247 
  
248 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2018H0260 
IRB Approval date:  11/20/2020 
Version:  3.0 
 
 
Page 7 of 9 
Form date: 07/18/16  
 
• The U.S. Food and Drug Administration (FDA), Department of Health and Human 
249 
Services (DHHS) agencies, and other federal and state entities; 
250 
• Governmental agencies in other countries; 
251 
• Governmental agencies to whom certain diseases (reportable diseases) must be 
252 
reported; and  
253 
• The Ohio State University units involved in managing and approving the research 
254 
study including the Office of Research and the Office of Responsible Research 
255 
Practices. 
256 
 
257 
V. 
Why will this information be used and/or given to others? 
258 
 
259 
• To do the research;  
260 
• To study the results; and  
261 
• To make sure that the research was done right.   
262 
 
263 
VI. 
 When will my permission end? 
264 
 
265 
There is no date at which your permission ends. Your information will be used 
266 
indefinitely. This is because the information used and created during the study may be 
267 
analyzed for many years, and it is not possible to know when this will be complete. 
268 
 
269 
VII. May I withdraw or revoke (cancel) my permission? 
270 
 
271 
Yes. Your authorization will be good for the time period indicated above unless you 
272 
change your mind and revoke it in writing. You may withdraw or take away your 
273 
permission to use and disclose your health information at any time. You do this by 
274 
sending written notice to the researchers. If you withdraw your permission, you will not 
275 
be able to stay in this study. When you withdraw your permission, no new health 
276 
information identifying you will be gathered after that date. Information that has already 
277 
been gathered may still be used and given to others. 
278 
 
279 
VIII. What if I decide not to give permission to use and give out my health 
280 
information? 
281 
 
282 
Then you will not be able to be in this research study and receive research-related 
283 
treatment.  However, if you are being treated as a patient here, you will still be able to 
284 
receive care. 
285 
 
286 
IX. 
 Is my health information protected after it has been given to others? 
287 
 
288 
There is a risk that your information will be given to others without your permission. Any 
289 
information that is shared may no longer be protected by federal privacy rules. 
290 
 
291 
X. 
May I review or copy my information? 
292 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2018H0260 
IRB Approval date:  11/20/2020 
Version:  3.0 
 
 
Page 8 of 9 
Form date: 07/18/16  
 
 
293 
Signing this authorization also means that you may not be able to see or copy your study-
294 
related information until the study is completed.   
295 
 
296 
15. Who can answer my questions about the study? 
297 
 
298 
For questions, concerns, or complaints about the study, or if you feel you have been 
299 
harmed as a result of study participation, you may contact Dr. H. Francis Farhadi at 
300 
614-366-7784. 
301 
 
302 
For questions related to your privacy rights under HIPAA or related to this research 
303 
authorization, please contact: 
304 
HIPAA Privacy Officer 
305 
Suite E2140 
306 
600 Ackerman Road 
307 
Columbus, OH 43202 
308 
614-293-4477 
309 
For questions about your rights as a participant in this study or to discuss other study-
310 
related concerns or complaints with someone who is not part of the research team, you 
311 
may contact Ms. Sandra Meadows in the Office of Responsible Research Practices at 1-
312 
800-678-6251. 
313 
 
314 
If you are injured as a result of participating in this study or for questions about a study-
315 
related injury, you may contact Dr. H. Francis Farhadi at 614-366-7784. 
316 
 
317 
 
318 
319 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2018H0260 
IRB Approval date:  11/20/2020 
Version:  3.0 
 
 
Page 9 of 9 
Form date: 07/18/16  
 
Signing the consent form 
320 
 
321 
I have read (or someone has read to me) this form and I am aware that I am being asked to 
322 
participate in a research study.  I have had the opportunity to ask questions and have had them 
323 
answered to my satisfaction.  I voluntarily agree to participate in this study.  
324 
 
325 
I am not giving up any legal rights by signing this form.  I will be given a copy of this 
326 
combined consent and HIPAA research authorization form. 
327 
 
328 
 
 
 
 
Printed name of subject 
 
Signature of subject 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
 
 
 
 
Printed name of person authorized to consent for subject 
(when applicable) 
 
Signature of person authorized to consent for subject  
(when applicable) 
 
 
 
 
 
AM/PM 
Relationship to the subject 
 
Date and time 
 
 
329 
 
330 
 
331 
Investigator/Research Staff 
332 
 
333 
I have explained the research to the participant or his/her representative before requesting the 
334 
signature(s) above.  There are no blanks in this document.  A copy of this form has been given 
335 
to the participant or his/her representative. 
336 
 
337 
 
 
 
 
Printed name of person obtaining consent 
 
Signature of person obtaining consent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
338 
Witness(es) - May be left blank if not required by the IRB 
339 
 
340 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
341