A Double-blind, Randomized, Placebo-controlled Trial of Naloxegol for Prevention of Post-operative Constipation in Spinal Surgery Patients
Phase: PHASE4
Conditions: Constipation
Sponsor: Massachusetts General Hospital

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Official Study Title: A Double-blind, Randomized, Placebo-controlled Trial of Naloxegol for Prevention of 
Post-operative Constipation in Spinal Surgery Patients 
 
NCT Number: NCT02946580 
Date of Document: January 2, 2019 
 
 
 

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A Double-blind, Randomized, Placebo-controlled Trial of Naloxegol for Prevention of Post-
operative Constipation in Spinal Surgery Patients 
 
Principal Investigator: Kyle Staller, MD, MPH 
 
Sponsor: AstraZeneca  
 
 
I. Background and Significance 
 
a.) Historical background 
Constipation remains one of the most common clinical conditions encountered by physicians 
with an estimated general population prevalence ranging from 2% to 28%1 generating 2.5 million 
physician visits per year2 with an annual direct medical cost of more than $230 million in the U.S. alone.3 
Despite the high prevalence of constipation in the population at large, comparatively little is known 
about secondary constipation amongst acutely-hospitalized individuals.  Indeed, hospitalized patients 
suffer disproportionately from constipation during their stays,4-6 with incident constipation occurring in 
6.8% of admitted stroke patients,7 approximately 70% of critically-ill ICU patients,8,9 and in more than 
70% of a geriatric hospitalized population.5  Prior studies have primarily focused on chronic constipation 
in the outpatient setting, using patient-reported outcomes that can be difficult to translate to 
hospitalized individuals.  In fact, inpatient constipation is more likely to arise as a secondary 
phenomenon from change in environment, emotional stressors, administration of constipating 
medications,3,6 alterations in splanchnic blood flow as a result of illness,10 dehydration,11 and decreased 
activity.3,12,13  Post-spinal surgery patients represent an ideal population for study, in that they are 
frequently immobile, receive constipating opioids frequently, and are otherwise healthy enough to 
undergo an elective surgical procedure.  Despite the fact that constipation is a known complication of 
spinal surgery that keeps patients in the hospital longer, there is no current standard of care for 
constipation prophylaxis in this population—or any hospitalized population.   
Naloxegol is a pegylated µ-opioid receptor antagonist that acts on µ-opioid receptors in the 
enteric nervous system with limited ability to cross in to the central nervous system; thus naloxegol can 
reverse the effects of systemic opioids in the gut without attenuating the analgesic properties of opioids 
on the brain. Two recent, phase 3, double-blind studies demonstrated that daily administration of 25 mg 
of po naloxegol resulted an improvement in bowel movement frequency and specifically a decreased 
time to first, post-dose spontaneous bowel movement in patients with non-cancer pain and opioid-
induced constipation.14 Importantly, there was no reduction in opioid-mediated analgesia. 
 
b.) Previous studies supporting the proposed research 
 
There is a paucity of studies examining the effect of constipation prophylaxis on incidence of 
constipation in hospitalized patients.  Notably, there are only four known studies examining this 
question and none have examined surgical patients.  The most relevant study randomized ICU patients 
to polyethylene glycol, lactulose, or placebo who did not have a bowel movement in the first three days 
of admission.15  They measured time to first defecation (after 3 days) and found that the median time 
from start of the study medication to first defecation was 75.0 hrs (IQR 36.0 hrs) for the placebo group, 
36.0 hrs (IQR 30.2 hrs) for the lactulose-treated patients (p = 0.001 vs. placebo), and 44.0 hrs (IQR 43.0 
hrs) for the PEG-treated patients (p = .001 vs. placebo and p = .1 vs. lactulose).   

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Our own recently-published data demonstrates that constipation prophylaxis reduced length of 
stay in elderly patients hospitalized with congestive heart failure who take laxatives at home.16  These 
patients received far fewer opioids than the typical spinal surgery patient. 
 
c.) Rationale behind the proposed research 
To our knowledge, there are no data addressing whether the impact of bowel prophylaxis on 
constipation in ICU or cancer patients translates to other populations, specifically surgical patients.  We 
have preliminary retrospective data demonstrating a decreased incidence of constipation in hospitalized 
patients, but these data are observational.   
Patients receiving naloxegol in the post-operative period after spinal surgery could potentially 
benefit from a decreased time to first spontaneous bowel movement after surgery and decreased 
incidence of overall inpatient constipation with its attendant complications. After surgery, this patient 
population is routinely maintained on a patient-controlled anesthesia (PCA) device for 18-30 hours 
before transitioning to oral pain medications for discharge and up to 2 week beyond. As such, patients 
treated post-operatively with naloxegol would potentially have improvement in comfort, decrease in 
delirium, and decreased time to discharge. A trial of prophylactic naloxegol in post-operative spinal 
surgery patients represents the logical next step in investigation, as spinal surgery patients are a 
microcosm for many of the aforementioned secondary drivers of constipation.   
 
II. Specific Aims 
 
The primary objective is to determine whether naloxegol prophylaxis decreases the median time 
to first spontaneous, rescue laxative-free, post-operative bowel movement in patients undergoing spinal 
surgery at Massachusetts General Hospital (MGH) compared to placebo.  The secondary objectives are 
to determine whether the aforementioned constipation prophylaxis reduces length of stay, improves 
patient satisfaction with their bowel management, and decreases need for rescue laxatives.  We also 
want to determine the incidence of diarrhea in each of the groups. 
 
III. Subject Selection 
 
The study population will include any adult patient undergoing non-urgent, elective spinal 
surgery (spinal fusions) at Massachusetts General Hospital who is admitted to the neurosurgery floor 
from the operating room are allowed to enroll within the confines of the eligibility caveats outlines 
below. Patients must fulfill all entry criteria to be enrolled in the study.  We have selected spinal fusion 
patients as they tend to have longer lengths of stay with higher analgesic requirements (especially 
opioids).  Furthermore, enhanced recovery after surgery (ERAS) protocols are not utilized in this patient 
population at MGH.   
 
a.) Inclusion criteria 
1. Male or female between the ages of 18 and  80 years undergoing non-urgent, elective spinal 
fusion at Massachusetts General Hospital who are admitted to the neurosurgery floor from the 
operating room 
2. Patients with preexisting opioid use will not be excluded 
3. Post-operative spinal surgery patients receiving opiods with preexisting constipation not 
meeting criteria for irritable bowel syndrome (IBS) receiving opioids  will not be excluded 
 
4. Patients with inactive non-GI cancer, or inactive GI cancer will not be excluded. 
 

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b.) Exclusion criteria 
1. Patients who are taken to the operating room from another inpatient floor or service (already 
hospitalized prior to surgery) 
2. Patients with evidence of bowel obstruction (a contraindication to laxatives)  
3. Patients unable to take oral medications by mouth or by enteric feeding tube (gastrostomy or 
jejunostomy) 
4. Patients with a documented or potential allergy or adverse reaction to the study medication 
from outpatient use 
5. Patients currently taking naloxegol in the outpatient setting 
6. Patients with a preoperative diagnosis of irritable bowel syndrome (IBS) obtained via Rome III 
questionnaire on screening 
7. Patients with disruptions to the blood-brain barrier (eg, multiple sclerosis, recent brain injury, 
Alzheimer’s disease, and uncontrolled epilepsy)  
8. Patients with active GI cancer involving the GI lumen (stomach cancer, small bowel cancer, or 
colorectal cancer) who could be at risk for bowel obstruction due to residual disease. 
9. Patients with history of disruption in the blood brain barrier, including those where the 
disruption is known to occur during the spinal fusion procedure 
10. Patients concomitantly using strong CYP3A4 inhibitors (eg, clarithromycin, ketoconazole), strong 
CYP3A4 inducers and other opioid antagonists. 
11. Patients with severe hepatic impairment. 
12. Patients with a previous history of or risk of bowel perforation. 
13. Patients with a post-op regional anesthetic technique employed like a continuous epidural or 
spinal.  
 
 
c.) Source of subjects and recruitment process 
 
Subjects will be recruited from the MGH outpatient neurosurgery clinics after the scheduling of 
their spinal fusion surgery. Subjects typically have two appointments before their surgery: an evaluation 
with a Neurosurgeon, and a pre-operative visit. A Neurosurgeon on the protocol will introduce the trial 
to the subject at the initial visit, and provide them with the contact information of the study staff. If the 
subject is interested in the trial and they contact study staff, study staff can follow-up by sending trial 
information and review the Inclusion/ Exclusion criteria to ensure the subject qualifies for the study. 
Subjects who qualify will be consented by a licensed Physician Investigator on the protocol at their pre-
operative visit. In this way, patients are not asked on the day of their procedure, when there is 
significant peri-procedural anxiety. 
IV. Subject Enrollment 
a.) Methods of enrollment 
1. Patients scheduled for spinal fusion surgery may learn about the study from their 
Neurosurgeon at their initial visit prior to their surgery and asked if they would like to hear 
more about the trial 
2. Any patients agreeing to hear more about the trial would learn more before beginning the 
informed consent process should they agree to participate 
3. A Neurosurgeon on the protocol will introduce the trial to the patient at the initial visit, and 
provide them with the contact information of the study staff.  

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4. If the patient is interested in the trial and they contact study staff, study staff can follow-up 
by phone or email with trial information, as well as determining whether they meet all of 
the inclusion criteria 
5. Subjects who qualify will be consented by a licensed Physician Investigator on the protocol 
at their pre-operative visit 
 b.) Procedures for obtaining informed consent 
1. Patients agreeing to participate would complete an informed consent with one of the 
licensed Physician Investigators listed on the protocol during their pre-operative visit.  
 
c.) Treatment assignment and randomization 
1. Patients who have been enrolled and consented in the trial will be randomized to the 
placebo or naloxegol arms 
2. A total of approximately 166 unique patients will be randomly assigned in a 1:1 ratio to 
receive either naloxegol 25 mg daily (as is consistent with FDA guidelines) or a matching 
placebo control 
3. There will be no stratification 
4. The study personnel and patients will be blinded to treatment allocation 
5. Patients who fulfill study admission criteria and have a signed consent form will be assigned 
a 3-digit sequential patient number. The number will be used throughout the study. 
6. Randomization will be conducted using the MGH research pharmacy’s internal 
randomization system. The research pharmacist will use an application on 
randomization.com to randomly decide the assignment (treatment vs. placebo) of the first 
participant. All subsequent participants will be randomized in a 1:1 ratio. Based on the 
randomized treatment assignment, an unblended pharmacist at MGH will prepare the study 
drug in a manner that ensures maintenance of the blind utilizing study-specific labels and 
completing details pertinent to the individual participant. 
7. This is a double blind study. The individual treatment assignment will not be revealed to 
patients or their representatives, study staff (except for the unblinded pharmacist), or the 
sponsor of the sponsor’s representatives, until all patients complete the study and the 
database is locked. The unblinded pharmacist will maintain the treatment assignment for 
each patient. 
V. Study Procedures 
a.) Study visits and parameters to be measured  
 
1. After informed consent, the initial study visit will occur with the research coordinator and 
will include completion of the Bowel Function Index,17 a short, validated questionnaire for 
the detection of opioid-induced constipation as well as collection of self-reported laxative 
and opioid use in the preceding 2 weeks, and the Rome III questionnaire to identify IBS. 
2. After confirming continued eligibility, the patient will return home prior to their scheduled 
surgery. 
 
 
 
 

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3. Schedule of Events: 
 
Study Period 
 
Enrollment 
Allocation 
Operation 
Hospitalization 
1st Bowel 
Movement 
Hospital 
Discharge 
Time Point 
-t2 
-t1 
0 
t1 (variable) 
tx 
ty 
Eligibility screen 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Allocation 
 
X 
 
 
 
 
Treatment group  
 
 
 
 
 
 
Control group 
 
 
 
 
 
 
Baseline laxative use 
X 
 
 
 
 
 
Baseline opioid use 
X 
 
 
 
 
 
Rome III questionnaire 
X 
 
 
 
 
 
1° outcome variable 
(time to first BM) 
 
 
 
 
X 
 
2° outcome variables 
 
 
 
X 
X 
 
Bowel Function Index 
X 
 
 
X 
X 
X 
Bowel satisfaction 
question 
 
 
 
 
 
X 
Adverse events 
 
 
 
X 
X 
X 
Cumulative opioid 
dose measurement 
 
 
 
 
 
X 
 
4. After confirming that inclusion and exclusion criteria continue to be satisfied on the day of 
surgery, the patient will be randomized using the MGH research pharmacy’s internal 
randomization system (randomization output must only be seen by unblinded pharmacist).   
a. Patients will receive their first dose of study drug in the Post-Anesthesia Care Unit 
(PACU) approximately two hours postoperatively  
b. Patients will undergo their scheduled operation without modification of the 
individual surgeon’s or hospital protocol 
5. Post-operative patients will be moved to the Post-Anesthesia Care Unit (PACU) per protocol 
for recovery before transfer to the inpatient floor 
6. On arrival to the neurosurgery floor, patients will be admitted as per hospital protocol 
7. Patients will receive the study medication daily as close to the initial administration time as 
possible pending nursing demands 
8. There will be no routine monitoring of labs or imaging for the purposes of the study outside 
of usual care on the floor 
9. Patients enrolled in the study will be allowed to be given Colace (Docusate) and Senna 
(Senokot) as standing laxative medications for prophylactic purposes. Other laxatives will 
not be allowed to be given for prophylactic purposes, but “prn” rescue medications will be 
allowed.   
b.) Drugs to be used 
1. The study drug and placebo will be supplied by the Sponsor and stored in the MGH inpatient 
pharmacy 

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2. Naloxegol is supplied in 25 mg tablets 
3. Matching placebo consists of an inert mixture supplied by the Sponsor in identical-appearing 
tablets 
4. Dosage and administration 
a. Subjects will be administered naloxegol 25 mg (as is consistent with FDA guidelines) 
or placebo once daily until their discharge from the hospital (variable timing), after 
two weeks, until they are off oral opioid pain medications, or until transfer to an 
acute care unit (i.e. intensive care unit) whichever comes first. The 25 mg tablets are 
not scored. 
b. Subjects with renal impairment (creatine clearance rate of less than 60 mL/min) will 
receive a 12.5 mg dose of naloxegol or placebo in place of the 25 mg dose as 
advised by FDA guidelines 
c. The Sponsor will supply both 25mg and 12.5 mg naloxegol tablets as well as 
matching placebo. 
d. Naloxegol will be administered as label indicated (1 hr pre first meal or 2 hr post 
meal) 
e. Inpatient neurosurgery nursing will be instructed to administer the medication 
orally once daily at a time corresponding to the initial preoperative dosing 
f. Subjects may receive naloxegol via a feeding tube as necessary. The naloxegol or 
placebo tablets can be crushed and mixed in water for patients who are unable to 
swallow. 
g. Subjects will not receive study drug if they are transferred to another unit of the 
hospital due to postoperative complications or if their length of stay is more than 2 
weeks.   
5. Treatment compliance 
a. Study drug will be administered on the MGH inpatient neurosurgery unit by nursing 
staff 
b. If a subject misses a dose, the missed dose will be recorded in the hospital’s 
inpatient electronic medication administration record (eMAR) as well as a reason for 
the missed dose as per hospital protocol 
c. Adverse Events. On the basis of clinical studies, the following adverse events may 
occur in subjects receiving naloxegol: 
i. >10%: abdominal pain (12-21%) 
ii. 1-10%: headache (4%), hyperhidrosis (≤3%), diarrhea (6-9%), flatulence (3-
6%), vomiting (5%) 
iii. <1% (limited to important or life-threatening): anxiety, arthritis, back pain, 
chills, gastrointestinal perforation, irritability, joint pain, yawning 
d. While the structure of naloxegol has been shown to prevent influx of the drug 
across the blood-brain barrier it is possible that interruption of the blood-brain 
barrier in patients with spinal surgery while taking naloxegol could result in 
decreased effectiveness of post-operative opioids. Patients will be withdrawn from 
the study if surgery results in tearing or breach of the dura matter as this could 
result in decreased effectiveness of post-operative opioids. Any observed decreased 
in effectiveness in post-operative opioids will be recorded as described in section 
V.c.3.f.  
6. Rescue medications 
a. If a subject experiences inadequate prevention of constipation while on the study 
drug or placebo, the patient may be administered a rescue medication (laxative) at 

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the discretion of the patient’s nurse consistent with “prn” orders or new orders 
from the medical team. Drugs that are available to treat constipation include: 
Colace (Docusate), Polyethylene glycol (Miralax), Senna (Senokot), magnesium 
citrate, and lactulose. The current standard protocol for laxative use in post-op 
settings is a course of Colace (Docusate) and Senna (Senokot). Because constipation 
is not a side effect of the medication, all patients will be able to receive laxative 
doses as needed at their request throughout the study consistent with hospital 
policies or at their nurse’s or physician’s discretion without restriction. 
7. Home opioid use 
a. All home opioids will be stopped on admission and patients placed on their 
surgeon’s standard pain control regimen, which includes an initial patient-controlled 
anesthesia (PCA) pump followed by a transition to oral opioids. 
c.)  Data to be collected and timeline for collection 
1. Initial data collection 
a. On study enrollment in the MGH Neurosurgery clinic, patients will complete the 
Rome III constipation module, Bowel Function Index, and a standardized assessment 
of laxative and opioid medications, doses, and frequency 
2. Procedure 
a. We will retrospectively use the medical record to determine procedure duration, 
attending physician, and immediate adverse events that occur during the planned 
procedure 
3. Hospital Day 
a. Patients will complete a Bowel Function Index questionnaire at the beginning of 
each hospital day 
b. PRIMARY OUTCOME: The primary endpoint of this study will be time to first post-
operative bowel movement, as defined by the first spontaneous bowel movement 
reported by nursing staff without use of a rescue laxative after transfer from the 
operating room to the hospital ward.  A bowel movement will be defined as a 
spontaneous passage of1 tablespoon or more of liquid or solid stool (excluding 
flatus), which can be measured and verified by nursing staff and was not the result 
of a rescue laxative.  Time will be measured in hour increments on standardized 
report forms, with bowel movement times occurring between hours rounded up or 
down to the nearest hour.  This will account for variations in nursing contact time 
with the patient, who would be expected to check in on their patients’ status at 
least once every hour. 
c. Any new rescue medications for constipations (laxatives) or use of “prn” orders will 
be retrospectively determined through the Electronic Medication Administration 
Record after discharge 
d. Feeding and IV fluid I/O will be determined through the Electronic Medication 
Administration Record after discharge 
e. Opioid type (generally via PCA pump) and cumulative dosage 
f. Adverse events: adverse events will be collected daily from the operative period 
through discharge and recorded on the CRF 
i. Definition of adverse events 
1. An adverse event is the development of an undesirable medical 
condition or the deterioration of a pre-existing medical condition 
following or during exposure to a pharmaceutical product, whether 

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or not considered causally related to the product.  An undesirable 
medical condition can be symptoms (eg, nausea, chest pain), signs 
(eg, tachycardia, enlarged liver) or the abnormal results of an 
investigation (eg, laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if 
no study treatment has been administered. The term AE is used to 
include both serious and non-serious AEs. 
ii. Treatment emergent adverse events (TEAE) 
1. Treatment emergent adverse events are defined as AEs that occur 
after the treatment start date and prior to the completion of the 
drug “washout” period. All adverse events for individual participants 
will be categorized as TEAEs or non-TEAEs in the CRF following 
completion of the study.  
iii. Definition of serious adverse event 
1. A serious adverse event is an AE occurring during any study phase 
(ie, run-in, treatment, washout, follow-up), that fulfils one or more 
of the following criteria: 
a. Results in death 
b. Is immediately life threatening 
c. Requires in-patient hospitalization or prolongation of 
existing hospitalization 
d. Results in persistent or significant disability/incapacity or 
substantial disruption of the ability to conduct normal life 
functions 
e. Is a congenital abnormality or birth defect 
f. Is an important medical event that may jeopardize the 
subject or may require medical intervention to prevent one 
of the outcomes listed above 
The causality of SAEs (their relationship to all study 
treatment/procedures) will be assessed by the 
investigator(s) and communicated to AstraZeneca. 
iv. Recording of adverse events 
1. Time period for collecting adverse events 
a. Adverse events will be collected daily from the operative 
period through discharge 
b. To allow for collection of any adverse events that may occur 
following discharge, daily post-discharge phone calls will be 
made to all patients for 3 days if they had a bowel 
movement during their hospitalization or until they have a 
bowel movement post-discharge. Adverse events will be 
recorded as described in section V.b.8.c.e. 
c. Any unresolved adverse events will be tracked via daily 
phone call to the patient by the study staff until they are 
resolved. Adverse events will be recorded as described in 
section V.b.8.c.e. 
d. Unanticipated problems involving risks to subjects or others 
including adverse events will be reported to the PHRC in 

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accordance with PHRC unanticipated problems reporting 
guidelines 
2. All adverse events will be recorded directly on the CRF. The 
following variables will be collected for each AE: 
i. AE (verbatim) 
ii. The date <<and time>> when the AE started and 
stopped 
iii. Whether the AE is serious or not 
iv. Information relevant in determining causality 
v. Action taken for study drug 
vi. Outcome 
b. In addition, the following variables will be collected for SAEs 
i. Date AE met criteria for serious AE 
ii. Date Investigator became aware of serious AE 
iii. AE is serious due to 
iv. Date of hospitalization 
v. Date of discharge 
vi. Probable cause of death 
vii. Date of death 
viii. Autopsy performed 
ix. Causality assessment in relation to Study 
procedure(s) 
x. Causality assessment in relation to Other 
medication 
xi. Description of AE. 
It is important to distinguish between serious and 
severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in 
Section V.c.3.eii. Reporting  of serious adverse 
events 
3. Causality Assessment 
a. The investigator or qualified subinvestigator is responsible 
for assessing the relationship to study drug therapy using 
clinical judgment and the following considerations 
i. No: Evidence exists that the adverse event has an 
etiology other than the study drug. For SAEs, an 
alternative causality must be provided (e.g., 
preexisting condition, underlying disease, 
intercurrent illness, or concomitant medication). 
ii. Yes: There is reasonable possibility that the event 
may have been caused by the investigational 
medicinal product. 
b. It should be emphasized that ineffective treatment should 
not be considered as causally related in the context of 
adverse event reporting. The relationship to study 
procedures (e.g., invasive procedures such as venipuncture 
or biopsy) should be assessed using the following 
considerations: 

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i. No: Evidence exists that the adverse event has an 
etiology other than the study procedure. 
ii. Yes: The adverse event occurred as a result of 
protocol procedures, (e.g., venipuncture) 
c. A summary of any causality assessment will be recorded in 
the CRF. 
4.  Reporting of serious adverse events 
a. A copy of the MedWatch/AdEERs report of any serious, 
unexpected adverse events that occur in accordance with 
the reporting obligations of 21 CFR 312.32 must be emailed 
or faxed to AstraZeneca at the time the event is reported to 
the FDA AT .  It is the responsibility of the investigator to 
compile all necessary information and ensure that the FDA 
receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are 
also submitted to AstraZeneca at the same time. 
 
When reporting to AstraZeneca, a cover page should 
accompany the MedWatch/AdEERs form indicating the 
following. 
          -Investigator Sponsored Study (ISS) 
          -The investigator IND number assigned by the FDA 
                        -The investigator’s name and address 
                        -The trial name/title and AstraZeneca ISS reference 
number 
 
Investigative site must also indicate, either in the SAE report or the 
cover page, the causality of events in relation to all study 
medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
 
Send SAE report and accompanying cover page by way of fax to 
AstraZeneca’s designated fax line: 1-302-886-4114 or by email to AE 
Mailbox Clinical Trial (TCS) 
<AEMailboxClinicalTrialTCS@astrazeneca.com>. Email is the 
preferred method. 
 
Serious adverse events that do not require expedited reporting to 
the FDA need to be reported to AstraZeneca preferably using the 
MedDRA coding language for serious adverse events.  These events 
will be reported on a weekly basis. 
 
In the case of blinded trials, AstraZeneca will request that the 
Sponsor either provide a copy of the randomization code/ code 
break information or unblind those SAEs which require expedited 
reporting. 

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All SAEs have to be reported to AstraZeneca, whether or not considered causally related to the 
investigational product.  All SAEs will be documented.  The investigator is responsible for informing the 
IRB and/or the Regulatory Authority of the SAE as per local requirements. 
4. Day of Discharge 
a. On the day of discharge from the hospital, the patient will complete an additional 
bowel satisfaction question: “How satisfied are you with the management of your 
bowels in the hospital?” which will be asked via standardized form at the time of 
discharge using a 5-point Likert scale consistent with previous work.4 
b. Length of stay will be determined from retrospective review of the medical record. 
We will specifically record the date/time of the discharge order.  
5. We will determine the incidence of diarrhea in each group via examination of the electronic 
medication record, which also includes mandatory reporting (with reason) for any held 
doses of the study medication. 
6. Unblinding procedure 
a. Unblinding may be necessary in order to make clinical decisions in the case of an 
adverse event. The need to unblind a participant will be determined by the PI in 
consultation with the clinical team.  
b. In order to unblind a participant, a member of the study staff will contact the site 
pharmacy and provide the patient’s identifying information. The site pharmacy may 
then inform the study staff of the patient’s medication status. Unblinding will 
recorded in the CRF.   
7. Withdrawal from study 
a. Withdrawal from the study may be necessary if: 
i. The subject violates the exclusion criteria or no longer meets the inclusion 
criteria. 
ii. The PI determines that termination is clinically necessary following an AE. 
iii. Spinal surgery results in tearing or breach of the dura matter 
iv. Non-compliance with study procedures 
v. The subject no longer wishes to participate in the study 
b. The reason for withdrawal will be recorded in the CRF. 
c. Administration of the study drug will cease immediately upon withdrawal.  
 
VI. Biostatistical Analysis 
 
1. Specific data variables to be collected 
a. Prospective 
i. Bowel Function Index  
ii. Home opioid use 
iii. Home laxative use 
iv. Bowel satisfaction 
v. Time to first bowel movement (primary outcome) 
vi. Adverse events 
vii. Pain VAS measurement 
viii. Safety (defined as occurrence of TEAEs segregated into serious and minor 
events) 
b. Chart review 

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i. Length of stay 
ii. In-hospital opioid use 
iii. In-hospital rescue laxative use 
2. Study endpoints – As above 
3. Statistical methods 
a. Analysis populations 
i. Intent-to-treat (ITT) population: all patients who are randomized will be 
included in the ITT population. This will be the primary population for all 
analyses of demographics, patient characteristics and disposition, and 
efficacy data. 
ii. Safety population: All patients who are randomized and receive any study 
treatment will be included in the safety population.  This will be the primary 
population for all analyses of safety data 
iii. Per-Protocol (PP) population: All patients who are randomized and receive 
the study medication on each day of their hospitalization. Major protocol 
violations include the following: 
1. Prohibited concomitant medication usage (specifically standing 
laxatives during hospitalization) 
The PP population may be used for supplementary analysis of selected 
efficacy and safety data, as appropriate. 
b. Endpoint analyses 
i. Primary endpoint: The primary endpoint of this study will be time to first 
post-operative bowel movement, as defined by the first spontaneous bowel 
movement reported by nursing staff without use of a rescue laxative after 
transfer from the operating room to the hospital ward.  A bowel movement 
will be defined as a spontaneous passage of 1 tablespoon or more of liquid 
or solid stool (excluding flatus), which can be measured and verified by 
nursing staff and was not the result of a rescue laxative.  Time will be 
measured in hour increments on standardized report forms, with bowel 
movement times occurring between hours rounded up or down to the 
nearest hour.  This will account for variations in nursing contact time with 
the patient, who would be expected to check in on their patients’ status at 
least once every hour.  
 
We will analyze the data using a time-to-event methodology and our 
primary endpoint, time to first bowel movement, will be compared between 
arms using median time to bowel movement as a group measure.  A log-
rank test with Kaplan-Meier estimations will compare the unadjusted 
medians between groups.  We will also calculate hazard ratios using Cox 
Proportional Hazards methods to control for known and putative risk factors 
for inpatient constipation—most importantly use of opioids during 
hospitalization.  In this case, a hazard ratio greater than 1 would correspond 
to a decreased time to first bowel movement.  The Cox model assumes that 
the risks are proportional.  A survival-type analysis is most appropriate as 
we are looking at time to event—a bowel movement—with potential 
censoring in the form of missed bowel movements and from those who 
receive a rescue laxative.  We feel that competing risks are unlikely to be a 
major factor in this study, as the majority of these surgeries are elective and 

14 
 
thus, we would be enrolling relatively-healthy subjects. We will also perform 
various post-hoc subgroup analyses including separate statistical analysis for 
opioid naive versus chronic opioid users and for patients with different 
spinal fusion types such as cervical vs lumbar vs thoracic etc. 
ii. Secondary endpoints:  
1. Length of stay, which will be defined from as the elapsed time (in 
hours) from admission to discharge.   
2. Need for rescue medications, which will be defined as 
administration of any laxative other than Colace (Docusate) and 
Senna (Senokot) after admission as determined from the hospital’s 
electronic medication administration record (which provides date, 
time, and type of medication). Rescue medications may be given 
after passage of 72 hours without a bowel movement.   
3. Patient’s satisfaction with their bowels by use of the Bowel Function 
Index pre-operatively and post-operatively, a validated instrument 
for opioid-induced constipation. 
4. Patients will answer a single question: “How satisfied are you with 
the management of your bowels in the hospital?” which will be 
asked via standardized form at the time of discharge using a 5-point 
Likert scale. 
5. Incidence of diarrhea in each group via examination of the 
electronic medication record 
d. Power analysis 
i. This is a randomized, double-blind, single-center clinical trial comparing 
prophylaxis with naloxegol to placebo for prevention of constipation in 
hospitalized, post-operative patients undergoing neurosurgical spinal fusion 
surgery at Massachusetts General Hospital.  The primary objective is to 
compare the median time to first post-operative bowel movement between 
the prophylaxis and the placebo groups.  We hypothesize that the median 
time to first bowel movement will be sooner in patients randomized to the 
prophylaxis group compared to the placebo group. 
ii. We have calculated that we will need a sample size of 186 subjects 
(including a 20% buffer for study dropout) to power this trial.  Using the 
limited available data from a previous trial, we assumed a control effect size 
of 75.0 hours and a treatment effect size of 36.0 hours as time to first bowel 
movement.  Although the van der Spoel trial15 saw a more pronounced 
effect with an alternative prophylaxis regimen (treatment effect of 36.0 
hours), we felt that the more conservative effect size would be appropriate 
given that the aforementioned trial evaluated critically-ill patients—likely 
subject to even more gastrointestinal motility effects of critical illness and 
more prolonged hospitalization.  Our subjects are generally healthy enough 
to undergo mostly elective spinal surgery and the effect of prophylaxis is 
likely to be less pronounced, so we chose a more conservative effect 
estimate.  Because our guidance study was based on an hours-to-first-bowel 
movement outcome, we specified a 1 subject per hour recruitment rate as 
the lowest possible value in the software program given we expect at best 
(assuming all patients enrolled) 10 patients per day to be enrolled.  The 
follow-up period is limited to the length of hospitalization, which has a 

15 
 
median value of 4 days in this population.  No interim analyses are planned.  
A total of 186 patients, approximately 93 in each arm, will be needed to 
detect a difference between 44 hours and 75 hours in median time to first 
bowel movement with a power of 80% using a two-sided p=0.05 level test 
allowing for a 20% censoring effect/study dropout.     
 
 
Power=0.80 
Power=0.90 
Effect Size 39 hours (75h vs 36h) 
90 subjects 
112 subjects 
Effect Size 31 hours (75h vs 44h) 
149 subjects 
188 subjects 
Effect Size 23 hours (75h vs 52h) 
279 subjects 
359 subjects 
 
iii. We chose to evaluate sensitivity at effect sizes with median time to bowel 
movement 8 hours sooner than our selected effect (representing the other 
effect group in the ICU study) and 8 hours later than our selected effect.  
We also varied the power between 0.80 and 0.90 with the unsurprising 
consequence of a large increase in sample size, which would be difficult in a 
single-center trial looking at a specific surgery type.    
iv. A sample size of 186 patients will allow the study to stay within the confines 
of the one site that has already signed on to the trial.  Assuming 10 spinal 
surgeries per day, it would be reasonable to assume a generous enrollment 
of 5 patients per day.  Thus, enrolment could conceivably last 37 surgical 
days—translating to 7 weeks given that spinal surgeries primarily occur on 
weekdays.  Follow-up will be limited to the length of hospitalization for each 
patient, with no intention to follow patients after discharge from the 
hospital. 
 
 
 
 

16 
 
 
Schema: 
 
 
  
 
    Patients undergoing         RANDOMIZE 
    Spinal surgery at MGH 
    Recruited: 196 pts 
    Enrolled: 186 pts 
 
 
 
 
 
 
 
VII. Risks and discomforts 
1. Drug side effects and adverse events 
a. On the basis of clinical studies, the following adverse events may occur in subjects 
receiving naloxegol: 
i. >10%: abdominal pain (12-21%) 
ii. 1-10%: headache (4%), hyperhidrosis (≤3%), diarrhea (6-9%), flatulence (3-6%), 
vomiting (5%) 
iii. <1% (limited to important or life-threatening): anxiety, arthritis, back pain, chills, 
gastrointestinal perforation, irritability, joint pain, yawning 
2. Psychosocial risks: none 
VIII. Potential benefits 
1. Potential benefits to participating individuals: Equipoise exists in the proposed trial because 
spinal surgery patients currently receive either no prophylaxis (the placebo/control group) or 
prophylaxis depending on the admitting provider without evidence as to the benefit of one 
treatment over lack of treatment.   
a. Decreased risk of opioid-induced constipation while in the hospital 
b. Less abdominal discomfort secondary to constipation 
c. Shorter length of hospital stay due to decreased constipation 
d. Decreased complications of constipation:  
i. Poor po intake 
ii. Nausea/vomiting 
iii. Potential decreased risk of infection 
2. Potential benefits to society 
a. More standardization of post-operative bowel regimens on patients receiving opioids 
b. Increased awareness of the occurrence of constipation in the post-operative patient 
receiving opioids 
c. Cost savings to the healthcare system from potentially decreased length of stay and 
decreased complications from post-operative constipation 
Follow 1st 
post-op 
bowel 
movement 
Naloxegol 25 mg daily 
N= 93 pts 
Placebo arm 
N= 93 pts 
Measure: 
Time to 
first BM 

17 
 
 
IX. Monitoring and Quality Assurance 
1. Good clinical practice 
a. The investigator will ensure that this study is conducted in accordance with the 
principles of “Good Clinical Practice”, as outlined in Title 21 of Code of Federal 
Regulations (CFR), Part 312, subpart D, “Responsibilities of Sponsors and Investigators”; 
21 CFR, part 50, “Protection of Human Subjects”; 21 CFR, part 54, “Financial Disclosure 
by Clinical Investigators”; 21 CFR, part 56, “Institutional Review Boards”; and 21 CFR, 
Part 11,“Electronic Records, Electronic Signature”, are adhered to. 
2. Institutional review board (IRB) approval 
a. The protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to the MGH IRB. Approval from 
the IRB must be obtained before starting the study and should be documented in a 
letter to the investigator specifying the protocol number, protocol version, protocol 
date, documents reviewed, and date on which the committee met and granted 
approval. Any modifications made to the protocol after receipt of IRB approval must 
also be submitted to the IRB for approval before implementation.  
3. Informed consent 
a. Written informed consent, in accordance with 21 CFR Part 50, must be obtained prior to 
participation in the study. Within the context of the inclusion criteria, a proportion of 
eligible patients may be exhibiting significant cognitive impairment and the lack of 
capacity to provide consent. As such, all patients will require surrogate consent by a 
legally authorized representative. The investigator or staff will determine the 
appropriate family member-person to contact regarding the study, based on the 
standard operating procedures of MGH and local and state laws. The signed consent 
form must remain in the patient’s medical chart and must be available for verification at 
any time. 
4. Liability and insurance 
a. The civil liability of the investigator, the persons instructed by the investigator and the 
hospital, practice, or institute in which they are employed, and the liability of the 
financial loss due to personal injury and other damage which may arise as a result of the 
carrying out of this study are governed by the terms and conditions set forth in the 
Clinical Trial Agreement and applicable law. 
5. Documentation of study findings 
a. Required information will be entered into the appropriate CRFs. All CRFs are to be 
completed accurately and promptly, and should be updated as needed so they reflect 
the latest information on the patient’s file. All records are to be kept in conformance 
with applicable guidelines and SOPs. When the study is completed, the investigator 
must retain the essential documents for as long as needed to comply with regulatory 
authority, local regulations and sponsor requirements further detailed in Section 10.2.5. 
The investigator shall notify the sponsor prior to moving or destroying any of the study 
documents.  
6. Study monitoring 
a. The sponsor representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities, and 

18 
 
upon request, inspecting the various records of the trial. The sponsor’s clinical monitors 
are responsible for inspecting the CRFs throughout the study to verify adherence to the 
protocol; completeness, accuracy, and consistency of data; and adherence to GCPs. The 
monitors should have access to patient medical records and other study-related records 
needed to verify entries on the CRFs. In accordance ICH Good Clinical Practice (ICH/GCP) 
guidelines, the sponsor’s clinical monitors must have direct access to the investigator’s 
source documentation in order to verify the data recorded in the CRFs for consistency.  
b. The monitor is responsible for routine review of the eCRFs at regular interval 
throughout the study to verify adherence to the protocol and the completeness, 
consistency, and accuracy of the data being entered on them. The monitor should have 
access to any patient records needed to verify the entries on the CRFs. The investigator 
agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are resolved. This study may be selected for audit by 
representatives of the sponsor’s Clinical Quality Assurance department or designee. 
Inspection of the site facilities (i.e., participant areas, drug storage areas, record storage 
areas, etc.) and review of study-related records may occur to evaluate the trial conduct 
and compliance with the protocol, ICH GCP, and applicable regulatory requirements. 
c. An independent Data and Safety Monitoring Board (DSMB) external to the sponsor and 
investigators will monitor data integrity and safety of participants throughout the life of 
the study. A DSMB is a formal committee that is established specifically to monitor data 
throughout the life of a study to determine if it is appropriate, from both the scientific 
and ethical standpoint, to continue the study as planned. The DSMB procedures are 
described in detail on the DSMB charter, which is attached separately.  
 
7. Access to Information for Auditing or Inspections 
a. Representatives of regulatory authorities, IRB, or of the Sponsor may conduct 
inspections or audits of this clinical study. If the investigator is notified of an inspection 
by a regulatory authority the investigator agrees to notify the Sponsor immediately. The 
investigator agrees to provide to representatives of a regulatory agency, IRB or IEC, or 
Sponsor access to source documents/records, facilities, and personnel for the effective 
conduct of any inspection or audit. 
8. Data quality assurance 
a. Data will be entered into a secure and validated database using eCRF’s. Data entered 
may be checked at the point of entry and through external validation checks for 
accuracy. After resolution of any discrepancies and automated data-review procedures, 
the final data sets will be subject to a quality assurance audit. When the database is 
declared to be complete and accurate, it will be locked. Any changes to the database 
after that time can only be made by written notice. The investigator will be responsible 
for ensuring the accuracy, completeness, and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports. Data reported on the CRFs, which are 
derived from source documents, should be consistent with source documents or the 
discrepancies should be explained. To ensure the quality of the clinical data across all 
participants and sites, a clinical data management review will be performed on all 
patient data. During this review, patient data will be checked for consistency, omissions, 
and any apparent discrepancies. In addition, the data will be reviewed for adherence to 
protocol and GCPs. To resolve any questions arising from the clinical data-review 
process, data queries will be sent for the site to complete. The principal investigator will 
electronically sign and date the indicated places on the CRF. This signature will indicate 

19 
 
that the principal investigator inspected or reviewed the data on the CRF and the data 
queries, and that the investigator agreed with the content. 
9. Study Files and Retention of Records 
a. The investigator must maintain adequate and accurate records to fully document the 
conduct of the study and to ensure that study data is subsequently verified. These 
documents should be classified into two separate categories: (1) investigator’s study 
file, and (2) patient clinical source documents. The investigator’s study file will contain 
the protocol/amendments, printed (or electronically archived) copies of the patient 
CRFs, IRB, and governmental approval with correspondence, informed consent, drug 
accountability (receipt/dispensing) records, staff curriculum vitae and authorization 
forms, information regarding monitoring activities, sponsor/investigator 
correspondence, and other appropriate documents and correspondence. 
b. Patient clinical source documents for this study would include, but are not limited to, 
the following: 
i. Patient identification (name, date of birth, gender) 
ii. Documentation that patient meets eligibility criteria, i.e., relevant medical 
history, physical examination, and confirmation of diagnosis 
iii. Dated notes of the day of entry into the study including study number, patient 
identification number, verification that the trial was discussed and written 
informed consent was obtained 
iv. Dated notes for each protocol assessment and documentation that protocol 
specific procedures were performed 
v. Study drug accountability (investigator must keep blinded records of volume of 
study drug given and timing of each daily dose based on the hospital chart; this 
will not entail review of the unblinded pharmacy records for the sake of 
maintaining the blind) 
vi. Documentation of all adverse events, including any action taken with regard to 
study drug and outcome 
vii. Concomitant medications (including start and end date, dose if relevant)  
viii. Date of trial completion and reason for early discontinuation, if applicable 
10. Confidentiality 
a. The investigator must ensure that all participants’ confidentiality will be strictly 
maintained and that their identities are protected from unauthorized parties. Only an 
identification code (i.e., not names) should be recorded on any form or biological 
sample submitted to the sponsor, IRB, or laboratory. The investigator must keep a 
screening log showing codes, names and addresses for all patients screened and for all 
patients enrolled in the trial. On CRFs or other documents that are submitted to the 
sponsor, participants should be identified by an identification code and not by their 
names. 
b. The investigator agrees that all information received from the Sponsor, including but not 
limited to the Investigator Brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of the Sponsor 
during the conduct of the study and thereafter. This information is not to be disclosed to 
any third party (except employees or agents directly involved in the conduct of the 
study or as required by law) without prior written consent from the Sponsor. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure 
by any employee or agent of the study site to any third party or otherwise into the 
public domain. 

20 
 
11. Publication 
a. After the completion of the study and the analysis of all data, the Sponsor will support 
efforts by all Study Investigators to jointly publish the primary study results.  
12. Protocol and Protocol Amendments 
a. The investigator is responsible for ensuring the study is conducted in accordance with 
the procedures and evaluations described in this protocol. No amendments will be 
permitted to this protocol or to the conduct of the study without approval from the 
Sponsor and if applicable, the IRB. These communications will be documented in 
writing. 
b. All protocol amendments must be submitted to the IRB in accordance with local 
requirements. Approval must be obtained before changes are implemented. 
 
 
 
 
 
 
 
 
 
 
 
 
 
X. References 
1. 
Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. 
The American journal of gastroenterology. 2004;99(4):750-759. 
2. 
Sonnenberg A, Koch TR. Physician visits in the United States for constipation: 1958 to 1986. 
Digestive diseases and sciences. 1989;34(4):606-611. 
3. 
Bharucha AE, Pemberton JH, Locke GR, 3rd. American Gastroenterological Association technical 
review on constipation. Gastroenterology. 2013;144(1):218-238. 
4. 
Cardin F, Minicuci N, Droghi AT, Inelmen EM, Sergi G, Terranova O. Constipation in the acutely 
hospitalized older patients. Archives of gerontology and geriatrics. 2010;50(3):277-281. 
5. 
Kinnunen O. Study of constipation in a geriatric hospital, day hospital, old people's home and at 
home. Aging. 1991;3(2):161-170. 
6. 
Ueki T, Nagai K, Ooe N, et al. Case-controlled study on risk factors for the development of 
constipation in hospitalized patients. Yakugaku zasshi : Journal of the Pharmaceutical Society of 
Japan. 2011;131(3):469-476. 
7. 
Ingeman A, Andersen G, Hundborg HH, Svendsen ML, Johnsen SP. In-hospital medical 
complications, length of stay, and mortality among stroke unit patients. Stroke; a journal of 
cerebral circulation. 2011;42(11):3214-3218. 
8. 
Guerra TL, Mendonca SS, Marshall NG. Incidence of constipation in an intensive care unit. 
Revista brasileira de terapia intensiva. 2013;25(2):87-92. 
9. 
Nassar AP, Jr., da Silva FM, de Cleva R. Constipation in intensive care unit: incidence and risk 
factors. Journal of critical care. 2009;24(4):630 e639-612. 

21 
 
10. 
Mutlu GM, Mutlu EA, Factor P. GI complications in patients receiving mechanical ventilation. 
Chest. 2001;119(4):1222-1241. 
11. 
Muller-Lissner SA, Kamm MA, Scarpignato C, Wald A. Myths and misconceptions about chronic 
constipation. The American journal of gastroenterology. 2005;100(1):232-242. 
12. 
Robson KM, Kiely DK, Lembo T. Development of constipation in nursing home residents. 
Diseases of the colon and rectum. 2000;43(7):940-943. 
13. 
Ross DG. Altered bowel elimination patterns among hospitalized elderly and middle-aged 
persons: quantitative results. Orthopaedic nursing / National Association of Orthopaedic Nurses. 
1995;14(1):25-31. 
14. 
Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced 
constipation in patients with noncancer pain. N Engl J Med. 2014;370(25):2387-2396. 
15. 
van der Spoel JI, Oudemans-van Straaten HM, Kuiper MA, van Roon EN, Zandstra DF, van der 
Voort PH. Laxation of critically ill patients with lactulose or polyethylene glycol: a two-center 
randomized, double-blind, placebo-controlled trial. Critical care medicine. 2007;35(12):2726-
2731. 
16. 
Staller K, Khalili H, Kuo B. Constipation prophylaxis reduces length of stay in elderly hospitalized 
heart failure patients with home laxative use. Journal of gastroenterology and hepatology. 2015. 
17. 
Rentz AM, Yu R, Muller-Lissner S, Leyendecker P. Validation of the Bowel Function Index to 
detect clinically meaningful changes in opioid-induced constipation. J Med Econ. 2009;12(4):371-
383.