Clinical trial NCT03235739
Conditions: Pain, Postoperative
Sponsor: The Cleveland Clinic
Start date: 2017-10-01; Completion date: 2022-05-23
Enrollment: 136 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to find out whether oral Naloxegol can reduce the side effects of opioid painkillers following surgery. This study aims to explore whether Naloxegol can similarly reduce opioid-induced side effects in post-surgical patients. About 130 surgery patients will participate in this study which is being conducted at Cleveland Clinic Main Campus.

Detailed description:
Opioids are the gold standard for postoperative pain management, but they have been shown to produce uncomfortable side effects such as urinary retention (an inability to completely empty the bladder), constipation and nausea/vomiting. Clinical evidence demonstrates that Naloxegol can safely and effectively block these undesirable side effects while maintaining the painkilling effects of opioids in outpatients suffering from opioid-induced constipation.

Arms: arm 1: Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first arm 2: Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first
Interventions: intervention 1: Naloxegol 25 MG intervention 2: Placebo
Intervention descriptions: intervention 1: Oral Naloxegol 25 MG intervention 2: matching oral placebo

Protocol documents:
ICF_001.pdf: 
 
 
Version 1.0 – May 23, 2017 
1
The Cleveland Clinic 
Consent to Participate in a Research Study 
 
ANCILLARY EFFECTS OF ORAL NALOXEGOL (MOVANTIK) 
 
Principal Investigator: 
 
Dr. Alparslan Turan, MD 
 
(216) 445-9857 
Study Coordinator:  
 
Steve Leung, MD  
                        (216)-636-5493 
 
After hours phone contact #:  
CCF Page Operator 
 
 
(216) 444-2200 
 
You are being invited to participate in a research study.  A research study is designed to answer 
specific questions about new ways to prevent, detect, and treat disease.  Being in a research study 
is different from being a patient.  The purpose of this document is to provide a written summary 
of the discussion and exchange of research information you had with the research team.  It is also 
for use as a reference during the study.   
 
Please note: 
 You are being asked to participate in a research study. 
 Ask as many questions as needed so you can make an informed decision. 
 Carefully consider the risks, benefits, and alternatives of the research. 
 Your decision to participate is completely voluntary and will have no effect on the 
quality of your medical care if you choose not to participate.  You can also withdraw 
from the study at anytime. 
 
This research study has been approved by the Institutional Review Board (IRB).  The IRB is a       
committee that reviews human research studies to ensure that the safety and welfare of research 
volunteers are protected in accordance with federal human subject regulations and ethical 
principles. 
 
1. INFORMATION ON THE RESEARCH 
 
Why is the research study being done? 
 
The purpose of this study is to find out whether oral Naloxegol can reduce the side effects 
of opioid painkillers following surgery.  Opioids are the gold standard for postoperative pain 
management, but they have been shown to produce uncomfortable side effects such as urinary 
retention (an inability to completely empty the bladder), constipation and nausea/vomiting.  
Clinical evidence demonstrates that Naloxegol can safely and effectively block these undesirable 
side effects while maintaining the painkilling effects of opioids in outpatients suffering from 
opioid-induced constipation.  This study aims to explore whether Naloxegol can similarly reduce 
opioid-induced side effects in post-surgical patients.  About 130 surgery patients will participate 
in this study which is being conducted at Cleveland Clinic Main Campus.  As a patient who is 
undergoing elective surgery at Cleveland Clinic, you are being invited to participate in this 
research study. 
 
What is involved if you decide to take part in this research study? 
 


 
 
Version 1.0 – May 23, 2017 
2
If you agree to participate in this study, you will be randomly placed into one of two 
treatment groups: Naloxegol or placebo.  Neither the study team nor you as the study participant 
can choose which group you are in.  Your group assignment is chosen by chance – like the flip of 
a coin.  You have an equal chance of being assigned to either treatment group. 
Participants in the Naloxegol group will be given the investigational drug, an oral tablet, 
on the morning of surgery as well as on post-operative days 1, 2 and 3.  Participants in the 
placebo group will receive an oral tablet that is equal in size, shape and color to the 
investigational drug according to the same time schedule.  Only the Pharmacy team will have 
access to which participants are in which group in the event of a safety or emergency situation. 
For both treatment groups, all intraoperative and postoperative pain medications will be 
left to the discretion of the staff anesthesiologist. 
 
You will also be asked to participate in the following study procedures:    
   
Bladder Scans 
 
Opioid-induced urine retention is a common side effect for patients, and it is our primary 
outcome measure in this study.  Therefore we will use a portable Bladder ScanTM BVI 3000® to 
measure the volume of urine that remains in the bladder following urination.  The scanner will be 
placed above the pubic area and held stationary during measurement of bladder diameter as well 
as residual urine volume.  Bladder scans take approximately 5 minutes and will be performed by 
trained MD research fellows twice per day on postoperative days 1, 2 and 3. 
 
Surveys/Questionnaires 
You will be asked to provide information about your social and medical history including 
but not limited to tobacco use, kidney disease, diabetes mellitus, chronic pain conditions, etc.  
You will also be asked to complete the following questionnaires: 
 
Opioid-Related Symptom Distress Scale – you will be asked about frequency, severity and 
discomfort for 12 opioid-related side effects  
 
Opioid Complications Survey – you will be asked about complications such as nausea, vomiting, 
itching, etc. 
 
Myles Quality of Recovery Scale – you will be asked about your early postoperative health 
status.   
 
Patient Satisfaction Survey – you will be asked at discharge about your satisfaction with your 
recovery. 
 
Lastly, you will be asked to let the study team collect demographic and clinical 
information from your electronic medical record throughout your enrollment in the study 
including but not limited to:   
 Height, weight, age, ethnicity, etc. 
 Preoperative laboratory results and medications 
 Intraoperative opioid consumption, operation time and surgery type 
 Postoperative opioid consumption, side effects and laboratory data 
 Functionality such as bathing, toileting, walking and moving 
 
Participation in this study will end on post-operative day 3 or the day you are discharged  
from the hospital, whichever comes first. 
 


 
 
Version 1.0 – May 23, 2017 
3
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U. S. law.  This Website will not include information that can identify you.  At most, 
the Website will include a summary of the results.  You can search the Website at any time.  
 
 
2. ALTERNATIVES 
 
What are the alternatives to participation in the research study?   
 
Agreeing to participate in this research will not change the normal medical care which 
you are receiving.  Your alternatives are to participate in this research or not to participate in this 
research, but this will change nothing about your medical care. 
 
3. RISKS 
 
What are the risks of participating in the research study? 
 
More Common: >10% 
 Abdominal pain 
 
Common:  1% to 10% 
 Nausea 
 Diarrhea 
 Headache  
 Vomiting  
 Flatulence 
 Hyperhidrosis 
 Nasopharyngitis (Respiratory) 
 
 
There may be unforeseen risks to an unborn child associated with taking Naloxegol.  
Therefore, if you are capable of giving birth to or fathering a child, you and your sexual partner 
should use adequate birth control measures while you are in the study.  These measures may 
include abstinence, oral contraceptives (birth control pills), IUD, diaphragm, approved hormone 
injections, condoms, or documentation of medical sterilization.  If you are unwilling to do this, 
we ask that you do not participate in this study. 
Pregnancy tests will be performed on all women of child-bearing potential before 
beginning the study.  If you or your spouse becomes pregnant while taking part in this study, you 
must notify the study doctor immediately.   
 
4. BENEFITS 
 
What are possible benefits of participating in the research? 
 
Participation in this research study may or may not reduce the unpleasant side effects of 
opioid use; however the knowledge to be gained may benefit surgical patients in the future.   
 


 
 
Version 1.0 – May 23, 2017 
4
5. COSTS 
 
Are there any costs to you if you participate in this study? 
 
Some of the services you will receive during this research study are considered to be 
conventional routine clinical services that you would have received even if you were not 
participating in the research study and will be billed to you or your health insurance plan.   
Examples of these routine services include your surgical procedure and all related tests, labs and 
images.  You are responsible for paying any deductibles, co-payments or co-insurance that are a 
normal part of your health insurance plan. 
The following research study services are being done only because you are participating 
in this research study and will be paid for by the study sponsor and will not be billed to you or 
your health insurance plan.  These “research only” services include: study drug or placebo and 
all bladder scans. 
 
6. COMPENSATION 
 
Are there any payments to you if you participate in this study? 
 
There is no financial compensation for participating in this study. 
 
What happens if I am injured as a result of participation in this research? 
 
In the event you are injured as a result of participation in this research, medical care is 
available to you.  The costs of such medical care will be billed to you or your insurance 
company.  There are no plans to provide compensation for lost wages, direct or indirect losses.  
The Cleveland Clinic will not voluntarily provide compensation for research related injury.  You 
are not waiving any legal rights by signing this form.  Further information about research related 
injury is available by contacting the Institutional Review Board at (216) 444-2924.   
 
7. PRIVACY AND CONFIDENTIALITY 
 
What will happen to your information that is collected for this research? 
 
Cleveland Clinic has rules and procedures to protect information about you.  Federal and 
State laws also protect your privacy. 
 
The research team working on the study will collect information about you.  This 
includes your health information, data collected for this research study, and personal identifying 
information including your name, address, date of birth and other identifying information. 
 
Generally, only people on the research team will know your identity and that you are in 
the research study.  However, sometimes other people at Cleveland Clinic may see or give out 
your information.  These include people who review research studies including the Institutional 
Review Board and Research Compliance, their staff, lawyers, or other Cleveland Clinic staff. 
 
People outside Cleveland Clinic may need to see your information for this study.  
Examples include government groups (such as the Food and Drug Administration), safety 
monitors, other hospitals in the study, and the sponsor of the research and their agents.  As 
Cleveland Clinic we will do our best to ensure your information is kept confidential and that only 


 
 
Version 1.0 – May 23, 2017 
5
the health information which is minimally required to conduct the study is used or disclosed to 
people outside Cleveland Clinic; however, people outside Cleveland Clinic who receive your 
information may not be covered by this promise. 
 
You do not have to give this permission to use and give out your information; however 
you will not be able to participate in this research study without providing this permission by 
signing this consent form.  The use and disclosure of your information has no expiration date. 
 
You may cancel your permission to use and disclose your information at any time by 
notifying the Principal Investigator in writing: Dr. Alparslan Turan, at the Cleveland Clinic, 
9500 Euclid Avenue/P77, Cleveland, Ohio 44195.  If you do cancel your permission to use and 
disclose your information, your participation in this study will end, and no further information 
about you will be collected.  However, your cancellation would not affect information already 
collected in the study.   
 
 
The results of this study will not be directly shared with participants, however any 
research that is published as a result of our findings will preserve the confidentiality of all 
participants and is accessible to the general public. 
 
8. CONFLICT OF INTEREST 
 
Do the researchers or institution have any conflicts of interest relating to this study? 
 
One or more of the Investigators conducting this study may serve as paid speakers, 
consultants to advisory committee members for the company that is paying for this research or a 
company that makes products used in this study.  These financial interests are within permissible 
limits established by the Cleveland Clinic Conflict of Interest Policy.  If you have any questions, 
please ask your study doctor or call the Institutional Review Board at (216) 444-2924. 
 
9. QUESTIONS 
 
Who do you call if you have any questions or problems?  
 
If you have any questions or concerns about the research or develop a research-related 
problem, you should contact Dr. Alparslan Turan at 216-445-9857 or Steve Leung at 216-636-
5493 during business hours or via the CCF operator (216) 444-2200 after business hours.  If you 
have any questions about your rights as a research subject, you should contact the Institutional 
Review Board at (216) 444-2924. 
 
10. VOLUNTARY PARTICIPATION   
 
What are your rights as a research participant? 
 
Taking part in this study is voluntary.  You will be told of any new, relevant information 
from the research that may affect your health, welfare, or willingness to continue in this study.  
You may choose not to take part or may leave the study at any time.  Withdrawing from the 
study will not result in any penalty or loss of benefits to which you are entitled.  If you decide to 


 
 
Version 1.0 – May 23, 2017 
6
withdraw from the study you should discuss with your study doctor your decision to ensure a 
safe withdrawal. 
 
 
11. SIGNATURES 
 
Statement of Participant 
 
I have read and have had verbally explained to me the above information and have had all my 
questions answered to my satisfaction.  I understand that my participation is voluntary and that I 
may stop my participation in the study at any time.  Signing this form does not waive any of my 
legal rights.   I understand that a copy of this consent will be provided to me.  By signing below, 
I agree to take part in this research study.   
 
 
_____________________________________________ 
Printed name of participant 
 
 
_____________________________________________ 
 
_______________ 
 
 
Participant Signature  
 
 
       
        
           Date 
 
 
 
 
 
 
 
Statement of Person Conducting Informed Consent Discussion 
 
I have discussed the information contained in this document with the participant and it is my 
opinion that the participant understands the risks, benefits, alternatives and procedures involved 
with this research study. 
 
 
_____________________________________________ 
Printed name of person obtaining consent 
 
 
_____________________________________________ 
 
_______________ 
 
 
Signature of person obtaining consent 
                     
           Date 
 
 
 
 
 
 

Prot_SAP_006.pdf: 
1 
 
 
 
Ancillary Effects of Oral Naloxegol (Movantik) 
NCT03235739 
 
 
Alparslan Turan MD¹, Wael Saasouh MD², Steve Leung MD², 
Karen Hovsepyan, MD2, Guangmei Mao, PhD, MPH³ 
and colleagues 
 
 
1 Department of Outcomes Research and General Anesthesiology, Anesthesiology Institute, 
Cleveland Clinic 
2 Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic  
3 Department of Quantitative Health Sciences, Cleveland Clinic 
 
Version 1: 19/03/2017 
Version 2: 11/10/2017 
Version 3: 1/17/2018 
Version 4: 10/30/2018 
Version 5: 11/26/2019 
 
 


2 
 
Summary of changes in Version 2: 
1. Page 14 table 1 - Sedation scores and follow-up on POD3 were removed from table 1 (to conform to the 
protocol text). Evening bladder scan timing description changed, since the is no evening drug administration 
2. Page 15 inclusion criteria – added revision arthroplasties and general anesthesia 
3. Page 15-Removed the requirement for PCA, added a general requirement for post-op opioids 
4. Page 17-The need for straight catheterization in PACU and/or on the floor when it is medically indicated 
(volumes exceeding 400 ml) will be recorded by the study team and subsequent bladder scan will therefore 
not be done. Postoperatively, all patients will be given intravenous or oral opioids for pain control. 
Clinicians will adjust analgesic management as necessary in an effort to adjust verbal response pain scores 
to less than 4. 
5. Bladder scan to be done on the evening of surgery. 
6. Patient clinically does not have ileus if he is passing gas (no need to record /look for bowel sounds) 
Summary of changes in Version 3: 
1. Page 16 Exclusion criteria- removed antihistamines, phenothiazines, antidepressants and antipsychotics 
Summary of changes in Version 4: 
1. Page 14 Secondary Aim Hypothesis – changed ORSDS questionnaire from being asked on first, second, 
and third post-operative days to just the first two post-operative days. 
2. Page 15 Study Overview – wording added to maintain consistency with previous revisions for including 
knee surgery cases 
3. Page 15 Table – bladder scanning during PACU stay omitted. Far right column in version 3 that represented 
nothing was removed for clarification. 
4. Page 22 Secondary and exploratory analysis - ORSDS was changed to only being asked on post-operative 
days 1 and 2. Myles Quality of Recovery scale was changed to only be asked on either post-operative day 
2 or the day of discharge. 
5. Removal of requirement for bladder scanning to be done on the evening of surgery 
Summary of changes in Version 5: 
1. Page 21 – “POD 1 to 3” changed to “POD 1 and 2” regarding ORSDS follow up 
2. Page 21 – “POD 1 and 3” changed to “POD 2” regarding Quality of Recovery follow up 
3. Page 21 – Added clause regarding loss of follow up rate and the need for extra patients to reach planned 
power to 136 patients with 2 pilots 
 


3 
 
Table of Contents 
Ancillary Effects of Oral Naloxegol (Movantik) ...................................................................................... 1 
1. 
INTRODUCTION ............................................................................................................................... 4 
A. 
Opioids Analgesics and side effects ................................................................................................. 4 
B. 
Opioid-related side effects - composite ............................................................................................ 7 
C. 
Naloxegol .......................................................................................................................................... 9 
D. Rational of the study ...................................................................................................................... 11 
2. 
STUDY OBJECTIVES ..................................................................................................................... 12 
A. 
Primary Aim ................................................................................................................................... 12 
B. 
Secondary Aims .............................................................................................................................. 12 
C. 
Exploratory Aims ........................................................................................................................... 13 
3. 
METHODS and STUDY DESIGN .................................................................................................. 14 
A. Study Overview .................................................................................................................................. 14 
B. Setting and Population ...................................................................................................................... 15 
C. Withdrawal Criteria ........................................................................................................................... 16 
D. Administration of Naloxegol ............................................................................................................. 16 
E. Protocol .............................................................................................................................................. 16 
F. Measurements .................................................................................................................................... 18 
G. Data Analysis ..................................................................................................................................... 20 
H. Sample Size Considerations .............................................................................................................. 21 
I. Blinding and unblinding .................................................................................................................... 22 
J. Treatment compliance ........................................................................................................................ 22 
4. Safety monitoring and reporting ......................................................................................................... 22 
5. Ethical and regulatory requirements .................................................................................................. 28 
6. Study Drug handling ............................................................................................................................. 29 
References .................................................................................................................................................. 31 
Appendix .................................................................................................................................................... 34 
 
 
 


4 
 
INTRODUCTION 
Pain is a psychological sensory experience, which is caused by various factors. Surgery results in 
tissue damage which leads to postoperative pain. Studies in recently developed animal models of 
postoperative pain have advanced our knowledge of the mechanisms of pain resulting from 
surgical incision and associated tissue injury. Postoperative pain results from combination of 
nociceptive and inflammatory components[1]. The nociceptive component results from activation 
of peripheral sensory neurons damaged by surgical incision, and fades gradually as tissues heal. 
The inflammatory component enhances pain sensitivity via release of mediators from the 
surgically injured tissue. Central neuronal sensitization also seems to contribute to postoperative 
pain and hyperalgesia. [1, 2] Due to aforementioned mechanisms, pain is present in spontaneous 
resting at the site of surgery plus surrounding tissues. Movement or touching of the wound site, 
breathing, coughing, and gastrointestinal motility can all evoke pain. Unrelieved postoperative 
pain leads to multiple physiological and psychological consequences, which worsen outcomes. For 
example, inadequate perioperative analgesia is associated with myocardial ischemia, impaired 
wound healing, delayed gastrointestinal motility, atelectasis, and postoperative pneumonia.[3-5] 
Furthermore, poorly controlled acute pain is strongly associated with development of persistent 
incisional pain, which can be devastating for patients. [6, 7] 
A. Opioids Analgesics and side effects  
Although the concept of “multimodal analgesia” of using different drugs with different 
mode of action to interfere with the pain pathway, such as using non-opioid adjuvants (e.g. 
NSAIDS, steroids, regional anesthesia) have been developed to improve postoperative pain 
management, opioids remain the cornerstone of treatment of postoperative pain. Opioids produce 
analgesia and other effects by binding to specific opioid receptors in the peripheral and central 
nervous system. Three types of opioid receptors and their subtypes have been discovered: mu, 
delta, and kappa receptors. The most commonly used opioids bind to mu receptors. The mu1 
receptor is responsible for the production of opioid-induced analgesia, whereas mu2 receptors 
provoke respiratory depression, cardiovascular effects, and inhibition of gastrointestinal motility 
commonly seen with opioids.[8-10] Sole reliance on opioids is often inadequate and leads to 
significant side effects.[11] 


5 
 
Adverse events associated with opioids include an increased risk of postoperative urinary 
retention (POUR). It has been shown in multiple studies that systemic opioids contribute to urinary 
retention. Opioids inhibit the release of acetylcholine and thereby decreases the parasympathetic 
output to the detrusor and thus bladder contractility. This effect is directly related to the dose of 
opioids given and the opioid sparing multi-modal analgesia has been shown to reduce urinary 
retention.[12, 13] The true incidence of POUR is unclear but is estimated to vary between 5-
70%.[14] 
The opiates or its analogues decrease the sensation of bladder fullness by partially 
inhibiting the parasympathetic nerves that innervate the bladder. In addition, opiates have been 
shown to increase the sphincter tone of the urinary bladder via sympathetic overstimulation, 
resulting in increased bladder outlet resistance. The combination of decreased sensation of fullness 
and increased outlet resistance increase the risk of urinary retention. Studies suggest that the half-
life of the opioid used has an impact on urinary function and risk of retention. 
Type of opioids used and delivery methods seem to affect the POUR as well. Studies that 
evaluated orthopedic patients who received fentanyl (short half-life) for post-operative analgesia 
noted that these patients experienced significantly less risk for urinary retention than those who 
received morphine (intermediate half-life). Several authors have demonstrated that the risk of 
retention is also increased in patients using PCA compared to those receiving intermittent IV or 
IM opioids. 
Although the cause of POUR is multifactorial and depends on type and duration of surgery 
as well as existence of comorbidities, systemic opioids are an important risk factor. Urinary 
retention requires urethral catheterization and potentially indwelling catheter, leading to patient 
discomfort, hemorrhage, and increased risk of UTI. Urinary catheters can provide an opportunity 
for gram negative bacterial infections that can lead to further urological and infectious 
manifestations (e.g. pyelonephritis, urosepsis, death).[15] Catheter-related UTI is responsible for 
13% of 100,000 nosocomial infection related deaths each year.[16] It affects about one million 
Americans annually and is a significant source of morbidity and mortality. It is the most common 
“preventable” nosocomial infection that accounts for over $400 million spent annually in the U.S. 
alone.[15, 17] Bacteria causing the UTI can potentially hematogenously spread and lead to surgical 
site infection.[18] Bacterial seeding from UTI is a special concern after certain type of surgery, 


6 
 
especially those with prosthetic hardware implanted. For instance, ample evidence related UTI 
with deep joint infection, hemiarthroplasties and total hip arthroplasties in orthopedic procedures, 
which carries significant morbidity and financial costs.  There is currently no effective medical 
treatment for POUR from opioids. Previous trials of using phenoxybenzamine to treat POUR have 
shown mixed results.[19, 20] Naloxone had been tried in the past its reversal of analgesia has 
limited its usefulness in the clinical setting.[21] Furthermore, naloxone’s short half-life of 1-1.5 
hours is outlasted by the opioids’ effects on the bladder. There is a need for an effective treatment 
to for urinary retention without mitigating the analgesic effects of opioids.[22] 
Postoperative ileus (POI) is common after surgery (incidence of 4.5%), and is a transient 
loss of peristalsis from inflammatory response and release of endogenous opioids from surgical 
stress.[23-25] POI contributes to patient discomfort, morbidity, and is the one of the major reasons 
for prolonged hospital stay and overall health care costs.[25, 26] Opioid receptors, belonging to 
the G-protein coupled receptor family, are found throughout the enteric nervous system. The 
actions of opioids on the GI tract are mainly mediated by mu-receptors which lead to: inhibition 
of release of excitatory acetylcholine, non-peristalsis contractions, decreased water/electrolyte 
secretion, and increased tone of pyloric and intestinal sphincters.[27-30] The result is an 
exacerbated postoperative ileus and prolongs the return of bowel function. The true incidence of 
POI is unknown and varies between the type of surgery but is estimated between 3-15%.[31] 
Currently there is no promising treatment for POI. Several peripheral opioid antagonists have been 
developed to treated opioid related POI but with limited application. [32, 33]  
Patients in the postoperative period will experience many unavoidable physiologic 
derangements as a result of anesthesia and surgery. Most studies have examined the effect of 
anesthetic practices on major clinical outcomes, such as recovery time, cardiovascular 
complications, stroke, length of hospital stay, and mortality. These endpoints are clinically relevant 
but do not necessarily reflect the overall state of recovery after anesthesia. Quality of Recovery 
(QoR), first developed in 2000 by Myles et al., is a psychometric has become an important clinical 
outcome in anesthesia research because it describes the global quality of life from the patients’ 
perspective after surgery and anesthesia.  It indicates the impact of adverse events on such as pain 
and immobility on the patient’s recovery and also indirectly reflects quality of health care.  The 
original quality of recovery 9 (QoR‐9) score was later evolved into a more extensive QoR-40 


7 
 
that has improved reliability and validity. The most recent validated version is a 15-item QoR scale 
as discussed by Stark et. al.[32] It incorporates five dimensions of health, including patient support, 
comfort, emotions, physical independence, and pain, and has been proven useful in multiple setting 
and languages. Quality of recovery will undoubtedly have influence patients’ satisfaction of their 
care, which in the current economic constraints of the healthcare system, and the fact that Centers 
of Medicare & Medicaid Services are linking hospital reimbursement based on patient’s 
satisfaction, quality of recovery has real financial implications. Opioid analgesia, although an 
indispensable part of postoperative pain management, is often needed to satisfy the high 
expectation of pain relief of patients. Overuse of opioids is associated with numerous side effects, 
(e.g. nausea and vomiting, delay return of bowel function, sleep disturbance, pruritus) which has 
negative impact on quality of recovery.  
B. Opioid-related side effects - composite 
In addition to urinary retention and postoperative ileus, other common side effects 
associated with opioids are nausea/vomiting, pruritus, and respiratory depression. Postoperative 
nausea and vomiting (PONV) affects about 20-70% of postoperative patients and are highly 
distressing to patients. It is mainly mediated by triggering of opioid-receptors in chemoreceptor 
trigger zone of the medulla. Opioid induced nausea and vomiting may prolong the recovery room 
time and a potential hospital stay and lower the degree of patient satisfaction. It has been shown 
in study that PONV has an impact on quality of recovery. In patients’ perspective, PONV is one 
the most undesirable outcomes in the recovery period. In fact, in one survey, patients were willing 
to pay out of their own expense to rid of nausea and vomiting completely. Another common side 
effect of opioid is pruritus, affecting up to 50% patient receiving intravenous opioids and an even 
higher incidence with neuraxial opioids. The current treatment of pruritus is with antihistamines, 
5-HT3-receptor antagonists, opiate-antagonists, propofol, and droperidol, with variable success 
and with each associated with its side effects.  Physicians often respond by dose reduction or 
discontinuation, which leads to inadequate analgesia and patient discomfort. Another important 
side effect is opioid induced respiratory depression which is an important source of adverse events 
in hospitalized patients [33]. Respiratory depression is common in the postoperative period and 
largely unrecognized, causing significant hypoxemia and potential harm[34].  


8 
 
Worth noting is that opioids might theoretically increases the risk of infections, which 
might have implications in surgical site infections and infections of hardware in certain surgeries. 
Opioids have long been recognized as are immune modulators compromising compromise both 
cellular and humoral immune functions.[35-37] The exact mechanism of this immune modulation 
is unclear but opioids are hypothesized to act centrally on the hypothalamus-pituitary-adrenal axis 
and peripherally on the immune cells directly.[38] Opioids bind to 3 major types of receptors: mu-
, delta-, and kappa-opioid receptors, which are all identified among immune cells, such as PMNs, 
macrophages, T-lymphocytes, splenocytes, and macrophages.[39] Opioids also alter the 
macrophage protein expression profile and impair macrophage function including chemo taxis and 
phagocytosis.[40-42] And finally, opioids reduce B-cell proliferation and antibody production.[43]  
Opioid-induced immunodysfunction can potentially lead to surgical site infection. This, a 
theory is supported by multiple animal studies demonstrating the effect of opioids on 
mortality.[44] Breslow et al. compared the effect opioids on infection. Mu-receptor knockout and 
wild-type mice were both pretreated with morphine and were inoculated with Salmonella and the 
knockout mice were resistant to infection, while the wild-type had 100 percent mortality.[45] 
Furthermore, there is evidence that increased doses of opioids are associated with wound infections 
in patients who suffer from major burn injuries.[46] High-dose opioids have been associated with 
surgical 
site 
infection 
(SSI) 
after 
colorectal 
surgery 
possibly 
secondary 
to 
immunosuppression.[47] It is plausible to assume that high dose opioids might contribute to SSI. 
Duration of hospitalization, or length of stay, is an important indicator of quality of care 
and inefficiencies of healthcare and has been used by multiple government agencies to measure 
quality of care from hospitals. The importance of this parameter was demonstrated by the effort to 
develop new surgical and anesthetic techniques that facilitate recovery in multiple areas of surgery 
to reduce stay in intensive care unit and length of stay in hospital. It was suggested that one major 
reason for prolonged duration of hospitalization is from postoperative complications and 
management of those complications. Prolonged hospitalization also translates to increased 
healthcare resources. In a study by Collins et al. examining risk factors that contribute to prolonged 
hospitalization of 23,919 adults undergoing major elective surgery, postoperative adverse events 
was associated with a high risk of prolonged hospitalization.[48] Opioids-related side effects affect 
postoperative recovery and contribute to prolonged hospital stay. For example, prolonged ileus has 


9 
 
multiple consequences, including decreased patients’ comfort, delay of mobilization, and 
pulmonary complications. For example, patient with opioid-induced ileus significantly stay longer 
in the hospital after abdominal surgery than those who do not (20 vs. 11 days, p<0.001). Another 
study of patients who underwent spine surgery and reported urinary retention was associated with 
longer hospital stay (3.94 d vs. 2.34 d; P=0.005). PONV, a considerable cause of discomfort, 
should not be taken lightly. PONV has been shown to prolong hospital stay. In severe PONV, it 
has been documented to cause suture dehiscence and aspiration, which will likely lead to additional 
treatment and extended hospitalization. In summary, opioid-related side effects hinder recovery 
and prolongs hospital stay. 
In summary, opioids provoke numerous severe complications that cause substantial patient 
morbidity. They also delay discharge, increase the cost of care, and reduce patient satisfaction. We 
have a strong need for a peripheral opioid antagonist that could be a part of a multimodal approach 
to manage and possibly prevent opioid induced side effects that has good oral bioavailability, 
effective, no effect on centrally mediated analgesia and favorable side effect profile.  
C. Naloxegol  
Peripheral opioid antagonists may prevent some opioid-induced side effects. Naloxegol 
(marketed as Movantik, by AstraZeneca) is a pegylated (PEG) derivative of naloxone that inhibits 
µ-opioid receptors. The PEG moiety offers several functions including reduced permeability and 
increased efflux (substrate for P-glycoprotein transporter) across the blood brain barrier making it 
a mainly peripherally acting µ -opioid receptor antagonist. At recommended doses, its ability to 
only act peripherally allows it to reverse peripheral opioid-related side effects without interfering 
with opioid-related analgesia or causing withdrawal, as seen with naloxone. The PEG moiety also 
increases oral bioavailability and allowing oral administration. Naloxegol was approved in 2014 
by the U.S. Food and Drug Administration after it passed phase III trials for opioid-induced 
constipation in adults with chronic non-cancer pain.  
Naloxegol binds to all three opioid receptors with greater affinity for µ- and K-receptors, 
the former (µ) being the main receptor implicated in its side effects related to the gut and bladder. 
The recommended dosage for adults is 12.5 mg to 25 mg daily. After intake orally, it is rapidly 
absorbed, reaching maximum concentration (C-max) in 2 hours with a second peak appearing 0.4-


10 
 
3 hours after the first peak. Its absorption is increased by a fatty meal. Its volume of distribution at 
the terminal phase is 968-2,140 L and it has low plasma binding (~4.2%) in humans. Clearance is 
mainly by hepatic metabolism (P450-CYP3A) with metabolites whose actions are yet to be 
defined. A small portion of naloxegol is elimination by renal excretion.  The half-life of naloxegol 
is 6-11 hours.  
Naloxegol does not significantly inhibit the CYP1A2, CYP2C9, CYP2D6, CYP3A4 or 
CYP2C19 or induce CYP1A2, CYP2B6 or CYP3A4 and is thus not expected to affect 
concentrations of drugs metabolized by these enzymes.  Drugs that inhibit CYP3A4 (e.g. 
ketoconazole, verapamil, cimetidine) might increase Naloxegol concentration, and might need 
dose adjustment. Naloxegol does not appear to affect the efficacy of other opioids when 
administered together. In a clinical study of healthy volunteers receiving morphine (5 mg/70 kg), 
naloxegol has no effect on the pharmacokinetics and metabolic profile of morphine.[49] 
Naloxegol is a well-tolerated drug for long-term use (up to 52 weeks) based on clinical 
trials.[50] The incidence of adverse events ranges from 8-19% and is dose-related.[51] Most 
adverse events were mild to moderate in intensity and mostly gastrointestinal related including 
abdominal pain, diarrhea, with a minority experiencing headache and hyperhidrosis.[51] The 
cardiovascular safety for naloxegol was extensively studied during phase III trials. AstraZeneca 
organized an independent committee, called Cardiovascular Event Adjudication Committee (CV-
EAC) to authenticate major adverse events including MACE (CV death, MI, stroke). Naloxegol 
was not associated with increased CV risk. The incidence of MACE was 0.6% for placebo versus 
0.4% for naloxegol and the incidence of MI was 0.3% for placebo versus 0.2% for naloxegol.[52] 
Multiple clinical trials have demonstrated the efficacy of naloxegol including relief of 
opioid-related side effects while without affecting increasing pain score and daily opioid dose. 
Two identical phase III, randomized, multi-centered, double blinded studies (KODIAC-04 and 
KODIAC-05) investigated the efficacy of 12.5 mg/day and 25 mg/day naloxegol versus placebo 
in adults patients with opioid-induced constipation over a 12 week treatment period.[51] Naloxegol 
was associated with a significant improvement in bowel function with 25 mg/day and was more 
effective than 12.5 mg/day. Furthermore, naloxegol did not alter pain scores, daily opioid 
requirements, or the incidence of opioid-withdrawal across all control and treatment groups.[51] 


11 
 
These findings prove naloxegol’s utility as a peripheral opioid antagonist in decreasing opioid’s 
side effects while maintaining analgesia. 
D. Rationale of the study 
Previous clinical evidence has already demonstrated naloxegol’s efficacy and safety in the 
treatment of opioid-induced constipation in the outpatient setting. To our knowledge, there have 
been no clinical studies that investigated its potential in the perioperative setting. Opioid analgesia 
has potential downsides including urinary retention, prolonged ileus, which translates to potential 
prolonged hospital stay and costs. The aim of this study is to test if the novel peripheral opioid 
receptor antagonist naloxegol is effective in mitigating these opioid-related side effects and 
reducing duration of hospitalization and overall costs. 
 
 


12 
 
1. STUDY OBJECTIVES 
This will be a prospective, randomized, double-blinded study and will be performed at the 
Cleveland Clinic Foundation. The study group will receive Naloxegol 25 mg to be given once in 
the morning every day and the control group will receive placebo.  
 
Specifically, the proposed research will have the following aims: 
 
A. Primary Aim 
To assess whether patients who received Naloxegol have a lower volume of residual urine 
in bladder. 
Hypothesis: Our primary hypothesis is that patients who received Naloxegol 25 mg given 
once in the morning every day will have lower volume of residual urine in bladder when compared 
to placebo.  
Post-void residual volume will be measured after asking patient to urinate independent of 
their previous urination. Post-void residual is a measurement of the urine that remains in the 
bladder less than 30 minutes following voiding that identifies urinary retention.  
Ultrasound has been used as an imaging modality to evaluate bladder function, and its use 
in the perioperative period as a diagnostic tool for POUR has gained popularity in the past decade. 
Several studies have shown good correlation between the volumes measured by bladder 
catheterization and by ultrasound. 
 
B. Secondary Aims 
Secondary Aim 1: 
To evaluate the effect of Naloxegol on other opioid related side effects.  
Hypothesis. Patients in Naloxegol group have fewer opioid-related side effects than control 
group. We will use a validated composite outcome, Opioid–Related Symptom Distress Scale 
(ORSDS), to evaluate opioid-related side effect. ORSDS is 4-point scale that evaluates 3 
symptom distress dimensions (frequency, severity, bothersomeness) for 12 opioid related side 


13 
 
effects [53]. ORSDS questionnaire will be administered by a trained research fellow on first, 
second, and third postoperative mornings while patients remain hospitalized. 
Secondary Aim 2: 
To assess whether Naloxegol is associated with lower need for indwelling urinary 
catheterization. 
Hypothesis: Our hypothesis is that patients who received Naloxegol 25 mg given once in the 
morning every day will have less need of indwelling catheterization determined by the residual 
volume to be above 400 ml when compared to placebo. 
 
Secondary Aim 3: 
To assess whether Naloxegol is associated with improved quality of recovery, as measured by 
the 15-item Quality of Recovery scale. 
Hypothesis: Our hypothesis is that patients who received Naloxegol 25 mg given once in the 
morning every day will have improved quality of recovery. Quality of recovery in the 
postoperative period is an important measure of the early postoperative health status of patients, 
and the 15-item Quality of Recovery scale is a validated and efficient measure[32]. Patients will 
be questioned on the morning of postoperative day (POD) 2 or day of discharge (whichever 
comes earlier). 
 
C. Exploratory Aims 
Exploratory Aim 1:  
To assess patient satisfaction with the quality of recovery. 
Hypothesis: Our hypothesis is that patients who received Naloxegol 25 mg given once in the 
morning every day will have improved satisfaction with the quality of recovery, as measured on 
a subjective 100-point scale (where 0 means not satisfied at all and 100 means completely 
satisfied). 
Exploratory Aim 2:  
To assess the effect of Naloxegol on opioid-related prolongation of hospital stay after surgery. 
Hypothesis. Patients in control group will have prolonged length of hospital stay compared to 
Naloxegol patients due to opioid-related adverse events. 
 


14 
 
2. STUDY DESIGN and METHODS  
A. Study Overview 
We propose to assess the effect of Naloxegol on reversing opioid-related side effects in 
patients recovering from elective primary hip surgery under spinal anesthesia who will be 
randomly assigned to oral Naloxegol or placebo for two postoperative days or until the date of 
discharge, whichever occurs earlier (Table 1). The design will be a randomized, double-blind, 
placebo-controlled trial of oral Naloxegol in adults having elective primary hip or knee surgery 
under spinal anesthesia. The study will be performed at the Cleveland Clinic hospitals. 
Table 1: study flowchart.(Detailed information will be in the CRF`s) 
 
Preopera
tive visit 
Morning 
of surgery 
During 
surgery 
PACU* 
POD** 1 
POD 2 
Day of 
discharge 
 
Screening for eligibility 
X 
X 
 
 
 
 
 
 
Consenting 
X 
 
 
 
 
 
 
 
Baseline medical, 
demographics, Apfel score, 
Patient functionality and 
drug history 
X 
X 
 
 
 
 
 
 
Pertinent blood studies 
(laboratory) 
X 
 
 
 
X 
X 
 
 
AE/SAE collection 
 
X 
 
 
X 
X 
 
 
Study drug (in morning, 1 hr 
before or 2 hr after meal) 
 
X 
 
 
X 
X 
 
 
Bladder scan at least 2 hours 
after study drug (morning) 
 
 
 
 
X 
X 
 
 
Bladder scan  (evening) 
 
 
 
X 
X 
X 
 
 
Intraoperative record data 
collection 
 
 
X 
 
 
 
 
 
Opioid–Related Symptom 
Distress Scale (ORSDS) 
 
 
 
 
X 
X 
X  
 
Opioid complications 
survey***  
 
 
 
X 
X 
X 
X 
 
Numerical pain score 
 
 
 
X 
X 
X 
X 
X 
Quality of recovery survey 
 
 
 
 
 
 
X 
 
* PACU = post-anesthesia care unit 
** POD = post-operative day 
*** Opioid complications survey includes nausea, vomiting, itching, ileus, anti-emetic use, anti-
pruritic use, anti-opioid use 
 
 
 


15 
 
B. Setting and Population 
 
i. Inclusion criteria 
For inclusion in the study subjects should fulfill the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures 
2. 
Female or male aged at least 18 years 
3. 
American Society of Anesthesiologists physical status 1-4; 
4. 
Scheduled for elective primary or revision hip or knee surgery under spinal or general 
anesthesia; 
5. 
Expected to have significant postoperative pain requiring administration of opioids 
6. 
Negative pregnancy test 
 
ii. Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Severe hepatic impairment, with/or twice the upper normal levels of liver enzymes 
2. 
Severe renal impairment, or creatinine level > 2.0 
3. 
History of bladder cancer 
4. 
Patients receiving perioperative regional anesthesia blocks 
5. 
Presence of a sacral nerve stimulator 
6. 
Medications (anticholinergic), conditions or comorbidity causing urinary retention 
7. 
Patient with planned requirement of indwelling urinary catheter insertion before or 
immediately post-surgery due to immobility 
8. 
Urinary Tract Infections and other urogenital comorbidity (incontinence, cysto-ureteric 
reflux, known bladder retention) or conditions which can cause urinary retention 
9. 
Severe peptic ulcer disease, diverticular disease, infiltrative gastrointestinal tract 
malignancies, or peritoneal metastases 


16 
 
10. Patients with known or suspected disruption of blood brain barrier, which may include but 
not limited to: Alzheimer’s disease, stroke, poliomyelitis, cerebral palsy, multiple sclerosis, 
spinal lesions, and Parkinson’s disease 
11. Gastrointestinal obstruction/Gastrointestinal perforation 
12. Strong CYP3A4 inhibitors (some antibiotics, antifungals, protease inhibitors, and 
antidepressants), Strong CYP3A4 inducers, Other opioid antagonists 
13. Hypersensitivity to MOVANTIK (naloxegol) or any of its excipients 
 
C. Withdrawal Criteria  
Patients will be free to withdraw from study at any time. Withdrawn patients will no longer 
receive study drug but will be contacted for follow up and safety checks if patient allows. 
 
D. Administration of Naloxegol  
The investigational drug for this study is Naloxegol 25 mg per dose to be given once in the 
morning every day (morning of surgery & on postoperative days- 1 hour before or 2 hours after 
the morning meal ). The placebo control is equal in size, shape, and color to the active tablets and 
administered according to the same protocol. The Pharmacy team will have the appropriate 
randomization in case of a safety or emergency situation, and the study drug label will mention 
that it is “Naloxegol or Placebo”. 
 
E. Protocol 
Patients must meet all inclusion and exclusion criteria to be eligible for the study. After 
eligibility is confirmed, patients will receive complete information about the study both verbally 
and in writing. Informed consent must be obtained from the patients prior to randomization and 
study-specific procedures. 
Anesthetic management will follow pre-established clinical and institutional guidelines. 
Patients can be pre-medicated and will receive spinal or general anesthesia per institutional routine 
according to attending anesthesiologist discretion. Spinal anesthesia will include the standard 
monitoring for the given operation, and will occur after the electrocardiogram and monitoring 
equipment are placed on the patient. Prophylactic antibiotics will be given per surgical routine. 
During the induction of general anesthesia, indwelling urinary catheters will be inserted only in 


17 
 
the patients with operation time exceeding 3 h or who required meticulous monitoring of the 
intraoperative fluid status. Intraoperative and postoperative fluid management will be left to 
discretion of the clinicians, who will be administrating them using institution standards.   
Randomization (1:1) will be web-based and initiated prior to conclusion of surgery; 
allocation will thus be concealed from investigators. Randomization will be stratified based on 
chronic opioid use (if present) to ensure balance between treatment groups within chronic opioid 
users and nonusers. Chronic opioid use will be defined as opioid use for more than 30 consecutive 
days, at a daily dose of 15 mg or more of morphine or equivalent, within the 3 months before 
surgery. The treatment groups will be oral Naloxegol and placebo.  
Naloxegol or placebo will be administered starting the first morning of surgery and 
continued for two postoperative days or until hospital discharge (whichever occurs first) with 25 
mg (or equivalent size and shape of Placebo). The post-operative study drug doses will be given 
in the morning 1 hour before or 2 hours after the morning meal. Intraoperative and postoperative 
pain medications will be left to discretion of the anesthesiologist.  
In the PACU and postoperative periods, patients will be managed at the discretion of the 
primary care team and the staff anesthesiologist. The need for straight catheterization in PACU 
and/or on the floor when it is medically indicated (volumes exceeding 400 ml) will be recorded by 
the study team and subsequent bladder scan will therefore not be done. Postoperatively, all patients 
will be given intravenous or oral opioids for pain control. Clinicians will adjust analgesic 
management as necessary in an effort to adjust verbal response pain scores to less than 4. 
Clinical evaluators for the outcomes will be blinded to group allocation and Pharmacy 
personnel not involved in evaluations will prepare the study drugs. Clinicians including nurses will 
be blinded to monitoring and will be required to perform their standard of care management after 
surgery. 
 
Enrollment procedures 
The following events will occur in order: 
1. Screening for eligible patients 
2. Informed consent 
3. Randomization 


18 
 
4. Administration of study drug starting the morning of surgery and for 2 additional mornings 
5. Collection of data 
6. Completion of CRF information 
 
The treatment periods extends from the morning of surgery until the earlier of POD 2 or hospital 
discharge. Study personnel will follow the study subject until the earlier of POD 2 or hospital 
discharge. In the case of an adverse event, the study subject will be followed until the resolution 
of the event. 
 
Handling incorrect randomization 
Any event where a subject receives the incorrect treatment or is assigned to the incorrect group 
will be recorded and judged as an unanticipated problem or protocol deviation at the discretion of 
the principal investigator. 
 
F. Measurements 
 
Data will be recorded on a case report form (CRF) which will be available electronically and on 
paper format. 
Demographic data to be obtained includes height (cm), weight (kg), age (yr), gender, physical 
status (ASA), and self-declared ethnicity. Patients will be questioned for social history (tobacco) 
and medical history (pulmonary disease, kidney disease, diabetes mellitus, neurological disease, 
chronic pain conditions, illegal drug usage, alcohol abuse, myocardial infarction, previous surgery 
or stent placement and medications usage). Available preoperative laboratory tests and medication 
list will be recorded. Individual risk for nausea and vomiting will be determined using the Apfel 
score.  
 
Data obtained from electronic medical records will include: operation time, surgery type, 
intraoperative opioid consumption, postoperative opioid consumption in PACU and in ward, 


19 
 
breakthrough pain medication requirements, pain scores in PACU and ward, requirement of 
oxygen in PACU and ward, nausea and vomiting, requirement of antiemetics, pruritus, 
requirement of antihistaminic medications, ambulation time, flatus, ileus, bowel movements, 
constipation, length of stay and any side effects or complications. Preoperative and postoperative 
laboratory data including but not limited to liver function and coagulations test results will also be 
collected from electronic medical records. Patient functionality will also be recorded including 
bathing, toileting, walking and moving. 
 
The Residual volume will be measured within 30 minutes after urination using the battery-
powered, portable Bladder scan™ BVI 3000® (Verathon, Bothell, WA, USA). The scanner will 
be placed on the suprapubic area and held stationary during measurement scanning. The diameter 
of the bladder and volume of urine will be calculated from the scan data. Scans will be repeated 
several times to ensure accuracy in measurements. The average of the measurements at each 
measurement time will be analyzed. All clinical procedures will be performed by trained MD 
research fellows in the ward twice daily. Surgical team will be blinded to volume determined by 
scanning and we will also record if they had ordered indwelling catheterization.  
 
We will use Myles QoR scale to formally evaluate quality of recovery on  2 or day of discharge 
(whichever comes earlier). Myles QoR scale is a validated scoring system allows quantification of 
patient’s early postoperative health status, which is also a description of quality of recovery[32]  
 
ORSDS is 4-point scale that evaluates 3 symptom distress dimensions (frequency, severity, 
bothersomeness for 12 opioid related side effects[53]. ORSDS questionnaire will be administered 
by a trained research fellow on first and second postoperative  days/day of discharge (whichever 
comes earlier)   
 
Patient satisfaction with their recovery will be questioned before discharge using a 0-100 scale 
(where 0 indicates no satisfaction and 100 indicates complete satisfaction).  
 
Adverse events and serious adverse events occurring at any time during the study period will be 
recorded on a specific form in the CRF. 


20 
 
 
G. Data Analysis 
Naloxegol group and placebo group will be compared for balance of baseline 
characteristics using standard descriptive statistics (i.e., mean ± standard deviation, median [Q1, 
Q3], or N (%) as appropriate) and standardized difference. The standardized difference is the 
difference in means or proportions divided by the pooled standard deviation. Any covariable with 
a standardized difference greater than 0.2 in absolute value will be regarded as a potential 
confounder, and will be adjusted for when comparing Naloxegol and placebo groups on all the 
outcomes. 
 
Primary analysis.  
We will test the primary hypothesis that subjects who received Naloxegol 25 mg given 
once in the morning every day will have lower volume of residual urine in bladder when compared 
to placebo. We will compare the randomized groups on the volume of residual urine in bladder, 
which will be measured twice per day for up to 3 days (i.e., a maximum of 6 measurement times 
in total), using a linear mixed model adjusting for the within-subject correlation (using an 
autoregressive correlation structure). At each measurement time, the average of the measurements 
will be analyzed. Any imbalanced baseline characteristics and volume of residual urine in bladder 
prior to the procedure will be included as covariates in the model. If the group-by-time interaction 
is non-significant (P > 0.20), we will assess the group difference on the volume of residual urine 
across over all the measurements. In the presence of a group-by-time interaction, the group 
difference will be assessed separately at each measurement time and a Bonferroni correction will 
be made for multiple comparisons to maintain the hypothesis-wise 2-sided type I error at 0.05 (the 
significance criterion will be 0.05 / 6).  
Second, we will assess the treatment effect within chronic opioid users and nonusers using 
the same statistical methods as above. The significance level will be 0.025 for each of the two 
subgroup analyses (Bonferroni correction).  
 
Secondary and exploratory analysis. 


21 
 
We will test the following three secondary hypotheses: subjects who received Naloxegol 
25 mg given once in the morning every day will have (1) fewer opioid-related side effects, (2) less 
need of indwelling catheterization determined by the residual volume to be above 400 ml, and (3) 
improved quality of recovery as compared to placebo. 
The two groups will be compared on the incidence of any opioid-related side effects using 
a logistic regression.  The frequency, severity, and bothersomeness for each of the 12 opioid-
related side effects on POD 1 and 2 will be summarized.  We will compare the two groups on 
incidence (any versus none) of need for indwelling urinary catheterization (defined as residual 
urine volume > 400 ml) using logistic regression. The two groups will also be compared on the 
Quality of Recovery scale measured on POD 2 (or day of discharge if it occurs earlier) using a 
linear mixed model with an autoregressive correlation structure. All the analyses will be adjusted 
for imbalanced baseline characteristics, if any. The hypothesis-wise 2-sided type I error for each 
of the secondary outcome will be controlled at 0.017 (i.e., 0.05/3, Bonferroni correction).   
In addition, we will summarize the following exploratory outcomes, including satisfactory 
of the quality of recovery (a subjective 100-point scale) and length of hospital stay after surgery.  
 
H. Sample Size Considerations 
The sample size consideration was based on the test for the primary hypothesis that patients 
who received Naloxegol 25 mg given once in the morning every day will have lower volume of 
residual urine in bladder when compared to placebo. We would need 62 patients per group [56] to 
have 90% power at a 2-sided alpha level of 0.05 to detect an effect size of 0.4 or more. The effect 
size estimation of 0.4 was very conservative as compared to the mean difference of 120 ml (SD: 
approximate 60 ml) in the volume of residual urine observed by Jose Carlos, I. T., et al [57]. The 
effect size is the difference in means of the two randomized groups divided by the pooled standard 
deviation. A maximum of six measurements are planned, twice per day for 3 days. However, we 
assumed 4 measurements per patients with a correlation of 0.3 to be conservative for the sample 
size calculation. Considering a loss of follow-up rate of 10%, we will need 12 more patients to 
reach the planned power with an end sample size of 136. A blinded data quality check will be 
conducted at 50% (68 patients) of the planned enrollment of 136 patients. In addition to the 136 
patients, we will enroll 2 pilot patients to test feasibility of recruitment, protocol adherence, 
randomization process, and data collection.  


22 
 
SAS software version 9.4 for Windows (SAS Institute, Cary, NC) will be used for all 
statistical analyses and graphics. 
 
 
I. Blinding and unblinding 
Study drug will be prepared by the hospital pharmacy and labeled as “Naloxegol 25 mg or 
Placebo”. Placebo will have an identical shape and color. Blinding will be maintained unless 
unblinding is requested for an adverse event or any other reason as deemed necessary.  
If clinically indicated, an investigator can request unblinding for a specific dose from the Pharmacy 
personnel. Such an event will be reported and documented. Unblinding can also be requested by 
the data safety and monitoring board at any time for safety concerns. 
 
J. Treatment compliance 
Subjects will be given clear instructions on medication doses and research-related follow-up prior 
to enrollment. A member of the study team will follow each patient for the duration of the 
intervention in order to ensure compliance with the protocol. Any deviations will be reported on 
the case report form and communicated as necessary. 
If the need arises to discontinue the investigational product, the investigator will inform Pharmacy 
personnel to halt any further drug dispensing. The team will also communicate with the primary 
care nursing staff to return any unused investigational drug to the pharmacy for proper disposal. 
 
4. Safety monitoring and reporting 
Definition of adverse events  
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 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 


23 
 
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. 
Adverse events of particular interest are: 
Opioid withdrawal: hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability 
Severe abdominal pain (>8/10) and/or diarrhea 
Gastrointestinal perforation 
 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase that fulfills one or more of 
the following criteria: 
Results in death 
Is immediately life-threatening 
Requires in-patient hospitalization or prolongation of existing hospitalization  
Results in persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
Is a congenital abnormality or birth defect 
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. 
 
Causality assessment 
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 


24 
 
For SAEs a causal relationship will also be assessed for other concomitant medications, study 
procedures, and comparator study drugs.  Note that for SAEs that could be associated with any 
study procedure the causal relationship is implied as ‘yes’. 
 
Time period for collection of adverse events 
Patients enrolled in the study will be followed until discharge from hospital. Adverse events 
occurring during this period will be recorded and communicated to the principal investigator and 
study team. Any events deemed serious by the principal investigator will be communicated to the 
IRB and Astra Zeneca as required and within 10 days of discovering the event. 
 
Follow-up of unresolved adverse events 
The principal investigator and the study team will follow any unresolved adverse events and 
communicate with the IRB and Astra Zeneca accordingly. 
The following variables will be collected for each AE: 
AE (verbatim) 
The date when the AE started and stopped 
Whether the AE is serious or not 
Investigator causality rating against the Investigational Product (yes or no) 
Action taken with regard to investigational product 
AE caused subject’s withdrawal from study (yes or no) 
Outcome of AE(s) 
In addition to the AE variables referenced above, the following variables will be collected for 
SAEs: 
Date AE met seriousness criteria  
Date Investigator became aware of serious AE 
AE is serious due to which criterion 
If hospitalization or prolongation of hospitalization: 
Date of hospitalization 


25 
 
Date of discharge 
If death: 
Probable cause of death 
Date of death 
Autopsy performed (Yes/no) and conclusion of cause of death from autopsy 
Causality assessment in relation to Study procedure(s) 
Causality assessment in relation to Other medication 
 
Description of AE(s) 
An AE of severe intensity need not necessarily be considered serious.  For example, nausea that 
persists for several hours may be considered severe nausea, but not a SAE. On the other hand, a 
stroke that results in only a limited degree of disability may be considered a mild stroke but 
would be a SAE. 
 
Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list 
of signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
 
Adverse Events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated laboratory values and/or vital signs 
should only be reported as AEs if they fulfill any of the SAE criteria or are the reason for 
discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information.  Wherever possible the reporting investigator uses the 
clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 


26 
 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE. 
 
Disease progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. Events, 
which are unequivocally due to disease progression, should not be reported as an AE during the 
study. 
 
Overdose 
Overdose in itself is not considered to be an AE or SAE.   
Investigator/site staff are responsible for recording and reporting overdose in accordance with the 
clinical study protocol instructions. All overdoses with AstraZeneca product are collected and 
reported to AstraZeneca.  Overdoses associated with SAEs will be reported according to SAE 
reporting.  All other overdoses can be sent to AstraZeneca on a monthly basis.  
The following information should be provided in the event of an Overdose (Overdose Report 
Form can be provided upon request):  
Details of the Patient who was dispensed study medication (Randomization code) 
Details of the Patient who took the overdose (demographic information, was patient a study 
participant?) 
Details of the drug overdose (total daily dose, route, formulation, Overdose start and stop dates) 
Was the overdose accidental or intentional?  
Was the overdose associated with an adverse event (serious or non-serious) 
Provide an Adverse Event description (use same wording as in CRF). Provide start and stop 
dates of the event, or indicate if the event is ongoing. 
Provide Investigator’s signature and date. 
 


27 
 
Pregnancy 
Pregnancy in itself is not considered to be an AE or SAE. However, if the subjects become 
pregnant during the study, Investigator/site staff are responsible for recording and reporting 
pregnancies and their pregnancy outcomes until pregnancy resolution in accordance with the 
clinical study protocol instructions. 
If a patient becomes pregnant during the course of the study the study medication should be 
discontinued immediately. The investigator must inform AstraZeneca of any pregnancies 
occurring in a female patient or a female partner of a male patient within 24 hours of when he or 
she becomes aware of it. 
 
Maternal exposure 
All reports of pregnancy with an AstraZeneca product (that is, those with or without associated 
SAE, AE or no symptoms) are collected and reported to AstraZeneca.  If the pregnancy is 
accompanied by an SAEs (e.g. events of congenital abnormality/birth defect, spontaneous 
miscarriage or ectopic pregnancy, or any complications in the subject which meet the criteria for 
a serious adverse event), it should be reported according to the SAE reporting requirement.   All 
other maternal exposure reports can be sent to AstraZeneca on a monthly basis.  
Normal births and elective abortions without complications are not considered to be SAEs. 
 
Paternal exposure  
If paternal exposure pregnancy occurs in the course of the study, then the Sponsor/Investigators 
should inform AstraZeneca within the same timeframe as the maternal exposure.  The female 
partner of the patient will be asked to consent to allow collection of information and follow-up 
on the pregnancy.  The outcome of the pregnancy is also followed and reported in accordance 
with the processes written in maternal exposure section. 
 
Reporting of serious adverse events  
Investigators and other site personnel must inform the FDA, via a MedWatch/AdEERs form, of 
any serious or unexpected adverse events that occur in accordance with the reporting obligations 
of 21 CFR 312.32, and will concurrently forward all such reports to AZ.  A copy of the 
MedWatch/AdEERs report must be faxed or email to AstraZeneca at the time the event is 
reported to the FDA.  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 


28 
 
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 to AstraZeneca by email to AE Mailbox Clinical 
Trial (TCS) <AEMailboxClinicalTrialTCS@astrazeneca.com> or by fax to 1-302-886-4114 (US 
Fax number). 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 on a 
monthly 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. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to the 
investigational product.  All SAEs will be documented in the study database.  The investigator is 
responsible for informing the IRB and/or the Regulatory Authority of the SAE as per local 
requirements. 
 
5. Ethical and regulatory requirements 
A regulatory binder will be kept at the Department of Outcomes Research including the following: 
 Delegation log: names and responsibilities of all study team members 
 Copy of the most recent study protocol 
 Copy of the most recent consent form 


29 
 
 Copy of the most recent case report form 
 Copies of any relevant communications with the IRB, sponsor, DSMB, pharmacy, or other 
entities 
 Audit reports 
The study site pharmacy will be responsible for the storage and control of study drug and placebo 
doses. Adequate records of receipt and dispensing of study drug will be kept and will be available 
for inspection if required. Any expired or unused drug will be disposed of as per an agreement 
with the sponsor. 
An independent data safety and monitoring board (DSMB) will be formed and will consist of at 
least 2 anesthesiologists and 1 statistician not included in the study team. The DSMB will review 
study data at the time of the blinded data quality check (Section H) and as required throughout the 
study. The DSMB can request unblinding of study data and has the authority to terminate the study 
if significant harm to study patients is suspected. 
The study will be conducted preserving the privacy and rights of all patients to the best of the study 
team’s ability. Protected health information will not be shared outside of the entities described in 
the consent form. All study-related information will be kept at the Department of Outcomes 
Research in compliance of existing rules. 
 
6. Study Drug handling 
Identity of investigational product(s) 
Naloxegol 25mg tablets and matching placebo will be used in the study.  This material will be 
supplied by AstraZeneca in unlabeled HDPE bottles containing 18 tablets per bottle.  Labels will 
be prepared at the study site according to Good Manufacturing Practice (GMP) and local 
regulatory guidelines. Labels will fulfill GMP Annex 13 requirements for labels. 
Storage 
Naloxegol will be stored in a secure location under appropriate storage conditions.  All study drug 
will be stored in original containers until dispensed to study subjects. Naloxegol and matching 


30 
 
placebo must be stored at controlled room temperature between 20-25°C (68-77°F).  Storage 
temperature must be monitored and temperature excursions reported to AstraZeneca. 
Accountability 
The PI and the study staff are responsible for maintaining accountability records for all study drugs 
according to local regulatory requirements.  Unused and expired study drugs will be disposed of 
in accordance with sponsor regulations. Copies of the study medication accountability records will 
be retained at completion of the study and will be made available for review in the event of an 
inspection or audit. 
 


31 
 
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34 
 
Appendix 
 
 
 
Opioid-Related Symptom Distress Scale (ORSDS) [53] 
 
 
 
 
 
 
 
 
 
 


35 
 
Quality of Recovery Scale 
QoR-15 (Development and Psychometric Evaluation of a Postoperative Quality of Recovery 
Score[32]