Conditions: Constipation
Keywords: Cancer Constipation Opioid
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 7
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the effect of naloxegol versus the patient's usual care in treating opioid-induced constipation, as well as the effect on the patient's quality of life and how much pain is experienced. Also, the purpose of this study is to compare whether treatment with naloxegol versus usual care has any impact on the number of hospital or clinic visits or telephone calls to the patient's physician that are related to constipation, and to determine the patient's preference for continuing to receive naloxegol as treatment for opioid-induced constipation.

Detailed description:
Opioid-induced constipation (OIC) is a common symptom in patients with cancer-related pain and requires burdensome self-titration of laxatives for prophylaxis and treatment. Consequently, naloxegol may have an important role in this setting. Naloxegol has been evaluated in relieving OIC with cancer patients in a randomized, double blind, placebo-controlled trial over 4 weeks with a 12-week extension phase. However, accrual was challenging and the trial was closed early. Given the complexity of cancer and its treatment, a key first step is to determine if evaluating naloxegol versus standard of care is feasible in the management of OIC in this setting.

Subjects will receive naloxegol 25mg daily or usual care for a 2-week initial treatment period followed by 3-day washout period, then a 2-week crossover treatment period where subjects will receive naloxegol or usual care. Treatment assignment during the initial and crossover treatment periods will be dictated by the randomization arm. Subjects will also have the option to participate in a 12-week extension phase of naloxegol.

Arms:
arm 1: Patients in Arm A will receive a single daily dose of 25mg naloxegol for the 2-week initial treatment period, followed by a 3-day washout period and 2-week crossover treatment period in which the patient will receive the treating physician's usual care for OIC using a stimulant laxative + rescue medication. arm 2: Patients in Arm B will receive the treating physician's usual care for OIC using a stimulant laxative + rescue medication for the 2-week initial treatment period, followed by a 3-day washout period and 2-week crossover period in which the patient will receive a single daily dose of 25mg naloxegol.

Interventions: intervention 1: naloxegol
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version 3.0 
 
 
 
 
 
Page 1 of 65 
Protocol Date 07/07/2016 
 
 
 
 
 
A Phase II, Randomized, Single Center, Pilot Feasibility Study to Evaluate Naloxegol  
for Opioid-Induced Constipation in Cancer Patients 
 
 
Principal Investigator 
Eric Roeland, MD 
Assistant Clinical Professor 
Department of Medicine 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: 858-534-3361 
Fax: 858-822-5380 
E-mail:  eroeland@ucsd.edu 
 
 
 
Study Agent:  
Naloxegol, MOVANTIKTM   
 
 
 
 
 
Initial Version  
03/10/2016 
Amendment 1  
04/18/2016 
Amendment 2  
07/07/2016 
 
LIST OF INVESTIGATORS 
 
 
PRINCIPAL INVESTIGATOR 
Eric Roeland, MD 
University of California, San Diego 
Moores Cancer Center  
3855 Health Sciences Drive #0987 
La Jolla, CA 92093-0987 
Ph: 858-534-3361 
F: 858-822-5380 
eroeland@ucsd.edu 
 
 


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Protocol Date 07/07/2016 
CO-INVESTIGATOR(S) 
Arlene Cramer, NP 
Department of Medical Center 
Moores Cancer Center  
3855 Health Sciences Drive #0658 
La Jolla, CA 92093-0658 
acramer@ucsd.edu 
 
Joseph Ma, PharmD 
Skaggs School of Pharmacy & Pharmaceutical Sciences 
University of California, San Diego 
9500 Gilman Drive #0714 
La Jolla, CA 92093-0714 
Ph: 858-822-3485 
F: 858-822-6857  
jdma@ucsd.edu 
 
 
BIOSTATISTICIAN 
James Proudfoot, M.Sc.  
Clinical and Translational Research Institute (CTRI) 
University of California, San Diego  
9500 Gillman Drive #0990  
La Jolla, CA 92093-0990  
jproudfoot@ucsd.edu 
 
Acknowledgements: 
The CTRI is partially supported by the National Institutes of Health, Grant UL1TR001442 of 
CTSA funding. 
 
 


Protocol Version 3.0 
 
 
 
 
 
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Protocol Date 07/07/2016 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
UCSD Principal Investigator 
 
 
_____________________________ 
Printed Name 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 


Protocol Version 3.0 
 
 
 
 
 
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Protocol Date 07/07/2016 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS.......................................................................................................................... 7 
STUDY SCHEMA ......................................................................................................................................... 8 
STUDY SUMMARY ...................................................................................................................................... 9 
1.0 
BACKGROUND AND RATIONALE ........................................................................................... 14 
1.1 
Disease Background ................................................................................................................ 14 
1.2 
Study Agent(s) ......................................................................................................................... 15 
1.3 
Other Agents ............................................................................................................................ 16 
1.4  
Rationale .................................................................................................................................. 16 
2.0 
STUDY OBJECTIVES ................................................................................................................ 17 
2.1 
Primary Objective ..................................................................................................................... 17 
2.2 
Secondary Objectives .............................................................................................................. 17 
2.3 
Exploratory Objectives ............................................................................................................. 17 
2.4 
Endpoints ................................................................................................................................. 17 
3.0 
PATIENT ELIGIBILITY ............................................................................................................... 18 
3.1 
Inclusion Criteria ...................................................................................................................... 18 
3.2  
Exclusion Criteria ..................................................................................................................... 18 
4.0 
TREATMENT PLAN ................................................................................................................... 19 
4.1 
Study Design ............................................................................................................................ 19 
4.2 
Treatment Administration ......................................................................................................... 22 
4.3 
Pre-Medications ....................................................................................................................... 23 
4.4 
Permitted Concomitant Therapy .............................................................................................. 23 
4.5 
Prohibited Concomitant Therapy ............................................................................................. 23 
4.6 
Adverse Drug Reactions, Dosing Delays/Dose Modifications  ................................................ 24 
4.7 
Duration of Study Treatment .................................................................................................... 26 
4.8 
Duration of Follow Up .............................................................................................................. 26 
4.9 
Discontinuation from Study Participation ................................................................................. 26 
5.0 
STUDY PROCEDURES ............................................................................................................. 26 
5.1 
Definitions of Study Assessments ........................................................................................... 27 
5.1.1  
Medical history 
27 
5.1.2 
Demographics 
27 
5.1.3 
Review subject eligibility criteria 
27 
5.1.4 
OIC confirmation 
27 
5.1.5 
Concomitant medications 
27 
5.1.6 
Physical exam 
27 
5.1.7 
Vital signs and height 
27 
5.1.8 
Performance status 
28 
5.1.9 
Adverse event assessment 
28 
5.1.10 
Hematology 
28 
5.1.11 
Serum chemistries 
28 
5.2 
Screening/Baseline Procedures............................................................................................... 30 
5.3 
Procedures During Initial Treatment and Crossover Treatment Phases ................................. 31 
5.3.1 
Day 1, Day 18 
31 
5.3.2 
Days 2-7, Days 9-14, Days 19-24 and Days 26-31 
31 


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5.3.3 
Day 8, Day 25 
32 
5.4 
Procedures During Optional Extension Phase (up to 12-weeks) ............................................ 32 
5.4.1 
Days 32-116 (Daily) 
32 
5.4.2 
Days 32, 39, 46, 53, 60, 67, 74, 81, 88, 95, 102, 109 (Weekly) 
32 
5.5 
End of Study Visit ..................................................................................................................... 32 
5.6 
Follow-up Procedures .............................................................................................................. 33 
6.0 
MEASUREMENT OF EFFECT ................................................................................................... 33 
6.1 
Safety/Tolerability .................................................................................................................... 33 
6.2 
Feasibility Assessment ............................................................................................................ 33 
6.3 
Efficacy Assessment ................................................................................................................ 33 
6.4 
Quality of Life ........................................................................................................................... 33 
7.0 
ADVERSE EVENTS ................................................................................................................... 33 
7.1 
Adverse Event Monitoring ........................................................................................................ 34 
7.2 
Severity .................................................................................................................................... 34 
7.3 
Seriousness ............................................................................................................................. 34 
7.4 
Relationship ............................................................................................................................. 35 
7.5 
Prior experience ....................................................................................................................... 35 
7.6 
Reporting Requirements for Adverse Events .......................................................................... 35 
7.6.1 
Safety Reporting 
35 
7.6.2 
Routine Reporting Requirements 
37 
8.0 
AGENT INFORMATION ............................................................................................................. 38 
8.1 
Naloxegol ................................................................................................................................. 38 
8.1.1 
Return and Retention of Study Drug 
39 
8.1.2 
Drug Accountability/Subject Compliance 
39 
9.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 39 
9.1 
Study Design/Study Endpoints ................................................................................................ 39 
9.2 
Sample Size and Accrual ......................................................................................................... 40 
9.2.1 
Evaluable Subjects and Subject Replacement 
40 
9.3  
Data Analyses Plans ................................................................................................................ 40 
9.3.1  
Primary Endpoint 
40 
9.3.2  
Safety Endpoint 
41 
9.3.3  
Secondary Endpoints 
41 
9.3.4 
Exploratory Endpoints 
41 
10.0 
STUDY MANAGEMENT ............................................................................................................. 42 
10.1 
Conflict of Interest .................................................................................................................... 42 
10.2 
IRB Approval and Consent ...................................................................................................... 42 
10.3 
Registration and Randomization Procedures .......................................................................... 42 
10.4 
Data Collection and Management ........................................................................................... 43 
10.5 
Subject Data Protection ........................................................................................................... 43 
10.6 
Data and Safety Monitoring/Auditing ....................................................................................... 43 
10.7 
Adherence to the Protocol ....................................................................................................... 44 
10.7.1 
Emergency Modifications 
44 
10.7.2 
Protocol Violations 
44 
10.8 
Amendments to the Protocol.................................................................................................... 44 
10.9  
Record Retention ..................................................................................................................... 44 


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10.10 Obligations of Investigators ...................................................................................................... 45 
11.0 
REFERENCES ........................................................................................................................... 46 
12.0 
APPENDICES ............................................................................................................................. 47 
Appendix A. ECOG Performance Status Scale ................................................................................... 47 
Appendix B. Strong and Moderate CYP3A4 and/or P-glycoprotein Inhibitors ..................................... 48 
Appendix C. Strong CYP3A4 and P-glycoprotein Inducers ................................................................. 49 
Appendix D.  Patient Study Drug Diary ................................................................................................ 50 
Appendix E.  Patient Medication Use Diary ......................................................................................... 56 
Appendix F.  Patient Bowel Movement Diary ....................................................................................... 57 
Appendix G.  Bristol Stool Scale (BSS)2 .............................................................................................. 58 
Appendix H.  Patient Assessment of Constipation Symptoms (PAC-SYM)15 ...................................... 59 
Appendix I.  Patient Assessment of Constipation Quality of Life (PAC-QOL)5 .................................... 60 
Appendix J.  Brief Pain Inventory-Short Form (BPI-sf)6 ....................................................................... 63 
Appendix K.  Equianlagesic Dosing Guidelines for Chronic Pain ........................................................ 65 
 
 
 


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LIST OF ABBREVIATIONS 
 
AdEERS 
Adverse Event Expedited Reporting System 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BPI-sf 
Brief Pain Inventory-Short Form 
BSS 
Bristol Stool Scale 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
Cytochrome P450 3A4 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDPE 
High-Density Polyethylene Bottles 
HIPAA 
Health Insurance Portability and Accountability Act 
HRPP 
Human Research Protections Program 
ICH 
International Conference on Harmonization 
IDS 
Investigational Drug Services 
IRB 
Institutional Review Board 
ISS 
Investigator-Sponsored Study 
MedDRA 
Medical Dictionary for Medical Activities 
NCI 
National Cancer Institute 
NOEL 
No Adverse Effect Level 
OIC 
Opioid-induced Constipation 
PAC-SYM  Patient Assessment of Constipation Symptoms 
PAC-QOL 
Patient Assessment of Constipation Quality of Life 
P-gp 
P-glycoprotein 
PO. 
Per os/by mouth/orally 
PRN 
Pro re nata/As needed 
SAE 
Serious Adverse Event 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
ULN 
Upper Limit of Normal 
UPR 
Unanticipated Problems involving Risk to subjects or others 
 


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STUDY SCHEMA  
 
 
 
 
 
 
 
  
 


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STUDY SUMMARY 
Title 
A Phase II, Randomized, Single Center, Pilot Feasibility Study to 
Evaluate Naloxegol for Opioid-Induced Constipation in Cancer Patients 
Short Title 
Naloxegol in Cancer Opioid-Induced Constipation 
Phase 
II 
Methodology 
Single-center, randomized, open-label crossover study  
Study Duration 
The anticipated total duration of this study is 1 year. 
Study Center(s) 
University of California, San Diego Moores Cancer Center 
Objectives 
The primary objective of this study is to evaluate the feasibility of 
naloxegol 25mg in the treatment of opioid-induced constipation (OIC) in 
comparison to usual care.   
 
We hypothesize that feasibility, defined as more than 70% of selected 
study subjects completing all study related procedures, will be achieved.   
 
Secondary Objectives include: 
• To determine the effect of naloxegol versus usual care on OIC as 
defined by ≤ 3 bowel movements per week. 
• To evaluate naloxegol versus usual care on stool quality using the 
Bristol Stool Scale (BSS).  
• To evaluate the occurrence of adverse events using the National 
Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  
• To evaluate health related quality of life utilizing the Patient 
Assessment of Constipation Symptoms (PAC-SYM), Patient 
Assessment of Constipation Quality of Life (PAC-QOL).  
• To evaluate changes in patient-reported pain using the Brief Pain 
Inventory Short Form (BPI-sf).  
 
Exploratory Objectives include: 
• To evaluate laxative compliance with weekly pill counts. 
• To evaluate healthcare resource utilization as defined by the number 
of emergency room visits, hospitalizations, telephone encounters, 
and EPIC mychart encounters regarding signs/symptoms associated 
with constipation between the two arms. 
• To determine patient preference to continue naloxegol in the optional 
12-week extension. 
Number of Subjects 
60 
Diagnosis and Main 
Inclusion Criteria 
Patient with a histologically confirmed cancer diagnosis and documented, 
confirmed OIC defined as ≤3 bowel movements and/or Bristol Stool Scale 
(BSS) rated 1-2 in more than 25% of defecations 1 over a 1-week OIC 
confirmation period at any time during screening and prior to initial 
treatment period Day 1. 
 
Key Inclusion Criteria: 
1. Male or female adults ≥18 years of age. 
2. Eastern Cooperative Oncology Group (ECOG) ≤3. 
3. Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 by 
Modification of Diet in Renal Disease (MDRD) 
4. Corrected serum calcium level ≤10.5 mg/dL. 
5. Estimated life expectancy ≥6 months.  
6. Negative pregnancy test prior to initiating study treatment for 
females of childbearing potential. 
 
 


Protocol Version 3.0 
 
 
 
 
 
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Key Exclusion Criteria 
1. Patients receiving the following medications within 3 days of 
Study Day 1 and/or are planned to receive throughout the 
duration of the study period: opioid antagonist, mixed antagonist, 
a strong CYP3A4 and/or P-glycoprotein (P-gp) inhibitor, a 
moderate CYP3A4 and/or P-gp inhibitor, and/or a strong CYP3A4 
inducer. 
2. Patient currently receiving or planned to receive concurrent total 
parenteral nutrition. 
3. Concurrent use of metoclopramide or use within 24 hours prior to 
study treatment (given elimination t½ 6 hours).  
4. Patients at high risk for bowel perforation. 
5. Constipation that was not primarily caused by opioids in the 
investigator’s medical opinion. 
6. A condition that may have affected the permeability of the blood-
brain barrier (e.g., known brain metastases, meningeal 
metastases, brain injury, multiple sclerosis, recent brain injury, 
uncontrolled epilepsy) 
7. Patient has clinically active diverticular disease. 
8. Past medical history of irritable bowel syndrome, signs of active 
gastrointestinal (GI) bleeding, acute surgical abdomen, bowel 
stents, indwelling peritoneal catheter, mechanical GI obstruction, 
fecal impaction, or fecal ostomy.   
9. Patient has motility/neurologic disorders including autonomic 
failure (spinal cord lesions, tumor invasion of nerves) and/or 
poorly controlled endocrine/metabolic disorders (hypercalcemia, 
hypokalemia, diabetes, hypothyroidism), as determined by the 
investigator. 
10. Uncontrolled cancer pain despite analgesic therapy 
11. Pregnant or lactating female; men planning to father a child or 
women planning a pregnancy while taking study drug or within 28 
days after the last dose of study drug  
 
Study Product(s), Dose, 
Route, Regimen 
Naloxegol (MOVANTIKTM) is a round, bi-convex, white film-coated tablet.   
Subjects will receive 25 mg of naloxegol once daily, as an oral tablet 
(PO).  Subjects will take naloxegol one hour before eating in the morning. 
Duration of 
administration 
Subjects will receive naloxegol or usual care for a 2-week initial treatment 
period followed by 3-day washout period, then a 2-week crossover 
treatment period where subjects will receive naloxegol or usual care.  
Treatment assignment during the initial and crossover treatment periods 
will be dictated by the randomization arm.  Subjects will also have the 
option to participate in a 12-week extension phase of naloxegol. 
Reference therapy 
Usual care in the palliative care clinic: stimulant laxative prophylaxis (up 
to 8 tablets/day of senna or up to 30mg/day of bisacodyl) and/or 
constipation treatment (osmotic laxative such as polyethylene glycol plus 
stimulant laxative). 
Statistical Methodology 
The primary aim of this study is feasibility - specifically, feasibility will be 
defined as completion of all study drugs over 4 weeks.  For the primary 
aim we believe an acceptable completion rate would be at least 70%. 
Assuming a true completion rate of 85% (HA), a sample size of 50 
patients would have an 80% power to show that the true rate is at least 
70% (H0), using a one-sided binomial exact test with ɑ=0.05.  Any dropout 
after the initatiion of study treatment will be categorized as non-
completion of study drugs. Thus we plan to recuit until 50 subjects have 
begun study treatment. 
 


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Protocol Date 07/07/2016 
Safety endpoints will be evaluated by monitoring adverse events adverse 
events from clinical and laboratory reporting, using the NCI-CTCAE. 
Trends in the distribution and severity of adverse events across the study 
groups will be assessed by examining the count of total adverse events 
and count of adverse events at each severity level over the course of the 
2 weeks for the initial treatment and over the 2 weeks of the crossover 
treatment phases of the study.  
 
Secondary outcome measures are the effect of naloxegol versus usual 
care on; bowel movements per week, stool quality using the BSS,2 
occurrence and grade of adverse events using the NCI CTCAE version 
4.03,3 health related quality of life utilizing the PAC-SYM4 & PAC-QOL,5 
and changes in patient reported pain using the Brief Pain Inventory.6  For 
variables in the secondary aim, we plan to use generalized linear mixed  
effects models (GLM) to determine the impact of naloxegol on each 
endpoint over the course of 2 weeks for the initial treatment and 
crossover treatment phases of the study, achieved by treating the 
crossover arm as a time-dependent covariate.  Within the GLM model; 
count of bowel movements per week will be assessed using a Poisson 
model. Stool quality (BSS, 7 point Likert-type scale), PAC-SYM (5 point 
Likert-scale), and PAC-QoL (5 point Likert-scale) will be assessed using 
an ordinal logistic model. The two parts of the BPI-sf (Intensity of pain 
and inference of pain) are calculated as the mean of several questions; 
as such they will be assessed as a continuous outcome with possible 
transformation for skewness if necessary.  To control for the multiple 
comparisons a Bonferroni-Holm (e.g. Stepwise Bonferroni) method will be 
applied to the combined secondary and exploratory analyses, using an 
omnibus α = 0.05. 
Exploratory aims include laxative compliance (weekly pill counts), 
healthcare resource utilization (per electronic medical record evaluation 
of emergency room visits, hospitalizations, telephone encounters, and 
Mychart encounters), and patient preference (as evidenced by patient 
desire to continue naloxegol optional 12-week extension).   
 
For analysis of differences in weekly pill counts between naloxegol and 
usual care, we plan to use a generalized linear mixed effects model  to 
determine the impact of naloxegol on weekly pill counts, over the course 
of 2 weeks for the initial treatment and crossover treatment phases of the 
study, achieved by treating the arms as a time-dependent covariate. 
Within this model the weekly pill counts will be assessed using a Poisson 
model.  Count of healthcare utilization resource, will be the sum of total 
utilizations (summed separately for each of the two weeks for initial 
treatment and cross over phase). Differences in healthcare utilization 
between the arms will be determined by fitting a Poisson regression 
model (or negative binomial in the case of over dispersion) of treatment 
arm on bi-weekly utilization count.  We will examine patient preference by 
calculating a 95% confidence interval for the proportion of patients who 
wish to continue the optional 12-week extension. 


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SCHEDULE OF EVENTS 
 
 
 
Screening 
(<21 days) 
Initial Treatment Period 
(2 weeks) 
 
Washout 
Period 
(3 days) 
Crossover Treatment Period 
(2 weeks) 
Optional Extension 
Period 
(up to 12 weeks) 
End of Study 
Visit (28d + 7d 
from last study 
treatment) 
Day 1 
(+/- 3) 
Days 
2-7 
(+/- 3) 
Day 8 
(+/- 3) 
Days 
9-14 
(+/- 3) 
Days 15-
17 
Day 
18 
(+/- 3) 
Days 
19-24 
(+/- 3) 
Day 25 
(+/- 3) 
Days 
26-31 
(+/- 3) 
Days 
32-116 
(+/- 3) 
Weekly 
(Days 32, 
39, 46…109) 
(+/- 3) 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical 
history, including OIC 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Opioid-induced 
constipation 
confirmation1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1:1 randomization1 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
 
 
 
X 
 
 
 
X2 
 
X2 
Vital signs 
X 
X 
 
 
 
 
X 
 
 
 
X2 
 
X2 
Height, weight 
X 
X 
 
 
 
 
X 
 
 
 
X2 
 
X2 
Eastern Cooperative 
Oncology Group 
(ECOG) 
Performance status 
X 
X 
 
 
 
 
X 
 
 
 
X2 
 
X2 
Concomitant 
medications3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serious Adverse 
Events with AEs9  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy test (if 
applicable)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete blood 
count (differential, 
platelets) 
X 
X 
 
 
 
 
X 
 
 
 
X2 
 
X2 
Comprehensive 
metabolic panel 
X 
X 
 
 
 
 
X 
 
 
 
X2 
 
X2 
Study drug 
dispensing 
 
X 
 
 
 
 
X 
 
 
 
X6 
 
 
Study drug 
 
 
 
 
X 
 
 
 
X6 
 
X 


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Screening 
(<21 days) 
Initial Treatment Period 
(2 weeks) 
 
Washout 
Period 
(3 days) 
Crossover Treatment Period 
(2 weeks) 
Optional Extension 
Period 
(up to 12 weeks) 
End of Study 
Visit (28d + 7d 
from last study 
treatment) 
Day 1 
(+/- 3) 
Days 
2-7 
(+/- 3) 
Day 8 
(+/- 3) 
Days 
9-14 
(+/- 3) 
Days 15-
17 
Day 
18 
(+/- 3) 
Days 
19-24 
(+/- 3) 
Day 25 
(+/- 3) 
Days 
26-31 
(+/- 3) 
Days 
32-116 
(+/- 3) 
Weekly 
(Days 32, 
39, 46…109) 
(+/- 3) 
 
accountability 
Patient study drug 
diary 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X6 
 
 
Pill count7 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Patient Assessment 
of Constipation 
Symptoms (PAC-
SYM) 
X5 
X 
 
X 
 
 
X 
 
X 
 
 
X8 
X 
Patient Assessment 
of Constipation 
Quality of Life (PAC-
QOL) 
X5 
X 
 
 
 
 
X 
 
 
 
 
X8 
X 
Brief Pain Inventory 
Short Form (BPI-sf) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X8 
X 
Bristol Stool Scale 
(BSS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Patient medication 
use diary3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Patient bowel 
movement diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
1. Randomization will occur within 3 days of initial treatment day.  Prior to randomization, patients will be asked to confirm whether they have experienced OIC during the past week (See Section 
5.1.4 for definition).  
2. During the optional extension period, physical exam, ECOG performance status, vital signs, height and weight, and laboratory tests will be performed once at the beginning of the treatment period 
(Day 32).  Thereafter, these procedures will be performed according to routine frequency for the participant’s oncology care.  If these procedures are performed as part of routine oncology care, 
results will be collected for the study.  At the end of study visit, if these procedures are performed as part of participant’s routine oncology care, results will be collected for the study 
3. To include a record of opioid medication use, over-the-counter analgesic medication use, rescue laxative use, and all other over-the-counter prn medications.   
4. Females of childbearing potential only; to be performed within 72 hours of initial treatment day. 
5. To be completed up to 2 weeks prior to initial treatment day 
6. Patients will be dispensed a 28-day supply of naloxegol at a time during the optional extension phase.  During the extension phase, patients will be asked to return to clinic for a new supply of 
naloxegol, return of any unused naloxegol, review of the previous month’s study drug diary, and pill count on Days 32, 60 and 88 of the extension period 
7. The study coordinator will perform weekly reminder calls to the participant to review requirements for completing patient questionnaires and diaries and to perform pill counts if no in-person visit 
has occurred with the patient during a previous week. 
8. To be completed every 28 days during the optional extension period at the time of study drug supply refill.  
9. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.3 will be used to assess, monitor , and grade AEs.


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
 
Opioid-Induced Constipation 
Despite being a very effective therapy in the treatment of cancer pain, opioids cause several 
undesired side effects.  The most common of these side effects is opioid-induced constipation 
(OIC) in 40-90% of patients taking opioids.7  OIC results from the binding of opioid agonists to μ-
opioid (pronounced “mu”) receptors located in the enteric nervous system, which leads to 
increased non-propulsive contracts and inhibition of water and electrolyte secretion.  Opioids 
also delay gastric emptying, increase pyloric tone, delay transit throughout the small and large 
intestines, increase resting anal sphincter pressure, and decrease secretion of electrolytes and 
water into the intestinal lumen.8  OIC can cause intense abdominal pain, nausea, and vomiting 
and, if untreated, can result in emergency department evaluation and even hospitalization.9  
Consequently, once a patient has experienced OIC, adherence to opioids decreases with 
subsequent influences on quality of life. 
 
Constipation is defined as difficult defecation with reduced number of bowel movements 
experienced outside the normal elimination patterns of an individual.  A proper constipation 
history includes more than simply asking when a patient’s last bowel movement occurred. The 
clinician needs to inquire regarding changes from the patient’s normal stool pattern and 
characteristics of the stool over time.  Although opioids are a very common cause of 
constipation, a thorough history should include information regarding other potential causes of 
constipation including: altered diet (dehydration, decreased oral intake), decreased physical 
activity, medications (5-HT3 receptor antagonists, calcium or aluminum-containing antacids, 
calcium channel blockers, anticholinergics, iron, and select chemotherapeutic agents), 
mechanical obstruction (intrinsic or extrinsic compression by masses), motility/neurologic 
disorders (autonomic failure, spinal cord lesions, tumor invasion of nerves), endocrine/metabolic 
disorders (hypercalcemia, hypokalemia, hypothyroidism).10   
 
Opioid-Induced Constipation Treatment 
Treatment of OIC includes both prophylaxis and therapeutic treatment.  Since opioids have the 
unintended consequence of slowing bowel motility, prophylaxis should begin at the initiation of 
an opioid regimen. Constipation prophylaxis can be approached in a stepwise additive fashion 
with stimulant laxatives such as senna (1-8 tabs/day) and bisacodyl (maximum 30 mg/day) as 
the agents of choice.  However, patients must titrate these stimulant laxatives based on diet, 
exercise, fluid intake, and concomitant medication use.  Consequently, titrating stimulant 
laxatives can result in under or overtreatment and be quite burdensome to patients. 
 
Ideally, OIC is prevented, but when it does occur in spite of prophylaxis, it can be effectively 
treated with the addition of other classes of laxatives (e.g. osmotics, softners).  However, the 
most specific drug class to specifically reverse OIC is the peripherally acting μ-opioid 
antagonists.  For example, methylnaltrexone (Relistor®) is a subcutaneous injection and 
treatment of OIC in patients with advanced medical illness11 and alvimopan (Entereg®) has 
restricted approval for shortening the course of postoperative ileus.12  Naloxegol (Movantik®), 
the most recently approved oral, peripherally acting, pegylated derivative of the μ-opioid 
receptor antagonist naloxone, has been evaluated in non-cancer pain and shown to reduce 
constipation without reducing opioid-mediated analgesia.13  With 25mg of oral naloxegol versus 
placebo subjects experienced an approximate 15% improvement in response rate (defined as at 
least 3 spontaneous bowel movements per week and at least one spontaneous bowel 
movement per week increase over baseline for at least 9 out of the 12 treatment weeks and 3 


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out of the last 4 treatment weeks during the double-blind treatment period.13  
 
Opioid-Induced Constipation Management by UCSD Palliative Care Team 
Given the vast majority of the patients evaluated by the UCSD Moores Cancer Center Palliative 
Care service have cancer-related pain and are taking opioids, we systematically educate our 
patients about the role of stimulant laxatives (i.e. up to 8 tablets/day of senna or up to 30mg/day 
of bisacodyl) in the prophylaxis of OIC.  For treatment of OIC in spite of stimulant laxative 
optimization, we generally recommend the addition of an osmotic laxative such as polyethylene 
glycol.  Suppositories and enemas are usually avoided given many of our cancer patients are 
receiving chemotherapy.  In general, the rectal route is avoided in cancer patients at risk for 
neutropenia given theoretical concerns of bacterial translocation.   
 
In review of our outpatient cancer patients over a two-month period (February to March 2015), 
there were 218 outpatient palliative care encounters at the Moores Cancer Center.  Of these 
encounters, 103 were unique patients with 68 new consults.  All patients routinely completed a 
standardized Likert scale rating 11 symptoms, including constipation.  Cancer types included 
breast, GI, genitourinary, gynecologic, hematologic, head and neck, neurologic, sarcoma, and 
thoracic cancers.  The median patient reported constipation score was 4.2 (0-10) with a median 
follow up of 27 days.  On average, patients reported a 17% decrease in constipation on a Likert 
scale by the first follow-up visit with usual care.  By the second follow-up visit, there was a 
reduction in constipation of 30%.  Overall, patients tolerate the scheduled stimulant laxatives 
with or without the osmotic laxative well.  However, the major complaint of patients in the 
management of OIC is the need to constantly titrate their stimulant laxative based on diet, water 
intake, chemotherapy, opioid-use, and medication side effect (e.g. 5HT3 antagonists). 
 
1.2 
Study Agent(s) 
 
For a detailed description of pre-clinical findings regarding naloxegol, please refer to the 
Investigator Brochure.  In brief, the mechanism of action of naloxegol has been characterized 
via in vitro binding assays.  Naloxegol binds to μ-, δ- and κ-opioid receptors and was shown to 
be a full and competitive antagonist at human μ-opioid receptors, with no significant agonist 
efficacy.  In vitro data indicate that naloxegol is a substrate for CYP3A4 and the P-gp 
transporter, and that CYP3A is the major CYP enzyme responsible for the metabolism of 
naloxegol.  Naloxegol is also a substrate of the P-gp transporter, which plays a role in limiting 
central nervous system access of naloxegol.  Safety pharmacology studies have examined 
potential effects on the central nervous, cardiovascular, GI, respiratory, and renal systems.  
According to the Investigator Brochure, no safety concerns for naloxegol were identified in such 
studies regarding central nervous, respiratory, or renal system functions.  Effects on the GI 
system were evaluated by measuring effects on gastric emptying and small intestinal transport 
in conscious rats.  Exposures at no adverse effect level (NOELs) were 15x and 112x the human 
exposure, respectively. Given the high exposures at which they occurred, these effects were 
considered not likely to be related to the primary pharmacology of the compound.  Effects on the 
cardiovascular system were assessed using conscious dog telemetry.  No drug related changes 
in cardiovascular parameters were observed at systemic exposure comparable to human 
exposures at the recommended human dose.  Naloxegol poses no genotoxic risk to humans 
based on the genotoxicity studies and was not carcinogenic in the mouse.   
  
Clinical effects of naloxegol have been studied in Phase I, Phase II and Phase III trials.  In a  
Phase IIb study in patients with OIC, mean naloxegol Cmax and AUC0-24 were similar between 
Day 1 and Day 28, with 70.6 ng/mL vs. 81.1 ng/mL for Cmax, and 328 vs. 335 ng·h/mL for AUC0-
24, respectively, following oral 25 mg once daily. The mean exposure values were comparable to 


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those observed in healthy volunteers.  Mean Tmax was less than 1.7 hours across dose groups 
and dosing days, indicating naloxegol was rapidly absorbed. Mean terminal half-life values were 
similar across dose levels (5 to 50 mg), ranging from 14.1 to 20.3 hours.  The primary route of 
naloxegol elimination is via hepatic metabolism, with renal excretion playing a minimal role.  
Naloxegol is a sensitive substrate of CYP3A4 enzyme and a substrate of P-gp transporter, and 
CYP3A4 is the major CYP enzyme responsible for the metabolism of naloxegol.  Concomitant 
use with dual P-gp or strong CYP3A4 inhibitors, or moderate CYP3A4 inhibitors, significantly 
increases naloxegol plasma concentrations (Appendices B and C). Conversely, concomitant 
use with a strong CYP3A4 inducer results in decreased plasma concentration. 
 
Two multi-center, placebo-controlled 12-week, intent-to-treat, Phase III studies have been 
completed to evaluate naloxegol efficacy in the treatment of OIC.  The primary endpoint in both 
studies was the proportion of patients who showed a pre-specified response, defined as at least 
3 spontaneous bowel movements per week and at least a 1 spontaneous bowel movements per 
week increase over baseline for at least 9 out of the 12 treatment weeks and 3 out of the last 4 
treatment weeks during the double-blind treatment period.  Symptom ratings for straining, stool 
consistency, and complete bowel movements were consistent with improvements in 
spontaneous bowel movement frequency and latency.  In both studies, for the naloxegol 25 mg 
group compared with placebo, the primary and all key secondary endpoints achieved statistical 
significance with p<0.025 in each case.  Compared to placebo, naloxegol 25 mg/day had a 
higher percentage of patients responding (40-44% vs. 29%), shorter median time to first post-
dose spontaneous bowel movement (6-12 vs. 36-37), and greater improvement in OIC 
symptoms.  In terms of safety data from these Phase III studies, the incidence of severe 
adverse events (SAEs) was similar across treatment groups. Pneumonia was the most 
frequently reported SAE overall, with no notable imbalance in frequency across treatment 
groups. 
 
1.3 
Other Agents 
 
Usual Care 
Usual care at the UCSD Moores Cancer Center palliative care clinic includes the use of 
stimulant laxative prophylaxis (up to 8 tablets/day of senna or up to 30mg/day of bisacodyl) 
and/or constipation treatment (primarily osmotic laxatives such as polyethylene glycol plus 
stimulant laxatives).  Stimulant laxatives (senna or bisacodyl) are used daily regardless of bowel 
movement as prophylaxis of OIC.  If OIC occurs despite optimal dosing of stimulant laxative, 
then a standard dose of polyethylene glycol (17 grams per day) is used for treatment of OIC 
until it resolves. 
 
1.4  
Rationale 
 
OIC is a common symptom in patients with cancer-related pain and requires burdensome self-
titration of laxatives for prophylaxis and treatment.  Consequently, naloxegol may have an 
important role in this setting.  Naloxegol has been evaluated in relieving OIC with cancer 
patients in a randomized, double blind, placebo-controlled trial over 4 weeks with a 12-week 
extension phase.  However, accrual was challenging and the trial was closed early.14  Given the 
complexity of cancer and its treatment, a key first step is to determine if evaluating naloxegol 
versus standard of care is feasible in the management of OIC in this setting.   
 
 


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2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
   
To evaluate the feasibility of naloxegol 25mg in the treatment of OIC in comparison to usual 
care. 
 
We hypothesize that feasibility, defined as more than 70% of selected study subjects completing 
all study related procedures, will be achieved.  
 
2.2 
Secondary Objectives  
 
1. To determine the frequency of naloxegol versus usual care on OIC as defined by ≤ 3 
bowel movements per week. 
2. To evaluate naloxegol versus usual care on stool quality using the Bristol Stool Scale 
(BSS).2 
3. To describe the adverse events associated with naloxegol when administered daily 
in this patient population and to compare the adverse evnets associate with 
Naloxegol with adverse events obsereved with usual care , using the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.03.3 
4. To evaluate health related quality of life utilizing the Patient Assessment of 
Constipation Symptoms (PAC-SYM)4 and Patient Assessment of Constipation 
Quality of Life (PAC-QOL).5 
5. To evaluate changes in patient reported pain using the Brief Pain Inventory-Short 
Form (BPI-sf).6 
 
2.3 
Exploratory Objectives 
 
1. To evaluate laxative compliance with weekly pill counts. 
2. To evaluate healthcare resource utilization as defined by the number of emergency 
room visits, hospitalizations, telephone encounters, and EPIC mychart encounters 
regarding signs/symptoms associated with constipation between the two arms. 
3. To determine patient preference to continue naloxegol in the optional 12-week 
extension. 
 
2.4 
Endpoints 
 
The primary endpoint on this study is defined as completion of all study drug over the first 4 
weeks of study treatment (initial and crossover treatment phases).   
 
Secondary endpoints include number of bowel movements per week, as captured on the Patient 
bowel movement diary (Appendix F), stool quality as measured by the Bristol Stool Scale 
(Appendix G), safety defined as the rate of drug-related adverse events experienced assessed 
according to the NCI’s CTCAE v4.03 toxicity criteria, and health related quality of life and pain 
measures as assessed by the PAC-SYM, PAC-QOL, and BPI-sf, within the first 4 weeks of 
study treatment (see section 9.3.3).   
 
Exploratory endpoints will include drug administration compliance as measured by weekly pill 
counts by a member of the study team, healthcare resource utilization as defined by the number 
of number of emergency room visits, hospitalizations, telephone encounters, and EPIC mychart 


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encounters related to signs and symptoms of constipation, and patient preference (yes/no) for 
naloxegol to treat OIC as defined by choice of participation in the optional extension phase of 
the study. 
3.0 
PATIENT ELIGIBILITY 
 
3.1 
Inclusion Criteria 
 
Subjects must meet all of the inclusion criteria to participate in this study. 
 
1. Patient has the ability to understand and the willingness to sign a written informed 
consent. 
2. Histologically confirmed cancer diagnosis. 
3. Documented, confirmed OIC defined ≤3 bowel movements and/or Bristol Stool Scale (BSS) 
1-2 (Appendix G) more than 25% of defecations1 per week over a 1-week OIC confirmation 
period at any time during screening and prior to initial treatment period Day 1. 
4. Patient is ≥18 years of age. 
5. Both men and women of all races and ethnic groups are eligible for this trial. 
6. ECOG Performance Status ≤3 (see Appendix A). 
7. Patient has adequate organ function as defined below: 
• The estimated glomerular filtration rate (GFR) greater than or equal to 30 
ml/min/1.73m2 by Modification of Diet in Renal Disease (MDRD) Study equation.  
• Corrected serum calcium ≤10.5 mg/dL 
8. Females of child-bearing potential and men with partners of child-bearing potential must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for 28 days 
following completion of therapy.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 
Female: 
• 
 No child bearing potential, including: 
o  Post-menopaual for at least 12 consecutive months (i.e., has had menses at 
any time in the preceding 12 consecutive months) 
o  Surgically Sterile - undergone a hysterectomy or bilateral oophorectomy 
• 
 With child bearing potential, must have  
o Negative pregnancy test within 72 hours prior to initiating study drug 
dosing 
o  Agree to use barrier contraceptives throughout the study 
 
Male: 
• 
 Surgically sterile 
• 
 Non-sterile: Agree to use barrier contraceptives throughout the study during 
intercourse with a female partner 
9. Patient has an estimated life expectancy ≥6 months in the opinion of the investigator. 
10. Patient is able to swallow and retain oral medication. 
 
3.2  
Exclusion Criteria 
 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 


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1. Patient has received any of the following agents within 3 days prior to Study Day 1 
and/or are planned to receive throughout the duration of the study: opioid antagonist and 
mixed agonist/antagonist (e.g. pentazocine, buprenorphine, nalbuphine, 
naloxone/naloxone combinations, naltrexone/naltrexone combinations, 
methylnaltrexone, alvimopan), a strong CYP3A4 and/or P-gp inhibitor, a moderate 
CYP3A4 and/or P-gp inhibitor, and/or a strong CYP3A4 inducer (see Appendices B 
and C). 
2. Patient currently receiving or planned to receive concurrent total parenteral nutrition. 
3. Patient currently receiving or planned to receive concurrent use of metoclopramide (or other GI 
prokinetic agents which can potentially slow the GI tract motilities) or use within 24 hours 
prior to study treatment (elimination t½ 6 hours).  
4. Patient is at high risk for bowel perforation. 
5. Patient has constipation that was not primarily caused by opioids, as determined by the 
investigator. 
6. Patient has a condition that may have affected the permeability of the blood-brain barrier 
(e.g., known brain metastases, meningeal metastases, brain injury, multiple sclerosis, 
recent brain injury, uncontrolled epilepsy). 
7. Patient has clinically active diverticular disease. 
8. Patient has a history of irritable bowel syndrome, signs of active GI bleeding, acute 
surgical abdomen, bowel stents, indwelling peritoneal catheter, mechanical GI 
obstruction, fecal impaction, or fecal ostomy.   
9. Patient has motility/neurologic disorders including autonomic failure (spinal cord lesions, 
tumor invasion of nerves) and/or poorly controlled endocrine/metabolic disorders 
(hypercalcemia, hypokalemia, diabetes, hypothyroidism), as determined by the 
investigator. 
10. Patient has uncontrolled cancer pain despite analgesic therapy. 
11. Patient has a severe organ impairment or uncontrolled medical disorder that would, in 
the investigator’s opinion, impair the ability to receive study treatment (i.e., uncontrolled 
diabetes, severe acute or chronic renal failure, severe pulmonary disease, severe 
hepatic impairment or active, uncontrolled infection, psychiatric illness/social situations 
that would limit compliance with study requirements). 
 
12. Patient has any other condition that, in the opinion of the investigator, may impact the 
absorption of oral medications. 
13. Patient is pregnant or nursing. There is a potential for congenital abnormalities and for 
this regimen to harm nursing infants. 
 
4.0 
TREATMENT PLAN 
 
4.1 
Study Design 
 
This is a single center, randomized, open-label crossover study.  We anticipate recruitment of 
approximately 60 total study participants at the UCSD Moores Cancer Center.  Study 
participants will be recruited across all oncology disease teams.  Potential participants will be 
identified in weekly palliative care or disease team patient triage meetings.    
 
In order to meet eligibility for participation, a patient must be ≥18 years old, have histologically 
confirmed cancer, an ECOG performance status ≤3, serum creatinine ≤1.5 x institution’s ULN, 
corrected serum calcium level ≤10.5 mg/dL, and life expectancy ≥ 6 months.  Qualifying 
subjects must have documented, confirmed OIC which is defined as ≤3 bowel movements 
and/or Bristol Stool Scale (BSS) 1-2 more than 25% of defecations1 during the preceding week.  


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Patients will be excluded if constipation is not primarily due to treatment with opioids or if they 
have signs or symptoms of a mechanical GI obstruction, fecal impaction, acute surgical 
abdomen, fecal ostomy, indwelling peritoneal catheter, bowel stents, signs of active GI bleeding, 
or are high risk for bowel perforation.  Any patient with a past medical history of irritable bowel 
syndrome, motility/neurologic disorder, poorly controlled endocrine/metabolic disorder, any 
condition that may have affected the permeability of the blood-brain barrier, and/or uncontrolled 
cancer pain despite analgesic therapy will also be excluded from participation.  Finally, in order 
to participate, patients cannot receive concurrent total parenteral nutrition and/or 
metoclopramide, and must discontinue use of the following medications within 3 days of Study 
Day 1: opioid antagonist, mixed antagonist, a strong CYP3A4 and/or P-gp inhibitor, a moderate 
CYP3A4 and/or P-gp inhibitor, and/or a strong CYP3A4 inducer (Appendices B,C).  
 
The primary objective of this study is to evaluate the feasibility of naloxegol 25mg in the 
treatment of OIC in comparison to usual care, defined as completion of all study drug over 4 
weeks, including initial and crossover treatment phases. 
Secondary objectives will seek to determine the effect of naloxegol versus usual care on OIC, to 
evaluate naloxegol versus usual care on stool quality (BSS), to describe the adverse events 
associated with naloxegol when administered daily in this patient population (NCI CTCAE 
v4.03), to evaluate health related quality of life (PAC-SYM and PAC-QOL), and to evaluate 
changes in patient reported pain (BPI-sf).  
 
Exploratory objectives will evaluate laxative compliance, healthcare resource utilization, and 
patient preference to continue naloxegol in the optional 12-week extension period. 
 
Following informed consent, patients will have the following procedures completed to confirm 
eligibility: physical exam with vital signs, height, and weight, ECOG performance status, 
complete blood count, comprehensive metabolic panel, and a serum pregnancy test (women of 
child-bearing potential only).  During this screening period, patients will also complete baseline 
PAC-SYM, PAC-QOL and BPI-sf questionnaires.  To confirm OIC, patients will be asked about 
their frequency of bowel movements in the last week and asked to recall the average BSS that 
they have experienced.  Upon confirmation of all eligibility criteria and within 72 hours of the 
initial dose of study treatment, patients will be randomized in a 1:1 ratio to either Arm A or Arm 
B by block randomization.  Randomization will be performed by CTRI using a randomization 
package in the software R (blockrand)15,16.  The CTRI office will provide the study coordinator 
with prestuffed envelopes numbered 1-62.  In the envelope, a paper will indicate the treatment 
assignment.  One envelope will be assigned to each patient by the study coordinator in order of 
accrual.  The number on the envelope will become the patient number and will be the 
identification number on all study documents.  Individual patient randomization arm must be 
assigned prior to the patient being treated on study.  The study coordinator will contact IDS 
once subject randomization arm has been confirmed.   
 
 


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REGIMEN DESCRIPTION 
Treatment 
Phase 
Arm A 
Arm B 
Schedule 
Cycle 
Length 
 
 
Initial 
Single 25 mg tablet 
 
Route: Orally, on an 
empty stomach 1 hour 
before breakfast or 2 
hours after first meal of 
the day 
 
Usual Care: stimulant 
laxative  (i.e. up to 8 
tablets/day of senna or 
up to 30mg/day of 
bisacodyl) ± osmotic 
laxative (e.g., 
polyethylene glycol) 
Daily, 
Days 1-14 
2 weeks 
(14 days) 
 
 
 
Cross-Over 
Usual Care: stimulant 
laxative ± osmotic 
laxative 
Single 25 mg tablet 
 
Route: Orally, on an 
empty stomach 1 hour 
before breakfast or 2 
hours after first meal of 
the day 
Daily, 
Days 18-31 
2 weeks 
(14 days) 
 
 
 
Extension 
(Optional) 
Single 25 mg tablet 
 
Route: Orally, on an 
empty stomach 1 hour 
before breakfast or 2 
hours after first meal of 
the day 
Single 25 mg tablet 
 
Route: Orally, on an 
empty stomach 1 hour 
before breakfast or 2 
hours after first meal of 
the day 
Daily, 
Days 32-
116 
12 weeks 
(84 days) 
 
 
Wash out: Based on an elimination half-life of 10 hours, a 3-day washout period (50 hours or 5 
half lives, approximately 48 hours) will occur before crossover.   
 
Optional 12-week extension: Patients on Arms A and B will have the option to continue on 
naloxegol at 25 mg daily for an additional 12-week extension phase upon completion of initial 
and crossover treatment phases.   
 
On Study Days 1, 18, 32, patients will undergo physical exam with vital signs and weight, ECOG 
performance status, complete blood count, comprehensive metabolic panel, and will receive a 
new treatment supply.  Pill counts and study drug accountability will also be performed.  
 
During initial and crossover treatment periods, patients will complete daily questionnaires and 
diaries, including the patient study drug diary, patient bowel movement diary, patient medication 
use diary, BSS, and BPI-sf.  Concomitant medications and adverse event data will also be 
collected daily.  All adverse events will be graded according to NCI CTCAE v4.03.  Weekly 
assessments will include patient completion of the PAC-SYM questionnaire.  Bi-weekly 
assessments include patient completion of the PAC-QOL questionnaire.  Pill counts will be 
performed weekly throughout the duration of study, and may be performed via telephone call by 
a member of the study team if no in-person visit has occurred with the patient during a previous 
week. 
 
During the optional extension phase, patients will be asked to return to clinic every 28 days for a 
new supply of naloxegol, return of any unused naloxegol, review of the previous month’s study 
drug diary, pill count and completion of PAC-SYM, PAC-QOL, and BPI-sf.  Concomitant 
medications and adverse event data will continue to be collected daily. 


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Within 28 days after the patient’s final dose of treatment on study, patients will undergo an end-
of-study visit during which a final pill count and study drug accountability will be performed.  
Final PAC-SYM, PAC-QOL, and BPI-sf questionnaires will also be completed.  Adverse event 
information will be collected until 28 days following final dose of study treatment.  
 
4.2 
Treatment Administration 
 
Patients in Arm A will receive a single daily dose of 25mg naloxegol for the 2-week initial 
treatment period, followed by a 3-day washout period and 2-week crossover treatment period in 
which the patient will receive the treating physician’s usual care for OIC using a stimulant 
laxative + rescue medication.    
 
Patients in Arm B will receive the treating physician’s usual care for OIC using a stimulant 
laxative + rescue medication for the 2-week initial treatment period, followed by a 3-day 
washout period and 2-week crossover period in which the patient will receive a single daily dose 
of 25mg naloxegol.  
 
Patients on Arms A and B will have the option to continue on naloxegol at 25 mg daily for an 
additional 12-week extension phase upon completion of initial and crossover treatment phases.  
 
Patients will be instructed to take naloxegol on an empty stomach at least 1 hour prior to the first 
meal of the day or 2 hours after the meal.  Tablets must be swallowed whole, and not crushed 
or chewed by the subject.  Subjects will also be instructed to avoid consumption of grapefruit or 
grapefruit juice as this is a potent inhibitor of the CYP3A4 enzyme.   
 
Patients will also be instructed to complete a daily study drug diary during the treatment phases 
when naloxegol is being administered.  Patients will be asked to bring their completed study 
drug diary with them during each visit for review with a member of the study team.  
 
If the patient misses their daily morning dose of naloxegol and it has been less than 2 hours 
since the missed dose, they will be instructed to take naloxegol as soon as it is remembered on 
the same day.   If it has been more than 2 hours since missing a dose, the patient will be 
instructed to skip the dose for that day not to make up that dose.  If the patient vomits after 
taking a dose, he/she will be instructed not to repeat the dose or attempt to make up that dose. 
 
If a patient takes more than the assigned daily dose of naloxegol, they should be monitored 
closely for evidence of opioid withdrawal symptoms and reversal of central analgesic effects.  In 
cases of known or suspected overdose, symptomatic treatment as well as monitoring of vital 
functions should be performed.  In cases of severe intoxication, intensive care procedures are 
recommended. Close medical supervision and monitoring should be  continued until the patient 
recovers.   
 
Any adverse events or serious adverse events resulting from known or suspected overdose will 
be reported according to instructions in Section 7.6 of the protocol. 
 
Treatment with naloxegol does not require that any pre-treatment parameters be met prior to 
dispensing and/or administration.  
 


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4.3 
Pre-Medications 
 
There are no required pre-medications on this study.  
 
4.4 
Permitted Concomitant Therapy 
 
Throughout the study, investigators will be encouraged to maintain a patient’s baseline pain 
control regimen, with dose adjustments made as clinically indicated throughout participation in 
the study.  It is anticipated that the majority of participants will be receiving a long-acting opioid 
for control of background pain and an immediate-release opioid as needed (“prn”) for 
breakthrough pain, although some may be receiving only a short-acting opioid on a scheduled 
basis.  Changes in the opioid regimen may be made to ensure appropriate pain control.  Any 
changes to the maintenance opioid dosing regimen will be recorded.  Concomitant non-opioid 
analgesics will be permitted, but investigators will be encouraged to maintain such drugs at 
stable doses on-study as possible.   
 
It is recognized that some patients may have their pain managed by physicians who are not co-
investigators on this study.  In these cases, patients will be asked to notify their UCSD treating 
investigator or study team member of any changes in a patient’s pain control regimen. 
 
Patients may take laxatives during the screening period of the study, but must discontinue use 
of laxatives at least 3 days prior to Study Day 1.  In addition, patients may take an opioid 
antagonist, mixed antagonist, a strong CYP3A4 and/or P-gp inhibitor, a moderate CYP3A4 
and/or P-gp inhibitor, and/or a strong CYP3A4 inducer during the screening period of the study, 
but must discontinue use of these agents at least 3 days prior to Study Day 1.  During the initial 
and cross over treatment periods, if a bowel movement has not occurred within at least 72 
hours, a patient may take bisacodyl as a laxative rescue medication in addition to the dosage of 
Naloxegol or stimulant laxative.  If after a minimum of 72 hours, the patient has not experienced 
a BM, he/she may take bisacodyl rescue therapy (10-15 mg dose or 2-3 tablets at a time).  If the 
patient remains constipated, bisacodyl rescue therapy may be repeated up to two additional 
times, as necessary, each 10-15 mg dose separated by 12 hour intervals.  It is recommended 
that the bisacodyl tablets be taken either at bedtime or before breakfast.  Of note, both the usual 
care arm and rescue therapy will use standard doses of bisacodyl (5-15 mg per day).  If after 3 
doses of rescue therapy, the patient still has not experienced a bowel movement, the 
investigator may prescribe a one-time use of an enema.  The timing of administration of this 
therapy will be noted on the patient medication use diary.  If these secondary interventions fail, 
the patient should be discontinued from the study and referred for additional medical evaluation.  
The investigator should recommend initiation of any therapy deemed most appropriate.  
 
Other medication, which is considered necessary for the patient’s safety and well-being, may be 
given at the discretion of the investigator, and will be recorded on the patient medication use 
diary as well as the concomitant medications case report form.  
 
4.5 
Prohibited Concomitant Therapy 
 
Unless there is a need for urgent intervention, additional medication for pain control or treatment 
of constipation (other than their maintenance opioid regimen and approved opioid medication for 
breakthrough pain) will not be allowed without prior approval from the principal investigator.  
This includes over-the-counter treatments for constipation and pain.   
 
Unless defined as part of the usual care treatment arm, prohibited laxatives will include the 


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following:  
• 
Milk of magnesia 
• 
Magnesium citrate 
• 
Non-absorbable phosphate 
• 
Cascara sagrada 
• 
Castor oil/mineral oil 
• 
Epsom salt 
• 
Lactulose 
• 
Docusate 
• 
Enemas (see Section 4.4 for 
exception to use) 
• 
Tegaserod 
• 
Lubiprostone (Amitiza®) 
• 
Drugs blocking fat absorption with 
an associated laxative effect 
• 
Prucalopride 
• 
Prune juice 
• 
Herbal preparations for constipation 
• 
Bulk laxatives, such as psyllium and 
methylcellulose 
• 
Any agent that is used in an off-label 
fashion to treat constipation (eg, 
colchicine, misoprostol, 
erythromycin, cholinesterase 
inhibitors such as donezepil) 
• 
Any experimental constipation 
therapy 
 
Prohibited medications include metoclopramide given its 5HT4 agonism at the stomach causing 
promotility.   
 
Opioid antagonists and mixed agonists/antagonists are also prohibited during study 
participation, which includes the following:  
• 
Pentazocine 
• 
Buprenorphine 
• 
Nalbuphine 
• 
Naloxone and other naloxone containing products, such as oxycodone/naloxone 
combinations (Targin®) 
• 
Naltrexone and other natrexone containing products such as morphine/naltrexone 
combinations (Embeda®) 
• 
Methylnaltrexone (Relistor®) 
• 
Alvimopan (Entereg®) 
 
Naloxegol is a sensitive substrate of CYP3A4 enzyme and a substrate of P-gp transporter, and 
CYP3A4 is the major CYP enzyme responsible for the metabolism of naloxegol.  Concomitant 
use with strong CYP3A4 and/or P-gp inhibitors, moderate CYP3A4 and/or P-gp inhibitors, 
and/or strong CYP3A4 inducers are prohibited during study participation.  Please see 
Appendices B and C for a list of these medications.   
 
Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) may be given to 
patients during study participation.  
 
4.6 
Adverse Drug Reactions, Dosing Delays/Dose Modifications  
 
From initial treatment period to end of study visit,  participants will be evaluated for possible 
toxicities that may have occurred during the previous treatment phase or drug dispensing 
cycle.  Any patient who receives treatment on this protocol will be evaluable for toxicity.  
Severity of all adverse events will be evaluated according to the NCI CTCAE v4.03.  Dose 
adjustments will be based on the naloxegol-related toxicity experienced during a treatment 
phase or newly encountered at the start of each treatment phase or drug dispensing cycle.  
Dose adjustments should be made according to the system showing the greatest degree of 
adverse event severity.  If a patient experiences multiple adverse events and there are 
conflicting recommendations, the investigator should use the recommended dose adjustment 


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that reduces or delays the dose to the greatest degree.  The participant may continue on 
therapy if the toxicity can be managed according to the dose modification guidelines as 
outlined below.   
A separate 12.5 mg tablet will be available for study participants who develop more severe GI 
adverse events. For study drug compliance the pharmacy will indicate the date, dosage and 
quantity of drug dispensed. The subject will also maintain a the patient study drug diary (see 
sections 5.1.13.1 and section 8.1.2) that will be reviewed along with study drug counts to ensure 
that all missed doses or dose changes have been documented. 
 
Patients requiring a delay of ≥2 weeks in initation of study participation or requiring more than 2 
dose adjustments during the course of naloxegol therapy will require authorization from the 
principal investigator to continue study participation. 
 
Table 1: Dose Modifications for Naloxegol-Related Nausea and/or Vomiting 
 
Vomiting 
Management for Naloxegol 
≤ Grade 1 
No action required. 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until < Grade 2.  Resume at reduced dose (12.5mg tablet). 
Grade 4 
Off protocol therapy 
Recommended management:  Dopamine antagonist antiemetic 
 
Table 2: Dose Modifications for Naloxegol-Related Diarrhea 
 
Diarrhea 
Management for Naloxegol 
≤ Grade 1 
No action required. 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until < Grade 2.  Resume at reduced dose (12.5mg tablet). 
Grade 4 
Off protocol therapy 
Recommended management:  Loperamide antidiarrheal therapy, 4 mg at first onset, followed by 2 mg with each 
loose motion until diarrhea-free for 12 hours (maximum dosage:  16 mg/24 hours).  Adjunct anti-diarrheal therapy is 
permitted and should be recorded when used. 
 
Table 3: Dose Modifications for Naloxegol-Related Abdominal Pain 
 
Abdominal Pain 
Management for Naloxegol 
≤ Grade 1 
No action required. 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until < Grade 2.  Resume at reduced dose (12.5mg tablet). 
Grade 4 
Off protocol therapy 
 
Table 4: Dose Modifications for Other Naloxegol-Related Toxicity  
 
Grade 
Management for Naloxegol 
≤ Grade 1 
No action required. 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until < Grade 2.  Resume at reduced dose (12.5mg tablet). 
Grade 4 
Off protocol therapy 
 
Dose Modifications for Renal Impairment 
 
If a participant’srenal function becomes compromised during the course of treatment with 
naloxegol, defined as GFR < 60 mL/min/1.73m2, the naloxegol dose will be reduced to 12.5 mg 
tablet once daily. 


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Rare cases of GI perforation associated with the use of other peripheral opioid antagonists in 
OIC have been reported to occur shortly after initiation with drug and appear to be more 
commonly reported in patients with multiple co-morbidities, particularly those that might impair 
the local or global structural integrity of the GI tract.  
 
Any at-risk patient who reports progressive or persistent severe abdominal pain should be 
evaluated immediately by their physician or referred for urgent medical assessment, especially 
in the presence of other symptoms such as fever, malaise or mental status changes. 
 
4.7 
Duration of Study Treatment 
 
In the absence of treatment delays due to adverse events, treatment may continue up to a total 
16 weeks (treatment periods including optional extension) or until: 
• 
Inter-current illness or worsening of a medical condition that prevents further 
administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Rescue therapy for patient’s constipation fails secondary interventions and/or the 
investigator believes that other treatment options may be more beneficial 
• 
The investigator believes that study treatment is jeopardizing patient safety 
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
4.8 
Duration of Follow Up 
 
Patients will be followed for occurrence of adverse events for 28 days after removal from 
treatment or until death, whichever occurs first.   Patients removed from treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event.  Patients will be asked to return to clinic for an end of study visit within 28 days of the 
final dose of study treatment. 
 
4.9 
Discontinuation from Study Participation 
 
Patients may be removed from study participation at any time or at the discretion of the 
investigator for any of the following reasons: 
• 
The patient or legal representative withdraws consent to participate; 
• 
The patient is lost to follow-up; 
• 
The patient dies; 
• 
The patient is non-compliant with study procedures; 
• 
The investigator believes that study treatment is jeopardizing patient safety. 
 
5.0 
STUDY PROCEDURES 
 
Refer to the study Schedule of Events for assessments to be performed. 
 
All patients will be closely monitored for safety and tolerability throughout treatment and at the 
completion of study treatment. 
 


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5.1 
Definitions of Study Assessments 
 
5.1.1  Medical history 
 
A complete medical, surgical and oncology history as well as history of OIC are obtained at 
screening. Any changes from Screening (e.g. worsening severity or abnormal findings) are 
considered to be adverse events (AEs). 
 
5.1.2 Demographics 
 
Demographic profile will include date of birth, sex, race, and ethnicity. 
 
5.1.3 Review subject eligibility criteria 
 
Review of eligibility criteria as described in Section 3 to ensure subject qualification for study 
entry. 
 
5.1.4 OIC confirmation 
 
Prior to randomization, patients will be asked to report the number of bowel movements and 
rate their stool quality (using BSS) they have had in the past week.  In order to meet study 
eligibility, the patient must report ≤3 bowel movements, or their estimated percentage of hard 
and lumpy stools (BSS of 1 or 2) > 25% during the preceding week.  OIC may be confirmed at 
any time during screening and prior to initial treatment period Day 1.  
 
5.1.5 Concomitant medications 
 
All concomitant therapy, including anticancer therapy, anesthetic agents, vitamins, 
homeopathic/herbal remedies, nutritional supplements, opioid medication use, over-the-counter 
analgesic medication use, rescue laxative use, and all other over-the-counter “as needed” (prn), 
received by patients from 3 days prior to Study Day 1 until 28 days after the last study dose will 
be recorded in the patient’s medical record. If a reportable adverse event deemed related to 
study intervention (see Section 7) occurs within 28 days after last study dose and the patient 
has not started a new treatment, recording of concomitant medications related to the treatment 
of that adverse event should continue until resolution of the adverse event. 
 
5.1.6 Physical exam 
 
A complete physical examination should include the evaluation of general appearance; 
evaluation of head, eyes, ears, nose, and throat (HEENT); and cardiovascular, pulmonary, 
abdominal, musculoskeletal, skin, lymph nodes, neurological, and genitourinary systems. 
Subsequent exams may be targeted as appropriate. 
 
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as adverse events if clinically 
significant. 
 
5.1.7 Vital signs and height  
 
Vital signs should include temperature, pulse, and blood pressure and weight. Height will only 
be collected at screening.  


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5.1.8 Performance status 
 
Performance status is evaluated by the Eastern Cooperative Oncology Group (ECOG) 
performance scale. 
 
5.1.9 Adverse event assessment 
 
Baseline assessment of subject status for determining adverse events.  Adverse events will be 
assessed using NCI CTCAE v4.03.  See Section 7 for Adverse Event monitoring and reporting. 
 
5.1.10 Hematology 
 
Complete blood count to include hemoglobin, platelets, total white blood cell count and 
differential. 
 
5.1.11 Serum chemistries 
 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, total protein, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, 
bicarbonate), glucose, and total bilirubin.  
 
5.1.12 
Pregnancy test (females of child bearing potential) 
 
See section 3.1 for definition.  
 
5.1.13 
Patient-Reported Measures 
 
All patient-reported measures will be completed via paper format, with materials provided to the 
patient by a study team member.  A study member will provide initial training to the patient on 
how to complete study-required questionnaires and diaries.  Patients are to complete the 
questionnaires and diaries in a quiet area, without assistance from family, friends or study team 
members.  Patients must be able to read and comprehend the questionnaire in the language 
presented, and will be translated into foreign languages as needed for patient recruitment.  
Patients must complete the questionnaires prior to any interventions or discussions regarding 
their OIC with the investigator or study team members. 
 
5.1.13.1 Patient Study Drug Diary  
 
Patients will complete a daily study drug diary (Appendix D) during the period of time 
that they are receiving naloxegol: initial treatment phase for patients randomized to Arm 
A, crossover treatment phase for those randomized to Arm B; extension phase for all 
patients who choose to continue receiving naloxegol for an additional 12 weeks following 
the crossover phase.  Participants will be asked to complete this diary even on days 
when a naloxegol dose was missed.  The study drug diary will be reviewed with the 
patient during each visit to clinic, and a copy will be collected by a member of the study 
team.  This diary will be used in combination with a pill count by the study team to 
support drug accountability.  
 
5.1.13.2  Patient Medication Use Diary 
 


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Patients will complete a daily medication use diary as a record of all oral and self-
administered medications received during the initial and crossover treatment periods 
(Appendix E).  This includes any vitamins, homeopathic/herbal remedies, nutritional 
supplements, opioid medication use, over-the-counter analgesic medication use, rescue 
laxative use, and all other over-the-counter “as needed” (prn) medications.  A copy of the 
medication use diary will be collected from the patient by a member of the study team 
during each visit to clinic and entries will be recorded on the concomitant medications 
case report form. 
 
5.1.13.3 Patient Bowel Movement Diary 
 
Patients will complete a daily bowel movement diary as a record of the number of daily 
bowel movements during the initial and crossover treatment periods (Appendix F).  
Participants will be asked to complete this diary even on days where no daily bowel 
movement has occurred.  A copy of the bowel movement diary will be collected from the 
patient by a member of the study team during each visit to clinic. 
 
5.1.13.4 Bristol Stool Scale (BSS) 
 
Subjects will rate stool consistency through completion of the Bristol Stool Scale (BSS) 
after each bowel movement.  The BSS was developed by Heaton at the University of 
Bristol and was first published in the Scandinavian Journal of Gastroenterology in 1997 
(Lewis and Heaton 1997).  It is a medical aid designed to classify feces into seven 
categories (Appendix G), as follows: 
• 
1 - Separate hard lumps, like nuts (hard to pass) 
• 
2 - Sausage-shaped, but lumpy 
• 
3 - Like sausage, but with cracks on its surface 
• 
4 - Like a sausage or snake, smooth and soft 
• 
5 - Soft blobs with clear cut edges (passed easily) 
• 
6 - Fluffy pieces with ragged edges, a mushy stool 
• 
7 - Watery, no solid peices 
 
Subjects will be asked to document a BSS score at the time of OIC confirmation and 
daily during the initial and crossover treatment periods. This score takes approximately 1 
minute to complete.  
 
5.1.13.5 PAC-SYM Questionnaire 
 
The PAC-SYM questionnaire12 (Appendix H) will be used to assess patient quality of 
life.  The PAC-SYM questionnaire is a 12-item questionnaire that evaluates the severity 
of symptoms of constipation in 3 domains (stool, rectal, and abdominal symptoms) on a 
5-point Likert scale ranging from 0 (absent) to 4 (very severe) in the 7 days prior to 
assessment.  The items of the instrument were developed through literature review and 
patient interviews.  The PAC-SYM has been extensively validated for constipation and is 
available in several languages.  The translations into local languages have been 
performed according to a linguistic validation process.  The PAC-SYM is validated for a 
7-day recall, therefore, participants will be asked to complete this questionnaire every 7 
days during the initial and crossover treatment periods, every 28 days during the 
optional extension phase and at the end of study visit.  This questionnaire takes 
approximately 5 minutes to complete.  


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5.1.13.6  PAC-QOL Questionnaire 
 
The PAC-QOL questionnaire13 (Appendix I) will be used to assess patient quality of life.  
The PAC-QOL questionnaire is a 28-item self-report instrument designed to evaluate the 
burden of constipation on patient’s everyday functioning and well being in the 2 weeks 
(14 days) prior to assessment.  Each item is rated on a 5-point Likert scale ranging from 
0 (not at all) to 4 (extremely).  Development of the PAC-QOL items was informed by both 
clinician and patient focus groups and the primary validation study evaluated use of the 
PAC-QOL in the US, Netherlands, Belgium, Canada, and Australia using French and 
Dutch translations in addition to the original English language based instrument.13  This 
questionnaire takes approximately 5 minutes to complete.  The instrument can be use to 
generate an overall score, but is also reported to assess 4 specific constipation-related 
domains, including: 1) worries and concerns (11 items), 2) physical discomfort (4 items), 
3) psychosocial discomfort (8 items), and 4) satisfaction (5 items).  The PAC-QOL is 
validated for a 2-week recall, therefore, participants will be asked to complete this 
questionnaire every 14 days during the initial and crossover treatment periods, every 28 
days during the optional extension phase and at the end of study visit.  This 
questionnaire takes approximately 5 minutes to complete.   
 
5.1.13.7  Brief Pain Inventory-Short Form (BPI-sf) 
 
The Brief Pain Inventory (BPI) is one of the most widely used measurement tools for 
assessing clinical pain.  The BPI allows patients to rate the severity of their pain and the 
degree to which their pain interferes with common dimensions of feeling and function.  
The BPI is available in two formats: the BPI-Short Form (BPI-sf), which is used for 
clinical trials, and the BPI-Long Form, which contains additional descriptive items that 
may be clinically useful.  For the purposes of this study, we will use the BPI-sf, a 9 item 
self-administered questionnaire used to evaluate the severity of a patient's pain and the 
impact of this pain on the patient's daily functioning (Appendix J). The patient is asked 
to rate their worst, least, average, and current pain intensity, list current treatments and 
their perceived effectiveness, and rate the degree that pain interferes with general 
activity, mood, walking ability, normal work, relations with other persons, sleep, and 
enjoyment of life on a 10 point scale.  The BPI-sf is validated for 24-hour recall.  
Participants will be asked to complete this questionnaire daily during the initial and 
crossover treatment periods, every 28 days during the optional extension phase, and at 
the end of study visit.  This questionnaire takes approximately 5 minutes to complete.  
 
 
5.2 
Screening/Baseline Procedures 
 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within 21 days prior to initiation of study treatment 
unless otherwise stated. The screening procedures include: 
• 
Written informed consent 
• 
Review of inclusion and exclusion criteria 
• 
Complete medical/surgical/OIC history 


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• 
OIC Confirmation (see Section 5.1.4)  
• 
Demographics 
• 
Documentation of concomitant medications 
• 
Complete physical examination, including vital signs, weight and height 
• 
ECOG performance status assessment 
• 
Complete blood count with differential and platelets 
• 
Comprehensive metabolic panel 
• 
Serum or urine pregnancy test (within 72 hours of Study Day 1) for females of child-
bearing potential (see inclusion/exclusion criteria) 
• 
PAC-SYM 
• 
PAC-QOL 
• 
BPI-sf 
• 
BSS 
 
Following confirmation of all eligibility criteria, subjects will be randomized in a 1:1 ratio to either 
Arm A or Arm B.  Randomization will occur within 3 days of the initial treatment phase. 
 
5.3 
Procedures During Initial Treatment and Crossover Treatment Phases 
 
During the initial and crossover treatment phases of the study, physical exam, ECOG 
performance status, vitals, weight, and laboratory tests will be performed on the first day of each 
treatment period. Thereafter, these procedures will be performed according to routine frequency 
for the participant’s oncology care.  If these procedures are performed as part of routine 
oncology care, results will be collected for the study. 
 
5.3.1 Day 1, Day 18  
• Documentation of concomitant medications, adverse events and serious adverse 
events 
• ECOG performance status assessment 
• Physical exam, vital signs, and weight 
• Complete blood count with differential and platelets 
• Comprehensive metabolic panel 
• Naloxegol dispensing (Arm A, Day 1 only; Arm B, Day 18 only) 
• Naloxegol administration (Arm A, Day 1; Arm B, Day 18) 
• Patient study drug diary (Arm A, Day 1; Arm B, Day 18) 
• PAC-SYM 
• PAC-QOL 
• BPI-sf 
• BSS 
• Patient medication use diary 
• Patient bowel movement diary 
 
5.3.2 Days 2-7, Days 9-14, Days 19-24 and Days 26-31 
• Documentation of concomitant medications, adverse events and serious adverse 
events 
• Naloxegol administration (Arm A, initial period only; Arm B crossover period only) 
• Patient study drug diary (Arm A, initial period only; Arm B crossover period only) 
• BPI-sf 
• BSS 


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• Patient medication use diary 
• Patient bowel movement diary 
 
5.3.3 Day 8, Day 25 
• Documentation of concomitant medications, adverse events and serious adverse 
events 
• Naloxegol administration (Arm A, initial period only; Arm B crossover period only) 
• Naloxegol pill count (Arm A, initial period only; Arm B crossover period only, via 
phone if in-person visit not conducted) 
• Patient study drug pill diary (Arm A, initial period only; Arm B crossover period only) 
• PAC-SYM 
• BPI-sf 
• BSS 
• Patient medication use diary 
• Patient bowel movement diary 
 
5.4 
Procedures During Optional Extension Phase (up to 12-weeks) 
 
Physical exam, ECOG performance status, vitals, weight, and laboratory tests will be performed 
at the start of the optional extension phase, on Day 32.  Thereafter, these procedures will be 
performed according to routine frequency for the participant’s oncology care.  If these 
procedures are performed as part of routine oncology care, results will be collected for the 
study.  
 
5.4.1 Days 32-116 (Daily) 
• Documentation of concomitant medications, adverse events and serious adverse 
events 
• ECOG performance status assessment (Day 32 only) 
• Physical exam, vital signs, weight (Day 32 only) 
• Complete blood count with differential and platelets (Day 32 only) 
• Comprehensive metabolic panel (Day 32 only) 
• Naloxegol dispensing (Day 32 only) 
• Naloxegol administration 
• Patient study drug diary 
 
 
5.4.2 Days 32, 39, 46, 53, 60, 67, 74, 81, 88, 95, 102, 109 (Weekly) 
In addition to daily assessments listed in Section 5.5.1, the following will be performed:  
• Naloxegol pill count (via phone if in-person visit not conducted) 
• PAC-SYM (Days 32, 60, 88 only) 
• PAC-QOL (Days 32, 60, 88 only) 
• BPI-sf (Days 32, 60, 88 only) 
 
5.5 
End of Study Visit 
 
The End of Study Visit will occur within 28 days of final day of study treatment.  This visit will be 
scheduled at the time of a routine oncology visit.  If physical exam, ECOG performance status, 
vitals, weight, and laboratory tests are performed at the End of Study timepoint as part of routine 
oncology care, results will be collected for the study. 


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• Documentation of adverse events and serious adverse events 
• Naloxegol pill count and final study drug accountability 
• PAC-SYM  
• PAC-QOL 
• BPI-sf 
• Return of unused study materials, including study medication, patient 
questionnaires and diaries 
 
5.6 
Follow-up Procedures 
 
Patients will be followed for occurrence of adverse events for 28 days after the final study 
treatment or until death, whichever occurs first.  Patients removed from treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event.  There are no additional follow-up requirements beyond the end of study visit, as detailed 
in Section 5.5 
 
6.0 
Measurement of Effect 
 
6.1 
Safety/Tolerability 
 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the NCI CTCAE v4.03 (http://ctep.cancer.gov/reporting/ctc.html) for reporting of 
adverse events.  Safety will be assessed within the first 4 weeks of study treatment. 
 
6.2 
Feasibility Assessment  
 
The primary endpoint on this study is defined as completion of all required study drugs  over the 
first 4 weeks of study treatment (initial and cross-over treatment phases).   
 
6.3 
Efficacy Assessment 
 
The efficacy of treatment with naloxegol versus treatment with usual care will be evaluated by 
the number of bowel movements per week, as captured on the Patient Bowel Movement Diary, 
and the stool quality as defined by the Bristol Stool Scale. These measures will be assessed 
within the first 4 weeks of study treatment. 
 
6.4 
Quality of Life 
 
Quality of Life will be assessed by the following instruments: PAC-SYM, PAC-QOL, and BPI-sf.  
These instruments are described further in Sections 5.1.13.5-5.1.13.7. Quality of life will be 
assessed within the first 4 weeks of study treatment. 
 
 
7.0 
ADVERSE EVENTS 
 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment, which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.  


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Progression of the cancer under study or events which are unequivocally due to disease 
progression should not be reported as an AE during the study (unless it is considered to be drug 
related by the investigator). 
 
7.1 
Adverse Event Monitoring 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during a trial. Additionally, certain AEs must be reported in an expedited manner to allow for 
optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
AE monitoring begins at the time of informed consent signature and ends 28 days following the 
last administration of study treatment. 
 
All patients experiencing an AE, regardless of its relationship to study drug will be monitored 
until:  
• 
the event resolves or the symptoms or signs that constitute the event return to 
baseline;  
• 
any clinically significant abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes observed; 
or 
• 
death. 
 
7.2 
Severity 
 
All AEs will be graded according to the NCI CTCAE v4.03. The NCI CTCAE v4.03 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
 
7.3 
Seriousness 
 
A “serious” adverse event (SAE) is defined in regulatory terminology as any untoward medical 
occurrence that: 


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1. Results in death. 
If death results from (progression of) the disease, the disease should be reported as the  
event itself. 
2. Is life-threatening. 
The patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
3. Requires in-patient hospitalization or prolongation of existing hospitalization.  
Note: Hospitalization (including hospitalization for an elective procedure) for a pre-
existing condition which has not worsened does not constitute a serious adverse event. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that may not result in hospitalization; development of drug 
abuse or drug dependency. 
 
Given that the Investigator’s perspective may be informed by having actually observed the 
event, and the Sponsor is likely to have broader knowledge of the drug and its effects to inform 
its evealuation of the significance of the event, if either the Sponsor or the Investigator belives 
that the event is serious, the event will  be considered serious. 
 
7.4 
Relationship 
 
The relationship to the IP of each AE/SAE will be evaluated by the investigator using the 
following levels: 
 
• 
Not related: The temporal relationship of the clinical event to the administration of IP 
makes a casual relationship unlikely; and other drugs, therapeautic intervention or 
underlying conditions provide a sufficient explanation for the obsereved event. 
• 
Related: The temporal relationship of the clinical event to the administration of the IP 
makes a casual relationship possible; and other drugs, therapeutic interventios or 
underlying conditions do not provide sufficient explanation for the obsereved event. A 
clear-cut temporal association with improvement on cessation of the study drug or 
recurrence upon rechallenge may also be oserved. 
 
7.5 
Prior experience 
 
Expected events are those that have been previously identified as resulting from administration 
of the agent. An AE is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in the current known adverse 
events listed in the agent clinical experience section of this protocol, the Investigator Brochure, 
or the current Product Label. 
 
7.6 
Reporting Requirements for Adverse Events 
 
7.6.1 Safety Reporting 
 


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A. Principal Investigator must be notified within 24 hours of learning of any SAE, regardless 
of attribution, occurring during the study or within 28 days of the last administration of the 
study drug.  
 
 
B. The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to subjects or 
others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. Any deviation from the protocol taken without prior Institutional Review Board 
(IRB) review to eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change 
to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 
 
C. This study sponsor is exempted from the IND Safety Reporting by the FDA.  
 
AstraZeneca is responsible for NDA expedited safety reporting to FDA in accordance with local 
regulatory requirements. Investigators should provide all available information at the time of 
SAE Report Form completion. Investigators should not wait to collect additional information to 
fully document the event before notifying AstraZeneca of an SAE. When additional information 
becomes available, investigators should submit a follow-up SAE Report Form (separate from 
the initial report form) with the new information. Any follow-up information to an SAE also needs 
to be provided to AstraZeneca within 24 hours of learning of the new information. 
 
AstraZeneca should be notified withing one (1) calendar day of initial receipt from the site for all 
fatal and life-threatening cases and within five (5) calendar days of initial receipt from the site for 
all other SAEs. 
 
 
When reporting to AstraZeneca, a cover page should accompany the MedWatch/AdEERs 
form indicating the following: 
• Investigator Sponsored Study (ISS) 
• The investigator’s name and address 
• The trial name/title and AstraZeneca ISS reference number (ESR-15-11108) 
 
The Principal Investigator 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..  


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7.6.2 Routine Reporting Requirements 
 
A. The UCSD HRPP must be notified of any AEs  that are not unanticipated problems 
involving risk to subjects or others (non-UPRs) at the time of the annual Continuing 
Review.  
B. SAEs that do not require expedited reporting will be reported to AstraZeneca at least 
every month preferably using the MedDRA coding language for SAEs.   
 
All SAEs must be reported to AstraZeneca, whether or not considered causally related to 
the investigational product.  All SAEs will be documented.  The Principal Investigator is 
responsible for informing the IRB and/or the Regulatory Authority of the SAE as per local 
requirements. 
 
7.6.3 Pregnancy Reporting Requirements 
 
If a patient becomes pregnant during the course of the study, naloxegol should be discontinued 
immediately. The Principal Investigator must be notified within 24 hours of any pregnancies 
occurring in a female patient or a female partner of a male patient. The Principal Investigator or 
designated site personnel will then inform AstraZeneca representatives no later than the end of 
the next business day of when he or she becomes aware of it. 
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that naloxegol may have 
interfered with the effectiveness of a contraceptive medication. Congenital abnormalities/birth 
defects, spontaneous miscarriages or ectopic pregnancy should be reported and handled as 
SAEs.  Elective abortions without complications should not be considered AEs unless they were 
therapeutic abortions. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up 
and documented. The outcomes of any conception occurring from the date of the first dose until 
12 weeks after the date of last dose will be followed up and documented. The Investigator 
should follow-up with the study patient or the female partner of the study patient, even if the 
patient was discontinued from the study. 
 
7.6.4 Adverse Event Data Collection 
 
The following data will be collected on an Adverse Event case report form for each adverse 
event experienced during the 30-day adverse event monitoring period: 
• 
Event term 
• 
Narrative description of event 
• 
Start and stop date/time of event   
• 
CTCAE grade 
• 
Seriousness (yes/no) – if yes, see further below 
• 
Relationship to protocol therapy  
• 
Action taken with regard to protocol therapy (including therapy start and stop dates) 
• 
Did AE cause subject’s withdrawal from study (yes/no)? 
• 
Outcome of treatment-related variable 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date Investigator became aware of serious AE 


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• 
Criteria met for “seriousness” (see Section 7.3) 
• 
If hospitalization or prolongation of hospitalization: 
o Date of hospitalization (if applicable) 
o Date of discharge (if applicable) 
• 
If death: 
o Date of death (if applicable) 
o Cause of death (if applicable) 
o 
Autopsy performed (yes/no) (if applicable) 
• 
Description of SAE(s) 
8.0 
AGENT INFORMATION 
 
8.1 
Naloxegol 
 
Please refer to Investigator’s Brochure for more comprehensive information. IDS will be 
responsible for all naloxegol storage, preparation, accountability, and dispensing throughout the 
trial.   
 
Other names for the drug: MOVANTIKTM 
 
Mechanism of action (or Product description):  Naloxegol is an antagonist of opioid binding 
at the mu-opioid receptor.  At recommended dose levels, naloxegol functions as a PAMORA 
(Peripherally Acting Mu-Opioid Receptor Antagonist) in tissues such as the bowel, thereby 
decreasing the constipating effects of opioids.  Naloxegol is a PEGylated derivative of naloxone, 
and a substrate for the P-gp.  The presence of the PEG moiety in naloxegol reduces its passive 
permeability as compared with naloxone.  Due to the reduced permeability and increased efflux 
of naloxegol across the blood-brain barrier, related to P-gp substrate properties, the central 
nervous system penetration of naloxegol is negligible at recommended dose levels, limiting the 
potential for interference with centrally mediated opioid analgesia. 
 
Availability: provided by AstraZeneca, free of charge 
 
How supplied: Study drug tablets are supplied as mauve, oval, biconvex, film coated, and 
intagliated with “nGL” on one side and “25” on the other.   
 
Tablets will be supplied in 25-mg dose form, in high-density polyethylene (HDPE) bottles.  IDS 
will dispense a 14-day supply of naloxegol at the initiation of the initial treatment phase for those 
patients randomized to Arm A.  For patients randomized to Arm B, IDS will dispense a 14-day 
supply of naloxegol at the initiation of the crossover treatment phase.   Patients who choose to 
participate in the optional extension portion of the study will receive a 28-day supply every 4 
weeks during the extension phase. 
 
Naloxegol will be packaged and labeled by AstraZeneca.  It will be clearly marked according to 
national requirements regarding use for clinical trial investigation only and will be labeled with 
drug name, study reference number, and storage conditions.   
 
Storage and stability: Naloxegol will be stored and locked in a secure location within IDS, with 
access restricted to pharmacy personnel only.  All study drug will be stored in original containers 
until dispensed to study subjects.  Naloxegol must be stored at room temperature between 20-
25C (68-77F).  Excursions are permitted to 15-30C (59-86F).  Storage temperature will be 


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monitored  
 
Preparation:  Given its oral formulation, there is no product preparation required.  IDS will 
prepare 14-day and 28-day supplies of naloxegol for dispensing to subjects according to 
randomization assignment and phase of study participation. 
 
Route of administration for this study:  Naloxegol will be administered as a single 25-mg 
tablet, once daily.  Subjects will be instructed to take naloxegol on an empty stomach 1 hour 
before breakfast or 2 hours after their first meal of the day. 
 
Side effects: The most common side effects associated with naloxegol are gastrointestinal in 
nature: abdominal pain, diarrhea, nausea, flatulence, vomiting, headache, and excessive 
sweating.  Patients taking naloxegol may also experience additional symptoms of opioid 
withdrawal, including chills, anxiety, irritability, and yawning.  There is also risk of developing 
abdominal or intestinal wall perforation.   
 
8.1.1 Return and Retention of Study Drug 
Remaining drug is to be destroyed on-site, according to UCSD Moores Cancer Center IDS drug 
destruction policy. 
 
8.1.2 Drug Accountability/Subject Compliance 
Records of study medications used, dosages administered, and intervals between visits will be 
kept during the study.  Subjects will be asked to fill out a daily study drug diary while taking 
naloxegol and bring with them, along with any unused study drug, when they return to clinic 
every 14 days during the initial and crossover treatment phases, and at each in-person visit 
during the optional extension phase.  A review of the subject-completed study drug diary and pill 
count will be performed by a member of the study team at each of these visits.  In addition, a 
study team member will contact the patient weekly via telephone to perform pill counts if no in-
person visit has occurred with the patient during a previous week. 
 
Final drug accountability will be noted at the completion of the trial.  Patients will be asked to 
return all unused medication at the end of the study. 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Study Endpoints 
 
The proposed study is a prospective, single-center, feasibility trial.  Ideally, a phase III placebo 
controlled trial would be completed to demonstrate the efficacy of naloxegol in cancer patients 
with OIC. However, placebo controlled trials are inherently difficult to accrue to in supportive 
oncology.  Plus, the prior attempt at a phase III placebo controlled trial failed to accrue patients, 
and was closed early. We believe that a more feasible trial design would be a randomized 
phase II crossover study. The crossover design has multiple advantages including the potential 
for increased statistical efficiency requiring smaller sample sizes. Additionally, the crossover 
study design should appeal to patients more so than a classic placebo-controlled study because 
all patients will receive the experimental drug that has the potential to offer benefit.  Additionally, 
patients will serve as their own controls, thus minimizing potential confounding factors.  A brief 
washout period before crossover of 3 days based on the elimination half-life of 10 hours (5 half 
lives, ~50 hours) is also clinically appropriate and is not expected to impact cancer patient 
symptom management.  Prior to embarking on a large phase III placebo controlled crossover 
study we propose to conduct a smaller simpler phase II crossover study to confirm feasibility of 


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the crossover strategy. 
 
9.2 
Sample Size and Accrual 
 
The primary aim of this study is feasibility – specifically feasibility will be defined as completion 
of all study drugs over 4 weeks.  For the primary aim we believe an acceptable completion rate 
would be at least 70%. Assuming a true completion rate of 85% (HA), a sample size of 50 
patients would have an 80% power to show that the true rate is at least 70% (H0), using a one-
sided exact test with ɑ=0.05. Any dropout or loss to follow up after the initatiion of study 
treatment will be categorized as a non-completer and remain in the analytic sample. Thus we 
plan to recuit until 50 subjects have commenced study treatment. 
 
The Palliative Care Service sees approximately 1,200 new inpatient consults and approximately 
250 new outpatient cancer consults per year, and is integrated into the cancer care delivery 
model.  OIC is a common symptom in patients with cancer-related pain and requires 
burdensome self-titration of laxatives for prophylaxis and treatment.  Potential study participants 
will be recruited primarily from the outpatient clinic at Moores Cancer Center, where an 
estimated 70% of our patient population is currently being treated for OIC.  We anticipate that 
enrollment will be completed in approximately 12 months, therefore, the expected accrual rate is 
approximately 5 patients per month. 
 
Accrual Targets 
Ethnic Category 
Sex 
Females 
Males 
Total 
Hispanic or Latino 
4 
3 
7 
Not Hispanic or Latino 
25 
28 
53 
Ethnic Category: Total of all subjects 
29 
31 
60 
Racial Category 
 
American Indian or Alaskan Native 
1 
1 
2 
Asian 
3 
2 
5 
Black or African American 
4 
2 
6 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
20 
25 
45 
Racial Category: Total of all subjects 
29 
31 
60 
 
9.2.1 Evaluable Subjects and Subject Replacement 
 
Analyses of secondary endpoints will be performed using data from patients that have both 
baseline and follow-up information.   
 
We will characterize patients that drop out early by comparing baseline demographic data of the 
early dropouts to the patients who complete treatment.  This will allow us to identify patients at 
risk of not completing treatment, which will provide critical information when defining eligibility 
criteria for future trials in this study population. 
 
9.3  
Data Analyses Plans 
 
All analyses will be conducted using the latest version of R. 
 
9.3.1  Primary Endpoint 
 
The primary aim of this study is feasibility – specifically feasibility will be defined as completion 


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of all study procedures over the first 4 weeks of study treatment.  For the primary aim we 
believe an acceptable completion rate would be ≥ 70%. We will assess this using a one-sided 
binomial exact test, where a p-value ≤0.05 will be considered statistically significant.  
 
9.3.2  Safety Endpoint 
 
Safety endpoints will be evaluated by monitoring AEs from clinical and laboratory reporting. 
Adverse events will be classified according to the NCI-CTCAE version 4.03.  Trends in the 
distribution and severity of the AEs across the study groups will be assessed by examining the 
count of total AEs and count of AEs at each severity level over the course of the 2 weeks for the 
initial treatment and over the 2 weeks of the crossover treatment phases of the study.  
9.3.3  Secondary Endpoints 
 
Secondary outcome measures are the effect of naloxegol versus usual care on; bowel 
movements per week, stool quality using the BSS,2 occurrence and grade of AEs using the NCI 
CTCAE version 4.03,3 health related quality of life utilizing the PAC-SYM4 & PAC-QoL,5 and 
changes in patient reported pain using the BPI-sf.6  
 
For variables in the secondary aim, we plan to use generalized linear mixed  effects models  to 
determine the impact of naloxegol on each endpoint over the course of 2 weeks for the initial 
treatment and crossover treatment phases of the study, achieved by including  treatment group 
as a categorical covariate, and including a categorical time effect to account for a potential 
period effect. .  Counts of bowel movements per week will be assessed using a Poisson model. 
Stool quality (BSS, 7 point Likert-type scale), PAC-SYM (5 point Likert-scale), and PAC-QOL (5 
point Likert-scale) will be assessed using an ordinal logistic model. The two parts of the BPI-sf 
(Intensity of pain and inference of pain) are calculated as the mean of several questions; as 
such they will be assessed as a continuous outcome with possible transformation for skewness 
if necessary. 
 
To control for the multiple comparisons, a Bonferroni-Holm (e.g. Stepwise Bonferroni) method 
will be applied to the combined secondary and exploratory analyses, using an omnibus α = 
0.05. 
 
9.3.4 Exploratory Endpoints 
 
Exploratory aims include laxative compliance (weekly pill counts), healthcare resource utilization 
(per electronic medical record evaluation of emergency room visits, hospitalizations, telephone 
encounters, and Mychart encounters), and patient preference (as evidenced by patient desire to 
continue naloxegol optional 12-week extension).   
 
For analysis of differences in weekly pill counts between naloxegol and usual care, we plan to 
use a Poisson generalized linear mixed effects model  to determine the impact of naloxegol on 
weekly pill counts, over the course of 2 weeks for the initial treatment and cross over phases of 
the study. 
 
Count of healthcare utilization resource- will be the sum of total utilizations (summed separately 
for each of the two weeks for initial treatment and cross over phase). Differences in healthcare 
utilization between the arms will be determined by fitting a Poisson regression model (or 
negative binomial in the case of over dispersion) of treatment arm on bi-weekly utilization count.  
We will examine patient preference by calculating a 95% confidence interval for the proportion 


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of patients who wish to continue the optional 12-week extension. 
 
10.0 
STUDY MANAGEMENT 
 
10.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed according to UCSD conflict of interest policy. 
 
10.2 
IRB Approval and Consent  
 
The IRB should approve the consent form and protocol prior to any study-related activities.  It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
 
10.3 
Registration and Randomization Procedures  
 
All patients must be registered with the UCSD Moores Cancer Center Clinical Trials Office 
before enrollment to study. Prior to registration, eligibility criteria must be confirmed and an 
eligibility checklist completed. Once eligibility is confirmed, patient will be given a unique 
sequential study number. 
 
Patients will be randomized in a 1:1 ratio to either Arm A or Arm B by block randomization within 
3 days of the initial study treatment day. Randomization will be performed by CTRI using a 
randomization package in the software R (blockrand)15,16.  The CTRI office will provide the study 
coordinator with prestuffed envelopes numbered 1-62.  In the envelope, a paper will indicate the 
treatment assignment.  One envelope will be assigned to each patient by the study coordinator 
in order of accrual.  The number on the envelope will become the patient number and will be the 
identification number on all study documents.  Individual patient randomization arm must be 
assigned prior to the patient being treated on study.  The study coordinator will contact IDS 
once subject randomization arm has been confirmed.     
 


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10.4 
Data Collection and Management 
 
Records and data to be obtained from the study subjects are detailed above in the Schedule of 
Events. Subject outcome information will be documented in the electronic medical record and 
subject’s research record.  Data for this study will be entered into a password-protected set of 
electronic case report forms via the Velos eResearch web-based system.  Velos eResearch is 
an integrated software system for managing clinical trials.  This system supports several clinical 
trial functions, including electronic case report forms, tracking and scheduling of subject visits 
and events, and study reporting.  The software links to the UCSD Health System’s EPIC 
Electronic Medical Record System to provide improved information and integration for clinical 
research projects. A robust support team assists investigators in implementing protocols and 
calendars and building electronic case report forms.  Velos provides automated data export 
procedures for designated users into Excel, and then transferred into R.  Access to the Velos 
database for this study will be limited to those users required to perform study-specific functions 
such as data entry and monitoring.  A designated study coordinator from the UCSD Moores 
Cancer Center Clinical Trials Office will be responsible for entering all study data. 
 
10.5 
Subject Data Protection 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or IRB access to 
subject’s medical information relevant to the study. 
 
10.6 
Data and Safety Monitoring/Auditing 
 
In addition to AE monitoring and clinical oversight by the principal investigator and co-
investigators, quality assurance of the study will be performed by a UCSD Moores Cancer 
Center Clinical Trials Office internal monitor. Monitoring intervals will be dependent upon the 
rate of enrollment, and are anticipated to occur approximately every 3-6 months.  
 
This study will also use the UCSD Moores Cancer Center DSMB to provide oversight in the 
event that this treatment approach leads to unforeseen toxicities. The DSMB will operate 
according to the DSMB charter. Data from this study will be reported every 6 months and will 
include: 
1) the protocol title, IRB protocol number, and the activation date of the study  
2) the number of patients enrolled to date  
3) the dates of  patient enrollment 
4) a summary of all adverse events regardless of grade and attribution   
5) endpoint evaluation for evaluable patients when available 
6) a summary of any recent literature that may affect the ethics of the study  
 
It will be left to the Investigator’s clinical judgment whether or not an AE is related and of 
sufficient severity to require the subject’s removal from treatment.  Subsequent review of 
serious, unexpected and related AEs by the principal investigator, DSMB, UCSD HRPP, and/or 
AstraZeneca may also result in suspension of further trial interventions/ administration of study 
drug at a site. The principal investigator or AstraZeneca retains the authority to suspend 
additional enrollment for the entire study as applicable. 
 


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10.7 
Adherence to the Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, investigators will conduct their research 
according to the plans reviewed and approved by the IRB.  
 
 
10.7.1 Emergency Modifications 
 
Investigators may implement a deviation from, or a change of, the protocol to eliminate apparent 
immediate hazards/risks to trial subjects without prior IRB approval. Any such emergency 
modification implemented must be noted and reported to the IRB along the lines of a protocol 
deviation or violation, depending on the nature of the modification. 
 
10.7.2 Protocol Violations 
 
Any unplanned variance from an IRB approved protocol is considered a violation and must be 
reported to the IRB in a timely fashion. 
A. Major violations must be reported to the IRB within 10 working days of awareness of the 
violation. 
Major violations include: 
• 
Instances that have harmed or increased the risk of harm to one or more 
research participants. 
• 
Instances that have damaged the scientific integrity of the data collected for the 
study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
B. Minor violations may be reported to the IRB at the time of the continuing review. 
Minor violations have no substantive effect on the risks to participants or on the 
scientific integrity of the research plan or the value of the data collected. 
 
10.8 
Amendments to the Protocol 
 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an amendment to 
the protocol substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the UCSD 
IRB for approval prior to implementation. 
 
10.9  Record Retention 
 
Study documentation includes all case report forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 


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reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
 
10.10 Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
 
 
 


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11.0 
REFERENCES 
 
1. 
Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology 2016;150:1393-
407. e5. 
2. 
Lewis S, Heaton K. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol 1997;32:920-4. 
3. 
National Cancer Institute. Common terminology criteria for adverse events (ctcae) 
version 4.03. 
http://wwwgooglecom/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CB4QFjAA&url=htt
p%3A%2F%2Fwwwhrcgovtnz%2Fsites%2Fdefault%2Ffiles%2FCTCAE%2520manual%2520-
%2520DMCCpdf&ei=2ptfVa-
tKpGuogTbo4HoCg&usg=AFQjCNG4OnSycmuS6wqwm2C0zVI8pT4qyA&sig2=K7D0s5d5nOM
k0CEi6X0rEw&bvm=bv93990622,dcGU;Accessed May 22, 2015. 
4. 
Frank L, Kleinman L, Farup C, Taylor L, Miner P. Psychometric validation of a 
constipation symptom assessment questionnaire. Scand J Gastroenterol 1999;34:870-7. 
5. 
Cook S, Bell T, Sweeney C, Fehnel S, Hollis K. (883): Impact on quality of life of 
constipation-associated gi symptoms related to opioid treatment in chronic pain patients: Pac-
qol results from the opioid survey. The Journal of Pain 2007;8:S71. 
6. 
Cleeland C, Ryan K. Pain assessment: Global use of the brief pain inventory. Ann Acad 
Med Singapore 1994;23:129-38. 
7. 
Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R. The 
prevalence, severity, and impact of opioid-induced bowel dysfunction: Results of a us and 
european patient survey (probe 1). Pain Med 2009;10:35-42. 
8. 
Lembo A, Camilleri M. Chronic constipation. N Engl J Med 2003;349:1360-8. 
9. 
Bell T, Annunziata K, Leslie J. Opioid-induced constipation negatively impacts pain 
management, productivity, and health-related quality of life: Findings from the national health 
and wellness survey. Journal of opioid management 2008;5:137-44. 
10. 
Roeland E, Buckholz G. Gi palliative care issues.  Palliative care: Springer; 2010:43-9. 
11. 
Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation 
in advanced illness. N Engl J Med 2008;358:2332-43. 
12. 
Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting μ opioid 
antagonist: Results of a multicenter, randomized, double-blind, placebo-controlled, phase iii trial 
of major abdominal surgery and postoperative ileus. Ann Surg 2004;240:728. 
13. 
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;370:2387-96. 
14. 
U.S. National Institutes of Health. Assessment of efficacy and safety in relieving opioid-
induced constipation in patients with cancer-related pain (nct 01384292). 
https://clinicaltrialsgov/ct2/show/NCT01384292?term=01384292&rank=1, Accessed May 22, 
2105. 
15. 
Slappendel R, Simpson K, Dubois D, Keininger DL. Validation of the pac-sym 
questionnaire for opioid-induced constipation in patients with chronic low back pain. European 
Journal of Pain 2006;10:209-17. 
 
 
 


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12.0 
APPENDICES 
 
Appendix A. ECOG Performance Status Scale 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities.  Up and about more than 
50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair 
5 
Dead. 
 
 
 


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Appendix B. Strong and Moderate CYP3A4 and/or P-glycoprotein Inhibitors 
 
Strong CYP3A4 inhibitors prohibited during study, include but are not limited to the following: 
Boceprevir 
Clarithromycin 
Conivaptan 
Grapefruit juice 
Indinavir 
Itraconazole  
Ketoconazole  
Lopinavir/ritonavir 
Mibefradil 
Nefazodone  
Nelfinavir 
Posaconazole  
Ritonavir, 
Saquinavir  
Telaprevir 
Telithromycin 
Voriconazole 
 
Moderate CYP3A4 inhibitors prohibited during study, include but are not limited to the following: 
Amprenavir 
Aprepitant, 
Atazanavir,  
Ciprofloxacin, 
Darunavir/ritonavir,  
Diltiazem,  
Erythromycin,  
Fluconazole,  
Fosamprenavir,  
Grapefruit juice, 
Imatinib,  
Verapamil 
 
P-glycoprotein inhibitors prohibited during study, include but are not limited to the following: 
Cyclosporine, 
Elacridar 
Erythromycin 
Itraconazole 
Ketoconazole 
Quinidine 
Ritonavir 
Valspodar 
Verapamil, 
 
Please refer to the U.S. Food and Drug Administration website for additional information: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm. 
 
 
 


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Appendix C. Strong CYP3A4 and P-glycoprotein Inducers 
 
Strong CYP3A4 inducers and/or P-glycoprotein inducers prohibited during study, include but are 
not limited to the following:  
• 
Avasimibe 
• 
Carbamazepine 
• 
Phenobarbital  
• 
Phenytoin  
• 
Rifabutin  
• 
Rifampin  
• 
St. John’s wort 
 
Please refer to the U.S. Food and Drug Administration website for additional information: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm. 
 
 
 
 


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Appendix D.  Patient Study Drug Diary 
 
 
 
 
 


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Appendix E.  Patient Medication Use Diary 
 
 
 
 
 


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Appendix F.  Patient Bowel Movement Diary  
 
 
 
 
 
 


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Appendix G.  Bristol Stool Scale (BSS)2 
 
 
 


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Appendix H.  Patient Assessment of Constipation Symptoms (PAC-SYM)15 
 
 
 
 
 


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Appendix I.  Patient Assessment of Constipation Quality of Life (PAC-QOL)5 
 
 
 
 


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Appendix J.  Brief Pain Inventory-Short Form (BPI-sf)6 
 
 


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Appendix K.  Equianlagesic Dosing Guidelines for Chronic Pain 
 
 
PO / PR 
IV / SC / IM 
3 
1 
 
PO 
APAP 325 + 
Codeine 30mg 
APAP 500 mg + 
hydrocodone 5mg 
APAP 325 + 
oxycodone 5mg 
~Morphine 
Equivalent 
3-4 mg 
5-6 mg 
7-8 mg 
 
PO / PR Dose (mg) 
Analgesic 
IV / SC / IM Dose (mg) 
150 mg 
Meperidine 
50 mg 
150 mg 
Tramadol 
- 
150 mg 
Codeine 
50 mg 
15 mg 
Hydrocodone 
- 
15 mg 
Morphine 
5 mg 
10 mg 
Oxycodone 
- 
3 mg 
Hydromorphone 
1 mg 
- 
Fentanyl 
0.05 mg 
(1000 mcg = 1 mg) 
 
PO Morphine 
Transdermal Fentanyl 
50mg PO in 24 hours 
~25 mcg patch Q72 hours 
 
Ferris FD, Pirrello RD: Improving Equianalgesic Dosing for Chronic Pain Management, 
American Association for Cancer Education Annual Meeting, oral presentation. Cincinnati, Ohio, 
Sept 2005.