Clinical trial NCT02977286
Conditions: Constipation
Sponsor: Tufts Medical Center
Start date: 2017-01-01; Completion date: 2019-10-09
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the addition of naloxegol (Movantik) to a laxative protocol in critically ill adults requiring scheduled opioid (e.g. fentanyl) therapy. Half of the participants will receive naloxegol and a laxative protocol and half the participants will receive a placebo and a laxative protocol.

Detailed description:
Among the more than 5 million adults who are admitted to the ICU each year in the USA, most have pain and thus receive a pain (analgesic) medication called an opioid. Opioid use in critically ill adults continues to increase given the greater awareness of untreated pain in the ICU and that an opioid-first approach be used to optimize patient safety and comfort and improve tolerance with breathing machines (i.e. mechanical ventilation). Similar to constipation, paralysis of the lower gastrointestinal (GI) tract is defined as the inability to pass stool due to impaired gut movement, and is a common effect of opioid use in the critically ill. Lower GI tract paralysis may lead to nausea, vomiting, aspiration, compromise the ability to administer tube feeds (enteral nutrition), an increase abdominal pain, delirium and delay getting off mechanical ventilation. One recent randomized study found that aggressive use of laxatives to prevent lower GI tract paralysis in critically ill adults was associated with lower daily organ dysfunction \[as measured by the Sequential Organ Failure Assessment (SOFA) score\]. The lower GI tract paralysis that occurs in the critically ill often responds poorly to laxative medication therapy (e.g., senna, bisacodyl, lactulose). While stool softener medications like docusate are routinely administered to patients on opioids, laxative-based protocols are frequently not initiated in the ICU until signs of lower GI tract paralysis start to appear. There is therefore an important and unmet need for a safe and efficacious medication to prevent lower GI tract paralysis in critically ill adults who are initiated on opioid therapy. Naloxegol (Movantik) is a naloxone-like drug that blocks the effect of opioids on the opioid µ receptor in the gut but is not absorbed in the brain (and therefore does not block the pain effects of opioids). Naloxegol is currently approved by the Food and Drug Administration (FDA) for the treatment of opioid-induced constipation (OIC) in non-ICU patients receiving scheduled moderate to high dose opioids for the treatment of chronic non-cancer pain. Naloxegol has a mechanism of action, efficacy, convenience of administration, and safety profile that make it an ideal candidate for use as a preventative medication for lower GI tract paralysis in critically ill adults receiving scheduled opioid therapy. The investigators propose a pilot study in which they will test the hypothesis that naloxegol (versus placebo) will reduce the time to the first spontaneous bowel movement (SBM) that an ICU patient has, that it will prevent lower GI tract paralysis in critically ill adults initiated on scheduled IV opioid therapy, and its use will not result in side effects that are concerning to doctors or patients. The investigators will randomize 36 critically ill ICU patients (18 in each arm) to receive naloxegol \[25mg or 12.5mg (in patients with a creatinine clearance ≤ 60ml/min)\] or placebo. This pilot study will provide valuable information to help guide future, larger studies evaluating the role of naloxegol in critically ill adults.

Arms: arm 1: Intervention: Naloxegol 25 mg (or 12.5 mg) tablet po (enteral) daily AND Docusate Sodium 100mg Oral Capsule twice daily AND Study laxative protocol daily \[that may include Senna 217 mg Oral Tablet, Polyethylene Glycols (Miralax), Magnesium Citrate Oral Liquid Product (Citromag), Bisacodyl 10 mg Suppository (Dulcolax) and Methylnaltrexone (Relistor)\] until one of the following:

1. Adverse event potentially attributable to the study drug.
2. Use of Relistor.
3. Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
4. The participant has been administered 10 days of study medication.
5. The participant is discharged from the ICU.
6. The participant requires the initiation of a strong CYP3A4 inhibitor medication.

Other Name: Movantik arm 2: Intervention: Placebo tablet po (enteral) daily AND Docusate Sodium 100 mg Oral Capsule twice daily AND Study laxative protocol daily \[that may include Senna 217 mg Oral Tablet, Polyethylene Glycols (Miralax), Magnesium Citrate Oral Liquid Product (Citromag), Bisacodyl 10 mg Suppository (Dulcolax) and Methylnaltrexone (Relistor)\] until one of the following:

1. Adverse event potentially attributable to the study drug.
2. Use of Relistor.
3. Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
4. The participant has been administered 10 days of study medication.
5. The participant is discharged from the ICU.
6. The participant requires the initiation of a strong CYP3A4 inhibitor medication.

Other Name: AstraZeneca provided Movantik placebo
Interventions: intervention 1: Naloxegol Oral Tablet intervention 2: Placebo Oral Tablet intervention 3: Docusate Sodium 100 Mg oral capsule [Colace] intervention 4: Senna 217 Mg Oral Tablet intervention 5: Polyethylene Glycols intervention 6: Bisacodyl 10 mg Suppository intervention 7: Magnesium Citrate Oral Liquid Product intervention 8: Methylnaltrexone
Intervention descriptions: intervention 1: Naloxegol Oral Tablet 25 mg (or 12.5 mg) po (enteral) daily intervention 2: Placebo Oral Tablet po (enteral) twice daily intervention 3: Docusate Sodium 100 mg po (enteral) twice daily intervention 4: Senna 127 mg oral tablet daily if no spontaneous bowel movement \>/=3 days after scheduled opioid initiation; increase to two senna 127 mg tables if no no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat two senna 127 mg tablets if no spontaneous bowel movement \>/=5 days after scheduled opioid initiation. Repeat two senna 127 mg tablets if no spontaneous bowel movement \>/=6 days after scheduled opioid initiation. intervention 5: Polyethylene Glycols 17 g daily if no spontaneous bowel movement \>/=3 days after scheduled opioid initiation; increase to 34 g daily if no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat 34 g daily if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation. Repeat 34 g daily if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation. intervention 6: Insert one suppository if no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation. Repeat if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation. intervention 7: Administer one 10 oz bottle if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation. intervention 8: Administer 8 mg or 16 mg (depending on subject's weight) subcutaneously x 1 if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation, consult surgery/gastroenterology and discontinue study medication.

Protocol documents:
ICF_002.pdf: 
Impact of Naloxegol (Movantik) on Prevention of Lower Gastrointestinal Tract 
Paralysis in Critically Ill Adults Initiated on Scheduled IV Opioid Therapy: A 
Randomized, Double-Blind, Placebo-Controlled, Phase II, Single-Center, Proof of 
Concept Study 
 
NCT02977286 
 
Version Date: September 22, 2018 
Approved on: October 25, 2018 




















Impact of Naloxegol (Movantik} on Prevention of Lower Gastrointestinal Tract Paralysis in Critically Ill
Adulls Initiated on Scheduled IV Opioid Therapy: A Randomized, Double-Blind, Placebo-Controlled. 
Phase 11, Single-Center, Proof of Concept Study 
Principal investigator: Erik Garpestad, MD 
DOCUMENTATION OF CONSENT 
I have been given a copy of this form. I had read it or it has been read to me. I understand the 
information and have had my questions answered to my satisfaction. I agree to take part in this
study. 
I understand that I will be informed of any new findings developed during the course of this research
study that may affect my willingness to stay in this research study. 
Date 
Subject's Signature 
I have fully explained to _________________ t.he nature and purpose of this 
Subject 
above-described study and the risks that are involved in its perfonmance. I have answered all
questions to the best of my ability. 
Printed Name of Principal Investigator 
Position 
or Person Conducting the Informed Consent Discussion
Date 
Principal Investigator or Representative's Signature 
Witness Signature (for Non-English Speaking Persons) 
Date 
Witness' Signature 
Witness Name 
Use below only when enrolling persons with impaired decisin-making capacity 
I have 
ation 
been 
and 
given 
have 
a copy 
had 
of 
my 
this 
questions 
form. I had 
answered 
read it 
to 
or it 
my 
has been 
satisfaction. 
read 
I 
to 
agree 
me. I 
to take 
understand 
part in 
the 
this 
study.
infonm
 
I 
study 
understand 
that may 
that I 
affect 
will 
my 
be infonmed 
willingness 
of 
to 
any 
stay 
new 
in this 
findings 
research 
developed 
study. 
during the course of this research
legally Authorized Re1:>resentative signature·
 
Version Date: September 22, 201 I; 
Page 100112 
TuHs MC.-diCcll ccntt-f/TUHS IRB » 12043 
Approved on 10/75/2018 


Impact of Naloxegol (Movantik) on Prevention of Lower Gastrointestinal Tract Paralysis in Critically Ill 
Adults Initiated on Scheduled IV Opioid Therapy: A Randomized, Double-Blind, Placebo-Controlled, 
Phase II, Single-Center, Proof of Concept Study 
Principal investigator: Erik Garpestad, MO 
Check the relationship of the legally authorized representative to the subject (list in order of 
recognized hierarchy): 
    1. The health care agent, upon proper invocation of the health care proxy
11 
2. Spouse
LI 
3. Adult children
I I 4. The subject's parent
n 5. Adult siblings
LI 6. Legally appointed guardian or conservator. 
I have fully explained to-------ë----- the nature and purpose of the 
Legally Authorized Representative 
above-described study and the risks that are involved in its performance. I have answered all 
questions to the best of my ability. 
Printed Name of Principal Investigator or 
Position 
Person Conducting the Informed Consent Discussion 
Date 
Signature of Principal Investigator or 
Person Conducting the Informed Consent Discussion 
Witness Signature (for Non-English Speaking Persons or Phone Consent) 
Date 
Witness' Signature 
Version /)al<:: SepfemlH!r 22, 2018 
Witness Name 
Page 11 of 12 
Tufts Medical Center/TUHS IR8 tt 1)().13 
Approved on 10/2S/2018 



Prot_000.pdf: 
1 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
 
 
 
 
 
 
 
Impact of Naloxegol (Movantik) on Prevention of Lower Gastrointestinal Tract Paralysis in 
Critically Ill Adults Initiated on Scheduled IV Opioid Therapy: A Randomized, Double-Blind, 
Placebo-Controlled, Phase II, Single-Center, Proof of Concept Study  
 
Sponsor:   
 
Tufts Medical Center, Boston, MA through an Investigator-Initiated Research Grant from AstraZeneca 
Pharmaceuticals 
 
Principal Investigator:    
 
Erik Garpestad, MD, Director, Medical ICU, Tufts Medical Center, Boston, MA 
 
Sub-Investigators: 
 
John W. Devlin, PharmD, FCCM, FCCP 
Professor of Pharmacy, Northeastern University;  
Scientific Staff, Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, Boston, 
MA 
 
Harmony Allison, MD, Division of Gastroenterology, Tufts Medical Center, Boston, MA 
 
Kari Roberts, MD, Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, 
Boston, MA 
 
Ioana Preston, MD, Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, 
Boston, MA 
 
Anthony Faugno, MD, Division of Pulmonary, Critical Care and Sleep Medicine, Boston, MA 
 
Matthew Duprey, PharmD, Division of Pulmonary, Critical Care and Sleep Medicine, Boston, MA 
 
Eric Anketell, MBA, RN, CCRN, Clinical Nursing Director, Medical ICU and The Neely Neuroscience 
Center, Tufts Medical Center, Boston, MA 
 
Robin Ruthazer, MPH, Department of Biostatistical Research, Tufts Medical Center, Boston, MA 
 
Haregwoin Woldetensay, Clinical Research Coordinator, Tufts Clinical and Translational Science 
Institute, Boston, MA 
 
 
 
 
 


2 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ...................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................... 5 
1. 
INTRODUCTION .............................................................................................................. 6 
1.1 
Background ......................................................................................................................... 6 
1.2 
Research hypothesis ............................................................................................................ 7 
1.3 
Rationale for conducting this study .................................................................................... 7 
1.4 
Benefit/risk and ethical assessment ..................................................................................... 7 
2. 
STUDY OBJECTIVES ..................................................................................................... 11 
2.1 
Primary objective .............................................................................................................. 12 
2.2 
Secondary objectives ........................................................................................................ 12 
2.3 
Safety objective ................................................................................................................. 13 
3. 
STUDY PLAN AND PROCEDURES ............................................................................. 14 
3.1 
Overall study design and flow chart ................................................................................. 15 
3.2 
Rationale for study design, doses and control groups ....................................................... 18 
4. 
SUBJECT SELECTION CRITERIA................................................................................ 18 
4.1 
Inclusion criteria ............................................................................................................... 18 
4.2 
Exclusion criteria .............................................................................................................. 19 
5. 
STUDY CONDUCT ......................................................................................................... 20 
5.1 
Restrictions during the study ............................................................................................ 20 
5.2 
Subject enrollment  
5.2.1 
Informed consent process ...................................................................................... 20 
5.2.2 
Procedures for randomization ........................................................................................... 22 
5.3 
Procedures for handling subjects incorrectly enrolled ...................................................... 23 
5.4 
Blinding and procedures for unblinding the study ............................................................ 23 
5.4.1 
Methods for ensuring blinding .......................................................................................... 23 
5.4.2 
Methods for unblinding the study ..................................................................................... 23 
5.5 
Treatments......................................................................................................................... 23 
5.5.1 
Identity of investigational product(s) ................................................................................ 23 
5.5.2 
Doses and treatment regimens .......................................................................................... 24 
5.5.3 
Additional study drug ....................................................................................................... 25 
5.5.4 
Labeling ............................................................................................................................ 26 


3 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
5.5.5 
Storage .............................................................................................................................. 26 
5.6 
Concomitant and post-study treatment(s) ......................................................................... 26 
5.7 
Treatment compliance ....................................................................................................... 27 
5.8 
Discontinuation of investigational product ....................................................................... 27 
5.8.1 
Procedures for discontinuation of a subject from investigational product ........................ 27 
5.9 
Withdrawal from study ..................................................................................................... 27 
6. 
COLLECTION OF STUDY VARIABLES ...................................................................... 27 
6.1 
Recording of data .............................................................................................................. 28 
6.2 
Data collection at enrolment and follow-up ...................................................................... 28 
6.2.1 
Enrollment procedures ...................................................................................................... 28 
6.2.2 
Follow-up procedures ....................................................................................................... 28 
6.3 
Efficacy ............................................................................................................................. 28 
6.3.1 
Efficacy variables .............................................................................................................. 28 
6.4 
Safety ................................................................................................................................ 28 
6.4.1 
Definition of adverse events ............................................................................................. 28 
6.4.2 
Definitions of serious adverse event ................................................................................. 28 
6.4.3 
Recording of adverse events ............................................................................................. 29 
6.4.4 
Reporting of serious adverse events.................................................................................. 29 
8. 
ETHICAL AND REGULATORY REQUIREMENTS .................................................... 29  
8.1 
Ethical conduct of the study .............................................................................................. 29 
8.2 
Ethics and regulatory review............................................................................................. 30 
8.3 
Informed consent .............................................................................................................. 30 
8.4 
Changes to the protocol and informed consent form ........................................................ 30 
8.5 
Audits and inspections ...................................................................................................... 30 
9. 
STUDY MANAGEMENT ............................................................................................... 31 
9.3 
Study timetable and end of study ...................................................................................... 32 
10. 
DATA MANAGEMENT .................................................................................................. 32 
11. 
EVALUATION AND CALCULATION OF VARIABLES 
11.1 
Calculation or derivation of efficacy variable(s)                           .................................... 32 
11.2 
Calculation or derivation of safety variable(s) .................................................................. 32 
11.2.1 
Other significant adverse events (OAE) ........................................................................... 32 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ....................... 32 
12.1 
Description of analysis sets ............................................................................................... 32 
12.1.1 
Efficacy analysis set .......................................................................................................... 32 
12.1.2 
Safety analysis set ............................................................................................................. 32 
12.2 
Methods of statistical analyses .......................................................................................... 32 


4 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
12.2.1 
Interim analyses ................................................................................................................ 33 
12.3 
Determination of sample size ............................................................................................ 33 
12.4 
Data monitoring committee .............................................................................................. 33 
13. 
LIST OF REFERENCES .................................................................................................. 35  
 
LIST OF TABLES 
 
Table 1 Study Plan 
 
 
 
 
 
 
 
 
 
15 
LIST OF APPENDICES 
Appendix 1.  Study Laxative Guideline  
 
 
 
 
 
 
 37 
 
Appendix 2.  Riker Sedation-Assessment Scale Score 
 
 
 
 
 
 38 
 
Appendix 3.  Numerical Pain Rating Scale 
 
 
 
 
 
 
 38  
 
Appendix 4.  Intensive Care Delirium Screening Checklist 
 
 
 
 
 39 
  
Appendix 5.  Bliss Stool Scale Score                                                                                                    40 
 
Appendix 6.  Clinical Opioid Withdrawal Scale Score                                                                        41 
 
Appendix 7.  Childs Pugh Score                                                                                                           42 
 
Appendix 8.  Data and Safety Monitoring Board Charter                                                                    43 
 
Appendix 9.  Daily Nursing Bedside Data Collection Form 
 
 
 
 
  47 
 
Appendix 10.  Daily Investigative Team Data Collection Form 
 
 
 
 
  53 
 
Appendix 11. Investigative Team Baseline Data Collection Form  
 
 
 
  57 
 
 


5 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
Abbreviations 
 
Abbreviation 
 
Explanation 
 
APACHE  
 
Acute Physiologic and Chronic Health Evaluation  
COWS  
 
Clinical Opioid Withdrawal Scale 
CVP 
 
 
Central venous pressure 
DSMB  
 
Data safety monitoring board 
ECG 
 
 
Electrocardiogram 
FDA 
 
 
Food and Drug Administration 
GI 
 
 
Gastrointestinal 
ICDCSC 
 
Intensive Care Delirium Screening Checklist 
ICU 
 
 
Intensive care unit 
INR 
 
 
International normalized ratio 
IV 
 
 
Intravenous 
IRB 
 
 
Institutional Review Board 
LAR 
 
 
Legally authorized representative 
MC 
 
 
Medical center 
NRS 
 
 
Numerical rating scale 
OIC 
 
 
Opioid induced constipation 
PAMORA 
 
Peripherally acting Mu opioid receptor antagonist 
SAE 
 
 
Serious adverse event 
SAS 
 
 
Sedation-Agitation Score 
SBM 
 
 
Spontaneous bowel movement 
SOFA  
 
Sequential organ failure assessment 
WOCBP 
 
Women of childbearing potential  
 
 
 
 


6 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
1. INTRODUCTION 
 
1.1 Background 
 
Among the more than 5 million adults who are admitted to an ICU each year in the USA, most receive IV 
opioid therapy.  Overall, IV opioid use in critically ill adults is increasing given the greater awareness of 
untreated pain in this population and a recent level 1 recommendation in the Society of Critical Care 
Medicine’s Pain, Agitation and Delirium Practice Guidelines for Critically Ill Adults that an analgesia-
first (analgo-sedation) approach be used to optimize patient safety and comfort and improve tolerance 
with mechanical ventilator support [1].  In critically ill adults with acute respiratory distress syndrome, 
high-dose infusions of opioids are frequently used to depress respiratory drive and reduce oxygenation 
needs.  
 
Paralysis of the lower gastrointestinal (GI) tract, defined as the inability to pass stool due to impaired 
peristalsis, is a common sequelae of opioid use in the critically ill. [2] As outlined in the 2012 
recommendation’s from the European Society of Intensive Care Medicine’s Working Group for Defining 
Gastrointestinal Function in Intensive Care Patients,  paralysis of the lower GI tract, defined as the 
absence of stool for 3 or more days, in the absence of mechanical GI obstruction, is the preferred 
terminology for opioid-associated bowel dysfunction rather than constipation given that the symptoms of 
constipation (e.g., painful defecation, abdominal pain, and a feeling of incomplete bowel evacuation) are 
not possible to evaluate in most patients in the ICU. Paralysis of the lower GI tract occurs in up to 72% of 
critically ill adults. [4-7]     
 
The frequent use in the ICU of tube feed formulations having low fiber, a lack of patient mobility, and 
restrictive fluid policies will further magnify the impact of opioids on the prevalence of lower GI tract 
paralysis in this population. [8-12]. Lower GI tract paralysis will often lead to nausea and vomiting, 
aspiration, compromise the ability to administer enteral nutrition (and thus reach nutritional goals), 
greater abdominal pain, and has been shown to delay extubation. Constipation in the critically ill has 
recently been reported to be associated with greater delirium [13] One recent randomized study found that 
aggressive use of laxatives to prevent lower GI tract paralysis in critically ill adults was associated with 
lower daily organ dysfunction [as measured by the Sequential Organ Failure Assessment (SOFA) 
score][14] The lower GI tract paralysis that occurs in the critically ill often responds poorly to stimulant 
and osmotic laxative therapy. [10, 11] 
 
1.2 Rationale for conducting this study 
 
While stool softeners are routinely administered to patients on opioids, laxative-based bowel protocols are 
frequently not initiated in the ICU until signs of lower GI tract paralysis start to become evident.  Even if 
laxatives were used earlier and more aggressively in the ICU care to prevent lower GI tract paralysis, a 
large proportion of patients receiving continuous IV opioid therapy would still not fully respond, and 
laxative-associated safety issues would increase. There is therefore an important unmet need for a safe 
and efficacious medication to prevent lower GI tract paralysis in critically ill adults who are initiated on 
IV opioid therapy. [10, 11] 
 
Naloxegol, a pegylated naloxone tablet formulated for once daily oral administration, is a peripherally 
acting μ opioid receptor antagonist with established efficacy and safety in treating opioid-induced 


7 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
constipation (OIC) in non-ICU patients receiving scheduled moderate to high dose opioids for the 
treatment of chronic non-cancer pain. [10] Naloxegol has a mechanism of action, efficacy, convenience of 
administration, and safety profile that make it an ideal candidate for use as a preventative medication for 
lower GI tract paralysis in critically ill adults receiving continuous IV opioid therapy. A Phase II, proof of 
concept  study to evaluate the efficacy and safety of naloxegol as a strategy to prevent lower GI tract 
paralysis in these high-risk critically ill adults, and to serve as  guide for future larger RCTs in this area, is 
crucial in filling a major knowledge and care gap in critical care practice.  
 
Despite the prevalence of lower GI tract paralysis in the ICU, large knowledge gaps exist regarding its 
epidemiology, the optimal way to define it, and the ideal methods that should be used to characterize its 
severity and resolution.  Moreover, the fact that that no lower GI tract paralysis prevention strategy has 
ever been evaluated in the critically ill using a randomized, controlled design makes it unclear what a 
reasonable treatment effect should be and what the variability would be for any particular efficacy 
outcome that is chosen.   
 
Therefore, while a strong rationale can be made that naloxegol may safely and effectively prevent lower 
GI tract paralysis in critically ill adults administered opioids, there is an important need for a rigorous 
Phase II proof of concept  study to help justify and inform future research efforts with naloxegol in this 
population. Such a Phase II proof of concept investigation should be randomized and double-blind and 
carefully evaluate the validity and feasibility of the different endpoints that can used to evaluate naloxegol 
safety and efficacy in the ICU patient at high risk for lower GI tract paralysis.  This Phase II proof of 
concept investigation will allow for a much better characterization of how lower GI tract paralysis 
develops (and resolves) in the critically ill and also help define the variability that exists around each of 
the clinical endpoints that are evaluated.  The recent finding that resolution of constipation will reduce 
organ dysfunction suggests that abdominal pressure monitoring may serve as an important secondary 
outcome in any study focused on evaluating the efficacy of a new intervention to reduce lower GI tract 
paralysis in critically ill adults. [14] This Phase II proof of concept  study is critical in not only justifying 
the potential completion of larger investigations in this area but also to ensure, if they are justified, that 
they are correctly designed in terms of sample size, primary and secondary outcomes and how potential 
confounders are identified and managed.  While larger investigations that have the power to evaluate 
important outcomes like nutrition delivery, delirium, use of early mobilization, duration of mechanical 
ventilation,  length of ICU stay, ICU mortality and healthcare costs are critical when evaluating the true 
clinical benefit/impact of naloxegol as a lower GI tract paralysis prevention strategy in the critically ill, 
given the substantial time, effort and expense of conducting large multicenter studies in this area, it is 
critical that future research efforts be meticulously planned through thoughtful and rigorous Phase II 
proof of concept  investigations like the one proposed.  
 
1.3 Research hypothesis  
 
Naloxegol will prevent lower GI tract paralysis in critically ill adults initiated on scheduled intravenous 
opioid therapy and its use will not lead to safety concerns.   
 
1.4 Benefit/risk and ethical assessment 
 
The package insert for naloxegol contains warnings that necessitate an assessment of the risk/benefit in 
the context of its planned use in this protocol.  
 


8 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Potential Benefits 
Lower GI tract paralysis occurs frequently in the ICU as a result of opioid initiation and is associated with 
substantial patient morbidity including discomfort, underfeeding, prolonged mechanical ventilation, 
delirium and potentially worsening organ dysfunction.  The administration of currently available 
laxative(s) frequently does not prevent lower GI tract paralysis and thus there is a need for efficacious and 
safe therapies to prevent lower GI tract paralysis secondary to opioid use in critically ill adults. Naloxogol 
(Movantik) is new oral gut-selective Mu-receptor antagonist that is FDA-approved for the treatment of 
opioid-induced constipation in non-critically ill adults without cancer.   In two large randomized 
controlled studies of patients with opioid-induced constipation (many of who were received one or more 
laxative treatments) it has been shown to be efficacious in quickly resolving opioid-induced constipation. 
If naloxegol is shown to be effective in preventing opioid-induced lower GI tract paralysis, it will 
represent an important advance in the care of the critically ill.   
 
Potential Risks 
 
a. Naloxegol is contraindicated in patients with known or suspected gastrointestinal obstruction and 
patients at increased risk for recurrent obstruction due to potential for gastric perforation.  
 
The following steps have been taken in the protocol to minimize the risk for this adverse event:   
Patients with proven or suspected gastric obstruction are excluded from the study.  
 
b. Naloxegol is contraindicated in patients concomitantly taking strong CYP3A4 inhibitors (e. g.,   
clarithromycin, ketcononazole) given the likehood that the concomitant use of these agents will lead 
to supratherapeutic serum concentration (which could potentially induce opioid withdrawal).   
 
The following steps have been taken in the protocol to minimize the risk for this adverse effect:  
Patients taking a strong CYP3A4 inhibitor are excluded from the study. If there is a clinical need to 
use a strong CYP3A4 inhibitor medication (and another therapeutic option without these properties is 
not available) then the subject will be removed from the study.  
 
c.  In the package insert, it is stated that naloxegol is contraindicated in patients concomitantly taking 
strong CYP3A4 inducers (e.g. rifampin, carbamazepine, St. John’s Wort) as it could significantly 
decrease plasma naloxegol concentratios and may decrease the efficacy of naloxegol (Movantik).  
 
The following steps have been taken in the protocol to minimize the risk for this effect. Patients 
taking a strong CYP3A4 inducer are excluded from the study. If there is a clinical need to use a 
strong CYP3A4 inducer medication (and another therapeutic option without these properties is not 
available) then the subject will be removed from the study.  
 
d. Cases of gastrointestinal perforation have been reported with the use of another peripherally acting 
mu opioid receptor antagonist (PAMORA) when used in patients who have a diffuse or local 
reduction in the structural integrity in the wall of the gastrointestinal tract.  
 
The following steps have been taken in the protocol to minimize the risk for this adverse effect.   The 
following patients are excluded from the study: i. admitted with an acute GI condition (e.g., clinical 
evidence of acute fecal impaction/complete obstruction, acute surgical abdomen, acute GI bleeding), 
ii. having a condition affect affecting GI motility or function (e.g. inflammatory bowel disease 


9 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
requiring immunosuppressive therapy, symptomatic Clostridium difficile, active diverticular disease, 
surgery on the colon or abdomen within 60 days of ICU admission or iii. having a history of 
constipation at the time of ICU admission.  
 
e. The effect of severe hepatic impairment (e.g. Cirrhosis with a Child-Pugh Class scale score of B or C) 
on the pharmacokinetics of naloxegol has not been evaluated.   
 
The following steps have been taken in the protocol to minimize the risk for this adverse effect:   
Patients with severe hepatic impairment are excluded from the study.  
 
f. Naloxegol has been very rarely associated with signs of opioid withdrawal.  
 
The following steps have been taken in the protocol to minimize the risk for this adverse effect:   
 
i. 
Patients having an acute disruption of the blood brain barrier (that could potentiate naloxegol 
absorption to the CNS) are excluded from the study.  
ii. 
Patients taking scheduled opioids at the time of ICU admission are excluded.  
iii. 
Each study patient will be carefully monitored before and 2 hours each study dose for signs 
of opioid withdrawal using the Clinical Opioid Withdrawal Scale (COWS) score. 
 
g.  No data regarding use of naloxegol in pregnancy and its use in a pregnant female taking opioids may 
precipitate opioid withdrawal in the infant.  
 
The following step has been taken in the protocol to minimize the risk for this adverse effect.  All 
female patients will be screened with a pregnancy test prior to study enrollment and if found to be 
pregnant will be excluded from the study.  
 
h. No data regarding use of naloxegol in lactating mothers and its use in a lactating female taking 
opioids may precipitate opioid withdrawal in the fetus.  
 
The following step has been taken in the protocol to minimize the risk for this adverse effect.   All 
lactating females will be excluded from the study.  
 
i. 
In the package insert, it is recommended that maintenance laxative therapy be discontinued before 
starting naloxegol and that laxative therapy should only be resumed in those patients who have OIC 
symptoms and after no sooner than 3 days after naloxegol was initiated. 
 
This recommendation is based on the treatment of OIC in an outpatient setting and is not based on the 
usual clinical practices that are used to prevent lower GI tract paralysis in the ICU.  Given that half 
the patients in the study will be randomized to placebo (in a blinded fashion), it is important that 
normal ICU lower GI tract paralysis prevention practices are incorporated into the research protocol.  
It is standard practice that all patients initiated on opioid therapy in the medical ICU at Tufts MC are 
started on scheduled docusate therapy and then managed with a step-wise laxative therapy (in a 
similar fashion to the laxative protocol developed for the study) as symptoms of lower GI tract 
paralysis develop and persist.  The study laxative protocol accounts for patients who do have a SBM 
(i.e., laxative therapy is down-titrated/stopped), and stool softness and frequency is carefully being 
monitored as part of the study, so it is not expected that study patients, regardless of study 


10 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
assignment, will receive a greater amount of laxative therapy than is clinically necessary to prevent 
lower GI tract paralysis.  
 
j. 
Scheduled use of opioids (≥ 100 mg morphine equivalents per day in the week  
prior to ICU admission) is a study exclusion criteria.  This is information may be considered sensitive 
information and should be carefully collected in a de-identified fashion.  
 
During the study screening process, the patient’s medical record will be reviewed to see if the patient 
has a history of opioid use (both prescribed and non-prescribed).  In addition, at the beginning of the 
consent discussion, the patient (legally authorized representative) will be asked whether the patient 
has used an opioid in the past week.  If such use is not detected (i.e., through both methods), the 
patient will be deemed NOT to meet this study exclusion criteria.  The study screening log (where the 
reason(s) for patient exclusion is documented) are completed de-identified so this information 
regarding opioid use will remain protected. If this opioid use history information is already 
documented in the patient record, then the patient will be excluded from study participation and the 
study team will never meet with the patient/authorized representative.  If this opioid use history 
information is not documented in the patient record, but then identified through a discussion with the 
patient (or legally authorized representative), it will remain in the confidence of the investigative team 
(ie. not provided to the medical team) and documented in a de-identified fashion only on the study 
screening log as an exclusion criteria.   
k. Removal of urinary (foley) catheters in the ICUs at Tufts MC is an important quality improvement 
initiative, will a urinary catheter be used solely for research purposes and is there a risk to inserting 
the bladder pressure transducer into a foley catheter that is already in place?  
The answer is never. The bladder pressure that is being measured for research purposes requires that a 
bladder catheter be in place (to aseptically insert the bladder pressure transducer into the bladder 
catheter, thus creating a closed system).   When the ICU team decides that a urinary catheter is no 
longer required for patient care then all bladder measuring will cease.  If a subject is enrolled in the 
study who does not have a urinary catheter in place, a urinary catheter will NOT be inserted for 
research purposes.  The study investigators met with the Tufts Med Center Urinary Tract Infection 
Committee chaired by Shira Doron, MD, last fall to discuss two issues  
1. The Tufts Medical Center Urinary Tract Infection Committee felt that the insertion of the 
pressure tranducer into the red foly port (ie breaking the seal) would not lead to a clinically 
significant enough risk for a caUTI that would preclude abdominal pressure monitoring as part of 
the study.  
Action: The investigators will raise the fact that there may be a very small risk for caUTI with 
abdominal pressure monitoring in the research protocol (in the risk/benefit portion) and will 
include a statement of this risk in the study ICF.  
 
2. The Tufts Medical Center Urinary Tract Infection Committee was concerned that foley catheters 
may be left in place longer for abdominal pressure monitoring than would be clinically required 
(particularly given that ICU clinicians may sometimes "search" for an excuse to keep the foley 
catheter in place).  Dr. Devlin (on behalf of Dr. Garpestad) emphasized that there was no intent, 
on the part of the investigators, to keep a foley in place longer than was clinically necessary.   In 
no instance, would a foley be inserted solely for abdominal pressure monitoring.  
 


11 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
The investigators will incorporate in the research protocol that MICU service will be formally 
asked each morning whether the foley catheter can come out of the patient (and to emphasize to 
the MICU team that a foley catheter should only remain in the patient if there is a clinical 
need).  The answer to this question will be formally documented on the daily bedside study data 
collection form.  
 
2. STUDY OBJECTIVES 
 
Given that there is no one “gold-standard” way to characterize the efficacy of naloxegol to prevent lower 
GI tract paralysis in critically ill adults administered scheduled opioids, given the Phase II, proof of 
concept nature of this investigation we plan to consider multiple outcomes to evaluate naloxegol’s 
efficacy in this population.   Since the original April 2015 protocol submission, in an effort to help better 
define those outcomes that are most relevant to clinicians when they are considering the efficacy (and 
safety) of a preventative strategy like naloxegol in their critically ill patients at risk for lower GI tract 
paralysis, we informally surveyed clinicians at Tufts Med Center (and elsewhere). Of note, time to the 
first spontaneous bowel movement (SBM) (which is directly related to our primary outcome of prevention 
of lower GI tract paralysis) was suggested most frequently as the most clinically relevant outcome when 
evaluating a new lower GI tract paralysis prevention intervention. Clinicians noted that once a patient 
receiving scheduled opioid therapy has their first SBM (and remained on any particular lower GI tract 
prophylaxis regimen) that the patient should ideally be expected to have a SBM at least daily. Therefore, 
these clinicians felt that comparing the ICU days without a SBM (noting that when 3 days without a SBM 
is met, the definition for lower GI tract paralysis is met) was also a clinically meaningful way to compare 
naloxegol with placebo.  While most respondents questioned whether it was necessary (or even possible) 
to rigidly define a SBM (e.g., based on a specific fecal output volume), they suggested that we collect the 
following data for each SBM [1. Stool volume (i.e., small, medium or large) and 2. Stool consistency (i.e. 
using the Bliss stool scale score)]  Clinicians generally felt that the other outcomes that were proposed in 
the previous version of this protocol (for both efficacy and safety) in April 2015 were all appropriate and 
should all be collected given the pilot nature of this investigation.  With the recently published study by 
Palacio de Azeda et al [13] that found that the use of an aggressive daily lactulose and enema protocol 
reduced the average daily SOFA (organ severity) score, and that highlighted that there may be an 
important connection between lower GI tract paralysis and abdominal pressure, we would like to 
incorporate collection of daily SOFA scores and thrice daily measurement of abdominal pressure as an 
efficacy outcome in the study.   Lastly, a recent paper found a strong relationship between delirium and 
lower GI tract paralysis in the critically ill and thus we propose to monitor each subject twice daily for 
delirium. [12]. 
 
Overall Study Aim 
The overall aim of this Phase II, proof of concept study is to evaluate the efficacy and safety of naloxegol 
(versus placebo) in preventing lower GI tract paralysis in critically ill adults initiated on scheduled 
intravenous (IV) opioid therapy. 
 
2. 1 Primary objective  
 
The primary objective of this single-center, Phase II, proof of concept study in critically ill adults initiated 
on scheduled IV opioid therapy is to compare the incidence of lower GI tract paralysis [from the time of a 
study enrollment (i.e., randomization) to ICU discharge, death or 10 days of study drug administration 
(whichever comes first)] between naloxegol 25mg daily and placebo-treated groups.   


12 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
Note:   
1. For the purposes of the study, any rectal output will be considered a SBM as long as it not temporally 
related to the insertion of a rectal tube or the insertion of a suppository (as per the study laxative protocol    
(Appendix 1).   
2. Patients with preexisting lower GI tract paralysis are excluded from the study.  
3. Patients not expected to survive their ICU stay are excluded from the study.  
 
2. 2 Secondary objectives  
 
To compare the efficacy of naloxegol (with placebo) in critically ill adults initiated on scheduled IV 
opioids on each of the following outcomes:  
  
During the period from time of scheduled opioid therapy initiation (IV fentanyl equivalent dose ≥ 
100 mcg/day) until ICU discharge, death or 10 days of study drug administration (whatever 
comes first): 
(Note: there are up to three days to enroll and randomize subject after the initiation of scheduled 
opioid therapy). 
 
a. Incidence  of lower GI tract paralysis (≥ 3 days without a SBM)  
b. Time to first SBM (in hours)  
c. Days without a SBM  
d. Average daily opioid requirement [in IV fentanyl equivalents (mcg)]. 
Note:   
1. For the purposes of inclusion in the study, only opioids administered by the IV route will be considered 
but to calculate the daily opioid requirement all opioids administered (regardless of route) will be 
considered.  All enteral/oral opioids will be reduced by 50% when converting to the IV fentanyl 
equivalent.  
2.  Administration of opioids will be mandated by the ICU team (as per routine clinical practice based on 
the ICU team evaluation of regular pain assessment scores) and will not be protocolized as part of the 
study.  
3.  While IV fentanyl is the most common IV opioid used in the medical ICU at Tufts MC, other opioids 
(e.g. IV and oral hyromorphone, oral oxycodone) are used at times.  Choice of opioid during routine 
patient care is currently not protocolized in the ICUs at Tufts MC and will not be protozolized as a part of 
this study.  The choice and amount of opioid administered each day will be collected as part of the study.  
 
During the period from time of study enrollment (i.e., randomization) to ICU discharge, death or 10 
days of study drug administration (whatever comes first): 
 
e. Time to first SBM  
f. Daily characterization of each SBM for size (small, medium or large)  
g. Daily characterization of each SBM for consistency (using the Bliss Stool Scale)  
h. Daily characterization of use of the study laxative guidelines.  
i. 
Daily volume of enteral nutrition administered.  
j. 
% of daily enteral nutrition goal met.  
k. Daily fluid balance (i.e., 24 hr ins and outs) 
l. 
Daily maximal pain scale score (using nurse-administered 10 point rating scale) 


13 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
m. Daily Sedation Assessment Scale (SAS) score 
a. Average 
b. Presence of coma (SAS = 1 or 2) 
n. Daily presence of delirium using the Intensive Care Delirium Screening Checklist (ICDSC) 
a. Proportion of patients ever found with delirium (ICDSC ≥ 4] 
b. Days with delirium 
c. Proportion of patients ever found with subsyndromal delirium [ICSDC = 1 to 3] 
d. Days with subsyndromal delirium 
o. Daily total sedation administered (in midazolam equivalents)  
p. Occurrence of lower GI tract paralysis requiring consultation by a gastroenterologist or a surgeon.  
q. Days without mechanical ventilation support. 
r. Duration of ICU stay. 
s. In patients having a clinical reason for foley catheter placement, abdominal pressure measurement 
every 8 hours:  
i) % patient of patients having abdominal pressure ≥ 12 mmHg;  ii) % patient of patients having 
abdominal pressure ≥ 20 mmHg;  iii) Average daily maximal abdominal pressure score 
t.     Time from first initiation of ≥ 100 fentanyl equivalents to administration of first dose of study   
        medication.  
 
2. 3 Safety objectives 
To compare the safety of naloxegol (with placebo) in critically ill adults initiated on scheduled IV opioids 
for each of the following outcomes:  
 
During the period from time of study enrollment (i.e. randomization) to ICU discharge, death or 10 
days of study drug administration (whatever comes first):  
 
a. Diarrhea:  
a. Daily presence 
b. Time from study drug initiation to first episode of diarrhea 
       Note:  Diarrhea is defined where ≥ 3 loose or watery stools 24 hour period as defined by a Bliss stool  
       scale score of 3 (loose and unformed stool) or 4 (liquid stool)].  
 
b.    Days without a diaper or rectal tube 
c.    Days without a rectal tube 
d.    Daily difference in the pre-dose and post-dose Clinical Opioid Withdrawal Scale (COWS) score (as   
       evaluated by the bedside nurse before and 2 hours after the administration of the daily study drug    
       dose).  
 
3. STUDY PLAN AND PROCEDURES  
 
This study will be conducted at Tufts Medical Center in Boston, MA.  No study-related procedures will 
be conducted at Northeastern University.  
 
3.1 Overall study design and study flow chart 
 


14 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
This will be a Phase II, proof of concept, single-center, randomized, double-blind, placebo-controlled 
pilot study to assess the efficacy and safety of naloxegol for preventing lower GI tract paralysis in 36 (18 
naloxegol; 18 placebo) medical critically ill adults who require scheduled IV opioid therapy. 


15 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
Table 1.    Study Plan  
 
Study period 
ICU admission 
and initiation of 
scheduled opioid 
Treatment 
Period 
(maximum of 10 days)  
Study drug 
stopped or 
early 
termination 
Discharge 
from ICU 
 
Study day 
Maximum of 72 hrs 
to enroll patient 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
Screening 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Use of study laxative guideline 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Administration of study medication  
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Baseline demographic information 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria  
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test for WOCBP 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy outcomes 
Monitoring that is a routine part of  care at Tufts MC 
Bedside nurse 
Documentation of all SBMs 
√ 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Volume of enteral nutrition administered 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Fluid balance 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Sedation assessment SAS q6h) 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Pain assessment (numerical rating q6h)  
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Delirium assessment (ICSDC q12h) 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Investigative team 
Documentation of study laxative 
guideline use 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
% of daily enteral nutrition goal achieved 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Daily opioid requirements 
√ 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Daily sedative requirements 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 


16 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Serum creatinine to calculate creatinine 
clearance 
√ 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Monitoring that is not a routine part of care at Tufts MC 
Bedside nurse 
Characterization of each SBM for size 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Characterization of each SBM using the 
Bliss Scale 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Measurement of bladder pressure in 
subjects with a foley catheter in place for 
a clinical reason (to estimate abdominal 
pressure) q8h 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Investigative team 
Requirement for mechanical ventilation 
√ 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
SOFA score calculation (daily)  
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Occurrence of lower GI tract paralysis 
requiring a GI or surgical consult 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Safety outcomes 
Monitoring that is a routine part of care at Tufts MC 
Bedside nurse 
Presence of diarrhea 
√ 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Investigative team  
Presence of a diaper or rectal tube 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Monitoring that is not a routine part of care at Tufts MC 
Bedside nurse 
Characterization of diarrhea using the 
Bristol Scale 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Evaluation for opioid withdrawal using 
the COWS scale before and 2 hours after 
each daily study dose 
 
√ 
√ √ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Additional assessments not included in table:  
1. Baseline demographics [age, gender, APACHE II score, Charlson comorbidy scale score, primary reason for ICU admission (based on 
APACHE III criteria)], baseline comorbidities potentially associated with an increased risk for lower gastrointestinal tract paralysis, treatments 


17 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
received at the time of ICU admission or administered after ICU admission that might influence SBM frequency and/or lower gastrointestinal 
tract paralysis incidence, and primary reason(s) for scheduled opioid initiation.  
2. Evaluation for adverse events 
 
Impact of Level of Sedation on Patient Assessments: Patients admitted to the Medical ICU at Tufts MC are generally maintained in an 
awake or lightly sedated state.  For a patient who may require a short period of deeper sedation all of the following assessments above 
will be able to be still evaluated/collected except:  COWS 


18 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
3.2 Rationale for study design, doses and control groups.  
 
There are many potential sources of bias in study that investigating the efficacy of safety of naloxegol for 
the prevention of lower GI tract paralysis in critically ill adults and thus a double-blind, placebo-
controlled study is the gold standard study design to use.   There is no reason to suggest that a dose of 
greater than 25mg daily of naloxegol (the current FDA-approved dose for the treatment of opioid induced 
constipation) is not the appropriate dose for this pilot investigation.  As outlined in the current package 
insert, the study dose will be reduced to 12.5mg daily when patients are concomitantly administered a 
moderate CYP314 inhibitor or who have renal dysfunction (calculated creatinine clearance ≤ 60 ml/min).   
Given that this is a randomized study, the treatment and control groups should be identical.  Initiation of 
docusate 100mg twice daily is a standard of practice in all patients receiving an opioid who are admitted 
to the medical ICU service at Tufts Medical Center.  Given that it remains unknown if naloxegol is 
efficacious in preventing lower GI tract paralysis in critically ill adults and that half the patients will be 
administered placebo, all patients will be managed with an aggressive standardized laxative protocol that 
is based on the most common clinical practices in the ICUs at Tufts Medical Center.  
 
4.  SUBJECT SELECTION CRITERIA 
 
The investigators will maintain a screening log for the duration of the study.  
 
Each patient will meet all of the inclusion criteria and none of the exclusion criteria.   A study screening 
sheet will be completed by a member of the investigative staff and confirmed by a second member of the 
investigation staff before randomization will occur.  
 
All patients consecutively admitted to the medical ICU service who are admitted to the MICU, CCU, 
SICU or NCCU at Tufts Medical Center will be screened on a daily basis (through review of the ICU 
admission note, available laboratory data, the medication administration record, and the patient flowsheet 
by one of the study investigators who will determine if the patient meets all inclusion and exclusion 
criteria for participation in the study.  
 
When the patient is found to meet all inclusion and no exclusion criteria, and Drs. Garpestad, Preston or 
Roberts have reviewed and signed the screening form, and the patient’s primary ICU attending has 
approved their enrollment, the subject/legally authorized representative will be approached (either in 
person or by phone (ie. invited to come to Tufts MC to discuss the study) during the periods of 7am to 
7pm.  
 
4. 1. Inclusion criteria  
 
a. Admitted to the medical ICU service. 
 
b. Age ≥ 18 years. 
 
c. Expected by the medical ICU attending physician to require admission to the MICU service for ≥ 48 
hours.  
 
d. Intravenous opioid administration in the prior 24 hours of ≥ 100 mcg fentanyl equivalents (including 
both scheduled and “as needed” therapy). 


19 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
e. No objections from the MICU or attending physician for enrollment.  
 
4. 2 Exclusion criteria 
 
a. Scheduled use of morphine, oxycodone, hydromorphone, fentanyl ≥ 100 mg morphine equivalents per 
day in the week prior to ICU admission as evaluated by medical record review and/or interview with 
patient and/or family.  
 
b. Scheduled use of methadone at any dose in the week prior to ICU admission as evaluated by medical 
record review and/or interview with patient and/or family.  
 
c. History of constipation (as defined by the scheduled use of bisacodyl, senokot, lactulose, PEG 3350 
(Miralax) and/or Fleet enema) prior to ICU admission as evaluated by medical record review and/or 
interview with patient and/or family.  
 
d. Current scheduled use a medication affecting gastric motility (i.e., metoclopramide, domperidone, 
erythromycin and loperamide).  
 
 
e. Current use of medication known to be a strong CYP3A4 inhibitor (itraconazole, lopinavir/ritonavir, 
clarithromycin, ritonavir, ketoconazole, indinavir/ritonavir, voriconazole, nefazodone). 
 
f. Current use of a medication known to be a strong CYP3A4 inducer (rifampin, carbamazepine, St. John’s 
Wort). 
 
g. Known serious or severe hypersensivity to naloxegol (Movantik) or any of its excipients.  
 
h. Patients admitted with a history of a neurologic condition that may affect the permeability of the blood-
brain barrier (e.g. multiple sclerosis, recent brain injury, Alzheimer’s disease, uncontrolled epilepsy, acute 
stroke, acute meningitis). 
 
i. Patients admitted with an acute GI condition (e.g., clinical evidence of acute fecal impaction/complete 
obstruction, acute surgical abdomen, acute GI bleeding).   
 
j. Patients with a condition affecting GI motility or function (e.g. inflammatory bowel disease requiring 
immunosuppressive therapy, symptomatic Clostridium difficile, active diverticular disease, surgery on the 
colon or abdomen within 60 days of ICU admission. 
 
k. Patients with underlying cancer who are at heightened risk of GI perforation such as those with 
underlying malignancies of the GI tract or peritoneum, recurrent or advanced ovarian cancer, vascular 
endothelial growth factor inhibitor treatment.  
 
l. Current use of total parenteral nutrition 
 
m Administration of enteral nutrition through a jejeunal tube.   
 
n. Severe hepatic dysfunction  


20 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
[Defined as either: i. INR ≥ 2.0 (not related to warfarin therapy) AND total bilirubin ≥ 2 or ii. Diagnosis of liver 
cirrhosis as defined by Child-Pugh classes B or C or iii. acute liver disease is the primary reason for admission to 
the ICU.]  
 
o. Inability to enroll in study and initiate study medication within 72 hours of the patient being first initiated on IV 
opioid therapy after ICU admission. 
 
p. Unreliable method for enteral, gastric and/or oral medication administration (e.g., no feeding tube, NG tube is 
on suction). 
 
q. Current or previous use of an opioid antagonist agent (e.g., naloxogel, methylnaltrexone) agent in the past 30 
days. 
 
r. Patients expected to expire within 24 hours. 
 
s. Pregnant or actively lactating females.  
 
t. Current participation in another interventional clinical study. 
 
u. Inability to obtain informed consent from either the subject or their legally authorized representative. 
 
5. STUDY CONDUCT 
 
5. 1 Restrictions during the study  
 
Restrictions regarding laxative use, restricted medications and requirements for change in the study drug 
dose are provided in Section 5.6 
 
5.2  Subject enrollment, randomization and the initiation of the investigational product 
 
5.2.1  Informed Consent Process 
 
All patients consecutively admitted to the medical ICU service who are admitted to the MICU, CCU, 
SICU or NCCU at Tufts MC will be screened on a daily basis (through review of the ICU admission note, 
available laboratory dat, the medication administration record, and the patient flowsheet by one of the 
study investigators who will determine if the patient meets all inclusion criteria and has no exclusion 
criteria participation in the study.  An enrollment screening sheet (submitted to IRB) will be reviewed and 
signed by either Dr. Garpestad, Dr. K. Roberts or Dr.Preston before the patient/LAR is approached for 
consent.   
 
For non-English speaking patients (legally authorized representatives) who are invited to participate in the 
study, and an IRB-approved Short Form consent exists for their language,  the IRB-approved consent 
Short Forms per the IRB’s Short Form policy will be used during the consent discussion.  
Informed consent will be obtained by Drs. Garpestad, Devlin, Duprey, Faugno, K. Roberts, or Preston. 
Approval will be obtained from the subject’s Medical ICU attending physician before a consent 
discussion occurs.  Dr. Devlin is a critical care pharmacist researcher with more than 20 years of 


21 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
experience in obtaining patient consent from critically patients (or their legally authorized 
representatives). In the numerous ICU clinical trials he has served as a co-investigator/research 
coordinator at Tufts Medical Center he has led consent discussions for more than 400 patients. Over the 
past 6 months, Dr. Duprey has been trained by Drs.Garpestad and Devlin to conduct high quality consent 
discussions for this study. During March/April 2017,  Drs. Garpestad and/or Devlin carefully evaluated 5 
different consent discussions conducted by Dr. Duprey using an IRB-approved review metric and found 
that Dr. Duprey can conduct high-quality consent discussions that meet all of the criteria of the Tufts MC 
IRB.  Drs. Devlin, Duprey and Faugno will always ensure that Dr. Garpestad (or Dr. Preston or Dr. K. 
Roberts) will always be available to participate in a consent discussion should questions (medical or 
otherwise) come up that Dr. Devlin, Dr. Duprey or Dr. Faugno feel he is not qualified to answer.  Given 
Drs Devlin, Faugno and Duprey’s experience in consent discussions with ICU patients/their 
representatives, there are no plans to have the PI or a medical Co-I be present during all or part of the 
consent process unless the ICU patient (or their representative) have questions that Dr. Devlin. Faugno, or 
Duprey cannot answer.  
All patients will be evaluated by a member of the investigative team to determine if they have the mental 
capacity to provide consent for study participation. For the purposes of this study, a patient will be 
deemed to be cognitively intact if they have an ICDSC=0 (i.e. neither delirium nor subsyndromal 
delirium) and are not sedated. It is expected that the vast majority of patients will be not able to initially 
provide consent given their critical care illness and the use of scheduled opioids that have sedative 
properties.  In addition, it is estimated that about two-thirds of the potential subjects will be mechanically 
ventilated and thus all be received sedative medications.  Furthermore, close to 70% of patients of all 
patients admitted to the ICU have delirium or subsyndromal delirium, cognitive states that prevent 
obtaining consent from subjects.  Drs. Garpestad, Preston, K. Roberts , Devlin, Duprey and Faugno will 
each be able to determine whether the subject is able to provide informed consent.  As per the ICF, a 
legally recognized representative will be recognized in the following order:  healthcare proxy (that is 
documented and verified) > spouse >adult child > parent of guardian > adult sibling.  
Before the enrollment of a decisionally-impaired subject Drs. Garpestad, Preston, K. Roberts, Devlin, 
Faugno and/or Duprey will confirm that the study is not prohibited by law for this subject.  The legally 
authorized representative will be contacted and invited to meet face-to-face with one of the investigators 
to provide written consent at Tufts Medical Center.  Permission will be obtained from the primary 
provider for the participation of the patient in the study before the legally authorized representative is 
contacted.  All consent discussions with a legally authorized representative will take place in location at 
Tufts MC that is both private and quiet (e.g., an ICU conference room). The legally authorized 
represenative (or the patient) will be provided with a copy of the consent form to read and all questions 
will be answered prior to their signing the consent.  All sections of the ICF will be carefully reviewed 
including the fact that the legally authorized representative is free to discontinue the participation of the 
subject at any time for any reason. No research related activities will occur prior to the consent being 
signed. The original signed ICF will be stored in the locked office of the investigator. A copy of the 
signed ICF will be given to the legally authorized representative and the methods (as outlined in the ICF) 
to research a member of the research team if they have additional questions will be emphasized.  The 
investigator’s recognize the potential vulnerability of the legally authorized representative in this setting 
(ie. having a relative who is critically ill) and thus will terminate the consent discussions in any situation 
where the legally authorized representative appears to be uncomfortable or apprehensive about providing 
consent for their relative to participate in the study.  In an effort to help recognize situations where the 
legally authorized representative may be apprehensive about providing consent, written informed consent 
will be obtained in the presence of the patient’s nurse.  The patient’s nurse is ideally suited to serve as a 


22 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
witness because they in fact may have met the legally authorized representative before. This procedure is 
frequently used for research studies in the ICUs at Tufts MC when consent is obtained from a legally 
authorized representative.  The investigator conducting the consent discussion with the legally authorized 
representative will confirm with the legally authorized represensative that the subject will be withdrawn 
from the study if they appear to be unduly distressed.   
 
Telephone Consent: 
 
In situations where it not possible for the LAR to physically come to Tufts Medical Center for an in 
person consent discussion (for example, lives outside of Boston area, inclement weather, LAR's 
schedule, study consent time frame, etc.), Drs. Garpestad, Devlin, Faugno or Duprey will conduct 
telephone consent:  
 
1) E-mail, fax, (or mail) the ICF to the LAR. (If mailed, 2 copies will be mailed, so the LAR can keep 
a copy.) 
2) The LAR will be instructed to contact Drs. Garpestad, Devlin, Faugno or Duprey after reviewing 
the ICF.  
3) The person consenting the LAR will have the same consent discussion via phone that they 
would have had in person (including asking questions to gauge comprehension and answering 
the LAR’s questions) 
4) A witness will be present during telephone consent (at Tufts Medical Center with the 
investigator conducting the consent process) 
5) If the LAR consents, the LAR will complete and sign the ICF (in all appropriate sections) and 
either e-mail a scanned PDF, fax, (or mail) the signed and dated ICF to the research team.  
6) The LAR should be instructed to keep one signed copy of the ICF for his/her own records. 
7) Once the ICF (signed & dated by the LAR) is received by the research team, the Investigator who 
explained the study should sign the appropriate signature line with the current date (the date 
they receive the ICF and sign, not the date they consented the LAR).  
8) Ensure all signatures and dates are accurately documented. Any errors should be noted in a 
note or memo to file.  
9) Document in a separate note to file/progress note, or with a note under the PI signature line on 
the ICF that consent was obtained over the phone with the actual date and mailed/e-
mailed/faxed back. For example “Discussed with [LAR name] via telephone on [insert date], and 
received signed consent form on [insert date].” 
 
No study-relacted activities will be conducted prior to consent being obtained.  
 
The investigative staff will regularly remind the ICU team that informed consent is indeed a process and 
that obtaining a signature on the ICF is part of that process. In all interactions with the subject (and their 
family) the investigative team will introduce ourselves so that the subject (and their family) can associate 
us with the study. We will also educate them on the study procedures as they progress. The trial requires 
that we explicitly interact with the subject through the study period. The patients cognitive status will be 
evaluated twice daily using the Intensive Care Delirium Screening Checklist (ICDSC) and their sedation 
level will be evaluated four times daily using the SAS.   When subjects are deemed to have an ICDSC 
score = 0 (ie.,neither subsyndromal delirium or delirium) and have a  SAS of 4 (ie. are awake) they will 
be considered to potentially have the potential capacity of providing informed consent. It should be noted 
there are other reasons besides delirium and sedation that would make a subject incapable for re-consent 


23 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
other than delirium.  The subject’s clinical team will also be asked to determine of they are now relying 
on the subject for decision making capacity.  Based on this process, on the day that the investigative team 
first determines that the subject has adequate decision making capacity to provide their own consent, the 
subject will be re-consented (in those situations where a legally authorized representative had originally 
provided consent). During this consent discussion the subject will be educated about the research that has 
been completed to date (in addition to what additional research activities lie ahead). If the subject does not 
wish to remain in the study, all study-related activities will stop and no research data collected to date will 
be used. This re-consent process and its result will be documented in the patient record.  
 
5.2.2 Procedures for randomization  
 
Subjects meeting all inclusion criteria and no exclusion criteria will be randomized by a pharmacist  
in the Tufts Medical Center investigational drug pharmacy to one of two study groups (ie. 
(naloxegol or placebo) on the first day.  Randomization (in blocks of 4) will take place by means of a  
computer-generated random-number table and will be developed by a pharmacist in the Tufts Medical  
Center investigational drug pharmacy.  This randomization schedule will assign each subject a study  
number, which will be used to identify treatment allocation (ie. naloxegol or placebo) and all study data  
that is collected during the study.   
 
5.3 Procedures for handling subjects incorrectly enrolled, randomized or initiated on the 
investigational product.  
 
Both the investigative team and the research pharmacists in the investigational drug pharmacy have 
extensive experience in conducting randomized, double-blind, medication-based trials in the ICUs at 
Tufts Medical Center.  An investigational screening sheet is always completed and verified by a 
secondary member of the investigative team before a patient/family is approached for consent and before 
randomization occurs.  Should the very unlikely situation occur that a patient is mistakenly enrolled in the 
study or consent is withdrawn by the patient (family member), a member of the investigative team will 
contact the study PI, the patient’s primary physician and the investigation drug pharmacy regarding this 
issue.  In all situations the Tufts Med Center IRB and AstraZeneca will be informed of this occurrence in 
a timely fashion.  
 
5.4 Blinding and procedures for unblinding the study  
 
5.4.1 Methods for ensuring blinding 
 
Subjects and all ICU caregivers will be unaware of the treatment assignments for the duration of the 
study.   The fact that AstraZeneca will be providing “the official” Movantik 12.5mg and 25mg placebo 
tablets for use in the study make it next to impossible for either the clinical or investigative team to know 
whether active drug or placebo drug is being administered.  
 
All investigators will remain blinded until the final study data set is analysed.  The study biostatistician 
will complete all analysis (including that required for intermittent analysis by the DSMB using a group A  
vs. group B approach.  The research pharmacist at Tufts Medical Center (or his/her designate) will have  
access to a computer randomization program in order to assign study treatment and he/she will be the 
only person who will have access to the treatment assignment group.  
 


24 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
5.4.2 Methods for unblinding the study 
 
If needed for medical reasons, a member of the investigative team will contact the research pharmacist (or 
designate) on a 24/7 basis to unblind the patient. In this instance the research pharmacist will provide the 
treatment allocation to a member of the clinical team.  The investigative team will remain blinded in all 
situations where a member of the clinical team is provided with the treatment allocation.  Any episode of 
unblinding will be documented by the research pharmacist.  
 
5.5 Treatments 
 
5.5.1 Identity of investigation products(s)  
 
The following investigative products will be used in this protocol: 
 
Treatment:  
 
Movantik 25mg tablet  
OR  
 
Movantik 12.5 mg tablet (for use in those situations where the protocol calls for the lower drug dose) 
 
Control:  
 
Placebo (Movantik) 25 mg tablet 
 
OR  
 
Placebo (Movantik) 12.5 mg (tablet) (for use in those situations where the protocol calls for the lower 
drug dose) 
 
Naloxegol placebo tablets and naloxegol active drug tables appear identical, even when crushed.  
 
5.5.2 Doses and treatment regiments 
 
Treatment arm: 
 
Naloxegol 25 mg daily [administered orally (or enterally)] 
 
A lower dose of naloxegol (12.5mg mg daily) will be administered in the following two situations:  
 
a. A patient who is receiving a moderate CYP3A4 inhibitor that includes diltiazem, erythromycin,  
fluconazole, or verapamil (at any dose)  
b. A patient with a calculated creatinine clearance (using the modified MDRD approach)  ≤ 60 
ml/min  
 
This based on the following information included in the Movantik package insert:  
 


25 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
1 
Under drug interactions:  The concomitant use of naloxegol and a moderate CYP3A4 
inhibitor may increase naloxegol serum concentrations.  If use cannot be avoided, the dose of 
naloxegol should be reduced to 12.5mg daily.   The investigators are hesitant to exclude all 
medical ICU patients receiving a moderate CYP3A4 inhibitors from the study given that the list 
of medications in this list is long and many are used with a high prevalence in the ICU (e.g. 
diltiazem, erythromycin, fluconazole, or verapamil).  With a 12.5 mg naloxegol tablet (and 
matching placebo) available from AstraZeneca, it will be feasible to administer the lower 12.5 mg 
daily naloxegol dose to subjects with this potential interaction without compromise the rigor or 
blinding of the study.  
2 
Under dosage and administration:  The starting dose for patients with a creatinine 
clearance ≤ 60 ml/min is 12.5 mg daily.  This dose recommendation is based on the fact that 
some patients with a creatine clearance ≤ 60ml/min who were exposed to naloxegol 25mg daily 
were shown to exhibit markedly higher systemic exposure to naloxegol compared to subjects with 
normal renal function.  Given that naloxegol is metabolized through the cytochrome P450 system 
of the liver, the reason for these high levels is not understood.  The investigators are hesitant to 
exclude all medical ICU patients with a calculated creatinine clearance ≤ 60 mL/min given that 
this population represents more than 50% of the medical ICU population.  With a 12.5 mg 
naloxegol tablet (and matching placebo) available from AstraZeneca, it will be feasible to 
administer the lower 12.5 mg daily naloxegol dose to subjects with renal dysfunction without 
compromise the rigor or blinding of the study.  
Note:   
 
Renal function often changes (either worsens or improves) during the ICU stay.  Therefore, the 
creatinine clearance will be calculated daily.  For a patient whose creatinine clearance drops to ≤ 
60ml/min during the study, the study drug dose will be reduced from 25mg daily to 12.5mg daily.  
For a patient whose creatinine clearance improves to ≥ 60ml/min during the study, the study drug 
dose will be increased to 25 mg daily.   
 
It is possible that medications with moderate CYP3A4 activity may either be clinical required or 
stopped during the period of the study.  If a patient requires the initiation of a medication with 
moderate CYP3A4 activity while receiving study medication (and other therapeutic alternatives 
without this property do not exist), then the study drug dose will be reduced to 12.5 mg daily.  If a  
medication with moderate CYP3A4 activity is stopped during the period of study drug 
administration then the study drug dose will be increased to 25mg daily on the day after the 
CYP 3A4 moderate inhibitor is stopped.  
 
If a patient enrolled in the study requires a strong CYP3A4 medication (and another therapeutic 
alternative without this property does not exist), then the patient will be removed from the study.  
 
Control arm:  
 
AstraZeneca Naloxegol 25 mg placebo daily [administered orally (or enterally)} 
 
A lower placebo dose of 12.5mg will be used for either of the above situations (ie. #1 or #2) where the 
12.5mg daily dose is warranted.  
 
Study drug administration:  
 
If oral study drug medication is not possible (e.g. intubation) then the study drug will be administered via 
a gastric or enteral tube as recommended in the Movantik package insert.  Tube feeds (if being 


26 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
administered) will be held for one hour and then the feeding tube will be flushed with 30 mL of sterile 
water (using a 60 mL oral syringe) given that no data exists as to whether naloxegol may bind to enteral 
nutrition.   Given that naloxegol (or matching placebo) is formulated as an easily crushed, film-coated 
tablet, the bedside nurse will crush the naloxegol (or matching placebo) tablet, mix in 60 mL of sterile 
water and draw up the contents (of the medication and sterile water) in a 60 mL oral syringe and 
administer via the gastric or enteral tube over 3-5 minutes.   The bedside nurse will rinse the vessel used 
to crush the medication with another 30mL of sterile water, draw up the contents into the oral syringe and 
administer over 3-5 minutes.  Tube feeds will then be restarted at the same pre-dose rate (i.e., if the 
patient was receiving tube feeds at the time of the study dose) one hour after the study drug dose is 
administered.  This is a method of administration of enteral drug administration that has been used in 
other ICU clinical studies where data on the enteral administration of the crushed tablet does not exist.  
 
5.5.3 Additional study drug  
 
Under no circumstances will additional study drug (other than that described in 5.5.1) be administered to 
a subject.  
 
5.5.4 Labeling 
 
Each dose of study medication (whether naloxogol or placebo) will be packaged in a unit of use package 
by the investigation drug service at Tufts Medical Center and hand delivered to subject’s bedside each 
morning.  Each package will be labeled with the following:  subject’s name, bed number, naloxegol or 
placebo, strength, the study number and a patient-specific bar code.   All normal medication 
administration screening and documentation procedures for medication administration in the medical ICU 
at Tufts Medical Center will be used (e.g. bar scanning, computerized medication administration profile 
etc) to prevent any potential sources for medication-related error.  
 
5.5.5 Storage 
 
All study medication (and placebo) will be stored in Tufts Medical Center Investigational Drug Pharmacy 
based on the most recent storage recommendations from AstraZeneca.  This storage area is in a 
completely different area of the pharmacy from where normal medication stock is stored. All usual study 
drug accountability procedures (as outlined in the policies and procedures of the Tufts MC Investigational 
Drug Pharmacy) will be used for this study.  Among the research team, Drs. Devlin and Duprey will be 
the primary liasons with members of the Tufts MC Investigational Drug Pharmacy.   
 
5.6 Concomitant and post-study treatment 
 
All patients enrolled in the study will be initiated on the following:  
 
1.  Docusate 100mg twice daily administered orally (or enterally).  
 
AND  
 
2. Study Laxative Guideline (see Appendix 1)  
 


27 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
A standard laxative guideline does not currently exist in any ICUs at Tufts Medical Center. Therefore in 
an effort to standardize the administration of laxatives in the study, the investigative team developed a 
study laxative guideline that is similar to current laxative prescribing practices in the medical ICU at Tufts 
MC for patients that do not have spontaneous bowel movement for ≥ 3 days.  Realizing the importance of 
having a formal, tiered laxative guideline that mimics that which is used in routine practice for medical 
ICU patients at Tufts Medical Center, the investigators basically formalized the approaches that are most 
commonly used in practice to develop (what is felt) to be a reasonably aggressive guideline. It should be 
noted that if study patient fails to have spontaneous bowel movement at 6 days (despite ever more 
intensive laxative treatment steps occurring), the patient will be removed from the study and the clinical 
ICU team will have the option of administering SC methylnaltrexone or intervening in whatever way 
these see fit to treat the constipation.  Of course, prior to study day #6, if the medical ICU team feels that 
a subject’s constipation is severe enough to warrant study removal (and perhaps methylnatrexone 
administration) then the subject would be removed from the study earlier. It will be communicated to 
each subject’s ICU physician that the study laxative guideline does not have to be rigidly followed if the 
subject’s physician deems that a deviation from the guideline is required based on their clinical evaluation 
of the subject.  
 
5.7 Treatment compliance 
 
Given that study drug administration will only occur in an ICU, and all drug will be administered by an 
experienced ICU nurse, treatment compliance should not be an issue.  The usual medication 
administration and documentation system will be employed for the study that involves the bedside nurse 
bar-scanning each study drug dose (to ensure correct patient and correct schedule) and the exact time each 
daily study drug dose is administered will be documented.  The investigative team will be in the ICU each 
morning to monitor all study procedures completed over the past 24 hours and will be available by pager 
on a 24/7 basis for any questions that the bedside nurse or any other member of the ICU clinical team may 
have regarding the study.    The study procedures outlined in Table 1 that will be completed by a member 
of the investigative team will be completed by Dr. Devlin, Dr. Duprey, Dr. Faugno or Dr. Garpestad.  
 
5.8 Discontinuation of investigational product 
 
5.8.1. Procedures for discontinuation of a subject from investigational product 
 
Study drug administration will be stopped when one of the following occurs:  
 
1. The subject experiences an adverse event potentially attributable to the study drug that is deemed, in 
the opinion of principal investigator, to warrant discontinuation of therapy.  
2. The patient requires use of the Level 4 Study Laxative Guideline (i.e., methylnaltrexone) 
3. Scheduled opioid therapy is stopped for ≥ 24 hours and the patient has had ≥ 1 SBM since the time of 
study enrollment.   
4. The patient has been administered 10 days of study medication.  
5. The patient is discharged from the ICU.  
6. The patient dies in the ICU. 
7. The patient requires a strong CYP3A4 inhibitor medication (and no other therapeutic alternative 
medication without this property can be used) 
8. The patient develops excessive diarrhea defined as ≥ 3 SBMs with a Bliss Score of 3 or 4 in a 24 hour 
period. When excessive diarrhea first occurs, study medication will be held.  In addition, all laxatives 


28 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
will be stopped (including docusate) and the investigative team will work with the subject’s clinical 
team to identify other possible causes for the excessive diarrhea (e.g. enteral nutrition formulation 
choice, C. difficile infection etc). In a further 24 hours (48 hours after the last study medication dose), 
if excessive diarrhea persists, the study medication will be permanently discontinued.  However, if the 
subject no longer has excessive diarrhea in a further 24 hours (48 hours after the last study medication 
dose), study medication will be resumed at the original dose.  If excessive diarrhea occurs again after 
study medication is resumed, then the study medication will be permanently stopped.  
 
Non-study naloxegol is currently not available at Tufts Medical Center given that is has not been added to 
the Tufts Medical Center medication formulary so there is no chance that a patient will be initiated on 
naloxegol after removal from the study while still a patient at Tufts Medical Center.  The care team for all 
patients removed from the study (who may been receiving naloxegol) will be notified that they should 
formally evaluate the patient for appropriate laxative orders, particularly in  
those situations where opioid therapy is continuing or where the patient has not had recently had 
spontaneous bowel movement.  
 
5.9 Withdrawal from study 
 
While 5.8.1 lists the reasons why study drug administration will cease, post-study drug discontinuation 
outcomes like duration of ICU stay will still be collected.  
 
Should consent for study participation be withdrawn all study data collection activities will cease and no 
study data collected before the time of withdrawal will be used.  
 
6.  COLLECTION OF STUDY VARIABLES 
 
6. 1 Recording of data 
 
As outlined above in Table 1,  study data that is not routinely documented on the ICU flowsheet or within 
the other section of the patient record (e.g. Soarian) will be documented by the bedside nurse on a daily 
nursing bedside data collection form (Appendix 9) . All other study data will be collected by the 
investigative team (Drs. Devlin, Duprey, Faugno or Garpestad) on the daily investigative team data 
collection form (Appendix 10).   
 
6.3 Efficacy  
 
6.3.1 List each efficacy variable 
 
As outlined in Table 1: 
 
Any SBMs 
Characterization of each SBM for size (small, medium or large)  
Characterization of each SBM for consistency (using the Bliss Stool Scale)  
Use of the study laxative guideline  
Daily volume of enteral nutrition administered  
Daily enteral nutrition goal 
Daily fluid balance (i.e., 24 hr ins and outs) 


29 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Pain scale score (using nurse-administered 10 point rating scale) every 6 hours 
Opioid requirement [in IV fentanyl equivalents (mcg)](all IV, SC, oral or transdermal use) 
Daily Sedation Assessment Scale (SAS) score (by nurse every q6h) 
Delirium using the Intensive Care Delirium Screening Checklist (ICDSC) (by nurse q12h) 
Daily total sedation administered (in midazolam equivalents)  
Occurrence of lower GI tract paralysis requiring consultation by a gastroenterologist or a surgeon 
Requirement for mechanical ventilation support 
Abdominal pressure (estimated by nurse measurement of bladder pressure every 8 hours 
 
6.4 Safety 
 
6.4.1 
List of each safety variable 
 
As outlined in Table 1: 
 
Presence of diarrhea 
Presence of diaper  
Presence of rectal tube  
Difference in the pre-dose and post-dose Clinical Opioid Withdrawal Scale (COWS) score (as evaluated 
by the bedside nurse before and 2 hours after the administration of the daily study drug dose).  
 
6.4.2 Definition for a serious adverse events and unanticipated problems: 
 
Serious Adverse Event: 
 
Events of a serious nature even if not related to the study (e.g. resulted in death, was life-threatening, 
resulted in hospitalization or prolongation of existing hospitalization, resulted in persistent or significant 
disability/incapacitation, may jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the other outcomes listed above).  
 
Unanticipated Problem:  
 
An event that meets all of the following criteria: 1) was unexpected; 2) was related or probably related to 
participation in the study, 3) may place subject(s) or others at greater risk of harm than previously 
recognized.  
 
Please note that these can include:  
 
i. events that are identified in the ICF, but that are more severe and longer lasting than expected. 
iii  events that were not expected to occur during the course of the study and that are not identified in the 
ICF(s). 
iv. any event about which the Principal Investigator is unsure, whether or not it meets the above criteria 
       
6.4.2 Recording and Reporting of adverse events 
 


30 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
All reportable new information that occurs in the study will be reported by the investigative team 
(sponsor) to the IRB as per the IRB’s reportable new information policy and to the study sponsor based 
on the sponsor’s reporting requirements that are outlined as follows:  
 
All reportable new information that occurs in the study will be reported by the investigative team 
(sponsor) to the IRB as per the IRB’s reportable new information policy and to the study sponsor based 
on the sponsor’s reporting requirements that are outlined as follows:   
 
The Sponsor is responsible for safety reporting of adverse events or adverse drug reactions  that arise 
during the Study in accordance with the Code of Federal Regulations Title 21, Part 312, section 312.32 
and 312.33to (i) the US Food and Drug Administration (FDA) ; (ii) any overseeing Institutional Review 
Boards; and (iii) all Investigators under this IND.  
 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to the 
investigational product.  All SAEs will be documented by the investigator.  The investigator is 
responsible for informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
 
The investigator will notify AstraZeneca (the Company) of all suspected unexpected serious adverse drug 
reactions (SUSARs) at the same time that the expedited IND safety reports are sent to the FDA.  
 
When reporting to AstraZeneca, a cover page should accompany the MedWatch form indicating the 
following: 
 
Investigator Sponsored Study (ISS) 
 
The investigator IND number assigned by the FDA 
 
The investigator’s name and address 
 
The trial name/title and AstraZeneca ISS reference number 
Investigative site must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined by the 
principal investigator. 
 
Send SAE report and accompanying cover page to AstraZeneca by email to AE Mailbox Clinical Trial 
(TCS) <AEMailboxClinicalTrialTCS@astrazeneca.com> or by fax to 1-302-886-4114 (US Fax number). 
Email is the preferred method.  
 
Serious adverse events that do not require expedited reporting to the FDA need to be reported to 
AstraZeneca preferably using the MedDRA coding language for serious adverse events at least <<on a 
monthly basis>>.   
 
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a copy of the 
randomization code/ code break information or unblind those SAEs which require expedited reporting.  
 


31 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to the 
investigational product.  All SAEs will be documented in the study database.  The investigator is 
responsible for informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
 
Note: As with any other clinical study, the patient’s physician may elect to discontinue the study drug at 
any time should an adverse effect develop that is felt to be attributable be to study drug administration.  
 
  
 
7.  BIOLOGICAL SAMPLING PROCEDURES 
 
No biological samples are being collected as part of this study.  
 
8.  ETHICAL AND REDULATORY REQUIREMENTS  
 
8.1 Ethical conduct of the study 
 
The study will be performed in accordance with ethical principles that have their origin in the 
declaration of Helsinki and are consistent with International Conference on Harmonization 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements, and the AstraZeneca 
policy on Bioethics and Human Biological Samples. 
 
8.2. Subject data protection  
 
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. All subjects will be de-identified using an unique subject number. Confidentially risks will 
be minimized given that no PHI or identifying information (other than a subject study code) will be used 
to identify study subjects. Demographic data for each subject will be maintained in a password-protected 
computer in Dr. Devlin’s locked office. Only Drs. Garpestad, Devlin, Duprey and Faugno  will engage in 
data collection for this study and all will be done on the hospital premises. All data entry will be entered 
on a data collection form on which patient identifying information will be excluded. De-identified data 
entry into department research computers is password protected.  Data will only be reported in aggregate 
form in any abstract or publication of the study results. All study data will be kept locked in the 
investigators office.  In additional to the investigative team, the Tufts MC IRB, the Medical 
Gastrointestinal Research Team at AstraZeneca, and the FDA will also have access to this data. Data is 
not being sent outside of Tufts Medical Center. Only the Tufts Medical Center Investigational Pharmacy 
will have access to the randomization (allocation) code.   The bedside nurse is not a member of the 
research team (please see Section 9).  
 
8.3 Ethics and regulatory review  
 
The Tufts Medical Center Institutional Review Board (IRB) will approve the final study protocol, 
including the final version of the ICF.  The investigator will ensure the distribution of these documents to 
the applicable to the IRB and to other members of the investigative team. The opinion of the IRB will be 
obtained in writing. The investigator will submit this written IRB approval to AstraZeneca or its 
representative before enrollment of any patient into the study occurs. This study protocol will be re-
approved by the IRB annually. 
 
8.4 Changes to the protocol and informed consent form 


32 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Study procedures will not be changed without the mutual agreement of the PI and AstraZeneca. If there 
are any substantial changes to the study protocol, then these changes will be documented in a study 
protocol amendment and where required in a new version of the studyprotocol. The amendment is to be 
approved by the IRB.  If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the 
IRB are to approve the revised ICF before the revised form is used. If local regulations require, any 
administrative change will be communicated to or approved by the IRB. 
 
8.5 Audits and inspections 
 
Authorized representatives from a regulatory authority, or the IRB may perform audits or inspections at 
the center, including source data verification. The purpose of an audit or inspection is to systematically 
and independently examine all study-related activities and documents, to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP, guidelines of the ICH, and any applicable regulatory requirements. The investigator will 
contact AstraZeneca or its representative immediately if contacted by a regulatory agency about an 
inspection at the center. 
 
9.  STUDY MANAGEMENT 
 
9.1 Study personnel: 
Neither the MICU team (ie. physicians) nor the bedside nurse will be part of the research team. As 
outlined in Table 1, the vast majority of the monitoring that the bedside nurse will be completing for the 
study will take place within the scope of their regular job duties.  The study monitoring that the bedside 
nurse will be asked to conduct outside of their regular duties will take no more than 10 minutes in total to 
conduct over a standard 12 hour nursing shift and are all within the scope of practice of an ICU nurse.  
The MICU team has no specific study-related activities to perform over and above maintaining an 
awareness that their patient may be in the study and contacting a member of the research team with any 
questions or concerns.  
 
9.2 Study drug administration 
Study medication will be administered by an experienced ICU bedside nurse. The investigative team will 
be in the ICU each morning to monitor all study procedures over the past 24 hours and is available by 
pager on a 24/7 basis for any questions that the bedside nurse or any other member of the ICU clinical 
team may have. The subject’s bedside ICU nurse (or his/her designate) will be present in the ICU (and 
close to the subject’s bedside) on a 24-7 basis during entire period of study drug administration.   
9.3 Facilities and equipment for managing emergencies    
All interventions, tests and procedures will occur while the subject is admitted to an ICU at Tufts MC 
under the care of the Medical ICU team. Each subject will be monitored on a 24/7 basis by a critical care 
nurse and a physician member of the ICU team is always in house to respond quickly to any emergencies. 
A member of the research team will always be available by pager on a 24/7 basis. Dr. Garpestad is a 
board-certified intensivist who has extensive experience in managing critically ill patients and any 
potential emergencies that may occur in this population. Drs. Devlin and Duprey are experienced critical 
care pharmacists who are used to working with critical care nurses and physicians to identify and help 
resolve drug-related problems and emergencies in the ICU setting.  All critical care nurses at Tufts 


33 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Medical Center are well-trained to help identify and resolve with the ICU medical team emergencies that 
occur in their patients.    
9.4 Training of study site personnel  
 
The PI will educate each research team member on their roles and responsibilities. This education and the 
roles and responsibilities of each research team member will be documented in the study regulatory 
binder(s).  Although neither the Medical ICU team nor bedside nurses will be members of the research 
team, a member of the investigative team will provide the Medical ICU nurses and physicians an 
overview of the study protocol and the specific data that will be collected as part of the study.  
 
9.4 Study agreement 
 
An agreement between AstraZeneca and Tufts Medical Center will be in place before any study-related 
activities take place.  
 
9.5 Study time line and end of study 
 
Protocol Finalization 
December, 2016 
Month 1 
Execution of research agreement 
January 2017, 
Month 2 
IRB approval 
January 2017  
Month 2 
First subject enrolled 
May 2017  
Month 6 
Subject #18 enrolled (50% enrollment) 
February 28, 2018 
Month 14 
Subject #36 enrolled (100% enrollment) 
December 31, 2018  
Month 23 
Publication  
March 31, 2019 
Month 27 
 
 
10.  DATA MANAGEMENT 
 
All study-related forms (including the original signed ICF) will be kept in a locked investigators office. 
One copy of the of the signed ICF will be included in the patient record and another copy will be provided 
to the patient/legally authorized representative. All study records will kept for whichever of the following 
is longest:  at least 7 years or for 2 years after the FDA approval of withdrawal of the FDA application.  
 
Robin Ruthazer, MPH, a senior biostatistician from the Institute for Clinical Research and Health Policy 
Studies at Tufts Medical Center will work closely with the rest of the research team to provide direction, 
guidance, and assistance regarding data management and analysis.  Ms. Ruthazer has worked with our 
group on prior studies. Drs. Devlin, Faugno and Duprey will check all subject case report forms (CRFs) 
for completeness at the time of data collection.  All data collection forms including the CRFs will be 
stored in a locked cabinet in Dr. Devlin’s locked office at all times.  Drs. Devlin and Duprey will conduct 
all data entry into MS Excel.  Both have extensive experience in entering data into MS Excel for other 
investigations our group has completed.  Drs. Garpestad will monitor the integrity of data entry. Data will 
be stored in a specified directory on Dr. Devlin’s computer, which is password-protected which will be 
located in his locked office (in a secure building) and backed up regularly.  
 
11.  EVALUATION AND CALCULATION OF VARIABLES 
 


34 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
11.1 Calculation or derivation of efficacy variables 
 
Please see table 1 and study objectives section 
 
11.2 Calculation or derivation of safety variables 
 
Please see table 1 and study objectives section 
 
12.  STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
 
12.1 Description of analysis sets   
 
All patients will be analyzed in the groups to which they were randomly assigned, according to the 
intention-to-treat principle. 
 
12. 2 Methods of statistical analysis  
 
Baseline characteristics of patients will be compared using standard univariate methods (chi-square test, t-
test) to confirm the randomization was successful in achieving comparable groups. To test the primary 
outcome (incidence of lower GI tract paralysis), given that there may be censoring (i.e., subject may die 
or withdraw from study before developing lower GI tract paralysis), we will present Kaplan-Meier curves 
for the naloxegol and placebo groups for the time to first development of lower GI tract paralysis (≥ 3 
days without a SBM after study randomization) during the ICU stay up to 10 days and compare the 
curves using a log-rank test.  If all subjects complete the study (e.g., no deaths, no withdrawal or loss-to-
follow-up for other reasons), then we will instead compare the proportion of patients that develop lower 
GI tract paralysis after study randomization during the ICU stay up to 10 days between the naloxegol and 
placebo groups using a chi-square test.  The secondary outcome, time to first SBM will be estimated 
using a Kaplan Meier time to event analysis and compared between groups using a log-rank test.  The 
secondary outcome of the number of ICU days without a SBM will be compared between the naloxegol 
and placebo groups using the Poisson regression for count data and adjusting for total number of days in 
the ICU (up to a maximum of 10) as an offset term in the Poisson model.  The secondary outcome of the 
average daily opioid requirements will be compared between groups using either a student t-test or 
nonparametric Wilcoxan rank-sum test if the assumptions of the student t-test fail to be met.  Length of 
mechanical ventilation and ICU stay will be reported as medians and interquartile ranges and will be 
compared using the Wilcoxon Rank Sum Test.  For all statistical tests of hypotheses, a two-sided p-value 
of  0.05 will be considered as statistically significant. As this is a Phase II proof of concept study a p 
value of <0.10 may still be worth consideration for future study, however.  All statistical analyses will be 
performed using SPSS 17.0. (SPSS, Chicago, IL) or other comparable commercially available statistical 
software. 
 
12.2.1 Interim analyses 
 
As outlined in the DSMB procedure, planned interim analyses will occur to evaluate safety after the 
enrollment of 10 subjects and after the enrollment of 20 subjects.  
 
12.2.2 Determination of sample size 
 


35 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
For the power analysis, the 4-day estimates of failure to defecate (i.e., failure to have a SBM) from the 
Kaplan-Meier plot presented in the Guardiola et. al. paper [4] was used as the estimate of lower GI tract 
paralysis.  The figure below shows that the estimate of the percent of patients who failed to defecate  (1 
minus plotted proportion with defecation) by day 4 was 40% in the Prophylaxis group (i.e., the 
intervention group) vs. 90% in the non-prophylaxis (Treatment) group (i.e., the control group)  (see 
yellow highlights in figure).  We believe the 4-day estimate will be strongly related to the primary 
outcome of lower GI tract paralysis (≥ 3 days without a SBM).  
 
 
 
 
 
 
 
 
 
For this Naloxogol randomized trial, we propose 
enrolling 36 subjects, 18 per group. The statistical 
power table below  shows this sample size yields 
over 95% power using an alpha of 0.05 if the true day 
4 estimated freedom of event (defecation) rates are 90% (Placebo) vs. 40% (Prophylactic treatment), all 
subjects have complete follow-up, and the analysis is done using the log-rank test to compare survival 
curves.  As sensitivity analysis, the table also shows the power of the study with this sample size under 
different scenarios.  Because this is not the final definitive study to determine efficacy, a less stringent 
alpha of 0.10 may be justified for this Phase II proof-of-concept study which, if positive, would be 
followed by a confirmatory study [15]. While we expect most subjects to finish the study (based on the 
inclusion criteria), we have shown the impact on the power if approximately 20% of subjects do not finish 
the study.   We have also varied the estimated proportion of patients failing to defecate by day 4 (i.e., not 
having a SBM) in the placebo group from 90% to 70% and in the prophylactic treated group from 40% to 
50%.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.3 Data monitoring committee 
 
A Data and Safety Monitoring Board (DSMB) will be formed for this study. The DSMB will consist of an 
intensivist, gastroenterologist and a pharmacist who have experience in the management of  


36 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
gastrointestinal-related conditions in the critically ill.  The study biostatistician, Robin Ruthazer, will also 
be a part of the DSMB in a consultative role. The DSMB will review all subject data (in a blinded 
fashion) after the enrollment of the first 10 subjects in the study and then after the enrollment of the first 
20 subjects.  Any unanticipated SAE will also automatically trigger a DSMB review.  The DSMB will 
meet at least once every 6 months in the event that the pace of study enrollment does not trigger a DSMB 
meeting in a particular 6 month period. DSMB members will not be associated with the study.  The study 
biostatistician will remain blinded until the final results of the study are analyzed.  If the DSMB requires 
the A group and B group coding, then the research pharmacist will send a confidential email to the DSMB 
that contains the A and B assignments. The charter for the DSMB is listed under Appendix 9.  
 
13.  LIST OF REFERENCES 
 
1. Barr J, Fraser GL, Puntillo K et al. Clinical practice guidelines for the management of pain,  
       agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263-306 
 
2. Reintam Blaser A, Malbrain MLNG, Starkopf J, et al. Gastrointestinal function in intensive care 
patients: terminology, definitions, and management. Recommendations of the ESICM Working 
Group on Abdominal Problems.  Intensive Care Med 2012;38(3):384-94 
 
3. Guardiola B1, Llompart-Pou JA, Ibáñez J, et al. Prophylaxis versus treatment use of laxative 
for paralysis of lower gastrointestinal tract in critically ill patients. J Clin Gastroenterol. 2016 
Feb;50(2):e13-8. 
 
4. Prat D, Messika J, Avenel A, et al.  Constipation incidence and impact in medical critical 
care patients: importance of the definition criterion. Eur J Gastroenterol Hepatol. 2016 
Mar;28(3):290-6.  
 
5. Guerra TL, Mendonça SS, Marshall NG. Incidence of constipation in an intensive care unit. Rev Bras 
Ter Intensiva. 2013 Apr-Jun;25(2):87-92. 
  
6. Nassar AP Jr1, da Silva FM, de Cleva R. Constipation in intensive care unit: incidence and risk 
factors. J Crit Care. 2009 Dec;24(4):630.e9-12. doi: 10.1016/j.jcrc.2009.03.007.  
 
7. Camilleri, M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J    
       Gastroenterol. 2011;106:835–842. 
 
8. Kalso E, Edwards JE, Moore A et al. Opioids in chronic non-cancer pain: systematic review of 
efficacy and safety. Pain 2004;112:372–80. 
 
9. Mostafa S, Bhandari S, Ritchie G, et al. Constipation and its implications in the critically ill patient. 
Brit J of Anaesthesia. 2003;91(6):815-19. 
 
10. Joint Commission Resources. Improving Care in the ICU. 1st ed. Oakbrook Terrace, IL: Joint 
Commission Resources; 2004. 
 
11. Khalid I, Doshi P, DiGiovine B. Early enteral nutrition and outcomes of critically ill patients treated 
with vasopressors and mechanical ventilation. Am J Crit Care. 2010;19(3):261-268.  


37 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
12. Smonig R, Wallenhorst T, Bouju P, et al.  Constipation is independently associated with with 
delirium in critically ill ill ventilated patients.  Intensive Care  Med (ahead of press Sept 10 2015)  
 
13. Palacio de Azevedo R, Resende Freitas FG, Ferreira EM, et al.  Daily laxative therapy reduces organ 
dysfunction in mechanically ventilated patients: A phase II randomized controlled study. Crit Care 
2015; 19:329 
 
14. Chey W, Webster L, Sostek M, et al. Naloxegol for opioid-induced constipation in patients with 
noncancer pain (KODIAC 04 and 05). N Engl J Med 2014;370:2387-96. 
 
15. Zheng et. al. The design of single arm clinical studies of combination anti-retroviral therapies for 
treatment-naïve HIV patients. AIDS Research and Human Retroviruses 201329(4) 652-657. 
 
 
 
 


38 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Appendix 1.  Study Laxative Guideline  
 
No spontaneous bowel movement in ≥ 3 daysA?  
 
Step 1: Initiate:  Senna one tablet (8.6 mg) PO/NG daily AND polyethylene glycol 3350 17 g PO/NG 
daily.  If SBM occurs then stop step 1 therapy but keep patient on docusate.  
 
No spontaneous bowel movement in ≥ 4 daysA?  
 
Step 2:  Increase Senna to 2 tablets (17.2 mg) PO/NG daily AND polyethylene glycol 3350 to 34 g 
PO/NG daily and insert a bisacodyl suppository 10mg PR x 1. If bowel movement occurs then stop all 
laxative study protocol therapy but keep patient on docusate. 
 
No spontaneous bowel movement in  ≥ 5 daysA?  
 
Step 3: Repeat Step 2 AND if no spontaneous bowel movement within 2 hours of administering the 
bisacodyl suppository, administer a 10oz bottle of magnesium citrate sodium phosphate. If bowel 
movement occurs then stop all study laxative protocol but keep patient on docusate.  
 
No spontaneous bowel movement in ≥ 6 daysA?  
 
Step 4:  Discontinue study medication (but do not unblind patient assignment). Repeat Step 3, 
initiate methylnatrexone (Relistor) sc x once and consider a consultation to gastroenterology or surgery.  
[Note:  If patient weight is 38-62 kg then methylnaltrexone dose = 8mg; if patient weight is 62-144 kg 
then methylnaltrexone dose = 12mg].  
 
 
AFrom the day of initiation of scheduled opioid therapy (ie. IV fentanyl ≥ 100mcg/day or 
equivalent) 
 
 
 
 
 
 
 
 
 
 
 
 


39 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Appendix 2.  Riker Sedation-Assessment Scale (SAS) Score 
 
Score 
Outcome 
7 
Dangerous agitation pulling at ET tube, trying to remove catheters, 
climbing over bedrail, striking at staff, thrashing side-to-side 
 
6 
Very agitated requiring restraint and frequent verbal reminding of 
limits, biting ETT 
 
5 
Agitated, anxious or physically agitated, calms to verbal instructions 
4 
Calm and cooperative, easily arousable, follows commands 
3 
Sedated, difficult to arouse but awakens to verbal stimuli or gentle 
shaking, follows simple commands but drifts off again 
 
2 
Very sedated, arouses to physical stimuli but does not communicate or 
follow commands, may move spontaneously 
 
1 
Unarousable, minimal or no response to noxious stimuli, does not 
communicate or follow commands 
 
 
 
Appendix 3   Numerical Pain Rating Scale 
 
1 
 
 
 
 
 
 
 
 
 
       10 
 
 
No pain 
 
 
 
 
 
 
 
 
 Severe 
                                                                                                                                     Pain  
 
 


40 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Appendix 4   Intensive Care Delirium Screening Checklist 
Date: 
 
 
Time: 
 
 
1. Altered level of consciousness  Choose ONE from A-E. 
Note: May need to reassess patient if recent administration of sedation therapy 
 
 
A. Exaggerated response to normal            Riker/SAS = 5, 6, or 7    Score 1 point 
     stimulation                                                                         
 
 
B. Normal wakefulness                                Riker/SAS = 4                Score 0 points 
 
 
C. Response to mild or moderate                Riker/SAS = 3                Score 1 point 
    stimulation (follows commands)        
Score 0 if LOC related to recent sedation/analgesia 
 
 
D. Response only to intense and  repeated stimulation (e.g. loud voice and pain) 
                                                                     SAS = 2   **Stop assessment 
 
-- 
E. No response                                            SAS = 1  **Stop assessment 
 
-- 
2. Inattention  Score 1 point for any of the following abnormalities: 
A. Difficulty in following commands OR 
B. Easily distracted by external stimuli  OR 
C. Difficulty in shifting focus 
Does the patient follow you with their eyes? 
 
 
3. Disorientation Score  1 point for any one obvious abnormality: 
A. Mistake in either time, place or person 
Does the patient recognize ICU caregivers who have cared for him/her and not 
recognize those that have not? What kind of place are you in? (list examples) 
 
 
4. Hallucinations or Delusions   Score 1 point for either : 
A. Equivocal evidence of hallucinations or a behavior due to hallucinations 
(Hallucination = perception of something that is not there with NO stimulus) OR 
B. Delusions or gross impairment of reality testing 
(Delusion = false belief that is fixed/unchanging) 
Any hallucinations now or over past 24 hrs? Are you afraid of the people or things 
around you?  [fear that is inappropriate to clinical situation] 
 
 
5. Psychomotor Agitation or Retardation  Score 1 point for either: 
A. Hyperactivity requiring the use of additional sedative drugs or restraints in 
order to control potential danger  (e.g. pulling IV lines out or hitting staff) OR 
B. Hypoactive or clinically noticeable psychomotor slowing or retardation 
Based on documentation and observation over shift by primary caregiver 
 
 
6. Inappropriate Speech or Mood     Score 1 point for either: 
A. Inappropriate, disorganized or incoherent speech OR 
B. Inappropriate mood related to events or situation 
Is the patient apathetic to current clinical situation (ie. lack of emotion)? 
Any gross abnormalities in speech or mood? Is patient inappropriatelydemanding? 
 
 
7. Sleep/Wake Cycle Disturbance    Score 1 point for: 
A. Sleeping less than four hours at night OR 
B. Waking frequently at night (do not include wakefulness initiated by medical 
staff or loud environment)  OR 
C. Sleep ≥ 4 hours during day  Based on primary caregiver assessment 
 
 
8. Symptom Fluctuation       Score 1 point for: 
fluctuation of any of the above items (ie. 1 – 7) over 24 hours (e.g. from one 
shift to another)                        Based on primary caregiver assessment 
 
 
TOTAL ICSDC SCORE (Add 1 – 8) 
 
 
A total ICSDC Score ≥ 4 has a 99% sensitivity correlation for a psychiatric diagnosis of delirium 


41 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Appendix 5.   Bliss Stool Scale Score 
 
Stool Consistency Classification System (Adopted from Zimmaro Bliss, et al. J. Wound Ostomy 
Contin. Nurs., 2001) 
 
                   1                                             2                                      3                                         4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


42 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Appendix 6.  Clinical Opioid Withdrawal Scale Score 
 


43 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Appendix 7.  Child Pugh Classification  
 
 


44 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Appendix 8.  DSMB Charter  
 
The Data and Safety Monitoring Board (DSMB) will act in an advisory capacity to Tufts Medical 
Center  to monitor participant safety, data quality and evaluate the progress of the study. Dr. Erik 
Garpestead, Tufts Medical Center is conducting the Impact of Naloxegol (Movantik) on the Impact 
of Naloxegol (Movantik) on Prevention of Lower Gastrointestinal Tract Paralysis in Critically Ill Adults 
Initiated on Scheduled IV Opioid Therapy: A Randomized, Double-blind, Placebo-Controlled, Pilot 
Study. This study is funded as an investigator initiated study by AstraZeneca.  
The DSMB responsibilities are to:  
 
evaluate the progress of the trial, including periodic assessments of data quality and timeliness, 
recruitment, accrual and retention, participant risk versus benefit, performance at  the trial site, 
and other factors that can affect study outcome; 
 
 
consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants or 
the ethics of the trial; 
 
 
review study performance, make recommendations and assist in the resolution of problems 
reported by the Principal Investigator; 
  
 
protect the safety of the study participants; 
 
 
make recommendations to the Principal Investigator, the Institutional Review Board at Tufts 
Medical Center and, if required, to the Food and Drug Administration (FDA) concerning 
continuation, termination or other modifications of the trial based on adverse effects of the 
treatment under study; 
 
 
ensure the confidentiality of the study data and the results of monitoring; and,  
 
 
assist the Institutional Review Board at Tufts Medical Center by commenting on any problems 
with study conduct, enrollment, sample size and/or data collection. 
 
The DSMB will discharge itself from its duties when the study is complete. 
Membership 
Paul Wischmeyer M.D., E.D.I.C.  Professor of Anesthesiology and Pediatrics (Nutrition Section),  
Associate-Chairman for Clinical and Translational Research, Director of Nutrition Therapy Services,  
University of Colorado School of Medicine,  will serve as both Chair and Safety Officer for the DSMB 
and is responsible for overseeing the meetings, developing the agenda in consultation with the Principal  
Investigator. Dr. Wischmeyer will also serve as the safety officer and thus be the primary contact for 
serious adverse event reporting. 
 


45 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Rob MacLaren, PharmD, Professor of Pharmacy, U of Colorado School of Pharmacy and Critical Care 
Pharmacy Specialist, U of Colorado Medical Center.   Dr. MacLaren has extensive critical care research 
experience, some of which is in the GI area.   Dr. MacLaren has previously served on study DSMBs 
 
Thormika Keo, MD, PhD, an attending gastrotenterologist from the Dallas VA hospital will serve as the 
third member of the DSMB.   
 
Robin Ruthazer, MPH, Senior statistician, Data Design and Research Center, Tufts Medical Center, 
Boston, MA will serve in a consultative role to the DSMB. 
 
At least 2 members of the DSMB must be present at a meeting to constitute a quorum.  
 
Board Process  
Dr. Wischmeyer in is his role as the DSMB’s safety officer, will receive all reports of serious and/or 
unanticipated adverse events (AE) for patients enrolled in the study and determine within 7 days of 
receiving each AE report whether the DSMB needs to be convened.  Please note that any unanticipated 
serious event will automatically trigger a DSMB review. 
 
Meetings of the DSMB will be held after the enrollment of the first 10 subjects in the study and then after 
the next 10 subjects. Any unexpected serious event will also automatically trigger a DSMB review. The 
DSMB will meet at least once every 6 months regardless of the pace of study enrollment. An emergency 
meeting of the DSMB may be called at any time by the Chair should participant safety questions or other 
unanticipated problems arise. 
 
Meetings shall be closed to the public because discussions may address confidential participant data. 
Meetings will be attended by the Principal Investigator and members of his/her staff. The study 
biostatistician will be invited to attend at the prerogative of the DSMB chair. Meetings may be convened 
as conference calls as well as in-person.   
 
Meeting Format 
 
DSMB meetings will consist of open and closed sessions. Discussion held in all sessions is confidential. 
The Principal Investigator and key members of the study team attend the open sessions. Open session 
discussion will focus on the conduct and progress of the study, including participant accrual, protocol 
compliance, and problems encountered. No study data (other than SAE reports and screening logs) will be 
presented in the open session. A member of the study staff will keep minutes of each open session and 
submit them within one week to Dr. Garpestad.  
 
The closed session will be attended by the DSMB members. The study statistician may be present, at the 
request of the DSMB. The study biostatistician, R. Ruthazer, will provided a blinded copy of the study 
data for patients enrolled to date (ie. group #1 vs. group #2) to the DSMB members no less than 7 days 
prior to the scheduled DSMB meeting.  The investigators will not see this report.  The code to unblind 
this report will only be provided by the Tufts Medical Center research pharmacist should the DSMB 
specifically request it. A member of the DSMB will keep minutes of each closed session and submit them 
within one week of the meeting to Dr. Garpestad who will forward this report to the Tufts MC IRB.  
 


46 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Each meeting must include a recommendation to continue or to terminate the study made by a formal 
DSMB majority or unanimous vote. Should the DSMB decide to issue a termination recommendation, the 
full vote of the DSMB is required.  
 
A recommendation to terminate the study may be made by the DSMB at any time by majority vote. The 
Chair should provide such a recommendation to Dr. Garpestad immediately by telephone and email that 
will then be communicated to Dr. Garpestad.  
 
Meeting Materials  
 
DSMB interim report templates will be prepared by the study staff, typically the statistician, to be 
reviewed by the DSMB members at the first meeting.  Interim data reports generally consist of two parts:  
 
 
Part 1 - Open Session Report and  
 
Part 2 - Closed Session Report  
 
Format and content of the reports for both the open and closed sessions and plans for interim analyses 
should be finalized and approved at the initial DSMB meeting, although changes throughout the trial may 
be requested by the Board. 
 
The reports will list and summarize safety data and describe the status of the study.  All meeting materials 
should be sent to the DSMB at least 7 to 14 days prior to the meeting. The reports are numbered and 
provided in sealed envelopes within an express mailing package or by secure email as the DSMB prefers. 
 
1. Part 1 - Open Session Reports: Open session reports generally include administrative reports by site 
that describe participants screened, enrolled, completed, and discontinued, as well as baseline 
characteristics of the study population. Other general information on study status may also be 
presented. Listings of adverse events and serious adverse events as well as any other information 
requested by the DSMB may also be in the open session report, but none of the specific patient data 
should be presented in a group #1 vs. group #2 fashion – even if the groups remain blinded to the 
investigators. The DSMB may direct additions and other modifications to the reports on a one-time or 
continuing basis.  
 
2. Part 2 – Closed Session Report:  Closed session reports generally present the same information as 
presented in the open session but also included the subject data in a blinded fashion by treatment 
group (e.g. group #1, group #2,) that will be focused on all safety outcomes/data.  The Closed Session 
reports should be destroyed at the conclusion of the meeting. If the meetings are held by telephone, 
printed copies of the closed reports should be destroyed immediately following the meeting.  If a 
study has an interim analysis, it is also discussed in the closed session. 
Reports from the DSMB 
A formal report containing the recommendations for continuation or modifications of the study will be 
prepared by the DSMB Chairperson. The draft report will be sent to the DSMB members not later than 
four weeks after the meeting. Once approved by the DSMB members, the DSMB Chair will forward the 
formal DSMB recommendation to the Principal Investigator. It is the responsibility of the Principal 


47 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Investigator to distribute the DSMB recommendation to all co-investigators and to ensure that copies are 
submitted to all the IRBs associated with the study. 
As previously stated, the formal DSMB report must include a recommendation to continue or to terminate 
the study. This recommendation should be made by formal majority vote. A termination recommendation 
may be made by the DSMB at any time by majority vote. In the event of a split vote in favor of 
continuation, a minority report should be contained within the regular DSMB report. The report should 
not include unblinded data or discussion of the unblinded data.  
Confidentiality  
All materials, discussions and proceedings of the DSMB are completely confidential. Members and other 
participants in DSMB meetings are expected to maintain confidentiality. 


48 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
IRB # 12043 Impact of Naloxegol (Movantik) on Prevention of Lower Gastrointestinal Tract Paralysis in Critically Ill Adults Initiated on Scheduled IV Opioid 
Therapy: A Randomized, Double-Blind, Placebo-Controlled, Phase II, Single-Center, Proof of Concept Study.  PI:  Erik Garpestad, MD  
 
Appendix 9.  Daily Nursing Data Collection Form.  
 
Subject ID: ______Subject Initials: _____ ICU Room:                *Date (of day shift):_________ Study day#____________  
*Note:  this monitoring form goes from 07:00h to 06:59h the next day 
 
Time of study drug administration :       ____h  (note: should be around 0900h; if patient on tube feeds, please hold 1 hour before & after administration 
; if patient is eating, administer 1 hour before or 2 hours after breakfast) 
[Complete study drug administration instructions on next page] 
 
Clinical Opioid Withdrawal Scale (COWS) Score to be completed 1 hour before and 2 hours after study drug administration (see next page) 
 
Spontaneous Bowel Movements 
(from 0800h to 07:59h) 
Time 
Size (indicate small (S), 
medium (M) or large (L) 
(Use best judgment) 
Bliss Stool Scale Score 
(see next page and on wall) 
Comments 
#1 
 
 
 
 
#2 
 
 
 
 
#3 
 
 
 
 
#4 
 
 
 
 
#5 
 
 
 
 
#6 
 
 
 
 
#7 
 
 
 
 
#8 
 
 
 
 
 
Does the patient have a urinary (foley) catheter in place for a clinical reason (s)  Yes______    No____ 
Was the patient’s ICU physician asked about whether the urinary (foley) catheter can be removed?    Yes       No______ 
Was the study laxative protocol utilized? Yes ____  No ____ 
If YES, which level? ____ 
 
 
Time frame 
Day Shift (0700 – 14:59h) 
Afternoon shift (15:00-22:59H) 
Night shift (23:00-06:59h) 


49 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Abdominal pressure score 
 
 
 
Time of evaluation  
 
 
 
 For any questions regarding this study please page Matthew Duprey, PharmD or John Devlin, PharmD at pager #2742 
initials of investigational team member completing/verifying form_____     date ________ 
 
Clinical Opioid Withdrawal Scale (COWS) Score 
1 hour before admin 
Time: ___________ 
2 hours after admin 
Time: __________ 
Heart Rate: 
0 = 80 bpm or below 
1 = 81 to 100 bpm 
2 = 101-120 bpm 
4 = 121+ bpm 
 
 
Sweating over past ½ hour not accounted for by room temperature or patient activity: 
0 = no chills or flushing  
 
 
1 = patient reports chills or flushing 
2 = flushed or observable moistness on face 
3 = beads of sweat on brow or face 
4 = sweat streaming off face 
 
 
Restlessness: 
0 = able to sit or lie still  
 
1 = patient reports difficulty sitting/lying still, but is able to do so 
3 = frequent shifting or extraneous movements of legs/arms 
5 = unable to sit/lie still for more than a few seconds 
 
 
Pupil Size: 
0 = pupils pinned or normal size for room light 
1 = pupils possibly larger than normal for room light 
2 = pupils moderately dilated 
 
 
5 = pupils so dilated that only the rim of the iris is visible 
 
 
Bone or Joint Aches (if Patient was Having Pain Previously, only the Additional Component Attributed to Opiate 
Withdrawal Scale): 
0 = not present 
 
1 = mild diffuse discomfort 
2 = patient reports severe diffuse aching of joints/muscles 
4 = patient is rubbing joints or muscles and is unable to sit still because of discomfort 
 
 
Runny Nose or Tearing Not Accounted for by Cold Symptoms or Allergies: 
0 = not present 
 
 
 
1 = nasal stuffiness or unusually moist eyes 
2 = nose is running or tearing 
 
4 = nose constantly running or tears streaming down cheeks 
 
 
GI Upset: Over Last ½ Hour: 
0 = no GI symptoms 
 
1 = stomach cramps 
 
2 = nausea or loose stool 
3 = vomiting or diarrhea  
5 = multiple episodes of vomiting or diarrhea 
 
 
Tremor Observation of Outstretched Hands: 
 
 


50 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
0 = no tremor 
 
 
1 = tremor can be felt by patient, but not observed 
2 = slight tremor observable 
4 = gross tremor or muscle twitching 
Yawning Observation During Assessment: 
0 = no yawning/intubated 
 
 
 
1 = yawning once or twice during assessment 
2 = yawning three or more times during assessment 
4 = yawning several times/minute 
 
 
Anxiety or Irritability: 
0 = none 
 
 
 
 
1 = patients reports increasing irritability or anxiousness 
2 = patient obviously irritable/anxious 
 
4 = patient so irritable or anxious that participation in the  
 
 
 
 
      assessment is difficult 
 
 
Gooseflesh Skin: 
0 = skin is smooth 
 
3 = piloerection of skin can be felt or hairs standing up on arms 
5 = prominent piloerection 
 
 
Total Score: 
5-12 = Mild 
13-24 = Moderate 
25-36 = Moderately Severe 
More than 36 = Severe Withdrawal 
 
 
Study Drug Administration Instructions 
 
If oral study drug medication is not possible (e.g. intubation) then the study drug should be administered via a gastric or enteral tube.   
 
Tube feeds (if being administered) should be held for one hour and the feeding tube will be flushed with 30 mL of sterile water.  
 
Crush the naloxegol (or matching placebo) tablet, mix in 60 mL of sterile water and draw up the contents (of the medication and sterile water) 
in a 60 mL oral syringe and administer via the gastric or enteral tube over 3-5 minutes.    
 
Rinse the vessel used to crush the medication with another 30 mL of sterile water, draw up the contents into the oral syringe and administer 
over 3-5 minutes.   
 
Restart tube feeds at the same pre-dose rate (i.e., if the patient was receiving tube feeds at the time of the study dose) one hour after the study 
drug dose is administered. 
 


51 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Appendix 10. Investigative Team Daily Data Collection Form.  
IRB # 12043 Impact of Naloxegol (Movantik) on Prevention of Lower Gastrointestinal Tract Paralysis in Critically Ill Adults Initiated on Scheduled IV Opioid 
Therapy: A Randomized, Double-Blind, Placebo-Controlled, Phase II, Single-Center, Proof of Concept Study.  PI:  Erik Garpestad, MD  
 
Subject ID: ______Subject Initials: _____ ICU Room:                *Date (of day shift):_________                         Study day#____________  
*Note:  this monitoring form goes from 0700h to 06:59h the next day 
Time frame 
Day Shift  
(0700 – 14:59h) 
Afternoon shift  
(15:00-22:59H) 
Night shift  
(23:00-06:59h) 
Fentanyl (mcg) 
 
 
 
 
Hydromorphone (mg) 
 
 
 
 
Morphine (mg) 
 
 
 
 
Oxycodone (mg) 
 
 
 
 
Hydrocodone (mg) 
 
 
 
 
Methadone (mg) 
 
 
 
 
Other Opioids: Name and Dose 
 
 
 
 
 
Diazepam (mg) 
 
 
 
 
Lorazepam (mg) 
 
 
 
 
Midazolam (mg) 
 
 
 
 
Dexmedetomidine (mcg) 
 
 
 
 


52 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Propofol (mg) 
 
 
 
 
Haloperidol (mg) 
 
 
 
 
Quetiapine (mg) 
 
 
 
 
Volume of enteral nutrition administered (mL) 
 
 
 
 
Enteral nutrition goal (mL) 
 
 
 
 
% of enteral nutrition goal reached 
 
 
 
 
Fluid balance (+ or – ) (mL) 
 
 
 
 
Lowest SAS 
 
 
 
 
Highest SAS 
 
 
 
 
ICDSC score (if evaluated during this shift) 
 
 
 
 
Lowest pain assessment score 
 
 
 
 
Highest pain assessment score 
 
 
 
 
Current Laxative Guideline Step (ie. 1, 2, 3 or 4) 
 
 
 
 
Laxatives administered (list all agents and doses) 
 
 
 
 
 
Requirement for mechanical ventilation? (Y/N) 
 
 
 
 
Presence of rectal tube? (Y/N) 
 
 
 


53 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
(Please note time of insertion if new) 
GI or Surgical consult for lower GI tract paralysis? 
Y/N 
 
 
 
 
SOFA Score (worst values over study day)  
 
 
Serum creatinine (worst value over study day) 
 
 
Calculated creatinine clearance (worst value over 
study day) 
 
initials of investigational team member completing/verifying form_____     date ________ 
 
 
Daily SOFA Calculator 
Pt Study ID: |__|__|__|   Pt Initials: |__|__|__|     
 
From:  |__|__|  |__|__|   |  2|  0|   |    |   
|__|__| : |__|__|       To:  |__|__|  |__|__|   |  2|  0|   |    |     |__|__| : |__|__|        
                   DD          MM              
YEAR 
                    HH            MM                             DD          MM            YEAR 
      HH            MM 
 
Please retain this worksheet at the site with the CRF. 
Calculate SOFA score using values from the 24 hour period prior to randomization. 
 
A. Please circle appropriate score                                                                               
 
 


54 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B. Please 
record below 
the actual 
values used in 
the scoring 
above. 
 
PaO2  |__|__|__| 
 
Organ System 
0 
1 
2 
3 
4 
Score 
 
RESPIRATION 
PaO2/FiO2 (mmHg) 
 
 
>400 
 
301-400 
 
201-300 
 
101-200 with 
respiratory 
support 
 
 
< 100 with 
respiratory 
support 
 
CARDIOVASCULAR 
Vasopressors 
(mcg/kg/min) 
 
No 
hypotension 
 
MAP < 70mmHg 
and 
No vasopressors 
 
Dopamine ≤ 5 
or 
Any dose 
Dobutamine 
 
 
Dopamine > 5 
or 
Epinephrine ≤ 0.1 
or 
Norepinephrine ≤ 0.1 
 
Dopamine >15 
or 
Epinephrine > 0.1 
or 
Norepinephrine > 0.1 
or  
any dose Vasopressin 
 
LIVER (bilirubin)     
(mg/dl) 
 
 
<1.2 
 
1.2 – 1.9 
 
 
2.0 – 5.9 
 
 
6.0 – 11.9 
 
 
≥ 12 
 
COAGULATION 
Platelets (x 103/L) 
 
 
>150 
 
101-150 
 
51-100 
 
21-50 
 
≤20 
 
RENAL 
Creatinine (mg/dL)) 
or 
urine output mL/hr 
 
 
<1.2 
 
1.2 - 1.9 
 
2.0 -3.4 
 
 
3.5 – 4.9 
 
or 
 
< 500 ml/day 
 
 
 ≥ 5.0 
 
or 
 
< 200 ml/day 
 
TOTAL SOFA= 
 


55 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
FiO2  
|__| . |__|__| 
 
MAP  
|__|__|__| 
 
Bilirubin |__|__|__| µmol/L 
 
Platelets |__|__|__| x 103/µL 
 
Creatinine |__|__|__| µmol/L  
or       Urine output |__|__|__|__| mL/day 
 
initials of investigational team member completing/verifying form_____     date ________ 
 


56 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Appendix 11. Investigative Team Baseline Data Collection Form 
 
Case Report Form  
Patient Initials ___  ___  ___ 
 
 
 
 
 
 
 
Patient Study Number: ___  ___  ___ 
 
Date of Randomization: ___/___/____  
 
 
 
Time: ___:___ (24 hr. clock) 
 
 
    
         mm   dd    yyyy 
 
Enrolled by: (please print) _______________________________ 
 
Signature: __________________________________________ 
 
Date: ___/___/____ 
 
Background Information regarding enrollment: 
 
________________________________________________________________________________________ 
 
________________________________________________________________________________________ 
 
________________________________________________________________________________________ 
 
Subject’s Contact Information:  
 
Primary phone number:  (______) ______-_______ 
 
 
 
 
 
 
 
 
Secondary phone number: 
(______) ______-_______ 
 
 
 
 
 
 
 
 
Address: ______________________________________ 
 
 
 
 
 
 
 
 
 
Street 
 
 
 
Apt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_________________________  _______ 
___________ 


57 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
 
 
 
 
 
 
City 
 
 
 
       State 
Zip 
 
Subject’s Legally Acting Representative: 
Name: _________________________________________ 
 
 
 
 
 
 
 
 
Relationship: ___________________________________ 
 
Primary phone number:  (______) ______-_______ 
 
 
 
 
 
 
 
 
Secondary phone number: 
(______) ______-_______ 
 
 
 
 
 
 
 
 
Address: ______________________________________ 
 
 
 
 
 
 
 
 
 
Street 
 
 
 
Apt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_________________________  _______ 
___________ 
 
 
 
 
 
 
 
City 
 
 
 
       State 
Zip 
 
initials of investigational team member completing/verifying form_____     date ________ 
 
 
 


58 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
Baseline Characteristics  
 
 
 
 
1. Date of Birth: ____/____/______ 
 
 
2. Age: ____ ____ years 
 
3. Gender:  M □  F □ 
 
4. Height: ____ ____ inches 
 
 
 
5. Weight: ____ ____ ____ kg 
 
6. Hospital admission date: (to study hospital) 
____/____/______ 
 
7. ICU admission date: (in study hospital)    
____/____/______ 
 
8. Location prior to hospitalization (includes hospitalization at Tufts Medical Center and any outside hospital) 
 
□ Home alone  
 
 
 
 
□ Senior housing (w/ minimal assisted living) 
□ Home with a spouse  
 
 
 
□ Assisted living facility 
□ Home with other family member/friends 
 
□ Long term care facility 
□ Rehabilitation 
 
 
 
 
□ Other: ______________________________ 
 
9. Location immediately prior to this ICU admission: 
 
□ Tufts emergency department  
 
 
□ ICU at outside hospital, admit date:  ____/____/______ 
□ Tufts hospital ward 
 
 
 
 
□ Ward at outside hospital, admit date:  ____/____/______ 
□ Tufts operating room following elective surgery 
□ Other: _________________________ 
□ Tufts operating room following emergency surgery 
Pt Number ____  ____  ____ 
 
Patient Initials ____  ____  ____  
Date ____/____/_____ 


59 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
10. Prior ICU stay during this hospital admission:  
□ Yes □ No 
 
 
If YES, specify unit: _______________ 
 
11. Was a tracheotomy present on admission to ICU? 
 
□ Yes □ No 
 
 
If YES, was it performed during this hospital admission? 
□ Yes □ No 
 
12. Start date of mechanical ventilation: 
 
Date: ____/____/______ Time: ____:____ (24hr clock) 
 
13. Admission APACHE III Diagnosis Code (Please see attached): ____ ____ 
 
 
If “other” has been selected in any category, please specify: ______________________________ 
 
14. APACHE II Score (Please see eattached): Calculate APACHE II score using values from the 24 hour period prior to randomization. 
 
 
APS: ____ 
 
 
Age Points: ____ 
 
Chronic Health Points: ____ 
 
 
            Total APACHE II: ____ 
 
initials of investigational team member completing/verifying form_____     date ________ 
 
 
 


60 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
 
 
 
 
15. Baseline SOFA Score (Please see attached): Calculate SOFA score using values from the 24 hour period prior to randomization. 
 
 
Total SOFA: ____ 
 
16. Last Spontaneous Bowel Movement (Per medical record review/family interview): 
 
 
Date: ____/____/______  
 
 
 
Time: ____:____ (24 hour clock) 
 
17. Current infusions at randomization: (check all that apply) 
 
 
Fentanyl: 
 
□ Yes □ No 
Start date: ____/____/______ 
Time: ____:____ 
Rate: _____mcg/hr 
 
Hydromorphone: 
□ Yes □ No 
Start date: ____/____/______ 
Time: ____:____ 
Rate: _____ mg/hr 
 
Morphine:  
□ Yes □ No 
Start date: ____/____/______ 
Time: ____:____  
Rate: _____ mg/hr 
 
Midazolam:  
□ Yes □ No 
Start date: ____/____/______  Time: ____:____  
Rate: _____ mg/hr 
 
Lorazepam:  
□ Yes □ No 
Start date: ____/____/______  Time: ____:____  
Rate: _____ mg/hr 
 
Propofol: 
 
□ Yes □ No 
Start date: ____/____/______  Time: ____:____  
Rate: _____ mcg/kg/min 
 
Dexmedetomidine: □ Yes □ No 
Start date: ____/____/______  Time: ____:____  
Rate: _____ mcg/kg/hr 
 
Other: _______________________ Start date: ____/____/______  Time: ____:____  
Rate: _____ ___/hr 
 
18. Opioid Medications at randomization: (check all that apply) 
 
 
Fentanyl: 
 
□ Yes □ No 
Start date: ____/____/______ 
Dose in last 24 hours ____ mcg 
 
Hydromorphone: 
□ Yes □ No 
Start date: ____/____/______ 
Dose in last 24 hours ____ mg 
 
Morphine:  
□ Yes □ No 
Start date: ____/____/______ 
Dose in last 24 hours ____ mg 
Pt Number ____  ____  ____ 
 
Patient Initials ____  ____  ____  
Date 
____/____/_____ 


61 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
Oxycodone: 
□ Yes □ No 
Start date: ____/____/______ 
Dose in last 24 hours ____ mg 
 
Hydrocodone: 
□ Yes □ No 
Start date: ____/____/______ 
Dose in last 24 hours ____ mg 
 
Methadone:  
□ Yes □ No 
Start date: ____/____/______ 
Dose in last 24 hours ____ mg 
 
 
Other: ______________________ Start date: ____/____/______ 
Dose in last 24 hours ____ mg 
 
19. Reason for Opioid Initiation: (check all that apply) 
 
 
□ Analgesia for Mechanical Ventilation 
 
 
□ Postoperative Pain 
 
□ Cancer Pain 
 
 
 
 
 
□ Periprocedural Pain 
 
□ Wound Care 
initials of investigational team member completing/verifying form_____     date ________ 
 
Baseline APACHE II Calculator 
 
 
 
 
 
 
 
 
 Pt Study ID: |__|__|__|   Pt Initials: |__|__|__|     
 
 From:  |__|__|  |__|__|   |  2|  0|   |    |    |__|__| : |__|__|       To:  |__|__|  |__|__|   |  2|  0|   |    |    |__|__| : |__|__|  
1) 
                  DD          MM 
           YEAR 
     HH           MM                                   DD             MM 
            YEAR 
     HH              MM 
    Please retain this worksheet at the site with the CRF. 
Calculate APACHE II score using values from the 24 hour period prior to randomization. 
Please circle appropriate range on form 
A.  Physiologic Variables Points 
PHYSIOLOGIC VARIABLE 
HIGH ABNORMAL RANGE 
  
 
 
LOW ABNORMAL RANGE 
PT 
SCORE 
4 
3 
2 
1 
0 
1 
2 
3 
4 
Temperature –core  (oC) 
> 41 
39-40.9 
  
38.5-38.9 36-38.4 
34-35.9 
32-33.9 
30-31.9 
< 29.9 
  
MAP (mmHg) 
> 160 
130-159 110-129 
  
70-109 
  
50-69 
  
< 49 
  
Heart Rate  
> 180 
140-179 110-139 
  
70-109 
  
55-69 
40-54 
< 39 
  
Respiratory Rate  
(non-ventilated or ventilated) 
> 50 
35-49 
  
25-34 
12-24 
10-11 
6-9 
  
< 5 
  
Oxygenation:       [A-aDO2 = (FiO2 x 710) – (PCO2 x 1.25) – PO2]   
FiO2 =                    PCO2 =                     PO2 =  
  


62 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
a. If FiO2 > 0.5 record A-aDO2 
> 500 
350-499 200-349 
  
< 200 
  
  
  
  
  
b. If FiO2 < 0.5 record only PaO2 
  
  
  
  
PO2 > 70 PO2 61-70 
  
PO2 55-60 PO2 < 55 
  
Arterial pH 
> 7.7 
7.6-7.69 
  
7.5-7.59 7.33-7.49 
  
7.25-7.32 7.15-7.24 
< 7.15 
  
Serum Na (mEq/L) 
> 180 
160-179 155-159 150-154 
130-149 
  
120-129 
111-119 
< 110 
  
Serum K (mEql/L) 
> 7 
6-6.9 
  
5.5-5.9 
3.5-5.4 
3-3.4 
2.5-2.9 
  
< 2.5 
  
**Serum Creatinine ** (mg/dL) 
> 3.5 
2-3.4 
1.5-1.9 
  
0.6-1.4 
  
<0.6 
  
  
  
Hematocrit (%) 
> 60 
  
50-59.9 
46-49.9 
30-45.9 
  
20-29.9 
  
< 20 
  
WBC (103/µL) 
> 40 
  
20-39.9 
15-19.9 
3-14.9 
  
1-2.9 
  
< 1 
  
Glasgow Coma Score (GCS)  
Score = 15 minus actual GCS (see below) 
  
Serum HCO3 (venous mEq/L) - not 
preferred, use only if no ABG's 
> 52 
41-51.9 
  
32-40.9 
22-31.9 
  
18-21.9 
15-17.0 
< 15 
  
                                                                ACUTE PHYSIOLOGY SCORE (APS):  Sum of the 12 individual variables 
  
** Acute Renal Failure – double the creatinine points for ARF (cr > 2.5 mg/dL in a subject with prior normal  kidney function) 
B.  Age Points - Assign points to age as follows: 
AGE (yrs) 
POINTS 
< 44 
0 
45-54 
2 
55-64 
3 
65-74 
5 
> 75 
6 
AGE SCORE =  
 
C. Chronic Health Points - If the patient has a 
history of : 
severe organ insufficiency or is immunocompromised 
assign points as follows: 
a.  For nonoperative or emergency postoperative pt -- 5 points 
b.  For elective postoperative pt -- 2 points 
CHRONIC HEALTH SCORE  
  
D.  APACHE II SCORE - Sum of A + B + C 
A.  APS points 
  
B.  Age points 
  
C.  Chronic Health points 
  
GLASCOW COMA SCALE 
1) 
Parameter 
2) 
Response 
Points Assigned 
(please circle) 
Eyes Open 
Spontaneously 
4 
On spoken command 
3 
On pain 
2 
No response 
1 
Best Motor 
Response 
To spoken command 
6 
To painful stimulus: 
 
Localized pain 
5 
Flexion withdrawal 
4 
Flexion abnormal 
3 
Extension 
2 
No response 
1 
Best Verbal 
Response 
(Not on ventilator) 
 
Oriented & converses 
5 
Disoriented & converses 
4 
Inappropriate words 
3 
Incomprehensible sounds 
2 
No response 
1 
(On ventilator) 
 
Appears oriented 
5 
Questionably oriented 
3 
Generally unresponsive 
1 
 
 


63 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
       APACHE II SCORE =  
  
 
 
 
 
 
 
 
 
 
SLEAP Study (Form 1-page 4/5) 
 
 
 
 
 
initials of investigational team member completing/verifying form_____     date ________ 
 
 
 
 
 
 
 
 
 
 
 
                                           Baseline SOFA Calculator 
 
 
 
 
 
 Pt Study ID: |__|__|__|   Pt Initials: |__|__|__|     
 
 From:  |__|__|  |__|__|   |  2|  0|   |    |   
|__|__| : |__|__|       To:  |__|__|  |__|__|   |  2|  0|   |    |     |__|__| : |__|__|        
 
                   DD          MM              YEAR 
                    HH            MM                             DD          MM            YEAR 
      HH            MM 
 
Please retain this worksheet at the site with the CRF. 
 
Calculate SOFA score using values from the 24 hour period prior to randomization. 
 
A. Please circle appropriate score                                                                               
 
 
CHRONIC HEALTH DEFINITONS Please check all that apply 
Organ insufficiency or immuno-compromised state evident prior to this hospital admission and conform to the following criteria: 
LIVER:  Biopsy proven cirrhosis and documented portal hypertension; episodes of past upper GI bleeding attributed to portal 
hypertension; or prior episodes of hepatic failure/encephalopathy/coma 
CARDIOVASCULAR:  New York Heart Association Class IV 
RESPIRATORY:  Chronic restrictive, obstructive, or vascular disease resulting in severe exercise restriction i.e. unable to climb 
stairs or perform household duties; or documented chronic hypoxia, hypercapnia, secondary polycythemia, severe pulmonary 
hypertension (>40 mmHg), or respirator dependency 
RENAL:  Receiving chronic dialysis 
IMMUNO-COMPROMISED:  The patient has received therapy that suppresses resistance to infection i.e. Immuno-suppression, 
chemotherapy, radiation, long term or recent high dose steroids, or has a disease that is sufficiently advanced to suppress 
resistance to infection (i.e. leukemia, lymphoma, AIDS) 


64 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B. Please record below the actual values used in the scoring above. 
 
PaO2  |__|__|__| 
Organ System 
0 
1 
2 
3 
4 
Score 
 
RESPIRATION 
PaO2/FiO2 (mmHg) 
 
 
>400 
 
301-400 
 
201-300 
 
101-200 with 
respiratory 
support 
 
 
< 100 with 
respiratory 
support 
 
CARDIOVASCULAR 
Vasopressors 
(mcg/kg/min) 
 
No 
hypotension 
 
MAP < 70mmHg 
and 
No vasopressors 
 
Dopamine ≤ 5 
or 
Any dose 
Dobutamine 
 
 
Dopamine > 5 
or 
Epinephrine ≤ 0.1 
or 
Norepinephrine ≤ 0.1 
 
Dopamine >15 
or 
Epinephrine > 0.1 
or 
Norepinephrine > 0.1 
or  
any dose Vasopressin 
 
LIVER (bilirubin)     
(mg/dl) 
 
 
<1.2 
 
1.2 – 1.9 
 
 
2.0 – 5.9 
 
 
6.0 – 11.9 
 
 
≥ 12 
 
COAGULATION 
Platelets (x 103/L) 
 
 
>150 
 
101-150 
 
51-100 
 
21-50 
 
≤20 
 
RENAL 
Creatinine (mg/dL)) 
or 
urine output mL/hr 
 
 
<1.2 
 
1.2 - 1.9 
 
2.0 -3.4 
 
 
3.5 – 4.9 
 
or 
 
< 500 ml/day 
 
 
 ≥ 5.0 
 
or 
 
< 200 ml/day 
 
TOTAL SOFA= 
 


65 
Drug Substance:  Movantik 
Study Number: ESR-15-11000 
Tufts IRB #12043 
Version:  Protocol version #19 
Date:  September 10, 2018 
 
 
 
FiO2  
|__| . |__|__| 
 
MAP  
|__|__|__| 
 
Bilirubin |__|__|__| µmol/L 
 
Platelets |__|__|__| x 103/µL 
 
Creatinine |__|__|__| µmol/L  
or       Urine output |__|__|__|__| mL/day 
 
initials of investigational team member completing/verifying form_____     date ________ 
 

SAP_001.pdf: 
Impact of Naloxegol (Movantik) on Prevention of Lower Gastrointestinal Tract 
Paralysis in Critically Ill Adults Initiated on Scheduled IV Opioid Therapy: A 
Randomized, Double-Blind, Placebo-Controlled, Phase II, Single-Center, Proof of 
Concept Study 
 
NCT02977286 
 
Version Date: September 22, 2018 
Approved on: October 25, 2018 


 
12.  STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
 
12.1 Description of analysis sets   
 
All patients will be analyzed in the groups to which they were randomly assigned, according to the 
intention-to-treat principle. 
 
12. 2 Methods of statistical analysis  
 
Baseline characteristics of patients will be compared using standard univariate methods (chi-square test, t-
test) to confirm the randomization was successful in achieving comparable groups. To test the primary 
outcome (incidence of lower GI tract paralysis), given that there may be censoring (i.e., subject may die 
or withdraw from study before developing lower GI tract paralysis), we will present Kaplan-Meier curves 
for the naloxegol and placebo groups for the time to first development of lower GI tract paralysis (≥ 3 
days without a SBM after study randomization) during the ICU stay up to 10 days and compare the 
curves using a log-rank test.  If all subjects complete the study (e.g., no deaths, no withdrawal or loss-to-
follow-up for other reasons), then we will instead compare the proportion of patients that develop lower 
GI tract paralysis after study randomization during the ICU stay up to 10 days between the naloxegol and 
placebo groups using a chi-square test.  The secondary outcome, time to first SBM will be estimated 
using a Kaplan Meier time to event analysis and compared between groups using a log-rank test.  The 
secondary outcome of the number of ICU days without a SBM will be compared between the naloxegol 
and placebo groups using the Poisson regression for count data and adjusting for total number of days in 
the ICU (up to a maximum of 10) as an offset term in the Poisson model.  The secondary outcome of the 
average daily opioid requirements will be compared between groups using either a student t-test or 
nonparametric Wilcoxan rank-sum test if the assumptions of the student t-test fail to be met.  Length of 
mechanical ventilation and ICU stay will be reported as medians and interquartile ranges and will be 
compared using the Wilcoxon Rank Sum Test.  For all statistical tests of hypotheses, a two-sided p-value 
of  0.05 will be considered as statistically significant. As this is a Phase II proof of concept study a p 
value of <0.10 may still be worth consideration for future study, however.  All statistical analyses will be 
performed using SPSS 17.0. (SPSS, Chicago, IL) or other comparable commercially available statistical 
software. 
 
12.2.1 Interim analyses 
 
As outlined in the DSMB procedure, planned interim analyses will occur to evaluate safety after the 
enrollment of 10 subjects and after the enrollment of 20 subjects.  
 
12.2.2 Determination of sample size 
 
For the power analysis, the 4-day estimates of failure to defecate (i.e., failure to have a SBM) from the 
Kaplan-Meier plot presented in the Guardiola et. al. paper [4] was used as the estimate of lower GI tract 
paralysis.  The figure below shows that the estimate of the percent of patients who failed to defecate  (1 
minus plotted proportion with defecation) by day 4 was 40% in the Prophylaxis group (i.e., the 
intervention group) vs. 90% in the non-prophylaxis (Treatment) group (i.e., the control group)  (see 
yellow highlights in figure).  We believe the 4-day estimate will be strongly related to the primary 
outcome of lower GI tract paralysis (≥ 3 days without a SBM).  
 
 


 
 
 
 
 
 
 
For this Naloxogol randomized trial, we propose 
enrolling 36 subjects, 18 per group. The statistical 
power table below  shows this sample size yields 
over 95% power using an alpha of 0.05 if the true day 
4 estimated freedom of event (defecation) rates are 
90% (Placebo) vs. 40% (Prophylactic treatment), all subjects have complete follow-up, and the analysis is 
done using the log-rank test to compare survival curves.  As sensitivity analysis, the table also shows the 
power of the study with this sample size under different scenarios.  Because this is not the final definitive 
study to determine efficacy, a less stringent alpha of 0.10 may be justified for this Phase II proof-of-
concept study which, if positive, would be followed by a confirmatory study [15]. While we expect most 
subjects to finish the study (based on the inclusion criteria), we have shown the impact on the power if 
approximately 20% of subjects do not finish the study.   We have also varied the estimated proportion of 
patients failing to defecate by day 4 (i.e., not having a SBM) in the placebo group from 90% to 70% and 
in the prophylactic treated group from 40% to 50%.