Conditions: Postoperative Gastrointestinal Dysfunction
Keywords: Bowel resection Gastrointestinal recovery peripherally acting mu-opioid receptor antagonist Bowel transection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
The objective of this study is to compare the efficacy of naldemedine versus placebo and to assess its effect on the time to gastrointestinal (GI) recovery following surgeries that include bowel resection and bowel transection.

Detailed description:

Arms:
arm 1: Participants will receive 1.25 milligrams (mg) naldemedine twice daily (BID) beginning on the day of surgery (Day 1) and for up to a maximum of 10 days post-surgery. arm 2: Participants will receive 2.5 mg naldemedine BID beginning on the day of surgery (Day 1) and for up to a maximum of 10 days post-surgery. arm 3: Participants will receive 5 mg naldemedine BID beginning on the day of surgery (Day 1) and for up to a maximum of 10 days post-surgery. arm 4: Participants will receive matching placebo BID beginning on the day of surgery (Day 1) and for up to a maximum of 10 days post-surgery.

Interventions: intervention 1: Naldemedine intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral tablet

Protocol document:
Prot_000.pdf: 
Shionogi Study Title: 
A Phase 2, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study of Naldemedine in Patients 
Undergoing Surgeries That Include a Bowel Resection or 
Bowel Transection 
Shionogi Study Number: 
1902G1721 
ClinicalTrials.gov 
Registration No. 
NCT04355169 
Study Document 
Protocol Version 3 
 June 18, 2020 
History of Protocol Amendments 
Original 
November 21, 2019 
•
Wording and description changed for clarification
•
Medical monitor’s information changed
Version 2 
February 14, 2020 
•
Range of differences across treatment groups, in time to GI2, was revised to be 24
hours instead of 18 hours
•
Section added to support addition of endpoint
Version 3 
June 18, 2020 
NCT #NCT04355169


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TITLE PAGE 
Protocol Title: 
A phase 2, multicenter, randomized, double-blind, placebo-controlled study of 
naldemedine in patients undergoing surgeries that include a bowel resection or bowel 
transection 
Protocol Number: 1902G1721 
Version: 3 
Compound Name (Number): 
Naldemedine (S-297995) 
Short Title: 
Naldemedine for patients undergoing surgeries that include a bowel resection or bowel 
transection 
Sponsor Name: 
Shionogi Inc. 
Legal Registered Address: 
Shionogi Inc. 
300 Campus Drive, Florham Park, NJ 07932 USA 
Regulatory Agency Identifying Number: Investigational New Drug (IND) 
 
Issue Date: 18 Jun 2020 
 Shionogi Inc. 
18 Jun 2020 




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PROTOCOL SUMMARY OF CHANGES: VERSION 3 
 
DOCUMENT HISTORY 
Document 
Date 
Version 3 
18 Jun 2020 
Version 2 
14 Feb 2020 
Original Protocol 
21 Nov 2019 
 
Version 3: 18 Jun 2020 
 
Section # and Name 
Description of Change 
(Deleted text shown with 
strikethroughs; added text 
shown with underlines) 
Brief Rationale 
Section 1.1, Synopsis, Section 
9.4.5.3, Exploratory Efficacy 
Endpoints 
• Effect of prior surgery 
(yes/no) on the GI2 
endpoint 
Added since Inclusion 
Criterion 5 was revised to 
allow 2 prior surgeries 
Section 1.1, Synopsis, Table 
1-1; Section 1.3, Schedule of 
Activities, Table 1-2; Section 3, 
Objectives and Endpoints, 
Table 3-1 
Day 0, 0.5-hour, postdose, 
presurgery pharmacokinetic 
blood sample removed 
To reduce the burden of 
venipuncture 
Section 1.1, Synopsis, Number 
of Patients; Section 4.1, Overall 
Design; Section 9.2, Sample 
Size Determination 
Patients to be screened 
changed from approximately 
425 to between 250 and 425, 
patients to be randomized 
changed from approximately 
340 to between 200 and 340, 
and patients to be in each 
treatment group changed from 
approximately 85 to between 
50 and 85 
The expectation of the 
range of differences across 
treatment groups, in time 
to GI2, was revised to be 
24 hours instead of 
18 hours, requiring less 
patients to achieve the 
desired 80% power for the 
primary objective 


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Section 1.3, Schedule of 
Activities, Figure 1-2 
Medical history row revised to 
include prior postoperative 
ileus and postoperative 
gastrointestinal dysfunction, 
prior and current therapy row 
revised to include preoperative 
bowel preparation and volume 
of intravenous fluids 
administered during surgery 
Recording these data may 
provide information for 
future study design 
Enhanced recovery protocol 
elements added 
To ensure all 7 elements 
of the enhanced recovery 
protocol (planned and 
actual) are recorded 
Baseline physical examination 
and electrocardiogram revised 
to allow preoperative physical 
examination and 
electrocardiogram without 
clinically significant abnormal 
findings within 2 weeks of the 
patient signing the informed 
consent form, and a urine 
pregnancy test was added from 
Day -14 to 0 
To reduce unnecessary 
duplicate preoperative 
physical examinations and 
electrocardiograms, and to 
identify pregnant patients 
earlier and exclude them 
from the study 
Section 5.2, Exclusion Criteria 
1. Scheduled to undergo a total 
colectomy or any procedure 
that results in a colostomy or 
ileostomy. 
To clarify that any 
procedure resulting in an 
ileostomy or colostomy is 
excluded. 
3. Emergency surgery 
There was no reason to 
exclude patients who 
needed emergency surgery 
if the protocol criteria 
could be met 
56. PreviousMore than 2 prior 
major abdominal 
surgerysurgeries (eg, 
gastrectomy, gastric bypass, 
gastric sleeve, lap banding, 
Whipple, pancreatic resection, 
total/subtotal colectomy, 
hemicolectomy, extensive 
bowel resection).hepatectomy, 
intestinal transplant). 
To allow patients with 
prior surgeries to enroll in 
the study 


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78. Chemotherapy within 4 
weeks prior to surgery; 
otherwise, patients with cancer 
are eligible. 
Clarification 
89. Scheduled to receive 
chemotherapy, 
immunotherapy, or radiation 
therapy intraoperatively or 
within 14 days after surgery; 
otherwise patients with cancer 
are eligible. 
Clarification 
Section 6.5, Medical History 
and Prior and Concomitant 
Therapy 
Title revised to include 
Medical History 
Updated to match section 
content 
Any prior history of 
postoperative ileus and 
postoperative gastrointestinal 
dysfunction must be recorded 
on the eCRF as part of the 
patient’s medical history. 
The preoperative bowel 
preparation, if any, must be 
recorded in the eCRF. 
Additionally, the total volume 
of intravenous fluids 
administered during the 
surgery must be recorded in 
the eCRF. 
To ensure histories of 
postoperative ileus and 
gastrointestinal function, 
preoperative bowel 
preparation, and total 
volume of intravenous 
fluids administered are 
recorded 
The following elements of the 
enhanced recovery protocol at 
the study site must be recorded 
as yes or no in the eCRF at 
Baseline (planned) and at the 
day of discharge or early 
termination (actual): 
• Three elements required by 
the protocol: 
o Early removal of the 
nasogastric tube, 
defined as removal of 
the nasogastric tube at 
the end of surgery 
o Early ambulation, 
defined as ambulation 
on Day 1 
To ensure the 3 elements 
of the enhanced recovery 
protocol required by the 
protocol and the 4 other 
elements at the study site 
(planned and actual) are 
recorded 


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o 
Early 
diet 
advancement on Day 1 
• Four other elements that 
may be used at the study 
site: 
o Antibiotic prophylaxis 
o Preoperative 
carbohydrate drink 
o Epidural anesthesia in 
addition to general 
anesthesia 
o Chewing gum 
postoperatively 
Section 7.1, Discontinuation of 
Study Treatment 
The patient has an unplanned 
ileostomy or colostomy during 
the surgical procedure. 
Clarification 
Section 8, Study Assessments 
and Procedures 
Procedures conducted as part 
of the patient’s routine clinical 
management (eg, physical 
examination, blood count, 
electrocardiogram [ECG]) and 
obtained before signing of the 
ICF may be utilized 
for Screening or Baseline 
purposes provided the 
procedures meet the 
protocol-specified criteria and 
are performed within the time 
frame defined in the SoA. 
Clarification 
Section 8.1.3.6, Effect of Prior 
Surgery on G12 Endpoint 
The effect of prior surgery 
(yes/no) on the GI2 endpoint 
will be assessed. 
Section added to support 
addition of endpoint 
Section 8.2.1, Physical 
Examinations 
Revised to match wording in 
Figure 1-2 and allow 
preoperative physical 
examination (within 2 weeks 
prior to the study patient 
signing the informed consent 
form) 
Clarification 
Section 8.2.3, 
Electrocardiograms 
Revised to match wording in 
Figure 1-2 and allow 
electrocardiogram 2 weeks 
prior to the patient signing the 
informed consent form 
Clarification 


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Section 9.2, Sample Size 
Determination 
The restricted mean survival 
time up to 240 hours for the 
time to event of GI2 was 
revised to between 44 and 
85 patients per treatment group 
to see a linear trend in RMST 
up to 240 hours across a 
24-hour difference between 
naldemedine 5 mg and 
placebo, following the Weibull 
distribution by referring to the 
survival curve for the time to 
the event of GI2 shown in the 
alvimopan package insert 
The target 18-hour 
difference was changed to 
a 24-hour difference 
Section 9.4.3, Medical History 
and Prior and Concomitant 
Therapies 
Title revised to include 
Medical History 
Updated to match section 
content 
Medical histories will be listed 
and summarized for the mITT 
Population. 
Inadvertently omitted 
previously 
Section 9.5, Interim Analyses 
A possible interim efficacy 
analysis was added, depending 
on the enrollment rate, that 
will be reviewed by the Data 
Monitoring Committee 
To provide flexibility to 
the study 
Section 10.3, Appendix 3: 
Adverse Events: Definitions 
and Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting 
• Any clinically significant 
abnormal laboratory 
findings or other abnormal 
safety assessments which 
are associated with the 
underlying disease, unless 
judged by the investigator 
to be more severe than 
expected for the patient’s 
condition. 
Correction since 
“clinically significant” 
necessary 
• Hospitalization for 
preplanned and elective 
procedures between 
discharge and follow-up to 
treat a pre-existing 
condition that did not 
worsen after start of study 
will not be considered an 
AE and therefore will not 
be considered an SAE 
Correction since 
prolonged hospitalization 
is considered an SAE 


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despite requiring 
hospitalization or 
prolonged hospitalization. 
Section 10.3.1, Definition of 
Serious Adverse Event 
If an event is not an AE per the 
definition above, then it cannot 
be an SAE even if serious 
conditions are met (eg, 
hospitalization for 
signs/symptoms of the disease 
under study, death due to 
progression of disease). 
Correction since 
hospitalization and death 
are considered SAEs 
Section 10.10, Appendix 10: 
Protocol Version History 
Strong cytochrome P450 3A 
(CYP3A) and P glycoprotein 
(P-gp) inhibitors (eg, 
clarithromycin, diltiazem, 
grapefruit juice, indinavir, 
ketoconazole, ritonavir) added 
as prohibited prior and 
concomitant therapy 
Correction 


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TABLE OF CONTENTS 
Title Page .............................................................................................................................1 
Protocol Summary of Changes: Version 3 ...........................................................................3 
Table of Contents .................................................................................................................9 
LIST OF IN-TEXT TABLES ............................................................................................12 
LIST OF IN-TEXT FIGURES ..........................................................................................12 
1. 
Protocol Summary .....................................................................................................13 
1.1 
Synopsis ...........................................................................................................13 
1.2 
Schema .............................................................................................................16 
1.3 
Schedule of Activities (SoA) ...........................................................................18 
2. 
Introduction ................................................................................................................24 
2.1 
Study Rationale ................................................................................................24 
2.2 
Background ......................................................................................................24 
2.3 
Benefit/Risk Assessment .................................................................................24 
3. 
Objectives and Endpoints ..........................................................................................25 
4. 
Study Design ..............................................................................................................27 
4.1 
Overall Design .................................................................................................27 
4.2 
Scientific Rationale for Study Design ..............................................................28 
4.3 
Justification for Dose .......................................................................................29 
4.4 
End of Study Definition ...................................................................................29 
5. 
Study Population ........................................................................................................30 
5.1 
Inclusion Criteria .............................................................................................30 
5.2 
Exclusion Criteria ............................................................................................31 
5.3 
Lifestyle Considerations ..................................................................................32 
5.4 
Screen Failures .................................................................................................32 
6. 
Study Treatment .........................................................................................................33 
6.1 
Study Treatments Administered.......................................................................33 
6.2 
Preparation/Handling/Storage/Accountability of Study Treatment .................34 
6.3 
Measures to Minimize Bias: Randomization and Blinding .............................35 
6.4 
Study Treatment Compliance ...........................................................................35 
6.5 
Medical History and Prior  and Concomitant Therapy ....................................35 
6.6 
Dose Modification of Study Treatment ...........................................................37 
6.7 
Treatment after the End of the Study ...............................................................37 
7. 
Discontinuation of Study Treatment and Patient Discontinuation/Withdrawal .........38 
7.1 
Discontinuation of Study Treatment ................................................................38 
7.2 
Patient Discontinuation/Withdrawal from the Study .......................................38 
7.3 
Lost to Follow-up .............................................................................................39 


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8. 
Study Assessments and Procedures ...........................................................................40 
8.1 
Efficacy Assessments .......................................................................................40 
8.1.1 
Primary Efficacy Assessments ...............................................................40 
8.1.1.1 
Time from End of Surgery to Time to First Toleration of 
Solid Food and First Bowel Movement .......................................40 
8.1.2 
Secondary Efficacy Assessments ...........................................................41 
8.1.2.1 
Time from End of Surgery to Time When the Discharge 
Order is Written ...........................................................................41 
8.1.2.2 
Reinsertion of the Nasogastric Tube ............................................41 
8.1.2.3 
Readmission within 30 Day After Hospital Discharge ................41 
8.1.3 
Exploratory Efficacy Assessments .........................................................41 
8.1.3.1 
Time from End of Surgery to Discharge Readiness.....................41 
8.1.3.2 
Time from End of Surgery to Time of Actual Discharge ............41 
8.1.3.3 
Prolonged Hospital Stay Due to Gastrointestinal Dysfunction ....41 
8.1.3.4 
Patients Who Achieve GI2 in Each Treatment Group By 
Postoperative Day ........................................................................41 
8.1.3.5 
Patients Who Receive Concomitant Medication That May 
Have a Laxative Effect .................................................................41 
8.1.3.6 
Effect of Prior Surgery on G12 Endpoint ....................................41 
8.2 
Safety Assessments ..........................................................................................42 
8.2.1 
Physical Examinations ...........................................................................42 
8.2.2 
Vital Signs ..............................................................................................43 
8.2.3 
Electrocardiograms ................................................................................43 
8.2.4 
Clinical Safety Laboratory Assessments ................................................43 
8.2.5 
Numerical Pain Rating Scale .................................................................43 
8.2.6 
Clinical Opiate Withdrawal Scale ..........................................................44 
8.2.7 
Intra-operative and Postoperative Opioid Analgesics ............................44 
8.3 
Adverse Events and Serious Adverse Events...................................................44 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information .......................................................44 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ......45 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events...................45 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .........45 
8.3.5 
Pregnancy ...............................................................................................45 
8.3.6 
Special Situations - Overdose and Medication Error .............................46 
8.4 
Treatment of Overdose ....................................................................................46 
8.5 
Pharmacokinetics .............................................................................................46 
8.6 
Pharmacodynamics ..........................................................................................47 
8.7 
Genetics............................................................................................................47 


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8.8 
Biomarkers .......................................................................................................47 
8.9 
Health Economics/Medical Resource Utilization and Health Economics .......47 
9. 
Statistical Considerations ...........................................................................................48 
9.1 
Statistical Hypotheses ......................................................................................48 
9.2 
Sample Size Determination ..............................................................................48 
9.3 
Populations for Analyses .................................................................................48 
9.4 
Statistical Analyses ..........................................................................................49 
9.4.1 
Patient Disposition .................................................................................51 
9.4.2 
Demographics and Baseline Characteristics ..........................................51 
9.4.3 
Medical History and Prior and Concomitant Therapies .........................51 
9.4.4 
Extent of Exposure and Treatment Compliance ....................................51 
9.4.5 
Efficacy Analyses ..................................................................................52 
9.4.5.1 
Primary Efficacy Endpoint ...........................................................52 
9.4.5.2 
Secondary Efficacy Endpoints .....................................................53 
9.4.5.3 
Exploratory Efficacy Endpoints ...................................................53 
9.4.6 
Safety Analyses ......................................................................................54 
9.4.7 
Other Analyses .......................................................................................55 
9.4.7.1 
Pharmacokinetic Analyses ...........................................................55 
9.5 
Interim Analyses ..............................................................................................57 
9.6 
Data Monitoring Committee ............................................................................57 
10. Supporting Documentation and Operational Considerations .................................58 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..........58 
10.1.1 
Regulatory and Ethical Considerations ..................................................58 
10.1.2 
Financial Disclosure ...............................................................................58 
10.1.3 
Informed Consent Process .....................................................................59 
10.1.4 
Data Protection .......................................................................................59 
10.1.5 
Dissemination of Clinical Study Data ....................................................59 
10.1.6 
Data Quality Assurance .........................................................................60 
10.1.7 
Source Documents .................................................................................60 
10.1.8 
Study and Site Closure ...........................................................................61 
10.1.9 
Publication Policy ..................................................................................61 
10.2 
Appendix 2: Clinical Laboratory Tests ............................................................62 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .............................................................63 
10.3.1 
Definition of Serious Adverse Event .....................................................65 
10.3.2 
Recording and Follow-up of Adverse Events and Serious Adverse 
Events .....................................................................................................66 
10.3.3 
Reporting of Serious Adverse Events ....................................................67 


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10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ......................................................................................................68 
10.5 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ...71 
10.6 
Appendix 6: List of Examples of Strong Cytochrome P450 3A Inducers .......75 
10.7 
Appendix 7: List of Examples of Strong Cytochrome P450 3A and 
P-glycoprotein Inhibitors .................................................................................76 
10.8 
Appendix 8: Numerical Pain Rating Scale ......................................................78 
10.9 
Appendix 9: Clinical Opiate Withdrawal Scale ...............................................79 
10.10 Appendix 10: Protocol Version History ..........................................................80 
10.11 Appendix 11: Investigator Signature Page .......................................................84 
10.12 Appendix 12: Abbreviations and Acronyms ....................................................85 
11. References ..................................................................................................................87 
 
LIST OF IN-TEXT TABLES 
Table 1-1 
Objectives and Endpoints ..................................................................... 13 
Table 1-2 
Schedule for Pharmacokinetic Sample Collection ................................ 23 
Table 3-1 
Objectives and Endpoints ..................................................................... 25 
Table 6-1 
Study Treatments .................................................................................. 33 
Table 6-2 
Dosing Instructions During the Treatment Period ................................ 34 
Table 9-1 
Mapping Information for Study Days ................................................... 50 
Table 10-1 
Protocol-required Laboratory Assessments .......................................... 62 
 
LIST OF IN-TEXT FIGURES 
Figure 1-1 
Study Schematic .................................................................................... 17 
Figure 1-2 
Schedule of Activities ........................................................................... 19 






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• 
Proportion of patients with clinically 
significant changes in clinical laboratory 
tests, vital signs, and ECGs 
• 
Change from baseline in pain intensity, as 
assessed on a Numerical Pain Rating Scale 
(NPRS) 
• 
Total dose of intra- and postoperative 
opioid analgesics in morphine milligram 
equivalents (MMEs) 
AUC = area under the plasma concentration-time curve; CL/F = apparent total clearance estimated 
according to: CL/F = Dose/AUC0-τ on Day 3 (for naldemedine only); Cmax = maximum observed plasma 
concentration on Day 3; ECGs = electrocardiograms; MRM/U, AUC = metabolic ratio of AUC0-last of nor- 
naldemedine to AUC0-last of naldemedine, corrected for molecular weight, defined as (nor-naldemedine 
AUC0-last)/(naldemedine AUC0-last) × (naldemedine molecular weight [570.64])/(nor-naldemedine 
molecular weight [516.55]) (for nor-naldemedine only); MRM/U, Cmax = metabolic ratio of Cmax of nor- 
naldemedine to Cmax of naldemedine, corrected for molecular weight, defined as (nor-naldemedine 
Cmax)/(naldemedine Cmax) × (naldemedine molecular weight [570.64])/(nor-naldemedine molecular weight 
[516.55]) (for nor-naldemedine only); Tmax = time to maximum plasma concentration on Day 3 
 
Overall Design: 
This is a Phase 2, multicenter, randomized, parallel-group, double-blind, 
placebo-controlled study in patients undergoing partial small or large bowel resection 
with primary anastomosis or radical cystectomy requiring bowel transection with primary 
anastomosis. Randomization will be stratified by the planned surgical procedure, ie, small 
bowel resection with primary anastomosis, large bowel resection with primary 
anastomosis, or radical cystectomy requiring bowel transection with primary 
anastomosis. 
 
Number of Patients: 
Between 250 to 425 patients will be screened to achieve between 200 and 340 randomly 
assigned patients, with between 50 and 85 patients in each of 4 treatment groups. The 
planned sample size of approximately 50 patients per group was determined by a 
simulation study with 10,000 iterations to see a linear trend across doses of 24 hours for a 
difference in the primary endpoint between naldemedine 5 mg and placebo. The 
maximum of 85 patients per group will detect an 18-hour difference under 80% power at 
a 2-sided significance level of 0.05. The final sample size between 50 and 85 patients per 
group will be determined by the number of patients enrolled during the fixed enrollment 
period. 
 
Treatment Groups and Duration: 
Throughout this protocol, study treatment refers to naldemedine 1.25 mg, naldemedine 
2.5 mg, naldemedine 5 mg, and matching placebo, unless otherwise noted. 
 
Test Drug and Dose: Naldemedine orally disintegrating tablet (ODT) will be 
administered as a dose of 1.25 mg, 2.5 mg, or 5 mg twice daily (BID). 
 
Control Drug and Dose: Matching placebo ODT will be administered BID. 


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Mode of Administration of Test and Control Drugs: The first dose of study treatment 
will be administered 30 minutes to 6 hours prior to the scheduled start of surgery on the 
operative day (Day 0), and the second dose will be administered postoperatively the 
evening of the operative day. Beginning on Day 1, patients will receive study treatment 
BID for up to 10 days postoperatively (ie, Day 10). Every effort will be made to give the 
Day 1 morning dose approximately 12 hours after the Day 0 evening dose and to give all 
morning and evening doses from Day 1 to Day 10 at approximately 12-hour intervals. 
 
The patient will be instructed to place the ODT on the tongue and to let it dissolve. 
Administration with water is not required, but water is allowed if the patient prefers. 
 
Duration of Administration of Test and Control Drugs: Duration of administration will 
be determined by the date on which the primary endpoint, GI2, is met or the date on 
which the discharge order is written, whichever occurs sooner, and will not exceed 
10 postoperative days (excluding the postoperative dose on Day 0). Note: Study 
treatment may be administered on the day of discharge. 
 
Study Duration for Individual Study Patients (Includes Screening, Treatment and 
Follow-up Periods): 
Study duration for individual patients is approximately 8 weeks. This includes the 
Screening Period (no more than 14 days), the Treatment Period (no more than 11 days), 
and the Follow-up Period (no more than 30 days after Day 10 or after the day of 
discharge [whichever is sooner]). 
 
Prior and Concomitant Therapy: 
Prohibited Prior and Concomitant Therapy: 
 
• Strong cytochrome P450 3A (CYP3A) inducers (eg, carbamazepine, 
enzalutamide, mitotane, phenytoin, rifampin, St. John’s Wort) 
• Strong CYP3A and P-glycoprotein (P-gp) inhibitors (eg, clarithromycin, 
diltiazem, grapefruit juice, indinavir, ketoconazole, ritonavir) 
• Other opioid antagonists 
• Prophylactic use of laxatives (eg, magnesium citrate, magnesium hydroxide, 
magnesium sulfate, castor oil, sodium phosphate, sodium biphosphate, 
polyethylene glycol enemas, and stimulant laxatives, including bisacodyl); 
however, if needed, laxatives may be used for rescue therapy 
 
Data Monitoring Committee: 
An independent Data Monitoring Committee (DMC) will be instituted for this study. The 
functions of the DMC are detailed in the DMC Charter. 
 
1.2 
Schema 
The study schema is provided in Figure 1-1. 




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1.3 
Schedule of Activities (SoA) 
The Schedule of Activities (SoA) is provided in Figure 1-2, and the schedule for 
pharmacokinetic sample collection is provided in Table 1-2. 


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Figure 1-2 
Schedule of Activities 
 
Procedure/Assessment 
Screening 
Period 
Treatment Period 
Follow- 
up Period 
Day −14 to 
0 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Days 5 to 
10 
Day 
of 
Dischargea 
Early 
Term- 
inationb 
End-of- 
study 
Visitc 
Baseline 
Before 
Surgery 
After 
Surgery 
Administrative assessments 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Demographics 
X 
Medical history, including prior 
postoperative ileus and 
postoperative gastrointestinal 
dysfunction 
Xd 
Prior and current therapies, 
including preoperative bowel 
preparation, volume of IV fluids 
administered during surgery, 
and intra-operative and 
postoperative opioid analgesicse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Time of beginning of surgery 
Xf 
Time of end of surgery 
Xf 
Enhanced recovery protocol 
elementsg 
X 
X 
X 
Clinical assessments 
Physical examination 
Xh 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Vital signs and blood pressurej 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
Xk 
X 
X 
Pain assessment on NPRSl 
X 
X 
X 
X 
X 
X 
X 
X 
COWS assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 


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Procedure/Assessment 
Screening 
Period 
Treatment Period 
Follow- 
up Period 
Day −14 to 
0 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Days 5 to 
10 
Day 
of 
Dischargea 
Early 
Term- 
inationb 
End-of- 
study 
Visitc 
Baseline 
Before 
Surgery 
After 
Surgery 
Laboratory assessments 
Routine laboratory testsm 
X 
X 
X 
Urine pregnancy testn 
X 
X 
Blood sampling to determine 
plasma drug concentration and 
to characterize PK 
See Table 1-2 
Study treatment (naldemedine or placebo) procedures 
Randomization and study 
treatment assignment by IWRS 
X 
Study treatment administrationo 
Xp 
Xq 
Xr 
Xr 
Xr 
Xr 
Xr 
Xr 
Study treatment: overdose or 
medication errors 
Xs 
Xs 
Xs 
Xs 
Xs 
Xs 
Xs 
Xs 
Efficacy assessments 
Re-insertion of nasogastric tube 
X 
X 
X 
X 
X 
First toleration of solid food and 
first bowel movement (GI2) 
Xt 
Xt 
Xt 
Xt 
Xt 
Xt 
Xt 
Time to discharge readinessu 
X 
X 
X 
X 
X 
X 
X 
Time discharge order written 
X 
Time of actual discharge 
(departure) from hospital 
X 
Re-admission to hospital within 
30 days after discharge 
X 
BID = twice daily; COWS = Clinical Opiate Withdrawal Scale; eCRF = electronic case report form; EDC = electronic data capture; IV = intravenous; 
IWRS = Interactive Web Response System; NPRS = Numerical Pain Rating Scale; PK = pharmacokinetics 


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a 
To be recorded in the eCRF through the End-of-study Visit, which will occur 30 days after Day 10 or after the day of discharge (whichever is sooner), with a 
window of + 3 days, but not < 30 days. Patients will receive no more than a total of 11 days of study treatment (Day 0 [day of surgery] plus up to 10 days 
beginning on Day 1). 
b 
These assessments will be performed for patients who discontinue study treatment and for those who are withdrawn from the study. 
c 
The End-of-study Visit will occur 30 days after Day 10 or after the day of discharge (whichever is sooner), with a window of + 3 days, but not < 30 days 
(preferably in person, but by phone if necessary). 
d 
Includes prior and current conditions and all past surgeries; to be recorded on eCRF. 
e 
Includes (as applicable to the study period) a review of prior and current therapies. The preoperative bowel preparation, if any, as well as the total volume of 
IV fluids administered during surgery, must be recorded in the eCRF. Intra-operative and postoperative opioid analgesics administered to patients will be 
recorded in the eCRF. 
f 
Time of the beginning of surgery is defined as the time when the first incision is made. Time of end of surgery is defined as the time the patient leaves the 
operating room. 
g 
The 3 enhanced recovery protocol elements required by the protocol (early removal of the nasogastric tube [defined as removal of the nasogastric tube at end 
of surgery], early ambulation [defined as ambulation on Day 1], early diet advancement on Day 1) and 4 other elements at the study site (antibiotic 
prophylaxis, preoperative carbohydrate drink, epidural anesthesia in addition to general anesthesia, and chewing gum postoperatively) must be recorded as 
yes or no in the eCRF at Baseline (planned) and at the day of discharge or early termination (actual). 
h 
A preoperative physical examination within 2 weeks prior to the patient signing the informed consent form may be used, as long as the eCRF is completed. 
i 
As per standard of care at the hospital or, for End-of-study Visit, at the hospital or doctor’s office. 
j 
To be measured once daily as close as possible after waking; vital signs include systolic/diastolic blood pressure (assessed after approximately 3 to 5 minutes 
of rest), and pulse rate. 
k 
To be performed any time from 14 days to day of surgery (Day –14 to Day 0, respectively). An electrocardiogram obtained within 2 weeks prior to the 
patient signing the informed consent form that shows no clinically significant abnormal finding may be used. 
l 
To be assessed once daily in the morning at approximately the same time of day; baseline is defined as the pain assessment on the morning of Day 1. 
m Hematology (platelet count, erythrocytes [red blood cell count], hemoglobin, hematocrit, leukocytes [white blood cell count with differential: neutrophil 
count, lymphocyte count, monocyte count, eosinophil count, basophil count]), clinical chemistry (blood urea nitrogen, creatinine, chloride, potassium, 
sodium, calcium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, international normalized ratio, total protein, and 
albumin). 
n 
Required for female patients of childbearing potential (that is, not surgically sterile by hysterectomy, bilateral oophorectomy, and/or bilateral salpingectomy 
or tubal ligation with appropriate documentation of such surgery OR not postmenopausal [defined as at least 12 months of spontaneous amenorrhea in a 
woman > 45 years of age]). If the urine pregnancy test is obtained prior to Day −1 and is negative, the test must be repeated on Day −1 or Day 0. Additional 
pregnancy testing is not required during the treatment period unless clinically indicated. 
o 
The actual date and time (24-hour clock) of all study treatment dosing and each meal prior to dosing will be recorded in the eCRF. 
p 
First dose is to be administered 30 minutes to 6 hours prior to the scheduled start of surgery on the operative day (Day 0). 


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q 
A second dose will be administered postoperatively the evening of the operative day (Day 0). 
r 
Beginning on Day 1, patients will receive study treatment BID for up to 10 days postoperatively (ie, Day 10). Every effort will be made to give all morning 
and evening doses at approximately 12-hour intervals. The duration of study treatment will be determined by the date on which the primary endpoint, GI2 
(patient tolerates solid food and has a bowel movement), is met or the date on which the discharge order is written, whichever occurs first, and will not 
exceed 10 postoperative days. Study treatment may be administered on the day of discharge. 
s 
Any overdose or medication error of the study treatment must be reported to the contract research organization’s medical monitor via eCRF (or paper form if 
EDC is not available) by the investigator or qualified designee using a Special Situations Report Form as soon as becoming aware. 
t 
To be assessed until both time to first toleration of solid food (defined as the time when the patient consumes a meal that requires chewing and has no 
significant nausea or vomiting, as per the judgment of the investigator, for 4 hours after that solid food) and first bowel movement occur and to be recorded 
in the eCRF. If a patient is discharged from the hospital prior to having a first bowel movement, he/she is to be instructed to inform the investigator or 
qualified designee by phone within 24 hours of having a first bowel movement up to and including Day 10. Additionally, the investigator or qualified 
designee will communicate (phone, text, or e-mail) with the patient daily up to and including Day 10 to record when the first bowel movement occurred. 
u 
Discharge readiness is defined as gastrointestinal recovery based on the clinical judgment of the investigator (yes or no). 




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2. INTRODUCTION 
2.1 
Study Rationale 
Gastrointestinal (GI) dysfunction is a common finding in the postoperative setting, with a 
delay in the return of GI function extending the length of hospitalization. Naldemedine is 
an orally administered, peripherally acting mu-opioid receptor antagonist (PAMORA). Its 
use is currently being studied in the perioperative setting to assess its effect on the time to 
GI recovery following surgeries that include bowel resection and bowel transection. 
 
2.2 
Background 
In the surgical setting, a temporary reduction or cessation of intestinal motility is 
common postoperatively. The pathophysiology of this condition is multifactorial and 
complex. Overall, intestinal equilibrium is altered, resulting in a loss of coordinated 
propulsive action and an accumulation of gas and fluids. Hospitalization may thus be 
prolonged, increasing patient exposure to such risks as hospital-acquired infection and 
deep vein thrombosis, as well as increasing healthcare costs. 
 
Naldemedine (also referred to as S-297995) is a PAMORA developed by Shionogi & Co. 
Ltd. Naldemedine as a 0.2-mg tablet for once-daily oral administration was approved in 
the US on 23 Mar 2017 for the treatment of opioid-induced constipation (OIC) in adult 
patients with chronic non-cancer pain, including patients with chronic pain related to 
prior cancer or its treatment who do not require frequent (eg, weekly) opioid dose 
escalation (see NDA 208854). A detailed description of the chemistry, pharmacology, 
efficacy, and safety of naldemedine is provided in the current edition of the Investigator’s 
Brochure and in the package insert for naldemedine 0.2-mg tablets (SYMPROIC® 
[naldemedine tablets for oral use]). 
 
Shionogi has developed an orally disintegrating tablet (ODT) formulation of naldemedine 
for short-term perioperative use in patients undergoing surgeries that include bowel 
resection and bowel transection. This Phase 2 controlled study will be conducted to 
evaluate the naldemedine ODT in patients undergoing partial small or large bowel 
resection with primary anastomosis or radical cystectomy requiring bowel transection 
with primary anastomosis. 
 
2.3 
Benefit/Risk Assessment 
Naldemedine has not previously been studied for short-term perioperative use in patients 
undergoing surgeries that include bowel resection and bowel transection. Therefore, the 
expected benefits and risks of naldemedine for this patient population are not known. 
 
Detailed information about naldemedine is provided in the current edition of the 
Investigator’s Brochure. 






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4. STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 2, multicenter, randomized, parallel-group, double-blind, 
placebo-controlled study in patients undergoing partial small or large bowel resection 
with primary anastomosis or radical cystectomy requiring bowel transection with primary 
anastomosis. Randomization will be stratified by the planned surgical procedure, ie, small 
bowel resection with primary anastomosis, large bowel resection with primary 
anastomosis, or radical cystectomy requiring bowel transection with primary 
anastomosis. 
 
This study consists of: 
 
• a Screening/Baseline period (Day –14 to Day 0) 
• a Treatment period (study treatment for no more than 11 days, including Day 0 
[day of surgery] plus up to 10 postoperative days). Duration of study treatment 
will be determined by the date on which the primary endpoint, GI2, is met or the 
date on which the discharge order is written, whichever occurs first, and will not 
exceed 10 postoperative days (excluding the postoperative dose on Day 0) 
• a Follow-up period 30 days after Day 10 or after the day of discharge (whichever 
is sooner), with a window of + 3 days, but not < 30 days (End-of-study Visit) or 
an Early Termination (ET) Visit (see Figure 1-1) 
 
Between 250 and 425 patients will be screened to determine eligibility to participate in 
the study. It is planned that between 200 and 340 patients will be randomly assigned in a 
ratio of 1:1:1:1 to study treatment, with approximately 50 patients assigned to each of 
4 treatment groups (see also Section 9.2). 
 
Enrolled patients will be managed preoperatively according to standard of care. On 
Day 0, before surgery, patients will be randomly assigned to 1 of 4 treatment groups to 
receive study treatment, as follows: 
 
● Naldemedine 1.25 mg: One 1.25 mg ODT twice daily (BID), identical in shape, 
size, and color to the 2.5- and 5-mg ODT 
● Naldemedine 2.5 mg: One 2.5 mg ODT BID, identical in shape, size, and color to 
the 1.25- and 5-mg ODT 
● Naldemedine 5 mg: One 5 mg ODT BID, identical in shape, size, and color to the 
1.25- and 2.5-mg ODT 
● Matching placebo: One ODT BID, identical in shape, size, and color to the 
naldemedine ODT 
 
Throughout this protocol, study treatment refers to naldemedine 1.25 mg, naldemedine 
2.5 mg, naldemedine 5 mg, and matching placebo, unless otherwise noted. 


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The first dose of study treatment will be administered 30 minutes to 6 hours prior to the 
scheduled start of surgery on the operative day (Day 0), and the second dose will be 
administered postoperatively the evening of the operative day. Beginning on Day 1, 
patients will receive study treatment BID for up to 10 days postoperatively (ie, Day 10). 
Every effort will be made to give the Day 1 morning dose approximately 12 hours after 
the Day 0 evening dose and to give all morning and evening doses from Days 1 to 10 at 
approximately 12-hour intervals. Note that duration of administration will be determined 
by the date on which the primary endpoint, GI2, is met or the date on which the discharge 
order is written, whichever occurs first, and will not exceed 10 postoperative days 
(excluding the postoperative dose on Day 0). Study treatment may be administered on the 
day of discharge. Details regarding study treatment administration are provided in 
Section 6.1. 
 
During the treatment period, procedures and assessments will be performed as specified 
in the Schedule of Activities (SoA) in Section 1.3. 
 
Patients will be discharged based on the clinical judgment of the investigator and 
standard of care at the study hospital. Patients who are discharged by Day 10 will have an 
End-of-study Visit 30 days after Day 10 or after the day of discharge (whichever is 
sooner), with a window of + 3 days, but not < 30 days. 
 
Patients who discontinue study treatment prior to meeting the primary endpoint, GI2, will 
have an ET Visit and will be followed until 30 days after the day of discharge for safety. 
Patients who are withdrawn from the study will have an ET and an End-of-study Visit. 
 
4.2 
Scientific Rationale for Study Design 
Prolonged hospitalization due to delay in return of GI function after bowel surgery may 
increase patient exposure to such risks as hospital-acquired infection and deep vein 
thrombosis, as well as increase healthcare costs. As described in Section 2.2, there is a 
need for a pharmacologic agent with an improved benefit/risk profile that can be 
administered to patients who are undergoing bowel resection and bowel transection. 
 
The current study (Study 1902G1721) with naldemedine (which is approved in the US 
for the treatment of OIC in adult patients with chronic noncancer pain, including patients 
with chronic pain related to prior cancer or its treatment who do not require frequent [eg, 
weekly] opioid dosage escalation), will be conducted to determine whether naldemedine 
can accelerate the time to upper and lower GI recovery following surgeries that include 
partial bowel resection with primary anastomosis and radical cystectomy with bowel 
transection and primary anastomosis. 
 
This study employs a standard interventional clinical study design and will be conducted 
at multiple hospitals. The design of this study allows assessment of the efficacy, safety, 
and tolerability of naldemedine administered orally by ODT at 3 different doses 
compared with placebo in patients undergoing partial small or large bowel resection with 
primary anastomosis or radical cystectomy requiring bowel transection with primary 
anastomosis. 


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The randomization and stratification for this study (Section 6.3) allows for a 
well-balanced distribution of patients across treatment groups and will help determine 
whether there is a dose response to allow the choice of the most effective dose. The 
double-blind, placebo-controlled design was chosen because blinding of patients and 
investigators/study personnel helps to prevent bias and the inclusion of placebo is 
appropriate for use in this patient population. 
 
4.3 
Justification for Dose 
Opioids exert their analgesic effects primarily through the central mu-opioid receptors 
and are commonly used to manage postoperative pain. In the postoperative setting, 
surgery on the GI tract is commonly associated with GI dysfunction, which may be 
caused by both endogenous and exogenous opioids, as well as other factors [1]. The GI 
dysfunction may delay a patient’s recovery after surgery and prolong hospitalization [2]. 
 
In the postoperative period, severe postoperative pain therapy may ideally be managed 
with an opioid analgesic, with maintenance of efficacious plasma opioid concentrations 
as the goal of therapy [3, 4]. In this setting, functional blockage of intestinal transit may 
be caused by binding of opioids at mu-opioid receptors in the enteric nervous system. 
Blockage of this binding is important and, for this purpose, the trough plasma 
concentration of naldemedine should be kept above the effective opioid concentration. 
 
Naldemedine 0.2 mg once daily improved the frequency of spontaneous bowel 
movements in Phase 3 trials (NCT01993940 and NCT01965158; data on file). In 
addition, naldemedine suppressed morphine-induced inhibition of small intestinal transit 
in rats; the amount of drug that produced the desired effect in 50% (ED50) was 
0.03 mg/kg. The maximum observed plasma concentration value with a naldemedine 
0.2-mg dose in humans and the plasma drug concentration 1 hour after oral 
administration of naldemedine 0.03 mg/kg (ED50) to rats (at the end of efficacy 
assessment) were 3.07 ng/mL (data on file) and 2.51 ng/mL (data on file), respectively. 
Because these values for efficacious anti-OIC plasma concentrations in humans and the 
anticonstipation effect in rats were close, a trough plasma naldemedine concentration of 
3.07 ng/mL in the clinical setting may be appropriate in managing postoperative GI 
motility. Based on the plasma concentration profile in humans after multiple-dose 
administration of naldemedine 3 mg on Day 1 (C12hr [the concentration 12 hours after 
administration], 9.47 ng/mL) (NCT01443403; data on file), it is estimated that 
administration of naldemedine 1.25 mg will provide a plasma drug concentration close to 
3.07 ng/mL 12 hours after administration. Therefore, the doses of naldemedine chosen in 
this study are 1.25 mg, 2.5 mg, and 5 mg administered BID. 
 
4.4 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last patient in the study. 
A patient is considered to have completed the study if he/she has completed all periods of 
the study through the End-of-study Visit, even if he or she completes study treatment 
prior to Day 10 because of meeting the primary endpoint, GI2 (see SoA in Section 1.3). 


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5. STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
 
5.1 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
 
Age 
1. Patient must be 18 to 80 years of age, inclusive, at the time of signing the 
informed consent form (ICF). 
 
Type of Patient and Disease Characteristics 
2. Scheduled to undergo 1 of the following procedures via open (nonlaparoscopic) 
surgery under general anesthesia: 
• partial small or large bowel resection with primary anastomosis 
• radical cystectomy requiring bowel transection with primary anastomosis 
3. Planned to be managed postoperatively with an enhanced recovery protocol, 
which, at a minimum, includes all of the following elements: 
• early removal of the nasogastric tube, which is defined as removal of the 
nasogastric tube at the end of surgery 
• early ambulation, which is defined as ambulation on Day 1 
• early diet advancement on Day 1 
4. Planned to receive primary postoperative pain management with opioid analgesia 
administered by any route. 
5. American Society of Anesthesiologists (ASA) Physical Status Score of I, II, or III 
(a normal healthy patient, a patient with mild systemic disease, or a patient with 
systemic disease, respectively). 
 
Sex 
6. Male or female 
Male patients: 
• There are no specific requirements for contraceptive measures for male 
patients. 
Female patients: 
• A female patient is eligible to participate if she is not pregnant (negative urine 
pregnancy test at Screening for a woman of childbearing potential [WOCBP]; 
see also Appendix 4), not breastfeeding, and at least 1 of the following 
conditions applies: 
i. 
Postmenopausal (defined as at least 12 months of spontaneous amenorrhea 
in a woman > 45 years) 


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ii. 
Surgically sterile by hysterectomy, bilateral oophorectomy, and/or 
bilateral salpingectomy or tubal ligation 
iii. 
Agree to use an acceptable effective form of birth control (with failure 
rates > 1% per year) from the start of Screening through 14 days after the 
last dose of study treatment, such as: 
(a) Progestogen-only oral hormonal contraception (where inhibition of 
ovulation is not the primary mode of action) 
(b) Male or female condom with or without spermicide 
(c) Cap, diaphragm, or sponge with spermicide 
 
Informed Consent 
7. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICF. 
 
5.2 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
 
Medical Conditions 
1. Scheduled to undergo a total colectomy or any procedure that results in a 
colostomy or ileostomy. 
2. Scheduled for endoscopic or laparoscopic surgery. 
3. Complete bowel obstruction. 
4. Complicated inflammatory bowel disease (such as ulcerative colitis or Crohn’s 
disease). 
5. More than 2 prior major abdominal surgeries (eg, gastrectomy, gastric bypass, 
gastric sleeve, lap banding, pancreatic resection, hepatectomy, intestinal 
transplant). 
 
Prior and Concomitant Therapy 
6. More than 3 doses of an opioid (regardless of the route of administration) during 
the 7 days prior to surgery. 
7. Chemotherapy within 4 weeks prior to surgery; otherwise, patients with cancer 
are eligible. 
8. Scheduled to receive chemotherapy, immunotherapy, or radiation therapy 
intraoperatively or within 14 days after surgery; otherwise, patients with cancer 
are eligible. 
9. Any prohibited medication within 14 days prior to the first dose of study 
treatment as specified in Section 6.5. 
 
Prior and Concurrent Clinical Study Experience 
10. Exposure to an investigational drug within 90 days prior to the start of Screening. 
11. Prior exposure to naldemedine. 


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Diagnostic Assessments 
12. Severe hepatic impairment. 
 
Other Exclusions 
13. Pregnancy or lactation. 
14. Presence of peritoneal catheter (eg, for dialysis or chemotherapy). 
15. Any other reason considered by the investigator or qualified designee to make the 
patient ineligible to take part in the study. 
 
5.3 
Lifestyle Considerations 
No meal, dietary, caffeine, alcohol, tobacco, or other lifestyle restrictions are required. 
 
5.4 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but 
are not subsequently entered in the study. 
 
Rescreening of patients who meet all entry criteria but who are not entered in the study 
because the date of surgery is rescheduled (by study site staff or by the patient) to a date 
more than 14 days after signing the ICF is permitted. Rescreened patients must resign the 
ICF if the surgery is rescheduled more than 14 days after the originally-scheduled 
surgery, and the medical monitor should be contacted to see if any screening tests will 
need to be repeated. Patients who are screen failures for any other reasons are not to be 
rescreened. 


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6. STUDY TREATMENT 
Study treatment is defined as naldemedine 1.25 mg, naldemedine 2.5 mg, naldemedine 
5 mg, and matching placebo. 
 
6.1 
Study Treatments Administered 
Study treatment is described in Table 6-1. 
 
Table 6-1 
Study Treatments 
 
Study Treatment 
Name: 
Naldemedine 
Naldemedine 
Naldemedine 
Matching 
Placebo 
Dosage formulation: 
ODT 
ODT 
ODT 
ODT 
Unit dose 
strength(s)/Dosage 
level(s): 
1.25 mg 
2.5 mg 
5 mg 
Not applicable 
Physical Description 
White to light 
yellow, round 
shaped plain 
tablets 
White to light 
yellow, round 
shaped plain 
tablets 
White to light 
yellow, round 
shaped plain 
tablets 
White to light 
yellow, round 
shaped plain 
tablets 
Route of 
Administration: 
Oral 
Oral 
Oral 
Oral 
Dosing Instructions: 
One 1.25-mg 
tablet BID 
Specific dosing 
instructions are 
provided in 
Table 6-2 
One 2.5-mg tablet 
BID 
Specific dosing 
instructions are 
provided in 
Table 6-2 
One 5-mg tablet 
BID 
Specific dosing 
instructions are 
provided in 
Table 6-2 
One placebo 
tablet BID 
Specific dosing 
instructions are 
provided in 
Table 6-2 
Packaging and 
Labeling: 
Study treatment 
for each patient 
will be provided 
in a wallet 
containing 
24 tablets for the 
entire study. Each 
wallet will be 
labeled as 
necessary per 
country 
requirement. 
Study treatment 
for each patient 
will be provided 
in a wallet 
containing 
24 tablets for the 
entire study. Each 
wallet will be 
labeled as 
necessary per 
country 
requirement. 
Study treatment 
for each patient 
will be provided 
in a wallet 
containing 
24 tablets for the 
entire study. 
Each wallet will 
be labeled as 
necessary per 
country 
requirement. 
Study treatment 
for each patient 
will be provided 
in a wallet 
containing 
24 tablets for the 
entire study. 
Each wallet will 
be labeled as 
necessary per 
country 
requirement. 
Manufacturer: 
Shionogi Pharma 
Co., Ltd. 
Shionogi Pharma 
Co., Ltd. 
Shionogi Pharma 
Co., Ltd. 
Shionogi 
Pharma Co., 
Ltd. 
BID = twice daily; ODT = orally disintegrating tablet 
 
Dosing instructions are provided in Table 6-2. Investigators are encouraged to consider 
the time of the surgery in order to ensure that the evening dose on Day 0 can be 
administered. 


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Table 6-2 
Dosing Instructions During the Treatment Period 
 
Study Treatment 
Dose 
Dosing Instructions 
Naldemedine 
1.25 mg 
Day 0 (Operative Day) 
Before surgery: Administer first dose 30 minutes to 
6 hours prior to the scheduled start of surgery. The 
patient will be instructed to place the orally 
disintegrating tablet (ODT) on the tongue and to let it 
dissolve. Administration with water is not required, but 
water is allowed if the patient prefers. 
After surgery: Administer second dose postoperatively 
on the evening of the day of surgery. 
Day 1 to Day 10 
Patients will receive study treatment twice daily (BID) 
for up to 10 days (ie, Day 10). Every effort will be made 
to give the Day 1 morning dose approximately 12 hours 
after the Day 0 evening dose and to give all morning and 
evening doses from Day 1 to Day 10 at approximately 
12-hour intervals. Duration of administration will be 
determined by the date on which the primary endpoint, 
GI2 (time from end of surgery to time to first toleration 
of solid food and first bowel movement), is met or the 
date on which the discharge order is written, whichever 
occurs first, and will not exceed 10 postoperative days. 
Study treatment may be administered on the day of 
discharge. 
2.5 mg 
5 mg 
Matching Placebo 
Not applicable 
 
6.2 
Preparation/Handling/Storage/Accountability of Study 
Treatment 
1. Wallets containing naldemedine and matching placebo must be stored according 
to the study treatment label at 59°F to 86°F (15°C to 30°C). The investigator or 
qualified designee must confirm that appropriate temperature conditions have 
been maintained during transit for all study treatment received and that any 
discrepancies are reported and resolved before use of the study treatment. 
2. Only study patients enrolled in the study may receive study treatment and the 
investigator or qualified study personnel may administer study treatment. All 
study treatment must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
3. The investigator or the head of the hospital (as applicable) is responsible for study 
treatment accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
treatment are provided in the Study Pharmacy Manual. 


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6.3 
Measures to Minimize Bias: Randomization and Blinding 
Eligible patients will be randomized in a ratio of 1:1:1:1 to one of the following treatment 
groups: naldemedine 1.25 mg, 2.5 mg, or 5 mg or placebo. Randomization will be 
stratified by the planned surgical procedure, ie, small bowel resection with primary 
anastomosis, large bowel resection with primary anastomosis, or radical cystectomy 
requiring bowel transection with primary anastomosis. All patients will be centrally 
randomized to study treatment using an Interactive Web Response System (IWRS). 
Before each site is initiated, the login information and directions for the IWRS will be 
provided. 
 
The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
patient’s treatment assignment is warranted. Patient safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding 
is warranted, the investigator should make every effort to contact the contract research 
organization (CRO) prior to unblinding unless this could delay emergency treatment of 
the patient. If a patient’s treatment assignment is unblinded, the CRO must be notified 
within 24 hours after breaking the blind, and the treatment assignment should not be 
disclosed to the CRO. The date and reason that the blind was broken must be recorded in 
the source documentation and the IWRS. 
 
6.4 
Study Treatment Compliance 
The investigator or qualified study personnel will administer study treatment to each 
patient and will observe the patient for compliance with taking the study treatment. Study 
treatment administration will be recorded in the electronic case report form (eCRF). In 
addition, if the patient refuses study treatment or if he or she vomits within 1 hour of 
dosing, this information will also be recorded in the eCRF. 
 
6.5 
Medical History and Prior and Concomitant Therapy 
Any prior history of postoperative ileus and postoperative gastrointestinal dysfunction 
must be recorded on the eCRF as part of the patient’s medical history. 
 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and herbal supplements) that the patient is receiving at the time of enrollment 
or receives during the study must be recorded in the eCRF along with the following 
information: 
 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose, route of administration, and frequency 
The preoperative bowel preparation, if any, must be recorded in the eCRF. Additionally, 
the total volume of intravenous fluids administered during the surgery must be recorded 
in the eCRF. 


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The CRO’s medical monitor should be contacted if there are any questions regarding 
permissible prior or concomitant therapy. 
 
In addition to the prior and concomitant therapy exclusions in Section 5.2, the following 
medications are prohibited for 14 days before the first dose of study treatment and 
through the end of study treatment: 
 
• Strong cytochrome P450 3A (CYP3A) inducers (eg, carbamazepine, 
enzalutamide, mitotane, phenytoin, rifampin, St. John’s Wort) (see Appendix 6) 
• Strong CYP3A and P-glycoprotein (P-gp) inhibitors (eg, clarithromycin, 
diltiazem, grapefruit juice, indinavir, ketoconazole, ritonavir) (see Appendix 7) 
• Other opioid antagonists 
• Prophylactic use of laxatives (eg, magnesium citrate, magnesium hydroxide, 
magnesium sulfate, castor oil, sodium phosphate, sodium biphosphate, 
polyethylene glycol enemas, and stimulant laxatives, including bisacodyl); 
however, if needed, laxatives may be used for rescue therapy 
 
Re-insertion of the nasogastric tube is permitted if needed (see Section 8.1.2.2). 
 
The following elements of the enhanced recovery protocol at the study site must be 
recorded as yes or no in the eCRF at Baseline (planned) and at the day of discharge or 
early termination (actual): 
 
• Three elements required by the protocol: 
o Early removal of the nasogastric tube, defined as removal of the nasogastric 
tube at the end of surgery 
o Early ambulation, defined as ambulation on Day 1 
o Early diet advancement on Day 1 
• Four other elements that may be used at the study site: 
o Antibiotic prophylaxis 
o Preoperative carbohydrate drink 
o Epidural anesthesia in addition to general anesthesia 
o Chewing gum postoperatively 
The investigator must determine appropriate management and treatment of the patient, as 
clinically indicated, in the event of signs or symptoms of any of the following: 
 
• Opioid withdrawal; if opioid withdrawal is suspected, the patient should be 
monitored 
• Severe hypersensitivity thought to be related to study treatment 
• Gastrointestinal perforation 


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6.6 
Dose Modification of Study Treatment 
Dose modification of study treatment is not permitted in the study. 
 
6.7 
Treatment after the End of the Study 
Study treatment will not be administered after the end of the study. 


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7. DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Treatment 
A patient may discontinue study treatment prior to Day 10 if he or she meets the primary 
endpoint, GI2, or on the date on which the discharge order is written, whichever occurs 
first. Discontinuation of study treatment for any other reason will be determined by the 
investigator if he or she believes that it is in best interest of the patient. Female patients 
who become pregnant during the study will be followed as described in Section 7.2, 
Section 8.3.5, and Appendix 4. The investigator will withdraw a patient from study 
treatment based on the management and discontinuation criteria for abnormal liver 
function tests (Appendix 5). The investigator should consider discontinuation of study 
treatment if opioid withdrawal is suspected on any assessment day. In addition, 
discontinuation of study treatment is required if: 
 
• The patient has an unplanned ileostomy or colostomy during the surgical 
procedure. 
• A patient has a score > 36 on the Clinical Opiate Withdrawal Scale (COWS) on 
any assessment day 
• Hypersensitivity thought to be related to study treatment occurs and is considered 
severe in intensity, as assessed by the investigator 
• There is any sign or symptom suggestive of gastrointestinal perforation, as 
assessed by the investigator 
 
See the SoA for data to be collected at the time of treatment discontinuation (eg, at the 
Early Termination Visit). 
 
7.2 
Patient Discontinuation/Withdrawal from the Study 
• A patient may withdraw from the study at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. However, unless there is a safety reason, 
the patient should remain in the study until the End-of-study Visit, even when off 
study treatment, to protect the integrity of the study and the patient’s well-being. 
• If the patient withdraws consent, the CRO may retain and continue to use any data 
collected before the withdrawal of consent. 
• If a patient withdraws consent, he/she may request destruction of any samples 
taken and not tested, and the investigator or qualified designee must document 
this in the site study records. 
• See the SoA for data to be collected at the time of patient 
discontinuation/withdrawal from the study. The reason for the patient’s 
withdrawal from the study and the withdrawal date should be recorded in the 
eCRF. 


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7.3 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she fails to return for the End-of- 
study Visit and is unable to be contacted by the hospital or doctor’s office staff (ie, does 
not respond to at least 2 telephone calls, 1 e-mail, and a registered letter). 
 
The following actions must be taken if a patient fails to return to the hospital or doctor’s 
office for the End-of-study Visit: 
 
• Before a patient is deemed lost to follow-up, the investigator, or qualified 
designee must make every effort to contact the patient and reschedule the missed 
End-of-study Visit as soon as possible. Contact will include at least 2 telephone 
calls, at least 1 e-mail, and a registered letter. The contact attempts should be 
within 30 days of the missed End-of-study visit and be documented in the 
patient’s medical record. 
• Should the patient continue to be unreachable by the above methods, he/she will 
be considered lost to follow-up. 


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8. STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA. Protocol waivers 
or exemptions are not allowed. 
• Adherence to the study requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All Screening evaluations must be completed and reviewed to confirm that 
potential patients meet all eligibility criteria. The investigator or qualified 
designee must maintain a screening log to record details of all patients screened 
and to confirm eligibility or record reasons for screen failure, as applicable. 
• Procedures conducted as part of the patient’s routine clinical management 
(eg, physical examination, blood count, electrocardiogram [ECG]) and obtained 
before signing of the ICF may be utilized for Screening or Baseline purposes 
provided the procedures meet the protocol-specified criteria and are performed 
within the time frame defined in the SoA. 
• Safety concerns should be discussed with the CRO immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study 
treatment. 
 
8.1 
Efficacy Assessments 
8.1.1 
Primary Efficacy Assessments 
8.1.1.1 
Time from End of Surgery to Time to First Toleration of Solid Food 
and First Bowel Movement 
The time from the end of surgery (defined as the time the patient leaves the operating 
room) to time to first toleration of solid food (defined as the time when the patient 
consumes a meal that requires chewing and has no significant nausea or vomiting, as per 
the judgment of the investigator, for 4 hours after that solid food) and first bowel 
movement (GI2) will be recorded in the eCRF. First toleration of solid food and first 
bowel movement will be recorded until the patient meets the primary endpoint described 
above. If the patient discontinues study treatment, the patient still needs to be followed 
for GI2 until the achievement of this endpoint or until he/she completes the study. If the 
patient is withdrawn from the study, first toleration of solid food and first bowel 
movement, as applicable, will be recorded at the ET Visit (see also Section 9.4.5.1). If a 
patient is discharged from the hospital prior to having a first bowel movement, the reason 
for discharge prior to having the first bowel movement will be recorded in the eCRF. 
Additionally, the patient will be instructed to inform the investigator or qualified 
designee by phone, text, or e-mail within 24 hours of having a first bowel movement up 
to and including Day 10. The investigator or qualified designee will communicate 
(phone, text, or e-mail) with the patient daily up to and including Day 10 to record when 
the first bowel movement occurred. 


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8.1.2 
Secondary Efficacy Assessments 
8.1.2.1 
Time from End of Surgery to Time When the Discharge Order is 
Written 
The time from the end of surgery (as defined for the primary endpoint) to the time when 
the discharge order is written will be recorded in the eCRF (see also Section 9.4.5.2). 
 
8.1.2.2 
Reinsertion of the Nasogastric Tube 
Whether a patient requires reinsertion of the nasogastric tube at any time during the 
postoperative treatment period will be recorded in the eCRF as yes or no along with the 
duration of the reinsertion (if applicable). 
 
8.1.2.3 
Readmission within 30 Day After Hospital Discharge 
Whether a patient is discharged by Day 10 and then readmitted for any reason within 
30 days after discharge will be recorded in the eCRF as yes or no, along with the reason 
why the patient is readmitted (if applicable). 
 
8.1.3 
Exploratory Efficacy Assessments 
8.1.3.1 
Time from End of Surgery to Discharge Readiness 
The time from the end of surgery (as defined for the primary endpoint) to the time to 
discharge readiness (defined as GI recovery based on the clinical judgment of the 
investigator) will be evaluated and recorded in the eCRF. 
 
8.1.3.2 
Time from End of Surgery to Time of Actual Discharge 
The time from the end of surgery (as defined for the primary endpoint) to time of actual 
discharge (departure) from the hospital will be recorded in the eCRF. 
 
8.1.3.3 
Prolonged Hospital Stay Due to Gastrointestinal Dysfunction 
Prolonged hospital stay (defined as hospitalization for ≥ 7 days postoperatively) due to 
GI dysfunction will be recorded in the eCRF. 
 
8.1.3.4 
Patients Who Achieve GI2 in Each Treatment Group By 
Postoperative Day 
The postoperative day for achievement of GI2 will be recorded in the eCRF. 
 
8.1.3.5 
Patients Who Receive Concomitant Medication That May Have a 
Laxative Effect 
Any concomitant medication that may have a laxative effect will be recorded in the 
eCRF. 
 
8.1.3.6 
Effect of Prior Surgery on G12 Endpoint 
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8.2 
Safety Assessments 
Safety assessments will include recording of adverse events (AEs), including those that 
are serious and those that result in discontinuation of study treatment; clinical laboratory 
test results; vital signs measurements; 12-lead ECG findings; physical examination 
findings; postoperative pain, as assessed on the Numerical Pain Rating Scale (NPRS); 
and the administration of intra-operative and postoperative opioid analgesics. 
 
Planned time points for all safety assessments are provided in the SoA. 
 
For any abnormal laboratory test results (defined as hematology or blood chemistry 
values outside the reference range) or other safety assessments (eg, physical examination, 
vital signs, ECGs) that worsen from baseline following exposure to study treatment, the 
investigator will consider whether those results are clinically significant. For test results 
that are abnormal at baseline and significantly worsen (as per the judgment of the 
investigator) following the initiation of the study, the investigator must also consider 
whether those results are clinically significant. Any test result that is considered by the 
investigator or qualified designee to be clinically significant is to be recorded in the eCRF 
as an AE. If an abnormal laboratory finding is associated with disease or organ toxicity, 
the investigator should report only the disease or organ toxicity as an AE. 
 
The investigator will consider test results to be clinically significant in the following 
circumstances: 
 
• Test results lead to any of the outcomes included in the definition of a serious 
adverse event (SAE) (see Section 8.3). 
• Test results lead to a change in study treatment administration or discontinuation 
from the study. 
• Test results lead to a concomitant drug treatment or other therapy. 
• Test results require additional diagnostic testing (except for a confirmatory test) 
or other medical intervention. 
• Test results meet the management and stopping criteria for abnormal liver 
function tests identified in Section 7.1 and Appendix 5. When any test result 
meets the management and stopping criteria for liver function abnormalities 
(Section 7.1 and Appendix 5), the results of further assessments and required 
follow-up should be recorded in the Liver Event Form. 
 
In addition, the investigator should use his or her judgment in assessing the clinical 
significance of test results. 
 
8.2.1 
Physical Examinations 
• A physical examination will be performed as per standard of care at the hospital 
or, for the End-of-study Visit, at the hospital or doctor’s office. A preoperative 
physical examination (within 2 weeks prior to the patient signing the ICF) may be 
used, as long as the eCRF is completed. As per 


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8.2.2 
Vital Signs 
• Systolic/diastolic blood pressure and pulse rate will be measured once daily as 
close as possible after waking and recorded in the eCRF. Blood pressure will be 
assessed after approximately 3 to 5 minutes of rest. 
• Blood pressure and pulse measurements will be measured with a completely 
automated device. Manual techniques will be used only if an automated device is 
not available. 
• Clinically significant changes in vital signs from baseline (as per the judgment of 
the investigator or qualified designee) will be recorded in the eCRF as AEs. 
 
8.2.3 
Electrocardiograms 
• A 12-lead ECG will be obtained at specified time points as outlined in the SoA 
(see Section 1.3). A 12-lead ECG obtained within 2 weeks prior to the patient 
signing the ICF that shows no clinically significant abnormal finding may be used 
for Screening or Baseline purposes. The ECG results will be recorded in the eCRF 
as normal, abnormal – not clinically significant, or abnormal – clinically 
significant. 
 
8.2.4 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed and the 
SoA in Section 1.3 for the timing and frequency. All protocol-required laboratory 
assessments must be conducted in accordance with the local laboratory manual 
and the SoA. 
• The investigator or qualified designee must review the laboratory test results and 
record any clinically significant changes occurring during the study in the AE 
section of the eCRF. Clinically significantly abnormal laboratory findings are 
those which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the patient’s condition (see 
Appendix 3). The laboratory reports must be filed with the source documents. 
• All laboratory tests with values considered clinically significantly abnormal 
should be repeated until the values return to normal or baseline or are no longer 
considered by the investigator to be clinically significant. 
o If such values do not return to normal or baseline within a period of time 
judged reasonable by the investigator, every effort should be made to 
determine the etiology and record it in the eCRF. 
• If laboratory values from unscheduled laboratory tests require a change in patient 
management or are considered by the investigator to be clinically significantly 
abnormal (eg, SAE or AE or dose modification), then the results must be recorded 
in the eCRF. 
 
8.2.5 
Numerical Pain Rating Scale 
The NPRS is an 11-point numerical scale on which patients will rate their pain on a scale 
of 0 (no pain at all) to 10 (worst possible pain) over the past 24 hours (see Appendix 8). 


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The scale is a reliable instrument for assessing pain intensity [6]. Pain will be assessed 
once daily in the morning at approximately the same time of day at the time points 
specified in the SoA, and the rating will be recorded in the eCRF (Section 1.3). 
 
8.2.6 
Clinical Opiate Withdrawal Scale 
The COWS is a clinician-administered scale that rates 11 common opiate withdrawal 
signs and symptoms on a scale of 0 to a maximum of 4 or 5, depending on the sign or 
symptom (see Appendix 9). The scale is a reliable instrument for assessing a patient’s 
level of opioid withdrawal [7]. Opioid withdrawal will be assessed using this instrument 
at the time points specified in the SoA, and the rating will be recorded in the eCRF 
(Section 1.3). 
 
8.2.7 
Intra-operative and Postoperative Opioid Analgesics 
Intra-operative and postoperative opioid analgesics administered to patients will be 
recorded in the eCRF (see also Section 9.4.6). Doses of these medications will be 
recorded as specified in the SoA (Section 1.3). 
 
8.3 
Adverse Events and Serious Adverse Events 
The definitions of an AE and an SAE can be found in Appendix 3. 
 
Adverse events reported by the patient (or, when applicable, by a caregiver, surrogate, or 
the patient’s legally authorized representative) must be captured in source documents. 
Abnormal laboratory test results, blood pressure, pulse rate, and ECG findings after the 
first dose that are considered to demonstrate a clinically significant change from baseline 
will be recorded in the eCRF as treatment-emergent adverse events (TEAEs). 
 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or study 
procedures, or caused the patient to discontinue study treatment or withdraw from the 
study (see Section 7). 
 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
All AEs/SAEs will be collected from the date of signing of the ICF until the End-of-study 
Visit at the time points specified in the SoA (Section 1.3). 
 
All SAEs will be recorded in the eCRF and reported to the CRO within 24 hours of 
awareness, as indicated in Appendix 3. The investigator or qualified designee will submit 
any updated SAE information to the CRO within 24 hours of awareness. 
 
The investigators or qualified designees are not obligated to actively seek AEs or SAEs 
after conclusion of the study participation. However, if the investigator or qualified 
designee learns of any SAE, including a death, at any time after a patient is no longer in 
the study, and the investigator or qualified designee considers the event to be reasonably 


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related to the study treatment or study participation, the investigator or qualified designee 
must promptly notify the CRO via phone, e-mail, or fax (see Appendix 3). Investigator 
assessment of causality must be included with all SAEs reported to the CRO. Serious 
adverse events with missing investigator causality will be followed up urgently until 
provided to the CRO. 
 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading questioning of the patient is the preferred method to identify AEs. 
 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator or qualified designee is required to 
proactively follow each patient at subsequent visits/phone contacts. All AEs/SAEs will be 
followed until resolution, stabilization, the event becomes chronic, or the event is 
otherwise explained or the patient is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Appendix 3. 
 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification by the investigator or qualified designee to the CRO of an 
SAE is essential so that legal obligations and ethical responsibilities for the safety 
of patients and the safety of an investigational study treatment are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRBs), and investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSARs; ie, those not listed as expected in the Investigator’s 
Brochure under Reference Safety Information for Assessment of Expectedness of 
Serious Adverse Reactions) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (eg, summary or listing of SAEs) from the CRO 
will review it and then file it with the Investigator’s Brochure and will notify the 
IRB, if appropriate, according to local requirements. 
 
8.3.5 
Pregnancy 
• Details of all pregnancies in female patients and female partners of male patients 
who receive naldemedine will be collected from the start of Screening through 
14 days after the last dose of study treatment. 


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• If a pregnancy is reported, the investigator or qualified designee should inform the 
CRO within 24 hours of learning of the pregnancy and should follow the 
procedures outlined in Appendix 4. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
8.3.6 
Special Situations - Overdose and Medication Error 
Overdose and medication error of the study treatment (as defined below) must be 
reported to the CRO’s medical monitor via eCRF (or paper form if EDC is not available) 
by the investigator or qualified designee using a Special Situations Report Form as soon 
as possible. If there are associated SAEs, the investigator or qualified designee must also 
complete and submit an SAE submission in EDC as well. A missed dose (or doses) of an 
investigational product is not to be reported as a medication error. 
 
• Overdose - intentional or unintentional intake of study treatment 1 tablet more 
than the dose required in the protocol. 
• Medication Error - any unintended error in the prescribing, dispensing, or 
administration of study treatment. Cases of patients missing doses of study 
treatment are not considered reportable as medication errors. 
 
8.4 
Treatment of Overdose 
In the event of an overdose, the investigator/treating physician will treat the patient 
according to standard of care. The treatment will depend on the adverse reactions that 
occur as a result of the overdose. Any event of overdose should be recorded in the eCRF 
(or paper form if EDC is unavailable) and reported as a special situation to the CRO’s 
medical monitor as soon as possible. 
 
8.5 
Pharmacokinetics 
• The actual date and time (24-hour clock) of all study treatment dosing and each 
meal prior to dosing will be recorded in the eCRF. 
• Blood samples of approximately 4 mL will be collected for measurement of 
plasma concentrations of naldemedine and nor-naldemedine at the time points 
specified in the SoA (Figure 1-2) and in Table 1-2. Instructions for the collection 
and handling of biological samples will be provided by the CRO in the PK 
laboratory manual. The actual date and time (24-hour clock time) of each sample 
will be recorded in the eCRF. 
• Samples will be used to analyze the plasma drug and metabolite concentrations of 
naldemedine and nor-naldemedine. Each plasma sample will be divided into 
2 aliquots (1 each for PK and a back-up). 
• Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
• Pharmacokinetic parameters and definitions are provided in Section 9.4.7.1.2. 
Further details will be provided separately in the statistical analysis plan (SAP). 


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8.6 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
 
8.7 
Genetics 
Genetics are not evaluated in this study. 
 
8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
 
8.9 
Health Economics/Medical Resource Utilization and Health 
Economics 
The proportion of patients discharged by Day 10 who are readmitted for any reason 
within 30 days after discharge from the hospital will be reported. 


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9. STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The study design and primary objective are based on the hypothesis that naldemedine 
1.25 mg, 2.5 mg, and/or 5 mg are superior to placebo for patients undergoing surgeries 
that include a bowel resection or bowel transection. 
 
9.2 
Sample Size Determination 
The planned sample size of between 44 and 85 patients per treatment in the mITT 
Population was determined by a simulation study with 10,000 iterations to provide 80% 
power to demonstrate the linear dose-response relationship between treatment groups 
(3 naldemedine groups and placebo group) in the primary endpoint at a 2-sided 
significance level of 0.05. In total, approximately 200 to 340 patients in the study will be 
required. 
 
The simulation estimated 44 patients per treatment group to see a linear trend in the 
restricted mean survival time (RMST) up to 240 hours for the time to the event of GI2 
across a 24-hour difference between naldemedine 5 mg and placebo under 80% statistical 
power at a 2-sided significance level of 0.05. Eighty-five patients per treatment group 
will be required to see a linear trend in RMST up to 240 hours across an 18-hour 
difference between naldemedine 5 mg and placebo. In addition, the time to the event of 
GI2 in each group follows the Weibull distribution by referring to the survival curve for 
the time to the event of GI2 shown in the alvimopan package insert. It was assumed that 
an independent censoring followed an exponential distribution with a rate such that 
approximately 20% of patients were censored within 240 hours. 
 
The final sample size will be dependent on the enrollment rate during the fixed 
enrollment period. A minimum of 44 patients per group in the mITT Population is 
desired. 
 
9.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
 
Population 
Description 
Enrolled 
All patients who signed the ICF. 
Randomized patients 
All patients randomly assigned to naldemedine 1.25 mg, 2.5 mg, 5 mg, 
or placebo. 
Modified Intention– 
to−Treat (mITT) 
All randomized patients who received at least 1 dose of study 
treatment and had at least 1 postbaseline efficacy assessment for the 
primary efficacy endpoint. 
Per Protocol Set 
All patients in mITT who did not have a major protocol deviation, as 
defined in a separate document. 
Safety 
All randomized patients who received at least 1 dose of the study 
treatment. The population will be analyzed according to the treatment 
that patients actually received, rather than the study treatment to which 
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Population 
Description 
Pharmacokinetic (PK) 
concentration 
All patients who received at least 1 dose of naldemedine and had at 
least 1 evaluable concentration of either naldemedine or nor- 
naldemedine in plasma. This population will be used for the 
concentration listing. 
Pharmacokinetic (PK) 
parameter 
All patients with at least 1 PK parameter estimated appropriately. This 
population will be used for PK parameter listings and summaries, 
plotting of the plasma concentration-time data, plasma concentration 
summaries, and statistical analysis. 
 
9.4 
Statistical Analyses 
The detailed statistical analysis methods will be specified in the separate SAP. Changes 
from analyses outlined in the protocol will be detailed and justified in the SAP. The 
initial SAP will have a version 1.0 available by first patient randomized and will be 
finalized before unblinding/database lock. The SAP will be finalized before scheduled 
database lock. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints. 
 
For programming and analysis purposes, the protocol study days will be mapped as 
shown in Table 9-1. 


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Table 9-1 
Mapping Information for Study Days 
 
Protocol 
Day 
Screening 
Period 
Treatment Period 
Follow 
-up 
Period 
Day −14 to 
0 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Days 5 to 
10 
Day of 
Discharge 
Early 
Termination 
End- 
of- 
study 
Visit 
Baseline 
Before 
Surgery 
After 
Surgery 
Mapped 
Analysis 
Day 
Day −14 to 
1 
Day 1 Before 
Surgery 
(surgery day) 
Day 1 After 
Surgery 
(surgery day) 
Day 2 
(Postop 
Day 1) 
Day 3 
(Postop 
Day 2) 
Day 4 
(Postop 
Day 3) 
Day 5 
(Postop 
Day 4) 
Days 6 to 
11 
(Postop 
Days 5 to 
10) 
Day of 
Discharge 
Early 
Termination 
End- 
of- 
study 
Visit 
Postop = postoperative 


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Unless otherwise noted, continuous variables will be summarized by using the number of 
non-missing observations, arithmetic mean, standard deviation (SD), median, minimum, 
and maximum values as descriptive statistics; categorical variables will be summarized 
by using the frequency count and the percentage of patients in each category as 
descriptive statistics. 
 
Patient study data, including data not appearing in tables, will be presented in by-patient 
data listings. In general, all tables and graphs will be presented by treatment group. 
Pharmacokinetic data and any derived data will be listed. All analyses and tabulations 
will be performed by using SAS Version 9.2 or higher, and Phoenix WinNonlin 
Version 6.2.1 or higher. 
 
If statistical tests are performed, they will be performed at the 0.05 significance level 
using 2-sided tests, except where otherwise noted. No multiplicity adjustment of 
statistical tests will be applied in this study. Missing data will not be replaced. 
 
9.4.1 
Patient Disposition 
Among the randomized patients in the Safety Population, and the mITT Population, the 
numbers and percentages of patients who complete the study and who withdraw from the 
study will be summarized. In addition, reasons leading to discontinuation from the study 
will be summarized for each treatment group. The number and percentage of patients for 
the randomized patients included in each analysis population will also be presented. 
 
9.4.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized with descriptive statistics 
for the mITT Population. 
 
9.4.3 
Medical History and Prior and Concomitant Therapies 
Medical histories will be listed and summarized for the mITT Population. 
 
Prior therapies for drugs will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Patients who received prior therapy will be listed and 
summarized for the Safety Population. Concomitant therapies for drugs will be coded 
using WHO-DD. Patients who receive concomitant therapy, including intra-operative and 
postoperative opioid analgesics, will be listed and summarized for the Safety Population. 
 
The 3 elements of the enhanced recovery protocol required by the protocol and the 4 
other elements at the study site will be listed for each patient and summarized for the 
mITT Population. 
 
9.4.4 
Extent of Exposure and Treatment Compliance 
Summary statistics for treatment duration will be presented by treatment group for the 
Safety Population. 


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Summary statistics for compliance with study drug administration will be presented by 
treatment group for the mITT Population. 
 
9.4.5 
Efficacy Analyses 
The mITT Population will be the primary population for efficacy analyses. 
 
9.4.5.1 
Primary Efficacy Endpoint 
The primary endpoint will be time from the end of surgery (defined as the time the 
patient leaves the operating room) to time to first toleration of solid food (defined as the 
time when the patient consumes a meal that requires chewing and has no significant 
nausea or vomiting, as per the judgment of the investigator, for 4 hours after that solid 
food) and first bowel movement (GI2). 
 
The mean survival time, which is also referred to as the RMST, of GI2 events within 
240 hours will be estimated using the area under the Kaplan-Meier (KM) curve. To 
demonstrate the linear dose-response relationship between treatment groups 
(3 naldemedine groups and placebo group) and the RMST, the linear contrast test for 
trend with contrast coefficients of (-3, -1, 1, 3) will be performed. If a dose-response 
relationship is detected, then pairwise comparisons of the RMST between each dose 
group of naldemedine and the placebo group will be conducted, and the treatment 
differences (with its 95% confidence interval [CI]) will be provided. If an event does not 
occur during the evaluation period of 240 hours, the patient will be censored at the time 
of his/her last nonmissing postbaseline assessment. The same analysis will be performed 
in the Per Protocol set. In addition, the reason for discharge prior to having the first bowel 
movement will be listed. 
 
Patients will continue to be evaluated for efficacy regardless of treatment adherence. The 
use of additional therapies or interventions that could treat any component of the primary 
endpoint (eg, motility agents, anti-emetics, laxatives, etc), may confound the results of 
the primary efficacy analysis. This list of therapies will be finalized before database lock. 
To examine this issue, the following exploratory analyses of the GI2 endpoint will be 
performed or provided: 
 
• Repeat of the primary analysis, excluding all patients who received additional 
therapies at any time postrandomization that could treat any of the components of 
the GI2 endpoint. It is recognized that this subset is selected based on 
postrandomization decisions, may be confounded with the treatment group, and 
may not represent a randomized subgroup of the primary endpoint. 
• Table of proportion of patients in each treatment group who received additional 
therapies that could treat any of the GI2 components. 
• Two-way table summarizing each patient’s status at the end of the trial regarding 
receipt of an additional therapy that could treat any of the GI2 components and 
whether the GI2 endpoint was achieved. For example, the rows can be yes/no for 
GI2 endpoint achieved, and the columns can be receipt of additional therapy. This 


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table will be done during the evaluation period of 240 hours for patients and by 
treatment group. 
• Proportion of patients in each group that achieve the GI2 endpoint, regardless of 
use of additional therapies that could treat any of the GI2 components. This will 
be tabulated cumulatively by day. The cumulative proportions achieving the GI2 
endpoint will be compared at Day 10 with the difference in proportions and an 
associated 95% CI will be provided. 
• Proportion of patients in each group that achieve the GI2 endpoint, where the use 
of additional therapies that could treat any of the GI2 components included in the 
analysis as a patient failure to achieve the GI2 endpoint, beginning with the day 
the patient first receives the additional therapy. This will be tabulated 
cumulatively by day. The cumulative proportions achieving the GI2 endpoint will 
be compared at Day 10, with the difference in proportions and an associated 95% 
CI provided. 
 
9.4.5.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be as follows: 
 
● Time from the end of surgery (as defined for the primary endpoint) to time when 
the discharge order is written 
● Proportion of patients requiring postoperative reinsertion of the nasogastric tube 
● Proportion of patients with nausea on Days 1 through 3 
● Proportion of patients with vomiting on Days 1 through 3 
● Proportion of patients discharged by Day 10 who are readmitted for any reason 
within 30 days after discharge from the hospital 
 
For time from the end of surgery to time when the discharge order is written, the same 
KM approach as used for the primary efficacy analysis will be performed. The proportion 
of patients for each of the other parameters will be summarized by treatment group. 
 
9.4.5.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints will be as follows: 
 
• Time from the end of surgery (as defined for the primary endpoint) to time to 
discharge readiness (defined as GI recovery based on the clinical judgment of the 
investigator) 
• Time from the end of surgery (as defined for the primary endpoint) to time of 
actual discharge (departure) from the hospital 
• Proportion of patients with prolonged hospital stay (defined as hospitalization for 
≥ 7 days postoperatively) due to GI dysfunction 
• Time from initial insertion of the nasogastric tube to removal of the nasogastric 
tube 


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• Proportion of patients with abdominal distention on Day 1 through the day on 
which GI2 is achieved 
• Proportion of patients with nausea on Day 4 through day of discharge 
• Proportion of patients with vomiting on Day 4 through day of discharge 
• Proportion of patients who achieve GI2 in each treatment group by postoperative 
day 
• Proportion of patients who receive concomitant medication that may have a 
laxative effect 
• Effect of prior surgery (yes/no) on the GI2 endpoint 
For time from the end of surgery to time to discharge readiness and to time of actual 
discharge from the hospital, the same KM approach as used for the primary efficacy 
analysis will be performed. The proportion of patients for each of the other parameters 
will be summarized by treatment group. 
 
9.4.6 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
 
Adverse events will be classified by system organ class and preferred term using Medical 
Dictionary for Regulatory Activities (MedDRA). Adverse events reported after the initial 
dose of study drug will be considered TEAEs and will be analyzed. 
 
The number and the percentage of patients who experienced TEAEs will be summarized 
by treatment group. Treatment-emergent SAEs, AEs related to study treatment, and 
TEAEs leading to discontinuation of study drug will also be summarized by treatment 
group. The number of occurrences of TEAEs, which are counted among patients 
reporting those TEAEs, will also be presented in the categories above in an overall 
summary. 
 
For the summary of TEAEs by system organ class and preferred term, the number and 
percentage of patients who experienced TEAEs will be presented for each treatment 
group. A summary of TEAEs by severity and by relationship to study treatment will be 
presented by system organ class, preferred term, and treatment group. 
 
All AEs, including AEs that have occurred before and after the first dose of the study 
treatment, will be listed. 
 
Summary statistics for laboratory tests and vital signs will be presented for all time 
points. The change from baseline to each time point in laboratory tests and vital signs will 
be summarized. In addition, the proportion of patients with clinically significant changes 
from baseline in laboratory tests, vital signs, and ECG data will be presented. Criteria for 
clinically significant changes in laboratory tests, vital signs, and ECG data will be 
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Summary statistics for NPRS, COWS, and intraoperative and postoperative MME opioid 
dose will be presented for all time points. The COWS score in each domain will be 
summarized categorically. The opioid dose recorded in the eCRF will be converted to the 
MME opioid dose using conversion factors. The details will be defined in the SAP. 
 
9.4.7 
Other Analyses 
9.4.7.1 
Pharmacokinetic Analyses 
All PK analyses will be performed on the PK Populations. 
 
9.4.7.1.1 
Plasma Concentration 
Plasma concentrations of naldemedine and nor-naldemedine will be listed and 
summarized by treatment and nominal sampling time with the number of non-missing 
observations (N), arithmetic mean (mean), standard deviation (SD) and coefficient of 
variation (CV%, calculated by SD/mean × 100), geometric mean and coefficient of 
variation for geometric mean (Geometric CV%), and median, minimum and maximum 
values at each sampling time. The Geometric CV% will be calculated as follows: 
Geometric CV% = [exp (sd2)-1]1/2 × 100, where SD is the standard deviation for natural 
log (ln)-transformed data. The time course profiles for plasma drug and metabolite 
concentrations will be presented graphically. 
 
For the summary of plasma drug and metabolite concentrations, concentrations below the 
lower limit of quantification (BLQ) will be treated as zero (0) for calculations of the 
mean, SD, CV%, and median, minimum, maximum values and will be treated as missing 
for calculation of the geometric mean and geometric CV% values. 
 
9.4.7.1.2 
Pharmacokinetic Parameters 
The following PK parameters will be calculated, whenever possible, for naldemedine and 
nor-naldemedine from plasma concentration data on Day 3 (immediately before the 
morning dose and 1 hour and 2, 4, 8, and 12 hours after the morning dose before 
administration of the evening dose) by non-compartmental methods. Other parameters 
may be computed, as appropriate, upon review of the data. The estimated PK parameters 
will be computed for each study patient using the actual sample collection times recorded 
in the eCRF during the study. 


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PK parameters: 
Cmax (ng/mL) 
Maximum observed plasma concentration on Day 3 
Tmax (hr) 
Time to maximum plasma concentration on Day 3 
AUC0-τ (ng·hr/mL) 
Area under the concentration-time curve over the dosing interval τ (12 hours) 
on Day 3, calculated by Linear Up/Log Down Trapezoidal Method 
CL/F (L/hr) 
Apparent total clearance estimated according to: CL/F = Dose/AUC0-τ on 
Day 3 (for naldemedine only) 
MRM/U, Cmax 
Metabolic ratio of Cmax of nor-naldemedine to Cmax of naldemedine, 
corrected for molecular weight, defined as (nor-naldemedine Cmax) / 
(naldemedine Cmax) × (naldemedine molecular weight [570.64]) / (nor- 
naldemedine molecular weight [516.55]) (for nor-naldemedine only) 
MRM/U, AUC 
Metabolic ratio of AUC0-τ of nor-naldemedine to AUC0-τ of naldemedine, 
corrected for molecular weight, defined as (nor-naldemedine AUC0-τ) / 
(naldemedine AUC0-τ) × (naldemedine molecular weight [570.64]) / (nor- 
naldemedine molecular weight [516.55]) (for nor-naldemedine only) 
 
The estimated PK parameters except for Tmax will be summarized by treatment with N, 
mean, SD, CV%, geometric mean, geometric CV%, median, minimum and maximum 
values. The Tmax will be summarized by analyte and dosing regimen with N, mean, SD, 
CV%, median, minimum and maximum values. If the number of PK parameter data is 
< 3, the data will not be summarized. 
 
Individual plasma concentrations, if deemed to be anomalous, may be excluded from the 
analysis at the discretion of the PK study director. Any such exclusion will be disclosed 
in the study report along with the justification for exclusion. 
 
For the calculations of PK parameters, BLQ before the occurrence of the first quantifiable 
concentration on Day 3 will be treated as zero, and BLQ after the first occurrence of the 
quantifiable concentration on Day 3 will be treated as missing. 
 
AUC0-τ will be calculated with observed plasma concentrations from time 0 to τ (actual 
time) on Day 3 without extrapolation or interpolation. The actual time for the predose 
(0 hours) on Day 3 will be replaced with 0. If observed plasma concentration at τ on 
Day 3 is BLQ, area under the plasma concentration-time curve from time zero to the time 
of the last quantifiable concentration after dosing (AUC0-last) will be used as AUC0-τ. 
 
Pharmacokinetic calculations will be performed by using WinNonlin Version 6.2.1 or 
higher. 
 
9.4.7.1.3 
Exposure-response Analysis 
An exploratory exposure-response analysis will be conducted for efficacy and safety and 
will be reported in a separate pharmacokinetic report. 


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9.5 
Interim Analyses 
A Data Monitoring Committee (DMC) will review all data when assessing the benefit 
versus risk of the ongoing results. Since such a review may include efficacy data, an 
alpha spending function will be included in the DMC Charter that allows for a small 
spend of alpha that will not impact the final alpha assessment level (eg, an alpha spend of 
0.0001 based on Haybittle–Peto could be used to control alpha for each interim analysis). 
The DMC Charter will specify the spending function to be used. 
 
In addition, depending on the enrollment rate, an interim efficacy analysis may be 
feasible. Based on the operational feasibility of such an interim analysis, the interim 
analysis could include a nonbinding futility assessment. For example, should the 
enrollment project that 85 patients per group is achievable and an interim analysis based 
on 44 patients per group can be conducted in a timely and worthwhile fashion prior to the 
last patient enrolled, then the DMC will review the interim analysis results. Details for 
interim analyses, including futility, will be provided in the DMC Charter and/or an 
accompanying DMC SAP. 
 
9.6 
Data Monitoring Committee 
A DMC will review the study data periodically as specified in a separate DMC Charter. 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
The investigator will be responsible for the following: 
 
• Submitting the protocol, protocol amendments, ICF, Investigator’s Brochure, and 
other relevant documents (eg, advertisements) to an IRB for review and approval 
by the IRB before the study is initiated at the study site. Competent authority 
notification, review, and approval may be required as appropriate according to 
local country requirements. 
• Providing written summaries of the status of the study to the IRB annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB 
• Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, and all other applicable local 
regulations 
 
Any amendments to the protocol will require competent authority and/or IRB approval 
(as appropriate) before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study patients. 
 
10.1.2 
Financial Disclosure 
Investigators will provide the sponsor with sufficient, accurate financial information as 
requested to allow the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
 
The information on financial disclosure for investigators will be addressed in a separate 
agreement between the sponsor and the investigator. 


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10.1.3 
Informed Consent Process 
• The investigator or his/her representative must explain the nature of the study to 
the patient or his/her legally authorized representative and answer all questions 
regarding the study. 
• Patients must be informed that their participation is voluntary. Patients will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, and Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB or 
study center. 
• The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date and time that 
written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
• Patients must be reconsented to the most current version of the ICF during their 
participation in the study. 
• A copy of the signed ICF must be provided to the patient or the patient’s legally 
authorized representative. 
 
10.1.4 
Data Protection 
• Patients will be assigned a unique identifier by the sponsor. Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; patient 
names or any information that would make the patient directly identifiable will 
not be transferred. 
• The patient must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection laws. The level of 
disclosure must also be explained to the patient who will be required to give 
consent for their data to be used as described in the informed consent. 
• The patient must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB members, and by inspectors from regulatory 
authorities. 
 
10.1.5 
Dissemination of Clinical Study Data 
All information regarding naldemedine supplied by the sponsor to the investigator is 
confidential information. The investigator agrees to use this information to conduct the 
study and will not use it for other purposes without the written consent from the sponsor. 
It is understood that there is an obligation to provide the sponsor with complete data 
obtained during the study. The information obtained from the clinical study will be used 
toward the development of naldemedine and may be disclosed to regulatory authorities, 
other investigators, corporate partners, or consultants as required. 
 
The sponsor will retain ownership of all data. All proposed publications based on the 
study will be subject to the sponsor’s approval requirements. 


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10.1.6 
Data Quality Assurance 
• All patient data required for the study will be recorded in an eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct 
by electronically signing the eCRF. 
• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF. 
• The investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source documents. 
• The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of patients are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
o Records and documents, including signed ICFs, pertaining to the conduct of 
this study must be retained. No records may be destroyed during the retention 
period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the 
sponsor. Records will be retained for the longest of the following periods: 
 At least 2 years after approval of the last marketing application 
 Three years after formal discontinuation of the clinical development of the 
investigational product or after discontinuation of the study 
 For a minimum of 15 years after the end of the clinical study or longer if 
required by local regulations and EU Directive 2003/63/EC Article 5.2 
 Other period in accordance with applicable local laws, regulations, and 
other regulatory requirements, whichever is latest 
 
10.1.7 
Source Documents 
• Source documents provide evidence of the existence of the patient and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available. 
• Source documents are defined as original documents, data, and records 
(eg, hospital records, clinical and office charts, laboratory notes, memoranda, 
patients’ diaries or evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after 


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verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, patient files, and records kept at the 
pharmacy, laboratories, and medico-technical departments involved in the clinical 
trial). 
 
10.1.8 
Study and Site Closure 
The sponsor/designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of the sponsor. 
 
A study site will be closed upon study completion at the site. A study site is considered 
closed when all required documents and study supplies have been collected, data have 
been collected, and a study-site closure visit has been performed. 
 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of patients by the investigator 
• Discontinuation of further study treatment development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IRBs, the regulatory authorities, and any contract research 
organizations used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The investigator shall promptly inform the 
patients and should assure appropriate patient therapy and/or follow-up. 
 
10.1.9 
Publication Policy 
• All information regarding study treatment/naldemedine supplied by the sponsor to 
the investigator is confidential. The investigator agrees to use this information to 
accomplish the study and must not use it for other purposes without consent from 
the sponsor. 
• The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
















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iii. 
Agree to use an acceptable effective form of birth control (with failure rates > 1% 
per year) from the start of Screening through 14 days after the last dose of study 
treatment, such as: 
a. Progestogen-only oral hormonal contraception (where inhibition of ovulation 
is not the primary mode of action) 
b. Male or female condom with or without spermicide 
c. Cap, diaphragm, or sponge with spermicide 
 
Pregnancy Testing: 
• WOCBP should only be eligible after a verbally confirmed menstrual period and a 
negative urine pregnancy test. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected. 
 
Collection of Pregnancy Information: 
Details of this procedure are described in Section 8.3.5. 
Male patients with partners who become pregnant 
• The investigator or qualified designee will attempt to collect pregnancy 
information on any male patient’s female partner who becomes pregnant while 
the male patient is in this study. This applies only to male patients who receive 
naldemedine. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator or qualified designee will record pregnancy 
information on the paper Pregnancy Form and submit it to the CRO within 
24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of 
the mother and child will be forwarded to the CRO. Generally, follow-up will be 
no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for the procedure. 
 
Female patients who become pregnant 
• The investigator or qualified designee will collect pregnancy information on any 
female patient who becomes pregnant while participating in this study. 
Information will be recorded on the appropriate form and submitted to the CRO 
within 24 hours of learning of a patient’s pregnancy. The patient will be followed 
to determine the outcome of the pregnancy. The investigator or qualified designee 
will collect follow-up information on the patient and the child and the information 
will be forwarded to the CRO. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 




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10.5 Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
Alanine 
aminotransferase 
(ALT) or 
aspartate 
aminotransferase 
(AST) - absolute 
ALT or AST > 8 × upper limit of normal (ULN)1 
See additional actions and follow-up assessments listed below. 
Increased 
bilirubin and 
international 
normalized ratio 
(INR) 
ALT or AST > 3 × ULN AND total bilirubin > 2 × ULN or INR 
> 1.5; also report as a serious adverse event (SAE).2 
Symptomatic 
ALT or AST > 3 × ULN accompanied by fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%); also, report as an SAE. 
Suggested Actions and Follow-up Assessments 
Actions 
Follow-up Assessments 
• Immediately discontinue study intervention. 
• Report the event to the contract research 
organization (CRO) within 24 hours 
• Complete the liver event electronic case 
report form (eCRF), and complete an SAE 
data collection tool if the event also met the 
criteria for an SAE.2 
• Perform liver chemistry follow-up 
assessments. 
• Monitor the patient until liver chemistry test 
abnormalities resolve, stabilize, or return to 
baseline (see MONITORING). 
• Do not restart/rechallenge patient with 
study intervention unless allowed per 
protocol and CRO approval is granted. 
• If restart/rechallenge is either not allowed 
per protocol or not granted, permanently 
discontinue study intervention. The patient 
may continue in the study for any protocol- 
specified follow-up assessments 
• Viral hepatitis serology3 
• Obtain INR and recheck with 
each liver chemistry assessment 
until the transaminases values 
show downward trend 
• Obtain blood sample for 
pharmacokinetic (PK) analysis 
immediately after the event 
occurs4 
• Serum creatine phosphokinase 
(CPK) and lactate 
dehydrogenase (LDH) 
• Fractionate bilirubin, if total 
bilirubin ≥ 2 × ULN 
• Obtain complete blood count 
with differential to assess 
eosinophilia 
• Record the appearance or 
worsening of clinical symptoms 
of liver injury, or 
hypersensitivity, on the adverse 
event (AE) eCRF 


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MONITORING: 
If ALT or AST > 3 × ULN AND total 
bilirubin > 2 × ULN or INR > 1.5: 
• Repeat liver chemistry tests (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase [ALP], bilirubin, and INR) and 
perform liver event follow-up assessments 
within 24 hours. 
• Monitor patient twice weekly until liver 
chemistry test abnormalities resolve, 
stabilize, or return to baseline. 
• A specialist or hepatology consultation is 
recommended. 
If ALT or AST > 3 × ULN AND total 
bilirubin < 2 × ULN or INR ≤ 1.5: 
• Repeat liver chemistry tests (include ALT, 
AST, ALP, bilirubin, and INR) and perform 
liver chemistry follow-up assessments within 
24 to 72 hours. 
• Monitor patients weekly until liver chemistry 
abnormalities resolve, stabilize, or return to 
baseline. 
• Record use of concomitant 
medications (including 
acetaminophen, herbal 
remedies, and other over-the- 
counter medications) on the 
concomitant medications eCRF. 
• Record alcohol use on the liver 
event alcohol intake eCRF. 
If ALT or AST > 3 × ULN AND 
total bilirubin > 2 × ULN or INR 
> 1.5: 
• Anti-nuclear antibody, anti–
smooth muscle antibody, Type 
1 anti-liver kidney 
microsomal antibodies, and 
quantitative total 
immunoglobulin G (IgG) or 
gamma globulins. 
• Serum acetaminophen adduct 
high performance liquid 
chromatography (HPLC) assay 
(quantifies potential 
acetaminophen contribution to 
liver injury in patients with 
definite or likely 
acetaminophen use in the 
preceding week [5]). 
• Liver imaging (ultrasound, 
magnetic resonance, or 
computerized tomography) 
and/or liver biopsy to evaluate 
liver disease; complete liver 
imaging and/or liver biopsy in 
eCRFs. 


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1. All events of ALT or AST > 3 × ULN AND total bilirubin > 2 × ULN or INR > 1.5 may indicate 
severe liver injury and must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis). The INR stated threshold value will not apply to patients receiving anticoagulants. 
2. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study intervention if ALT or AST > 3 × ULN 
and total bilirubin > 2 × ULN. Additionally, if serum bilirubin fractionation testing is unavailable, 
record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of 
direct bilirubin elevations suggesting liver injury. 
3. hepatitis A immunoglobulin M (IgM) antibody; hepatitis B surface antigen (HBsAg) and hepatitis B 
core antibody (HBcAb); hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid 
antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); and hepatitis E 
IgM antibody. 
4. Pharmacokinetic sample may not be required for patients known to be receiving placebo or 
noncomparator interventions. Record the date/time of the PK blood sample draw and the date/time of 
the last dose of study intervention prior to the PK blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the patient’s best approximation. If the date/time of the last dose 
cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do 
not obtain a PK sample. Instructions for sample handling and shipping are in the PK laboratory 
manual. 


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ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; 
ULN = upper limit of normal 


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10.6 Appendix 6: List of Examples of Strong Cytochrome P450 3A 
Inducers 
Strong CYP3A inducers include, but are not limited to, the following: 
 
• St John’s Wort extract 
• apalutamide 
• avasimibe 
• carbamazepine 
• enzalutamide 
• ivosidenib 
• lumacaftor 
• mitotane 
• phenobarbital 
• phenytoin 
• rifabutin 
• rifampin 
• rifapentine 


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10.7 Appendix 7: List of Examples of Strong Cytochrome P450 3A 
and P-glycoprotein Inhibitors 
Strong CYP3A and P-gp inhibitors include, but are not limited to, the following: 
 
• grapefruit juice 
• atazanavir/ritonavir 
• boceprevir 
• clarithromycin 
• cobicistat 
• conivaptan 
• cyclosporine 
• danoprevir/ritonavir 
• diltiazem 
• erythromycin 
• elvitegravir/ritonavir 
• faldaprevir 
• gemfibrozil/itraconazle 
• glecaprevir 
• idelalisib 
• indinavir 
• indinavir/ritonavir 
• itraconazole 
• ketoconazole 
• lopinavir/ritonavir 
• mibefradil 
• mifepristone 
• nefazodone 
• nelfinavir 
• paritaprevir/ritonavir/ombitasvir 
• paritaprevir/ritonavir/ombitasvir/dasabuvir 
• posaconazole 
• ribociclib 
• ritonavir 
• saquinavir 
• saquinavir/ritonavir 
• simeprevir/odalasvir 


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• telaprevir 
• telithromycin 
• tipranavir/ritonavir 
• troleandomycin 
• voriconazole 


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10.8 Appendix 8: Numerical Pain Rating Scale 
 


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10.9 Appendix 9: Clinical Opiate Withdrawal Scale 
 


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10.10 Appendix 10: Protocol Version History 
The Summary of Changes Table for Version 3 of the protocol is located directly before 
the Table of Contents. 
 
Version 2: 14 Feb 2020 
 
Section # and Name 
Description of Change 
Brief Rationale 
Sponsor Signatory Page 
Medical monitor’s name and 
contact information changed 
Administrative change 
Section 1.1, Synopsis, Table 
1-1 Section 1.3, Schedule of 
Activities, Figure 1-2 
Section 3, Objectives and 
Endpoints, Table 3-1 
Section 8.1.1.1, Time from End 
of Surgery to Time to 
Toleration of Solid Food and 
First Bowel Movement 
Section 9.4.5.1, Primary 
Efficacy Endpoint 
“First” added before toleration 
of food in primary endpoint 
Clarification 
Section 1.1, Synopsis, Overall 
Design 
Section 4.1, Overall Design 
Section 6.3, Measures to 
Minimize Bias: Randomization 
and Blinding 
“Primary” added before 
anastomosis after small and 
large bowel resection in 
randomization statement 
Clarification 
Section 1.1, Synopsis, Number 
of Patients 
Section 4.1, Overall Design 
Number of screened patients 
changed from 680 to 425 
Correction 
Section 1.1, Synopsis, 
Concomitant Therapy 
Section 6.5, Prior Therapy and 
Concomitant Therapy 
Strong cytochrome P450 3A 
(CYP3A) and P-glycoprotein 
(P-gp) inhibitors (eg, 
clarithromycin, diltiazem, 
grapefruit juice, indinavir, 
ketoconazole, ritonavir) added 
as prohibited prior and 
concomitant therapy 
Request from regulatory 
agency 
Section 1.1, Synopsis, 
Treatment Groups and Duration 
Section 1.2, Schema, Figure 1-1 
Section 1.3, Schedule of 
Activities, Figure 1-2 
Section 4.1, Overall Design 
Description of when the End- 
of-study Visit will occur 
revised from 30 days after Day 
10 to 30 days after Day 10 or 
after the day of discharge 
(whichever is sooner) 
Clarification 


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Section 1.3, SOA, Figure 1-2 
Section 8.2.6, Clinical Opiate 
Withdrawal Scale 
Section 9.4.6, Safety Analyses 
Section 10.9, Appendix 9, 
Clinical Opioid Withdrawal 
Scale 
Clinical Opiate Withdrawal 
Scale (COWS) assessment 
added along with a description 
that the score in each domain 
will be summarized 
categorically 
Request from regulatory 
agency to monitor patients 
for signs/symptoms of 
opioid withdrawal 
Section 5.4, Screen Failures 
Sentences added allowing 
rescreening of patients who 
met all entry criteria but whose 
surgery was rescheduled more 
than 14 days after signing the 
informed consent form (ICF) 
and stating that these patients 
must resign the ICF if the 
rescheduled surgery is more 
than 14 days after the 
originally-scheduled surgery 
and the medical monitor 
should be contacted to see if 
any screening tests will need to 
be repeated 
Administrative change to 
allow patients who met the 
entry criteria to participate 
in the study even though 
their surgeries were 
rescheduled 
Section 6.5, Prior Therapy and 
Concomitant Therapy 
Wording for prohibited 
medications revised from up to 
end of treatment to through the 
end of study treatment 
Clarification 
Section 6.5, Prior Therapy and 
Concomitant Therapy 
Section 9.4.3, Prior and 
Concomitant Therapies 
Sentences added citing the 4 
enhanced recovery protocol 
elements that must be captured 
in the electronic case report 
form (eCRF) and that the 
investigator should determine 
the appropriate management of 
patients with signs/symptoms 
of opioid withdrawal, severe 
hypersensitivity to study 
treatment, and gastrointestinal 
perforation; statistical analyses 
modified to state that elements 
of the enhanced recovery 
protocol will be listed for each 
patient and summarized 
Request from regulatory 
agency 
Section 7.1, Discontinuation of 
Study Treatment 
Sentence added that the 
investigator should consider 
Request from regulatory 
agency to add specific 


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discontinuation of study 
treatment if opioid withdrawal 
is suspected, and that study 
treatment must be discontinued 
if patients have a COWS score 
> 36, severe hypersensitivity 
thought to be related to study 
treatment, or signs/symptoms 
of gastrointestinal perforation 
guidance regarding 
discontinuation in specific 
situations 
Section 8.1.1.1, Time from End 
of Surgery to Time to 
Toleration of Solid Food and 
First Bowel Movement 
Section 9.4.3, Prior and 
Concomitant Therapies Section 
9.4.5.1, Primary Efficacy 
Endpoint 
Sentence added to record the 
reason for discharge prior to 
having the first bowel 
movement in the eCRF and 
text and e-mail added as ways 
to contact the investigator 
within 24 hours of the first 
bowel movement after 
discharge; statistical analyses 
modified to state that the 
reason for discharge prior to 
having the first bowel 
movement will be listed 
Request from regulatory 
agency (reason for 
discharge); administrative 
change (provision for text 
and e-mail communication 
contact) 
Section 8.1.2.2, Reinsertion of 
the Nasogastric Tube 
“Postoperative” added to 
define when to capture 
reinsertion of the nasogastric 
tube 
Clarification 
Section 8.2.5, Numerical Pain 
Rating Scale 
Phrase specifying pain to be 
assessed once daily in the 
morning at approximately the 
same time of day added 
Clarification 
Section 8.3.1, Time Period and 
Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information 
Section 8.3.2, Method of 
Detecting Adverse Events and 
Serious Adverse Events 
Sentence referencing 
Appendix 3 for information 
about recording, evaluating, 
and assessing causality of 
adverse events and serious 
adverse events moved from 
Section 8.3.1 to 8.3.2 
Clarification 
Section 9.4, Statistical Analyses Table 9-1 added to show how 
protocol study days will be 
mapped to analysis study days 
For programming and 
analysis purposes to 
ensure compliance with 
CDISC requirements 
Section 9.4.7.1.3, Exposure- 
response Analysis 
Section added that an 
exploratory exposure-response 
analysis will be conducted for 
Clarification 


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efficacy and safety and 
reported in a separate 
pharmacokinetic report 
Section 10.2, Appendix 2: 
Clinical Laboratory Tests 
International normalized ration 
(INR) added to clinical 
chemistry 
Addition to ensure 
consistency with revised 
liver safety criteria in 
Section 10.5 
Section 10.3.3, Reporting of 
Serious Adverse Events 
Fax added as a way to report a 
new serious adverse event or 
update data on a serious 
adverse event after electronic 
data capture is taken offline 
Administrative change 
Section 10.5, Appendix 5: 
Liver Safety: Suggested 
Actions and Follow-up 
Assessments 
Alanine aminotransferase 
(ALT) ≥ 3 × upper limit of 
normal (ULN) was revised to 
ALT or aspartate 
aminotransferase (AST) > 8 × 
ULN for the liver chemistry 
study treatment stopping 
criteria; bilirubin was revised 
to total bilirubin, ALT or AST 
≥ 3 × ULN AND bilirubin ≥ 2 
× ULN (> 35% direct 
bilirubin) OR international 
normalized ratio (INR) > 1.5 
was revised to ALT or AST > 
3 × ULN AND total bilirubin < 
2 × ULN or INR ≤ 1.5, and 
ALT ≥ 3 × ULN AND 
bilirubin ≥ 2 × ULN or INR 
> 1.5 was revised to ALT or 
AST > 3 × ULN AND total 
bilirubin > 2 × ULN or INR 
> 1.5 under the monitoring 
actions; and a flowchart was 
added 
Requested by regulatory 
agency 
Section 10.7, Appendix 7: List 
of Examples of Strong 
Cytochrome P450 3A and 
P-glycoprotein Inhibitors 
List of strong CYP3A and 
P-gp inhibitors added 
Requested by regulatory 
agency 
Section 10.8, Appendix 8: 
Numerical Pain Rating Scale 
Numerical Pain Rating Scale 
added 
Clarification 


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10.11 Appendix 11: Investigator Signature Page 
Study Title: 
A phase 2, multicenter, randomized, double-blind, 
placebo-controlled study of naldemedine in patients 
undergoing surgeries that include a bowel resection or 
bowel transection 
Study Number: 
1902G1721 
Date of Original: 
21 Nov 2019 
Date of Latest Version: 
18 Jun 2020 (Version 3) 
 
I have read the protocol described above. I agree to comply with all local and country 
regulatory requirements and to conduct the study as described in the protocol. 
 
 
 
 
 
 
Signed: 
 
Date:  
 
 
<enter name and credentials> 
<enter title> 
<enter affiliation> 


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10.12 Appendix 12: Abbreviations and Acronyms 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ASA 
American Society of Anesthesiologists 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-last 
area under the plasma concentration-time curve from time zero to 
the time of the last quantifiable concentration after dosing 
AUC0-τ 
area under the concentration-time curve over the dosing interval τ 
(12 hours) on Day 3, calculated by Linear Up/Log Down 
Trapezoidal Method 
BID 
twice daily 
BLQ 
below the lower limit of quantification 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CI 
confidence interval 
CL/F 
apparent total clearance estimated according to: CL/F = Dose/AUC0- 
τ on Day 3 (for naldemedine only) 
Cmax 
maximum observed plasma concentration on Day 3 
COWS 
Clinical Opiate Withdrawal Scale 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED50 
amount of drug that produced the desired effect in 50% 
EDC 
electronic data capture 
ET 
early termination 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GI2 
time from end of surgery to time to first toleration of solid food and 
first bowel movement 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HIPAA 
Health Information Portability and Accountability Act 
HPLC 
high performance liquid chromatography 
ICF 
informed consent form 


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ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
Mean 
arithmetic mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention–to-Treat 
MME 
morphine milligram equivalent 
MRM/U, AUC 
metabolic ratio of AUC0-last of nor-naldemedine to AUC0-last of 
naldemedine, corrected for molecular weight, defined as (nor- 
naldemedine AUC0-last)/(naldemedine AUC0-last) × (naldemedine 
molecular weight [570.64])/(nor-naldemedine molecular weight 
[516.55]) (for nor-naldemedine only) 
MRM/U, Cmax 
metabolic ratio of Cmax of nor-naldemedine to Cmax of naldemedine, 
corrected for molecular weight, defined as (nor-naldemedine 
Cmax)/(naldemedine Cmax) × (naldemedine molecular weight 
[570.64])/(nor-naldemedine molecular weight [516.55]) (for nor- 
naldemedine only) 
N 
number of non-missing observations 
NPRS 
Numerical Pain Rating Scale 
ODT 
orally disintegrating tablet 
OIC 
opioid-induced constipation 
PAMORA 
peripherally acting mu-opioid receptor antagonist 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
postop 
postoperative 
RBC 
red blood cell 
RMST 
restricted mean survival time 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
schedule of activities 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum plasma concentration on Day 3 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
woman of childbearing potential 


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11. 
REFERENCES 
1. Madbouly KM, Senagore AJ, Delaney CP. Endogenous morphine levels after 
laparoscopic versus open colectomy. Br J Surg. 2010;97(5):759-64. 
2. Delaney CP. Clinical perspective on postoperative ileus and the effect of opiates. 
Neurogastroenterol Motil. 2004;16 Suppl 2:61-6. 
3. Sam WJ, MacKey SC, Lötsch J, Drover DR. Morphine and its metabolites after 
patient-controlled analgesia: considerations for respiratory depression. J Clin Anesth. 
2011;23(2):102-6. 
4. Thirlwell MP, Sloan PA, Maroun JA, Boos GJ, Besner JG, Stewart JH, et al. 
Pharmacokinetics and clinical efficacy of oral morphine solution and controlled- 
release morphine tablets in cancer patients. Cancer. 1989;63(11 Suppl):2275-83. 
5. James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of acetaminophen-adduct in adults with acetaminophen overdose 
and acute liver failure. Drug Metab Dispos. 2009;37:1779-84. 
6. Jensen MP, Turner JA, Romano JM, Fisher LD. Comparative reliability and validity 
of chronic pain intensity measures. Pain. 1999:83(2):157-62. 
7. Wesson DR, Lind W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive 
Drugs. 2003;35[2]:253-9. 


 
18-Jun-2020 23:38:01 GMT+0000 
Approval 
18-Jun-2020 23:39:56 GMT+0000 
Final Approval 
 
 
Electronic Signature Page for 
 
 
 
 
 
Electronic Signature Page for 
 


 
 
 
Erratum 
 
 
Date: 
22 July 2020 
 
Study Number: 
Protocol 1902G1721 Version 3 
 
 
Section 8.2.1 (Physical Examinations) of Protocol 1902G1721 Version 3, issued 
18 June 2020, includes the extraneous words, “As per,” which should be disregarded: 
 
 
 


22-Jul-2020 14:01:11 GMT+0000 
Approval 
22-Jul-2020 14:02:00 GMT+0000 
Final Approval 
 
 
Electronic Signature Page for 
 
 
 
 
 
Electronic Signature Page for 
 

SAP_001.pdf: 
Shionogi Study Title: 
A Phase 2, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study of Naldemedine in Patients 
Undergoing Surgeries That Include a Bowel 
Resection or Bowel Transection 
Shionogi Study Number: 
1902G1721 
ClinicalTrials.gov 
Registration No. 
NCT04355169 
Study Document 
Statistical Analysis Plan Version 1 
2 July 2020 
History of Statistical Analysis Plan Amendments 
Version 1 (Original) 
2 July 2020 
NCT #NCT04355169


Statistical Analysis Plan 
Study Title: 
A phase 2, multicenter, randomized, double-blind, 
placebo-controlled study of naldemedine in patients 
undergoing surgeries that include a bowel resection 
or bowel transection 
Study Number: 
1902G1721 
Study Phase: 
2 
Product Name: 
S-297995 
Sponsor: 
Shionogi Inc. 
Version Number: 
1 
Issue Date: 
2 July 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi. This Confidential Material 
should only be viewed by those individuals or companies that have been given prior 
written authorization to do so by Shionogi (“Authorized Users”). This Confidential 
Material should not be made available in any form to any person or company, other 
than the Authorized Users and their respective employees or associates on a need-to-
know basis, without the written consent from Shionogi. 
 
 




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Statistical Analysis Plan: 1902G1721 
2 July 2020 
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Confidential 
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RECORDS ON REVISIONS 
Document History 
Version Number 
Date 
1 
2 July 2020 
 
 


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Page 4 of 30 
TABLE OF CONTENTS 
SIGNATURE PAGE .....................................................................................................2 
RECORDS ON REVISIONS ........................................................................................3 
TABLE OF CONTENTS ...............................................................................................4 
LIST OF IN-TEXT TABLES ........................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................7 
1. 
INTRODUCTION .................................................................................................9 
2. 
OVERVIEW ..........................................................................................................9 
3. 
STUDY OBJECTIVES ..........................................................................................9 
3.1 
Primary Objective ........................................................................................9 
3.2 
Secondary Objective ....................................................................................9 
3.3 
Other Objectives ........................................................................................10 
4. 
STUDY DESIGN .................................................................................................10 
4.1 
Study Blinding and Randomization ...........................................................10 
4.2 
Sample Size ................................................................................................10 
5. 
ANALYSIS POPULATIONS .............................................................................10 
5.1 
Modified Intention-to-treat Population ......................................................10 
5.2 
Per-protocol Set .........................................................................................11 
5.3 
Safety Analysis Population ........................................................................11 
5.4 
Pharmacokinetic Concentration Population ...............................................11 
5.5 
Pharmacokinetic Parameter Population .....................................................11 
6. 
STATISTICAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ........................................................................................................11 
6.1 
Statistical Reporting ...................................................................................11 
6.2 
Statistical Testing .......................................................................................12 
6.3 
Analysis Visit Windows ............................................................................12 
6.4 
Missing Data ..............................................................................................12 
6.5 
Definition ...................................................................................................12 
6.5.1 
Study Day.........................................................................................12 
6.5.2 
Baseline ............................................................................................12 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..............13 
7.1 
Patient Disposition .....................................................................................13 
7.2 
Demographic and Baseline Characteristics ...............................................13 
8. 
STUDY CONDUCT ............................................................................................14 
8.1 
Treatment Exposure and Compliance ........................................................14 
8.2 
Prior and Concomitant Medications and Therapies ...................................14 
8.3 
Protocol Deviation .....................................................................................14 
9. 
EFFICACY ..........................................................................................................15 


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Page 5 of 30 
9.1 
Primary Endpoint .......................................................................................15 
9.1.1 
Primary Analysis ..............................................................................15 
9.1.2 
Supplementary Analysis ..................................................................16 
9.1.3 
Subgroup Analysis ...........................................................................17 
9.2 
Secondary Endpoints .................................................................................17 
9.2.1 
Time from the End of Surgery to Time when the Discharge Order is 
Written .............................................................................................17 
9.2.2 
Proportion of Patients Requiring Postoperative Re-insertion of the 
Nasogastric Tube .............................................................................18 
9.2.3 
Proportion of Patients with Nausea on Days 1 through 3 ................18 
9.2.4 
Proportion of Patients with Vomiting on Days 1 through 3 ............18 
9.2.5 
Proportion of Patients Discharged by Day 10 who are Re-admitted 
for Any Reason Within 30 Days after Discharge from the Hospital18 
9.3 
Exploratory Endpoints ...............................................................................19 
9.3.1 
Time from the End of Surgery to Time to Discharge Readiness .....19 
9.3.2 
Time from the End of Surgery to Time to Actual Discharge from the 
Hospital (Length of Stay).................................................................19 
9.3.3 
Proportion of Patients with Prolonged Hospital Stay due to GI 
Dysfunction ......................................................................................19 
9.3.4 
Time from Initial Insertion of the Nasogastric Tube to Removal of 
the Nasogastric Tube........................................................................19 
9.3.5 
Proportion of Patients with Abdominal Distension on Day 1 through 
the Day on which GI2 is Achieved ..................................................20 
9.3.6 
Proportion of Patients with Nausea on Day 4 through Day of 
Discharge .........................................................................................20 
9.3.7 
Proportion of Patients with Vomiting on Day 4 through Day of 
Discharge .........................................................................................20 
9.3.8 
Proportion of Patients who Achieve GI2 in Each Treatment Group 
by Postoperative Day .......................................................................21 
9.3.9 
Proportion of Patients who Receive Concomitant Medication that 
May Have a Laxative Effect ............................................................21 
9.3.10 
Effect of Prior Surgery on the GI2 Endpoint ...................................21 
10. SAFETY ..............................................................................................................21 
10.1 
Adverse Events ..........................................................................................21 
10.2 
Vital Signs ..................................................................................................23 
10.3 
Laboratory Evaluations ..............................................................................23 
10.4 
Electrocardiograms ....................................................................................24 
10.5 
Physical Examinations ...............................................................................24 
10.6 
Pain Intensity as Assessed on Numerical Pain Rating Scale .....................24 
10.7 
Clinical Opiate Withdrawal Scale ..............................................................25 


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10.8 
Opioid analgesics .......................................................................................25 
10.9 
Analysis for ClinTrial.gov .........................................................................25 
11. Pharmacokinetics .................................................................................................26 
11.1 
Plasma Drug Concentrations of Naldemedine and Nor-naldemedine .......26 
11.2 
PK Parameters for Naldemedine and Nor-naldemedine on Day 3 ............26 
12. INTERIM ANALYSES .......................................................................................27 
13. PROGRAMMING CONVENTIONS ..................................................................28 
13.1 
Formatting and Programming Rule ...........................................................28 
13.2 
Sample SAS Code ......................................................................................30 
14. REFERENCES ....................................................................................................30 
 
LIST OF IN-TEXT TABLES 
Table 1 
Mapping Information for Study Days ............................................12 
Table 2 
Demographic and Baseline Characteristics ...................................13 
Table 3 
Definition of Adverse Event Terms ...............................................22 
Table 4 
Definition of Specific TEAE .........................................................23 
Table 5 
Criteria for Laboratory Tests .........................................................24 
Table 6 
Conversion Factor ..........................................................................25 
Table 7 
Category .........................................................................................29 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BLQ 
below the limit of quantification 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration 
CL/F 
apparent total clearance 
COVID-19 
Coronavirus disease 2019 
COWS 
clinical opiate withdrawal scale 
CV 
coefficient of variation 
DEC 
decrease 
DMC 
data monitoring committee 
ET 
early termination 
CRF 
case report form 
INC 
increase 
INR 
international normalized ratio 
KM 
Kaplan Meier  
mITT 
Modified Intention-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MME 
morphine milligram equivalent 
MRM/U 
metabolic ratio 
NPRS 
numerical pain rating scale 
PK 
Pharmacokinetic 
PK-C 
pharmacokinetic concentration 
PK-P 
Pharmacokinetic parameter 
PPS 
Per-protocol Set 
PT 
preferred term, prothrombin time 
RMST 
restricted mean survival time 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
STEAE 
Serious treatment-emergent adverse event 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
Tmax 
time to maximum plasma concentration 


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ULN 
upper limit of normal 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods and data handlings to 
be employed for the analysis of the study protocol 1902G1721, Version 3, dated 18 June 
2020. Table, figure, and listing (TFL) mock-ups are provided in the TFL shells prepared 
separately.  
All the analyses described in the SAP will be performed in the Biostatistics Center, 
Biometrics, Shionogi Inc. Any deviations from the final SAP will be documented in the 
clinical study report. 
2. OVERVIEW 
This is a Phase 2, multicenter, randomized, parallel-group, double-blind, placebo-
controlled study in patients undergoing partial small or large bowel resection with 
primary anastomosis or radical cystectomy requiring bowel transection with primary 
anastomosis. 
The study will consist of 3 study periods:  
● a Screening/Baseline period (Day –14 to Day 0) 
● a Treatment period (study treatment for no more than 11 days, including Day 0 
[day of surgery] plus through 10 postoperative days).  
● a Follow-up period 30 days after Day 10 or after the day of discharge (whichever 
is sooner), with a window of + 3 days, but not < 30 days (End-of-study Visit) or 
an Early Termination (ET) Visit. 
3. STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is: 
● To compare the efficacy of naldemedine 1.25 mg, 2.5 mg, and 5 mg and placebo 
for the primary endpoint.  
- 
The primary endpoint is the time from the end of surgery to time to first 
toleration of solid food and first bowel movement (GI2). 
3.2 
Secondary Objective 
The secondary objective of the study is: 
● To compare the efficacy of naldemedine 1.25 mg, 2.5 mg, and 5 mg and placebo 
for the secondary endpoints.  
- 
Secondary endpoints are the time from the end of surgery to time when the 
discharge order is written, proportion of patients requiring postoperative 
reinsertion of the nasogastric tube, proportion of patients with nausea on Days 
1 through 3, proportion of patients with vomiting on Days 1 through 3 and 


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proportion of patients discharged by Day 10 who are readmitted for any 
reason within 30 days after discharge from the hospital. 
3.3 
Other Objectives 
● To compare the efficacy of naldemedine 1.25 mg, 2.5 mg, and 5 mg and placebo 
for the exploratory endpoints 
● To characterize the pharmacokinetics (PK) profile of naldemedine 1.25 mg, 2.5 
mg, and 5 mg and its metabolite (nor-naldemedine) for the PK endpoints. 
● To compare the safety of naldemedine 1.25 mg, 2.5 mg, and 5 mg and placebo for 
the safety endpoints 
4. STUDY DESIGN 
4.1 
Study Blinding and Randomization 
Eligible patients will be randomized in a ratio of 1:1:1:1 to one of the following treatment 
groups: naldemedine 1.25 mg, 2.5 mg, or 5 mg or placebo. Randomization will be 
stratified by the planned surgical procedure, ie, small bowel resection with primary 
anastomosis, large bowel resection with primary anastomosis, or radical cystectomy 
requiring bowel transection with primary anastomosis. All patients will be centrally 
randomized to study treatment using an Interactive Web Response System (IWRS). 
4.2 
Sample Size 
The sample size of between 44 and 85 per group will be required for the Modified 
Intention-To-Treat (mITT) Population to provide at least 80% power.  The simulation 
estimated 44 patients per treatment group to see a linear trend in the restricted mean 
survival time (RMST) up to 240 hours for the time to the event of GI2 in across a 24-hour 
difference between naldemedine 5 mg and placebo under 80% statistical power at a 2-
sided significance level of 0.05. Eighty-five patients per treatment group will be required 
to see a linear trend in RMST up to 240 hours across an 18-hour difference between 
naldemedine 5 mg and placebo. The final sample size will be dependent on the 
enrollment rate during the fixed enrollment period.  A minimum of 44 patients per group 
in the mITT population is desired. 
5. ANALYSIS POPULATIONS 
5.1 
Modified Intention-to-treat Population 
The mITT Population will include all randomized patients who received at least 1 dose of 
study treatment and had at least 1 postbaseline efficacy assessment for the primary 
efficacy endpoint, which includes all three components (end of surgery time, time when 
the patient first tolerates solid food, and time of first bowel movement) of the time to 
event of GI2. Patients will be analyzed according to the treatment to which they were 
randomized.   
This population will be the primary efficacy analysis population. 


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5.2 
Per-protocol Set 
The Per-protocol Set (PPS) will include all patients in the mITT Population who did not 
have a major protocol deviation, as defined in a separate document, Protocol Deviation 
Plan. Major protocol deviations for the PPS will be determined prior to unblinding of the 
study data.   
This population will be used in a supplementary analysis for the primary endpoint. 
5.3 
Safety Analysis Population 
The Safety Analysis Population will include all randomized patients who received at least 
1 dose of the study treatment. The population will be analyzed according to the treatment 
that patients actually received, rather than the study treatment to which patients were 
randomized. 
This population will be used in all safety analyses. 
5.4 
Pharmacokinetic Concentration Population 
The Pharmacokinetic Concentration (PK-C) Population will include all patients who 
received at least 1 dose of naldemedine and had at least 1 evaluable concentration of 
either naldemedine or nor-naldemedine in plasma. This population will be used for the 
concentration listing. 
5.5 
Pharmacokinetic Parameter Population 
The Pharmacokinetic Parameter (PK-P) Population will include all patients with at least 1 
PK parameter estimated appropriately. This population will be used for PK parameter 
listings and summaries, plotting of the plasma concentration-time data, plasma 
concentration summaries, and statistical analysis. 
6. STATISTICAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
6.1 
Statistical Reporting 
Unless otherwise noted, continuous variables will be summarized by using the number of 
nonmissing observations, arithmetic mean, standard deviation (SD), median, and 
minimum, and maximum values as summary statistics; categorical variables will be 
summarized by using the frequency count and the percentage of patients in each category.   
Patient study data, including data not appearing in tables, will be presented in by-patient 
data listings. In general, all tables will be presented by treatment group. Individual patient 
data and any derived data will be presented by treatment and patient. 
All analyses will be performed using SAS® Version 9.4 or higher (SAS Institute, Cary, 
NC, USA), or WinNonlin Version 6.2.1 or higher (Certara, St Louis, MO, USA). 


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6.2 
Statistical Testing 
All statistical tests will be performed at the 2-sided significance level of 0.05, unless 
otherwise noted. No multiplicity adjustment will be made in this study.  
6.3 
Analysis Visit Windows 
No analysis visit window will be applied. The data will be collected according to Figure 
1-2 and Table 1-2 in the protocol and analyzed according to the time point collected on 
the case report form (CRF).  
6.4 
Missing Data 
Missing values will not be imputed. All statistical analyses will be based on observed 
cases unless otherwise noted. 
6.5 
Definition 
6.5.1 
Study Day 
For programming and analysis purposes, the study days specified in the protocol will be 
mapped as shown in Table 1. Study day will be presented in this SAP in the same way as 
presented in the protocol, while TLF shells and TLFs will present “Surgery Day” or 
“Postop Day X” as shown in parentheses in this mapping table.  
Table 1 
Mapping Information for Study Days 
  
 
Study Day 0 will be the day of surgery, and any other study day will be calculated 
relative to Study Day 0. Therefore, Day 1 will start at midnight after surgery of that 
calendar day and Day X (X = 1, 2, .., 10) will start at midnight of the X-th day. “Study 
Day” will simply be represented as “Day” hereafter in this SAP.  
6.5.2 
Baseline 
Baseline except for the Numerical Pain Rating Scale (NPRS) will be defined as the last 
value obtained before randomization. The baseline value for NPRS will be the value as 
assessed on the morning of Day 1. 


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7. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
7.1 
Patient Disposition 
The number of patients who failed the Screening Period (ie, screen failure) and its 
proportion to enrolled patients will be summarized along with the reason for not being 
randomized to treatment. 
A summary table will be produced detailing the number of subjects randomized, the 
number of patients who completed the study, and the number of patients who prematurely 
discontinued from the study. In addition, the reason for discontinuation from the study 
will be summarized. 
The number and proportion of patients in each analysis population to the randomized 
population will be summarized, as well as the reasons for exclusion from the mITT 
Population, the PPS, the Safety Analysis Population, PK-C and PK-P Populations. 
7.2 
Demographic and Baseline Characteristics 
Demographic data and baseline characteristics shown in Error! Reference source not 
found. will be summarized descriptively as described in Section 6.1 for the mITT 
Population and the Safety Analysis Population. Prior surgeries can be any abdominal 
surgery except: gastrectomy, gastric bypass, gastric sleeve, lap banding, pancreatic 
resection, hepatectomy, intestinal transplant. Prior surgeries will be identified and 
finalized by the Shionogi Medical Monitor prior to database lock and unblinding. The 
categories used to summarize these data are shown in Table 7. 
Table 2 
Demographic and Baseline Characteristics 
 
Continuous variable 
• 
Age 
Categorical variables 
• 
Sex 
• 
Surgical procedure 
• 
Fertility status for females 
• 
Race 
• 
Ethnicity 
• 
Elements of the enhanced recovery protocol 
• 
Prior surgery 
 
Medical histories will be summarized by treatment group for the mITT Population. The 
reported medical history terms will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) Version 23.0. 


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8. STUDY CONDUCT 
8.1 
Treatment Exposure and Compliance 
For the mITT Population and the Safety Analysis Population, the duration of treatment 
exposure and treatment compliance rate will be summarized descriptively by treatment 
group. The categories used in the summary of frequency counts (if applicable) are shown 
in Table 6. 
The duration of treatment exposure will be defined as the dosing period during which a 
patient took the study drug: 
(final dose date) – (initial dose date) + 1 [day] 
The treatment compliance rate will be defined as: 
(total number of tablets that patients actually took during duration of treatment exposure) 
/ (total number of tablets that patients should have taken during duration of treatment 
exposure) × 100 [%] 
A dose will be considered one tablet. Patients will receive the study drug twice daily 
through Day 10; a total of two tablets per day will be administered. However, depending 
on the time surgery is done, patients may not take study drug after surgery on Day 0, 
which means the number of tablets can be one on Day 0. 
8.2 
Prior and Concomitant Medications and Therapies 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary (WhoDrugDDEB3 – 201909). Prior medications and therapies 
will be defined as medication taken prior to Day 0. Concomitant medications and 
therapies will be defined as medication taken after first dosing. 
For the mITT population, the number and proportion of patients who took prior and 
concomitant medications will be summarized with WHO Drug Dictionary Preferred 
Term (PT) by category (laxative, opioid, and others) for each treatment group. If a patient 
has more than 1 drug that codes to the same PT, the patient will be counted only once for 
that PT. 
The number and proportion of patients who took prior and concomitant therapies will be 
summarized by the preferred term in each treatment group for the mITT population. 
Patients for whom a particular therapy name was reported more than once will be counted 
only once for that therapy.  
8.3 
Protocol Deviation 
For all randomized patients, major protocol deviations relating to PPS will be listed. 
Major protocol deviations, including protocol deviations related to COVID-19, will be 
specified in the “Protocol deviation plan” separately. A final list of major protocol 
deviations will be determined based on the data review prior to database lock. 


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9. EFFICACY 
Efficacy analyses will be performed for the mITT population unless otherwise specified.  
9.1 
Primary Endpoint 
The time from the end of surgery (defined as the time the patient leaves the operating 
room) to time to first toleration of solid food (defined as the time when the patient 
consumes a meal that requires chewing and has no significant nausea or vomiting, as per 
the judgment of the investigator, for 4 hours after that solid food) and first bowel 
movement (GI2) will be the primary endpoint and called ”Time to event of GI2”.  The 
time to event of GI2 will be the later time at which all of the following criteria are met: 
• First toleration of solid food (as defined above)  
• First bowel movement after surgery  
If one of three time components (end of surgery time, time when the patient first tolerates 
solid food, and time of first bowel movement) is missing, time to event of GI2 will be 
considered as missing.  
If time to event of GI2 does not occur during the evaluation period of 240 hours, the 
patient will be censored at the time of his/her last nonmissing postbaseline assessment. 
9.1.1 
Primary Analysis 
The primary objective is to compare the efficacy of naldemedine 1.25 mg, 2.5 mg, and 5 
mg and placebo for the primary endpoint. 
Let 𝜇̂𝑘𝑔(𝑡) be the estimate of RMST at time t for the surgical procedure k (k=1,2,3) and 
treatment group g (g=1,2,3,4). Let 𝜇̂𝑘(𝑡) = (𝜇̂𝑘1(𝑡), 𝜇̂𝑘2(𝑡), 𝜇̂𝑘3(𝑡),𝜇̂𝑘4(𝑡))𝑇 be the vector 
of estimates of RMST for surgical procedure k. 𝑐= (−3, −1,1,3)𝑇 is defined as contrast 
coefficient. The null hypothesis will be 
𝐻0: 𝑐𝑇𝜇1(𝑡) = 𝑐𝑇𝜇2(𝑡) = 𝑐𝑇𝜇3(𝑡) = 0 
and test statistics T will be 
𝑇=
∑
𝑐𝑇𝜇̂𝑘(𝑡)
3
𝑘=1
√∑
{𝑉𝑎𝑟[𝑐𝑇𝜇̂𝑘(𝑡)]}
3
𝑘=1
 
, where 
𝑉𝑎𝑟[𝑐𝑇𝜇̂𝑘(𝑡)] = 9 ∗𝑉𝑎𝑟[𝜇̂𝑘1(𝑡)] + 1 ∗𝑉𝑎𝑟[𝜇̂𝑘2(𝑡)] + 1 ∗𝑉𝑎𝑟[𝜇̂𝑘3(𝑡)] + 9
∗𝑉𝑎𝑟[𝜇̂𝑘4(𝑡)] 


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Therefore p-value will be 
2{1 −Φ(|𝑇𝑜𝑏𝑠|)} 
, where Φ(∙) will be standard normal distribution and 𝑇𝑜𝑏𝑠 will be the observed test 
statistics. 
For pairwise comparison between treatment groups i and j (i, j =1,2,3,4), the null 
hypothesis will be   
𝐻0: 𝜇1𝑖(𝑡) −𝜇1𝑗(𝑡) = 𝜇2𝑖(𝑡) −𝜇2𝑗(𝑡) = 𝜇3𝑖(𝑡) −𝜇3𝑗(𝑡) = 0 
and test statistics S will be 
𝑆=
∑
{𝜇̂𝑘𝑖(𝑡) −𝜇̂𝑘𝑗(𝑡)}
3
𝑘=1
√∑
{𝑉𝑎𝑟[𝜇̂𝑘𝑖(𝑡)] + 𝑉𝑎𝑟[𝜇̂𝑘𝑗(𝑡)]}
3
𝑘=1
 
1) The mean survival time, which is also referred to as the RMST, of GI2 events within 
240 hours will be estimated using the area under the Kaplan-Meier (KM) curve. To 
demonstrate the linear dose-response relationship between treatment groups (3 
naldemedine groups and placebo group) and the RMST, the linear contrast test for 
trend with contrast coefficients of (-3, -1, 1, 3) will be performed based on the test 
statistics T described above. Two types of KM curve with 95% confidence bound 
and point estimate line only  will be provided. SAS code will be provided in section 
13.2. 
2) Pairwise comparisons of all treatments will be undertaken based on the test 
statistics S described above and the differences of treatment means including their 
95% confidence interval (CI) will be calculates as 
1
3 ∑{𝜇̂𝑘𝑖(𝑡) −𝜇̂𝑘𝑗(𝑡)}
3
𝑘=1
± 𝑧𝛼/2 × 1
3 √∑{𝑉𝑎𝑟[𝜇̂𝑘𝑖(𝑡)] + 𝑉𝑎𝑟[𝜇̂𝑘𝑗(𝑡)]}
3
𝑘=1
 
 𝑧𝛼/2 is the upper 100α % quantile of the standard normal distribution. 
9.1.2 
Supplementary Analysis 
The following supplementary analyses will be undertaken using the mITT population, 
unless otherwise noted: 
• Repeat of the primary endpoint analysis, based on the PPS. 
• Repeat of the primary endpoint analysis, excluding all patients who received 
additional therapies that could impact the primary endpoint at any time until the 


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day GI2 is achieved or Day 10 or withdrawal or discharge day, whichever comes 
first.  The list of all patients who received additional therapies that could impact the 
primary endpoint at any time until achievement of the GI2 endpoint or completion 
of the study will be provided by the Shionogi Medical Monitor prior to database 
lock and unblinding. 
• For each treatment group, a two-way table summarizing the proportion of patients 
by achievement of GI2 until 240 hours (yes/no) and additional therapies received 
that could impact the primary endpoint at any time (yes/no) until Day 10 or 
withdrawal or discharge day, whichever comes first. 
• Proportion of patients achieving GI2 by treatment group and cumulative day. As 
for the definition of cumulative day, if patients achieved GI2 on a certain day, GI2 
will be considered as sustained through Day 10 or withdrawal or discharge day, 
whichever comes first (called “last day”). Pairwise comparison as Cochran Mantel 
Haenszel test adjusted by surgical procedure will be applied to the proportion at 
Day 10.  
• Proportion of patients achieving GI2 by treatment group, surgical procedure, and 
cumulative day.  
9.1.3 
Subgroup Analysis 
RMST will be calculated and two types of KM curve with 95% confidence bound and 
point estimate line only will be provided by following subgroups.  
• Surgical procedure (Small bowel resection with primary anastomosis, large bowel 
resection with primary anastomosis, or radical cystectomy requiring bowel 
transection with primary anastomosis) 
• Prior surgery (No prior surgery, 1 prior surgery, 2 prior surgeries) 
• Epidural anesthesia (yes/no) 
• Enhanced recovery protocol (all aspects of ERP versus those that had only the 3 
that were mandated) 
9.2 
Secondary Endpoints 
9.2.1 
Time from the End of Surgery to Time when the Discharge Order 
is Written 
The time from the end of surgery to time when the discharge order is written will be the 
hours between date and time of surgery and date and time of writing the discharge order. 
The censoring will be defined in the same manner as defined for the primary endpoint. 
9.2.1.1 
Analysis 
Pairwise comparison will be applied to the time from the end of surgery to time when the 
discharge order is written in the same way as described in section 9.1.1. A Kaplan-Meier 
curve will be provided by treatment group.  
 


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9.2.2 
Proportion of Patients Requiring Postoperative Re-insertion of the 
Nasogastric Tube 
The proportion of patients requiring postoperative re-insertion of the nasogastric tube will 
be calculated based on the number of patients requiring postoperative re-insertion of the 
nasogastric tube. Patients in the mITT Population who do not have postoperative re-
insertion of the nasogastric tube will be excluded from the denominator. 
9.2.2.1 
Analysis 
Pairwise comparison as Cochran Mantel Haenszel test adjusted by surgical procedure 
will be applied to the proportion. 
9.2.3 
Proportion of Patients with Nausea on Days 1 through 3 
Nausea will be as reported as an adverse event. The following proportions will be 
calculated by treatment group. 
(1) The proportion of patients who completed the study on Day 1, 2 and 3 with 
nausea between Day 1 and Day 3 
(2) The proportion of patients with nausea between first dosing and Day 1 
9.2.3.1 
Analysis 
Pairwise comparison as Cochran Mantel Haenszel test adjusted by surgical procedure 
will be applied to the proportion of patients who completed the study on Day 1, 2 and 3 
with nausea between Day 1 and Day 3 defined in 1) of section 9.2.3. 
9.2.4 
Proportion of Patients with Vomiting on Days 1 through 3 
Vomiting will be as reported as an adverse event. The proportions described in section 
9.2.3 will be calculated for vomiting. 
9.2.4.1 
Analysis 
The proportion will be analyzed in the same way as section 9.2.3.1. 
9.2.5 
Proportion of Patients Discharged by Day 10 who are Re-admitted 
for Any Reason Within 30 Days after Discharge from the Hospital 
The proportion of patients discharged by Day 10 who are re-admitted to the hospital for 
any reason will be calculated. Similarly, the proportion of patients discharged by Day 10 
who are re-admitted to the hospital for Postoperative GI dysfunction-related causes will be 
also calculated. 
9.2.5.1 
Analysis  
Each proportion will be analyzed in the same way as described in section 9.2.2.1. 


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9.3 
Exploratory Endpoints 
9.3.1 
Time from the End of Surgery to Time to Discharge Readiness 
The time from the end of surgery to time to discharge readiness will be the hours between 
the date and time of surgery and the date and time of discharge readiness. The censoring 
will be defined in the same manner as defined for the primary endpoint. 
9.3.1.1 
Analysis 
Treatment groups will be compared based on the time from the end of surgery to time to 
discharge readiness in the same way as described in section 9.1.1. A Kaplan-Meier curve 
will be provided by treatment group to make the comparison.  
9.3.2 
Time from the End of Surgery to Time to Actual Discharge from 
the Hospital (Length of Stay) 
The time from the end of surgery to time to actual discharge from the hospital will be the 
hours between the date and time of surgery and the date and time of actual discharge. The 
censoring will be defined in the same manner as defined for the primary endpoint. 
9.3.2.1 
Analysis 
Treatment groups will be compared based on the time from the end of surgery to time to 
actual discharge from the hospital in the same way as described in section 9.1.1. A 
Kaplan-Meier curve will be provided by treatment group to make the comparison.  
9.3.3 
Proportion of Patients with Prolonged Hospital Stay due to GI 
Dysfunction 
The proportion of patients with prolonged hospital stay due to GI dysfunction for each 
treatment group will be calculated.  
9.3.3.1 
Analysis 
The proportion will be analyzed in the same way as described in section 9.2.2.1. 
9.3.4 
Time from Initial Insertion of the Nasogastric Tube to Removal of 
the Nasogastric Tube 
The time from initial insertion of the nasogastric tube to removal will be calculated 
between these two time points for each patient, expressed in hours with two decimals. It 
will be summarized by treatment group. 
9.3.4.1 
Analysis 
Summary statistics will be provided by treatment group. A pairwise comparison as 
ANCOVA adjusted by surgical procedure will be performed. Kaplan-Meier curves by 
treatment group for time to removal of the nasogastric tube from initial insertion will be 
provided. 


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9.3.5 
Proportion of Patients with Abdominal Distension on Day 1 
through the Day on which GI2 is Achieved 
Abdominal distension will be as reported as an adverse event. The following proportions 
in the mITT Population will be calculated.  
(1) The proportion of patients who achieved GI2 after Day 1  
a) And who had abdominal distension on Day 1 through the day on which GI2 is 
achieved 
b) And who had abdominal distension other than the time window above in a) 
from first dose to Day 10 or withdrawal or discharge day. 
c) And who did not have abdominal distension 
(2) The proportion of patients who did not achieve GI2 after Day 1  
a) And who had abdominal distension from first dose to Day 10 or withdrawal or 
discharge day 
b) And who did not have abdominal distension  
9.3.5.1 
Analysis 
Pairwise comparison as Cochran Mantel Haenszel test adjusted by surgical procedure 
will be applied to the proportion of patients who achieved GI2 after Day 1 and had 
abdominal distension on Day 1 through the day on which GI2 is achieved defined in (1) – 
a) of section 9.3.5. 
9.3.6 
Proportion of Patients with Nausea on Day 4 through Day of 
Discharge 
Nausea will be as reported as an adverse event. The following proportions will be 
calculated.  
(1) Proportion of patients who completed the study up to at least Day 4 with nausea 
occurring at least once between Day 4 and discharge  
(2) Proportion of patients who completed the study up to at least Day 4 without 
nausea occurring at any time between Day 4 and discharge  
(3) Proportion of patients who were discharged prior to Day 4  
9.3.6.1 
Analysis 
Pairwise comparison as Cochran Mantel Haenszel test adjusted by surgical procedure 
will be applied to the proportion of patients who completed the study up to at least Day 4 
with nausea occurring at least once between Day 4 and discharge defined in (1) of  
section 9.3.5. 
9.3.7 
Proportion of Patients with Vomiting on Day 4 through Day of 
Discharge 
Vomiting will be as reported as an adverse event. The proportions described in  
section 9.3.6 will be calculated for vomiting. 


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9.3.7.1 
Analysis 
The proportion will be analyzed in the same way as described in section 9.3.5.1. 
9.3.8 
Proportion of Patients who Achieve GI2 in Each Treatment Group 
by Postoperative Day 
The proportion of patients who achieved GI2 by study day will be calculated by treatment 
group. The denominator will be the number of patients who stayed in the study by each 
study day. 
9.3.8.1 
Analysis 
The proportion will be analyzed at each postoperative day in the same way as described 
in section 9.2.2.1. 
9.3.9 
Proportion of Patients who Receive Concomitant Medication that 
May Have a Laxative Effect 
The proportion of patients who received concomitant medication during study drug 
exposure that may have a laxative effect will be calculated. Concomitant medication with 
a laxative effect can be bisacodyl, macrogol and docusate sodium, but is not limited to 
these. They will be identified and finalized by the Shionogi Medical Monitor prior to 
database lock and unblinding.   
9.3.9.1 
Analysis 
The proportion will be analyzed in the same way as described in section 9.2.2.1. 
9.3.10 
Effect of Prior Surgery on the GI2 Endpoint 
The proportion of patients who achieved of GI2 until 240 hours (yes/no) by prior surgery 
(no prior surgery, 1 prior surgery or 2 prior surgery) will be calculated. Prior surgeries 
can be any abdominal surgery except: gastrectomy, gastric bypass, gastric sleeve, lap 
banding, pancreatic resection, hepatectomy, intestinal transplant.  Prior surgeries will be 
identified and finalized by the Shionogi Medical Monitor prior to database lock and 
unblinding.  
9.3.10.1 
Analysis 
Pairwise comparison as Cochran Mantel Haenszel test adjusted by prior surgery will be 
applied to the proportion. 
10. 
SAFETY 
All safety analyses will be performed for the Safety Analysis Population. 
10.1 Adverse Events 
Adverse events (AEs) will be coded and classified by System Organ Class (SOC) and PT 
using MedDRA Version 23.0. Unless otherwise specified, analyses will be based on 


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treatment-emergent adverse events (TEAEs), which is any AE reported after the first 
dose of the study drug.  
The number and proportion of patients who experienced at least 1 TEAE will be 
summarized by treatment group. The proportions will be presented along with the 
95%Cis, calculated with the Clopper-Pearson method. The number of TEAEs reported 
will also be calculated. TEAEs with an outcome of death, other serious treatment-
emergent adverse events (STEAEs), severe TEAEs, TEAEs leading to discontinuation of 
the study drug, treatment-related TEAEs, treatment-related TEAEs with an outcome of 
death, other treatment-related STEAEs, severe treatment-related TEAEs, and 
treatment-related TEAEs leading to discontinuation of the study drug will be summarized 
in the same manner. The definitions of these events are shown in Table 3. 
Table 3 
Definition of Adverse Event Terms 
Term 
Definition 
TEAE with an outcome of death 
TEAE with “Fatal” in terms of outcome 
Other STEAE 
TEAE with “Serious” in terms of seriousness excluding 
TEAE with an outcome of death 
TEAE leading to discontinuation of the 
study drug 
TEAE with “Drug withdrawn” in terms of the action 
taken for study drug 
Severe TEAE 
TEAE with “Severe” in terms of severity 
Treatment-related TEAE 
TEAE with “Related” in terms of the causal relationship 
with study drug 
Treatment-related TEAE with an 
outcome of death 
Treatment-related TEAE with “Fatal” in terms of 
outcome 
Other treatment-related STEAE 
Treatment-related TEAE with “Serious” in terms of 
seriousness excluding treatment-related TEAE with an 
outcome of death 
Severe treatment-related TEAE 
Treatment-related TEAE with “Severe” in terms of 
severity 
Treatment-related TEAE leading to 
discontinuation of the study drug 
Treatment-related TEAE with “Drug withdrawn” in terms 
of the action taken for study drug 
STEAE = serious treatment-emergent adverse event; TEAE = treatment-emergent adverse event. 
The number and proportion of patients who experience TEAEs will be summarized by 
SOC and PT for each treatment group. For these summaries, patients with multiple 
TEAEs will be counted only once within an SOC and PT. TEAEs with an outcome of 
death, other STEAE, TEAEs leading to discontinuation of the study drug, 
treatment-related TEAEs, treatment-related TEAEs with an outcome of death, and other 
treatment-related STEAEs will be summarized in the same manner. 
TEAEs relating to opioid withdrawal defined in Table 4 will also be summarized. 
The proportion of specific TEAEs relating to gastrointestinal disorders and opioid 
withdrawal defined in Table 4 and all TEAEs by severity will be plotted. 


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Table 4 
Definition of Specific TEAE 
Specific TEAE 
Definition 
Gastrointestinal 
disorders   
All Preferred Terms under Gastrointestinal Disorders (SOC) 
Opioid withdrawal 
All Preferred Terms (Cholinergic rebound syndrome, Delusion of 
parasitosis,  Drug rehabilitation, Drug withdrawal convulsions, Drug 
withdrawal headache, Drug withdrawal maintenance therapy, Drug 
withdrawal syndrome, Drug withdrawal syndrome neonatal, Rebound effect, 
Steroid withdrawal syndrome, Withdrawal arrhythmia, Withdrawal 
catatonia, Withdrawal syndrome) under Drug withdrawal (MedDRA SMQ) 
 
The number and proportion of patients who experience TEAEs in each category of 
severity will be summarized by SOC and PT for each treatment group. Patients who 
experience the same TEAE more than once in different categories will be counted only 
once by the worst severity. Treatment-related TEAEs will be summarized in the same 
manner. 
10.2 Vital Signs 
Summary statistics for vital signs (systolic blood pressure [SBP] and diastolic blood 
pressure [DBP] and pulse rate) will be calculated for each time point and for the change 
from baseline to each time point measured after randomization.  Clinical significance will 
be defined as follows. 
• SBP value >= 160 or Increase (INC) >= 20 
• SBP value <= 90 or Decrease (DEC) >= 20   
• DBP value >= 105 or INC >= 15 
• DBP value <= 50 or DEC >= 15  
• Pulse rate value >= 120 or INC >= 15 
• Pulse rate value <= 50 or DEC >= 15 
10.3 Laboratory Evaluations 
Summary statistics for laboratory test data will be calculated for each time point and for 
the change from baseline to each time point measured after randomization. Categorical 
parameters at each scheduled time point measured at baseline and after randomization 
will be summarized by using the frequency count and the percentage of patients in each 
category. Shift tables from baseline to the observed value in each time point will be 
presented for categorical parameters. 
The number and proportion of patients who meet the prespecified criteria shown in  
Table 5 will be summarized by treatment group for each time point. Patients with 
laboratory abnormalities at least once throughout the study (including measurements 
collected outside of the analysis visit window) will be summarized in the same manner. 


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Table 5 
Criteria for Laboratory Tests 
Laboratory Test (Unit) 
Criteria 
ALT (U/L) 
Value > 3 × ULN 
 
Value > 8 × ULN 
AST (U/L) 
Value > 3 × ULN 
 
Value > 8 × ULN 
AST (U/L) or ALT (U/L) 
Value > 3 × ULN 
 
Value > 5 × ULN 
 
Value > 8 × ULN 
AST (U/L) or ALT (U/L) 
+ total bilirubin (mg/dL) or PT-INR 
Meet all of the following criteria: 
• 
AST ≥ 3 × ULN or ALT ≥ 3 × ULN  
• 
Total bilirubin value ≥ 2 × ULN or PT-INR>1.5 
AST (U/L) or ALT (U/L) 
+ other conditions 
Meet all of the following criteria: 
• 
AST ≥ 3 × ULN or ALT ≥ 3 × ULN  
• 
accompanied by fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%) 
Total bilirubin 
Value > 2 × ULN 
PT-INR 
Value > 1.5 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; 
PT = prothrombin time; ULN = upper limit of normal 
10.4 Electrocardiograms 
Electrocardiogram findings (normal, abnormal – not clinically significant, abnormal – 
clinically significant) will be summarized for each time point measured after 
randomization by treatment group. 
10.5 Physical Examinations 
Summary of the overall assessment by time point will be presented as categories (normal, 
abnormal – clinically significant, abnormal -  not clinically significant,  not done). The 
same summary by body system (autoimmune, cardiovascular, dermatological, 
ears/nose/throat, endocrine/metabolic, gastrointestinal, genito-urinary, 
hematologic/lymphatic, hepatic, immunological, musculoskeletal, neurological, 
ophthalmological, psychological, respiratory) will be presented. 
10.6 Pain Intensity as Assessed on Numerical Pain Rating Scale 
Values will be summarized using statistics for continuous variables for all available days. 
In addition, from Day 2 onwards the change from baseline will be summarized using 
statistics for continuous variables. 
 


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10.7 Clinical Opiate Withdrawal Scale 
Total scores across all domains will be summarized using statistics for continuous 
variables on each day. The proportion of patients in each score category by domain will 
be calculated.  
10.8 Opioid analgesics 
Morphine milligram equivalent (MME) (mg) will be calculated as (dose of opioid 
analgesics) x (conversion factor). The conversion factor by opioid type is shown in  
Table 6 below; the table will be updated prior to database lock if additional opioid types 
need to be added.  
MMEs will be summarized as continuous variables on each day.  
Table 6 
Conversion Factor 
Opioid Type (Route) 
Unit 
Conversion 
Factor 
LEVOMETHADONE 
mg 
8 
LEVORPHANOL 
mg 
7.5 
HYDROMORPHONE 
mg 
4 
METHADONE 
mg 
4 
OXYMORPHONE 
mg 
3 
FENTANYL (Topical or Transdermal) 
ug/hour 
2.4 
OXYCODONE 
mg 
1.5 
HYDROCODONE 
mg 
1 
MORPHINE 
mg 
1 
CODEINE 
mg 
0.15 
DIHYDROCODEINE 
mg 
0.15 
FENTANYL (Intravenous, Sublingual or Transmucosal) ug 
0.1 
MEPERIDINE 
mg 
0.1 
BUTORPHANOL 
mg 
0 
PENTAZOCINE 
mg 
0 
TAPENTADOL 
mg 
0 
TRAMADOL 
mg 
0 
BUPRENORPHINE 
mg 
0 
SUFENTANIL 
mg 
0 
 
10.9 Analysis for ClinTrial.gov 
This section specifies the safety analyses only for ClinTrial.gov, and the summary will 
not be included in the clinical study report.  


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The number and proportion of patients who experience TEAEs excluding treatment-
related TEAE with an outcome of death and other STEAEs by SOC and PT will be 
summarized. 
11. 
Pharmacokinetics 
11.1 Plasma Drug Concentrations of Naldemedine and Nor-
naldemedine  
Plasma drug concentrations of naldemedine and nor-naldemedine will be listed for the 
PK-C Population and summarized for the PK-P Population by actual treatment group, 
and nominal sampling time with the number of nonmissing observations (N), arithmetic 
mean (mean), standard deviation (SD) and coefficient of variation (CV%, calculated by 
SD/mean × 100), geometric mean and coefficient of variation for geometric mean 
(Geometric CV%), and median, minimum and maximum values at each sampling time 
presented. The Geometric CV% will be calculated as follows: Geometric CV% = [exp 
(sd2)-1]1/2 × 100, where SD is the standard deviation for natural log (ln)-transformed data. 
The time course profiles for plasma drug and metabolite concentrations will be presented 
graphically.  
For the summary of plasma drug and metabolite concentrations, concentrations below the 
limit of quantification (BLQ) will be treated as zero (0) for calculations of the mean, SD, 
CV%, and median, minimum, maximum values and will be treated as missing for 
calculation of the geometric mean and geometric CV% values. 
Data will be summarized by nominal sampling time, using the following times: 
• Day 2 immediately before the morning dose 
• Day 3 immediately before the morning dose and 1 hour and 2, 4, 8, and 12 hours 
after the morning dose before administration of the evening dose 
• Day 4 immediately before the morning dose 
11.2 PK Parameters for Naldemedine and Nor-naldemedine on Day 3 
The PK parameters will be estimated using the PK-P Population. The following PK 
parameters will be calculated, whenever possible, for naldemedine and nor-naldemedine 
from plasma concentration data on Day 3 (immediately before the morning dose and 1 
hour and 2, 4, 8, and 12 hours after the morning dose before administration of the 
evening dose) by noncompartmental methods. Other parameters may be computed, as 
appropriate, upon review of the data. The following estimated PK parameters will be 
computed for each study patient using the actual sample collection times:  
• Cmax – maximum observed plasma concentration on Day 3 
• Tmax – time to maximum plasma concentration on Day 3. If Tmax is the actual time 
for the predose (0 hours) on Day 3, Tmax will be calculated as 0. 
• AUC0-τ – area under the concentration- time curve over the dosing interval τ (12 
hours) on Day 3; calculated by linear up/log down trapezoidal method. AUC0-τ will 


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be calculated with observed plasma concentrations from time 0 to τ (actual time) 
on Day 3 without extrapolation or interpolation. The actual time for the predose (0 
hours) on Day 3 will be replaced with 0. If the observed plasma concentration at τ 
on Day 3 is BLQ, the area under the plasma concentration-time curve from time 
zero to the time of the last quantifiable concentration after dosing (AUC0-last) will 
be used as AUC0-τ. 
• CL/F – apparent total clearance estimated as CL/F = dose/AUC0-τ on Day 3 (for 
naldemedine only) 
• MRM/U, Cmax – metabolic ratio of Cmax of nor-naldemedine to Cmax of naldemedine, 
corrected for molecular weight, defined as: 
o 
𝐶𝑚𝑎𝑥 of nor−naldemedine 
𝐶𝑚𝑎𝑥 of naldemedine
∗ 570.64
516.55 
(for nor-naldemedine only) 
• MRM/U, AUC – metabolic ratio of AUC0-τ of nor-naldemedine to AUC0-τ of 
naldemedine, corrected for molecular weight, defined as: 
o 
𝐴𝑈𝐶0−τ of nor−naldemedine 
𝐴𝑈𝐶0−τ of naldemedine
∗ 570.64
516.55 
(for nor-naldemedine only) 
The estimated PK parameters except for Tmax will be summarized by actual treatment 
group with N, mean, SD, CV%, geometric mean, geometric CV%, median, minimum and 
maximum values. The Tmax will be summarized by analyte and dosing regimen with N, 
mean, SD, CV%, median, minimum and maximum values. If the number of patients with 
PK parameter data is < 3, the data will not be summarized. 
Individual plasma concentrations, if deemed to be anomalous, may be excluded from the 
analysis at the discretion of the PK study director. Any such exclusion will be disclosed 
in the study report along with the justification for exclusion. 
For the calculations of PK parameters, BLQ before the occurrence of the first quantifiable 
concentration on Day 3 will be treated as zero, and BLQ after the first occurrence of the 
quantifiable concentration on Day 3 will be treated as missing. 
Pharmacokinetic calculations will be performed by using WinNonlin Version 6.2.1 or 
higher. 
12. 
INTERIM ANALYSES 
A Data Monitoring Committee (DMC) will review all data when assessing the benefit 
versus risk of the ongoing results. Since such a review may include efficacy data, an 
alpha spending function will be included in the DMC charter that allows for a small 
spend of alpha that will not impact on final alpha assessment level (eg, an alpha spend of 
0.0001 based on Haybittle–Peto could be used to control alpha for each interim analysis). 
The DMC charter will specify the spending function to be used. 


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In addition, depending on the enrollment rate, an interim analysis of efficacy may be 
feasible.  Based on the operational feasibility of such an interim analysis, the interim 
analysis could include a non-binding futility assessment.  For example, should the 
enrollment project that 85 patients per group is achievable and an interim analysis based 
on 44 patients per group can be conducted in a timely and worthwhile fashion prior to the 
last patient enrolled, then the DMC will review the interim analysis results. Details for 
interim analyses, including futility, will be provided in the DMC Charter, and/or an 
accompanying DMC Statistical Analysis Plan. 
13. 
PROGRAMMING CONVENTIONS 
13.1 Formatting and Programming Rule 
Unless otherwise noted, the following conventions should be used when constructing the 
TFLs: 
● Every summary table and figure will clearly specify the analysis population being 
summarized. Listings will be prepared for all patients randomized. 
● Rounding for all variables will occur only as the last step, immediately prior to 
presentation in TFLs. No intermediate rounding will be performed on derived 
variables. The standard rounding practice of rounding numbers ending in 0-4 
down and numbers ending in 5-9 up will be employed. 
● The presentation of numerical values will adhere to the following guidelines: 
- 
Raw measurements will be reported to the number of significant digits as 
captured electronically or on the CRFs. 
- 
Means, SDs, minimums, medians, and maximums will be reported to 1 
decimal place beyond the number of decimal places with which the original 
endpoint is presented. 
- 
Calculated percentages will be reported to 1 decimal place. 
- 
Calculated hours will be presented to 2 decimal places.  
● All means presented will be arithmetic unless otherwise stated.  
● For PK concentrations and PK parameters, 
- 
Arithmetic mean, geometric mean, median, minimum, and maximum will be 
presented to the same precision as raw data 
- 
Standard deviation will be presented to the same precision as the arithmetic 
mean 
- 
Coefficient of variation (%) and coefficient of variation (%) for geometric 
mean will be presented with one decimal place. 
- 
Individual actual date and time of study treatment dosing, meal prior to 
dosing, and PK sampling will be reported with the same format as the source 
data. 
- 
Individual actual time (i.e., the difference between dosing and PK sampling 
time) for PK analysis will be reported with two decimal places.   


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- 
Individual concentrations will be reported with the same precision as the 
source data. 
- 
Individual PK parameters Cmax will be reported with the same precision as the 
source data. 
- 
Individual PK parameters Tmax will be reported with two decimal places 
- 
Individual PK parameters AUC0-τ will be reported with four significant digits. 
- 
Individual PK parameters CL/F will be presented to three significant digits. 
- 
Individual PK parameters MRM/U, Cmax and MRM/U, AUC will be presented with 
three decimal places. 
● Table 7 shows the category displayed in analysis and summary. 
Table 7 
Category 
Data 
Category 
Age 
18<= x < 65, 65 < x < 74, 75<=x<=80 
Sex 
Male, Female 
Surgical procedure 
Small bowel resection with primary anastomosis, large 
bowel resection with primary anastomosis, or radical 
cystectomy requiring bowel transection with primary 
anastomosis 
Fertility status for females 
Surgically sterile, post-menopausal, potentially able to 
bear children 
Race 
American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or Other Pacific 
Islander, White, Other, Not provided 
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino, Unknown, 
Not provided 
Elements of the enhanced recovery 
protocol 
(required) Early removal of the nasogastric tube defined 
as removal of the nasogastric tube at the end of surgery, 
early ambulation defined as ambulation on Day 1, early 
diet advancement on Day 1 
(non-required) Antibiotic prophylaxis, preoperative 
carbohydrate drink, epidural anesthesia in addition to 
general anesthesia, chewing gum postoperatively 
Elements of the enhanced recovery 
protocol (binary) 
All non-required (defined as all of 4 non-mandated ERP 
elements), not all non-required (defined as otherwise all 
non-required) 
Epidural anesthesia 
Yes (defined as Yes in epidural anesthesia in addition to 
general anesthesia in ERP), No (defined as No in epidural 
anesthesia in addition to general anesthesia in ERP) 
Prior surgery 
No prior surgery, 1 prior surgery and 2 prior surgeries 
Treatment compliance 
x <80%, 80% <= x <=100%, 100% < x 
 


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13.2 Sample SAS Code 
When dataset A has time of GI2 and censored information, there are mainly 3 steps to 
calculate RMST.  
(1) GI2 after 240 hours should be censored before calculating RMST until 240 hours. 
DATA B; 
 SET A; 
 
IF (hour > 240) then status=0; 
RUN; 
(2) The program below will provide 𝜇̂𝑘𝑔(𝑡) in the dataset C0. The number of GI2 
(saved in a variable ‘Failed’) will be given in the dataset C1, where hour is GI2 
time, status=0 if censored, 1 if not censored, surgery is surgery procedure, 
treatment is treatment group. 
ODS OUTPUT MEANS=C0 CENSOREDSUMMARY=C1; 
PROC LIFETEST DATA=B TIMELIM=240; 
  
BY surgery;  
TIME hour*status (0); 
TEST treatment; 
RUN;  
(3) Standard deviation of each RMST √𝑉𝑎𝑟[𝜇̂𝑘𝑔(𝑡)] will be given as ‘sd’. The test 
statistics T and S defined in section 9.1.1 will be calculated by these estimates of 
RMST and SDs. 
DATA D; 
 
MERGE C0(IN = A) C1; 
 
BY treatment surgery; 
 sd = StdErr *SQRT((Failed – 1)/Failed); 
 
IF A; 
RUN; 
 
14. 
REFERENCES 
1. Hasegawa, T., et al. (2020) Restricted mean survival time as a summary measure of 
time-to-event outcome, Pharmaceutical Statistics, 1-18.