Conditions: Chronic Idiopathic Constipation
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 156
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of oral administration of lubiprostone 24 μg twice daily (BID) for 4 weeks in participants with chronic idiopathic constipation (CIC) compared with placebo.

Detailed description:
The drug being tested in this study is called lubiprostone. Lubiprostone is being tested to treat people who have chronic idiopathic constipation. This study will look at the frequency of spontaneous bowel movements (SBMs) in people who take lubiprostone compared to placebo.

The study will enroll 150 participants. Participants will be randomly assigned (by chance, like flipping a coin) equally to one of the two treatment groups, which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Lubiprostone 24 μg
* Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient

All participants will be asked to take one capsule with breakfast and one capsule with dinner each day throughout the study. All participants will be asked to record each time they have a SBM and all details of each SBM (including the consistency of the stool and the difficulty they have in passing it) in a diary.

This multi-center trial will be conducted in South Korea. The overall time to participate in this study is 8 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Arms:
arm 1: Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks. arm 2: Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.

Interventions: intervention 1: Placebo intervention 2: Lubiprostone
Intervention descriptions: intervention 1: Lubiprostone placebo-matching capsules intervention 2: Lubiprostone capsules

Protocol document:
Prot_000.pdf: 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of Lubiprostone for the Treatment of Chronic 
Idiopathic Constipation 
Lubiprostone for the Treatment of Chronic Idiopathic Constipation
Sponsor:
Takeda Development Center Asia, Pte. Ltd.
21 Biopolis Road
Nucleos North Tower, Level 4
Singapore 138567
Study Number:
Lubiprostone -3002
IND Number:
Not applicable
EudraCT Number:
Not applicable
Compound:
Lubiprostone
Date:
14 May 2015
Amendment Number:
Not applicable
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Takeda Development Center (TDC) sponsored investigators per individual country requirements 
will be provided with emergency medical contact information cards to be carried by each 
subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Asia Pacific Contact
Serious adverse event and pregnancy reporting
Contracted CRO contact 
(Refer to the Study Team Contact list)
Cc both TDC Europe and TDC Asia
TDC Europe:
TDC Asia: 
Medical Monitor
(medical advice on protocol and compound)
Contracted CRO contact
(Refer to the Study Team Contact list)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the 
study)
 
Takeda Development Centre Europe Ltd
61 Aldwych
London, WC2B 4AE
United Kingdom 
Email: 
Office: 


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer and other signatories, as applicable can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
 
Science
Date
 
Statistician
Date
, 
, GI TAU
Date


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CONFIDENTIAL
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
package insert and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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CONFIDENTIAL
TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................10
3.0
STUDY REFERENCE INFORMATION ......................................................................12
3.1
Study-Related Responsibilities.................................................................................12
3.2
Principal Investigator/ Coordinating Investigator .....................................................12
3.3
List of Abbreviations ...............................................................................................13
3.4
Corporate Identification...........................................................................................14
4.0
INTRODUCTION.........................................................................................................15
4.1
Background .............................................................................................................15
4.1.1
Unmet Need—Burden of Disease................................................................15
4.1.2
Product Name and Chemical Name.............................................................15
4.1.3
Summary of Nonclinical Data .....................................................................15
4.1.3.1
Pharmacology.........................................................................................15
4.1.3.2
Pharmacokinetics....................................................................................16
4.1.3.3
Safety Pharmacology, General Pharmacology, and Toxicity...................16
4.1.4
Summary of Clinical Data...........................................................................16
4.2
Rationale for the Proposed Study.............................................................................18
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................19
5.1
Objectives................................................................................................................19
5.2
Endpoints.................................................................................................................19
5.2.1
Primary Endpoints.......................................................................................19
5.2.1.1
Efficacy..................................................................................................19
5.2.2
Secondary Endpoints...................................................................................19
5.2.2.1
Efficacy..................................................................................................19
5.2.3
Additional Endpoints ..................................................................................19
5.2.3.1
Efficacy..................................................................................................19
5.2.3.2
Safety.....................................................................................................19
5.2.4
Exploratory.................................................................................................20
5.2.4.1
Sensation of Incomplete Evacuation .......................................................20
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................21
6.1
Study Design ...........................................................................................................21


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6.2
Justification for Study Design, Dose, and Endpoints ................................................22
6.3
Premature Termination or Suspension of Study or Investigational Site.....................24
6.3.1
Criteria for Premature Termination or Suspension of the Study...................24
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites ..24
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s).........................................................25
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............26
7.1
Inclusion Criteria .....................................................................................................26
7.2
Exclusion Criteria ....................................................................................................26
7.3
Excluded Medications and Procedures.....................................................................28
7.3.1
Excluded Medications.................................................................................28
7.3.2
Drugs Permitted with Condition..................................................................29
7.3.2.1
Exceptions to Excluded Medications ......................................................29
7.3.3
Excluded Procedures...................................................................................30
7.4
Diet, Fluid, Activity Control ....................................................................................30
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................30
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................32
7.7
Procedure for Reduction of Study Drug Dose Due to Adverse Events......................32
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................33
8.1
Study Medication and Materials...............................................................................33
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................33
8.1.1.1
Investigational drug................................................................................33
8.1.1.2
Rescue Medication .................................................................................33
8.1.2
Storage........................................................................................................33
8.1.3
Dose and Regimen ......................................................................................34
8.1.4
Overdose.....................................................................................................34
8.2
Investigational drug Assignment and Dispensing Procedures...................................34
8.3
Randomization Code Creation and Storage..............................................................35
8.4
Investigational Drug Blind Maintenance ..................................................................35
8.5
Unblinding Procedure..............................................................................................35
8.6
Accountability and Destruction of sponsor-Supplied Drugs .....................................35
9.0
STUDY PLAN ..............................................................................................................38
9.1
Study Procedures.....................................................................................................38
9.1.1
Informed Consent Procedure.......................................................................38
9.1.2
Demographics, Medical History, and Medication History Procedure...........38


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9.1.3
Physical Examination Procedure .................................................................38
9.1.4
Weight, Height............................................................................................38
9.1.5
Vital Sign Procedure ...................................................................................39
9.1.6
Primary Efficacy Endpoint..........................................................................39
9.1.7
Secondary Efficacy Endpoints.....................................................................39
9.1.7.1
SBM Frequency at Weeks 2, 3 and 4 ......................................................39
9.1.7.2
Proportion of Subjects Who Have a SBM Within 24 Hours After First 
Dose.......................................................................................................39
9.1.7.3
Degree of Straining.................................................................................39
9.1.7.4
Stool Consistency...................................................................................39
9.1.7.5
Assessments of Abdominal Symptoms ...................................................39
9.1.7.6
Weekly Responder Rate .........................................................................39
9.1.8
Additional Endpoints ..................................................................................40
9.1.8.1
Quality of Life Evaluation ......................................................................40
9.1.8.2
Safety Endpoints ....................................................................................40
9.1.9
Exploratory Endpoint..................................................................................40
9.1.9.1
Sensation of Incomplete Evacuation .......................................................40
9.1.10
Documentation of Concomitant Medications...............................................40
9.1.11
Documentation of Concurrent Medical Conditions......................................40
9.1.12
Procedures for Clinical Laboratory Samples................................................41
9.1.13
Contraception and Pregnancy Avoidance Procedure....................................43
9.1.14
Pregnancy ...................................................................................................44
9.1.15
Documentation of Screen Failure ................................................................45
9.1.16
Documentation of Randomization ...............................................................45
9.1.17
Subject Diary ..............................................................................................45
9.2
Monitoring Subject Treatment Compliance..............................................................46
9.3
Schedule of Observations and Procedures................................................................46
9.3.1
Screening Period.........................................................................................46
9.3.2
Study Entrance/Randomization ...................................................................47
9.3.3
Double-Blind Treatment Period...................................................................48
9.3.4
Final Visit or Early Termination Visit .........................................................49
9.3.5
Follow-up Period ........................................................................................49
9.3.6
Post Study Care...........................................................................................50
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................51
10.1
Definitions...............................................................................................................51


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10.1.1
PTEs...........................................................................................................51
10.1.2
AEs.............................................................................................................51
10.1.3
Additional Points to Consider for PTEs and AEs.........................................51
10.1.4
SAEs...........................................................................................................53
10.1.5
Severity of PTEs and AEs ...........................................................................54
10.1.6
Causality of AEs .........................................................................................54
10.1.7
Relationship to Study Procedures................................................................54
10.1.8
Start Date....................................................................................................55
10.1.9
Stop Date ....................................................................................................55
10.1.10
Frequency ...................................................................................................55
10.1.11
Action Concerning Study Medication..........................................................55
10.1.12
Outcome .....................................................................................................55
10.2
Procedures...............................................................................................................56
10.2.1
Collection and Reporting of AEs.................................................................56
10.2.1.1
PTE and AE Collection Period ...............................................................56
10.2.1.2
PTE and AE Reporting ...........................................................................56
10.2.2
Collection and Reporting of SAEs...............................................................57
10.2.3
Reporting of Abnormal Liver Function Tests ..............................................57
10.3
Follow-up of SAEs ..................................................................................................58
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................58
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................59
12.0
DATA HANDLING AND RECORDKEEPING............................................................60
12.1
CRFs (Electronic)....................................................................................................60
12.2
Record Retention .....................................................................................................60
13.0
STATISTICAL METHODS..........................................................................................62
13.1
Statistical Analysis Plan...........................................................................................62
13.1.1
Analysis Sets...............................................................................................62
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................63
13.1.3
Efficacy Analysis........................................................................................64
13.1.3.1
Primary Endpoint ...................................................................................64
13.1.3.2
Secondary Endpoints..............................................................................65
13.1.3.3
Additional Endpoints..............................................................................66
13.1.3.4
Exploratory Endpoint .............................................................................67
13.2
Interim Analysis and Criteria for Early Termination ................................................67


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13.3
Determination of Sample Size..................................................................................67
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................68
14.1
Study-Site Monitoring Visits ...................................................................................68
14.2
Protocol Deviations..................................................................................................68
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................68
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................70
15.1
IRB and/or IEC Approval ........................................................................................70
15.2
Subject Information, Informed Consent, and Subject Authorization .........................71
15.3
Subject Confidentiality ............................................................................................72
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................72
15.4.1
Publication and Disclosure..........................................................................72
15.4.2
Clinical Trial Registration...........................................................................73
15.4.3
Clinical Trial Results Disclosure .................................................................73
15.5
Insurance and Compensation for Injury....................................................................73
16.0
REFERENCES..............................................................................................................74
LIST OF IN-TEXT TABLES
Table 4.a
Summary of Efficacy of Lubiprostone 24 µg BID in Phase 3 Studies .................18
Table 6.a
Rome III Diagnostic Criteria for Functional Constipation...................................23
Table 8.a
Dose and Regimen .............................................................................................34
Table 9.a
Clinical Laboratory Tests...................................................................................42
Table 9.b
Acceptable Methods of Contraception................................................................44
Table 10.a
Takeda Medically Significant AE List................................................................54
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................22
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................75
Appendix B
Responsibilities of the Investigator.....................................................................77
Appendix C
Elements of the Subject Informed Consent.........................................................79
Appendix D
Investigator Consent to Use of Personal Information..........................................82
Appendix E
Sample of Subject Diary and The Bristol Stool Scale .........................................83


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Asia, Pte. Ltd.
Compound:
Lubiprostone
Title of Protocol: A Phase 3, Multicenter, Randomized, 
Double-Blind, Parallel-Group, Placebo-Controlled Study 
to Evaluate the Efficacy and Safety of Lubiprostone for the 
Treatment of Chronic Idiopathic Constipation.
IND No.: 
Not Applicable 
EudraCT No.: 
Not applicable
Study Number: Lubiprostone - 3002
Phase: 3
Study Design:
This is a phase 3, parallel-group, comparison study with a 2-week Screening Period and subsequent 4-week 
(28 days) randomized, placebo-controlled, Double-Blind Treatment Period.
During the Screening Period, the defecation behavior of each subject will be recorded to confirm he/she has 
constipation. Use of all existing laxatives will be stopped at the beginning of the Screening Period (Visit 1). Subjects 
are instructed not to change their diet or lifestyle habits during the study. A total of 10 mg of bisacodyl suppository 
(or any equivalent drug) may be prescribed as a standard rescue medication if a subject has no adequate bowel 
movement for 3 consecutive days during the study. When bisacodyl suppository does not improve constipation, 
glycerin enema (or equivalent drug) may be given. Subjects are instructed to complete the diary before using these 
rescue medications.
If these rescue medications fail to improve constipation, the investigator may decide to use another rescue 
medication. No rescue medication may be given from 24 hours before and until 48 hours after the first dose of study 
drug (Day 1). Subjects who use a rescue medication within 24 hours before the first dose of study drug on Day 1 
should be withdrawn from the study. Those who use a rescue medication within 48 hours after dosing on Day 1 will 
be discontinued from the study by the investigator. The dose and mode of administration of rescue medications must 
be recorded in the electronic case report form (eCRF).
Subjects whose constipation is confirmed during the Screening Period are randomized in the Double-Blind 
Treatment Period. Others whose constipation does not satisfy the criteria during the 2 week Screening Period or 
those who receive a rescue medication within 24 hours prior to the first dose on Day 1,are ineligible for
randomization in the Double-Blind Treatment Period and will be excluded from the study. Subjects who satisfy the 
inclusion criteria and do not meet the exclusion criteria will be randomized to 1 of the treatment groups in the order 
of the number assigned. Approximately 150 subjects with chronic idiopathic constipation (CIC) will be randomized 
equally in a 1:1 manner into 2 groups (75 subjects each) in a double-blinded manner.
Primary Objectives:
The primary objective is to evaluate the efficacy and safety of oral administration of 24 μg of lubiprostone twice 
daily (BID) for 4 weeks in subjects with CIC compared with placebo.
Secondary Objectives:
None
Subject Population: Male and nonpregnant, nonlactating female subjects 19 years of age and older with CIC.
Number of Subjects:
Lubiprostone 24 μg group: Approximately 75 randomized
Placebo group: Approximately 75 randomized
Estimated total: Approximately 150 randomized
Number of Sites: 
Estimated total: Approximately 10 sites in Korea


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Dose Level(s):
24 μg lubiprostone capsule or matching placebo taken BID
Route of Administration:
Oral
Duration of Treatment:
BID for 4 weeks
Period of Evaluation:
Up to 56 days
Main Criteria for Inclusion:
Male and nonpregnant, nonlactating females aged 19 years or older who experience spontaneous bowel movement 
(SBM) frequency less than 3 times per week on average for the last 6 months or longer, including during the 
Screening Period. At the start of the Screening Period these subjects must also have been experiencing SBMs with 
≥1 of the following 3 symptoms for the last 6 months or longer, in at least 1 out of every 4 bowel movements: 
scybalum stool or hard feces, straining, or the sensation of incomplete evacuation.
Main Criteria for Exclusion:
Subjects who have known mechanical obstruction, whose constipation is attributable to drug use or to whom a 
prohibited concomitant medication is required to be administered during the study; subjects having chronic 
constipation due to a secondary cause; subjects in whom there is sufficient criteria for irritable bowel syndrome 
(IBS) or functional defecation disorder, subjects whose SBM frequency is 3 or more per week, subjects whose SBM 
frequency has been less than 3 times per week for less than 6 months in duration or symptoms associated with SBM 
have been present for less than 6 months, Subject who received treatment with a rescue medication within 24 hours 
prior to the first dose in the morning of Day 1: bisacodyl suppository, which is a standard laxative, glycerin enema, 
or any other rescue medication; subjects who have megacolon/megarectum or have received a diagnosis of intestinal 
pseudo-obstruction, have hypersensitivity to lubiprostone or any of its excipients, a significant history of 
cardiovascular, liver, lung, kidney, neurological, or mental disease (including existing alcohol or drug abuse 
problem) or a systemic disease, or any significant clinical findings or clinical laboratory results as deemed by the 
investigator. Subjects with confirmed or suspected organic disorders of the large intestine (obstruction, stenosis, 
carcinoma, or inflammatory bowel disease), a polyp confirmed by total colonoscopy and requiring treatment, 
subjects who have been hospitalized for gastrointestinal or abdominal surgery within 3 months prior to screening. 
Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is SBM frequency in Week 1 of administration. Secondary endpoints for this 
study are SBM frequency (Weeks 2, 3, and 4), proportion of subjects who have a SBM within 24 hours after first 
dose, degree of straining (Weeks 1, 2, 3, and 4), stool consistency (Weeks 1, 2, 3, and 4), abdominal symptoms
(bloating and discomfort) (Weeks 1, 2, 3, and 4), and weekly responder rate (Weeks 1, 2, 3, and 4).
Statistical Considerations:
The primary efficacy variable will be analyzed using the van Elteren test stratified by pooled center. Secondary 
endpoints will also be analyzed by the van Elteren test (for ordinal data) or Cochran-Mantel-Haenszel (CMH) test 
(for binary data). Additionally logistic regression analyses will also be performed for binary and ordinal data. All 
analyses will account for pooled center either as a stratification factor or as a factor in the regression model.
Sample Size Justification: 
Assuming equal allocation, a power of 90%, an alpha level of 0.05 for a 2-sided test, a placebo mean of 4 (standard 
deviation of 2.7), and a treatment mean of 5.9 (standard deviation of 4) for SBM frequency at Week 1 and using the 
Wilcoxon-Mann-Whitney test, a total sample size of 146 is required. Assuming a drop-out rate of 3% by Day 4 a 
total of 150 subjects are needed.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/ Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate 
in the study. Selection criteria for this investigator will include significant knowledge of the 
study protocol, the study medication, their expertise in the therapeutic area and the conduct of 
clinical research as well as study participation. The Signatory Coordinating Investigator will be 
required to review and sign the clinical study report and by doing so agrees that it accurately 
describes the results of the study.


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3.3
List of Abbreviations 
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
BID
twice daily
BM
bowel movement
BPM
beats per minute
BUN
blood urea nitrogen
CIC
chronic idiopathic constipation
Cl-
chloride ions
ClC-2
chloride channel
CMH
Cochran-Mantel-Haenszel
CRO
contract research organization
CRP
C-reactive protein
ECG
electrocardiogram
eCRF
electronic case report form 
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
GMP
Good Manufacturing Practice
hCG
human chorionic gonadotropin
HDPE
high-density polyethylene 
IBS
irritable bowel syndrome
ICH
International Conference on Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
LDH
lactic dehydrogenase
LFT
liver function tests
LOCF
last observation carried forward
LS
least squares
MAO
monoamine oxidase inhibitor(s)
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume


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MedDRA
Medical Dictionary for Regulatory Activities
MED ID
medication identification
PAC-QOL
Patient Assessment of Constipation-Quality of Life Questionnaire
PED
pharmacologically effective dose
PK
pharmacokinetic
PP
per protocol
PT
preferred term
PTE
pretreatment event
QD
Once daily
RBC
red blood cell
RDW
red (cell) distribution width
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SBM
spontaneous bowel movement
SNRI
serotonin-norepinephrine reuptake inhibitor
SOC
system organ class
SOP
standard operating procedure
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TID
3 times daily
TMF
trial master file
TSH
thyroid stimulating hormone
UK
United Kingdom
ULN
upper limit of normal
US
United States
WBC
white blood cell
WHO
World Health Organization
3.4
Corporate Identification 
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte. Ltd.
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center, Inc. Americas
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
4.1.1
Unmet Need—Burden of Disease 
Constipation occurs when narrowing of the intestinal tract obstructs stool passage and intestinal 
propulsion decreases due to motion abnormality or defecation impairment occurs; it is 
pathologically classified into either idiopathic or secondary constipation, depending on the 
clinical condition of the patient. Most constipation can be associated with factors such as a diet 
low in soluble and insoluble fibers, inadequate exercise, medication use (in particular, opiate 
analgesics, anticholinergic antidepressants, antihistamines, and vinca alkaloids), bowel, 
neuromuscular, or metabolic disorders, or poor abdominal pressure or muscular atony. 
Constipation is considered idiopathic when its cause is unclear. Chronic idiopathic constipation 
(CIC) is defined by infrequent or difficult passage of stool and associated symptoms, such as 
abdominal bloating and discomfort, straining at defecation, and hard or lumpy stools. In CIC, 
these symptoms may be the result of abnormal colonic motility that can delay the transit of 
intestinal contents and impede the evacuation of rectal contents. One approach to the treatment 
of CIC is the stimulation of secretion of fluid into the abdominal lumen [1].
4.1.2
Product Name and Chemical Name
Lubiprostone is chemically designated as: (−)-7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-
hydroxy-6-xooctahydrocyclopenta[b]pyran-5-yl]heptanoic acid. It has been developed as a soft 
gelatin capsule containing 24 μg of liquid lubiprostone in a medium chain triglyceride for oral 
administration. Lubiprostone is a member of a class of compounds called prostones and directly 
activates the mammalian chloride channels, ClC-2, located in the apical membrane of the human 
intestinal epithelial cells. This activation causes an increase in chloride ions (Cl-) and subsequent 
secretion of intestinal fluid into the lumen without altering sodium and potassium concentrations 
in the serum. By increasing intestinal fluid secretion, lubiprostone facilitates the passage of stool 
and alleviates symptoms associated with CIC. Patch clamp cell studies in human cell lines have 
indicated that most of the beneficial biological activity of lubiprostone and its metabolites is 
observed only on the apical (luminal) portion of the gastrointestinal epithelium. Therefore, 
systemic absorption of lubiprostone and its only measurable active metabolite M3 is not required 
for pharmacological activity. Additionally, ClC-2 plays an important role in the restoration of the 
tight junction complexes and recovery of barrier function within the body [2]. Lubiprostone has 
been shown to stimulate the recovery of mucosal barrier function in ex vivo studies of the 
intestine and colon through the restoration of these tight junction complexes [3].
4.1.3
Summary of Nonclinical Data 
4.1.3.1
Pharmacology
In in-vitro studies, lubiprostone selectively activated ClC-2 chloride ion channels. In-vivo studies 
in a number of animal models have shown that oral lubiprostone accelerates water and 


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electrolyte secretion in the intestinal tract with no effect on serum electrolyte concentrations. 
These findings suggest that lubiprostone increases secretion of intestinal fluids and improves the 
movement of feces in the intestine by activating ClC-2 in intestinal epithelial cells and increasing 
chloride ion secretion in the gastrointestinal lumen.
4.1.3.2
Pharmacokinetics
The pharmacokinetics (PK) of lubiprostone were evaluated using radiolabeled lubiprostone 
(3H-lubiprostone) in rats, mice, rabbits, dogs, and monkeys. The maximum plasma radioactivity 
was observed at 0.25 to 2 hours after oral dosing of 3H-lubiprostone in rats, within 15 minutes in 
mice, 0.5 to 3 hours in dogs, and 4 to 5 hours in rabbits and monkeys. The half-life (t1/2) was 
about 2 to 3 hours in rats and mice, 2 to 13 hours in dogs, and about 9 hours in rabbits and 
monkeys. Very little unchanged lubiprostone was found in plasma of these animals, suggesting 
rapid metabolism of the drug after dose.
An evaluation of the effect of lubiprostone on enzyme induction and inhibition indicated that 
lubiprostone is unlikely to induce clinically significant drug interactions. On tissue distribution, 
tissue radioactivity concentration after dosing of 3H-lubiprostone was relatively high in the liver 
and gastrointestinal tract. Radioactivity in each tissue decreased over time, and was mostly 
below the detection limit at 48 hours after dosing. The amount of lubiprostone excreted in urine 
and feces was similar in rats. Urine was the main excretion route of the drug in mice, rabbits, 
dogs, and monkeys. The total excretion rate of the drug up to 48 hours after dosing was 73% to 
95% relative to the dose in these animals.
4.1.3.3
Safety Pharmacology, General Pharmacology, and Toxicity
A safety and general pharmacological study has shown little effect of lubiprostone on the central 
nervous, cardiovascular, or respiratory systems; its effect on the smooth muscle was observed 
only at higher doses. Single- and repeat-dose toxicity studies revealed no significant toxicity 
findings relevant to dosing in humans. A reproductive toxicity study also reported that toxicities 
occurred only at doses much higher than the pharmacologically effective dose (PED). 
Lubiprostone did not induce abortion and showed no carcinogenic effect in these studies.
4.1.4
Summary of Clinical Data 
Lubiprostone has been approved for use in patients with chronic idiopathic constipation since 
January 2006 and been marketed in the United States (US) under the trade name Amitiza since 
April 2006 for CIC, irritable bowel syndrome (IBS) with constipation and for opioid-induced 
constipation. Other approvals include: Japan, Switzerland, the United Kingdom, Ireland, 
Belgium, Luxembourg and the Netherlands. 
Lubiprostone has been administered to humans in at least 30 clinical studies. 
The pivotal phase 3 studies included 2 multicenter, double-blind, randomized, 
placebo-controlled, efficacy and safety studies (SC0131 and SC0232) for the treatment of 


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occasional constipation conducted in the US, and 1 placebo-controlled study (SC0831) in 
subjects with CIC conducted in Japan.
In SC0131 and SC0232, the efficacy and safety of a 24 μg twice daily (BID) dose of 
lubiprostone was compared with placebo. In both studies, following a 2-week Baseline/Washout 
Period, subjects received 4 weeks of double-blind medication. No dose escalation was permitted 
during either study. Each study was powered to detect a difference of 2 spontaneous bowel 
movements (SBMs) between the placebo and lubiprostone groups after 1 week of treatment. The 
primary and secondary efficacy endpoints were the same in both studies. The overall mean 
number of days on study drug was 27.1 days for SC0131 and 26.8 days for SC0232. The mean 
actual daily exposure was 1.9 capsules/day in both the placebo and lubiprostone groups in both 
studies. In terms of dose, the median actual daily exposure in the lubiprostone group was 46 μg 
in both SC0131 and SC0232. 
SC0131 evaluated 242 subjects, and SC0232 evaluated 237 subjects. In the primary efficacy 
analysis in each study, the mean SBM frequency during Week 1 was significantly higher 
(p<0.0001) in the lubiprostone group than in the placebo group. 
The overall treatment effect across all weeks was also significant (p<0.0001) in both studies. In 
SC0131, the median number of SBMs at Week 1 was 3.0 in the placebo group and 5.0 in the 
lubiprostone group; in SC0232, the values were 3.5 and 5.0, respectively. In both studies, the 
baseline median number of SBMs in both treatment groups was 1.5.
In SC0831, 124 Japanese subjects with CIC were randomly assigned to 24µg oral lubiprostone 
BID (62 subjects) or matching placebo (62 subjects) for a 4-week treatment duration. Eligibility 
criteria, endpoints and assessments were similar to the 2 previously conducted pivotal phase 3 
trials in the US.
In SC0831, lubiprostone showed a highly similar efficacy and safety profile in Japanese patients 
when compared to data from previous pivotal US trials (Table 4.a).


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Table 4.a
Summary of Efficacy of Lubiprostone 24 µg BID in Phase 3 Studies
Study No./Phase 
(Analysis Set, Analysis 
Method)
Country
Treatment Group
(Number of Subjects)
Baseline SBM
(Mean±SD)
(p-value) (a)
SBM at Week 1
(Mean±SD)
(p-value) (a)
SC0131
Phase 3 (ITT, LOCF)
US
Placebo (N = 122)
1.47±1.32
3.46±2.28
Lubiprostone (N=129)
1.47±1.32
(p=0.612)
5.69±4.41
(P<0.001)
SC0232
Phase 3 (ITT, LOCF)
US
Placebo (N=118)
1.52±0.80
3.99±2.70
Lubiprostone (N=119)
1.28±0.88
(p=0.012)
5.89±4.02
(P<0.001)
SC0831
Phase 3 (FAS)
Japan
Placebo (N=62)
1.68±0.77
2.93±1.82
Lubiprostone (N=61)
1.65±0.78
(p=0.873)
5.37±2.78
(P<0.001)
Source: Studies SC0131, SC0232, SC0831.
FAS=full analysis set, ITT=intent-to-treat, LOCF=last observation-carried-forward.
(a) Difference from placebo.
Note: SBM at Week 1 was the primary efficacy variable in Studies SC0131, SC0232, and SC0831.
4.2
Rationale for the Proposed Study
Lubiprostone has been approved for use in patients with CIC since January 2006 in the United 
States, November 2009 in Switzerland, September 2012 in the UK, and since February 2015 in 
Ireland, Belgium, Luxembourg and the Netherlands based on similarly designed phase 3 studies.
This phase 3, randomized, double-blind, placebo-controlled study is aimed at scientifically and 
objectively evaluating the efficacy and safety of lubiprostone in subjects with CIC and 
confirming that data on efficacy and safety from previously conducted studies in the US 
population is consistent with that in the Korean population. The study design allows for 
independent assessment of efficacy and safety in these subjects to support registration. 


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
The primary objective of this study is to evaluate the efficacy and safety of oral administration of 
lubiprostone 24 μg BID for 4 weeks in subjects with CIC compared with placebo.
5.2
Endpoints
5.2.1
Primary Endpoints 
5.2.1.1
Efficacy
SBM frequency in Week 1 of administration.
5.2.2
Secondary Endpoints
5.2.2.1
Efficacy

SBM frequency (Week 2, 3, and 4).

Proportion of subjects who have a SBM within 24 hours after first dose.

Mean degree of straining (Week 1, 2, 3, and 4).

Mean degree of stool consistency (Week 1, 2, 3, and 4).

Weekly abdominal symptoms score (bloating and discomfort) (Week 1, 2, 3, and 4).

Weekly responder rate (Week 1, 2, 3 and 4).
5.2.3
Additional Endpoints
5.2.3.1
Efficacy 

Quality of life evaluation using the standard Patient Assessment of Constipation—Quality of 
Life (PAC-QOL) Questionnaire.
5.2.3.2
Safety
The safety of lubiprostone will be evaluated by the following parameters:

Adverse events.

Clinical laboratory values.

Vital signs, including body temperature, blood pressure, and heart rate.

Body weight and height.

Physical examination.


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5.2.4
Exploratory
5.2.4.1
 
 


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 3, randomized, double-blind, parallel-group, placebo-controlled study in subjects 
with CIC as determined by the Rome III Diagnostic Criteria for Functional Constipation [4]. 
This study consists of a 14-day Screening Period and a subsequent 4-week (28 days) Double-
Blind Treatment Period in which subjects will receive either lubiprostone or matching placebo 
BID. Subjects will be randomized to either active lubiprostone or placebo in a 1:1 ratio. 
During the Screening Period, the defecation behavior of each subject is recorded in a diary to 
confirm he/she has constipation. Use of all existing laxatives is stopped at the beginning of the 
Screening Period (Visit 1). Subjects are instructed not to change their diet or lifestyle habits 
during the study. A total of 10 mg of bisacodyl suppository (or any equivalent drug) may be 
prescribed as a standard rescue medication if a subject has no adequate bowel movement for 3 
consecutive days during the Screening Period of the study. When bisacodyl suppository does not 
improve constipation, glycerin enema (or equivalent drug) will be given. Subjects are instructed 
to complete their diaries before using rescue medications.
The subject diary will be distributed on Study Days -15, -1, 8 and 15. Subjects will be instructed 
to keep the diary every day including on the morning of Visit 1.
If the rescue medications fail to improve constipation, the investigator may decide to use another 
rescue medication. The recommendation may include a medication from the excluded
medication list other than any form of polyethylene glycol (PEG), linaclotide, methylnaltrexone, 
or prucalopride, all of which are considered prohibited rescue medications. No rescue medication 
may be given 24 hours prior to and until 48 hours after the first dose of the study drug (Day 1). 
Subjects who use a rescue medication within 24 hours before the first dose of study drug on Day 
1 should be withdrawn from the study. Those who use a rescue medication within 48 hours after 
dosing on Day 1 will be discontinued from the study by the investigator. The dose and mode of 
administration of rescue medications must be recorded in the electronic case report form (eCRF).
Approximately 150 subjects whose constipation is confirmed during the Screening Period will be 
randomized in the Double-Blind Treatment Period to receive either lubiprostone or matching 
placebo BID. Others whose constipation does not satisfy the criteria during the 14-day Screening 
Period or those who receive a rescue medication within 24 hours prior to the first dose on Day 1 
are ineligible for randomization in the Double-Blind Treatment Period and therefore will be 
excluded from the study. Subjects who satisfy the inclusion criteria and do not meet the 
exclusion criteria are randomized to 1 of the treatment groups in the order of the number 
assigned. Approximately 150 subjects with CIC will be randomized to 2 groups: active treatment 
or placebo in a 1:1 ratio (75 subjects each) in a double-blinded manner.
Subjects will be instructed to take 1 capsule BID, orally, at the same time of day, preferably in 
the morning with breakfast and in the evening with dinner. Subjects are to begin their study drug 
treatment in the morning with breakfast following Visit 2. 


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Subjects will return to the study site on approximately Study Days 8, 15, and 29 during the 
4 weeks of double-blind treatment and will be followed for an additional 2 weeks during the 
Follow-Up Period, in which no treatment will be administered. 
At the investigator’s discretion, with consideration to subject’s bowel movement frequency and 
consistency, dose adjustments (dose reduction) may be made in a double-blind manner. Dose 
adjustment should be documented in the subject’s source notes. Procedure for reduction of study 
drug dose due to Adverse Events is described in Section 7.7.
Subjects who withdraw prematurely will be seen within 1 week of discontinuation for an Early 
Termination Visit. A schematic of the study design is included as Figure 6.a. A schedule of 
assessments is listed in Appendix A.
Figure 6.a
Schematic of Study Design
Lubiprostone 24 μg BID
(N=75)
Screening Period
(2 Weeks)
Follow-up Period
(2 Weeks)
Double-Blind Treatment 
Period (4 Weeks)
Placebo BID
(N=75)
Note: Randomization occurs on Day -1 of the Screening Period. The first dose of study drug is administered the next 
day, on Day 1 of the Double-Blind Treatment Period.
Note: There is no treatment during the Follow-up Period.
6.2
Justification for Study Design, Dose, and Endpoints
Constipation is generally considered as infrequent and difficult passage of stool. It is typically 
defined as a condition of having fewer than 3 BMs a week [1]. However, stool shape and the 
subject’s own perception other than stool frequency need to be considered for evaluation of 
disturbance in bowel movement [5]. 
The Rome Foundation, an international organization that classifies functional gastrointestinal 
disorders, published the definition of functional constipation in 2006 (“constipation without 
gastrointestinal tract abnormalities”) as shown in Table 6.a.The Rome Foundation requires use of 
multiple indices for diagnosis of functional constipation. The definition is characterized by the 
“criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis” 
[4].


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Table 6.a
Rome III Diagnostic Criteria for Functional Constipation
C3. Functional Constipation (*)
1.
Satisfies at least 2 of the following:
a)
Straining in at least 1 out of every 4 bowel movements.
b)
Scybalum stool or hard feces in ≥25% of defecations.
c)
Sensation of incomplete evacuation in ≥25% of defecations.
d)
Sensation of anorectal obstruction/blockade in ≥25% of defecations.
e)
Manual maneuvers to facilitate defecation (eg, digital evacuation, support of the pelvic floor) in ≥25% of 
defecations.
f)
Fewer than 3 defecations per week.
2.
Loose stool rarely present without use of laxatives.
3.
Does not satisfy the diagnostic criteria for IBS.
Source: Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders [4].
*At least 2 of the criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.
The major symptom of CIC is a decrease in SBM frequency. SBM has been assessed in previous 
studies in CIC, and is typically calculated by stool frequency in a week (SBM denotes a bowel 
movement occurring without the use of a laxative, suppository, or enema within the preceding 
24 hours) [6,7]. 
This phase 3, randomized, double-blind, placebo-controlled study is aimed at scientifically and 
objectively evaluating the efficacy and safety of lubiprostone in subjects with CIC. The study 
design allows for independent assessment of efficacy and safety in these subjects to support 
registration. 
SBM at week 1 is proposed as the primary endpoint in this bridging study. Lubiprostone is 
expected to improve stool frequency within a short period of treatment.
In a late phase 2 study and 2 phase 3 studies supporting applications, subjects treated with 
lubiprostone showed a significant increase in SBM frequency relative to subjects treated with 
placebo using this endpoint as the primary efficacy endpoint. Use of the same primary endpoint 
allows for direct comparison of efficacy data in the Korean population.
SBM frequency at other time points during the study and weekly responder rates will be 
evaluated to support the continuous effect of lubiprostone. 
Drug effect on straining, stool consistency, and abdominal symptoms (bloating and discomfort) 
are selected as secondary endpoints because these are common symptoms of CIC. Addition of 
these endpoints to frequency of bowel movement assessment provides a comprehensive 
evaluation of the effect of treatment.
The phase 1 study 99101 examined single oral doses of lubiprostone ranging from 6 µg to 96 µg; 
the results of this study demonstrated that there was a noticeable increase in pharmacodynamic 
effects when the lubiprostone dose was increased from 24 µg to 48 µg, and the maximum 
tolerated single dose based on the results of this study was determined to be 96 µg. The phase 1 
study 99102 examined daily doses of lubiprostone ranging from 72 µg (24 µg 3 times daily 


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[TID]) to 108 µg (36 µg TID); the results of this study showed a lack of additional 
pharmacodynamic effects at doses above 24 µg TID, suggesting a saturation effect of 
lubiprostone pharmacodynamics at this dose level. The phase 2b study SC9921 examined 
lubiprostone doses of 24 µg (24 µg once daily [QD]), 48 µg (24 µg BID), and 72 µg (24 µg TID) 
over a 3-week Double-Blind Treatment Period. Results from this study showed that all 3 doses of 
lubiprostone were more effective than placebo in relieving constipation, with the 48 µg and 72 
µg doses having similar effects on constipation. The overall tolerability of the 48 µg dose was 
considered better than the 72 µg dose, so it was chosen for further development in the Phase 3 
studies conducted in the United States.
A Japanese phase 2b dose-finding study CC0721 was conducted to verify validity of preceding 
data generated in the US population for Japanese patients. CC0721 examined lubiprostone doses 
of 16 µg (8 µg BID), 32 µg (16 µg BID), and 48 µg (24 µg BID) over a 2-week Double-Blind 
Treatment Period. Results from this study showed that the two higher doses of lubiprostone were 
more effective than placebo in relieving constipation, with the 48 µg dose providing best effects 
on constipation. The overall tolerability of the 48 µg dose was considered well suited, so this 
dose was chosen for further development in the phase 3 studies conducted in Japan, confirming 
preceding data generated in SC9921 in the United States.
The efficacy and safety of the lubiprostone 24 µg BID dose has been demonstrated in previously 
conducted phase 3 studies in CIC. The 24 µg BID dose will be used in this study for 4 weeks in 
subjects with CIC.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known benefit:risk profile for lubiprostone, such that the 
benefit:risk is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.


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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to dispensing of study 
medication on Day -1.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and 
dates a written, informed consent form and any required privacy authorization prior to the 
initiation of any study procedures. 
3. The subject has a history of constipation defined as having SBM frequency of less than 3 
times per week on average for 6 months or longer and for whom the same SBM frequency is 
observed during the Screening Period.
4. The subject has had 1 or more of the symptoms associated with SBM (described below) for 6 
months or longer at the start of Screening:
a) Scybalum stool or hard feces in at least 1 out of every 4 bowel movements.
b) Sensation of incomplete evacuation in at least 1 out of every 4 bowel movements.
c) Straining in at least 1 out of every 4 bowel movements.
5. The subject rarely has loose stools without the use of laxatives.
6. The subject is willing and able to keep a diary on his/her own and willing and able to 
complete a questionnaire.
7. The subject is male or female and aged 19 years or older, at the time of signing an informed 
consent.
8. A female subject of childbearing potential* who is sexually active agrees to use routinely 
adequate contraception* from signing of informed consent throughout the duration of the 
study and 14 days after the last dose of study drug.
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.13 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.14 Pregnancy.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any investigational compound within 30 days prior to Screening.
2. The subject has received lubiprostone in a previous clinical study or as a therapeutic agent.


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3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress. 
4. The subject has, in the judgment of the investigator, clinically significant abnormal 
hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening. 
5. The subject has a history or clinical manifestations of significant mechanical obstruction 
(intestinal obstruction due to tumor, hernia etc).
6. The subject has a history of hypersensitivity or allergies to lubiprostone or any of its 
excipients.
7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year prior to the Screening Visit. 
8. The subject is required to take excluded medications as listed in Section 7.3.1.
9. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such 
time period. 
10. Subject whose constipation is considered to be due to drugs or to whom a prohibited 
concomitant medication has been administered.
11. Subject having chronic constipation due to a secondary cause (medications, diabetes mellitus, 
hypothyroidism, depression, etc.)
12. Subject in whom there is sufficient criteria for irritable bowel syndrome (IBS) or functional 
defecation disorder.
13. Subject whose SBM frequency is 3 or more per week.
14. Subject whose SBM frequency has been less than 3 times per week for less than 6 months in 
duration or whose symptoms associated with SBM have been present for less than 6 months 
(hard feces, sensation of incomplete evacuation, or straining).
15. Subject who received treatment with a rescue medication within 24 hours prior to the first 
dose in the morning of Day 1: bisacodyl suppository, which is a standard laxative, glycerin 
enema, or any other rescue medication.
16. Subject who has megacolon/megarectum or has received a diagnosis of intestinal 
pseudo-obstruction.
17. Subject with confirmed or suspected organic disorders of the large intestine (obstruction, 
stenosis, carcinoma, or inflammatory bowel disease). Organic disorders of the large intestine 
can be confirmed or ruled out using the results of enema X-ray examination or total 
colonoscopy performed in the previous 2 years. If the subject has no history or shows no 
current evidence of weight loss, anemia, or rectal bleeding, organic disorders may be ruled 


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out based on the results of such testing performed in the past 3 years. Any subject in whom 
total colonoscopy has detected a polyp requiring treatment is excluded from this study.
Note: Subject should not be screened unless at least 7 days have passed since an enema X-ray 
examination, sigmoidoscopy or total colonoscopy have been performed. See Section 7.3.3
and 7.4.
18. Subject who has been hospitalized for gastrointestinal or abdominal surgery within 3 months 
prior to Screening.
19. Subject who has a significant cardiovascular, liver, lung, kidney, neurological, or mental 
disease (including existing alcohol or drug abuse problem) or a systemic disease.
20. Subject who has significant clinical findings or in whom a significant abnormality has been 
found in hematology test, serum chemistry, or urinalysis.
21. Subject in whom noncompliance with the study protocol (administration schedule, visit 
schedule, diary completion or other study procedure) is expected.
22. The subject has a history of malignant disease (except basal cell carcinoma) within 5 years 
prior to Screening. 
23. The subject has any screening abnormal laboratory value that suggests a clinically significant 
underlying disease or condition that may prevent the subject from entering the study; or the 
subject has: creatinine >1.5 mg/dL, alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) >2 times the upper limit of normal (ULN), or total bilirubin 
>2.0 mg/dL with AST/ALT elevated above the limits of normal values.
24. Subject who the investigator/subinvestigator has determined ineligible to participate in this 
study for any reason other than the above.
7.3
Excluded Medications and Procedures 
7.3.1
Excluded Medications
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.
Due to the potential influence on the efficacy evaluation of lubiprostone, the following 
medications are to be excluded during the course of the study and must be discontinued no later
than Day -15 of the Screening Period through the Final Visit or Early Termination Visit:

Anticholinergic drugs or drugs with anticholinergic effect (except ipratropium bromide or 
any inhaled or nasal-spray forms of this medication). 

Opioids.

Antispasmodics. 

Cholinesterase inhibitors.


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
Antidiarrheal medications. 

Anticonstipation medications (eg, linaclotide). 

Gastrointestinal prokinetic agents. 

Laxative agents (eg, PEG 3350), including homeopathic remedies.

Tricyclic antidepressants. 

Any medications at the discretion of the investigator known to relieve or cause constipation 
or constipation symptoms.
The use of excluded medications listed above should be documented as concomitant 
medications. The Medical Monitor must be notified in advance (or as soon as possible thereafter) 
of any instances in which excluded medications are taken, or to be taken. Continued participation 
of the subject will be at the discretion of the Sponsor.
7.3.2
Drugs Permitted with Condition
7.3.2.1
Exceptions to Excluded Medications
If subject has a confirmed diagnosis of clinical depression and he/she has been treated 
with selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake 
inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOI), treatment must have been at a 
stable dose for at least 30 days prior to the Screening Visit and not likely to change during the 
study. Antidepressants must not be suddenly stopped or reduced as doing so may provoke 
withdrawal symptoms or other untoward symptoms. The investigator determines how to handle 
subjects using antidepressants on an individual subject basis without compromising the safety of 
the subject.
Rescue medication use is determined and prescribed depending on the subject’s clinical 
condition. 10 mg of bisacodyl suppository may be prescribed as a standard rescue medication if a 
subject has no adequate bowel movement for 3 consecutive days during the study. When 
bisacodyl suppository does not improve constipation, glycerin enema (or any equivalent drug) 
may be given.
Subjects are instructed to complete their diaries before taking rescue medications. No rescue 
medication may be used within 24 hours before and 48 hours after the start of the Double-Blind 
Treatment Period (Day 1).
Subjects who use a rescue medication within 24 hours before the first dose of study drug on Day 
1 should be withdrawn from the study. Those who use a rescue medication within 48 hours after 
dosing on Day 1 will be discontinued from the study by the investigator. The dose and mode of 
administration of rescue medications must be recorded in the electronic case report form (eCRF).
The use of excluded medications with exceptions mentioned above should be documented as 
concomitant medications, as applicable. The Sponsor’s medical monitor or designee must be 


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notified in advance (or as soon as possible thereafter) of any instances in which any drugs 
permitted with condition are taken, or to be taken. Continued participation of the subject will be 
at the discretion of the Sponsor.
7.3.3
Excluded Procedures
Invasive procedures such as enema X-ray, total colonoscopy and sigmoidoscopy are not allowed 
7 days prior to Screening until the Final Visit as these procedures could affect bowel habits 
observed subsequently. Subject should not be screened (including diary keeping) unless at least 7 
days have passed since an enema X-ray examination, sigmoidoscopy or total colonoscopy have 
been performed.
The Medical Monitor must be notified in advance (or as soon as possible thereafter) of any 
instances of excluded procedures being performed. Continued participation of the subject will be 
at the discretion of the Sponsor.
7.4
Diet, Fluid, Activity Control
The investigator, subinvestigator, and study coordinator should advise subjects to comply with 
the following instructions:
The following instructions are given to each subject.

Discontinuation of all laxatives and prohibited drugs (including dietary fiber supplement).

No change in diet or lifestyle habits during the study. Subjects should maintain their usual 
caffeine and alcohol intake during the study. 
The subject diary will be distributed, and subjects will be instructed to keep the diary every day 
including on the morning of Visit 1. The data to capture in the diary include the following: time 
of defecation, stool consistency [every time], degree of straining during defecation, degree of 
sensation of complete evacuation, and abdominal symptoms such as bloating and discomfort. 
Subjects will be instructed to begin taking study drug BID, beginning the morning after Visit 2 
(1 capsule in the morning with breakfast and 1 capsule in the evening with dinner and about 240 
mL of water during each administration). Subjects will be instructed to record the date and time 
of consumption of the study drug in the diary.
Note: Subjects should not be screened unless at least 7 days have passed since an enema X-ray 
examination, sigmoidoscopy or total colonoscopy have been performed.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the electronic case report form (eCRF) using the following 
categories. For screen failure subjects, refer to Section 9.1.15.
1. Pretreatment event (PTE) or adverse event (AE). The subject has experienced a PTE or AE 
that requires early termination because continued participation imposes an unacceptable risk 


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to the subject’s health or the subject is unwilling to continue because of the PTE or AE (this 
includes when there are safety concerns in a subject after dose reduction).

Liver function test (LFT) abnormalities.
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.12), if the following circumstances occur at any 
time during study medication treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
2. Significant protocol deviation. The discovery after the first dose of study medication that the 
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. 
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE or lack of efficacy). 
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.14.
7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
8. Unblinding of subject treatment.
9. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.


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7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit, with a follow up telephone contact 14 
days later. Discontinued or withdrawn subjects will not be replaced.
7.7
Procedure for Reduction of Study Drug Dose Due to Adverse Events
If a subject experiences an adverse event during the Double-Blind Treatment Period, the 
investigator may decide to reduce the dose or discontinue treatment as needed based on the type 
and severity of the adverse event. 
For a dose reduction, either the morning (with breakfast) or evening (with dinner) dose is 
discontinued. As a general rule, the investigational drug blind shall not be broken by the 
investigator, even when the dose in a subject is reduced. 
If the report of an adverse event from a subject calls for dose reduction at a point other than the 
scheduled visit, the investigator determines whether to reduce the dose in the subject. If dose 
reduction is determined necessary, the investigator must instruct the subject how to reduce the 
dose. 
If the dose is reduced or treatment discontinued in a subject, the reason for dose reduction or 
discontinuation as well as relevant details should be recorded in the eCRF of the subject. The 
lubiprostone dose cannot be increased after reduction.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to all or any of the drugs defined below.

Lubiprostone 24 μg capsules.

Placebo capsules to match lubiprostone 24 μg.
Investigational material is encapsulated in clear orange soft gelatin capsules and packaged into 
60 count high-density polyethylene (HDPE) bottles, including a rayon filler, induction sealed and 
closed with a child-resistant cap. Each bottle contains enough capsules to treat subjects for 
28 days + a 2-day window during the Double-Blind Treatment Period, and will be labeled with a 
single-panel label including pertinent study information. As this study is double-blind, all study 
medication will be packaged, labeled, and dispensed in a blinded manner.
The bottle will contain an unique medication identification (MED ID) number and will be 
dispensed via the Interactive Web Response System (IWRS), with 1 bottle dispensed per subject.
An IWRS program will be used to manage inventory, assist the site in dispensing the proper 
investigational drug to the subjects, record accountability and support the return to sponsor or 
designee of these investigational drugs after study completion.
8.1.1.1
Investigational drug
Lubiprostone 24 μg and placebo will be supplied by the sponsor. All drugs supplied by the 
sponsor will be manufactured, tested, and released according to Good Manufacturing Practice 
(GMP).
8.1.1.2
Rescue Medication 
A total of 10 mg of bisacodyl suppository (or an equivalent drug) may be prescribed as a 
standard rescue medication if a subject has no adequate BM for 3 consecutive days during the 
study. When bisacodyl suppository does not improve constipation, glycerin enema (or equivalent 
drug) may be given. Subjects are instructed to complete their diaries before using these drugs. 
No rescue medication may be used within 24 hours before and 48 hours after the start of the 
Double-Blind Treatment Period (Day1).
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. Investigational drug must be stored under 


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the conditions specified on the label, and remain in the original bottle until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day.
Temperature excursion must be reported to the sponsor or designee.
8.1.3
Dose and Regimen
Subjects will be dispensed 1 bottle of study medication at Visit 2 (Day -1) and will be required to 
take 2 capsules daily, 1 in the morning and 1 in the evening with food. Subjects will be instructed 
to start study medication in the morning of the following day (Day 1). 
Table 8.a describes the dose and regimen as it will be administered to each subject in each 
treatment group during the 4 weeks of the Double-Blind Treatment Period.
Table 8.a
Dose and Regimen
Treatment Group
Dosage
Timing of Dose and Regimen
Morning (AM)
Evening (PM)
Placebo 
1 placebo capsule taken by mouth 
BID for 4 weeks
Administered orally with
breakfast and 240 mL of 
water
Administered orally 
with dinner and 240 mL 
of water
Lubiprostone 
1 lubiprostone 24 μg capsule taken 
by mouth BID for 4 weeks
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE eCRF according to Section 10.0, 
Pretreatment Events and Adverse Events.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Investigational drug Assignment and Dispensing Procedures
The investigator or investigator’s designee will access the IWRS at Screening/ Visit 1 to obtain 
the subject study number. 
After study eligibility is confirmed (ie. at Visit 2), the investigator or the investigator’s designee 
will utilize the IWRS to randomize the subject into the study. During this contact, the 
investigator or designee will provide the necessary subject-identifying information, including the 


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subject number assigned at Screening. The MED ID number of the investigational drug to be 
dispensed will then be provided by the IWRS. 
If the investigational drug is lost or damaged, the site can request a replacement from IWRS. 
(Refer to IWRS manual provided separately.) 
If a dose was missed, the subject is to leave the capsule in the bottle and resume regular 
administration at the next scheduled dose time. The subject is instructed to note the missing dose 
in the daily diary.
Instructions for subjects on how to store investigational drug will be provided by the investigator 
or investigator’s designee.
Unused medication should be returned at Visit 5.
8.3
Randomization Code Creation and Storage 
The sponsor or designee will generate the randomization schedule prior to the start of the study; 
IWRS will be used in a centralized fashion for subject randomization and study medication 
assignments. All randomization information will be stored in a secured area, accessible only by 
authorized personnel.
8.4
Investigational Drug Blind Maintenance 
The investigational drug blind will be maintained using the IWRS.
8.5
Unblinding Procedure 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IWRS.
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the 
same information (except the time) must be recorded on the eCRF.
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
8.6
Accountability and Destruction of sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects randomized in the study. To document 


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appropriate use of sponsor-supplied drug (lubiprostone and matching placebo), the investigator 
or designee must maintain records of all sponsor-supplied drug delivery to the site, site 
inventory, dispensation and use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by recording in IWRS. If there are any 
discrepancies between the packing list versus the actual product received, Takeda must be 
contacted to resolve the issue. The packing list should be filed in the investigator’s essential 
document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Continuously monitoring expiration dates if the expiry date is provided to the investigator or 
designee.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the MED ID used to prepare each dose.

Verifying that all containers/ bottles used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
lubiprostone and matching placebo on a sponsor-approved drug accountability log. The 
following information will be recorded at a minimum: protocol number and title, name of 
investigator, site identifier and number, description of sponsor-supplied drugs, expiry date, date 
and amount dispensed including initials or signature of the person dispensing the drug, and the 
date and amount returned to the site by the subject, including the initials or signature of the 
person receiving the sponsor-supplied drug. The log should include all required information as a 
separate entry for each subject to whom sponsor-supplied drug is dispensed. 
All study drugs that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 


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retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction.
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabeled with the new expiry date at that site. In such cases, 
Takeda or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the sites.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2 and Appendix C.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include age, sex, race as described by the subject, 
and smoking status of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.11).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within1 month prior to signing of informed 
consent.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; 
(11) genitourinary system; and (12) other. All subsequent physical examinations should assess 
clinically significant changes from the assessment prior to first dose examination.
9.1.4
Weight, Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. Height will be measure at Visit 1 and weight will be measured at Visit 1 and 5.The Takeda 
standard for collecting height is centimeters without decimal places and for weight it is 
kilograms (kg) with 1 decimal place. 


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9.1.5
Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, sitting blood pressure (resting more 
than 5 minutes), and pulse (bpm).
9.1.6
Primary Efficacy Endpoint 
The primary efficacy endpoint is SBM frequency at Week 1, the data for which will be collected 
in a subject diary; see Appendix E. Subjects will be given a diary to complete at home, where 
they will record the date and time of each BM.
9.1.7
Secondary Efficacy Endpoints
9.1.7.1
SBM Frequency at Weeks 2, 3 and 4
This secondary endpoint will be collected as specified for the primary analysis. 
9.1.7.2
Proportion of Subjects Who Have a SBM Within 24 Hours After First Dose
The proportion of subjects with an SBM within 24 hours after first dose in Week 1 will be 
assessed and derived from the data on SBMs collected in the subject diary.
9.1.7.3
Degree of Straining
For each subject, the degree of straining will be scored on a 5-point scale, with a higher score 
indicating more severe straining, and averaged for all SBMs at Weeks 1, 2, 3, and 4. The degree 
of straining for each SBM will be collected in the subject diary.
9.1.7.4
Stool Consistency
Stool consistency will be scored using the Bristol Stool Chart (see Appendix E) and the mean 
provided for all SBMs at Weeks 1, 2, 3 and 4. Stool consistency will be collected in the subject 
diary for each SBM recorded.
9.1.7.5
Assessments of Abdominal Symptoms
The abdominal symptoms (bloating and discomfort upon waking in the morning) will be scored 
weekly on a 5-point scale, with a higher score indicating more severe symptoms. This will be 
assessed at Baseline and at Weeks 1, 2, 3, and 4. Subjects will be instructed to record weekly 
abdominal symptoms assessment in the diary. Diary entries will be reviewed at each study visit 
as per protocol schedule.
9.1.7.6
Weekly Responder Rate
Weekly responder rate will be assessed at each week and will be derived from the data on SBMs 
collected in the subject diary.


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Responder analysis will be performed at each week. A non-responder will be defined as any 
subject with a spontaneous BM frequency rate of less than 3 for a given week, any subject who 
dropped out during or prior to the given week due to lack of efficacy, or any subject who used 
rescue medication during or within 24 hours prior to the given week. Otherwise, the subject will 
be considered a responder. A responder with a spontaneous BM frequency rate ≥3 but <4 will be 
considered a moderate responder. Otherwise, the subject will be a full responder (≥4 SBM).
9.1.8
Additional Endpoints
9.1.8.1
Quality of Life Evaluation
The PAC-QOL is a health related QOL instrument designed specifically to evaluate an adult 
subject’s assessment of constipation over time. It is self administered assessment consisting of 
28 items and is designed to cover the 2 weeks prior to the questionnaire being completed. Each 
item is scored from 0 to 4; a lower score is better. The 28 items are grouped into 4 subscales: 
physical discomfort, psychosocial discomfort, worries and concerns, and satisfaction.
The PAC-QOL will be assessed at Day -1 (prior to the start of study drug), mid-way through the 
Double-Blind Treatment Period on Day 15, and at the end of the Double-Blind Treatment Period, 
on Day 29.
9.1.8.2
Safety Endpoints
Safety endpoints include adverse events, vital signs, clinical laboratory tests, physical 
examinations, and body weight.
9.1.9
Exploratory Endpoint
9.1.9.1
 
9.1.10 Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.
9.1.11 Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, 


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electrocardiogram (ECG), or physical examination abnormalities noted at the screening 
examination. The condition (ie, diagnosis) should be described.
9.1.12 Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The 
maximum volume of blood at any single visit is approximately 8 mL, and the approximate total 
volume of blood for the study is 24 mL.
Details of these procedures will be provided in the Central Laboratory Manual.
Table 9.a presents the clinical laboratory tests that will be utilized during this study.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBC
WBC with differential
Hemoglobin
Hematocrit
Platelets
MCV
MCH
RDW
ALP
Albumin
ALT
AST 
Total bilirubin
Direct bilirubin
Total protein
Total Cholesterol
Triglyceride
Glucose
Creatinine
BUN
Creatine kinase
Uric acid
GGT
LDH
Potassium
Sodium
Chloride
Calcium
Phosphorous
Magnesium
TSH (Visit 1)
CRP (Visit 1)
Qualitative urinalysis (a) 
Microscopic analysis 
(only if positive dipstick 
results) (b)
Other:
Serum:
Urine:
Female subjects only:
Beta hCG (for pregnancy) Visits 1 and 5
female subjects of childbearing potential only
Female subjects only: 
hCG for pregnancy Visit 2
female subjects of childbearing potential only.
Drug screen for drugs of abuse at Visit 1
BUN=blood urea nitrogen, CRP= C-reactive protein, GGT= gamma-glutamyl transpeptidase, hCG=human 
chorionic gonadotropin, hpf=high-power field, LDH= lactic dehydrogenase, MCH=mean corpuscular hemoglobin, 
MCV=mean corpuscular volume, RBC= red blood cell, RDW=red (cell) distribution width, TSH= thyroid-
stimulating hormone, WBC=white blood cell.
(a) Qualitative urinalysis: pH, specific gravity, protein, glucose, occult blood, urobilinogen, bilirubin, ketone and
leukocyte esterase.
(b) Microscopic analysis: RBC/hpf, WBC/hpf, epithelial cells, casts, etc.
Blood is collected for hematology and blood biochemistry, and urine is collected for urinalysis at 
Visit 1 (Screening), and Visit 5 (at the completion of the Double-Blind Treatment Period), and, if 
applicable, at an Early Termination Visit. Women of childbearing potential undergo pregnancy 
test by serum at Visit 1 and 5 (or Early Termination Visit) and by urine at Visit 2. No pregnancy 
test is performed on women who have not menstruated for a year or longer. 


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The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis (excluding pregnancy tests). The results of laboratory tests will be returned to the 
investigator, who is responsible for reviewing and filing these results.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48-72 hours after the abnormality was noted.
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN 
in conjunction with total bilirubin >2 ×ULN.)
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements).
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used.
9.1.13 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 14 days after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with 
a nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years since last 
regular menses, confirmed before any study medication is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.


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An acceptable method of contraception is defined as one that has no higher than a 1% failure 
rate. In this study, where medications and devices containing hormones are included, the only 
acceptable methods of contraception are:
Table 9.b
Acceptable Methods of Contraception
Barrier Methods (a)
Intrauterine Devices (IUDs)
Hormonal Contraceptives

Male condom PLUS
spermicide.

Cap (plus spermicidal cream or
jelly) PLUS male condom and
spermicide.

Diaphragm (plus spermicidal
cream or jelly) PLUS male
condom and spermicide.

Copper T PLUS condom or
spermicide.

Progesterone T PLUS condom or
spermicide.

Implants.

Hormone shot/injection.

Combined pill.

Minipill.

Patch.

Vaginal ring PLUS male
condom and spermicide.
IUD=intrauterine device. 
(a) Barrier methods: to be used each time the subject has intercourse.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy and donation of ova during the course 
of the study.
During the course of the study, regular serum and urine hCG pregnancy tests will be performed 
for women of childbearing potential only, and subjects will receive continued guidance with 
respect to the avoidance of pregnancy as part of the study procedures (Appendix A). In addition 
to a negative serum hCG pregnancy test at Screening, subjects also must have a negative urine 
hCG pregnancy test prior to dispensing of study medication at Visit 2.
9.1.14 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug (lubiprostone or matching placebo) should be immediately discontinued. 
If the pregnancy occurs during administration of active study medication, eg, after Visit 2 or 
within 14 days of the last dose of active study medication, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects randomized to placebo need not be followed. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received.


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All pregnancies in subjects on active study drug including comparator will be followed up to 
final outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted (first well baby visit).
9.1.15 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible at this visit, the investigator should complete the eCRF. 
The IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason).
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.16 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the Double-Blind Treatment Period.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
If the subject is found to be eligible the subject will be randomized to either lubiprostone or 
placebo using IWRS. Instructions on accessing and using the IWRS will be provided in a 
separate manual. Blinded details of subject treatment allocation (MED ID numbers) will be 
provided via the IWRS. 
9.1.17 Subject Diary
The study diary will be a paper diary distributed to each subject on Study Days -15, -1, 8, and 15. 
Subjects will be instructed to record in the diary every day, including the morning of Visit 1 
(Day -15, the first day of the Screening Period). Subjects will continue to record their defecation 
behavior in the diary to confirm he/she has constipation. Use of all laxatives will be stopped at 


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the beginning of the Screening Period (Visit 1), and subjects will be instructed not to change 
their diets or lifestyle habits during the study. 
The study diary will be collected and reviewed for completeness on Study Days -1, 8, 15, 29 and 
any unscheduled visit. The authorized study personnel will transcribe all data collected from the 
diary into the eCRF. All information collected from the diary will be analyzed for primary and 
secondary endpoints in the study.
All subjects should be instructed about diary completion at every study visit. Documentation that 
subjects are appropriately instructed (and re-instructed as necessary) on diary completion should 
be recorded in the subject’s source notes. 
Subjects who are not consistent or thorough with study diary completion may receive phone 
reminders if deemed necessary by the investigators. The authorized study personnel providing
phone reminders must document the phone contact process in the subject’s source notes.
A sample of the diary is located in Appendix E; it provides a sample of the types of questions 
that the diary asks as a way of helping the subject to record defecation behavior.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study medication bottles/ unused medications to each 
dispensing site visit. 
If a subject is persistently noncompliant with the study medication, it may be appropriate to 
withdraw the subject from the study. All subjects should be reinstructed about the dosing 
requirement during study contacts. The authorized study personnel conducting the re-education 
must document the process in the subject source records.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). The recommended visit 
windows for Visits 2, 3, 4, and 5 are within 2 days of the required visit. 
9.3.1
Screening Period
Subjects will be screened within 2 weeks prior to Randomization. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.15 for procedures for documenting screening failures.
Procedures to be completed at Screening (Visit 1) include:

Sign informed consent.

Record demographics, medical history, and medication history. Includes the results at
Screening for IBS. The results of enema X-ray examination or total colonoscopy performed 
in the past 2 years are referred to in order to confirm organic disorders have been ruled out. 
For subjects who have no history or show no current evidence of weight loss, anemia, or 


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rectal bleeding, the examination results of the past 3 years may be used to rule out organic 
disorders.

Perform physical examination.

Measure vital signs, weight, and height.

Record the use of concomitant medications, including previous use of laxatives/drugs used 
for constipation.

Instruct subject to stop the use of all existing laxatives/drugs used for constipation.

Document concurrent medical conditions.

Pretreatment adverse events assessment.

Collect blood and urine samples for laboratory tests and urine drug screen. Serum hCG 
pregnancy test is required for women of child-bearing potential only.

Dispense study diary and provide instructions on diary completion.

Distribute rescue medications prescription.

Eligibility assessment (review Inclusion/ Exclusion criteria).

Access IWRS to obtain subject number.

Guidance on the avoidance of pregnancy and ova donation.
9.3.2
Study Entrance/Randomization 
Randomization will take place on Day -1. The following procedures will be performed and 
documented during Randomization:

Review diary entries for completeness and compliance. Evaluate the need for providing 
phone reminders to subjects who are not consistent or thorough with study diary completion. 

Check the use of rescue medication (by diary).

Measurement of vital signs.

Record the use of concomitant medications.

Urine hCG pregnancy test (for females of childbearing potential only).

Abdominal symptom assessment review (by diary).

Pretreatment Adverse Events assessment.

PAC-QOL Questionnaire.

Eligibility assessment (review Inclusion/ Exclusion criteria).

Access IWRS for Randomization and MED ID.


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
Dispensing of study medication via IWRS.

Dispense study diary. Re-instruct subject on diary completion.

Distribute rescue medications prescription as necessary. 

Schedule next visit 7 days from first dose of study medication.

Instruct subject to bring the study medication bottle and the completed diary at Visit 3.

Guidance on the avoidance of pregnancy and ova donation.
No rescue medication may be used within 24 hours before and 48 hours after the first dose of the 
study drug (Day 1). Subjects who use a rescue medication within 24 hours before the first dose 
of study drug on Day 1 should be withdrawn from the study. Those who use a rescue medication 
within 48 hours after dosing on Day 1 will be discontinued from the study by the investigator. 
The dose and mode of administration of rescue medications must be recorded in the electronic 
case report form (eCRF).
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IWRS as described in Section 9.3.2. 
Subjects will be instructed to start study medication the following day (Day 1) as described in 
Section 6.1. Subjects will be instructed to take 1 capsule BID, orally, at the same time of day, 
preferably in the morning with breakfast and in the evening with dinner. The procedure for 
documenting screening failures is provided in Section 9.1.15.
9.3.3
Double-Blind Treatment Period
The following tests and procedures will be performed and documented during the Double-Blind 
Treatment Period (First Dose/ Day 1 through Visit 5/ Day 29).

Record the use of concomitant medications.

Adverse Events assessment.

Document dose adjustment (dose reduction) when applicable.

Calculate and document study medication return, accountability and compliance. 

Review diary entries for completeness and compliance. Evaluate the need for providing 
phone reminders to subjects who are not consistent or thorough with study diary completion
(Visit 3/ Day 8 and Visit 4/ Day 15). 

Abdominal symptom assessment review (by diary).

Check the use of rescue medication (by diary).

PAC-QOL Questionnaire (Visit 4/ Day 15).

Dispense study diary (Visit 3/ Day 8 and Visit 4/ Day 15). Re-instruct subject on diary 
completion.


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
Distribute rescue medications prescription at Visit 3/ Day 8 and Visit 4/ Day 15 as necessary. 

Instruct subject to bring the study medication bottle and the completed diary at next 
scheduled visit.

Guidance on the avoidance of pregnancy and ova donation.
The investigator may reduce the dose due to adverse events, based on the type and severity of the 
adverse event. As a general rule, the investigational drug blind shall not be broken by the 
investigator for dose adjustment.
9.3.4
Final Visit or Early Termination Visit
The Final Visit will be performed at the end of Week 4 (Day 29) or at the Early Termination 
Visit. For all subjects receiving study medication, the investigator must complete the End of 
Study eCRF page. Subjects who withdraw prematurely will be seen within 1 week of 
discontinuation for an Early Termination Visit.
The following tests and procedures will be performed:

Perform physical examination including weight.

Measurement of vital signs.

Record the use of concomitant medications.

Collect blood and urine samples for laboratory tests. Serum hCG pregnancy test is required 
for women of child-bearing potential only.

Calculate and document study medication return, accountability and compliance. 

Abdominal symptom assessment review (by diary).

PAC-QOL Questionnaire.

Check the use of rescue medication (by diary).

Review diary entries for completeness and compliance.

Adverse Events assessment.

Guidance on the avoidance of pregnancy and ova donation.

Access IWRS to update subject status.
9.3.5
Follow-up Period
Follow-up Period will begin the first day after the Final Visit/ Early Termination Visit and will 
continue up to 14 Days.
Subjects who completed the study will be contacted through phone for Follow Up interview 14 
days after the Final Visit. Subjects will answer questions about adverse events and concomitant 


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medication use (including rescue medications). This will include any pregnancy reporting in 
female subjects.
Subjects who are withdrawn prematurely should return to the site within 1 week after the last 
taken dose for all procedures scheduled for Early Termination Visit. Efforts should be made to 
follow up with a telephone contact 14 days after the last dose of study medication or Early 
Termination Visit.
9.3.6
Post Study Care
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as 
required.


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug.
10.1.3
Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant 
medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as 
a PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s).


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Laboratory values:

A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values are the result of pathology for which there is an overall 
diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be reported 
appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) 
or an AE (worsening or complication occurs after start of study medication). Investigators 
should ensure that the event term recorded captures the change in the condition (eg, 
“worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. Investigators should ensure that the AE term recorded captures the change in the
condition (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.


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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page
of the eCRF.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.


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
Includes any event or synonym described in the Takeda Medically Significant AE List
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6
Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments.
10.1.7
Relationship to Study Procedures
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The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 
10.1.8
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.9
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died.
10.1.10
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.11
Action Concerning Study Medication 

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Dose Reduced – the dose was reduced due to the particular AE.

Unknown – only to be used if it has not been possible to determine what action has been
taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE
eg, the study has been terminated, the subject died, dosing with study medication was already
stopped before the onset of the AE.
10.1.12
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not
returned to the normal range or to Baseline; the subject died from a cause other than the
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the
observed study period has got worse than when it started; is an irreversible congenital
anomaly; the subject died from another cause with the particular AE/PTE state remaining
“Not recovered/not resolved”.


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
Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with
permanent/significant impairment (eg, recovered from a cardiovascular accident but with
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death.

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication 
(Study Visit 1, Day -15) or until screen failure. For subjects who discontinue prior to study 
medication administration, PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (Day 1). Routine collection of AEs will continue until Final Visit or Early 
Termination Visit.
A follow-up phone contact will be made to each subject 14 days following the last dose of study 
drug to collect any AEs that may have occurred. The stop date of the AE/serious PTE is the date 
at which the subject recovered, the event resolved but with sequelae or the subject died.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes 
in laboratory values have returned to Baseline or there is a satisfactory explanation for the
change. Non-serious PTEs, related or unrelated to the study procedure, need not to be 
followed-up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All PTEs and AEs will be documented in the PTE/AE page of the 
eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event:
1. Event term.
2. Start and stop date.


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3. Severity.
4. Investigator’s opinion of the causal relationship between the event and administration of
study medication(s) (related or not related) (not completed for PTEs).
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details
of the suspected procedure.
6. Action concerning study medication (not applicable for PTEs).
7. Outcome of event.
8. Seriousness.
PAC-QOL and subject diary will not be used as a primary means to collect AEs. However, 
should the investigator become aware of a potential AE through the information collected with 
this instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be 


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completed providing additional information on relevant recent history, risk factors, clinical signs 
and symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.12 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including investigators and 
IRBs or IECs, as applicable, in accordance with national regulations where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as expedited report 
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit:risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal products administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary.
12.1
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will provide investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the eCRF. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of or addition to the 
data on the eCRFs should be made by the investigator with use of change and modification 
records of the eCRFs (Data Clarification Form) provided by the sponsor. The principal 
investigator must review the data change for completeness and accuracy, and must sign, or sign 
and seal, and date.
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by study monitors. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 


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electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. 
The investigator should contact and receive written approval from the sponsor before disposing 
of any such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical Analysis Plan
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject 
evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
Total Set
The total set consists of all subjects who signed the informed consent form including subjects 
withdrawn prior to randomization (defined as not randomized subjects).
Full Analysis Set
This will consist of all subjects randomized to receive study treatment whether or not they 
received treatment. Subjects will be assigned to the randomized treatment group regardless of 
treatment received.
Per-Protocol Analysis Set
The Per-Protocol (PP) population will consist of subjects in the FAS with the additional 
following criteria for exclusion:

Did not receive study treatment as per randomization schedule.

Dose of randomized treatment was not adjusted.

Violated inclusion criteria, such as:
–
Does not have a history of constipation defined as SBM frequency of less than 3 times 
per week on average for 6 months or longer (and observed during Screening Period).
–
Does not have SBMs with ≥1 of the following 3 symptoms for the last 6 months or 
longer, in at least 1 out of every 4 bowel movements: scybalum stool or hard feces, 
straining, or the sensation of incomplete evacuation. 
–
The subject rarely has loose stools without the use of laxatives.

Violated exclusion criteria, such as:
–
The subject has a history or clinical manifestations of significant mechanical obstruction 
(intestinal obstruction due to tumor, hernia etc).


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–
Has chronic constipation due to a secondary cause (medications, diabetes mellitus, 
hypothyroidism, depression, etc).
–
Has sufficient criteria for IBS or there is a functional defecation disorder.
–
SBM frequency is 3 or more per week.
–
SBM frequency has been less than 3 times per week for less than 6 months in duration or 
whose symptoms associated with SBM have been present for less than 6 months (hard 
feces, sensation of incomplete evacuation, or straining).
–
Received treatment with a rescue medication within 24 hours prior to the first dose on the 
morning of Day 1.
–
Has megacolon/megarectum or has received a diagnosis of intestinal pseudo-obstruction.
–
Has confirmed or suspected organic disorders of the large intestine (obstruction, stenosis, 
carcinoma, or inflammatory bowel disease). Any subject in whom total colonoscopy has 
detected a polyp requiring treatment is excluded from this study.
–
Has been hospitalized for gastrointestinal or abdominal surgery within 3 months before 
the start of this study.
–
Use of any excluded medications, procedures or treatments prior to the assessment of the 
primary endpoint.
Any other significant event interfering with efficacy evaluation of primary endpoint, to be 
decided at the Targeted Data Review Meeting.
Subjects will be assigned to the treatment group dependent upon the actual treatment randomized 
and received.
Safety Analysis Set
This will consist of all subjects who receive study treatment. Subjects will be assigned to the 
treatment group dependent upon the actual treatment received.
The analysis populations must be identified before database lock by the Responsible Medical 
Officer, the Coordinating Study Manager and the Study Statistician. The reason(s) for exclusion 
of subjects from the analysis populations must be documented, signed and filed in the Trial 
Master File (TMF).
The FAS will be used for efficacy analyses. Supportive analyses based on the PP will be 
performed for the primary efficacy variable. Definitions of criteria constituting major deviations 
will be provided, prior to unblinding.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized descriptively.


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13.1.3 Efficacy Analysis
Two-sided tests at a significance level of =5% will be used throughout unless otherwise stated. 
The null hypothesis is that lubiprostone is equal to placebo against the alternative that 
lubiprostone is different to placebo. All analyses will be performed using the FAS. Analyses 
specified for the PP are to be regarded as supportive evidence. There will be no adjustment for 
multiplicity.
All efficacy endpoints will be summarized by treatment and visit. If baseline measures are also 
defined and collected for an efficacy endpoint then change from Baseline at each visit will also 
be presented by summary statistics by treatment and visit. Baseline is defined as the last recorded 
measurement prior to treatment. For parameters based on diary data, baseline values will be 
derived using the data from the Screening Period.
Centers may be pooled geographically if necessary for analysis purposes.
The LOCF technique will be used to impute missing values. For a given subject, the most recent 
nonmissing treatment-period data point will be carried forward to the subsequent week where 
data are missing. Supportive analyses will be conducted without missing value imputation (ie, 
without LOCF) and with a ‘worse-case’ scenario where missing values are assigned the worst 
case values recorded in the study by any subject for that endpoint at that time.
13.1.3.1 Primary Endpoint
The primary endpoint for the study is the frequency of SBM at Week 1. An SBM is defined as 
any BM that does not occur within 24 hours after rescue medication use. The SAP will contain 
more details on the handling of rescue medication and missing or partial data. 
In order to adjust for early withdrawals, weekly SBM frequency rates will be calculated as 
follows:
(Number of SBMs / Number of Days) × 7
The number of days in the denominator above is the number of days during the week that the 
subject was in the study. Weeks will be calculated as 168-hour intervals starting with the exact 
time of the first intake of study drug. The number of days will generally be 7 unless a subject 
drops out during a treatment week. If the number of days is less than 4, then the data will be 
considered insufficient and the rate will be set to missing.
The primary endpoint will be analyzed using van Elteren’s test stratified by center to examine 
the difference between lubiprostone and placebo. Additionally the endpoint will be analyzed 
using analysis of variance (ANOVA) models with center and treatment in the model as a 
sensitivity analysis. The estimated least squares (LS) means, related mean difference and 
associated 95% CI will also be presented to aid interpretation of the clinical effect. The 
interaction between treatment and center will also be examined in a separate ANOVA model.
This endpoint will be analyzed for the FAS. A sensitivity analysis using the PP will also be 
presented.


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To examine the effects of any dose reduction in response to an AE an additional sensitivity 
analysis will also be performed. This will be performed on the FAS where data from those 
subjects with a dose reduction will be excluded from the time of dose reduction and subjects will 
be treated as a drop-out from this time point onwards. Additionally, another factor will be added 
to the ANOVA model to examine the effect of dose reduction, this will be performed on the 
FAS, with no subjects excluded.
13.1.3.2 Secondary Endpoints
All secondary endpoints will be analyzed for the FAS only. 
SBM Frequency at Week 2, 3 and 4
The secondary endpoint will be analyzed as specified for the primary endpoint separately for 
each week. 
Proportion of Subjects With an SBM Within 24 hours After First Dose
The proportion of subjects with an SBM within 24 hours after first dose in Week 1 will be 
analyzed by a Cochran-Mantel-Haenszel (CMH) test stratified by center. Additionally a logistic 
regression model will be used with treatment and center as factors as a sensitivity analysis. The 
estimated odds ratio and associated 95% CI will also be presented to aid interpretation of the 
clinical effect. The interaction between treatment and center will not be examined in a separate 
model.
Mean Degree of Straining (Week 1, 2, 3, and 4)
For each subject, the mean degree of straining will be averaged for all SBMs in a given week. 
The mean degree of straining will then be analyzed by van Elteren tests, stratified by center, at 
Weeks 1, 2, 3, and 4 separately. Additionally the endpoint will be analyzed using ANOVA 
models with center and treatment in the model as a sensitivity analysis. 
Mean Degree of Stool Consistency (Week 1, 2, 3, and 4)
Stool consistency will be analyzed in the same manner described for the degree of straining.
Weekly Abdominal Symptoms Score (Bloating and Discomfort) (Week 1, 2, 3, and 4)
The abdominal symptoms (bloating and discomfort upon waking in the morning) will be 
analyzed separately by van Elteren tests, stratified by center, at Weeks 1, 2, 3, and 4. 
Additionally a cumulative logistic regression model will be used with treatment and center as 
factors as a sensitivity analysis. The estimated odds ratio and associated 95% CI will also be 
presented to aid interpretation of the clinical effect. The interaction between treatment and center 
will also be examined in a separate model.


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Weekly Responder Rate (Week 1, 2, 3, and 4)
Weekly responder rate (non-responder/ moderate responder/ full responder) will be analyzed by 
van Elteren tests, stratified by center, at Weeks 1, 2, 3, and 4 separately. Additionally a 
cumulative logistic regression model will be used with treatment and center as factors as a 
sensitivity analysis. The estimated odds ratio and associated 95% CI will also be presented to aid 
interpretation of the clinical effect. The interaction between treatment and center will also be 
examined in a separate model. A non-responder will be defined as any subject with a 
spontaneous BM frequency rate of less than 3 for a given week, any subject who dropped out 
during or prior to the given week due to lack of efficacy, or any subject who used rescue 
medication during or within 24 hours prior to the given week. Otherwise, the subject will be 
considered a responder. A responder with a spontaneous BM frequency rate ≥3 but <4 will be 
considered a moderate responder. Otherwise, the subject will be a full responder (≥4 SBM).
13.1.3.3 Additional Endpoints
Efficacy
PAC-QOL Questionnaire: The PAC-QOL will be analyzed separately for the first 24 items that 
comprise the Dissatisfaction Index and for the last 4 items that comprise the Satisfaction 
Subscale at Baseline, and at Weeks 2 and 4. 
The Dissatisfaction Index will be analyzed using van Elteren’s test stratified by center to 
examine the difference between lubiprostone and placebo. Additionally the endpoint will be 
analyzed using ANOVA models with center and treatment in the model as a sensitivity analysis. 
The estimated LS means, related mean difference and associated 95% CI will also be presented 
to aid interpretation of the clinical effect. 
The Satisfaction Index will be categorized by combined scores of the 4 items as either poor 
(0-4), fairly good (5-8), good (9-12), or excellent (13-16) and will be analyzed by van Elteren 
tests, stratified by center, at Baseline, and at Weeks 2 and 4 separately. Additionally a 
cumulative logistic regression model will be used with treatment and center as factors as a 
sensitivity analysis. The estimated odds ratio and associated 95% CIs will also be presented to 
aid interpretation of the clinical effect.
Safety
Adverse events will be summarized using the safety analysis set. No statistical testing or 
inferential statistics will be generated. 
All AEs will be coded using the MedDRA. Data will be summarized using preferred terms (PTs) 
and primary system organ class (SOC).
Vital signs, clinical laboratory values, and body weight will be summarized by treatment group 
for both actual and change from baseline values.


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13.1.3.4 Exploratory Endpoint
 
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size 
Assuming equal allocation, a power of 90%, an alpha level of 0.05 for a 2-sided test, a placebo 
mean of 4 (standard deviation of 2.7), and a treatment mean of 5.9 (standard deviation of 4) for 
SBM frequency at Week 1 and using the Wilcoxon-Mann-Whitney test, a total sample size of 
146 is required. The Wilcoxon-Mann-Whitney test is a non-parametric test of the null hypothesis 
that the distribution is the same for both placebo and treatment responses against the alternative 
that there is a location difference between the 2. The estimates of placebo and treatment response 
are based on a previous study conducted by Sucampo Pharmaceuticals in the US (Protocol No. 
RTU/0211SC0131).
The primary endpoint requires subjects to complete at least 4 days of the study diary, therefore 
assuming a drop-out rate of 3% by Day 4 an additional 4 subjects are required, giving a total of 
150 subjects.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (contract research organization [CRO]) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), and review of eCRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the 
sponsor or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the Food and Drug Administration [FDA], the 
United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 


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guarantee access for quality assurance auditors to all study documents as described in Section 
14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable local requirements in Korea. The 
sponsor or designee will require documentation noting all names and titles of members who 
make up the respective IRB or IEC. If any member of the IRB or IEC has direct participation in 
this study, written notification regarding his or her abstinence from voting must also be obtained. 
Those Americas sites unwilling to provide names and titles of all members due to privacy and 
conflict of interest concerns should instead provide a Federal Wide Assurance Number or 
comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
submitted to a central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of 
the protocol and subject informed consent must be obtained and submitted to the sponsor or 
designee before commencement of the study (ie, before shipment of the sponsor-supplied drug or 
study specific screening activity). The IRB or IEC approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (eg, informed 
consent form) reviewed; and state the approval date. The sponsor or designee will ship 
drug/notify site once the sponsor or designee has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor or designee has received permission from 
competent authority to begin the trial. Until the site receives drug/notification no protocol 
activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form and the subject information sheet 
(if applicable) further explain the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the subject is not 
capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRFs).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail.


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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee.


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16.0
REFERENCES
1. National Institute of Diabetes and Digestive and Kidney Diseases. Constipation. National 
Institute of Diabetes and Digestive and Kidney Diseases. Accessed 16 February 2015. 
Available at: http://www.niddk.nih.gov/health-information/health-topics/digestive-
diseases/constipation/Documents/Constipation_508.pdf.
2. Nighot PK, Blikslager AT. Chloride channel ClC-2 modulates tight junction barrier function 
via intracellular trafficking of occludin. Am J Physiol Cell Physiol 2012;302(1):C178-87.
3. Moeser AJ, Nighot PK, Engelke KJ, Ueno R, Blikslager AT. Recovery of mucosal barrier 
function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 
chloride channel, lubiprostone. Am J Physiol Gastrointest Liver Physiol 2007;292(2):G647-
56.
4. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterology 2006;130(5):1480-91.
5. National Institute of Diabetes and Digestive and Kidney Diseases. Bristol Stool Form Scale. 
National Institute of Diabetes and Digestive and Kidney Diseases. Accessed 16 February 
2015. Available at: http://en.wikipedia.org/wiki/Bristol_stool_scale.
6. Mueller-Lissner S, Kamm MA, Wald A, Hinkel U, Koehler U, Richter E, et al. Multicenter, 
4-week, double-blind, randomized, placebo-controlled trial of sodium picosulfate in patients 
with chronic constipation. Am J Gastroenterol 2010;105(4):897-903.
7. Kamm MA, Muller-Lissner S, Talley NJ, Tack J, Boeckxstaens G, Minushkin ON, et al. 
Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-
controlled multinational study. Am J Gastroenterol 2005;100(2):362-72.


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Appendix A
Schedule of Study Procedures
Study Day/Week
Screening Randomization
Treatment
Follow-up 
Period
Day -15
Day -1 (a)
First Dose
Day 1 (b) Week 1 Week 2
Final Visit or 
Early 
Termination 
Visit 
Week 4 (c)
Follow-up 
Phone 
Contact 
Week 6 (o)
Visit Windows (Days): (+/- 2 days)
-15 to -1
-1
1
8
15
29
43
Visit Number:
1
2
N/A
3
4
5
N/A
Informed consent
X
Demographics and medical history (d)
X
Inclusion/exclusion criteria (e)
X
X
Medication history
X
Physical examination
X
X
Vital signs (f) 
X
X
X
Weight and height (g)
X
X
Concomitant medications
X
X
X
X
X
X
X
Concurrent medical conditions
X
Clinical laboratory tests (h)
X
X
Pregnancy test (i)
X
X
X
Urine drug screen
X
Access IWRS for Subject ID/MED 
ID/Subject Status
X
X
X
Dispense investigational drug
X
Distribute rescue medications prescription 
as necessary
X
X
X
X
Drug return/accountability/compliance
X
X
X
Dispense study diary 
X
X
X
X
Efficacy:
Abdominal symptom assessment review 
(by diary)
X
X
X
X
PAC-QOL
X
X
X
Use of rescue medication (by diary)
X
X
X
X
Diary-keeping by subjects (j)
X
X
X
X
X
X
Diary collection/ compliance check (k)
X
X
X
X
Safety:
Guidance on avoidance of pregnancy and 
ova donation
X
X
X
X
X
Pretreatment adverse events (l)
X
X
Adverse events (m)
X
X
X
X
X
Dose reduction (optional) (n)
X
X
Phone interview
X
Footnotes are on last table page.


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N/A= not applicable.
(a) Subjects will be randomized on Day -1, the last day of the Screening Period. They will also receive their bottle of dispensed 
investigational study drug on Day -1, although they will be instructed to take the first dose the next day, on Day 1.
(b) Day 1 is the first day of study drug administration. Subjects are to take 1 capsule of lubiprostone 24 µg or placebo with 240 
mL of water in the morning with breakfast, and again in the evening with dinner. Repeat this regimen for 4 weeks.
(c) Conduct Final Visit procedures for subjects discontinued early per Section 7.6. Subjects who withdraw prematurely should 
return within 1 week of discontinuation for an Early Termination Visit. 
(d) Includes the results at Screening for IBS. The results of enema X-ray examination or total colonoscopy performed in the past 
2 years are referred to in order to determine organic disorders that can be ruled out. For subjects who have no history or show no 
current evidence of weight loss, anemia, or rectal bleeding, the examination results of the past 3 years may be used to rule out 
organic disorders.
(e) Subject eligibility is to be reconfirmed for all criteria on Day -1, Randomization Day, including diary data.
(f) Vital signs=blood pressure (systolic and diastolic), body temperature, and pulse rate.
(g) Height will be measured at Visit 1 and weight will be measured at Visit 1 and 5. 
(h) Hematology: hemoglobin, hematocrit, RBC, WBC with differential, platelets, MCV, MCH, RDW.
Serum chemistry: ALP, Albumin, ALT, AST, total bilirubin, direct bilirubin, total protein, total cholesterol, triglyceride, glucose, 
creatinine, BUN, creatine kinase, uric acid, GGT, LDH, Na, K, Cl, Ca, P, Mg, (TSH [performed to exclude hypothyroidism] and 
CRP levels are measured at Visit 1 only).
Urinalysis: pH, specific gravity, protein, glucose, occult blood, urobilinogen, bilirubin, ketone and leukocyte esterase.
Microscopic analysis (only if positive dipstick results).
(i) In women of childbearing potential only. Serum hCG pregnancy test conducted at Screening and at Final Visit (Early 
Termination Visit), and urine hCG pregnancy test conducted at Visit 2.
(j) Diary-keeping by subjects will be continuous from Day -15 throughout the Screening Period and the Double-Blind Treatment 
Period to Day 29 (Final Visit). There will be no diary-keeping in the Follow-up Period.
(k) Subjects who are not consistent or thorough with study diary completion may receive phone reminders if deemed necessary 
by the investigators. The authorized study personnel providing phone reminders must document the phone contact process in the 
subject’s source notes.
(l) Pretreatment adverse events: an adverse event in subjects who have signed informed consent to participate in the study that 
occurs prior to administration of any study medication; the event does not necessarily have to have a causal relationship with 
study participation. The pretreatment adverse events are assessed from Day -15 to hour 0 on Day 1, when study drug is 
administered.
(m) Pregnancy reporting in Follow-Up Period occurs at 2 weeks after the last dose of study drug.
(n) The investigator may reduce the dose due to adverse events depending on the type or severity of the adverse event. As a 
general rule, the investigational drug blind shall not be broken by the investigator for dose adjustment. Reasons for dose 
reduction or discontinuation as well as relevant details are recorded in the eCRFs.
(o) Efforts should be made to follow up with a telephone contact 14 days after the last dose of study medication or Early 
Termination Visit for subjects who are withdrawn from the study prematurely.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities: 
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard 
panel) screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with 
the study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), 
IRB/IEC, and the monitor may inspect the records. By signing a written informed consent 
form, the subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a research-
related injury to the subject.


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19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the subject otherwise is entitled, and that the subject may 
discontinue participation at any time without penalty or loss of benefits to which the subject 
is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
subject’s willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or 
provided as a separate document) describing to the subject the contemplated and permissible 
uses and disclosures of the subject’s personal information (including personal health 
information) for purposes of conducting the study. The subject authorization must contain the 
following statements regarding the uses and disclosures of the subject’s personal 
information:
a) That personal information (including personal health information) may be processed by 
or transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) It is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) That personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) That subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and


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e) That the subject’s identity will remain confidential in the event that study results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening throughout the duration of the study. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject 
is found to be pregnant during study, study medication will be discontinued and the 
investigator will offer the subject the choice to receive unblinded treatment information.
26. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.


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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Sample of Subject Diary and The Bristol Stool Scale
This table provides a sample of the subject diary, which will be provided to subjects on Day -15 
of the Screening Visit and in which they are to record every defecation event from Day -15 until 
Day 29. The diary prompts the subject to record all details of each event including the 
consistency of the stool and the difficulty they have in passing it. The second page of the 
appendix is the Bristol Stool Scale, which will be supplied to the subjects as an aid.
A. Date and time they take the study drug
B. After a bowel movement:
a. Date and time
b. Stool consistency
1 = Hard and round (difficult-to-pass) stool like those of rabbits
2 = Sausage-shaped but hard stool
3 = Sausage-shaped stool with cracks on the surface
4 = Sausage-shaped, soft stool with smooth surface, or coiled stool (like a snake)
5 = Soft, half-solid (and easy-to-pass) stool with clear crease
6 = Unshaped, loose stool with small, irregular-shaped pieces, or mushy stool
7 = Watery stool without solid pieces (entirely liquid)
c. Degree of straining:
0 = No straining
1 = Mild straining
2 = Moderate straining
3 = Strong straining
4 = Very strong straining
d. 
Yes = 
No= 
C. Abdominal symptom (bloating and discomfort)
Abdominal bloating:
0 = None (no abdominal distention)
1 = Mild (Slight abdominal distention)
2 = Moderate (Abdominal distention clearly felt)
3 = Severe (Severe abdominal distension)
4 = Very severe (Extremely strong abdominal distension)
Abdominal discomfort:
0 = None (no abdominal discomfort)
1 = Mild (Slight abdominal discomfort)
2 = Moderate (Abdominal discomfort clearly felt)
3 = Severe (Abdominal discomfort with pain)
4 = Very severe (Abdominal discomfort with severe pain)
D. Date and time a rescue medication was used (if applicable)
E. Concomitant drugs (if applicable)


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The investigator or clinical research coordinator will instruct the subjects to keep the diary 
throughout the study. If the investigator or coordinator asks a subject about diary entries and 
adds a note or corrects the diary for clarification, each note/correction will be marked with the 
date and signature and the reason for the correction. The investigator will maintain the diaries as 
part of the subject’s file at the site. 
Source: National Institute of Diabetes and Digestive and Kidney Diseases. [5]


 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled
Study to Evaluate the Efficacy and Safety of Lubiprostone for the Treatment of Chronic
Idiopathic Constipation
Clinical Science Approval
14-May-2015 19:46
Clinical Science Approval
15-May-2015 07:59
Statistical Approval
15-May-2015 08:54

SAP_001.pdf: 
Certain information within this statistical analysis plan has been redacted (ie, specific content is 
masked irreversibly from view with a blue or black bar) to protect either personally identifiable 
information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


CROSS-REGIONAL TEMPLATE 
Template Number: 
C-TMPL-DO-801 
Page: 
1 of 31 
Version Number: 
1.2 
Effective Date: 
14 Sep 2015 
This version replaces: 
1.1 
Parent Document: 
C-SOP-DO-800 
Template Title: 
Statistical Analysis Plan (Legacy Takeda) 
Printed or downloaded documents must be verified against the effective version. 
CONFIDENTIAL INFORMATION 
Do not distribute outside of Takeda without a confidentiality agreement. 
TAKEDA DEVELOPMENT CENTER 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: LUBIPROSTONE-3002 
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of Lubiprostone for the Treatment of Chronic 
Idiopathic Constipation 
PHASE 3 
Version: Final 
Date: 12th April 2017 
Prepared by:  
 , M.Sc.  
, GI TAU 
CONFIDENTIAL PROPERTY OF TAKEDA 


 
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CONFIDENTIAL INFORMATION 
Do not distribute outside of Takeda without a confidentiality agreement. 
 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. 




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Printed or downloaded documents must be verified against the effective version. 
CONFIDENTIAL INFORMATION 
Do not distribute outside of Takeda without a confidentiality agreement. 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................................... 1 
1.0 
APPROVAL SIGNATURES ...................................................................................... 3 
2.0 
TABLE OF CONTENTS .................................................................................................................. 4 
3.0 
LIST OF ABBREVIATIONS ............................................................................................................ 6 
4.0 
OBJECTIVES .................................................................................................................................. 8 
4.1. 
PRIMARY OBJECTIVES ................................................................................................. 8 
4.2. 
STUDY DESIGN .......................................................................................................... 8 
5.0 
ANALYSIS ENDPOINTS ............................................................................................................... 10 
6.0 
DETERMINATION OF SAMPLE SIZE .......................................................................................... 11 
7.0 
METHODS OF ANALYSIS AND PRESENTATION ...................................................................... 12 
7.1 
GENERAL PRINCIPLES [OR CONSIDERATIONS] .............................................................. 12 
7.2 
ANALYSIS SETS ........................................................................................................ 13 
7.3 
DISPOSITION OF SUBJECTS ....................................................................................... 15 
7.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ........................................................ 16 
7.5 
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS ........................................ 16 
7.6 
MEDICATION HISTORY AND CONCOMITANT MEDICATIONS ............................................. 16 
7.7 
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................................ 17 
7.8 
EFFICACY ANALYSIS ................................................................................................. 19 
7.8.1 
Primary Efficacy Endpoint(s) .................................................................................. 21 
7.8.2 
Secondary Efficacy Endpoint(s) .............................................................................. 22 
7.8.3 
Additional Efficacy Endpoint(s) ............................................................................... 25 
7.9 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS ...................................................... 26 
7.10 
OTHER OUTCOMES ................................................................................................... 26 
7.11 
SAFETY ANALYSIS .................................................................................................... 26 
7.11.1 
Adverse Events ...................................................................................................... 26 
7.11.2 
Clinical Laboratory Evaluations ............................................................................... 28 
7.11.3 
Vital Signs .............................................................................................................. 29 
7.11.4 
12-Lead ECGs ....................................................................................................... 30 
7.11.5 
Other Observations Related to Safety ..................................................................... 30 
7.12 
INTERIM ANALYSIS .................................................................................................... 30 
7.13 
CHANGES IN THE STATISTICAL ANALYSIS PLAN ............................................................ 30 
8.0 
REFERENCES ............................................................................................................................... 31 


 
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CONFIDENTIAL INFORMATION 
Do not distribute outside of Takeda without a confidentiality agreement. 
 
 


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Statistical Analysis Plan (Legacy Takeda) 
 
Printed or downloaded documents must be verified against the effective version. 
CONFIDENTIAL INFORMATION 
Do not distribute outside of Takeda without a confidentiality agreement. 
3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
BID 
bis in die (twice a day) 
BM 
bowel movement 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CIC 
chronic idiopathic constipation 
CPK 
creatine phosphokinase 
CRF 
case report form 
ECG 
electrocardiogram 
FAS 
full analysis set 
GGT 
γ-glutamyl transferase 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IVRS 
Interactive Voice Response System 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
PAC-QoL 
patient assessment of constipation – quality of life 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
QOL 
quality-of-life 
PPS 
per protocol set 
PRO 
patient-reported outcome 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SBM 
spontaneous bowel movement 
SD 
standard deviation 
SDB 
standard database 
TLGs 
tables, listings, and graphs 
ULN 
upper limit of normal 
WHODrug 
World Health Organization Drug Dictionary 


 
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4.0 
OBJECTIVES 
4.1. 
PRIMARY OBJECTIVES 
The primary objective of this study is to evaluate the efficacy and safety of oral administration of 
lubiprostone 24 μg BID for 4 weeks in subjects with CIC compared with placebo. 
 
4.2. 
STUDY DESIGN 
This is a phase 3, randomized, double-blind, parallel-group, placebo-controlled study in subjects 
with CIC as determined by the Rome III Diagnostic Criteria for Functional Constipation [4]. 
This study consists of a 14-day Screening Period,a subsequent 4-week (28 days) Double- Blind 
Treatment Period in which subjects will receive either lubiprostone or matching placebo BID and 
a 2 week follow-up period. Subjects will be randomized to either active lubiprostone or placebo 
in a 1:1 ratio. During the Screening Period, the defecation behavior of each subject is recorded in 
a diary to confirm he/she has constipation. The subject diary will be distributed on Study Days -
15, -1, 8 and 15. Subjects will be instructed to keep the diary every day including on the morning 
of Visit 1 for the entire week.  
Use of all existing laxatives is stopped at the beginning of the Screening Period (Visit 1). 
Subjects are instructed not to change their diet or lifestyle habits during the study. A total of 10 
mg of bisacodyl suppository (or any equivalent drug) may be prescribed as a standard rescue 
medication if a subject has no adequate bowel movement for 3 consecutive days during the 
Screening Period of the study. When bisacodyl suppository does not improve constipation, 
glycerin enema (or equivalent drug) will be given. Subjects are instructed to complete their 
diaries before using rescue medications.  
If the rescue medications fail to improve constipation, the investigator may decide to use another 
rescue medication. The recommendation may include a medication from the excluded 
medication list other than any form of polyethylene glycol, linaclotide, methylnaltrexone, or 
prucalopride, all of which are considered prohibited rescue medications. No rescue medication 
may be given 24 hours prior to and until 48 hours after the first dose of the study drug (Day 1). 
Subjects who use a rescue medication within 24 hours before the first dose of study drug on Day 
1 should be withdrawn from the study. Those who use a rescue medication within 48 hours after 
dosing on Day 1 will be discontinued from the study by the investigator. The dose and mode of 
administration of rescue medications must be recorded in the electronic case report form (eCRF). 
Approximately 150 subjects whose constipation is confirmed during the Screening Period will be 
randomized in the Double-Blind Treatment Period to receive either lubiprostone or matching 
placebo BID. Others whose constipation does not satisfy the criteria during the 14-day Screening 
Period or those who receive a rescue medication within 24 hours prior to the first dose on Day 1 
are ineligible for randomization in the Double-Blind Treatment Period and therefore will be 
excluded from the study. Subjects who satisfy the inclusion criteria and do not meet the 


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5.0 
ANALYSIS ENDPOINTS 
Spontaneous bowel movement (SBM) frequency in Week 1 of study drug administration. 
Primary Endpoint 
SBM frequency (Week 2, 3, and 4). 
Secondary Endpoints 
Proportion of subjects who have a SBM within 24 hours after first dose. 
Mean degree of straining (Week 1, 2, 3, and 4). 
Mean degree of stool consistency (Week 1, 2, 3, and 4). 
Weekly abdominal symptoms score (bloating and discomfort) (Week 1, 2, 3, and 4). 
Weekly responder rate (Week 1, 2, 3 and 4) 
Quality of life evaluation using the standard Patient Assessment of Constipation—Quality of 
Additional Endpoints 
Life (PAC-QOL) Questionnaire. 
The safety of lubiprostone will be evaluated by the following parameters: 
Safety 
Adverse events (AEs) 
Clinical laboratory values. 
Vital signs, including body temperature, blood pressure, heart rate, and body weight. 
Physical examination. 
Exploratory Endpoints 


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6.0 
DETERMINATION OF SAMPLE SIZE 
Assuming equal allocation, a power of 90%, an alpha level of 0.05 for a 2-sided test, a placebo 
mean of 4 (standard deviation of 2.7), and a treatment mean of 5.9 (standard deviation of 4) for 
SBM frequency at Week 1 and using the Wilcoxon-Mann-Whitney test [1], a total sample size of 
146 is required. The Wilcoxon-Mann-Whitney test is a non-parametric test of the null hypothesis 
that the distribution is the same for both placebo and treatment responses against the alternative 
that there is a location difference between the two. The primary analysis will be conducted using 
the van Elteren test, which is a stratified version of the Wilcoxon-Mann-Whitney test, use of the 
Wilcoxon-Mann-Whitney test for sample size estimation will provide an approximate sample 
size for the van Elteren analysis. The estimates of placebo and treatment response are based on a 
previous study conducted by Sucampo Pharmaceuticals in the United States of America 
(Protocol No.  RTU/0211SC0131). 
The primary endpoint requires subjects to complete at least 4 days of the study diary, therefore 
assuming a non-evaluable rate of 3% by Day 4 an additional 4 subjects are required, giving a 
total of 150 subjects. 


 
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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
GENERAL PRINCIPLES [OR CONSIDERATIONS] 
Continuous data will be summarized using number of subjects (N), mean, standard deviation 
(SD), median, minimum, and maximum. Summary statistics for continuous data will only 
include subjects with a non-missing value for the data being summarized. 
Categorical data will be summarized using the number and percent of subjects for each category 
where appropriate. Missing categories will be used for categorical data when missing data is 
present. The calculation of percentages will take into account missing responses. 
All confidence intervals, statistical tests, and resulting p-values will be reported as 2-sided unless 
otherwise stated. P-values (when rounded to three decimals) less than or equal to α (=0.05) are 
reported as “statistically significant”. 
Means, LS means, and medians will be presented to 1 more decimal place than the recorded data. 
Where presented, SDs and standard errors  will be presented to 2 more decimal places than the 
recorded data. Confidence intervals for parameter estimates will be presented using the same 
number of decimal places as those recorded for the parameter point estimate.  
Alternative methods of analysis of the data may be considered prior to un-blinding should some 
of the assumptions underlying the proposed analyses not be met. However, the reasons for any 
departures from the planned approach and methods will be documented fully. 
Centers may be pooled geographically if necessary for analysis purposes. 
Version 9.4 or later of SAS®, will be used to provide all data summaries, statistical analyses, and 
data listings. 
 


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Study Visit Windows 
For BM data the assignment of data to each week (1, 2, 3 and 4) will be calculated from the date 
and time of the morning dose on Day 1. If no morning dose was taken on Day 1, then the date of 
Day 1 will be used and the time of the first recorded morning dose will be used.  Weeks will be 
calculated as 168-hour intervals starting from this time. Note that any diary entries prior to this 
will be assigned to the screening period. Where missing dates or times do not allow the 
assignment of diary data to a treatment period (Screening or double blind) then it will be 
assumed that all data in the Screening booklet was recorded during Screening and all data in the 
remaining booklets were recorded after the booklets were provided to subjects. Abdominal 
symptom assessments will be assigned to the week as recorded in the diary. PAC-QOL is 
assessed at Day -1, Week 2 (Day 15) and Week 4 (Day 29).  PAC-QOL assessments will be 
assigned to the time point relating to the visit at which they are recorded, regardless of actual 
study day. Assessments conducted at an Early Termination Visit will be assigned to the next 
scheduled visit that would have taken place if the subject had not discontinued, e.g. if the subject 
withdraws prior to Week 2 then the Early Termination Visit assessment will map to Week 2, 
whereas if the Early Termination Visit occurs after Week 2 then the assessment will be assigned 
to Week 4. 
Study Day/Week 
Screening 
Double Blind Treatment Period 
Follow-up 
Phone 
Contact 
Screening 
Randomization First Dose Week 1 
Week 2 
Final Visit / Early 
Termination Visit 
Week 4 
Visit Number: 
1 
2 
- 
3 
4 
5 
- 
Day 
-15 
-1 
1 
8 
15 
29 
43 
7.2 ANALYSIS SETS 
Total Set: The total set consists of all subjects who signed the informed consent form, including 
subjects withdrawn prior to randomization. 
Full Analysis Set (FAS): This will consist of all subjects randomized to receive study treatment 
whether or not they received treatment. Subjects will be reported according to their randomized 
treatment group regardless of treatment received. 
Per-Protocol Analysis Set (PPS): The PPS will consist of subjects in the FAS with the additional 
following criteria for exclusion: 
•
Did not receive study treatment as per randomization schedule (including not receiving
any randomized treatment)
•
Dose of randomized treatment was adjusted.


 
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• Violated inclusion criteria, such as: 
o Does not have a history of constipation defined as SBM frequency of less than 3 
times per week on average for 6 months or longer (and observed during Screening 
Period). 
o Does not have SBMs with ≥1 of the following 3 symptoms for the last 6 months 
or longer, in at least 1 out of every 4 bowel movements: scybalum stool or hard 
feces, straining, or the sensation of incomplete evacuation. 
o The subject rarely has loose stools without the use of laxatives. 
• Violated exclusion criteria, such as: 
o The subject has a history or clinical manifestations of significant mechanical 
obstruction (intestinal obstruction due to tumor, hernia etc). 
o Has chronic constipation due to a secondary cause (medications, diabetes 
mellitus, hypothyroidism, depression, etc). 
o Has sufficient criteria for IBS or there is a functional defecation disorder. 
o BM frequency is 3 or more per week. 
o SBM frequency has been less than 3 times per week for less than 6 months in 
duration or whose symptoms associated with SBM have been present for less than 
6 months (hard feces, sensation of incomplete evacuation, or straining). 
o Received treatment with a rescue medication within 24 hours prior to the first 
dose on the morning of Day 1. 
o Has megacolon/megarectum or has received a diagnosis of intestinal pseudo-
obstruction. 
o Has confirmed or suspected organic disorders of the large intestine (obstruction, 
stenosis, carcinoma, or inflammatory bowel disease). Any subject in whom total 
colonoscopy has detected a polyp requiring treatment is excluded from this study. 
o Has been hospitalized for gastrointestinal or abdominal surgery within 3 months 
before the start of this study. 
o Use of any excluded medications, procedures or treatments prior to the 
assessment of the primary endpoint. 
Any other significant event interfering with efficacy evaluation of primary endpoint, to be 
decided at the Targeted Data Review Meeting, for example,. Definitions of criteria constituting 
major deviations will be provided, prior to unblinding. 
Therefore subjects will be reported according to their treatment group. 


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Safety Analysis Set (SAF): This will consist of all subjects who receive study treatment. Subjects 
will be assigned to the treatment group according to the actual treatment received. 
The FAS will be used for efficacy analyses. Supportive analyses based on the PP will be 
performed for the primary efficacy variable. The SAF will be used for all safety analyses. 
7.3 DISPOSITION OF SUBJECTS 
A summary of screened subjects will display the number of subjects screened and the number of 
subjects in the Total Set, FAS, SAF and PPS; overall and at each center.   Reason for exclusion 
from each analysis population will also be presented. 
Subject disposition will be summarized for the Total Set and will include the frequency and 
percentage of subjects who completed each visit, the frequency and percentage of subjects who 
were screen failures, the frequency and percentage of subjects who discontinued prematurely 
from the study along with the frequency and percentage of subjects for each reason for screen 
failure/discontinuation. This information will be displayed by treatment. 
The primary reason for screen failure should be recorded using the following categories: 
1. Pretreatment event (PTE) or adverse event (AE),
2. Did not meet inclusion criteria or did meet exclusion criteria.
3. Significant protocol deviation.
4. Lost to follow-up.
5. Voluntary withdrawal (specify reason).
6. Study termination.
7. Other (specify reason).
The primary reason for discontinuation should be recorded using the following categories: 
1. PTE or AE, including liver function test (LFT) abnormalities.
2. Significant protocol deviation.
3. Lost to follow-up.
4. Voluntary withdrawal.
5. Study termination.
6. Pregnancy.
7. Lack of efficacy.
8. Unblinding of subject treatment.
9. Other.
Significant protocol deviations for the FAS will be summarized according to the category of 
deviation, by site and treatment group. 


 
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7.4 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics will include age (years) at date of informed consent, 
race, ethnicity, smoking status, gender, height (cm), weight (kg) at Screening, body mass index 
(BMI) (kg/m2) at Screening. 
 
Demographic and baseline characteristics will be summarized by randomised treatment group 
and total for the Total Set. Subjects in the Total Set who were screen failures will be included in 
a ‘Screen Fail’ group for presentation purposes and included in the total column. 
 
7.5 MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS 
Any significant relevant illness that was resolved before screening will be recorded as medical 
history. Any relevant illness that is present at the day of the screening visit will be documented 
as concomitant illness. Medical histories and concomitant illnesses will be coded according to 
the Medical Dictionary for Regulatory Activities (MedDRA), current version. Medical histories 
and concomitant illnesses will be summarized separately, by system organ class (SOC) and 
preferred term (PT). Frequencies and percentages will be displayed by treatment and in total. 
 
7.6 MEDICATION HISTORY AND CONCOMITANT MEDICATIONS 
Medication history information includes any medication relevant to eligibility criteria and 
efficacy/safety evaluation stopped at or within 1 month prior to signing of informed consent. 
 
Concomitant medication is any medication other than the IMP that is administered during the 
trial including screening. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHODrug). Concomitant medications and medication history 
will be summarized separately for the SAF as the frequency and percentage of patients taking 
each medication. If a patient took a particular coded medication more than once, the patient will 
be counted only once for that medication total. If a patient took more than one medication in a 
particular therapeutic class, the patient will be counted only once in that therapeutic class total. 
 
A total of 10 mg of bisacodyl suppository (or an equivalent drug) may be prescribed as a 
standard rescue medication if a subject has no adequate BM for 3 consecutive days during the 
study. When bisacodyl suppository does not improve constipation, glycerin enema (or equivalent 
drug) may be given. Rescue treatment will be summarized for the FAS by the frequency and 
percentage of patients for each applied type and time to active rescue treatment. 
 


 
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7.7 STUDY DRUG EXPOSURE AND COMPLIANCE 
Study drug exposure and compliance will be summarized by randomised treatment group for the 
SAF and FAS respectively. No inferential statistics will be presented. Subject diary compliance 
will be presented summarized by randomised treatment group and total for the FAS for both 
screening and double blind periods separately. 
 
Duration of exposure to drug (days) will be calculated as the number of days from the date of 
first dose to the date of last dose of study drug inclusive. So that exposure = date of last dose- 
date of first dose + 1. Exposure will be summarised as a continuous variable. Doses taken after 
Day 28 will be included in the calculation of compliance, as specified compliance is calculated 
up to the date of the last dose taken, 
 
Study drug is dispensed to subjects on Day -1 only. Subjects are supplied with a bottle 
containing enough drug for 28 days + 2 extra days.  Subjects will be required to bring their study 
drug bottle with them for each visit of the double blind treatment period; Day 8 (visit 3), Day 
15(visit 4) and Day 29 (visit 5). Subjects also record their daily medication intake in their diary. 
 Study drug compliance will be calculated by: 
 
 
 
Overall compliance calculation is considered to indicate compliance with the dosing regimen 
rather than dosing duration, e.g. if a subject takes all expected doses whilst in the study but 
withdraws early then compliance will be considered 100%.  
Overall compliance will be calculated using:  
The number of capsules taken is defined as the difference between the total number of 
capsules dispensed and the total number of capsules remaining at the last visit. 
 The number of capsules expected to be taken is defined as the number of capsules 
prescribed per day (BID dosing) multiplied by the number of days from Day 1 to the date of last 
dose (last dose date – Day 1 date). If the last dose was a morning dose then this will be increased 
by 1, if the last dose was an evening dose then this number will be increased by 2. This is to 
account for the fact that the subject may stop dosing in the morning or evening of the last dose 
date.  
 
Week 1 compliance will be calculated using: 






×
 taken
be
 
 to
expected
 
capsules
 
of
number 
 taken
capsules
 
of
number 
100


 
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The number of capsules taken is derived from the subject diary and will be calculated as 
the number of completed dosing entries in the diary for the first 7 days following randomization 
(i.e. Day 1 to Day 7 inclusive). This should be 2 per day, a morning and evening dosing record). 
The number of expected capsules to be taken will be calculated as 14 (7 days of BID 
dosing) if the subject has not withdrawn prior to completing 7 days of dosing. If the subject has 
withdrawn early (less than 7 days on treatment) then this number will be calculated as for overall 
compliance. 
Overall study drug compliance should also be calculated from the subject’s diary, where the 
number of tablets taken is derived from the number of completed entries (there should be 2 per 
day, a morning and evening record). The number of expected capsules is calculated as before. If 
there is a discrepancy between calculated compliance values then unless there is a recorded 
comment explaining the discrepancy and indicating that the diary value is correct (e.g. a 
comment may have been recorded indicating that some tablets were lost) the overall compliance 
calculated using capsule counts will be taken as the correct value. 
 
Study drug compliance will be summarized, for overall compliance and for compliance during 
Week 1, as a continuous variable and additionally, as a categorical variable, with the following 
categories: 
• Compliance < 70% 
• Compliance ≥ 70% and < 90% 
• Compliance ≥ 90% and < 110% 
• Compliance >110% 
Compliance with the diary will also be assessed. During the double blind period there should be 
2 records of study drug intake per day, note that if a dose was missed then ‘Not taken’ should be 
ticked, therefore there should be 2 entries per day, regardless of actual doses taken. Also for each 
day there are two questions requiring an answer (Yes/No): “Did you have bowel movement 
today?” and “Did you use rescue medication today?” A diary shall be considered compliant for 
that day if all expected entries for that day are recorded. At a minimum this will mean both 
questions have been answered and two drug accountability records (either time or ‘Not taken’). 
If ‘Yes’ has been answered to any question then at least one related entry should be present for 
that day, with all expected data fields completed. Compliance during the screening period will be 
similar, except that no study drug intake is recorded and bowel movement is captured either as ‘I 
did not have a bowel movement today” ticked or at least one completed bowel movement record. 
Subject Diaries are dispensed on Day -15 (visit 1) Day -1, Day 8 and Day 15. Diary compliance 
checks are conducted at each visit, except screening and follow-up. Diary compliance should be 
calculated as: 


 
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Subject diary compliance will be summarized, for overall compliance during the double blind 
period and Week 1, as a continuous variable and additionally, as a categorical variable, with the 
following categories: 
• Compliance < 70% 
• Compliance ≥ 70% and < 80% 
• Compliance ≥ 80% and < 90% 
• Compliance ≥ 90% and < 100% 
• Compliance  = 100% 
 
7.8 EFFICACY ANALYSIS 
The primary and secondary endpoints will be derived from the daily diary data entered by 
patients.  
Two-sided tests at a significance level of α=5% will be used throughout unless otherwise stated. 
The null hypothesis is that lubiprostone is equal to placebo against the alternative that 
lubiprostone is different to placebo. All analyses will be performed using the FAS. Analyses 
specified for the PP are to be regarded as supportive evidence. There will be no adjustment for 
multiplicity. 
All efficacy endpoints will be summarized by treatment and visit. If baseline measures are also 
defined and collected for an efficacy endpoint then change from Baseline at each visit will also 
be presented by summary statistics by treatment and visit. Change from baseline will be 
calculated as (post-baseline value) – (baseline value). Baseline is defined as the last recorded 
measurement prior to treatment.  
For diary data, baseline values will be the average of all diary data from the screening period 
(Days –14 through –1, inclusive, relative to day of first dose). If more than 14 days of diary data 
are collected during the screening period only the data from Day -14 onwards will be used. If 
fewer than 8 days are available then the baseline value will be set to missing. 
 
Centers may be pooled geographically if necessary for analysis purposes. This will be 
determined before database lock.  






×
completed
 
be
 
 to
expected
 
days
 
of
number 
completed
 
days
 
of
number 
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For weekly SBM frequency, at least 4 days of diary data are required to compute a weekly 
estimate, if there are less than 4 days recorded in a week then the SBM frequency for that week 
will be set to missing. 
As the primary endpoint is within the first week of study treatment and only 4 days of diary 
collection are required it is not anticipated that missing values should be a cause of concern 
therefore the LOCF technique will be used to impute missing values for efficacy analysis 
purposes only. For a given subject, the most recent nonmissing data point will be carried forward 
to the subsequent week where data are missing. Details for each efficacy parameter are given 
below. It is expected, based on previous studies, that the number of subjects with in-sufficient 
post baseline data for the primary endpoint will be small therefore a simple approach to handling 
missing data will be used. Where there is no post baseline efficacy data then the baseline value 
will be used, it is expected that the number of SBMs should increase for those on treatment, 
therefore using a baseline value for missing post baseline data assumes no treatment effect, this 
approach can be considered conservative,.  To examine the effect of the requirement to have at 
least a minimum of 4 days post baseline efficacy data for the primary endpoint an additional 
analysis, stratified by centre,  of the primary endpoint, using the stratified van Elteren test [2], 
will be conducted using all valid SBM data post baseline even when less than 4 days data is 
present, only where there is no post baseline data will baseline be used in this analysis. 
An SBM is defined as any BM that does not occur within 24 hours after rescue medication use. 
Certain periods after taking rescue medication will be defined as “blackout periods” during 
which BMs are considered as non-spontaneous. Blackout periods, including those with missing 
or partial times for rescue medication use in the diary, will be handled as follows: 
0-24 hours post rescue medication intake if the time is fully specified. 
0-24 hours post rescue medication intake if the hour is present, but the minute is missing. The 
blackout time will commence from the imputed time. If the minutes are incomplete or missing 
from either the rescue medication or bowel movement entry then it is assumed that the missing 
values are zero and an imputed time will be calculated. e.g.  
1 5 _ _ 
= 1 
5 0 0 
2 1 5 _ 
= 2 
1 5 0 
 
0-48 hours, beginning from midnight on the day the rescue medication intake is recorded for, if 
the hour is missing from the time entry for the rescue medication. 
Box plots will be produced for each weekly measure (SBM frequency, mean degree of straining, 
mean degree of stool consistency and weekly abdominal symptoms scores) by treatment over 
time from baseline to Week 4. Additionally graphs presenting histograms of SBM frequency will 
also be produced by treatment for each week. 
 


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7.8.1 
Primary Efficacy Endpoint(s) 
The primary efficacy endpoint is SBM frequency at Week 1; an SBM is defined as any BM that 
does not occur within 24 hours after rescue medication use. Since rescue medication use will be 
disallowed during Week 1, the SBM frequency should equal the BM frequency. In the case of 
protocol violators, the analysis will be based on SBMs.  
In order to adjust for early withdrawals or those with less than 7 days diary data, weekly SBM 
frequency will be calculated as follows: 
7 x (Number of SBMs / Number of days) 
Where the number of days is the number of days during the week that the subject was in the 
study. Weeks will be calculated as 168-hour intervals starting from the day after randomization 
(Day1), if there is no time recorded for the morning dose on Day1 then the time of the first 
recorded morning dose will be used.  The number of days will generally be 7 unless a subject 
drops out during a treatment week. If the number of days is less than 4, then the data will be 
considered insufficient and the frequency will be missing.  
Primary Analysis 
Since outliers are commonly observed in these data, parametric models may not be robust. The 
efficacy data will therefore be analyzed by a van Elteren test stratified by center. If necessary, 
small centers will be pooled as mentioned above. This procedure will test the null hypothesis of 
equal SBM rates between treatments at the end of Week 1 versus the alternative hypothesis of 
non-equality between the 2 groups; the test will be conducted at a 2-sided significance level of 
0.05. A related 95% confidence interval and point estimate will be provided for the treatment 
difference; the confidence interval will be estimated by inverting the hypothesis test. This 
endpoint will be analyzed for the FAS.  
Sensitivity Analyses 
The primary analysis as described above will be repeated using the PP rather than the FAS. An 
additional sensitivity analysis using the FAS assuming a ‘worse-case’ scenario approach will 
also be conducted, where missing values, including those with < 4 days diary data, are assigned 
the worst case values (the lowest SBM frequency for week 1) recorded in the study by any 
subject for that endpoint at that time. 
Additionally the endpoint will be analyzed using robust analysis of variance (ANOVA) models 
(by M-estimation [3] using PROC ROBUSTREG in SAS) with center and treatment in the model 
as a sensitivity analysis using the FAS. The interaction between treatment and center will also be 
examined in a separate model, using robust ANOVA methods as previously described. 
To examine the effects of any permanent dose reduction in response to an AE (as recorded on the 
eCRF) an additional sensitivity analysis will also be performed. This will be performed on the 


 
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FAS where data from those subjects with a dose reduction will be excluded from the time of 
dose reduction (taken as date of last BID dose + 12 hours, e.g. if the evening dose is removed 
then the time will be from the morning dose + 12 hours, if the morning dose is removed then it 
will be from the previous day’s evening dose + 12 hours) and subjects will be treated as a drop-
out from this time point onwards. This will be implemented using robust ANOVA. Additionally, 
another factor will be added to the robust ANOVA model to examine the effect of dose reduction 
(), this will be performed on the FAS. This analysis will not be carried out if the number of 
subjects with a dose reduction within the first week is less than 5%. 
 
7.8.2 
Secondary Efficacy Endpoint(s) 
The interaction of treatment and center and the effect of dose reduction will not be examined for 
any secondary endpoints. All secondary endpoints will be analyzed for the FAS only. 
The secondary endpoint will be analyzed as specified for the primary endpoint separately for 
each week. 
SBM frequency at Week 2, 3 and 4 
Additionally for patients with a missing Week 2 frequency estimate (where diary days < 4 in 
Week 2) the Week 1 estimate will be carried forward, if available. For the worse-case analysis all 
missing Week 2 values will be assigned the lowest SBM frequency for week 2.  
 
 
The 24 hour period will be taken from the time of the first recorded dose in the patient diary. If 
the efficacy data is missing for the first 24 hours following this dose then it will be assumed that 
the patient did not experience any BM (including SBMs) during this period, this is based on the 
assumption that a patient is more likely to complete the diary on any particular day if they 
experience a BM than if they did not. The proportion of subjects with an SBM within 24 hours 
after first dose in Week 1 will be analyzed by a Cochran-Mantel-Haenszel (CMH) test stratified 
by center. Additionally a logistic regression model will be used with treatment and center as 
factors as a sensitivity analysis. The estimated odds ratio and associated 95% CI for both 
methods will be presented to aid interpretation of the clinical effect.  
Proportion of subjects with an SBM within 24 hours after first dose 
 
For each BM patients should indicate the degree of straining associated with that BM. The 
degree of straining is a 5 point scale: 
Mean Degree of Straining (Week 1, 2, 3, and 4) 
 
0 = No straining 


 
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1 = Mild straining 
2 = Moderate straining 
3 = Strong straining 
4 = Very strong straining 
 
For each subject, the mean degree of straining will be averaged for all SBMs in a given week. 
The mean degree of straining will then be analyzed by van Elteren tests, stratified by center, at 
Weeks 1, 2, 3, and 4 separately. A related 95% confidence interval and point estimate will be 
provided for the treatment difference; the confidence interval will be estimated by inverting the 
hypothesis test.  
 
Additionally the endpoint will be analyzed using robust analysis of variance (ANOVA) models 
with center and treatment in the model as a sensitivity analysis. 
 
If there are no SBMs during the week or if there are SBMs but all ratings are missing, then the 
LOCF method will impute the average from the average used for the most recent week. For 
Week 1 analysis where there is no value to carry forward then a value of 4 will be assumed. This 
assumption will be carried into later weeks if LOCF does not provide an estimate. 
 
For each BM patients should indicate the type of stool consistency associated with that BM. The 
degree of stool consistency is assessed using the Bristol Stool Scale [3]; a 7 point scale, where 
decreasing values indicate harder stools: 
Mean Degree of Stool Consistency (Week 1, 2, 3, and 4) 
 
Type 1 
 
Separate hard lumps, like nuts (hard to 
pass) 
Type 2 
 
Sausage-shaped but lumpy 
Type 3 
 
Like a sausage but with cracks on its 
surface 
Type 4 
 
Like a sausage or snake, smooth and soft 
Type 5 
 
Soft blobs with clear-cut edges (passed 
easily) 
Type 6 
 
Fluffy pieces with ragged edges, a mushy 
stool 


 
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Type 7 
 
Watery, no solid pieces, entirely liquid 
 
Stool consistency will be analyzed in the same manner described for the degree of straining. For 
Week 1 analysis where there is no value to carry forward then a value of 1 will be assumed. This 
assumption will be carried into later weeks if LOCF does not provide an estimate. 
 
The abdominal symptom score should be completed by patients in their diary, every 7 days on 
the last day of each treatment week upon waking in the morning. Patients should indicate the 
degree of abdominal bloating and discomfort experienced over the past week.  
Weekly Abdominal Symptoms Score (Bloating and Discomfort) (Week 1, 2, 3, and 4)  
 
 
Abdominal Bloating 
0 = None: No abdominal distension    
1 = Mild: Slight abdominal distension    
2 = Moderate: Abdominal distension clearly felt 
3 = Severe: Severe abdominal distension             
4 = Very severe: Extremely strong abdominal distension 
Abdominal Discomfort 
0 =  None: No abdominal discomfort      
1 = Mild: Slight abdominal discomfort    
2 = Moderate: Abdominal discomfort clearly felt       
3 = Severe: Abdominal discomfort with pain                
4 = Very severe: Abdominal discomfort with severe pain 
 
The abdominal symptoms (bloating and discomfort) will be analyzed separately by van Elteren 
tests, stratified by center, at Weeks 1, 2, 3, and 4. A related 95% confidence interval and point 
estimate will be provided for the treatment difference; the confidence interval will be estimated 
by inverting the hypothesis test. 
 
Additionally a cumulative logistic regression model will be used with treatment and center as 
factors as a sensitivity analysis. The estimated odds ratio and associated 95% CI will also be 
presented to aid interpretation of the clinical effect. The interaction between treatment and center 
will also be examined in a separate model. 
 
 If the assessment ratings are missing, then the LOCF method will impute the value from the 
value used for the most recent week. For Week 1 analysis where there is no value to carry 
forward then a value of 4 will be assumed. This assumption will be carried into later weeks if 
LOCF does not provide an estimate. 
 
 
Weekly Responder Rate (Weeks 1, 2, 3, and 4) 
Weekly responder rate will be assessed at each week and will be derived from the data on SBMs 
collected in the subject diary. Responder analysis will be performed at each week. A non-


 
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responder will be defined as any subject with a spontaneous BM frequency rate of less than 3 for 
a given week, any subject who dropped out during or prior to the given week due to lack of 
efficacy, or any subject who used rescue medication during or within 24 hours prior to the given 
week. Otherwise, the subject will be considered a responder. A responder with a spontaneous 
BM frequency rate ≥ 3 but <4 will be 
considered a moderate responder. Otherwise, the subject will be a full responder (≥ 4 SBM). 
 
Weekly responder rate (non-responder/ moderate responder/ full responder) will be analyzed by 
van Elteren tests, stratified by center, at Weeks 1, 2, 3, and 4 separately. Additionally a 
cumulative logistic regression model will be used with treatment and center as factors as a 
sensitivity analysis. The estimated odds ratio and associated 95% CI will also be presented to aid 
interpretation of the clinical effect. The interaction between treatment and center will also be 
examined in a separate model. 
7.8.3 
Additional Efficacy Endpoint(s) 
PAC-QOL Questionnaire:  
The PAC-QOL will be analyzed separately for the first 24 items that comprise the Dissatisfaction 
Index and for the last 4 items that comprise the Satisfaction Subscale at Baseline, and at Weeks 2 
and 4. As the PAC-QoL is performed during the visit missing data should only occur when the 
entire questionnaire is missing, rather than individual items. When the PAC-QoL is missing then 
LOCF will be used to carry forward the nearest previous value. 
The Dissatisfaction Index will be analyzed using van Elteren’s test stratified by center to 
examine the difference between lubiprostone and placebo. Additionally the endpoint will be 
analyzed using ANOVA models with center and treatment in the model as a sensitivity analysis. 
The estimated LS means, related mean difference and associated 95% CI will also be presented 
to aid interpretation of the clinical effect. 
The Satisfaction Index will be categorized by combined scores of the 4 items as either poor (0-
4), fairly good (5-8), good (9-12), or excellent (13-16) and will be analyzed by van Elteren tests, 
stratified by center, at Baseline, and at Weeks 2 and 4 separately. Additionally a cumulative 
logistic regression model will be used with treatment and center as factors as a sensitivity 
analysis. The estimated odds ratio and associated 95% CIs will also be presented to aid 
interpretation of the clinical effect. 
 
 
 


 
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7.9 PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS 
Not applicable. 
7.10 OTHER OUTCOMES 
Not applicable. 
7.11 SAFETY ANALYSIS 
Safety analyses include AEs, clinical laboratory values, vital signs, and other safety parameters. 
All safety summaries will be based on the SAF. The analysis of safety data will be restricted to 
descriptive statistics only unless otherwise specified. 
7.11.1 Adverse Events 
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.  
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.  
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. AEs are captured from when informed consent 
has been given until last follow-up visit. 
Treatment-emergent adverse events (TEAEs) will be defined as any AE that occurs after the first 
dose of study drug and up to the last dose or early termination plus applicable follow up (two 
weeks). An AE with a completely or partially missing onset date will be counted as a TEAE, 
unless the partial date information available clearly indicates that the event happened out of the 
treatment period (e.g. a stop date earlier than the date of first dose).Only TEAEs will be included 
in summary tables.  
 
There are no AEs of special interest defined for the study. 
The MedDRA dictionary, current version, will be used to code all AEs reported during the trial 
by SOC and PT.   
All TEAE summaries will be arranged in alphabetical order of SOC then by descending 
frequency (subject frequency) of the preferred term (PT) within the lubiprostone treatment 
group. 


 
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AEs with missing intensity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. If the relationship of an event is missing, the relationship for the 
event will be considered to have been related. In the cases where a subject has multiple AEs with 
the same SOC or PT the AE with the maximum intensity or strongest relationship will be 
summarized. When calculating the frequency and percentage of subjects who reported TEAEs, a 
subject will be counted only once for each SOC or PT when multiple TEAEs are coded to the 
same SOC or preferred term. Thus, if a subject has two distinct AEs, each of which corresponds 
to a distinct preferred term but both of which correspond to the same SOC, then that subject will 
be counted once at that SOC subject-count summary level and once at each of the two preferred-
term subject-count summary levels. 
 
The number and percentage of subjects with TEAEs will be summarized in several different 
tables: 
 
• Overview of TEAEs (including number and percentage of patients and events) 
• All TEAEs by SOC and PT. 
• All TEAEs by SOC. 
• All TEAEs by PT. 
• Most frequent TEAEs by PT (occurring in ≥5% of subjects within one treatment group). 
• Most frequent non-serious TEAEs by PT (occurring in ≥5% of subjects within one 
treatment group). 
• Relationship of TEAEs to Study Drug by SOC and PT(not related, related). 
• Drug-Related TEAEs by SOC and PT 
• Intensity of TEAEs by SOC and PT 
• Intensity of Drug-Related TEAEs by SOC and PT 
• TEAEs Leading to Study Drug Discontinuation by SOC and PT 
• Serious TEAEs by SOC and PT 
• Pretreatment Events by SOC and PT 
• Pretreatment Serious Events by SOC  and PT 
• Listing of Deaths, Other Serious Adverse Events, and Certain Other Significant Adverse 
Events 
 
Subject mappings will also be produced for: 
• TEAEs 
• TEAEs leading to study drug discontinuation 
• Serious TEAEs 
 
A list of PTEs by subject number and MedDRA coding will be presented separately. PTEs will 
be summarized by SOC and PT. 
 


 
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7.11.2 Clinical Laboratory Evaluations 
Laboratory values will be summarized, for absolute and change from baseline values (the last 
recorded value prior to randomization, including any values recorded at unscheduled visits) and 
will be presented by parameter and scheduled visit for the SAF. All recorded laboratory tests will 
be performed at a central laboratory, except for pregnancy tests. All laboratory test parameters 
will be displayed in individual subject data listings in standard international (SI) units and as 
reported. Shifts in laboratory test values will be presented as cross-tabulations (baseline versus 
post-baseline) of numbers of subjects with low, normal and high values relative to the normal 
range used at the central laboratory. This classification will be based on the low, normal and high 
alert flags reported by the central laboratory. If a subject has multiple values post baseline (e.g. 
values from scheduled and unscheduled visits), the most extreme result will be used for shift 
tables. Shift tables will be produced for all clinical laboratory tests with reference ranges. 
Individual results for clinical hematology and chemistry laboratory tests that meet the predefined 
criteria for markedly abnormal values (MAV) (Appendix 1) will be summarized in tables, MAV 
tables will include values recorded at scheduled and unscheduled visits.. 
 
The following tables will be produced: 
• Summary of Laboratory Test Results and Change from Baseline by Study Visit 
• Number and Percent of Subjects in Categories of Urine Laboratory Parameters by Visit 
• Summary of Shifts of Laboratory Test Results 
• Number and Percent of Subjects With MAVs of Laboratory Parameters 
• Number and Percent of Subjects With Elevated Liver Enzyme Laboratory Parameters 
 
Subject mappings will also be produced for: 
 
• The Number and Percent of Subjects With MAVs of Laboratory parameters 
• Subjects With Elevated Liver Enzyme Laboratory Parameters 
 
Listings of all clinical safety laboratory data will be provided for all subjects. Listings will be 
produced for each of hematology, serum chemistry and urinalysis categories. Laboratory data outside 
of the normal reference range will be indicated in the listings. In addition, MAVs will also be 
flagged. 


 
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Table 7.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Red blood cells (RBC) 
White blood cells (WBC) with 
differential 
Hemoglobin 
Hematocrit 
Platelets 
mean corpuscular volume (MCV) 
mean corpuscular hemoglobin (MCH) 
red (cell) distribution width (RDW) 
 
ALP 
ALT 
Albumin 
AST  
Total bilirubin 
Direct bilirubin 
Total protein 
Total Cholesterol 
Triglyceride 
Glucose 
Creatinine 
Blood urea nitrogen (BUN) 
Creatine kinase 
Uric acid 
Gamma GT (GGT) 
Lactic dehydrogenase (LDH) 
Potassium 
Sodium 
Chloride 
Calcium 
Phosphorous 
Magnesium 
Thyroid Stimulating Hormone (TSH) (Visit 1) 
C Reactive Protein (CRP) (Visit 1) 
Qualitative urinalysis (a)  
 
Microscopic analysis (only 
if positive dipstick results) 
(b) 
 
Other: 
Serum: 
Urine: 
Female subjects of childbearing potential only: 
Beta hCG (for pregnancy) Visits 1 and 5 
 
Female subjects of childbearing potential only: 
hCG for pregnancy Visit 2. 
Drug screen for drugs of abuse at Visit 1. 
(a) Qualitative urinalysis: pH, specific gravity, protein, glucose, occult blood, urobilinogen, bilirubin, ketone and 
leukocyte esterase. 
(b) Microscopic analysis: RBC/hpf, WBC/hpf, epithelial cells, casts, etc. 
 
 
7.11.3 Vital Signs 
Vital signs, including body temperature (°C), respiratory rate (breaths per minute), sitting blood 
pressure (mmHg) and pulse (bpm), will be measured at Day -15 (Screening), Day -1 
(Randomization), and Day 29 (Final Visit or Early Termination). Weight (kg) and height (cm) 
will also be measured at Screening. Measures taken on Day -1 will be considered as baseline 
values. Vital signs will be summarized by scheduled visit and treatment group for the SAF. 
Change from baseline ((the last recorded value prior to randomization, including any values 


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recorded at unscheduled visits)) will also be summarized for Day 29. No statistical analysis will 
be performed on vital signs data. Individual results for vital signs parameters that meet the 
predefined criteria for MAVs will be summarized in tables, MAV tables will include values 
recorded at scheduled and unscheduled visits. 
The following tables and subject mappings will be produced: 
•
Summary of Vital Signs Parameters and Change from Baseline by Visit
•
Number and Percent of Subjects With MAVs of Vital Signs Parameters
•
Subject Mappings for the Number and Percentage of Subjects With MAVs of Vital Signs
Parameters
Listings of all vital signs will be provided for all subjects. MAVs will also be flagged in the listings. 
7.11.4 12-Lead ECGs 
Not applicable. 
7.11.5 Other Observations Related to Safety 
Not applicable. 
7.12 INTERIM ANALYSIS 
Not applicable. 
7.13 CHANGES IN THE STATISTICAL ANALYSIS PLAN  
This SAP provides more details for the protocol specified analyses and includes additional 
analysis not presented in the protocol.. 


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8.0 
REFERENCES 
[1] H. B. Mann and D. R. Whitney, “On a Test of Whether one of Two Random Variables is Stochastically 
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[2] P. H. van Elteren, “On the combination of independent two sample tests of Wilcoxon,” Bulletin of the 
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