Clinical trial NCT03573908
Conditions: Irritable Bowel Syndrome Characterized by Constipation
Sponsor: Ironwood Pharmaceuticals, Inc.
Start date: 2018-06-20; Completion date: 2019-04-10
Enrollment: 614 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy on abdominal symptoms (abdominal bloating, abdominal discomfort, and abdominal pain) and safety of linaclotide 290 μg administered orally to patients with IBS-C.

Detailed description:
This study consists of a 12-week Treatment Period followed by 4-week Randomized Withdrawal (RW) Period.

Arms: arm 1: Participants receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period. At Week 12 participants are rerandomized to receive either linaclotide 290 µg or placebo for 4 weeks in the Randomized Withdrawal Period. arm 2: Participants receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period. At Week 12 participants are switched to receive linaclotide 290 µg for 4 weeks during the Randomized Withdrawal Period.
Interventions: intervention 1: Linaclotide intervention 2: Placebo
Intervention descriptions: intervention 1: Oral capsule intervention 2: Matching placebo oral capsule

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: MCP-103-312 
Final Version, 26 March 2018 
Study Title: 
A Phase 3b, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Trial of Linaclotide 290 μg Administered Orally 
for 12 Weeks Followed by a 4-week Randomized Withdrawal 
Period in Patients with Irritable Bowel Syndrome with 
Constipation 
Study Number: 
MCP-103-312 
Study Phase: 
3b 
Product Name: 
Linaclotide 
Indication: 
Irritable Bowel Syndrome with Constipation 
Investigators: 
Multicenter 
Sponsor: 
Ironwood Pharmaceuticals, Inc. 
301 Binney Street 
Cambridge, MA 02142 
Sponsor Contact: 
 
Medical Monitor: 
 
 
Date 
Original Protocol: 
26 March 2018 
Confidentiality Statement 
The contents of this document are confidential and belong to Ironwood Pharmaceuticals, Inc. 
Except as may be otherwise agreed to in writing, by accepting or reviewing these materials, 
you (including any colleagues or subordinates) agree to hold such information in confidence 
and not to disclose it to others (except where required by applicable law), nor to use it for 
unauthorized purposes. In the event of actual or suspected breach of this obligation, 
Ironwood should be promptly notified. 


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SYNOPSIS 
Trial Number: 
MCP-103-312 
Trial Title: 
A Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial of 
Linaclotide 290 µg Administered Orally for 12 Weeks Followed by a 4-week Randomized 
Withdrawal Period in Patients with Irritable Bowel Syndrome with Constipation 
Trial Centers: 
Approximately 80 in the United States 
Development Phase: 3b 
Objective(s): 
To evaluate the efficacy on abdominal symptoms (abdominal bloating, abdominal discomfort, 
and abdominal pain) and safety of linaclotide 290 µg administered orally to patients with 
irritable bowel syndrome with constipation (IBS-C). 
Methodology: 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 
consisting of 4 distinct periods, as illustrated in the figure below. The trial will enroll patients 
who have IBS-C diagnosed using Rome III criteria. Eligible patients will be randomized to 
1 of 2 treatments: linaclotide 290 µg or placebo (1:1) once daily. Patients who complete the 
12-week Treatment Period will enter the 4-week Randomized Withdrawal (RW) Period and be 
allocated to study drug in a double-blind manner, as follows: 
• Patients randomized to linaclotide 290 µg during the Treatment Period will be 
rerandomized to linaclotide 290 µg or placebo (1:1) 
• Patients randomized to placebo during the Treatment Period will be allocated to linaclotide 
290 µg 
 


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Overview of Trial Design 
 
Trial Periods 
1. Screening Period: The Screening Period starts with the signing of the informed consent 
form (ICF; Appendix 1) and may last for up to 21 days. During this period, patient 
eligibility for entry into the Pretreatment Period will be determined. The end of the 
Screening Period coincides with the start of the Pretreatment Period. If the patient 
meets the entry criteria assessed at the Screening Visit and does not require a washout 
of prohibited medicines (see Appendix 2), the Screening Visit and Pretreatment Visit 
may be combined into one visit. 
2. Pretreatment Period: The Pretreatment Period is defined as the 14 to 21 days 
immediately before the Randomization Visit. During this period, patients will provide 
the following information in a handheld electronic diary (eDiary):  
◦ 
Daily Bowel Movement (BM)-related Symptom-severity Assessments on an event-
driven basis (meaning these are assessments made at the time the event occurs) 
Screening
Period
Pretreatment
Period
Treatment Period 
Day 1 to Day 85 
14 to 21 days 
Up to 21 days 
Week 4 Visit 
(Day 29±3) 
Week 8 Visit 
(Day 57±3) 
Screening 
Visit 
(Day -42 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -14) 
Randomization 
Visit
(Day 1) 
Week 16/ 
End-of-Trial 
Visit** 
(RW Day 29+3) 
No Treatment 
Note: there is no Day 0. 
RW=Randomized Withdrawal 
 
* RW Day 1 is the day after the Week 12/End-of-Treatment-Period Visit. 
** This visit represents the end of the trial. 
Linaclotide 290 µg 
Placebo 
Week 12/ 
End-of-Treatment-
Period Visit 
(Day 85+3) 
Randomized 
Withdrawal Period 
RW Day 1* to 
RW Day 29 
Linaclotide 290 µg 
Linaclotide 290 µg 
Placebo 


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◦ 
Daily Abdominal Symptom-severity Assessments in an evening report 
◦ 
Weekly Patient Assessment of Constipation Severity 
◦ 
Weekly Patient Assessment of IBS Symptom Severity 
◦ 
Weekly Patient Assessment of Adequate Relief 
◦ 
Use of Bisacodyl or Other Laxatives, Suppositories, or Enemas on an event-driven 
basis 
Patients who satisfy all entry criteria will enter the Treatment Period. 
3. Treatment Period: The Treatment Period begins with treatment assignment and lasts 
for 12 weeks. Patients will be randomly assigned to 1 of 2 treatments: linaclotide 
290 µg or placebo. Patients will take their initial dose of study drug at the trial center 
during the Randomization Visit, after fasting for 2 hours. On all other days, study drug 
will be taken once daily in the morning at least 30 minutes before breakfast. Patients 
will continue to use the handheld eDiary to provide their Daily BM-related and 
Abdominal Symptom-severity Assessments, weekly assessments (as described above 
and including Weekly Patient Assessment of Treatment Satisfaction), and Use of 
Bisacodyl or Other Laxatives, Suppositories, or Enemas. Other patient-reported 
outcomes assessments (IBS Quality of Life Questionnaire [IBS-QOL] and CDC 
Healthy Days Core Module [CDC HRQOL-4]) will be administered at trial visits 
throughout the Treatment Period. Patients will complete a Week 4 Visit, Week 8 Visit, 
and Week 12/End-of-Treatment-Period (ETP) Visit during the Treatment Period (see 
Schedule of Evaluations). 
4. Randomized Withdrawal (RW) Period: The RW Period is defined as the 4 weeks 
immediately following the Treatment Period. Patients who complete the 12-week 
Treatment Period and return for the Week 12/ETP Visit will enter the 4-week RW 
Period and be allocated to study drug in a double-blind manner, as follows: 
◦ 
Patients randomized to linaclotide 290 µg during the Treatment Period will be 
rerandomized to linaclotide 290 µg or placebo (1:1) 
◦ 
Patients randomized to placebo during the Treatment Period will be allocated to 
linaclotide 290 µg 
Patients will take their first dose of study drug in the RW Period the day after the 
Week 12/ETP Visit (this will be considered RW Day 1). As during the Treatment 
Period, study drug will be taken once daily in the morning at least 30 minutes before 
breakfast. Patients will continue to use the handheld eDiary to provide their daily 
assessments, weekly assessments, and laxative use. Other patient-reported outcomes 
will be administered at the trial visit during the RW Period. At the end of the RW 
Period, patients will complete the Week 16/End-of-Trial (EOT) Visit. 
 


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Trial Procedures 
During the Pretreatment, Treatment, and RW Periods, patients will enter information into the 
eDiary. Certain information will be entered by the patient on an event-driven basis, in a daily 
evening report, and on a weekly basis, as specified below. 
Daily Assessments: The following information will be entered into the eDiary each day: 
• Diary for IBS Symptoms for Constipation-Predominant (DIBSS-C) 
- 
Daily BM-related Symptom-severity Assessments (entered by the patient for each BM 
on an event-driven basis): 
◦ 
BM day and time 
◦ 
Association with a sense of a complete evacuation (yes/no) 
◦ 
Stool consistency using the Bristol Stool Form Scale (BSFS; 1=Separate hard 
lumps like nuts [difficult to pass] to 7=Watery, no solid pieces [entirely liquid]) 
◦ 
Straining on a 5-point ordinal scale (1=Not at all to 5=An extreme amount 
[extremely severe straining]) 
◦ 
Stool consistency using a 5-point ordinal scale (1=Very hard to 5=Very loose and 
watery) 
- 
Daily Abdominal Symptom-severity Assessments (entered by the patient in a daily 
evening report): 
◦ 
Rating of abdominal pain at its worst during the previous 24 hours on an 11-point 
numerical rating scale (NRS; 0=No abdominal pain to 10=Worst possible 
abdominal pain) 
◦ 
Rating of abdominal discomfort at its worst during the previous 24 hours on an 
11-point NRS (0=No abdominal discomfort to 10=Worst possible abdominal 
discomfort) 
◦ 
Rating of abdominal bloating at its worst during the previous 24 hours on an 
11-point NRS (0=No abdominal bloating to 10=Worst possible abdominal 
bloating) 
• Use of Bisacodyl or Other Laxatives, Suppositories, or Enemas 
- 
The day and time will be entered by the patient for each use of protocol-permitted 
bisacodyl (tablets or suppositories) or other laxatives, suppositories, or enemas on an 
event-driven basis 
 


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Weekly Assessments: The following information will be entered by the patient into the eDiary 
once per week at the same time as the daily evening report: 
• Weekly Patient Assessment of Constipation Severity (5-point ordinal scale; 1=None to 
5=Very severe) 
• Weekly Patient Assessment of IBS Symptom Severity (5-point ordinal scale; 1=None to 
5=Very severe) 
• Weekly Patient Assessment of Adequate Relief (yes/no) 
• Weekly Patient Assessment of Treatment Satisfaction (5-point ordinal scale; 1=Not at all 
satisfied to 5=Very satisfied; captured each week after the Randomization Visit) 
 
Trial Visit Assessments: The following information will be captured in the eDiary at visits 
during the Treatment Period and RW Period: 
• IBS Quality of Life Questionnaire (IBS-QOL, captured at the Randomization Visit before 
the first dose of study drug and all subsequent trial visits) 
• CDC Healthy Days Core Module (CDC HRQOL-4, captured at the Randomization Visit 
before the first dose of study drug, the Week 12/ETP Visit, and the Week 16/EOT Visit) 
 
Concomitant Medicine 
• Rescue Medicine: During the Pretreatment, Treatment, and RW Periods, patients may use 
dispensed, protocol-permitted laxatives (bisacodyl, as tablets or suppositories) as Rescue 
Medicine when at least 72 hours have passed since their previous BM or when their 
symptoms become intolerable. In order to qualify for randomization into the Treatment 
Period, patients must not have used Rescue Medicine on the day before the Randomization 
Visit or on the day of the Randomization Visit up until the time of the clinic visit. Patients 
must agree to refrain from using Rescue Medicine from the time they arrive at the clinic 
for the Randomization Visit through the day after randomization. 
• Prohibited Medicine: Medicines that are not permitted during the Pretreatment, Treatment, 
and RW Periods are listed in Appendix 2. 
 
Number of Patients: 
Approximately 600 IBS-C patients (300 patients per treatment group) will be randomized into 
the Treatment Period. 


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Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria 
To be eligible to participate in the trial, patients must meet the following criteria: 
1. Patient has given consent by signing an ICF. 
2. Patient is ambulatory (females must also be non-pregnant) and is aged 18 years or older at 
the Screening Visit. Lactating females must agree not to breastfeed. 
3. Female patients of childbearing potential (ie, women who are not postmenopausal or who 
have not had a bilateral oophorectomy, hysterectomy, or tubal ligation) who are sexually 
active with a male partner must agree to use one of the following methods of birth control 
from the date they sign the ICF until 24 hours after their final dose of study drug: 
a. Hormonal contraception (ie, oral contraceptive, contraceptive implant, or injectable 
hormonal contraceptive) 
b. Double-barrier birth control (eg, condom plus intrauterine device, diaphragm plus 
spermicide) 
c. Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy 
4. Females of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative urine pregnancy test at the Randomization Visit prior to 
dosing. 
5. Patient meets the colonoscopy requirements as defined by the American 
Gastroenterological Association guidelines and described in Appendix 3. (Note: Patients 
who receive narcotic anesthesia for a colonoscopy are eligible to enter the Pretreatment 
Period on the fifth day after the colonoscopy.) 
6. Patient meets Rome III criteria for IBS (1): reports abdominal pain or discomfort at least 
3 days/month during the 3 months before the diagnosis with the onset at least 6 months 
before the diagnosis, associated with two or more of the following features: 
a. Improved with defecation 
b. Onset associated with a change in frequency of stool 
c. Onset associated with a change in form (appearance) of stool 
Note: the diagnosis can be made at the Screening Visit or can be based on symptoms that 
the patient had before starting chronic treatment with linaclotide (LINZESS®), 
lubiprostone (AMITIZA®), or plecanatide (TRULANCE™). 
7. During the time when the Rome III criteria for IBS were met, the patient had hard or 
lumpy stools (Bristol Stool Form Scale [BSFS] scores of 1 or 2) with at least 25% of BMs 
and had loose (mushy) or watery stools (BSFS scores of 6 or 7) with less than 25% of BMs 
in the absence of antidiarrheal or laxative use. 


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8. Patient reports <3 BMs (with each BM occurring in the absence of any laxative, 
suppository, or enema use during the preceding 24 hours) per week for at least 12 weeks, 
before the Screening Visit or before starting chronic treatment with linaclotide 
(LINZESS®), lubiprostone (AMITIZA®), polyethylene glycol 3350 (MiraLAX®), 
plecanatide (TRULANCE™), or any laxative. 
9. Patient has an average score for abdominal pain at its worst of ≥3.0, as reported in the 
eDiary using an 11-point numerical rating scale (NRS) during the 14 days before the 
Randomization Visit and including the data entry into the eDiary made in clinic at the 
Randomization Visit prior to randomization. 
10. Patient reports ≤6 complete spontaneous BMs (CSBMs) and ≤10 spontaneous BMs 
(SBMs) in the eDiary occurring over the 14 days before the Randomization Visit and 
including the data entry into the eDiary made in clinic at the Randomization Visit prior to 
randomization. (Note: A CSBM is an SBM that is associated with a sense of complete 
evacuation. An SBM is a BM that occurs in the absence of laxative, suppository, or enema 
use on the calendar day of the BM or the calendar day before the BM as evidenced by the 
patient-reported laxative use via the eDiary.) 
11. Patient is compliant (as defined in the trial procedures section below) with eDiary 
completion by adequately responding to eDiary questions (ie, completing the daily evening 
report) on 10 or more of the 14 days before the Randomization Visit. 
12. Patient is willing to discontinue any laxatives used before the Pretreatment Visit in favor 
of the protocol-defined Rescue Medicine (bisacodyl tablets or suppositories). 
13. Patient is fluent in English or Spanish. 
14. Patient agrees to refrain from making any new, major life-style changes that may affect 
IBS-C symptoms (eg, starting a new diet or changing his or her exercise pattern) from the 
time of signature of the ICF to the last trial visit. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible to participate in the trial: 
1. Patient reports loose (mushy) or watery stools (BSFS score of 6 or 7) in the absence of any 
laxative, suppository, enema, or prohibited medicine (as described in Appendix 2) for 
>25% of BMs during the 12 weeks before the Screening Visit. 
2. Patient has clinically significant concurrent illness or findings on a physical examination 
or clinical laboratory tests (clinical chemistry panel, complete blood count [CBC], urine 
drug screen) after signing the ICF but before receiving the first dose of study drug. (Note: 
The investigator will determine if a particular finding is clinically significant. In making 
this determination, the investigator will consider whether the particular finding could 
prevent the patient from performing any of the protocol-specified assessments, could 


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represent a condition that would exclude the patient from the trial, could represent a safety 
concern if the patient participates in the trial, or could confound the trial-specified 
assessments of safety or efficacy.) 
3. Patient has been diagnosed with or has a family history of familial adenomatous polyposis, 
hereditary nonpolyposis colorectal cancer, or any other form of familial colorectal cancer. 
4. Patient has a prior history of inflammatory bowel disease (IBD). 
5. Patient currently has clinically significant symptoms such as lower GI bleeding (rectal 
bleeding or heme-positive stool), iron-deficiency anemia, weight loss, or systemic signs of 
infection or colitis. 
6. Patient currently has active peptic ulcer disease (ie, not adequately treated or stable with 
therapy). 
7. Patient has a history of diverticulitis or any chronic condition (eg, chronic pancreatitis, 
polycystic kidney disease, ovarian cysts, endometriosis) with ongoing symptoms that can 
be associated with abdominal pain or discomfort and could confound the assessments in 
this trial. 
8. Patient has a central nervous system cause of constipation (eg, Parkinson's disease, spinal 
cord injury, and multiple sclerosis). 
9. Patient has ever had any of the following diseases or conditions that can be associated with 
constipation: pseudo-obstruction, megacolon, megarectum, bowel obstruction, descending 
perineum syndrome, solitary rectal ulcer syndrome, systemic sclerosis. 
10. Patient has ever had a fecal impaction that required hospitalization or emergency room 
treatment, or has a history of cathartic colon, laxative or enema abuse, ischemic colitis, or 
pelvic floor dysfunction (unless successful treatment has been documented by a normal 
balloon expulsion test). 
11. Patient has a known or suspected structural abnormality of the gastrointestinal (GI) tract 
(eg, mechanical gastrointestinal obstruction) or a disease or condition that can affect GI 
motility. 
12. Patient has a history of hypersensitivity to linaclotide or to any of the excipients contained 
in the study drug (active or placebo) as described in Section 7.1. 
13. Patient has had surgery that meets any of the following criteria: 
a. Bariatric surgery for treatment of obesity, or surgery to remove a segment of the GI 
tract at any time before the Screening Visit 
b. Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months 
before the Screening Visit 
c. An appendectomy or cholecystectomy during the 60 days before the Screening Visit 
d. Other major surgery during the 30 days before the Screening Visit 


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14. Patient has a history of cancer other than treated basal cell or squamous cell carcinoma of 
the skin. (Note: Patients with a history of cancer are allowed if the malignancy has been in 
a complete remission for at least 5 years before the Randomization Visit. A complete 
remission is defined as the disappearance of all signs of cancer in response to treatment.) 
15. Patient has a history of diabetic neuropathy. 
16. Patient has untreated hypothyroidism or treated hypothyroidism for which the dose of 
thyroid hormone has not been stable for at least 6 weeks at the time of the Screening Visit. 
17. Patient has a recent history (during the 12 months before the Randomization Visit) of drug 
or alcohol abuse. (Note: Patients with a history of drug or alcohol abuse that was 
diagnosed greater than 12 months before the Randomization Visit may be enrolled if they 
have exhibited no actual abuse during the 12 months before the Randomization Visit.) 
18. Patient reports a BSFS score of 6 (loose, mushy stools) for >1 SBM or a BSFS score of 7 
(watery stools) with any SBM occurring over the 14 days before the Randomization Visit 
and including the data entry into the eDiary made in the clinic at the Randomization Visit 
prior to randomization. 
19. Patient used Rescue Medicine (bisacodyl tablet or suppository) or any other laxative, 
suppository, or enema, on the day before or the day of the Randomization Visit prior to 
randomization. 
20. Patient reported using a Prohibited Medicine (excluding laxatives, suppositories, and 
enemas) during the Pretreatment Period or is not willing or able to abide by the restrictions 
regarding use of Prohibited Medicines defined in Appendix 2. (Note: The use of fiber, bulk 
laxatives, or stool softeners [such as docusate] is acceptable provided the patient has been 
on a stable dose during the 30 days before the Screening Visit and plans to continue on a 
stable dose throughout the trial.) 
21. Patient has been hospitalized for a psychiatric condition or has made a suicide attempt 
during the two years before the Randomization Visit. 
22. Patient has taken commercially available linaclotide (LINZESS®) or plecanatide 
(TRULANCE™) or received an investigational drug during the 30 days before the 
Screening Visit. 
23. Patient has an acute or chronic condition that, in the investigator's opinion, would limit the 
patient's ability to complete or participate in this clinical trial. 
24. Patient has previously entered the Pretreatment Period of this trial. 
25. Patient is directly or indirectly involved in the conduct and administration of this trial as an 
investigator, sub-investigator, study coordinator, other trial staff member, or employee of 
Ironwood Pharmaceuticals, Forest Laboratories, Actavis, or Allergan; or the patient is a 
first-degree family member, significant other, or relative residing with one of the above 


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persons involved directly or indirectly in the trial; or the patient is enrolled in this trial at 
another clinical trial site. 
 
Test Product, Dosage, and Mode of Administration: 
Linaclotide 290 µg oral capsule administered in a double-blind manner once daily in the 
morning at least 30 minutes before breakfast. 
Reference Therapy, Dosage, and Mode of Administration: 
Matching placebo oral capsule administered in a double-blind manner once daily in the 
morning at least 30 minutes before breakfast. 
Duration of Treatment:  
The test product and reference therapy will be administered for 16 weeks. Total patient 
participation is expected to last for up to 162 days. 
Criteria for Evaluation: 
Primary Efficacy Assessments 
The following efficacy assessments entered in the eDiary are used to determine the primary 
efficacy endpoint: daily patient assessments of abdominal bloating, abdominal discomfort, and 
abdominal pain at their worst over the last 24 hours (each on an 11-point NRS). 
Additional Efficacy Assessments 
In addition to the primary efficacy assessments, additional efficacy assessments are based on 
daily assessments of SBMs and CSBMs (including number and day/time of BMs, laxative use, 
and completeness of evacuation), stool consistency as measured on both the 7-point BSFS and 
5-point ordinal scale, and straining as measured on a 5-point ordinal scale. Additional efficacy 
assessments based on weekly assessments include the Weekly Patient Assessment of 
Constipation Severity, the Weekly Patient Assessment of IBS Symptom Severity, the Weekly 
Patient Assessment of Adequate Relief, and the Weekly Patient Assessment of Treatment 
Satisfaction. 
Safety Measures: 
AE recording (each visit), clinical laboratory measures (chemistry and hematology: Screening, 
Randomization, Week 12/ETP, and Week 16/EOT Visits), body weight (each visit), vital sign 
parameters (each visit). 
Statistical Methods:  
Analysis Populations 
• The Screened Population consists of all patients who had a Screening Visit (Visit 1) and 
were assigned a patient identification (PID) number. 
• The Intent-to-Treat (ITT) Population consists of all randomized patients. 
• The RW Population consists of all patients who were rerandomized or allocated to study 
drug upon completion of the Treatment Period. 
• The Safety Population consists of all patients who received at least one dose of study drug. 
 


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General Methods 
Efficacy outcomes from the Treatment Period will be based on the ITT Population and will be 
summarized by treatment group assigned at the Randomization Visit. Efficacy outcomes from 
the RW Period only or from the Combined Treatment and RW Period will be based on the RW 
Population and will be summarized by treatment sequence determined at the Week 12/ETP 
Visit. Treatment periods will be summarized for safety in the same manner as efficacy; 
however, safety summaries (Safety Population) will be based on actual treatment received. 
Descriptive statistics including the number of patients, mean, minimum and maximum, and 
standard deviation (SD) will be calculated for continuous variables. Frequencies and 
percentages for each category will be calculated for categorical variables. Percentages will be 
based on the total number of non-missing values. The number missing will be presented, but 
without a percentage. All hypothesis tests will be two-sided at a 5% significance level, and 
95% confidence intervals (CIs) will be used, unless stated otherwise. 
Primary Efficacy Endpoint 
• Change from Baseline in Abdominal Score at Each Week 
A patient’s daily Abdominal Score is calculated as the average of the daily patient 
assessments of abdominal bloating at its worst, abdominal discomfort at its worst, and 
abdominal pain at its worst. If 2 or more of the individual daily abdominal symptoms are 
missing, then the Abdominal Score for that day will be missing. The weekly Abdominal 
Score is the average of the non-missing Abdominal Scores during each week (Weeks 1-12) 
in the trial. The baseline Abdominal Score is the average of the non-missing Abdominal 
Scores during the 14-day Pretreatment Period and the day of the Randomization Visit 
reported prior to randomization. Change from baseline will be calculated for each week as 
the weekly score minus the baseline score. 
 
Primary Efficacy Analysis 
Inferential testing between the linaclotide 290 µg and placebo groups with regard to the 
change from baseline in abdominal score over the Treatment Period will be evaluated 
employing a mixed model with repeated measures (MMRM) framework with week 
(categorical), treatment, geographic region, and week-by-treatment fixed effects, patient as the 
random effect, and baseline value as a covariate. An unstructured covariance structure will be 
utilized. Descriptive statistics based on the MMRM model will include least-squares (LS) 
mean change from baseline for each treatment, the LS mean difference between linaclotide 
290 µg and placebo, corresponding 95% CIs, and the p-value associated with the comparison. 


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Clinical Trial Protocol: MCP-103-312 
 
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Secondary Efficacy Endpoints 
• Change from Baseline in 12-week Abdominal Score (Cumulative Distribution Function 
[CDF]) 
Daily Abdominal Score is calculated as described for the primary endpoint above. The 
12-week Abdominal Score is the average on the non-missing Abdominal Scores reported 
over the course of the Treatment Period. The baseline Abdominal Score is the average of 
the non-missing Abdominal Scores during the 14-day Pretreatment Period and the day of 
the Randomization Visit reported prior to randomization. Change from baseline will be 
calculated as the 12-week score minus the baseline score. 
• 6/12 Week Abdominal Score Responder 
A 6/12 Week Abdominal Score Responder is a patient who meets the Weekly Abdominal 
Score Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For 
each week in the Treatment Period, a Weekly Abdominal Score Responder is a patient 
who has an improvement from baseline of at least 2 points (ie, a -2 change from baseline) 
in the respective weekly abdominal score. If a patient did not enter information into the 
eDiary on at least 4 days for a particular Treatment Period week, the patient will not be 
considered a Weekly Abdominal Score Responder for that week. 
 
Secondary Efficacy Analysis 
The CDFs for linaclotide 290 µg and placebo will be estimated for the Change from Baseline 
in 12-week Abdominal Score endpoint. The CDFs will be compared using the Wilcoxon rank 
sum test with Hodges-Lehmann estimator for the median difference. 
A secondary time-course analysis of the Change from Baseline in Abdominal Score (see 
primary endpoint definition above) will also be conducted. Using the MMRM framework 
defined in the primary analyses, treatment difference between linaclotide 290 µg and placebo 
will be assessed at each individual week. For each week, descriptive statistics based on the 
MMRM model will include the LS mean change from baseline for each treatment, the LS 
mean difference between linaclotide 290 µg and placebo, corresponding 95% CIs, and the 
p-value associated with the treatment comparison. 
For the secondary responder endpoint, the proportion of responders in the linaclotide 290 µg 
group will be compared to the proportion of responders in the placebo group using a Cochran-
Mantel-Haenszel (CMH) test controlling for geographic region. The number and percent of 
responders, the difference in responder rates between the linaclotide 290 µg and placebo 
groups, the odds ratio relative to placebo, all corresponding 95% CIs, and the p-value 
associated with the CMH test will be presented. 


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Clinical Trial Protocol: MCP-103-312 
 
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Controlling for Multiplicity 
The overall family-wise Type I error rate for the primary and secondary efficacy analyses will 
be controlled at the α=0.05 level by employing a fixed-sequence procedure as described 
below. Following the fixed-sequence procedure, if the primary hypothesis between the placebo 
group and the linaclotide 290 µg group is statistically significant (α=0.05) in the ITT 
Population, then the primary objective of the trial will have been achieved and the next 
hypothesis can be tested; otherwise, testing will stop. The testing of each sequential hypothesis 
is conditional on all the previous hypotheses being rejected at the 0.05 level of significance. If 
a hypothesis is not rejected at the 0.05 level of significance, then all remaining hypotheses are 
deemed not statistically significant. All hypothesis testing will be two-sided. 
1. Linaclotide vs. placebo – Change from Baseline in Abdominal Score (primary efficacy 
analysis) 
2. Linaclotide vs. placebo – Change from Baseline in 12-week Abdominal Score (CDF) 
(secondary efficacy analysis) 
3. Linaclotide vs. placebo – 6/12 Week Abdominal Score Responder (secondary efficacy 
analysis) 
4. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 12 
5. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 10 
6. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 8 
7. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 6 
8. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 4 
9. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 2 
10. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 1 
 


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Clinical Trial Protocol: MCP-103-312 
 
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Additional Efficacy Endpoints 
Additional efficacy endpoints will be explored outside of the formal testing procedures 
described above. These endpoints will include: 
• 6/12 Week Abdominal Pain and Constipation (APC) +1 Responder 
• Change from Baseline in Abdominal Pain at its Worst at Each Week 
• Change from Baseline in CSBM Frequency Rate at Each Week 
• Change from Baseline in SBM Frequency Rate at Each Week 
• Change from Baseline in BSFS (Stool Consistency) at Each Week 
• Change from Baseline in Stool Consistency at Each Week 
• Change from Baseline in Straining at Each Week 
• Change from Baseline in Abdominal Discomfort at its Worst at Each Week 
• Change from Baseline in Abdominal Bloating at its Worst at Each Week 
• Percent Change from Baseline in Abdominal Pain at its Worst at Each Week 
• Change from Baseline in Percent of Days with Use of Rescue Medicine 
• SBM Within 24 Hours After First Dose Responder 
• 6/12 Week Abdominal Pain 30% Responder 
- 
≥30% decrease from baseline in abdominal pain for ≥6 of 12 weeks 
• 6/12 Week Abdominal Pain Responder 
- 
≥2-point improvement from baseline in abdominal pain for ≥6 of 12 weeks 
• 6/12 Week Abdominal Discomfort Responder 
- 
≥2-point improvement from baseline in abdominal discomfort for ≥6 of 12 weeks 
• 6/12 Week Abdominal Bloating Responder 
- 
≥2-point improvement from baseline in abdominal bloating for ≥6 of 12 weeks 
• 6/12 Week CSBM Responder 
- 
Increase of ≥1 CSBM/week from baseline for ≥6 of 12 weeks 
• Treatment Satisfaction 
• Adequate Relief 
• 6/12 Week Adequate Relief Responder 
• Change from Baseline in Constipation Severity 


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Clinical Trial Protocol: MCP-103-312 
 
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• Change from Baseline in IBS Symptom Severity 
 
Additional Efficacy Analyses 
Change-from-baseline endpoints and Treatment Satisfaction will be analyzed utilizing the 
same MMRM methods as described above for the primary analysis, and by visit as described 
for the secondary analyses. Responder endpoints will be analyzed using the methodology 
defined for the secondary responder analysis. 
RW Period Analysis 
All RW endpoints will be summarized for the RW Period only and for the Combined 
Treatment and RW Period using descriptive statistics and 95% CIs for each treatment 
sequence. No statistical inference will be performed. 
Safety Analysis 
All safety parameters will be analyzed descriptively in accordance with the General Methods. 
Sample Size 
The sample size of 600 patients (300 patients per treatment group) was chosen to ensure 
adequate power for testing the fixed-sequence procedure for the primary and secondary 
efficacy endpoints as defined above. 
The power calculations for the primary endpoint are based on the placebo and linaclotide 
290 µg treatment groups from the Phase 3 trial LIN-MD-31. The patients in LIN-MD-31 are 
considered representative of the patient population for this trial. Using a resampling with 
replacement-based simulation (1000 iterations) and controlling for multiplicity as outlined 
above, the trial will have >99% power to reject the primary endpoint and ~94% power to reject 
all primary and secondary hypotheses defined in the testing process. 
Final Date: 26 March 2018 
 


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Clinical Trial Protocol: MCP-103-312 
 
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SCHEDULE OF EVALUATIONS 
Schedule of Evaluations MCP-103-312 
Trial Period → 
Screening 
Period 
(Up to 21 days) 
Pretreatment 
Period 
(14 to 21 days) 
Treatment Period 
(12 weeks) 
Randomized 
Withdrawal 
(RW) Period 
(4 weeks)q 
Visit → 
Screening Visit 
Pretreatment 
Visit 
Randomization 
Visit 
Week 4 
Visit 
Week 8 
Visit 
Week 12/End-
of-Treatment-
Period Visit 
Week 16/ 
End-of-Trial 
Visit r 
Visit Days → 
Day -42 through 
Day -15 
Day -21 to 
Day -14 
Day 1 
Day 29±3 
Day 57±3 
Day 85+3 
RW Day 29+3 
Visit Number → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Trial Procedure ↓ 
 
 
 
 
 
 
 
Signature of ICF 
X 
 
 
 
 
 
 
Inclusion and Exclusion Criteria 
Verification 
X 
X 
X* 
 
 
 
 
IWRS Registration a 
X 
X 
X† 
X 
X 
X 
X 
Medical History b 
X 
 
 
 
 
 
 
Prior IBS-C Symptom 
Management Assessment c 
X 
 
 
 
 
 
 
Physical Examination d 
X 
 
 
 
 
X* 
X 
Body Weight and Height e 
X 
X 
X* 
X 
X 
X* 
X 
Seated Vital Signs f 
X 
X 
X* 
X 
X 
X* 
X 
Prior and Concomitant Medicines g 
X 
X 
X* 
X 
X 
X* 
X 
Clinical Laboratory Tests h 
X 
 
X* 
 
 
X* 
X 
Pregnancy Test i 
X 
 
X* 
 
 
X* 
X 
Laxative/Suppository/ Enema 
Washout Instructions j 
X 
 
 
 
 
 
 
AE Evaluations k 
 
X 
X* 
X 
X 
X* 
X 
eDiary Registration and Training  l 
 
X 
X* 
X 
X 
X* 
X 
Daily and Weekly Assessments m 
 
X 
X* 
X 
X 
X* 
X 


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Clinical Trial Protocol: MCP-103-312 
 
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Schedule of Evaluations MCP-103-312 
Trial Period → 
Screening 
Period 
(Up to 21 days) 
Pretreatment 
Period 
(14 to 21 days) 
Treatment Period 
(12 weeks) 
Randomized 
Withdrawal 
(RW) Period 
(4 weeks)q 
Visit → 
Screening Visit 
Pretreatment 
Visit 
Randomization 
Visit 
Week 4 
Visit 
Week 8 
Visit 
Week 12/End-
of-Treatment-
Period Visit 
Week 16/ 
End-of-Trial 
Visit r 
Visit Days → 
Day -42 through 
Day -15 
Day -21 to 
Day -14 
Day 1 
Day 29±3 
Day 57±3 
Day 85+3 
RW Day 29+3 
Visit Number → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Trial Procedure ↓ 
 
 
 
 
 
 
 
eDiary Compliance Verification 
and Reminder n 
 
 
X* 
X 
X 
X* 
X 
Rescue Medicine Dispensed o 
 
X 
X 
X 
X 
X 
 
Patient eDiary Entry, in Clinic 
 
 
X* 
X 
X 
X* 
X 
Randomization 
 
 
X† 
 
 
X 
 
IBS-QOL 
 
 
X† 
X 
X 
X 
X 
CDC HRQOL-4 
 
 
X† 
 
 
X 
X 
Study Drug Dispensed 
 
 
X† 
X 
X 
Xs 
 
Study Drug Administration p 
 
 
X 
 
 
 
 
Study Drug Accountability 
 
 
 
X 
X 
X 
X 
AE=adverse event; BM=bowel movement; CBC=complete blood count; CDC HRQOL-4=Centers for Disease Control and Prevention Healthy Days Core 
Module; CIC=chronic idiopathic constipation; eDiary=electronic diary; EOT=End-of-Trial; ETP=End-of-Treatment-Period; IBS-C=irritable bowel syndrome 
with constipation; IBS-QOL=irritable bowel syndrome quality of life questionnaire; ICF=informed consent form; IWRS=interactive web response system; 
RW=randomized withdrawal. 
* Done prior to randomization; † Done predose 
a. 
Site personnel will interact with IWRS to register the patient visit. Refer to the IWRS User Manual. 
b. Includes diagnosis using Rome IV criteria for IBS, which will be collected as part of the patient’s disease-specific history. Rome IV diagnosis has no bearing 
on patient eligibility to participate in the trial (patients will be enrolled based Rome III criteria). 
c. 
Prior IBS-C symptom management assessment includes prior treatments taken for IBS-C, lifestyle and diet modifications for alleviating symptoms of IBS-C, 
assessment of satisfaction with prior interventions’ ability to relieve bowel and abdominal symptoms, and primary reason for stopping use. 
d. A physical examination includes the following: general appearance, HEENT (head, ears, eyes, nose, and throat), neck, cardiovascular, thorax/lungs, breasts, 
abdomen, rectal, genitourinary, musculoskeletal, lymph nodes, skin, neurologic, and mental status. A rectal examination should be performed during the 


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Clinical Trial Protocol: MCP-103-312 
 
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Screening Period on all patients who do not require a colonoscopy (refer to Appendix 3). After the Screening Period, the rectal examination is optional and 
may be performed at the discretion of the investigator. Breast and genitourinary examinations are optional at the discretion of the investigator. 
e. 
Height is measured only at the Screening Visit. 
f. 
Vital signs must be obtained in the seated position and include oral temperature, respiratory rate, blood pressure, and pulse. Pulse and blood pressure 
readings will be taken after the patient has been sitting for five minutes. 
g. At the Screening Visit, information related to concomitant medicine that patients are taking on the day of the visit will be captured as well as their prior use 
of certain IBS-C or CIC (approved or unapproved) prescription medications (see Section 7.7 Concomitant Medicines). 
h. Chemistry, CBC, and urine drug screen. The urine drug screen will be performed at the Screening Visit only. 
i. 
To be eligible to continue in the trial, a negative serum pregnancy test must be documented at the Screening Visit. A negative urine pregnancy test must be 
documented at the Randomization Visit and the Week 12/ETP Visit (prior to randomization), and a negative serum pregnancy test must be documented at 
the Week 16/End-of-Trial (EOT) Visit. 
j. 
Study coordinator will instruct patients about the use of laxatives, suppositories, and enemas (refer to Appendix 2). 
k. All AEs occurring after the patient signs the ICF will be captured. 
l. 
At the Pretreatment Visit and all subsequent visits, the study coordinator will register the patient visit to the clinic in the patient’s eDiary. At the Pretreatment 
Visit, the study coordinator will instruct the patients about the use of the eDiary. Refer to the eDiary User Manual. 
m. An eDiary will be used for recording Daily BM-related Symptom Severity Assessments, Daily Abdominal Symptom-severity Assessments, Weekly 
Assessments, and Use of Bisacodyl or Other Laxatives, Suppositories, or Enemas. Patients will enter BMs and laxative use in the eDiary on an event-driven 
basis, and will complete an evening entry each day to record daily abdominal assessments and any BMs and/or laxative use not previously recorded for that 
day. 
n. At the Randomization Visit and all subsequent visits, the study coordinator will review the eDiary entry information to verify patient compliance with the 
daily eDiary completion requirement. After determining the patient’s compliance, the study coordinator will remind patients to complete the eDiary daily 
(except at the Week 16/EOT visit). eDiary questions may be found in the eDiary User Manual. 
o. Rescue Medicine (oral bisacodyl or bisacodyl suppositories) will be supplied to patients at the Pretreatment Visit and, if needed, at subsequent study drug 
dispensing visits. 
p. Study drug will be administered in the clinic at the Randomization Visit. Patients are instructed to fast for 2 hours before this clinic visit. On all other days, 
study drug will be taken once daily in the morning at least 30 minutes before breakfast. 
q. The RW Period will start the day after the Week 12/ETP Visit (this will be considered RW Day 1). 
r. 
Patients who are randomized but do not complete the Treatment Period or RW Period (withdraw consent or are discontinued before they have completed 
12 weeks or 4 weeks of treatment, respectively), will be considered Treatment Period or RW Period withdrawals, respectively, and should complete the 
procedures required at the EOT Visit (even if out of window). 
s. 
Patients will take their first dose of study drug in the RW Period on RW Day 1 (ie, the day after the Week 12/ETP Visit). 
 
 


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Clinical Trial Protocol: MCP-103-312 
 
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TRIAL IDENTIFICATION 
A summary of key trial participants is provided in Table 1. All trial contact details will be 
provided prior to the Site Initiation Visit. Rather than contacting individuals listed within the 
table, sites should use the toll-free medical hotline for medical inquiries and the dedicated 
serious adverse event (SAE) fax/email for communication regarding SAEs, as listed below. 
Table 1. 
Key Trial Participants 
Role 
Contact Information 
Sponsor: 
Ironwood Pharmaceuticals, Inc. 
301 Binney Street 
Cambridge, MA 02142 
617-621-7722 (Main Telephone) 
617-494-0908 (Main Fax) 
www.ironwoodpharma.com 
Sponsor Contact: 
 
 
 
Sponsor Clinical Lead: 
 
 
Sponsor Medical Monitor: 
 
 
 
Sponsor Safety Officer: 
 
 
 
Clinical Laboratory: 
 
 
 
 
 
 
 
 
 
 


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Clinical Trial Protocol: MCP-103-312 
 
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Role 
Contact Information 
Toll-free Medical Hotline Number: 
1-800-201-8725 
Dedicated Serious Adverse Event (SAE) 
Facsimile Number and Email: 
Fax: 1-617-933-7688 
clinicalsafety@ironwoodpharma.com 
 


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Clinical Trial Protocol: MCP-103-312 
 
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TABLE OF CONTENTS 
SYNOPSIS .......................................................................................................................................2 
SCHEDULE OF EVALUATIONS ...............................................................................................17 
TRIAL IDENTIFICATION ...........................................................................................................20 
LIST OF ABBREVIATIONS ........................................................................................................28 
1. 
ETHICAL CONSIDERATIONS ...........................................................................................31 
1.1 
INSTITUTIONAL REVIEW BOARD........................................................................31 
1.2 
PATIENT INFORMATION AND CONSENT ...........................................................31 
2. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ............................32 
3. 
INTRODUCTION .................................................................................................................33 
3.1 
IBS-C ...........................................................................................................................33 
3.2 
LINACLOTIDE ...........................................................................................................33 
3.3 
LINACLOTIDE CLINICAL DEVELOPMENT .........................................................34 
4. 
TRIAL OBJECTIVES ...........................................................................................................37 
5. 
INVESTIGATIONAL PLAN ................................................................................................38 
5.1 
OVERALL TRIAL DESIGN AND PLAN .................................................................38 
5.1.1 
Trial Periods .......................................................................................................39 
5.1.1.1 
Screening Period ......................................................................................39 
5.1.1.2 
Pretreatment Period ..................................................................................40 
5.1.1.3 
Treatment Period ......................................................................................40 
5.1.1.4 
Randomized Withdrawal (RW) Period ....................................................41 
5.2 
RATIONALE FOR TRIAL DESIGN AND CONTROL GROUP .............................41 
5.3 
TRIAL DURATION ....................................................................................................41 
6. 
SELECTION OF TRIAL POPULATION .............................................................................42 
6.1 
INCLUSION CRITERIA.............................................................................................42 
6.2 
EXCLUSION CRITERIA ...........................................................................................43 
6.3 
DISCONTINUATION OF PATIENTS FROM THERAPY OR ASSESSMENT ......46 
6.4 
REPLACEMENT PROCEDURES .............................................................................47 
7. 
TREATMENTS .....................................................................................................................48 
7.1 
TREATMENTS ADMINISTERED ............................................................................48 
7.2 
IDENTITY AND STORAGE OF INVESTIGATIONAL PRODUCT .......................48 
7.3 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS....................48 
7.4 
SELECTION OF DOSAGE IN THE STUDY ............................................................49 
7.5 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT ...............................49 
7.6 
BLINDING ..................................................................................................................50 
7.7 
CONCOMITANT MEDICINES .................................................................................51 
7.8 
TREATMENT COMPLIANCE ..................................................................................52 
8. 
STUDY PROCEDURES AND ASSESSMENTS .................................................................53 


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8.1 
EFFICACY ASSESSMENTS .....................................................................................53 
8.1.1 
Primary Efficacy Assessments ...........................................................................53 
8.1.2 
Secondary Efficacy Assessments .......................................................................54 
8.1.3 
Additional Efficacy Assessments ......................................................................54 
8.1.4 
Health Economics and Outcomes Research Assessments .................................59 
8.1.5 
Completion of eDiary Assessments ...................................................................59 
8.2 
SAFETY ASSESSMENTS ..........................................................................................60 
8.2.1 
Adverse Events ..................................................................................................60 
8.2.1.1 
Definitions................................................................................................60 
8.2.1.2 
Classification of an Adverse Event ..........................................................61 
8.2.1.3 
Procedures for Recording Adverse Events ..............................................64 
8.2.1.4 
Procedures for Collecting and Reporting Serious Adverse Events .........65 
8.2.2 
Clinical Laboratory Determinations ..................................................................67 
8.2.3 
Vital Signs ..........................................................................................................68 
8.2.4 
Physical Examination.........................................................................................69 
8.2.5 
Medical History .................................................................................................69 
8.2.6 
Prior IBS-C Symptom Management Assessment ..............................................70 
9. 
DATA QUALITY ASSURANCE .........................................................................................71 
9.1 
DATA MONITORING ................................................................................................71 
9.2 
DATA RECORDING AND DOCUMENTATION ....................................................71 
10. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ......................73 
10.1 
ANALYSIS POPULATIONS .....................................................................................73 
10.1.1 
Screened Population...........................................................................................73 
10.1.2 
Intent-to-Treat Population ..................................................................................73 
10.1.3 
Randomized Withdrawal (RW) Population .......................................................73 
10.1.4 
Safety Population ...............................................................................................73 
10.2 
GENERAL METHODS...............................................................................................73 
10.2.1 
Patient Disposition .............................................................................................74 
10.2.2 
Demographics and Baseline Characteristics ......................................................74 
10.2.3 
Protocol Deviations ............................................................................................74 
10.2.4 
Prior and Concomitant Medicines .....................................................................75 
10.3 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................75 
10.3.1 
Exposure to Study Drug .....................................................................................75 
10.3.2 
Measurement of Treatment Compliance ............................................................76 
10.3.3 
eDiary Compliance ............................................................................................76 
10.4 
EFFICACY ANALYSES ............................................................................................76 
10.4.1 
Primary Efficacy Endpoint ................................................................................77 
10.4.2 
Primary Efficacy Analysis .................................................................................78 


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10.4.3 
Secondary Efficacy Endpoints ...........................................................................78 
10.4.4 
Secondary Efficacy Analysis .............................................................................79 
10.4.5 
Controlling for Multiplicity ...............................................................................79 
10.4.6 
Additional Efficacy Endpoints ...........................................................................80 
10.4.7 
Additional Efficacy Analysis .............................................................................83 
10.4.8 
Randomized Withdrawal Period Endpoints .......................................................84 
10.4.9 
Randomized Withdrawal Period Analyses ........................................................84 
10.5 
HEALTH ECONOMICS AND OUTCOMES RESEARCH ANALYSES ................85 
10.5.1 
IBS-QOL ............................................................................................................85 
10.5.2 
CDC HRQOL-4 .................................................................................................85 
10.6 
SAFETY ANALYSES.................................................................................................85 
10.6.1 
Adverse Events ..................................................................................................85 
10.6.2 
Clinical Laboratory Parameters .........................................................................87 
10.6.3 
Vital Signs ..........................................................................................................88 
10.7 
INTERIM ANALYSIS ................................................................................................88 
10.8 
DETERMINATION OF SAMPLE SIZE ....................................................................88 
11. CHANGES IN THE CONDUCT OF THE TRIAL OR PLANNED ANALYSES...............89 
12. TRIAL SPONSORSHIP ........................................................................................................90 
12.1 
TRIAL TERMINATION .............................................................................................90 
12.2 
REPORTING AND PUBLICATION ..........................................................................90 
13. INVESTIGATOR OBLIGATIONS ......................................................................................91 
13.1 
DOCUMENTATION ..................................................................................................91 
13.2 
PERFORMANCE ........................................................................................................91 
13.3 
USE OF INVESTIGATIONAL MATERIALS ...........................................................92 
13.4 
CASE REPORT FORMS ............................................................................................92 
13.5 
RETENTION AND REVIEW OF RECORDS ...........................................................92 
13.6 
PATIENT CONFIDENTIALITY ................................................................................93 
14. APPENDICES .......................................................................................................................94 
15. REFERENCE LIST .............................................................................................................117 
 


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LIST OF IN-TEXT TABLES 
Table 1. 
Key Trial Participants ........................................................................................20 
Table 2. 
Adverse Event Causality ....................................................................................63 
 


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LIST OF IN-TEXT FIGURES 
Figure 1. 
Overview of Trial Design ..................................................................................39 
 


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Clinical Trial Protocol: MCP-103-312 
 
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LIST OF APPENDICES 
Appendix 1 
Elements of Informed Consent ..........................................................................95 
Appendix 2 
Concomitant and Prohibited Medications..........................................................97 
Appendix 3 
Summary of American Gastroenterological Association Guidelines ..............100 
Appendix 4 
Bristol Stool Form Scale ..................................................................................101 
Appendix 5 
IBS-QOL ..........................................................................................................102 
Appendix 6 
CDC HRQOL-4 ...............................................................................................110 
Appendix 7 
Prior IBS-C Symptom Management Assessment ............................................112 
Appendix 8 
Investigator’s Signature ...................................................................................116 
 
 


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Clinical Trial Protocol: MCP-103-312 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
APC 
Abdominal Pain and Constipation 
BM 
bowel movement 
BMI 
body mass index 
BP 
blood pressure 
BSFS 
Bristol Stool Form Scale 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIC 
chronic idiopathic constipation 
CBC 
complete blood count 
CDC HRQOL-4 
Centers for Disease Control and Prevention Healthy Days Core Module 
CDF 
cumulative distribution function 
CFTR 
cystic fibrosis transmembrane conductance regulator 
cGMP 
cyclic guanosine monophosphate 
CMH 
Cochran-Mantel-Haenszel 
CRO 
contract research organization 
CSBM 
complete spontaneous bowel movement 
DHHS 
Department of Health and Human Services 
DR 
delayed release 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EOT 
End of Trial 
ETP 
End of Treatment Period 
FDA 
Food and Drug Administration 
GC-C 
guanylate cyclase-C 


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GCP 
good clinical practice 
GI 
gastrointestinal 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HT 
hydroxytryptophan 
IBD 
inflammatory bowel disease 
IBS 
irritable bowel syndrome 
IBS-C 
irritable bowel syndrome with constipation 
IBS-D 
irritable bowel syndrome with diarrhea 
IBS-M 
irritable bowel syndrome mixed 
IBS-U 
unclassified irritable bowel syndrome 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IR 
immediate release 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive web response system 
LAR 
legally authorized representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model with repeated measures 
NDA 
New Drug Application 
NEAE 
newly-emergent adverse event 
NRS 
numerical rating scale 
PCS 
potentially clinically significant 
PID 
patient identification 
QOL 
quality of life 
RW 
Randomized Withdrawal 
SAE 
serious adverse event 


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SAP 
statistical analysis plan 
SBM 
spontaneous bowel movement 
SD 
standard deviation 
SE 
standard error  
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
US 
United States 
 


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1. 
ETHICAL CONSIDERATIONS 
This clinical trial is designed to comply with the International Conference on Harmonisation 
(ICH) Guidance on General Considerations for Clinical Trials, ICH E8 (published in the US 
Federal Register Volume 62, page 66113, December 17, 1997) and Good Clinical Practice 
(GCP): Consolidated Guidance, ICH E6 (published in the US Federal Register, Volume 62, page 
25692, May 9, 1997). The trial will be conducted in full compliance with the US Food and Drug 
Administration (FDA) guidelines for GCP and in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki. 
1.1 
INSTITUTIONAL REVIEW BOARD 
Obtaining approval by the Institutional Review Board (IRB) prior to the start of the trial will be 
the responsibility of the investigator. A copy of the approval letter will be transmitted to the 
Sponsor or designee. During the course of the trial, the investigator will provide timely and 
accurate reports to the IRB on the progress of the trial, and will notify the IRB of serious adverse 
events (SAEs) or other significant safety findings in a manner consistent with IRB policies and 
ICH and GCP requirements. The trial protocol (and any amendments), Informed Consent Form 
(ICF; Appendix 1), and associated documentation will be approved by the IRB prior to trial 
initiation, in compliance with 21 CFR Part 56. 
1.2 
PATIENT INFORMATION AND CONSENT 
Before entry into the trial, patients will be provided with a written explanation of the trial 
describing the nature of the study, as well as its purpose, expected duration, and the benefits and 
risks involved in trial participation per 21 CFR Part 50. Patients will then be given the 
opportunity to ask questions and will be informed of their right to withdraw from the trial 
without prejudice. After this explanation and before entering the trial, the patient will voluntarily 
sign an ICF. 
If new information becomes available that may be relevant to the patient’s consent and 
willingness to participate in the trial, the ICF will be revised and any currently enrolled patient 
will be made aware of the new information and asked if he/she wishes to continue in the trial. 
The revised consent form will be submitted to the IRB for review and approval prior to its use. 


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2. 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE 
This trial will be performed at approximately 80 trial centers in the US. The investigator at the 
trial center will be responsible for ensuring that the trial is conducted according to the signed 
Clinical Trial Agreement, the protocol, IRB requirements, and GCP guidelines. 
The investigator will be responsible for the oversight of the site’s conduct of the trial, which will 
consist of completing all protocol assessments, maintaining the trial file and the patient records, 
drug accountability, corresponding with the IRB, and completing the electronic case report forms 
(eCRFs). 
Ironwood Pharmaceuticals, Inc. and Allergan, Plc are development partners for this trial. 


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3. 
INTRODUCTION 
3.1 
IBS-C 
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal (GI) disorder 
characterized by recurrent symptoms of abdominal pain and/or discomfort, accompanied by 
altered bowel function and a feeling of bloating.(2-6) In moderate to severe cases of IBS, an 
overall deterioration in quality of life (QOL) is often present.(7) IBS is one of the most 
frequently seen disorders in the United States; data suggest the prevalence of IBS is 11-14% of 
the adult population.(7) IBS is subtyped as IBS with diarrhea (IBS-D) or IBS with constipation 
(IBS-C), based on Rome criteria. Patients who meet criteria for both diarrhea and constipation 
are subtyped as IBS mixed (IBS-M); patients who do not fit into any of these three subtypes are 
classified as having unclassified IBS (IBS-U).(8) 
3.2 
LINACLOTIDE 
Linaclotide (LINZESS®) is an orally-administered, minimally-absorbed 14-amino acid synthetic 
peptide agonist of guanylate cyclase C (GC-C) approved by FDA in 2012 for the treatment of 
IBS-C and chronic idiopathic constipation (CIC) in adults. As a GC-C agonist, linaclotide and its 
active metabolite improve bowel symptoms and abdominal pain via agonism of cyclic guanosine 
monophosphate (cGMP) on the intestinal mucosa. Linaclotide induces fluid secretion in two 
ways: 1) by increasing intracellular cGMP leading to activation of cystic fibrosis transmembrane 
conductance regulator (CFTR) ion channels, resulting in secretion of chloride and bicarbonate 
into the intestinal lumen, resulting in accelerated transit;(9) and 2) by inhibiting sodium 
reabsorption in the colon.(10) These effects on fluid dynamics within the GI tract are believed to 
play a role in accelerating intestinal transit and increasing stool water, which in turn results in 
softer stools. Orally administered linaclotide has also been shown to reduce visceral 
hypersensitivity in animal models and abdominal pain in patients with IBS-C.(11) Linaclotide is 
believed to reduce abdominal pain by acting locally in the intestinal mucosa to reduce firing of 
mechanosensitive afferent nerve fibers. 


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3.3 
LINACLOTIDE CLINICAL DEVELOPMENT 
The clinical development program for LINZESS® that culminated in FDA approval for use in 
adult patients with IBS-C included two large double-blind, placebo-controlled registration 
trials.(12, 13) These trials evaluated the safety and efficacy of linaclotide at a dose of 290 µg, 
administered as an oral capsule. One trial had a 26-week Treatment Period and one trial had a 
12-week Treatment Period followed by a 4-week Randomized Withdrawal Period; however, the 
overall design of both Phase 3 trials was identical through the first 12 weeks of the Treatment 
Period. Both trials met all pre-specified primary and secondary efficacy endpoints. For each of 
the four primary efficacy parameters, the linaclotide dose group in both trials had statistically 
significantly higher proportions of responders compared with placebo (controlling for 
multiplicity). For all secondary efficacy change-from-baseline parameters (including complete 
spontaneous bowel movement [CSBM] frequency rate, spontaneous bowel movement [SBM] 
frequency rate, stool consistency, straining, abdominal bloating, abdominal discomfort, 
abdominal pain, and abdominal pain-free days) and responder parameters (6/12 Week CSBM +1 
Responder and 6/12 Week Abdominal Pain Responder), the linaclotide group demonstrated 
statistically significant improvement compared with the placebo group (p<0.01 for all secondary 
parameters controlling for multiplicity) in both trials. 
Linaclotide was well-tolerated in these trials.(12, 13) There were no deaths. One patient died 
during the Screening Period but never received either linaclotide or placebo. There were a total 
of 15 SAEs in the 2 trials. There were 9 (1.1%) SAEs in placebo-treated patients and 6 (0.7%) 
SAEs in linaclotide-treated patients. Overall, there was no obvious pattern in the types of SAEs 
experienced in either the placebo or linaclotide group. There were no SAEs of diarrhea. 
Treatment-emergent AEs (TEAEs) occurred in 54.9% of placebo-treated and 60.8% of 
linaclotide-treated patients. Diarrhea was the most frequent TEAE and was reported in 3.0% of 
patients treated with placebo and 19.8% of patients treated with linaclotide. Diarrhea was 
generally mild to moderate in severity. Diarrhea resulted in the discontinuation of 0.4% of 
patients treated with placebo and 5.3% treated with linaclotide. 


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More recently, a Phase 2b, multicenter, randomized, double-blind, double-dummy, placebo-
controlled, parallel-group, dose-range-finding study evaluated 2 different delayed release (DR) 
tablet formulations of linaclotide (DR1 and DR2), the FDA-approved 290-µg LINZESS® (the 
immediate release [IR] capsule formulation of linaclotide), and placebo administered once daily 
for 12 weeks. A total of 532 patients with IBS-C (Rome III criteria) were randomized in equal 
proportions to 1 of 8 treatment groups: 
• Linaclotide DR1 (30 µg, 100 µg, 300 µg) 
• Linaclotide DR2 (30 µg, 100 µg, 300 µg) 
• Linaclotide IR (LINZESS®) 290 µg 
• Placebo 
All 532 patients randomized to treatment (ITT Population) took at least 1 dose of study drug 
(Safety Population). Demographics and baseline clinical characteristics were generally similar 
across the 8 treatment groups, which each included 66-67 patients. Results for the linaclotide IR 
290 µg and placebo groups are summarized below. 
The key efficacy endpoints were: change from baseline (CFB) in weekly abdominal pain (-1.9 in 
the linaclotide IR group versus -1.4 in the placebo group), CFB in weekly CSBM frequency rate 
(2.1 in the linaclotide IR group versus 1.1 in the placebo group; p<0.05), and 6/12 Week 
Abdominal Pain and Constipation (APC) +1 Responder (31.8% in the linaclotide IR group 
versus 21.2% in the placebo group). Improvements from baseline in the individual abdominal 
symptoms (abdominal bloating, abdominal discomfort, and abdominal pain) and in the 
abdominal score (a multi-component score based on these individual abdominal symptoms) were 
seen in the linaclotide IR group compared with the placebo group. 


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Linaclotide IR was well-tolerated in this study and safety results were consistent with the known 
safety profile of linaclotide. There were no deaths in the study. Two patients reported on-
treatment SAEs: 1 placebo patient (pneumonia and sepsis) and 1 linaclotide IR patient 
(gastroenteritis); all 3 SAEs were considered unrelated to study drug by the investigator. As in 
previous linaclotide trials, the most common TEAE was diarrhea (13.6% in the linaclotide IR 
group versus 1.5% in the placebo group). All diarrhea events were mild or moderate in severity. 
Diarrhea resulted in the discontinuation of 6.1% of patients treated with linaclotide IR and 0% of 
patients treated with placebo. 
Refer to the Investigator’s Brochure for a more detailed description of the chemistry, 
pharmacology, efficacy, and safety of linaclotide, based on studies conducted in animals, healthy 
volunteers, and in patients with IBS-C and CIC. 


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4. 
TRIAL OBJECTIVES 
The objective of this trial is to evaluate the efficacy on abdominal symptoms (abdominal 
bloating, abdominal discomfort, and abdominal pain) and safety of linaclotide 290 µg 
administered orally to patients with irritable bowel syndrome with constipation (IBS-C). 


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5. 
INVESTIGATIONAL PLAN 
5.1 
OVERALL TRIAL DESIGN AND PLAN 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 
consisting of 4 distinct periods, as illustrated in Figure 1 below. The trial will enroll patients who 
have IBS-C diagnosed using Rome III criteria. Eligible patients will be randomized to 1 of 
2 treatments: linaclotide 290 µg or placebo (1:1) once daily. Patients who complete the 12-week 
Treatment Period will enter the 4-week Randomized Withdrawal (RW) Period and be allocated 
to study drug in a double-blind manner, as follows: 
• Patients randomized to linaclotide 290 µg during the Treatment Period will be rerandomized 
to linaclotide 290 µg or placebo (1:1) 
• Patients randomized to placebo during the Treatment Period will be allocated to linaclotide 
290 µg 
 


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Figure 1. 
Overview of Trial Design 
 
 
5.1.1 
Trial Periods 
5.1.1.1 
Screening Period 
The Screening Period starts with the signing of the informed consent form (ICF; Appendix 1) 
and may last for up to 21 days. During this period, patient eligibility for entry into the 
Pretreatment Period will be determined. The end of the Screening Period coincides with the start 
of the Pretreatment Period. If the patient meets the entry criteria assessed at the Screening Visit 
and does not require a washout of prohibited medicines (see Appendix 2), the Screening Visit 
and Pretreatment Visit may be combined into one visit. 
Screening 
Period 
Pretreatment 
Period 
Treatment Period 
Day 1 to Day 85 
14 to 21 days 
Up to 21 days 
Week 4 Visit 
(Day 29±3) 
Week 8 Visit 
(Day 57±3) 
Screening 
Visit 
(Day -42 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -14) 
Randomization 
Visit
(Day 1) 
Week 16/ 
End-of-Trial 
Visit** 
(RW Day 29+3) 
No Treatment 
Note: there is no Day 0. 
RW=Randomized Withdrawal 
 
*RW Day 1 is the day after the Week 12/End-of-Treatment-Period Visit. 
** This visit represents the end of the trial. 
Linaclotide 290 µg 
Placebo 
Week 12/ 
End-of-Treatment-
Period Visit 
(Day 85+3) 
Randomized 
Withdrawal Period 
RW Day 1* to 
RW Day 29 
Linaclotide 290 µg 
Linaclotide 290 µg 
Placebo 


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5.1.1.2 
Pretreatment Period 
The Pretreatment Period is defined as the 14 to 21 days immediately before the Randomization 
Visit. During this period, patients will provide the following information in a handheld electronic 
diary (eDiary): 
• Daily Bowel Movement (BM)-related Symptom-severity Assessments on an event-driven 
basis (meaning these are assessments made at the time the event occurs) 
• Daily Abdominal Symptom-severity Assessments in an evening report 
• Weekly Patient Assessment of Constipation Severity 
• Weekly Patient Assessment of IBS Symptom Severity 
• Weekly Patient Assessment of Adequate Relief 
• Use of Bisacodyl or Other Laxatives, Suppositories, or Enemas on an event-driven basis 
 
Patients who satisfy all entry criteria will enter the Treatment Period. 
5.1.1.3 
Treatment Period 
The Treatment Period begins with treatment assignment and lasts for 12 weeks. Patients will be 
randomized to 1 of 2 treatments: linaclotide 290 µg or placebo (1:1). Patients will take their 
initial dose of study drug at the trial center during the Randomization Visit, after fasting for 
2 hours. On all other days, study drug will be taken once daily in the morning at least 30 minutes 
before breakfast. Patients will continue to use the handheld eDiary to provide their Daily BM-
related and Abdominal Symptom-severity Assessments, weekly assessments (as described above 
and including Weekly Patient Assessment of Treatment Satisfaction), and Use of Bisacodyl or 
Other Laxatives, Suppositories, or Enemas. Other patient-reported outcomes assessments (IBS 
Quality of Life Questionnaire [IBS-QOL] and CDC Healthy Days Core Module [CDC 
HRQOL-4]) will be administered at trial visits throughout the Treatment Period. Patients will 
complete a Week 4 Visit, Week 8 Visit, and Week 12/End-of-Treatment-Period (ETP) Visit 
during the Treatment Period (see Schedule of Evaluations). 


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5.1.1.4 
Randomized Withdrawal (RW) Period 
The RW Period is defined as the 4 weeks immediately following the Treatment Period. Patients 
who complete the 12-week Treatment Period and return for the Week 12/ETP Visit will enter the 
4-week RW Period and be allocated to study drug in a double-blind manner, as follows: 
• Patients randomized to linaclotide 290 µg during the Treatment Period will be rerandomized 
to linaclotide 290 µg or placebo (1:1) 
• Patients randomized to placebo during the Treatment Period will be allocated to linaclotide 
290 µg 
 
Patients will take their first dose of study drug in the RW Period the day after the Week 12/ETP 
Visit (this will be considered RW Day 1). As during the Treatment Period, study drug will be 
taken once daily in the morning at least 30 minutes before breakfast. Patients will continue to use 
the handheld eDiary to provide their daily assessments, weekly assessments, and laxative use. 
Other patient-reported outcomes will be administered at the trial visit during the RW Period. At 
the end of the RW Period, patients will complete the Week 16/End-of-Trial (EOT) Visit. 
5.2 
RATIONALE FOR TRIAL DESIGN AND CONTROL GROUP 
A double-blind, placebo-controlled, parallel-group trial design was chosen in accordance with 
the concepts in ICH E10, Choice of Control Groups and Related Issues in Clinical Trials, in 
order to provide comparable treatment groups and minimal chance of selection or investigator 
bias. The trial has a 14-21 day Pretreatment Period to establish a baseline without therapy and to 
familiarize patients with data collection methodology (ie, eDiary), a 12-week Treatment Period 
to compare the test treatment to a placebo control, and a 4-week RW Period to determine if a 
rebound (or worsening of symptoms from baseline) or other withdrawal effects might occur after 
linaclotide treatment has been withdrawn. 
5.3 
TRIAL DURATION 
The test product and reference therapy will be administered for a total of 16 weeks. Total patient 
participation is expected to last for up to 162 days. 


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6. 
SELECTION OF TRIAL POPULATION 
6.1 
INCLUSION CRITERIA 
To be eligible to participate in the trial, patients must meet the following criteria: 
1. Patient has given consent by signing an ICF. 
2. Patient is ambulatory (females must also be non-pregnant) and is aged 18 years or older at 
the Screening Visit. Lactating females must agree not to breastfeed. 
3. Female patients of childbearing potential (ie, women who are not postmenopausal or who 
have not had a bilateral oophorectomy, hysterectomy, or tubal ligation) who are sexually 
active with a male partner must agree to use one of the following methods of birth control 
from the date they sign the ICF until 24 hours after their final dose of study drug: 
a. Hormonal contraception (ie, oral contraceptive, contraceptive implant, or injectable 
hormonal contraceptive) 
b. Double-barrier birth control (eg, condom plus intrauterine device, diaphragm plus 
spermicide) 
c. Maintenance of a monogamous relationship with a male partner who has been surgically 
sterilized by vasectomy 
4. Females of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative urine pregnancy test at the Randomization Visit prior to 
dosing. 
5. Patient meets the colonoscopy requirements as defined by the American Gastroenterological 
Association guidelines and described in Appendix 3. (Note: Patients who receive narcotic 
anesthesia for a colonoscopy are eligible to enter the Pretreatment Period on the fifth day 
after the colonoscopy.) 
6. Patient meets Rome III criteria for IBS (1): reports abdominal pain or discomfort at least 
3 days/month during the 3 months before the diagnosis with the onset at least 6 months 
before the diagnosis, associated with two or more of the following features: 
a. Improved with defecation 
b. Onset associated with a change in frequency of stool 
c. Onset associated with a change in form (appearance) of stool 
Note: the diagnosis can be made at the Screening Visit or can be based on symptoms that the 
patient had before starting chronic treatment with linaclotide (LINZESS®), lubiprostone 
(AMITIZA®), or plecanatide (TRULANCE™). 


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7. During the time when the Rome III criteria for IBS were met, the patient had hard or lumpy 
stools (Bristol Stool Form Scale [BSFS] scores of 1 or 2) with at least 25% of BMs and had 
loose (mushy) or watery stools (BSFS scores of 6 or 7) with less than 25% of BMs in the 
absence of antidiarrheal or laxative use. 
8. Patient reports <3 BMs (with each BM occurring in the absence of any laxative, suppository, 
or enema use during the preceding 24 hours) per week for at least 12 weeks, before the 
Screening Visit or before starting chronic treatment with linaclotide (LINZESS®), 
lubiprostone (AMITIZA®), polyethylene glycol 3350 (MiraLAX®), plecanatide 
(TRULANCE™), or any laxative. 
9. Patient has an average score for abdominal pain at its worst of ≥3.0, as reported in the eDiary 
using an 11-point numerical rating scale (NRS) during the 14 days before the Randomization 
Visit and including the data entry into the eDiary made in clinic at the Randomization Visit 
prior to randomization. 
10. Patient reports ≤6 complete spontaneous BMs (CSBMs) and ≤10 spontaneous BMs (SBMs) 
in the eDiary occurring over the 14 days before the Randomization Visit and including the 
data entry into the eDiary made in clinic at the Randomization Visit prior to randomization. 
(Note: A CSBM is an SBM that is associated with a sense of complete evacuation. An SBM 
is a BM that occurs in the absence of laxative, suppository, or enema use on the calendar day 
of the BM or the calendar day before the BM as evidenced by the patient-reported laxative 
use via the eDiary.) 
11. Patient is compliant (as defined in the trial procedures section below) with eDiary completion 
by adequately responding to eDiary questions (ie, completing the daily evening report) on 10 
or more of the 14 days before the Randomization Visit. 
12. Patient is willing to discontinue any laxatives used before the Pretreatment Visit in favor of 
the protocol-defined Rescue Medicine (bisacodyl tablets or suppositories). 
13. Patient is fluent in English or Spanish. 
14. Patient agrees to refrain from making any new, major life-style changes that may affect IBS-
C symptoms (eg, starting a new diet or changing his or her exercise pattern) from the time of 
signature of the ICF to the last trial visit. 
 
6.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will not be eligible to participate in the trial. 
1. Patient reports loose (mushy) or watery stools (BSFS score of 6 or 7) in the absence of any 
laxative, suppository, enema, or prohibited medicine (as described in Appendix 2) for >25% 
of BMs during the 12 weeks before the Screening Visit. 


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2. Patient has clinically significant concurrent illness or findings on a physical examination or 
clinical laboratory tests (clinical chemistry panel, complete blood count [CBC], urine drug 
screen) after signing the ICF but before receiving the first dose of study drug. (Note: The 
investigator will determine if a particular finding is clinically significant. In making this 
determination, the investigator will consider whether the particular finding could prevent the 
patient from performing any of the protocol-specified assessments, could represent a 
condition that would exclude the patient from the trial, could represent a safety concern if the 
patient participates in the trial, or could confound the trial-specified assessments of safety or 
efficacy.) 
3. Patient has been diagnosed with or has a family history of familial adenomatous polyposis, 
hereditary nonpolyposis colorectal cancer, or any other form of familial colorectal cancer. 
4. Patient has a prior history of inflammatory bowel disease (IBD). 
5. Patient currently has clinically significant symptoms such as lower GI bleeding (rectal 
bleeding or heme-positive stool), iron-deficiency anemia, weight loss, or systemic signs of 
infection or colitis. 
6. Patient currently has active peptic ulcer disease (ie, not adequately treated or stable with 
therapy). 
7. Patient has a history of diverticulitis or any chronic condition (eg, chronic pancreatitis, 
polycystic kidney disease, ovarian cysts, endometriosis) with ongoing symptoms that can be 
associated with abdominal pain or discomfort and could confound the assessments in this 
trial. 
8. Patient has a central nervous system cause of constipation (eg, Parkinson's disease, spinal 
cord injury, and multiple sclerosis). 
9. Patient has ever had any of the following diseases or conditions that can be associated with 
constipation: pseudo-obstruction, megacolon, megarectum, bowel obstruction, descending 
perineum syndrome, solitary rectal ulcer syndrome, systemic sclerosis. 
10. Patient has ever had a fecal impaction that required hospitalization or emergency room 
treatment, or has a history of cathartic colon, laxative or enema abuse, ischemic colitis, or 
pelvic floor dysfunction (unless successful treatment has been documented by a normal 
balloon expulsion test). 
11. Patient has a known or suspected structural abnormality of the gastrointestinal (GI) tract (eg, 
mechanical gastrointestinal obstruction) or a disease or condition that can affect GI motility. 
12. Patient has a history of hypersensitivity to linaclotide or to any of the excipients contained in 
the study drug (active or placebo) as described in Section 7.1. 
13. Patient has had surgery that meets any of the following criteria: 
a. Bariatric surgery for treatment of obesity, or surgery to remove a segment of the GI tract 
at any time before the Screening Visit 


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b. Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months before 
the Screening Visit 
c. An appendectomy or cholecystectomy during the 60 days before the Screening Visit 
d. Other major surgery during the 30 days before the Screening Visit 
14. Patient has a history of cancer other than treated basal cell or squamous cell carcinoma of the 
skin. (Note: Patients with a history of cancer are allowed if the malignancy has been in a 
complete remission for at least 5 years before the Randomization Visit. A complete remission 
is defined as the disappearance of all signs of cancer in response to treatment.) 
15. Patient has a history of diabetic neuropathy. 
16. Patient has untreated hypothyroidism or treated hypothyroidism for which the dose of thyroid 
hormone has not been stable for at least 6 weeks at the time of the Screening Visit. 
17. Patient has a recent history (during the 12 months before the Randomization Visit) of drug or 
alcohol abuse. (Note: Patients with a history of drug or alcohol abuse that was diagnosed 
greater than 12 months before the Randomization Visit may be enrolled if they have 
exhibited no actual abuse during the 12 months before the Randomization Visit.) 
18. Patient reports a BSFS score of 6 (loose, mushy stools) for >1 SBM or a BSFS score of 7 
(watery stools) with any SBM occurring over the 14 days before the Randomization Visit and 
including the data entry into the eDiary made in the clinic at the Randomization Visit prior to 
randomization. 
19. Patient used Rescue Medicine (bisacodyl tablet or suppository) or any other laxative, 
suppository, or enema, on the day before or the day of the Randomization Visit prior to 
randomization. 
20. Patient reported using a Prohibited Medicine (excluding laxatives, suppositories, and 
enemas) during the Pretreatment Period or is not willing or able to abide by the restrictions 
regarding use of Prohibited Medicines defined in Appendix 2. (Note: The use of fiber, bulk 
laxatives, or stool softeners [such as docusate] is acceptable provided the patient has been on 
a stable dose during the 30 days before the Screening Visit and plans to continue on a stable 
dose throughout the trial.) 
21. Patient has been hospitalized for a psychiatric condition or has made a suicide attempt during 
the two years before the Randomization Visit. 
22. Patient has taken commercially available linaclotide (LINZESS®) or plecanatide 
(TRULANCE™) or received an investigational drug during the 30 days before the Screening 
Visit. 
23. Patient has an acute or chronic condition that, in the investigator's opinion, would limit the 
patient's ability to complete or participate in this clinical trial. 
24. Patient has previously entered the Pretreatment Period of this trial. 


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25. Patient is directly or indirectly involved in the conduct and administration of this trial as an 
investigator, sub-investigator, study coordinator, other trial staff member, or employee of 
Ironwood Pharmaceuticals, Forest Laboratories, Actavis, or Allergan; or the patient is a first-
degree family member, significant other, or relative residing with one of the above persons 
involved directly or indirectly in the trial; or the patient is enrolled in this trial at another 
clinical trial site. 
 
6.3 
DISCONTINUATION OF PATIENTS FROM THERAPY OR 
ASSESSMENT 
A premature discontinuation will occur when a patient who signed the ICF ceases participation 
in the trial, regardless of circumstances, before the completion of the protocol. Patients can 
prematurely discontinue or be prematurely discontinued by the investigator or Sponsor from the 
trial at any time for any reason including the following: 
• Failure to meet Inclusion/Exclusion Criteria (Screening or Pretreatment Failure) 
• Adverse event (AE) 
• Lack of efficacy 
• Protocol violation 
• Non-compliance with study drug 
• Withdrawal of consent 
• Lost to follow-up (every effort must be made to contact the patient; a certified letter must be 
sent) 
• Trial termination by Sponsor 
• Pregnancy 
• Other, such as administrative reasons 
 


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Patients who are randomized but do not complete the Treatment Period or RW Period (withdraw 
consent or are discontinued before they have completed 12 weeks or 4 weeks of treatment, 
respectively) will be considered Treatment Period or RW Period withdrawals, respectively, and 
should complete the procedures required at the Week 16/EOT Visit (even if out of window) at 
the time of their discontinuation. The reasons for premature discontinuation from the trial will be 
documented on the study termination form of the eCRF. All data on the patient prior to 
discontinuation will be made available to Ironwood (or designee). Any patient who withdraws 
because of an AE will be followed until the AE resolves, stabilizes, or can be explained as being 
unrelated to study drug. The trial centers should make a reasonable effort to follow pregnant 
patients until delivery or end of the pregnancy. 
If a patient does not return for a scheduled termination visit (EOT Visit), the trial center should 
contact the patient. Every effort is to be made to contact the patient, including sending a certified 
letter. In every case, the patient outcome, including lost to follow-up information, will be 
documented. 
The investigator may allow a patient to stop taking study drug for up to 3 days should an 
intolerable AE occur. If the investigator believes that the patient is unable to resume dosing or 
requires a suspension of dosing on more than one occasion, the investigator should contact the 
Medical Monitor to discuss the patient’s continued participation in the trial. 
6.4 
REPLACEMENT PROCEDURES 
Patients in this trial who prematurely discontinue treatment will not be replaced. 


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7. 
TREATMENTS 
7.1 
TREATMENTS ADMINISTERED 
Study drug in the form of oral capsules will be provided by Ironwood or designee. For the 
double-blind Treatment Period and RW Period, patients will be supplied with identically 
appearing capsules containing linaclotide 290 µg or placebo. 
Linaclotide will be provided as 290-µg oral capsules containing active pharmaceutical ingredient 
with the following excipients: microcrystalline cellulose, calcium chloride dihydrate, l-leucine, 
hypromellose, and gelatin. 
Matching placebo will be provided as oral capsules containing microcrystalline cellulose and 
gelatin. 
7.2 
IDENTITY AND STORAGE OF INVESTIGATIONAL PRODUCT 
All study drug will be supplied in bottles containing thirty-five (35) capsules of linaclotide 
290 µg or matching placebo capsules. Bottles will have child-resistant screw-top caps and will be 
uniquely numbered and labeled in a double-blind fashion that conforms to regulatory 
requirements. 
All study drug will be provided by Ironwood or designee. Linaclotide 290 µg and matching 
placebo capsules will be stored at the trial center in an appropriate secure, temperature-controlled 
area at 77°F (25°C), excursions permitted to 59-86°F (15-30°C). Any deviations from the storage 
conditions must be reported to Ironwood and use of the study medication suspended until 
authorization for its continued use has been provided by Ironwood. 
7.3 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS 
The patient identification (PID) number will consist of 7 digits; 
 
 
The patient will retain 
the same PID number (which is also the Screening Number) throughout the Treatment Period. 


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Patients who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized into the trial at the Randomization Visit on Day 1. Approximately 600 patients will 
be randomized to 1 of 2 treatments: linaclotide 290 µg or placebo (1:1). Patients who complete 
the Treatment Period will enter the RW Period and be allocated to study drug as follows. 
• Patients randomized to linaclotide 290 µg during the Treatment Period will be rerandomized 
to linaclotide 290 µg or placebo (1:1) 
• Patients randomized to placebo during the Treatment Period will be allocated to linaclotide 
290 µg 
 
Randomization numbers will be assigned by an interactive web response system (IWRS). 
7.4 
SELECTION OF DOSAGE IN THE STUDY 
The 290-µg dose of linaclotide was selected for this Phase 3b trial to further evaluate the efficacy 
of the FDA-approved dose of linaclotide on abdominal symptoms (abdominal bloating, 
abdominal discomfort, and abdominal pain) in IBS-C patients. 
7.5 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT 
All study drug will be administered orally once daily. Patients who meet all eligibility criteria at 
the Screening and Pretreatment Visits will be randomized to treatment (as described in 
Section 7.3) at the Randomization Visit (randomization number assigned by IWRS) and 
dispensed one bottle containing 35 tablets. Additional bottles will be dispensed at subsequent 
visits per the Schedule of Evaluations. Patients will be instructed to take one capsule in the 
morning at least 30 minutes before breakfast. Patients will take their initial dose of study drug 
(one capsule) at the trial center during the Randomization Visit; patients must have fasted for at 
least 2 hours prior to arriving at the clinic for this visit. Patients will take study drug as usual in 
the morning before the Week 12/ETP Visit. Patients will be instructed to return all unused study 
drug and bottles to the study center at the visits defined in the Schedule of Evaluations. 


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At the Week 12/ETP Visit, patients who have not withdrawn from the Treatment Period will be 
rerandomized by the IWRS (as described in Section 7.3) and dispensed a bottle containing 
35 tablets of double-blind study drug for the RW Period. Treatment will be taken according to 
the dosing instructions for the Treatment Period. Patients will take their initial dose of study drug 
in the RW Period (1 tablet) on RW Day 1 (ie, the day after the Week 12/ETP Visit). 
7.6 
BLINDING 
The Sponsor study personnel, the investigator and all other site study personnel, and the patient 
will remain blinded to individual patient treatment assignments throughout the trial. Specific 
designated personnel in the Drug Safety and Pharmacovigilance group at Ironwood may be 
unblinded to the treatment assignment of individual patient for regulatory reporting purposes. 
Patient randomization codes for the Treatment Period and for the RW Period will be generated 
by Allergan and implemented by the IWRS vendor (an electronic version will be stored on a 
secure server). The Treatment Period randomization list will identify each patient by 
randomization number and include the patient’s corresponding treatment assignment. The RW 
Period list will be stratified by the treatment assigned in the Treatment Period and will include 
the stratum, patient's rerandomization number, and the corresponding treatment assignment. The 
medication code list will be supplied by Almac Clinical Services to the IWRS vendor. 
In case of an emergency, the IWRS will be accessed to obtain the study drug assignment of a 
patient. Accessing the IWRS for emergency unblinding should be done only in an emergency 
that necessitates identifying the study drug for the welfare of the patient, and only after 
unsuccessfully attempting to contact the Medical Monitor or designee. If the blind is broken, the 
trial center will notify the Ironwood contact (see the Study Identification information in the 
Synopsis) immediately. An explanation for breaking the blind will be recorded on the relevant 
eCRF. Breaking the code at the trial center will disqualify the patient from further participation 
in the trial (refer to Section 6.3 for details regarding procedures and follow-up for patients who 
are discontinued from therapy). 


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7.7 
CONCOMITANT MEDICINES 
A complete list of drugs that are conditionally allowed and drugs that are not allowed as 
concomitant medicines for either episodic or chronic use or as Rescue Medicine is provided in 
Appendix 2. During the Pretreatment, Treatment, and RW Periods, patients may use dispensed, 
protocol-permitted laxatives (bisacodyl tablets or suppositories) as Rescue Medicine when at 
least 72 hours have passed since their previous BM or when their symptoms become intolerable. 
In order to qualify for randomization into the Treatment Period, patients must not have used 
Rescue Medicine on the day before the Randomization Visit or on the day of the Randomization 
Visit prior to randomization. Patients must agree to refrain from using Rescue Medicine from the 
time they arrive at the clinic for the Randomization Visit through the day after randomization. 
At the Screening Visit, all ongoing medicines or investigational products taken by the patient 
will be recorded. Past use of certain medications to manage IBS-C symptoms, even if not 
ongoing at the time of the Screening Visit, will be recorded in the Prior IBS-C Symptom 
Management Assessment (refer to Section 8.2.6 and Appendix 7) at the Screening Visit. 
Any over-the-counter or prescription laxatives, suppositories, or enemas used to treat IBS-C may 
not be used during the Pretreatment, Treatment, and RW Periods and may not be used on the day 
before the Pretreatment Visit. Other prohibited medicines may not be used during the 
Pretreatment, Treatment, and RW Periods and may not be used during the 14 days before the 
Pretreatment Visit (refer to Appendix 2). Thereafter, any changes in concomitant medicines or 
new medicines added will be recorded on the eCRF. Concomitant medicines will be recorded at 
study visits throughout the entire trial. Rescue Medicine use will be documented by the patient 
via eDiary. 


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7.8 
TREATMENT COMPLIANCE 
Study drug will be administered to the patient by study center staff at the Randomization Visit. 
For all other days in the Treatment Period and RW Period, study drug will be taken by the 
patient once daily in the morning at least 30 minutes before breakfast. Study drug accountability 
will be closely monitored during the Treatment Period and RW Period by counting the number 
of capsules returned and recording that information on the eCRF. Every effort will be made to 
collect all unused study drug. Additionally, patients will be asked about the number of capsules 
lost and that information will be recorded on the eCRF. 


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8. 
STUDY PROCEDURES AND ASSESSMENTS 
8.1 
EFFICACY ASSESSMENTS 
8.1.1 
Primary Efficacy Assessments 
The efficacy assessments that will be used to determine the primary efficacy endpoint (Section 
10.4.1) are the daily patient assessments of abdominal pain, abdominal discomfort, and 
abdominal bloating at their worst (ie, the components of the abdominal score). 
Daily Patient Assessment of Abdominal Pain at its Worst 
Patient assessment of abdominal pain at its worst will be collected via a daily evening report in 
the eDiary. The rating of abdominal pain at its worst during the previous 24 hours on an 11-point 
NRS will be provided by the patient answering the following question: 
“How would you rate your worst abdominal pain in the past 24 hours?” 
<eDiary presents NRS where 0 is anchored with “No abdominal pain” and 10 is anchored with 
“Worst possible abdominal pain”> 
Daily Patient Assessment of Abdominal Discomfort at its Worst 
Patient assessment of abdominal discomfort at its worst will be collected via a daily evening 
report in the eDiary. The rating of abdominal discomfort at its worst during the previous 
24 hours on an 11-point NRS will be provided by the patient answering the following question: 
“How would you rate your worst abdominal discomfort in the past 24 hours?” 
<eDiary presents NRS where 0 is anchored with “No abdominal discomfort” and 10 is anchored 
with “Worst possible abdominal discomfort”> 
Daily Patient Assessment of Abdominal Bloating at its Worst 
Patient assessment of abdominal bloating at its worst will be collected via a daily evening report 
in the eDiary. The rating of abdominal bloating at its worst during the previous 24 hours on an 
11-point NRS will be provided by the patient answering the following question: 


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“How would you rate your worst abdominal bloating in the past 24 hours?” 
 <eDiary presents NRS where 0 is anchored with “No abdominal bloating” and 10 is anchored 
with “Worst possible abdominal bloating”> 
8.1.2 
Secondary Efficacy Assessments 
The efficacy assessments that will be used to determine the secondary efficacy endpoints are the 
daily patient assessments of abdominal pain, abdominal discomfort, and abdominal bloating at 
their worst, as described in Section 8.1.1. 
8.1.3 
Additional Efficacy Assessments 
In addition to the primary/secondary efficacy assessments, the following efficacy assessments 
are used in determining the additional efficacy endpoints. 
Complete Spontaneous Bowel Movement 
The CSBM assessment is based on the eDiary questions that determine whether a BM is a 
CSBM: 
• BM Day and Time 
Patients will report BMs on an event-driven basis. An evening report will ask whether the 
patient entered all BMs for that day, and collect BMs not previously entered for that day.  
• Association with a Sense of Complete Evacuation 
This is assessed by the patient answering the following eDiary question for each BM: 
“Did you feel like you completely emptied your bowels after your bowel movement?” 
1=Yes 
2=No 
• Day of Any Laxative Use 
Patients will report use of bisacodyl or other laxatives, suppositories, or enemas on an event-
driven basis. An evening report will ask whether the patient entered all laxative use for that 
day, and collect bisacodyl or other laxatives, suppositories, or enemas not previously entered 
for that day. 
 


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Each day of the Pretreatment, Treatment, and RW Periods, the patient will complete eDiary 
entries on an event-driven basis to report BMs, and whether the BM was associated with a sense 
of complete evacuation. (The patient is also asked to provide assessments of stool consistency 
and straining, which are described below.) The patient will also complete eDiary entries on an 
event-driven basis to report use of protocol-permitted bisacodyl (tablets or suppositories) or other 
laxatives, suppositories, or enemas to treat their symptoms. Patients will complete a daily 
evening report to enter any BMs and laxative usage not previously reported by the patient for 
that day (recall is limited to 24 hours or to the time of the previous evening’s report). 
Spontaneous Bowel Movement 
The SBM assessment is based on the eDiary questions (described above) that determine whether 
a BM is an SBM: 
• BM day and time 
• Day of Any Laxative Use 
 
Stool Consistency (BSFS) 
Patient assessment of stool consistency will be collected using two questions by eDiary entry on 
an event-driven basis (ie, for each BM reported in the eDiary). 
For each BM, the patient assesses his/her stool using the BSFS (Appendix 4) which depicts the 
stool consistency characteristics along with descriptions for each of them. The patient assigns a 
corresponding score for each BM. The BSFS is a well-accepted and widely-used measurement of 
stool consistency.(14) The 7-point ordinal BSFS is provided below (see Appendix 4 for full scale 
including pictures): 
“Please describe the form of your stool using the following scale where:” 
1=Separate hard lumps like nuts (difficult to pass) 
2=Like a sausage but lumpy 
3=Like a sausage but with cracks on the surface 
4=Like a sausage or snake, smooth and soft 


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5=Soft pieces with clear-cut edges (easy to pass) 
6=Fluffy pieces with ragged edges, a mushy stool 
7=Watery, no solid pieces (entirely liquid) 
 
The patient also assesses his/her stool using a 5-point ordinal scale described below. 
Straining 
Patient assessment of straining will be collected by eDiary entry on an event-driven basis (ie, for 
each BM reported in the eDiary). For each BM, degree of straining will be assessed by the 
patient using the following 5-point ordinal scale: 
“How much did you strain during your bowel movement?” 
1=Not at all 
2=A little (mild straining) 
3=A fair amount (moderate straining) 
4=A large amount (severe straining) 
5=An extreme amount (extremely severe straining) 
 
Stool Consistency (5-point ordinal scale) 
In addition to the patient assessment of stool consistency using the BSFS (described above), 
patients will also assess stool consistency by daily eDiary entry on an event-driven basis using a 
5-point ordinal scale: 
“How would you describe the consistency of your stool?” 
1=Very hard 
2=Hard 
3=Neither too hard nor too soft 
4=Loose but not watery 
5=Very loose and watery 


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Weekly Patient Assessment of Constipation Severity 
Patient assessment of constipation severity will be reported weekly by eDiary entry. The rating 
of constipation severity during the previous 7 days on a 5-point ordinal scale will be provided by 
the patient answering the following question: 
“On average, how would you rate your constipation during the past 7 days?” 
1=None 
2=Mild 
3=Moderate 
4=Severe 
5=Very severe 
 
Weekly Patient Assessment of IBS Symptom Severity 
Patient assessment of IBS symptom severity will be reported weekly by eDiary entry. The rating 
of IBS symptom severity during the previous 7 days on a 5-point ordinal scale will be provided 
by the patient answering the following question: 
“On average, how would you rate your IBS symptoms during the past 7 days?” 
1=None 
2=Mild 
3=Moderate 
4=Severe 
5=Very severe 
 


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Weekly Patient Assessment of Adequate Relief 
Patient assessment of adequate relief of IBS symptoms will be reported weekly by eDiary entry. 
The rating of adequate relief during the previous 7 days on a binary scale will be provided by the 
patient answering the following question: 
“Overall, have you had adequate relief from your IBS symptoms during the past 7 days?” 
1=Yes 
2=No 
 
Weekly Patient Assessment of Treatment Satisfaction 
Patient assessment of treatment satisfaction will be reported weekly by eDiary entry each week 
after the Randomization Visit. Patients will answer the following question on a 5-point ordinal 
scale: 
“Overall, how satisfied are you with the study medication’s ability to relieve your IBS 
symptoms?” 
1=Not at all satisfied 
2=A little satisfied 
3=Moderately satisfied 
4=Quite satisfied 
5=Very satisfied 
 


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8.1.4 
Health Economics and Outcomes Research Assessments 
IBS-QOL 
The IBS-QOL is an instrument for assessing the impact of IBS on a patient’s quality of life 
(Appendix 5).(15) The IBS-QOL will be completed at the Randomization Visit prior to the 
patient receiving study drug and at subsequent visits as specified in the Schedule of Evaluations. 
At each of the designated visits, the assessment will be triggered by site personnel on the 
patient’s eDiary for the questionnaire to be self-administered by the patient. 
CDC Healthy Days Core Module (CDC HRQOL-4) 
The CDC Healthy Days Core Module (CDC HRQOL-4; Appendix 6) assesses a person’s 
perceived health status through 4 questions that assess self-rated health, numbers of recent days 
when physical health or mental health was not good, and number of recent days with limitations 
due to poor physical or mental health.(16) For the CDC HRQOL-4 items, recent is defined as 
during the past 30 days. The CDC HRQOL-4 will be completed at the Randomization Visit prior 
to the patient receiving study drug and at subsequent visits as specified in the Schedule of 
Evaluations. At each of the designated visits, the assessment will be triggered by site personnel 
on the patient’s eDiary for the questionnaire to be self-administered by the patient. 
8.1.5 
Completion of eDiary Assessments 
To ensure patient compliance with the completion of the evening eDiary report, alarms occurring 
at 8, 9, 10, and 11 PM will be programmed to alert the patient that he/she has not completed the 
evening eDiary report. Upon completion of the evening eDiary report, the alarm will no longer 
be active for the remainder of that day. If the patient does not complete the evening report prior 
to midnight, that day’s evening report will no longer be available for reporting by the patient and 
all evening assessments for that day will be considered missing. 
Patient compliance with the daily eDiary completion requirement will be verified by site staff as 
specified in the Schedule of Evaluations. 


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8.2 
SAFETY ASSESSMENTS 
Safety will be evaluated by AE reports (discussed herein), standard clinical laboratory 
assessments, vital signs, physical examinations, and medical history. Planned timepoints for all 
safety assessments are provided in the Schedule of Evaluations. 
8.2.1 
Adverse Events 
8.2.1.1 
Definitions 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug-related. 
An AE, therefore, can be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
Serious Adverse Event 
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results in 
any of the following outcomes: 
• Death 
• Life-threatening experience: An AE is considered "life-threatening" if, in the view of either 
the investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might have 
caused death. 
• Inpatient hospitalization or prolongation of an existing hospitalization: AEs requiring 
hospital admissions that are less than 24 hours in duration do not meet this criterion. A 
scheduled hospitalization for a preexisting condition that has not worsened during 
participation in the trial does not meet this criterion. Preplanned hospitalizations for an 
elective medical/surgical procedure or routine check-ups do not meet this criterion. 


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• Persistent or significant disability or incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly or birth defect 
• Is considered to be an important medical event: Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Treatment-emergent Adverse Event 
A treatment-emergent AE (TEAE) is an event that emerges, or a preexisting event that worsens, 
any time after administration of the first dose of study drug (Day 1). 
8.2.1.2 
Classification of an Adverse Event 
8.2.1.2.1 
Severity 
The investigator or delegated physician will provide an assessment of the severity of each AE by 
recording a severity rating in the patient’s source documentation and on the AE page of the 
patient’s eCRF. Severity, which is a description of the intensity of manifestation of the AE, is 
distinct from seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality. Severity will be assessed according to the 
following scale: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
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Severe: 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
AEs should be recorded using the maximum intensity of the event (eg, if a subject reported 
nausea lasting 3 days, one start date and stop date should be recorded along with the maximum 
intensity experienced for that event over that 3-day timeframe). 
8.2.1.2.2 
Relationship to Study Drug 
For all AEs, the investigator must provide an assessment of causal relationship to study drug. 
The investigator must assess the relationship of each AE (including SAEs) to the use of a study 
drug using a 2-category scale (not related or related) based on clinical judgment and using all 
available information, and may include consideration of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, preexisting 
conditions, concomitant use of other drugs, and presence of environmental or genetic factors 
• The temporal association between drug exposure and onset of the AE 
• Whether the manifestations of the AE are consistent with known actions or toxicity of the 
investigational product 
• Whether the AE resolved or improved with stopping use of the study drug; judgment should 
be used if multiple products are discontinued at the same time 
 
The causality assessment must be recorded in the patient’s source documentation and on the AE 
page of the patient’s eCRF. The causal relationship between study drug and the AE will be 
assessed using the categories shown in Table 2. 


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Table 2. 
Adverse Event Causality 
Category 
Definition 
Not related 
An AE is not associated with study medication if: 
- 
Lack of a temporal relationship to study drug administration makes a 
causal relationship improbable (eg, the event did not occur within a 
reasonable time frame following administration of the study 
medication); and/or 
- 
Other causative factor(s) (eg, a preexisting clinical condition, other 
concomitant treatments) more likely explain the occurrence of the 
event, and 
- 
The event did not improve with stopping of the investigational 
product, and/or 
- 
The event did not recur upon re-exposure with investigational product 
Related 
An AE is attributed to the study medication if: 
- 
A temporal relationship to study drug administration makes a causal 
relationship plausible (eg, the event occurred within a reasonable time 
frame following administration of study medication); and/or 
- 
Other causative factor(s) (eg, the subject’s clinical condition, other 
concomitant treatments) either do not explain the event or are less 
equally likely to have led to the occurrence of the event, or 
- 
The event improved with stopping of the investigational product, 
and/or 
- 
The event recurred upon re-exposure with investigational product 
 
8.2.1.2.3 
Laboratory Abnormalities 
The investigator will review clinical laboratory values for significance and consideration as an 
AE. All of the following laboratory abnormalities should be captured as AEs: 
• Any laboratory test result that meets criteria for an SAE 
• Any laboratory abnormality that results in discontinuation 
• Any laboratory abnormality that requires the patient to receive specific corrective therapy 
• Any laboratory abnormality that the investigator considers to be clinically significant 
 


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Ongoing abnormal laboratory values/conditions that are being treated at baseline will be captured 
as an AE if the condition increases in severity and/or frequency during the course of the trial or if 
the condition requires more frequent treatment. If a patient is treated for an abnormal laboratory 
value just before the Screening Visit, then the medical history should reflect the severity of the 
condition before treatment. 
8.2.1.3 
Procedures for Recording Adverse Events 
The investigator will record all AEs from the time informed consent is obtained until completion 
of trial participation (eg, early termination or Week 16/EOT Visit). At each trial visit, the 
investigator will inquire about the occurrence of AEs/SAEs since the last visit. 
The occurrence of an AE or SAE may come to the attention of trial center personnel during trial 
visits and interviews of a trial patient presenting for medical care, or upon review by a site 
monitor. All AEs including SAEs will be captured on the appropriate eCRF. Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study drug (assessed only by those with the training and authority to make a 
diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study 
must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution or stabilization. 
Any medical condition that is present at the time that the patient is screened and does not 
deteriorate (worsen in severity and/or frequency) should be recorded as Medical History and not 
as an AE. However, if the patient’s condition deteriorates at any time during the trial, it will be 
recorded as an AE. AEs characterized as intermittent require documentation of onset and 
duration of each episode. 
Pretreatment AEs will be collected and captured in the patient’s source documentation from the 
time the patient signs the ICF until the patient receives study drug. Pretreatment AEs in 
randomized patients will additionally be entered on the AE page of the patient’s eCRF. 
Laboratory abnormalities, changes in vital signs, and physical examination findings should be 
considered AEs and reported on the AE page of the patient's eCRF only if the investigator 
considers them clinically significant and/or they necessitate intervention. 


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8.2.1.4 
Procedures for Collecting and Reporting Serious Adverse Events 
The investigator or designee is to report any SAE to Ironwood Pharmacovigilance (see below) 
using the SAE Form within 24 hours of becoming aware of the event that occurred during the 
reporting period. 
Ironwood Pharmacovigilance Contact Information 
Ironwood Pharmaceuticals, Inc. 
clinicalsafety@ironwoodpharma.com 
Fax:  1-617-933-7688 
 
The SAE Form, which is to be completed in English and signed by the investigator (or designee), 
is to include as much information as possible, but at a minimum must contain the following: 
• SAE term 
• Serious criteria 
• Severity 
• Causality assessment 
• Narrative explaining the context of the SAE outcome 
 
If not all information on the SAE Form is available at the time of the initial report, follow-up 
SAE reports will be completed and submitted within the same reporting timelines as initial 
reports. 
The investigator or designee is required to follow SAEs until resolution regardless of whether the 
patients are still participating in the trial. Resolution is defined as: 
• Resolved with or without residual effects (sequelae) 
• A return to baseline for a preexisting condition 
• The investigator does not expect any further improvement or worsening of the event 
• Fatal outcome: If an autopsy is performed on a deceased patient, the autopsy report and death 
certificate must be provided to Ironwood as soon as it is available. 
 


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8.2.1.4.1 
Reporting of SAEs to the IRB 
The investigator will receive prompt notification of SAEs, with the use of the study product, that 
are both unexpected and related, or any finding that suggests a significant risk for patients. The 
investigator will promptly inform the IRB of the notification and insert the notification in the 
Investigator’s Regulatory Binder in accordance with local regulations. 
All applicable expedited safety reports will be forwarded, by Ironwood, to the investigator. 
The investigator will inform Ironwood of any local regulatory or IRB requirements not covered 
by the procedures in this or the prior section. 
8.2.1.4.2 
Reporting of Pregnancy 
Any female patient who becomes pregnant while participating in the trial will be withdrawn from 
the trial. 
Information on any pregnancies in female patients, or the female partner of a male patient, will 
be collected from the Screening Visit until the completion of the Week 16/EOT Visit. 
If the patient or the female partner of a male patient becomes pregnant after receiving study drug 
during the course of trial, the investigator will collect and record the pregnancy information on 
the Pregnancy Reporting Form and submit it to Ironwood within 24 hours of learning of the 
pregnancy. (Note: If the female partner of a male patient becomes pregnant, the investigator must 
attempt to obtain consent to collect pregnancy information [including status of the newborn, if 
applicable] before reporting information to Ironwood). If not all information on the Pregnancy 
Reporting Form is available at the time of the initial report, follow-up Pregnancy Reporting 
Forms will be completed and submitted within 24 hours of becoming aware of new information. 
The investigator is required to attempt follow-up on the pregnancy until the completion of the 
pregnancy. Information on the status of the mother and newborn will be forwarded to Ironwood 
within 24 hours of the investigator becoming aware. Generally, follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. 


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While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be an SAE and reported as such. A 
spontaneous abortion is always considered to be an SAE and will be reported as such. 
Furthermore, any SAE occurring as a result of a post-trial pregnancy and considered reasonably 
related to the investigational product by the investigator, will be reported to Ironwood as 
described in Section 8.2.1.4. While the investigator is not obligated to actively seek this 
information in former trial participants, he or she may learn of an SAE through spontaneous 
reporting. 
8.2.2 
Clinical Laboratory Determinations 
See below for the list of clinical laboratory tests to be performed and refer to the Schedule of 
Evaluations for the timing and frequency. All protocol-required laboratory assessments, as 
defined below, must be conducted in accordance with the laboratory manual and the Schedule of 
Evaluations. 
The tests detailed below will be performed (additional tests may be performed at any time during 
the trial as determined necessary by the investigator or as required by local regulations): 
• Hematology: 
Absolute and differential white blood cell count, erythrocyte count, 
hemoglobin, hematocrit, platelet count, and red blood cell indices (mean 
corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular 
hemoglobin concentration) 
• Chemistry: 
Sodium, magnesium, potassium, calcium, chloride, glucose, blood urea 
nitrogen, creatinine, total protein, alkaline phosphatase, albumin, total 
bilirubin, aspartate aminotransferase, alanine aminotransferase, 
bicarbonate, phosphate, cholesterol, and uric acid 
• Other: 
Urine drug screening (cocaine, barbiturates, amphetamines, opiates, 
benzodiazepine, alcohol, and cannabinoids) (Screening Visit only). 
Clinical significance of a positive urine drug screen will be assessed by the 
investigator; positive results for cocaine, barbiturates, and cannabinoids 
are exclusionary. 


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• Pregnancy test: Serum human chorionic gonadotropin pregnancy test (for women of 
childbearing potential only) should be conducted at the Screening Visit 
and Week 16/EOT Visit. A negative urine pregnancy test must be 
documented at the Randomization Visit and the Week 12/ETP Visit for 
the patient to be eligible for randomization and dosing with study drug. 
Positive results on the pregnancy test will exclude a patient from 
participating or continuing in the trial. 
 
The investigator must review each laboratory report, document this review, and record any 
clinically relevant changes occurring during the trial in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. All laboratory tests with abnormal 
values considered clinically significant during participation in the trial should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
investigator or Medical Monitor. If such values do not return to normal/baseline within a period 
of time judged reasonable by the investigator, the etiology should be identified and the Sponsor 
notified. If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in patient management or are considered 
clinically significant by the investigator (eg, SAE or AE or study drug discontinuation), the 
results must be recorded in the eCRF. 
8.2.3 
Vital Signs 
Vital sign measurements will be performed as outlined in the Schedule of Evaluations. Oral 
temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure (BP) will be 
assessed. Blood pressure and pulse measurements will be assessed with a completely automated 
device; manual techniques will be used only if an automated device is not available. 
BP and pulse measurements should be preceded by at least 5 minutes of rest for the patient in a 
quiet setting without distractions (eg, television, cell phones). 


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8.2.4 
Physical Examination 
A complete physical examination will be performed as outlined in the Schedule of Evaluations, 
by the investigator or a licensed health professional listed on Form FDA 1572. Any physical 
examination abnormality that the investigator considers to be potentially clinically significant 
and changed from the baseline will be reported as an AE. A complete physical examination will 
include, at a minimum, assessment of the general appearance of the patient and the HEENT 
(head, eyes, ears, nose, and throat), cardiac, respiratory, gastrointestinal, musculoskeletal, 
neurological, and dermatological systems. Height (only at screening) and weight will also be 
measured and recorded. 
A rectal examination should be performed during the Screening Period in all patients who do not 
require a colonoscopy (refer to Appendix 3). After the Screening Period, the rectal examination 
is optional and may be performed at the discretion of the investigator. For all physical 
examinations, the breast and genitourinary examinations are optional and may be performed at 
the discretion of the investigator. 
8.2.5 
Medical History 
A complete medical history, including disease-specific history, will be provided by the patient at 
the Screening Visit. 
As part of their disease-specific history, patients will be asked questions to determine whether 
they also meet the Rome IV criteria for IBS, as described below. 
Patient reports recurrent abdominal pain, on average at least 1 day/week during the 3 months 
before the diagnosis, with the onset at least 6 months before the diagnosis, associated with 2 or 
more of the following features: 
a. Related to defecation 
b. Associated with a change in frequency of stool 
c. Associated with a change in form (appearance) of stool 
 
Rome IV diagnosis has no bearing on patient eligibility to participate in the trial (patients will be 
enrolled based on Rome III criteria for IBS, as detailed in Section 6.1). 


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8.2.6 
Prior IBS-C Symptom Management Assessment 
The prior IBS-C symptom management assessment (Appendix 7) will be performed at the 
Screening Visit, and includes prior treatments taken for IBS-C, lifestyle and diet modifications 
for alleviating the symptoms of IBS-C, assessment of satisfaction with prior interventions’ 
ability to relieve bowel and abdominal symptoms, and primary reason for stopping use. 


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9. 
DATA QUALITY ASSURANCE 
9.1 
DATA MONITORING 
Before any patient enters the trial, a representative of Ironwood or its authorized designee will 
meet with the investigator and his/her staff to review the procedures to be followed while 
conducting the trial and to train them on recording the data on the eCRFs using the electronic 
data capture (EDC) system. 
After the first patient signs the ICF, the Ironwood representative, a site monitor, will periodically 
monitor the progress of the trial by conducting monitoring visits. This site monitor will also be 
able to review the status of data queries remotely, possibly warranting more frequent 
communication with the investigator and his/her staff. The investigator will make available to the 
site monitor the computer that accesses the eCRFs during monitoring visits. The investigator and 
his/her staff will be responsible for reviewing eCRFs, resolving data queries generated by the site 
monitor via the system, providing missing or corrected data, approving all changes performed on 
his/her data, and endorsing the patient data within the EDC system. This approval method will 
include applying an electronic signature, which is a uniquely assigned username and password 
that together will represent a traditional handwritten signature. 
9.2 
DATA RECORDING AND DOCUMENTATION 
All data collected in the context of this trial will be stored and evaluated in such a way as to 
guarantee patient confidentiality in accordance with the legal stipulations applying to 
confidentiality of data. Trial records (eg, essential documents [commonly called regulatory 
documents], correspondence) will be retained at the trial center, along with adequate source 
documentation, according to FDA and ICH requirements. All trial records must be available for 
inspection by Ironwood, its authorized designee, and the FDA. 


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Data collection will involve the use of the 
 EDC system, to which only 
authorized personnel will have access. In addition to periodic monitoring occurring within the 
system by Sponsor site monitors, programmatic edit checks and manual review procedures will 
be used to review the data for completeness, logic, and adherence to the study protocol. As a 
result of this monitoring and these checks, data queries may be electronically issued to the 
clinical trial centers and electronically closed by those centers. The identifying information 
(assigned username, date, and time) for both the originator of the query (if created during the 
monitoring process) and the originator of the data change (if applicable), as well as the 
investigator’s approval of all changes performed on his/her patients’ data, will be collected. 


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10. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
10.1 
ANALYSIS POPULATIONS 
10.1.1 
Screened Population 
The Screened Population consists of all patients who had a Screening Visit (Visit 1) and were 
assigned a PID number. 
10.1.2 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population consists of all randomized patients. 
10.1.3 
Randomized Withdrawal (RW) Population  
The RW Population consists of all patients who were rerandomized or allocated to study drug 
upon completion of the Treatment Period. 
10.1.4 
Safety Population 
The Safety Population consists of all patients who received at least one dose of study drug. 
10.2 
GENERAL METHODS 
Efficacy outcomes from the Treatment Period will be based on the ITT Population and will be 
summarized by treatment group assigned at the Randomization Visit. Efficacy outcomes from 
the RW Period only or from the Combined Treatment and RW Period will be based on the RW 
Population and will be summarized by treatment sequence determined at the Week 12/ETP Visit. 
Treatment periods will be summarized for safety in the same manner as efficacy; however, safety 
summaries (Safety Population) will be based on the actual treatment received. 
Descriptive statistics including the number of patients, mean, minimum and maximum, and 
standard deviation (SD) will be calculated for continuous variables. Frequencies and percentages 
for each category will be calculated for categorical variables. Percentages will be based on the 
total number of non-missing values. The number missing will be presented, but without a 
percentage. All hypothesis tests will be two-sided with a 5% significance level, and 95% 
confidence intervals (CIs) will be used, unless stated otherwise. 


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10.2.1 
Patient Disposition 
Screen failures (ie, patients who entered the Screening Period but not the Pretreatment Period) 
and pretreatment failures (ie, patients who entered the Pretreatment Period but were not 
randomized) and reason for failure will be tabulated. 
Patient counts for the ITT Population will be provided by trial center and geographic region. 
Descriptive summaries will be presented for the ITT Population, the Safety Population, for those 
who completed the Treatment Period, and for those who prematurely discontinued (including the 
reason for premature discontinuation as recorded on the trial completion form). 
Similar to the Treatment Period, descriptive summaries of patients who were rerandomized for 
the RW Period, completed the RW Period, and prematurely discontinued during the RW Period 
plus reasons for premature discontinuation will be presented for the RW Population. 
10.2.2 
Demographics and Baseline Characteristics 
Demographic parameters (age, age group, race, ethnicity, sex), and baseline characteristics 
(weight; height; and body mass index, calculated as weight in kg/[height in m])2) will be 
summarized descriptively for the Safety and ITT Populations. Baseline efficacy parameters 
(including SBM frequency, CSBM frequency, BSFS score, stool consistency, straining, 
abdominal score, abdominal bloating, abdominal discomfort, and abdominal pain) will be 
summarized descriptively for the ITT Population. 
10.2.3 
Protocol Deviations 
Protocol deviations and Important Protocol Deviations (IPD) will be identified and documented 
for all ITT patients prior to unblinding. IPDs will be determined based on blinded review of all 
protocol deviations and protocol deviation categories. IPD categories include, but are not limited 
to: 


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• Those who entered the trial even though they did not satisfy the entry criteria 
• Those who developed withdrawal criteria during the trial but were not withdrawn 
• Those who received the wrong treatment or incorrect dose 
• Those who received an excluded concomitant treatment 
 
10.2.4 
Prior and Concomitant Medicines 
Prior and concomitant medicines will be classified using the most current version of the WHO 
Drug Dictionary available at the start of the trial (or newer). 
Prior medicines are defined as any medicines taken prior to the date of first dose of study drug. 
Concomitant medicines are defined as any medicines taken on or after the date of first dose of 
study drug during the defined period (Treatment/RW). Any medicines started after the date of 
last dose of study drug for the defined period (Treatment/RW) will be excluded from the 
summaries related to concomitant medicines for that period. 
Prior medicine use, concomitant medicine in the Treatment Period, and concomitant medication 
use in the RW Period use will be summarized. Multiple medicines used by a patient in the same 
category (based on Anatomical-Therapeutic-Chemical classification) will be counted only once. 
10.3 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
10.3.1 
Exposure to Study Drug 
Exposure to study drug, calculated as the number of days from the date of first dose taken to the 
date of last dose taken, will be summarized by treatment group for the Treatment Period (Safety 
Population) and by treatment sequence for the RW Period (RW Population). 


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10.3.2 
Measurement of Treatment Compliance 
Dosing compliance for a specified period is defined as the total number of capsules actually 
taken by a patient during that period divided by the number of capsules that were expected to be 
taken during the same period, multiplied by 100. The total number of capsules actually taken will 
be calculated based on the following equation: total number of capsules dispensed – (number of 
capsules returned + number of capsules lost). The total number of capsules expected to be taken 
during a specified period equals the number of days in the period. 
Descriptive statistics for study drug compliance for the Treatment Period overall, and for each of 
the 3 consecutive 4-week periods in the Treatment Period (consistent with study drug 
dispensing) will be presented for the Safety Population. Similarly, descriptive statistics for the 
RW Period will be presented for the RW Population. 
10.3.3 
eDiary Compliance 
eDiary compliance will be based on the percentage of complete eDiary entries made by a patient. 
A complete eDiary entry is defined as one in which the patient responds to every eDiary question 
asked in the evening report on that day. The questions that are asked weekly will not be included 
in the determination of a complete entry. 
Descriptive statistics for eDiary compliance (%) and the patients with ≥80%/<80% complete 
eDiary entries during the Pretreatment, Treatment, and RW Periods will be presented. 
10.4 
EFFICACY ANALYSES 
All efficacy analyses to address the objectives of the trial will be based on the ITT Population for 
outcomes occurring during the Treatment Period. Additional exploratory analyses will be defined 
and clearly specified for the RW Period. 


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Baseline values for efficacy parameters are derived from the eDiary and eCRF data collected in 
the Pretreatment Period, specifically, the period of time from 14 days prior to randomization up 
to the time of randomization. Baseline values for patient symptom severity parameters (eg, 
abdominal symptoms [pain, bloating, discomfort], constipation severity) will be the average of 
the non-missing severity scores reported during this period. The baseline CSBM and SBM 
weekly rates will be derived based on the number of CSBMs and SBMs a patient had during this 
period. Baseline BSFS score, stool consistency, and straining will be calculated as the average of 
the non-missing values associated with the SBMs reported by the patient during this period. 
Trial centers will be pooled together by geographic region (details to be provided in the 
Statistical Analysis Plan [SAP]). In lieu of trial center, geographic region will be used in 
analyses adjusting for center-to-center variability. 
Sensitivity analyses of the key endpoints will include, but are not limited to, a multiple 
imputation approach. If the normality assumption of the errors is violated for the key mixed 
model with repeated measures (MMRM) or analysis of covariance (ANCOVA) analyses, ranked 
or other appropriate analyses will be applied. 
The overall family-wise Type I error rate for the primary and secondary efficacy analyses will be 
controlled at a two-sided 0.05 significance level. 
10.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
• Change from Baseline in Abdominal Score at Each Week 
A patient’s daily Abdominal Score is calculated as the average of the daily patient 
assessments of abdominal bloating at its worst, abdominal discomfort at its worst, and 
abdominal pain at its worst. If 2 or more of the individual daily abdominal symptoms are 
missing, then the Abdominal Score for that day will be missing. The weekly Abdominal 
Score is the average of the non-missing Abdominal Scores during each week (Weeks 1-12) in 
the trial. The baseline Abdominal Score is the average of the non-missing Abdominal Scores 
during the 14-day Pretreatment Period and the day of the Randomization Visit reported prior 
to randomization. Change from baseline will be calculated for each week as the weekly score 
minus the baseline score. 
 


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10.4.2 
Primary Efficacy Analysis 
Inferential testing between the linaclotide 290 µg and placebo groups with regard to the change 
from baseline in abdominal score over the Treatment Period will be evaluated employing a 
mixed model with repeated measures (MMRM) framework with week (categorical), treatment, 
geographic region, and week-by-treatment fixed effects, patient as the random effect, and 
baseline value as a covariate. An unstructured covariance structure will be utilized. Descriptive 
statistics based on the MMRM model will include least-squares (LS) mean change from baseline 
for each treatment, the LS mean difference between linaclotide 290 µg and placebo, 
corresponding 95% CIs, and the p-value associated with the comparison. 
10.4.3 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Change from Baseline in 12-week Abdominal Score (Cumulative Distribution Function 
[CDF]) 
Daily Abdominal Score is calculated as described for the primary endpoint in Section 10.4.1. 
The 12-week Abdominal Score is the average on the non-missing Abdominal Scores reported 
over the course of the Treatment Period. The baseline Abdominal Score is the average of the 
non-missing Abdominal Scores during the 14-day Pretreatment Period and the day of the 
Randomization Visit reported prior to randomization. Change from baseline will be 
calculated as the 12-week score minus the baseline score. 
• 6/12 Week Abdominal Score Responder 
A 6/12 Week Abdominal Score Responder is a patient who meets the Weekly Abdominal 
Score Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For each 
week in the Treatment Period, a Weekly Abdominal Score Responder is a patient who has an 
improvement from baseline of at least 2 points (ie, a -2 change from baseline) in the 
respective weekly abdominal score. If a patient did not enter information into the eDiary on 
at least 4 days for a particular Treatment Period week, the patient will not be considered a 
Weekly Abdominal Score Responder for that week. 
 


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10.4.4 
Secondary Efficacy Analysis 
The CDFs for linaclotide 290 µg and placebo will be estimated for the Change from Baseline in 
12-week Abdominal Score endpoint. The CDFs will be compared using the Wilcoxon rank sum 
test with Hodges-Lehmann estimator for the median difference. 
A secondary time-course analysis of the Change from Baseline in Abdominal Score (see primary 
endpoint definition in Section 10.4.1) will also be conducted. Using the MMRM framework 
defined in the primary analyses, treatment difference between linaclotide 290 µg and placebo 
will be assessed at each individual week. For each week, descriptive statistics based on the 
MMRM model will include the LS mean change from baseline for each treatment, the LS mean 
difference between linaclotide 290 µg and placebo, corresponding 95% CIs, and the p-value 
associated with the treatment comparison. 
For the secondary responder endpoint, the proportion of responders in the linaclotide 290 µg 
group will be compared to the proportion of responders in the placebo group using a Cochran-
Mantel-Haenszel (CMH) test controlling for geographic region. The number and percent of 
responders, the difference in responder rates between the linaclotide 290 µg and placebo groups, 
the odds ratio relative to placebo, all corresponding 95% CIs, and the p-value associated with the 
CMH test will be presented. 
10.4.5 
Controlling for Multiplicity 
The overall family-wise Type I error rate for the primary and secondary efficacy analyses will be 
controlled at the α=0.05 level by employing a fixed-sequence procedure as described below. 
Following the fixed-sequence procedure, if the primary hypothesis between the placebo group 
and the linaclotide 290 µg group is statistically significant (α=0.05) in the ITT Population, then 
the primary objective of the trial will have been achieved and the next hypothesis can be tested; 
otherwise, testing will stop. The testing of each sequential hypothesis is conditional on all the 
previous hypotheses being rejected at the 0.05 level of significance. If a hypothesis is not 
rejected at the 0.05 level of significance, then all remaining hypotheses are deemed not 
statistically significant. All hypothesis testing will be two-sided. 


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1. Linaclotide vs. placebo – Change from Baseline in Abdominal Score (primary efficacy 
analysis) 
2. Linaclotide vs. placebo – Change from Baseline in 12-week Abdominal Score (CDF) 
(secondary efficacy analysis) 
3. Linaclotide vs. placebo – 6/12 Week Abdominal Score Responder (secondary efficacy 
analysis) 
4. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 12 
5. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 10 
6. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 8 
7. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 6 
8. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 4 
9. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 2 
10. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 1 
 
10.4.6 
Additional Efficacy Endpoints 
Additional efficacy endpoints will be explored outside of the formal testing procedures described 
in Section 10.4.5. These endpoints will include: 
• 6/12 Week Abdominal Pain and Constipation (APC) +1 Responder 
A 6/12 Week APC +1 Responder is a patient who meets the Weekly APC +1 Responder 
criteria for at least 6 out of the 12 weeks of the Treatment Period. For each week in the 
Treatment Period, a Weekly APC +1 Responder is a patient who has an increase from 
baseline of at least 1 in the respective CSBM weekly rate and has a decrease from baseline of 
at least 30% in the respective weekly abdominal pain score. If a patient did not enter 
information into the eDiary on at least 4 days for a particular Treatment Period week, the 
patient will not be considered a responder for that week. 
• Change from Baseline in Abdominal Pain at its Worst at Each Week 
Abdominal pain is measured daily using an 11-point NRS. For each week on treatment, the 
weekly abdominal pain score is the mean of the non-missing daily values. 
• Change from Baseline in CSBM Frequency Rate at Each Week 
A patient’s weekly CSBM frequency rate is the CSBM rate (CSBMs/week) calculated for 
that week. 


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• Change from Baseline in SBM Frequency Rate at Each Week 
A patient’s weekly SBM frequency rate is the SBM rate (SBMs/week) calculated for that 
week. 
• Change from Baseline in BSFS (Stool Consistency) at Each Week 
Stool consistency is measured using the 7-point BSFS. The patient’s BSFS score for each 
week on treatment is the mean of the non-missing BSFS scores from the SBMs reported by 
the patient during the week. 
• Change from Baseline in Stool Consistency at Each Week 
Stool consistency is measured using a 5-point ordinal scale. The patient’s stool consistency 
score for each week on treatment is the mean of the non-missing stool consistency scores 
from the SBMs reported by the patient during the week. 
• Change from Baseline in Straining at Each Week 
Straining is measured using a 5-point ordinal scale. The patient’s straining score for each 
week on treatment is the mean of the non-missing straining scores from the SBMs reported 
by the patient during the week. 
• Change from Baseline in Abdominal Discomfort at its Worst at Each Week 
Abdominal discomfort is measured daily using an 11-point NRS. For each week on 
treatment, the weekly abdominal discomfort score is the mean of the non-missing daily 
values. 
• Change from Baseline in Abdominal Bloating at its Worst at Each Week 
Abdominal bloating is measured daily using an 11-point NRS. For each week on treatment, 
the weekly abdominal bloating score is the mean of the non-missing daily values. 
• Percent Change from Baseline in Abdominal Pain at its Worst at Each Week 
Percent change will be calculated as 100 * the Change from Baseline in Abdominal Pain at 
Worst at each week divided by the baseline abdominal pain score. 
• Change from Baseline in Percent of Days with Use of Rescue Medicine 
The percent of days using per-protocol rescue medicine or any other laxative, suppository, or 
enema during at each week be calculated as 100 * the number of days rescue medicine was 
used during the week divided by the total number of days on treatment. 


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• SBM Within 24 Hours After First Dose Responder 
A patient meets the SBM Within 24 Hours After First Dose Responder criteria if the amount 
of time between the time of first dose of study medication reported at the randomization visit 
and the time of first reported SBM is less than or equal to 24 hours. 
• 6/12 Week Abdominal Pain 30% Responder 
A 6/12 Week Abdominal Pain 30% Responder is a patient who meets the Weekly Abdominal 
Pain 30% Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For 
each week in the Treatment Period, a Weekly Abdominal Pain 30% Responder is a patient 
who has a decrease from baseline of at least 30% in the respective weekly abdominal pain 
score. If a patient did not enter information into the eDiary on at least 4 days for a particular 
Treatment Period week, the patient will not be considered a Weekly Abdominal Pain 30% 
Responder for that week. 
• 6/12 Week Abdominal Pain Responder 
A 6/12 Week Abdominal Pain Responder is a patient who meets the Weekly Abdominal Pain 
Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For each week 
in the Treatment Period, a Weekly Abdominal Pain Responder is a patient who has an 
improvement from baseline of at least 2 points (ie, a -2 change from baseline) in the 
respective weekly abdominal pain score. If a patient did not enter information into the eDiary 
on at least 4 days for a particular Treatment Period week, the patient will not be considered a 
Weekly Abdominal Pain Responder for that week. 
• 6/12 Week Abdominal Discomfort Responder 
A 6/12 Week Abdominal Discomfort Responder is a patient who meets the Weekly 
Abdominal Discomfort Responder criteria for at least 6 out of the 12 weeks of the Treatment 
Period. For each week in the Treatment Period, a Weekly Abdominal Discomfort Responder 
is a patient who has an improvement from baseline of at least 2 points (ie, a -2 change from 
baseline) in the respective weekly abdominal discomfort score. If a patient did not enter 
information into the eDiary on at least 4 days for a particular Treatment Period week, the 
patient will not be considered a Weekly Abdominal Discomfort Responder for that week. 
• 6/12 Week Abdominal Bloating Responder 
A 6/12 Week Abdominal Bloating Responder is a patient who meets the Weekly Abdominal 
Bloating Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For 
each week in the Treatment Period, a Weekly Abdominal Bloating Responder is a patient 
who has an improvement from baseline of at least 2 points (ie, a -2 change from baseline) in 
the respective weekly abdominal bloating score. If a patient did not enter information into the 
eDiary on at least 4 days for a particular Treatment Period week, the patient will not be 
considered a Weekly Abdominal Bloating Responder for that week. 


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• 6/12 Week CSBM Responder 
A 6/12 Week CSBM Responder is a patient who meets the Weekly CSBM Responder criteria 
for at least 6 out of the 12 weeks of the Treatment Period. For each week in the Treatment 
Period, a Weekly CSBM Responder is a patient who has an increase from baseline of at least 
1 in the respective CSBM weekly rate. If a patient did not enter information into the eDiary 
on at least 4 days for a particular Treatment Period week, the patient will not be considered a 
Weekly CSBM Responder for that week. 
• Treatment Satisfaction 
Treatment satisfaction is measured on a 5-point ordinal scale. Treatment satisfaction will be 
analyzed separately for each Treatment Period week. 
• Adequate Relief 
Assessment of adequate relief during the previous 7 days is measured on a binary scale 
(yes/no). Assessment of adequate relief will be analyzed separately for each Treatment 
Period week. 
• 6/12 Week Adequate Relief Responder 
A 6/12 Week Adequate Relief Responder is a patient who reports Adequate Relief for at least 
6 out of the 12 weeks of the Treatment Period. 
• Change from Baseline in Constipation Severity 
Constipation severity is measured weekly using a 5-point ordinal scale. Change from 
baseline will be calculated at each week. 
• Change from Baseline in IBS Symptom Severity 
IBS symptom severity is measured weekly on a 5-point ordinal scale. Change from baseline 
will be calculated at each week. 
 
10.4.7 
Additional Efficacy Analysis 
Change-from-baseline endpoints and Treatment Satisfaction will be analyzed utilizing the same 
MMRM methods as described for the primary analysis in Section 10.4.2, and by visit as 
described in Section 10.4.4. Responder endpoints will be analyzed using the methodology 
defined in Section 10.4.4. 


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10.4.8 
Randomized Withdrawal Period Endpoints 
For the RW Period, statistical analyses will be presented by treatment; there are 3 possible 
treatment sequences: 
1. 290 μg-290 μg (linaclotide 290 µg administered in the Treatment Period, followed by 
linaclotide 290 µg in the RW Period) 
2. 290 μg-Placebo (linaclotide 290 µg administered in the Treatment Period, followed by 
placebo in the RW Period) 
3. Placebo-290 μg (placebo administered in the Treatment Period, followed by linaclotide 
290 µg in the RW Period) 
 
The following endpoints will be calculated for the RW Period following the methods described 
for the primary and secondary endpoints in Sections 10.4.2 and 10.4.4: 
• Change from Baseline in Abdominal Score at Each Week 
• Change from Baseline in Abdominal Bloating at its Worst at Each Week 
• Change from Baseline in Abdominal Discomfort at its Worst at Each Week 
• Change from Baseline in Abdominal Pain at its Worst at Each Week 
• Change from Baseline in CSBM Frequency Rate at Each Week 
• Change from Baseline in SBM Frequency Rate at Each Week 
• Change from Baseline in BSFS (Stool Consistency) at Each Week 
• Change from Baseline in Stool Consistency at Each Week 
• Change from Baseline in Percent of Days with Use of Rescue Medicine 
 
10.4.9 
Randomized Withdrawal Period Analyses 
All RW Period endpoints will be summarized for the RW Period only and for the Combined 
Treatment and RW Period using descriptive statistics and 95% CIs for each treatment sequence 
(sequences are defined in Section 10.4.8). No statistical inference will be performed. Baseline for 
all RW Period endpoints will be defined as described in Section 10.4. 


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10.5 
HEALTH ECONOMICS AND OUTCOMES RESEARCH ANALYSES 
Health economics and outcomes research analyses will be based on the ITT Population for the 
Treatment Period and on the RW Population for the RW Period. 
10.5.1 
IBS-QOL 
The IBS-QOL parameters consist of the overall average score and eight subscale scores (ie, 
dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, 
sexual, and relationships). For the Week 12/ETP Visit and the Week 16/EOT Visit, change from 
baseline in the IBS-QOL overall average score and the subscale scores will be analyzed using an 
ANCOVA model with fixed effect terms for treatment group and geographic region and the 
corresponding baseline IBS-QOL score as a covariate. 
10.5.2 
CDC HRQOL-4 
The CDC HRQOL-4 (the Healthy Days Core Module) consists of 4 questions. Self-rated general 
health, physically unhealthy days, mentally unhealthy days, and poor physical/mental days are 
collected. Unhealthy days, defined as the minimum of the sum of physically unhealthy days and 
mentally unhealthy days, or 30 days, will be calculated and reported. Descriptive summaries for 
the derived unhealthy days and the change from baseline will be summarized descriptively at 
each visit. Treatment difference between the change from baseline score will be performed using 
ANCOVA model with fixed effect terms for treatment group and geographic region and the 
corresponding baseline measure as a covariate. 
10.6 
SAFETY ANALYSES 
All safety parameters will be analyzed descriptively in accordance with the general methods 
described in Section 10.2. 
10.6.1 
Adverse Events 
Adverse Event Verbatim Terms will be coded in the EDC system against the most current 
version of MedDRA available at the start of the trial (or newer). 
An AE that occurs during the Treatment Period will be considered a treatment-emergent AE 
(TEAE) for the Treatment Period if it was not present prior to the date of the first dose of double-


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blind study drug, or was present prior to the date of the first dose but increased in severity during 
the Treatment Period. 
Similarly, an AE that occurs on or after the date of the first dose of double-blind study drug for 
the RW Period (up to 1 day after the last dose of double-blind study drug) will be considered a 
TEAE for the RW Period if it was not present prior to the date of first dose of study drug for the 
Treatment Period, or was present prior to the to the date of the first dose for the Treatment Period 
but increased in severity on or after the date of the first dose for the RW Period. 
An AE that occurs on or after the date of the first day of dosing in the RW Period (up to 1 day 
after the last dose of double-blind study drug) will be considered a newly-emergent adverse 
event (NEAE) for the RW Period if it was not present prior to the date of the first calendar day of 
dosing in the RW Period, or was present prior to the date of the first calendar day of dosing in 
the RW Period, but increased in severity on or after the date of the first calendar day of dosing in 
the RW Period. 
If more than one AE is reported prior to the first dose of double-blind study drug and coded to 
the same preferred term, the AE with the greatest severity will be used as the benchmark for 
comparison with the AEs occurring during the Treatment and RW Periods that were also coded 
to that preferred term. An AE that occurs more than 1 day after the last dose of double-blind 
study drug will not be counted as a TEAE or NEAE. 
For the Treatment and RW Periods, the number and percentage of patients reporting TEAEs in 
each treatment group and treatment sequence, respectively, will be tabulated by system organ 
class (SOC) and preferred term; by SOC, preferred term, and severity; and by SOC, preferred 
term, and relationship to study drug. If a patient has more than one TEAE coded to the same 
preferred term, the patient will be counted only once for that preferred term by identifying those 
TEAEs with the highest severity and the closest relationship to study drug. Similar tabulations 
will be presented for the number and percentage of patients reporting NEAEs in the RW Period 
by treatment sequence. 


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The distribution of TEAEs by severity and relationship to study drug will be summarized by 
treatment group for the Treatment Period. Similarly, the distribution of TEAEs and NEAEs by 
severity and relationship to study drug will be summarized by treatment sequence for the RW 
Period. 
The incidence of common TEAEs, on-therapy SAEs, and AEs leading to premature 
discontinuation of study drug will be summarized by preferred term and treatment group for the 
Treatment Period and treatment sequence for the RW Period. In addition, the incidence of fatal 
SAEs (ie, events that caused death), if any, will be summarized separately by treatment group for 
the Treatment Period and treatment sequence for the RW Period, and preferred term. 
Listings will be presented for patients with SAEs, patients with AEs leading to discontinuation, 
and patients who die (if any). 
10.6.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values (in standard units) and changes from the 
baseline values at each assessment time point will be presented by treatment group for the 
Treatment Period and by treatment sequence for the Combined Treatment and RW Period, for 
each clinical laboratory parameter. 
The number and percentage of patients with potentially clinically significant (PCS) post-baseline 
clinical laboratory values will be tabulated by treatment group for the Treatment Period and by 
treatment sequence for the RW Period and the Combined Treatment and RW Period. The criteria 
for PCS laboratory values will be detailed in the SAP. The percentages will be calculated relative 
to the number of patients with available non-PCS baseline values and at least 1 assessment in the 
corresponding post-baseline period. The numerator will be the total number of patients with 
available non-PCS baseline values and at least 1 PCS value in the corresponding post-baseline 
period. A supportive listing of patients with PCS post-baseline values will be provided, including 
the PID number, trial center, and baseline and post-baseline values. A listing of all AEs for 
patients with PCS laboratory values will also be provided. 


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10.6.3 
Vital Signs 
Descriptive statistics for vital signs (ie, pulse rate, systolic and diastolic BP, respiratory rate, 
temperature, and body weight) and changes from baseline at each visit and at the end of the 
period/trial will be presented by treatment group for the Treatment Period and by treatment 
sequence for the Combined Treatment and RW Period. 
The number and percentage of patients with PCS post-baseline vital signs will be tabulated by 
treatment group for the Treatment Period and by treatment sequence for the Combined 
Treatment and RW Period. A vital sign value will be considered PCS if it meets both the 
observed value criterion and the change from baseline value criterion. The criteria for PCS vital 
sign values will be detailed in the SAP. The percentages will be calculated relative to the number 
of patients with baseline values and at least 1 assessment in the corresponding post-baseline 
period. The numerator will be the total number of patients with available non-PCS baseline 
values and at least 1 PCS value in the corresponding post-baseline period. A supportive listing of 
patients with PCS post-baseline values will be provided, including the PID number, trial center, 
and baseline and post-baseline values. A listing of all AEs for patients with PCS vital sign values 
will also be provided. 
10.7 
INTERIM ANALYSIS 
No interim analysis is planned for this trial. 
10.8 
DETERMINATION OF SAMPLE SIZE 
The sample size of 600 patients (300 patients per treatment group) was chosen to ensure 
adequate power for testing the fixed-sequence procedure for the primary and secondary efficacy 
endpoints as defined in Section 10.4.5. 
The power calculations for the primary endpoint are based on the placebo and linaclotide 290 µg 
treatment groups from the Phase 3 trial LIN-MD-31. The patients in LIN-MD-31 are considered 
representative of the patient population for this trial. Using a resampling with replacement-based 
simulation (1000 iterations) and controlling for multiplicity as outlined above, the trial will have 
>99% power to reject the primary endpoint and ~94% power to reject all primary and secondary 
hypotheses defined in the testing process. 


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11. 
CHANGES IN THE CONDUCT OF THE TRIAL OR 
PLANNED ANALYSES 
Any amendment to this protocol will be provided to the investigator in writing by Ironwood or 
designee. No protocol amendment regarding reportable deviations as defined by the IRB may be 
implemented (with the exceptions noted below) before it has been approved by the IRB, 
submitted by the Sponsor to the FDA, and the signature page, signed by the investigator, has 
been received by Ironwood or designee. If the protocol is amended to eliminate or reduce the risk 
to patients, the amendment may be implemented before IRB review and approval. However, the 
IRB must be informed in writing of such an amendment, and approval must be obtained within 
reasonable time limits. Deviating from the protocol is permitted only if absolutely necessary for 
the safety of the patients and must immediately be reported to Ironwood or designee. 


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12. 
TRIAL SPONSORSHIP 
12.1 
TRIAL TERMINATION 
Ironwood reserves the right to terminate the trial in its entirety or at a specific center at any time. 
12.2 
REPORTING AND PUBLICATION 
All data generated in this trial will be the property of Ironwood and its partner, Allergan, Plc. An 
integrated clinical and statistical report will be prepared at the completion of the trial. 
Publication of the results by the investigator will be subject to mutual agreement between the 
investigator and Ironwood. 


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13. 
INVESTIGATOR OBLIGATIONS 
13.1 
DOCUMENTATION 
The investigator must provide the following to Ironwood or designee prior to the start of the trial 
in accordance with ICH E6 and FDA regulations: 
• A completed and signed Form FDA 1572. If, during the course of the trial, any changes are 
made that are not reflected on Form FDA 1572, a new Form FDA 1572 must be completed 
and returned to Ironwood or designee for submission to the FDA 
• A fully executed Clinical Trial Agreement 
• The curricula vitae for the investigator and all sub-investigators listed on Form FDA 1572, 
including a copy of each physician’s license 
• A copy of the initial IRB approval for conducting the trial. If the trial is ongoing, renewals 
must be submitted at yearly intervals. All amendments to the protocol must be submitted and 
approved by the IRB, as stated in Section 1.1 
• A copy of the IRB-approved ICF 
• A copy of the IRB-approved HIPAA authorization form 
• A list of the IRB members or the DHHS general assurance number 
• A copy of the laboratory reference ranges 
• The Investigator’s Statement page in this protocol signed and dated by the investigator 
• Financial disclosure agreements completed and signed by the investigator and each sub-
investigator listed on Form FDA 1572. If there are any relevant changes, the investigator 
(and any sub-investigator) will provide an updated financial disclosure agreement to the 
Sponsor at the time of the change, and up to 1 year after the completion of the trial 
 
13.2 
PERFORMANCE 
The investigator must demonstrate reasonable efforts to obtain qualified patients for the trial. 


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13.3 
USE OF INVESTIGATIONAL MATERIALS 
The investigator will acknowledge that the drug supplies are investigational and as such must be 
used strictly in accordance with the protocol and only under the supervision of the investigator or 
sub-investigators listed on Form FDA 1572. Study drug must be stored in a safe and secure 
place. The investigator must maintain adequate records documenting the receipt, registration 
within IWRS, and disposition of all trial supplies. Ironwood or designee will supply forms on 
which to record the date the study drug was received and a dispensing record in which to record 
each patient’s use. All unused study drug must be returned to Ironwood’s designee. It is the 
investigator’s responsibility to ensure that patients return their study drug. 
13.4 
CASE REPORT FORMS 
All data relating to the study will be recorded on eCRFs to be provided by Ironwood or designee 
via the EDC system, or if applicable, paper CRFs. The eCRFs and paper CRFs are to be 
completed at the time of the patient’s visit, except for results of tests performed outside the 
investigator’s office. The investigator is responsible for verifying that all data entries on the 
eCRFs and paper CRFs are accurate and correct. The investigator must sign the completed eCRF 
before its submission to Ironwood or designee. 
13.5 
RETENTION AND REVIEW OF RECORDS 
The investigator must maintain the documentation relating to this trial. If Ironwood or the FDA 
wishes to review any documentation relating to the trial, the investigator must permit access to 
such records. 
Federal regulations require that the investigator retain a copy of all records that support eCRFs 
and paper CRFs for this trial (eg, ICFs, clinical laboratory reports, source documents, study drug 
dispensing records) for whichever of the following is the shortest: 
• Two years following the date of approval by the FDA of the study drug for the purposes that 
were the subject of the investigation; or 
• Five years following the date on which the results of the investigation were submitted to the 
FDA in support of, or as part of, a New Drug Application (NDA) for the study drug for the 
purposes that were the subject of the investigation 
 


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If the investigation does not result in the submission of the data in support of, or as part of, an 
NDA, records must be retained for two years following notification by Ironwood that the entire 
clinical investigation (not merely the investigator’s portion) is completed, terminated, or 
discontinued or for two years following withdrawal of the Investigational New Drug Application 
or NDA. 
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the trial records, custody must be transferred to a person who will accept the 
responsibility. Ironwood must be notified in writing of the name and address of the new 
custodian. 
13.6 
PATIENT CONFIDENTIALITY 
All patient records will only be identified by initials and PID number. Patients’ names are not to 
be transmitted to Ironwood or its authorized designee. The investigator will keep a Master 
Patient List on which the PID number and the full name, address, and telephone number of each 
patient is listed. 


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14. 
APPENDICES 


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APPENDIX 1 
ELEMENTS OF INFORMED CONSENT 
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained from each patient participating in a clinical research. This consent must include the 
following items: 
• A statement that the trial involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s participation 
• A description of any reasonably foreseeable risks or discomforts to the patient 
• A description of any benefits to the patient or to others that may reasonably be expected from 
the research. If the patient is to be paid for participating in the trial, the consent form must 
state the amount that he/she will receive and the schedule of payment (to ensure neither 
coercion nor undue influence) 
• A disclosure of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the patient 
• A statement describing the extent, if any, to which confidentiality of records identifying the 
patient will be maintained and noting the possibility that the FDA, Ironwood, the IRB, or an 
authorized CRO may inspect the records 
• For research involving more than minimal risk, an explanation of whether any medical 
treatment is available if injury occurs and, if so, what it consists of or where further 
information may be obtained 
• An explanation of whom to contact, including the relevant telephone number, for answers to 
pertinent questions about the research and the research patient’s rights and whom to contact 
in the event of a research-related injury to the patient. (Note: in some cases, it may be 
necessary to identify a person other than the investigator as the contact. The guidance of the 
IRB may be required.) 
• A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the patient is otherwise entitled, and that the patient may 
discontinue participation at any time without penalty or loss of benefits to which the patient 
is otherwise entitled 
• A statement that the particular treatment or procedures may involve risks to the patient (or to 
the embryo or fetus if the patient is, or may become, pregnant) that are at present 
unforeseeable 


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• The expected circumstances for which the patient’s participation may be terminated by the 
investigator without regard to the patient’s consent 
• Any additional costs to the patient that may result from participation in the research 
• The consequences of a patient’s decision to withdraw from the research and procedures for 
an orderly termination of the patient’s participation 
• A statement that significant new findings developed during the course of the research that 
may relate to the patient’s willingness to continue participation will be provided to the patient 
• The approximate number of patients involved in the trial 
• A statement of consent (eg, “I agree to participate...”) 
• A place for the patient’s signature and date of signing 
• A statement that a description of this clinical trial will be available on 
http://www.ClinicalTrials.gov  
 
A copy of the signed consent form will be given to the patient. 


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APPENDIX 2 
CONCOMITANT AND PROHIBITED MEDICATIONS 
Rescue Medicine to Manage Constipation 
Rescue Medicine, which will be selected by and dispensed to patients, will be a choice of 5-mg 
bisacodyl tablets or 10-mg bisacodyl suppositories. During the Pretreatment, Treatment, and RW 
Periods, patients may use dispensed, protocol-permitted laxatives (bisacodyl tablets or 
suppositories) as Rescue Medicine when at least 72 hours have passed since their previous BM 
or when their symptoms become intolerable. In order to qualify for randomization into the 
Treatment Period, patients must have refrained from using Rescue Medicine on the day before 
the Randomization Visit and on the day of the Randomization Visit prior to randomization. 
Patients must agree to refrain from using Rescue Medicine from the time they arrive at the clinic 
for the Randomization Visit through the day after randomization. 
Prohibited Medicine 
All medicine listed in the sections below (“1-day Washout” and “14-day Washout”) are excluded 
during the Pretreatment, Treatment, and RW Periods. A 1-day washout means that the particular 
medicine is not allowed during the day before the Pretreatment Visit; a 14-day washout means 
that the particular medicine is not allowed during the 14 days before the Pretreatment Visit. 
1-DAY WASHOUT (no medicine during the day before the Pretreatment Visit) 
1. Any over-the-counter or prescription laxative, suppository, or enema (eg, polyethylene 
glycol, lactulose, Fleet’s) and any herbal or natural agent that a person might take for 
constipation. Note: The use of fiber, bulk laxatives, stool softeners (surfactants such as 
docusate), and probiotics is acceptable, provided the patient has been on a stable dose 
during the 30 days before the Screening Visit and plans to continue stable dosing 
throughout the trial. 
2. Any medicine used to treat diarrhea (eg, bismuth subsalicylate, kaolin). 
3. NSAIDs if taken for abdominal pain or discomfort. 
 


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14-DAY WASHOUT (no medicine during the 14 days before the Pretreatment Visit) 
1. Drugs with known pharmacological activity at 5-hydroxytryptophan (HT)4, 5-HT2b or 
5-HT3 receptors (eg, cisapride, tegaserod, ondansetron, tropisetron, granisetron, 
dolasetron, and mirtazapine). 
2. Any treatment specifically taken for IBS-C or CIC alone or in combination, including 
lubiprostone (an approved chloride channel activator that enhances intestinal fluid 
secretion), linaclotide, plecanatide, colchicine, and misoprostol. Note: Patients may not 
have taken commercially available linaclotide or plecanatide, or participated in a 
linaclotide or plecanatide clinical study, during the 30 days before the Screening Visit. 
3. Prokinetic agents (eg, metoclopramide, itopride, prucalopride, and domperidone). 
4. Anti-cholinergic agents (eg, dicyclomine, flavoxate, scopolamine, hyoscyamine, 
propantheline, oxybutynin, tolterodine, solefenacin, darifenacin, and trospium). Note: 
inhaled ipratropium and tiotropium are permitted. 
5. Bile acid sequestrants (eg, cholestyramine and colestipol). 
6. Cholinomimetic agents (eg, bethanechol, pyridostigmine, tacrine, and physostigmine). 
Note: intraocular cholinomimetic agents (eg, pilocarpine) are permitted. 
7. Antipsychotic agents (eg, risperidone, haloperidol, droperidol, chlorpromazine, 
perphenazine, all phenothiazines, quetiapine, olanzapine, and clozapine) unless the 
patient has been on a stable dose for 30 days before the Screening Visit and there is no 
plan to change the dose after the Screening Visit. Note: paliperidone is permitted without 
restriction. 
8. Antidepressants unless the patient has been on a stable dose for 30 days before the 
Screening Visit and there is no plan to change the dose after the Screening Visit. 
Specifically included are the following: 
◦ 
Tricyclic antidepressants (eg, amitriptyline, imipramine, and nortriptyline); 
◦ 
Monoamine oxidase inhibitors (eg, furazolidone, isocarboxazid, pargyline, 
phenelzine, and selegiline tranylcypromine); 
◦ 
Selective serotonin reuptake inhibitors (eg, fluoxetine, sertraline, paroxetine, and 
citalopram); 
◦ 
Serotonin and norepinephrine reuptake inhibitors (eg, venlafaxine and desvenlafaxine 
succinate) 
◦ 
Others (eg, trazodone, and bupropion). 


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9. Calcium channel blocker verapamil unless the patient has been on a stable dose for 
30 days before the Screening Visit and there is no plan to change the dose after the 
Screening Visit. Note: all other calcium channel blockers (eg, nifedipine, diltiazem, 
amlodipine, felodipine, nicardipine, nimodipine, nisoldipine) are permitted and may be 
used without restriction. 
10. Oral and parenteral antibiotics (however, 1 standard regimen [up to 10 days] of oral 
antibiotics is permitted during the Treatment or RW Periods). 
11. Any investigational or imported drugs that have not been approved for human use by the 
US FDA during the 30 days before the Screening Visit. 
12. All narcotics either alone or in combination (eg, tramadol, codeine, morphine, 
propoxyphene, loperamide, diphenoxylate, and paregoric). Note: narcotics used as 
anesthesia for a colonoscopy require a 5-day wash-out prior to the patient entering into 
the Pretreatment Period. 
13. Any medicine taken for the purpose of losing weight (eg, orlistat, phentermine, 
phendimetrazine, diethylpropion, benzphetamine, and sibutramine). 
14. Any medicine that is known to cause diarrhea (eg, acarbose). 
15. Proton pump inhibitors (eg, omeprazole, lansoprazole, esomeprazole, pantoprazole, 
rabeprazole) unless the patient has been on a stable dose for 30 days before the Screening 
Visit and there is no plan to change the dose after the Screening Visit. 
16. Iron (as either a supplement or to treat iron-deficiency anemia) is acceptable, provided 
the patient has been on a stable dose for 30 days before the Screening Visit and plans to 
continue stable dosing throughout the trial. 
17. Others: barbiturates (eg, butalbital and phenobarbital) and chronic oral or parenteral 
glucocorticoids (which must be discontinued at least 3 months before the Screening Visit; 
however, one 10-day course of oral or one injection of parenteral glucocorticoids is 
permitted during the Pretreatment, Treatment, or RW Periods). Pregabalin is acceptable, 
provided the patient has been on a stable dose during the 30 days before the Screening 
Visit and plans to continue stable dosing throughout the trial. 
 


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APPENDIX 3 
SUMMARY OF AMERICAN 
GASTROENTEROLOGICAL ASSOCIATION 
GUIDELINES 
1. Patients aged 50 years and older must have had a colonoscopy with negative findings 
during the 10 years before the Screening Visit. If there were polyps on the most recent 
colonoscopy, the patient may be enrolled, provided there were 2 or fewer small (<1 cm) 
tubular adenomas without appreciable villous tissue or high-grade dysplasia and provided 
the colonoscopy was performed during the 5 years before the Screening Visit. (Note: 
Patients who have only hyperplastic polyps are eligible.)  
2. Patients who have a first-degree relative with colorectal cancer or adenomatous polyps 
diagnosed before age 60 or 2 first-degree relatives with colorectal cancer diagnosed at 
any age must have had a colonoscopy with negative findings during the 5 years before 
the Screening Visit. This applies to patients who are ≥40 years old and to patients 
<40 years old who are ≤10 years from the age when their youngest relative was found to 
have one of the conditions described above. 
3. Patients who have a first-degree relative with colorectal cancer or adenomatous polyps 
diagnosed at age 60 or older or 2 second-degree relatives with colorectal cancer 
diagnosed at any age must have had a colonoscopy with negative findings during the 
10 years before the Screening Visit. This applies to patients who are ≥40 years old and to 
patients <40 years old who are ≤10 years from the age when their youngest relative was 
found to have one of the conditions described above. 
4. Patients of any age who have alarm symptoms must have had a colonoscopy with 
negative findings after the onset of the alarm symptoms and during the 5 years before the 
Screening Visit. Alarm symptoms include lower GI bleeding (rectal bleeding or heme-
positive stool), iron-deficiency anemia, unexplained clinically-significant weight loss, 
and systemic signs of infection or colitis. In addition, patients with a family history of 
celiac disease or inflammatory bowel disease must have had a colonoscopy with negative 
findings during the five years before the Screening Visit. 
 
Note: All information required by the Inclusion Criterion will be captured on the eCRFs. Patients 
who receive narcotics as anesthesia for a colonoscopy are eligible to enter the Pretreatment 
Period on the fifth day after the colonoscopy. 
Source: Winawer, et al (2003) 


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APPENDIX 4 
BRISTOL STOOL FORM SCALE 
 
Source: Lewis SJ, Heaton KW. Scand J Gastroenterol (1997) 
Type 1 - Separate hard lumps like nuts (difficult to pass) 
 
Type 2 - Like a sausage but lumpy 
Type 3 - Like a sausage but with cracks on the surface 
 
Type 4 - Like a sausage or snake, smooth and soft 
Type 5 - Soft pieces with clear-cut edges (easy to pass) 
 
Type 6 - Fluffy pieces with ragged edges, a mushy stool 
 
Type 7 - Watery, no solid pieces (entirely liquid) 
 
 


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APPENDIX 5 
IBS-QOL 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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Clinical Trial Protocol: MCP-103-312 
 
26 March 2018 
 
Confidential 
Page 106 of 118 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Linaclotide 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: MCP-103-312 
 
26 March 2018 
 
Confidential 
Page 107 of 118 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Linaclotide 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: MCP-103-312 
 
26 March 2018 
 
Confidential 
Page 108 of 118 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Linaclotide 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: MCP-103-312 
 
26 March 2018 
 
Confidential 
Page 109 of 118 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


Linaclotide 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: MCP-103-312 
 
26 March 2018 
 
Confidential 
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APPENDIX 6 
CDC HRQOL-4 
Healthy Days Core Module (CDC HRQOL– 4) 
1. Would you say that in general your health is 
 
 
 
 
 
 
 
 
2. Now thinking about your physical health, which includes physical illness and injury, for how many 
days during the past 30 days was your physical health not good? 
 
 
 
 
 
3. Now thinking about your mental health, which includes stress, depression, and problems with 
emotions, for how many days during the past 30 days was your mental health not good? 
 
 
 
 
 
Please Read 
a. Excellent 1 
b. Very good 2 
c. Good 
3 
d. Fair 
4 
or 
e. Poor 
5 
 
Do not read these responses 
Don’t know/Not sure 
7 
Refused 
9 
 a. Number of Days _ _ 
 b. None 
8 8 
 Don’t know/Not sure 7 7 
Refused 
9 9 
 a. Number of Days _ _  
b. None 
8 8 
If both Q2 AND Q3 = “None,” skip next question 
 Don’t know/Not sure 7 7 
Refused 
9 9 


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4. During the past 30 days, for about how many days did poor physical or mental health keep you 
from doing your usual activities, such as self-care, work, or recreation? 
 
 
 
 
 
 
 a. Number of Days _ _ 
b. None 
8 8 
 Don’t know/Not sure 7 7 
Refused 
9 9 
 


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26 March 2018 
 
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APPENDIX 7 
PRIOR IBS-C SYMPTOM MANAGEMENT 
ASSESSMENT 
The Prior IBS-C Symptom Management Assessment will be incorporated within the patient’s 
source documentation. 
 


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Prior IBS-C Symptom Management Assessment 
This questionnaire is to be administered by the Coordinator 
Treatment or Modification 
Has the 
patient 
ever used 
this 
treatment 
for IBS-C? 
1. Yes 
2. No 
If yes, when was the last 
time it was taken/used? 
1. Currently using (record 
con meds in eCRF) 
2. Less than 6 months ago 
3. More than 6 months but 
less than 1 year ago 
4. Over one year ago 
If used, how satisfied was the patient with the 
treatment or modification’s ability to relieve: 
If the patient stopped taking this 
medication, what was the primary 
reason? 
1. Not applicable, currently taking 
2. Did not improve abdominal symptoms 
3. Did not improve bowel symptoms 
4. Experienced side effects 
5. Costs too much 
6. Other 
Bowel symptoms 
(eg, constipation)? 
1. Not at all satisfied 
2. A little satisfied 
3. Moderately satisfied 
4. Quite satisfied 
5. Very satisfied 
Abdominal symptoms (eg, 
bloating, discomfort, pain)? 
1. Not at all satisfied 
2. A little satisfied 
3. Moderately satisfied 
4. Quite satisfied 
5. Very satisfied 
Diet modification 
 
 
 
 
 
Lifestyle modification 
(eg, exercise, psychological 
therapy, meditation) 
 
 
 
 
 
PEG Laxatives (OTC) 
 
 
 
 
 
PEG Laxatives (prescription) 
 
 
 
 
 
Bulk Laxatives 
 
 
 
 
 
Stimulant Laxatives 
 
 
 
 
 
Stool Softeners* 
 
 
 
 
 
Linaclotide (GC-C agonist) 
 
 
 
 
 
Plecanatide (GC-C agonist) 
 
 
 
 
 
Lubiprostone (Chloride 
channel activator) 
 
 
 
 
 
Antispasmodics 
 
 
 
 
 
Tegaserod (5-HT4 agonist) 
 
 
 
 
 
Opioid Pain Medication 
 
 
 
 
 


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Other (eg, probiotics, 
peppermint oil, 
antidepressants, other non-
opioid pain medications, 
prucalopride [5-HT4 agonist], 
tenapanor [NHE3 inhibitor]) 
Write in: 
______________________ 
______________________ 
______________________ 
 
 
 
 
 
 
 
* Note: Combination products, including docusate with stimulant laxatives (either bisacodyl or Senna) should be recorded according to the stimulant laxative 
included in the product. If this is a docusate plus bisacodyl combination product, this should be recorded as a bisacodyl product. If this is a docusate plus Senna 
combination product, this should be recorded as a Senna product.  
Examples of combination stool softener and laxative products include: 
Senekot-S, Senna Plus, Senna S, Senosol-SS, Peri-Colace (all of these contain Senna) 
Generic products would say Docusate plus Senna or bisacodyl 
 


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Treatment Examples: 
PEG Laxatives  
Some examples are: 
MiraLax 
Dulcolax Balance 
Polyethylene Glycol (PEG) 
 
Bulk Laxatives 
Psyllium products 
Some examples are: 
Metamucil 
Metamucil Sugar Free 
Psyllium Husk 
Wheat Dextrin products 
Some examples are: 
Benefiber 
Wheat Dextrin 
 
Stimulant Laxatives 
Bisacodyl products 
Some examples are: 
Dulcolax 
Bisacodyl 
Ex-Lax Ultra Strength 
Senna products 
Some examples are: 
Senna 
Senakot 
Ex-Lax Regular strength 
Ex-Lax Maximum strength 
 
Stool Softeners* 
Docusate products 
Some examples are: 
Docusate sodium 
Colace 
Dulcolax Stool Softener 
 


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Clinical Trial Protocol: MCP-103-312 
 
26 March 2018 
 
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APPENDIX 8 
INVESTIGATOR’S SIGNATURE 
Study Title: 
A Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel-
group Trial of Linaclotide 290 µg Administered Orally for 12 Weeks 
Followed by a 4-week Randomized Withdrawal Period in Patients 
with Irritable Bowel Syndrome with Constipation 
Study Number: 
MCP-103-312 
Final Date: 
26 March 2018 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the trial as described in the protocol. 
 
 
Signed: 
 
 
Date:  
 
 
 
Print Name: 
 
 


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26 March 2018 
 
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15. 
REFERENCE LIST 
1. Drossman DA, Corazziari E, Delvaux N, Spiller R, Talley NJ, Thompson CA, et al. Rome 
III:  The functional gastrointestinal disorders. 3 ed. McLean, VA: Degnon Associates; 2006. 
2. Sandler RS, Jordan MC, Shelton BJ. Demographic and dietary determinants of constipation 
in the US population. Am J Public Health. 1990;80(2):185-9. 
3. Camilleri M, Prather CM. The irritable bowel syndrome: mechanisms and a practical 
approach to management. Ann Intern Med. 1992;116(12 Pt 1):1001-8. 
4. Thompson WG. Irritable bowel syndrome: pathogenesis and management. Lancet. 
1993;341(8860):1569-72. 
5. Lynn RB, Friedman LS. Irritable bowel syndrome. N Engl J Med. 1993;329(26):1940-5. 
6. Zighelboim J, Talley NJ. What are functional bowel disorders? Gastroenterology. 
1993;104(4):1196-201. 
7. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable 
bowel syndrome. Gastroenterology. 2002;123(6):2108-31. 
8. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterology. 2006;130:1480-91. 
9. Forte LR. Guanylin regulatory peptides: structures, biological activities mediated by cyclic 
GMP and pathobiology. Regul Pept. 1999;81(1-3):25-39. 
10. Sindic A, Schlatter E. Cellular Effects of Guanylin and Uroguanylin. J Am Soc Nephrol. 
2005;17(3):607-16. 
11. Castro J, Harrington AM, Hughes PA, Martin CM, Ge P, Shea CM, et al. Linaclotide Inhibits 
Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and 
Extracellular Cyclic GMP. Gastroenterology. 2013;145(6):1334-46. 
12. Chey WD, Lembo AJ, Lavins BJ, Shiff SJ, Kurtz CB, Currie MG, et al. Linaclotide for 
Irritable Bowel Syndrome With Constipation: A 26-Week, Randomized, Double-blind, 
Placebo-Controlled Trial to Evaluate Efficacy and Safety. The American Journal of 
Gastroenterology. 2012;107(11):1702-12. 
13. Rao S, Lembo AJ, Shiff SJ, Lavins BJ, Currie MG, Jia XD, et al. A 12-week, randomized, 
controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and 
safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 
2012;107(11):1714-24; quiz p.25. 
14. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997;32(9):920-4. 


Linaclotide 
 
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Clinical Trial Protocol: MCP-103-312 
 
26 March 2018 
 
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15. Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons 
with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 
1998;43(2):400-11. 
16. Prevention CfDCa. Measuring Healthy Days: Population Assessment of Health-Related 
Quality of Life. Centers for Disease Control and Prevention [Internet]. 2000. Available from: 
https://www.cdc.gov/hrqol/pdfs/mhd.pdf. 
 


The data and information related to my line function, which has been included 
with this file, are truthful and accurate.
Signature Page for VV-CLIN-001329 
v1.0
Approval
Approval
Approval

SAP_001.pdf: 
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Ironwood Document No. MCP-103-312-1619-sap 
TITLE PAGE 
Ironwood Pharmaceuticals, Inc. 
301 Binney Street 
Cambridge, MA 02142 
MCP-103-312 
A Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial of 
Linaclotide 290 μg Administered Orally for 12 Weeks Followed by a 4-week Randomized 
Withdrawal Period in Patients with Irritable Bowel Syndrome with Constipation 
STATISTICAL ANALYSIS PLAN
Final Version 1.0: 27 November 2018 
 


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Statistical Analysis Plan: MCP-103-312 
27 November 2018 
 
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Ironwood Document No. MCP-103-312-1619-sap 
TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................................................. 1 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 4 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
LIST OF ABBREVIATIONS ........................................................................................................................................ 6 
1.0 
INTRODUCTION ........................................................................................................................................... 8 
2.0 
STUDY OBJECTIVES ................................................................................................................................... 9 
3.0 
STUDY DESIGN .......................................................................................................................................... 10 
3.1 
General Description ........................................................................................................................ 10 
3.2 
Discussion of Study Design, Including Choice of Control Groups ................................................. 10 
3.3 
Treatments Administered ................................................................................................................ 11 
3.4 
Methods of Assigning Subjects to Treatment Groups ..................................................................... 11 
3.5 
Blinding .......................................................................................................................................... 11 
4.0 
DETERMINATION OF SAMPLE SIZE ...................................................................................................... 12 
5.0 
PHARMACOKINETICS, EFFICACY AND SAFETY ASSESSMENTS ................................................... 13 
5.1 
Study Schematic and Schedule of Assessment ............................................................................... 13 
5.2 
Pharmacokinetic Assessments ........................................................................................................ 17 
5.3 
Efficacy Assessments ...................................................................................................................... 17 
5.3.1 
Primary Efficacy Assessments .......................................................................................... 17 
5.3.2 
Secondary Efficacy Assessments ...................................................................................... 18 
5.3.3 
Additional Efficacy Assessment ....................................................................................... 18 
5.3.4 
Health Outcomes Assessments ......................................................................................... 21 
5.4 
Safety Assessments ......................................................................................................................... 22 
5.4.1 
Adverse Events ................................................................................................................. 22 
5.4.2 
Medical History ................................................................................................................ 23 
5.4.3 
Physical Examination ....................................................................................................... 23 
5.4.4 
Vital Signs ........................................................................................................................ 23 
5.4.5 
Clinical Laboratory Data .................................................................................................. 23 
6.0 
Statistical Methods ........................................................................................................................................ 25 
6.1 
General Methods ............................................................................................................................. 25 
6.2 
Adjusting for Covariates ................................................................................................................. 25 
6.3 
Handling of Dropouts/Missing data imputation method ................................................................. 25 
6.4 
Interim Analysis and Data Monitoring............................................................................................ 25 
6.5 
Multicenter Studies ......................................................................................................................... 25 
6.6 
Multiple Comparisons/Multiplicity ................................................................................................. 26 
6.7 
Use of an efficacy subset ................................................................................................................ 26 
6.8 
Active Control to Show Equivalence .............................................................................................. 26 
6.9 
Examination of Subgroups .............................................................................................................. 26 
7.0 
ANALYSIS METHODS ............................................................................................................................... 28 
7.1 
Patient Populations .......................................................................................................................... 28 
7.1.1 
Screened Population ......................................................................................................... 28 
7.1.2 
Safety Population .............................................................................................................. 28 
7.1.3 
Intent-to-Treat Population................................................................................................. 28 
7.1.4 
Randomized Withdrawal Population ................................................................................ 28 
7.2 
Protocol Deviations ......................................................................................................................... 28 
7.3 
Patient Disposition .......................................................................................................................... 29 


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Ironwood Document No. MCP-103-312-1619-sap 
7.4 
Demographics and Other Baseline Characteristics ......................................................................... 29 
7.5 
Measurement of Treatment Compliance ......................................................................................... 30 
7.6 
Extent of Exposure .......................................................................................................................... 30 
7.7 
Prior and Concomitant Medication ................................................................................................. 30 
7.8 
eDiary Compliance ......................................................................................................................... 31 
7.9 
Efficacy Analysis ............................................................................................................................ 31 
7.9.1 
Primary Endpoint .............................................................................................................. 32 
7.9.2 
Secondary Efficacy Endpoints .......................................................................................... 34 
7.9.3 
Additional Efficacy Endpoints .......................................................................................... 35 
7.9.4 
Randomized Withdrawal Period Endpoints ...................................................................... 38 
7.10 
Positive control ............................................................................................................................... 39 
7.11 
Safety Analysis ............................................................................................................................... 39 
7.11.1 
Adverse Events ................................................................................................................. 39 
7.11.2 
Clinical Laboratory Parameters ........................................................................................ 41 
7.11.3 
Vital Signs ........................................................................................................................ 42 
7.11.4 
Other Safety Parameters ................................................................................................... 43 
7.12 
Health Outcomes Analysis .............................................................................................................. 43 
7.12.1 
Irritable Bowel Syndrome–Quality of Life Assessment (IBS-QOL) ................................ 43 
7.12.2 
CDC Healthy Days Core Module (CDC HRQOL-4) ....................................................... 44 
8.0 
CHANGES FROM ANALYSES PLANNED IN THE PROTOCOL ........................................................... 45 
9.0 
DATA HANDLING CONVENTIONS ........................................................................................................ 46 
9.1 
Visit Time Windows for Safety Analysis ....................................................................................... 46 
9.2 
Visit Time Windows for Efficacy Analysis .................................................................................... 46 
9.3 
Pooling of Trial Centers .................................................................................................................. 49 
9.4 
Derived Efficacy Variables ............................................................................................................. 49 
9.4.1 
Patient Recall for eDiary Data .......................................................................................... 49 
9.4.2 
Handling of Missing eDiary Data ..................................................................................... 50 
9.4.3 
Weekly Stool Frequency Rates ......................................................................................... 51 
9.4.4 
Other Weekly Scores Derivation ...................................................................................... 52 
9.5 
Repeated or Unscheduled Assessments of Safety Parameters ........................................................ 53 
9.6 
Missing Date of the Last Dose of Study Drug ................................................................................ 53 
9.7 
Missing Severity Assessment for Adverse Events .......................................................................... 53 
9.8 
Missing Relationship to Study Drug for Adverse Events ............................................................... 53 
9.9 
Missing Date Information for Adverse Events................................................................................ 53 
9.10 
Missing Date Information for Prior or Concomitant Medications .................................................. 56 
9.10.1 
Incomplete Start Date ....................................................................................................... 56 
9.10.2 
Incomplete Stop Date ....................................................................................................... 57 
9.11 
Character Values of Clinical Laboratory Parameters ...................................................................... 57 
10.0 
REFERENCES .............................................................................................................................................. 59 
APPENDIX 1: 
BRISTOL STOOL FORM SCALE ................................................................................................ 60 
APPENDIX 2: 
IBS-QOL ......................................................................................................................................... 61 
APPENDIX 3: 
CDC HRQOL-4 .............................................................................................................................. 69 
 


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Statistical Analysis Plan: MCP-103-312 
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Ironwood Document No. MCP-103-312-1619-sap 
LIST OF IN-TEXT TABLES 
Table 5.1-1 
Schedule of Evaluations ........................................................................................................... 14 
Table 6.9-1 
Subgroup Variables .................................................................................................................. 27 
Table 7.11-1 
Adverse Event Classification ................................................................................................... 40 
Table 7.11-2 
Criteria for Potentially Clinically Significant Laboratory Results ........................................... 41 
Table 7.11-3 
Criteria for Potentially Clinically Significant Vital Signs........................................................ 43 
Table 7.12-1 
Irritable Bowel Syndrome–Quality of Life Questionnaire ....................................................... 44 
Table 9.1-1 
Visit Time Windows for Safety Analysis ................................................................................ 46 
Table 9.2-1 
Analysis Time Windows for Efficacy Analysis ....................................................................... 47 
Table 9.2-2 
Analysis Time Windows for Efficacy Analysis – Weekly Assessments ................................. 48 
Table 9.3-1 
Definition of Geographic Regions ........................................................................................... 49 
Table 9.11-1 
Examples of Coding Special Character Values for Clinical Laboratory Parameters ............... 58 
 
 
 


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Ironwood Document No. MCP-103-312-1619-sap 
LIST OF IN-TEXT FIGURES 
Figure 3.2-1 
Overview of Study Design ....................................................................................................... 11 
 
 
 
 
 


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Statistical Analysis Plan: MCP-103-312 
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Ironwood Document No. MCP-103-312-1619-sap 
LIST OF ABBREVIATIONS  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
APC 
Abdominal Pain and Constipation 
AST 
aspartate aminotransferase 
BM 
bowel movement 
BP 
blood pressure 
bpm 
beats per minute 
BSFS 
Bristol Stool Form Scale 
CBC 
complete blood count 
CDC HRQOL-4 
CDC Healthy Days Core Module 
CIC 
chronic idiopathic constipation 
CMH 
Cochran-Mantel-Haenszel 
CSBM 
complete spontaneous bowel movement 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EOT 
End-of-Treatment Period 
HEENT 
head, ears, eyes, nose, throat 
IBS-C 
Irritable Bowel Syndrome with Constipation 
ICF 
informed consent form 
IPD 
Important Protocol Deviations 
ITT 
Intent-to-Treat 
IWRS 
interactive web response system 


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Ironwood Document No. MCP-103-312-1619-sap 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
LS 
least-squares 
MCMC 
Monte-Carlo Markov chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
Mixed Model Repeated Measures 
NRS 
numerical rating scale 
OC 
observed case 
PCS 
potentially clinically significant 
PID 
patient identification number 
RM 
rescue medication 
RW 
randomized withdrawal 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBM 
spontaneous bowel movement  
SD 
standard deviation 
SI 
Le Système International d’Unités (International System of Units) 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 


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Ironwood Document No. MCP-103-312-1619-sap 
1.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and/or specified in the protocol of 
Study MCP-103-312 (dated 26 March 2018). Specifications for the tables, figures, and data 
listings are contained in a separate document.  
 


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Ironwood Document No. MCP-103-312-1619-sap 
2.0 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the efficacy on abdominal symptoms (abdominal 
bloating, abdominal discomfort, and abdominal pain) and safety of linaclotide 290 µg 
administered orally to patients with irritable bowel syndrome with constipation (IBS-C). 
 


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Ironwood Document No. MCP-103-312-1619-sap 
3.0 
STUDY DESIGN 
3.1 
GENERAL DESCRIPTION 
The MCP-103-312 study is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, 16-week study, consisting of 4 distinct periods (Screening, Pretreatment, 
Treatment, and Randomized Withdrawal). The study will enroll patients who have IBS-C 
diagnosed using Rome III criteria. Approximately 600 eligible patients will be randomized in 
equal proportions to one of two treatments: linaclotide 290 µg or placebo. 
The length of this trial is 18-22 weeks, with 4 distinct periods, including up to 21 days of 
Screening, 14 to 21 days of Pretreatment, 12 weeks of double-blind treatment, and 4 weeks of 
randomized withdrawal. During the Pretreatment Period, patients will provide daily information 
on bowel habits, symptom severity, and use of Rescue Medicine. Patients meeting all of the entry 
criteria for this trial at the end of the Pretreatment Period will enter the Treatment Period.  
Patients who complete the 12-week Treatment Period and return for the Week 12/ETP Visit will 
enter the 4-week Randomized Withdrawal (RW) period and be allocated to study drug in a 
double-blind manner, as follows: 
• Patients randomized to linaclotide 290 µg during the Treatment Period will be 
rerandomized to linaclotide 290 µg or placebo (1:1) 
• Patients randomized to placebo during the Treatment Period will be allocated to 
linaclotide 290 µg 
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF 
CONTROL GROUPS 
A double-blind, placebo-controlled, parallel-group study design was chosen in accordance with 
the concepts in ICH E10, Choice of Control Groups and Related Issues in Clinical Trials, in 
order to provide comparable treatment groups and minimal chance of selection or investigator 
bias. The study has a 14- to 21-day Pretreatment Period to establish a baseline without therapy 
and to familiarize patients with data collection methodology (i.e., electronic diary [eDiary]), and 
a 12-week Treatment Period to compare the test treatment to the placebo control, and a 4-week 
RW period to evaluate persistence of treatment effect, the incidence of rebound (or worsening of 
symptoms from baseline) or other withdrawal effects, and potential need for retreatment. 


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Ironwood Document No. MCP-103-312-1619-sap 
Figure 3.2-1 
Overview of Study Design 
 
 
3.3 
TREATMENTS ADMINISTERED 
Patients will be instructed to take one capsule in the morning at least 30 minutes before 
breakfast. Study drug in the form of 290 ug linaclotide or placebo oral capsules will be provided 
by Ironwood or designee. For the double-blind Treatment Period and RW Period. 
3.4 
METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
Patients who meet all the inclusion criteria and none of the exclusion criteria will be randomized 
into the study at the Randomization Visit on Day 1. Approximately 600 patients will be 
randomized in equal proportions to either linaclotide 290 µg or placebo. 
Patients receiving linaclotide 290 µg during the Treatment Period who complete the 12-week 
Treatment Period and agree to continue into the 4-week RW period will be randomized in equal 
proportion to either remain on linaclotide 290 µg or switch to placebo; all patients receiving 
placebo during the Treatment Period will be allocated to linaclotide 290 µg for the RW Period.  
Randomization numbers will be assigned by interactive web response system (IWRS). 
3.5 
BLINDING 
This study is a double-blind study. 
Screening 
Period 
Pretreatment 
Period 
Treatment Period 
Day 1 to Day 85 
14 to 21 days 
Up to 21 days 
Week 4 Visit 
(Day 29±3) 
Week 8 Visit 
(Day 57±3) 
Screening 
Visit 
(Day -42 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -14) 
Randomization 
Visit
(Day 1) 
Week 16/ 
End-of-Trial 
Visit** 
(RW Day 29+3) 
Note: there is no Day 0. 
RW=Randomized Withdrawal 
 
*RW Day 1 is the day after the Week 12/End-of-Treatment-Period Visit 
**This visit represents the end of the trial. 
Week 12/ 
End-of-Treatment-
Period Visit 
(Day 85+3) 
Randomized 
Withdrawal Period 
RW Day 1* to 
RW Day 29 


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Ironwood Document No. MCP-103-312-1619-sap 
4.0 
DETERMINATION OF SAMPLE SIZE 
The sample size of 600 patients (300 patients per treatment group) was chosen to ensure 
adequate power for testing the fixed-sequence procedure for the primary and secondary efficacy 
endpoints (Section 6.6). 
The power calculations for the primary endpoint are based on the placebo and linaclotide 290 µg 
treatment groups from the Phase 3 trial LIN-MD-31. The patients in LIN-MD-31 are considered 
representative of the patient population for this trial. Using a resampling with replacement-based 
simulation (1000 iterations) and controlling for multiplicity as outlined above, the trial will have 
>99% power to reject the primary endpoint and ~94% power to reject all primary and secondary 
hypotheses defined in the testing process. 


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5.0 
PHARMACOKINETICS, EFFICACY AND SAFETY ASSESSMENTS 
5.1 
STUDY SCHEMATIC AND SCHEDULE OF ASSESSMENT 
The schedule of evaluations for Study MCP-103-312 is presented in Table 5.1-1. 
 
 


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Table 5.1-1 
Schedule of Evaluations 
MCP-103-312 
Trial Period → 
Screening 
Period 
(Up to 21 days) 
Pretreatment 
Period 
(14 to 21 days) 
Treatment Period 
(12 weeks) 
Randomized 
Withdrawal 
(RW) Period 
(4 weeks)q 
Visit → 
Screening Visit 
Pretreatment 
Visit 
Randomization 
Visit 
Week 4 
Visit 
Week 8 
Visit 
Week 12/End-
of-Treatment-
Period Visit 
Week 16/ 
End-of-Trial 
Visit r 
Visit Days → 
Day -42 through 
Day -15 
Day -21 to 
Day -14 
Day 1 
Day 29±3 
Day 57±3 
Day 85+3 
RW Day 29+3 
Visit Number → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Trial Procedure ↓ 
 
 
 
 
 
 
 
Signature of ICF 
X 
 
 
 
 
 
 
Inclusion and Exclusion Criteria 
Verification 
X 
X 
X* 
 
 
 
 
IWRS Registration a 
X 
X 
X† 
X 
X 
X 
X 
Medical History b 
X 
 
 
 
 
 
 
Prior IBS-C Symptom 
Management Assessment c 
X 
 
 
 
 
 
 
Physical Examination d 
X 
 
 
 
 
X* 
X 
Body Weight and Height e 
X 
X 
X* 
X 
X 
X* 
X 
Seated Vital Signs f 
X 
X 
X* 
X 
X 
X* 
X 
Prior and Concomitant Medicines g 
X 
X 
X* 
X 
X 
X* 
X 
Clinical Laboratory Tests h 
X 
 
X* 
 
 
X* 
X 
Pregnancy Test i 
X 
 
X* 
 
 
X* 
X 
Laxative/Suppository/ Enema 
Washout Instructions j 
X 
 
 
 
 
 
 
AE Evaluations k 
 
X 
X* 
X 
X 
X* 
X 
eDiary Registration and Training  l 
 
X 
X* 
X 
X 
X* 
X 
Daily and Weekly Assessments m 
 
X 
X* 
X 
X 
X* 
X 


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MCP-103-312 
Trial Period → 
Screening 
Period 
(Up to 21 days) 
Pretreatment 
Period 
(14 to 21 days) 
Treatment Period 
(12 weeks) 
Randomized 
Withdrawal 
(RW) Period 
(4 weeks)q 
Visit → 
Screening Visit 
Pretreatment 
Visit 
Randomization 
Visit 
Week 4 
Visit 
Week 8 
Visit 
Week 12/End-
of-Treatment-
Period Visit 
Week 16/ 
End-of-Trial 
Visit r 
Visit Days → 
Day -42 through 
Day -15 
Day -21 to 
Day -14 
Day 1 
Day 29±3 
Day 57±3 
Day 85+3 
RW Day 29+3 
Visit Number → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Trial Procedure ↓ 
 
 
 
 
 
 
 
eDiary Compliance Verification 
and Reminder n 
 
 
X* 
X 
X 
X* 
X 
Rescue Medicine Dispensed o 
 
X 
X 
X 
X 
X 
 
Patient eDiary Entry, in Clinic 
 
 
X* 
X 
X 
X* 
X 
Randomization 
 
 
X† 
 
 
X 
 
IBS-QOL 
 
 
X† 
X 
X 
X 
X 
CDC HRQOL-4 
 
 
X† 
 
 
X 
X 
Study Drug Dispensed 
 
 
X† 
X 
X 
Xs 
 
Study Drug Administration p 
 
 
X 
 
 
 
 
Study Drug Accountability 
 
 
 
X 
X 
X 
X 
AE=adverse event; BM=bowel movement; CBC=complete blood count; CDC HRQOL-4=Centers for Disease Control and Prevention Healthy Days Core 
Module; CIC=chronic idiopathic constipation; eDiary=electronic diary; EOT=End-of-Trial; ETP=End-of-Treatment-Period; IBS-C=irritable bowel syndrome 
with constipation; IBS-QOL=irritable bowel syndrome quality of life questionnaire; ICF=informed consent form; IWRS=interactive web response system; 
RW=randomized withdrawal. 
* Done prior to randomization; † Done predose 
a. 
Site personnel will interact with IWRS to register the patient visit. Refer to the IWRS User Manual. 
b. Includes diagnosis using Rome IV criteria for IBS, which will be collected as part of the patient’s disease-specific history. Rome IV diagnosis has no bearing 
on patient eligibility to participate in the trial (patients will be enrolled based Rome III criteria). 
c. 
Prior IBS-C symptom management assessment includes prior treatments taken for IBS-C, lifestyle and diet modifications for alleviating symptoms of IBS-C, 
assessment of satisfaction with prior interventions’ ability to relieve bowel and abdominal symptoms, and primary reason for stopping use. 
d. A physical examination includes the following: general appearance, HEENT (head, ears, eyes, nose, and throat), neck, cardiovascular, thorax/lungs, breasts, 
abdomen, rectal, genitourinary, musculoskeletal, lymph nodes, skin, neurologic, and mental status. A rectal examination should be performed during the 


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Screening Period on all patients who do not require a colonoscopy. After the Screening Period, the rectal examination is optional and may be performed at 
the discretion of the investigator. Breast and genitourinary examinations are optional at the discretion of the investigator. 
e. 
Height is measured only at the Screening Visit. 
f. 
Vital signs must be obtained in the seated position and include oral temperature, respiratory rate, blood pressure, and pulse. Pulse and blood pressure 
readings will be taken after the patient has been sitting for five minutes. 
g. At the Screening Visit, information related to concomitant medicine that patients are taking on the day of the visit will be captured as well as their prior use 
of certain IBS-C or CIC (approved or unapproved) prescription medications. 
h. Chemistry, CBC, and urine drug screen. The urine drug screen will be performed at the Screening Visit only. 
i. 
To be eligible to continue in the trial, a negative serum pregnancy test must be documented at the Screening Visit. A negative urine pregnancy test must be 
documented at the Randomization Visit and the Week 12/ETP Visit (prior to randomization), and a negative serum pregnancy test must be documented at 
the Week 16/End-of-Trial (EOT) Visit. 
j. 
Study coordinator will instruct patients about the use of laxatives, suppositories, and enemas. 
k. All AEs occurring after the patient signs the ICF will be captured. 
l. 
At the Pretreatment Visit and all subsequent visits, the study coordinator will register the patient visit to the clinic in the patient’s eDiary. At the Pretreatment 
Visit, the study coordinator will instruct the patients about the use of the eDiary. Refer to the eDiary User Manual. 
m. An eDiary will be used for recording Daily BM-related Symptom Severity Assessments, Daily Abdominal Symptom-severity Assessments, Weekly 
Assessments, and Use of Bisacodyl or Other Laxatives, Suppositories, or Enemas. Patients will enter BMs and laxative use in the eDiary on an event-driven 
basis, and will complete an evening entry each day to record daily abdominal assessments and any BMs and/or laxative use not previously recorded for that 
day. 
n. At the Randomization Visit and all subsequent visits, the study coordinator will review the eDiary entry information to verify patient compliance with the 
daily eDiary completion requirement. After determining the patient’s compliance, the study coordinator will remind patients to complete the eDiary daily 
(except at the Week 16/EOT visit). eDiary questions may be found in the eDiary User Manual. 
o. Rescue Medicine (oral bisacodyl or bisacodyl suppositories) will be supplied to patients at the Pretreatment Visit and, if needed, at subsequent study drug 
dispensing visits. 
p. Study drug will be administered in the clinic at the Randomization Visit. Patients are instructed to fast for 2 hours before this clinic visit. On all other days, 
study drug will be taken once daily in the morning at least 30 minutes before breakfast. 
q. The RW Period will start the day after the Week 12/ETP Visit (this will be considered RW Day 1). 
r. 
Patients who are randomized but do not complete the Treatment Period or RW Period (withdraw consent or are discontinued before they have completed 
12 weeks or 4 weeks of treatment, respectively), will be considered Treatment Period or RW Period withdrawals, respectively, and should complete the 
procedures required at the EOT Visit (even if out of window). 
s. 
Patients will take their first dose of study drug in the RW Period on RW Day 1 (ie, the day after the Week 12/ETP Visit). 
 
 


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5.2 
PHARMACOKINETIC ASSESSMENTS  
There are no pharmacokinetic assessments planned for this study. 
5.3 
EFFICACY ASSESSMENTS 
5.3.1 
Primary Efficacy Assessments 
The efficacy assessments that will be used to determine the primary efficacy endpoint are the 
daily patient assessments of abdominal bloating, abdominal discomfort, and abdominal pain at 
their worst (ie, the components of the abdominal score). 
Daily Patient Assessment of Abdominal Pain at its Worst 
Patient assessment of abdominal pain at its worst will be collected via a daily evening report in 
the eDiary. The rating of abdominal pain at its worst during the previous 24 hours on an 11-point 
NRS will be provided by the patient answering the following question: 
“How would you rate your worst abdominal pain in the past 24 hours?” 
<eDiary presents NRS where 0 is anchored with “No abdominal pain” and 10 is anchored with 
“Worst possible abdominal pain”> 
 
Daily Patient Assessment of Abdominal Discomfort at its Worst 
Patient assessment of abdominal discomfort at its worst will be collected via a daily evening 
report in the eDiary. The rating of abdominal discomfort at its worst during the previous 
24 hours on an 11-point NRS will be provided by the patient answering the following question: 
“How would you rate your worst abdominal discomfort in the past 24 hours?” 
<eDiary presents NRS where 0 is anchored with “No abdominal discomfort” and 10 is anchored 
with “Worst possible abdominal discomfort”> 
 
Daily Patient Assessment of Abdominal Bloating at its Worst 
Patient assessment of abdominal bloating at its worst will be collected via a daily evening report 
in the eDiary. The rating of abdominal bloating at its worst during the previous 24 hours on an 
11-point NRS will be provided by the patient answering the following question: 
“How would you rate your worst abdominal bloating in the past 24 hours?” 
<eDiary presents NRS where 0 is anchored with “No abdominal bloating” and 10 is anchored 
with “Worst possible abdominal bloating”> 
 


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5.3.2 
Secondary Efficacy Assessments 
The efficacy assessments that will be used to determine the secondary efficacy endpoints are the 
daily patient assessments of abdominal pain, abdominal discomfort, and abdominal bloating at 
their worst, as described in Section 5.3.1. 
5.3.3 
Additional Efficacy Assessment 
In addition to the primary/secondary efficacy assessments, the following efficacy assessments 
are used in determining the additional efficacy endpoints. 
Complete Spontaneous Bowel Movement 
The CSBM assessment is based on the eDiary questions that determine whether a BM is a 
CSBM: 
BM Day and Time 
Patients will report BMs on an event-driven basis. An evening report will ask whether the patient 
entered all BMs for that day, and collect BMs not previously entered for that day.  
Association with a Sense of Complete Evacuation 
This is assessed by the patient answering the following eDiary question for each BM: 
“Did you feel like you completely emptied your bowels after your bowel movement?” 
1=Yes 
2=No 
Day of Any Laxative Use 
Patients will report use of bisacodyl or other laxatives, suppositories, or enemas on an event-
driven basis. An evening report will ask whether the patient entered all laxative use for that day, 
and collect bisacodyl or other laxatives, suppositories, or enemas not previously entered for that 
day. 
Each day of the Pretreatment, Treatment, and RW Periods, the patient will complete eDiary 
entries on an event-driven basis to report BMs, and whether the BM was associated with a sense 
of complete evacuation. (The patient is also asked to provide assessments of stool consistency 
and straining, which are described below.) The patient will also complete eDiary entries on an 
event-driven basis to report use of protocol-permitted bisacodyl (tablets or suppositories) or other 
laxatives, suppositories, or enemas to treat their symptoms. Patients will complete a daily 
evening report to enter any BMs and laxative usage not previously reported by the patient for 
that day (recall is limited to 24 hours or to the time of the previous evening’s report). 


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Spontaneous Bowel Movement 
The SBM assessment is based on the eDiary questions (described above) that determine whether 
a BM is an SBM: 
• BM day and time 
• Day of Any Laxative Use 
Stool Consistency 
Patient assessment of stool consistency will be collected using two questions by eDiary entry on 
an event-driven basis (ie, for each BM reported in the eDiary). 
 
BSFS 
For each BM, the patient assesses his/her stool using the BSFS which depicts the stool 
consistency characteristics along with descriptions for each of them.  The 7-point ordinal BSFS 
is provided below (see Appendix 1 for full scale including pictures): 
“Please describe the form of your stool using the following scale where:” 
1=Separate hard lumps like nuts (difficult to pass) 
2=Like a sausage but lumpy 
3=Like a sausage but with cracks on the surface 
4=Like a sausage or snake, smooth and soft 
5=Soft pieces with clear-cut edges (easy to pass) 
6=Fluffy pieces with ragged edges, a mushy stool 
7=Watery, no solid pieces (entirely liquid) 
 
5-point ordinal scale 
Patients will also assess stool consistency by daily eDiary entry on an event-driven basis using a 
5-point ordinal scale: 
“How would you describe the consistency of your stool?” 
1=Very hard 
2=Hard 
3=Neither too hard nor too soft 
4=Loose but not watery 
5=Very loose and watery 


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Straining 
Patient assessment of straining will be collected by eDiary entry on an event-driven basis (ie, for 
each BM reported in the eDiary). For each BM, degree of straining will be assessed by the 
patient using the following 5-point ordinal scale: 
“How much did you strain during your bowel movement?” 
1=Not at all 
2=A little (mild straining) 
3=A fair amount (moderate straining) 
4=A large amount (severe straining) 
5=An extreme amount (extremely severe straining) 
Weekly Patient Assessment of Constipation Severity 
Patient assessment of constipation severity will be reported weekly by eDiary entry. The rating 
of constipation severity during the previous 7 days on a 5-point ordinal scale will be provided by 
the patient answering the following question: 
“On average, how would you rate your constipation during the past 7 days?” 
1=None 
2=Mild 
3=Moderate 
4=Severe 
5=Very severe 
Weekly Patient Assessment of IBS Symptom Severity 
Patient assessment of IBS symptom severity will be reported weekly by eDiary entry. The rating 
of IBS symptom severity during the previous 7 days on a 5-point ordinal scale will be provided 
by the patient answering the following question:  
“On average, how would you rate your IBS symptoms during the past 7 days?” 
1=None 
2=Mild 
3=Moderate 
4=Severe 
5=Very severe 


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Weekly Patient Assessment of Adequate Relief 
Patient assessment of adequate relief of IBS symptoms will be reported weekly by eDiary entry. 
The rating of adequate relief during the previous 7 days on a binary scale will be provided by the 
patient answering the following question: 
“Overall, have you had adequate relief from your IBS symptoms during the past 7 days?” 
1=Yes 
2=No 
Weekly Patient Assessment of Treatment Satisfaction 
Patient assessment of treatment satisfaction will be reported weekly by eDiary entry each week 
after the Randomization Visit. Patients will answer the following question on a 5-point ordinal 
scale: 
“Overall, how satisfied are you with the study medication’s ability to relieve your IBS 
symptoms?” 
1=Not at all satisfied 
2=A little satisfied 
3=Moderately satisfied 
4=Quite satisfied 
5=Very satisfied 
5.3.4 
Health Outcomes Assessments 
5.3.4.1 
IBS-QOL 
The IBS-QOL is an instrument for assessing the impact of IBS on a patient’s quality of life 
(Appendix 2).(1) The IBS-QOL will be completed at the Randomization Visit prior to the 
patient receiving study drug and at subsequent visits as specified in the Schedule of Evaluations 
(Table 5.1-1). At each of the designated visits, the assessment will be triggered by site personnel 
on the patient’s eDiary for the questionnaire to be self-administered by the patient. 
5.3.4.2 
CDC Healthy Days Core Module (CDC HRQOL-4) 
The CDC Healthy Days Core Module (CDC HRQOL-4; Appendix 3) assesses a person’s 
perceived health status through 4 questions that assess self-rated health, numbers of recent days 
when physical health or mental health was not good, and number of recent days with limitations 
due to poor physical or mental health.(2) For the CDC HRQOL-4 items, recent is defined as 
during the past 30 days. The CDC HRQOL-4 will be completed at the Randomization Visit prior 
to the patient receiving study drug and at subsequent visits as specified in the Schedule of 
Evaluations (Table 5.1-1). At each of the designated visits, the assessment will be triggered by 
site personnel on the patient’s eDiary for the questionnaire to be self-administered by the patient. 


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5.4 
SAFETY ASSESSMENTS 
The safety parameters will include adverse events (AEs), clinical laboratory and vital sign 
parameters, and physical examination. 
5.4.1 
Adverse Events 
The AE assessment (interview) will be collected from the time the patient signed the informed 
consent obtained until completion of trial participation (eg, early termination or Week 16/EOT 
Visit). At each trial visit, the investigator will inquire about the occurrence of AEs/SAEs since 
the last visit. 
5.4.1.1 
Causality Assessment 
Causal relationship must be assessed according to the following scale: 
• Related 
An AE is attributed to the study medication if: 
• A temporal relationship to study drug administration makes a 
causal relationship plausible (eg, the event occurred within a 
reasonable time frame following administration of study 
medication); and/or 
• Other causative factor(s) (eg, the subject’s clinical condition, other 
concomitant treatments) either do not explain the event or are less 
equally likely to have led to the occurrence of the event, or 
• The event improved with stopping of the investigational product, 
and/or 
• The event recurred upon re-exposure with investigational product 
• Not Related 
Any other event (refer to Section 8.2.1.2.2 of the protocol for details) 
5.4.1.2 
Severity Assessment 
Severity will be assessed according to the following scale: 
• Mild 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
• Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort, but poses no significant or permanent risk of harm to 
the research participant. 
• Severe 
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 


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5.4.1.3 
Serious Adverse Events 
All adverse events will be categorized as Serious (as defined in the MCP-103-312 Protocol, 
Section 8.2.1.1) or Non-Serious. 
5.4.2 
Medical History 
A complete medical history will be performed as defined in the Schedule of Evaluations 
(Table 5.1-1). 
5.4.3 
Physical Examination 
A complete physical examination will be performed as defined in the Schedule of Evaluations 
(Table 5.1-1). A physical examination will include the following assessments: general 
appearance; head, ears, eyes, nose, and throat (HEENT); neck; cardiovascular; thorax/lungs; 
abdomen; musculoskeletal; lymph nodes; skin; neurologic; and mental status. Breast, 
genitourinary, and rectal examinations are optional at the discretion of the investigator, except as 
described in the Schedule of Evaluations (Table 5.1-1). 
5.4.4 
Vital Signs 
Vital sign measurements will be performed as defined in the Schedule of Evaluations 
(Table 5.1-1). Vital sign measurements include oral temperature (°C), respiratory rate, systolic 
and diastolic blood pressure (BP), and pulse. Pulse and BP readings will be taken after the 
patient has been seated for at least 5 minutes. 
5.4.5 
Clinical Laboratory Data 
Fasted blood and urine samples for clinical laboratory tests will be collected at the days and 
times defined in the Schedule of Evaluations (Table 5.1-1). A central laboratory will be used to 
evaluate all blood and urine samples (except the urine pregnancy test). 
The following clinical laboratory tests will be performed: 
Hematology: Absolute and differential white blood cell count, erythrocyte count, hemoglobin, 
hematocrit, platelet count, and red blood cell indices (mean corpuscular volume, mean 
corpuscular hemoglobin, and mean corpuscular hemoglobin concentration) 
Chemistry: 
Sodium, magnesium, potassium, calcium, chloride, glucose, blood urea nitrogen, 
creatinine, total protein, alkaline phosphatase, albumin, total bilirubin, aspartate 
aminotransferase, alanine aminotransferase, bicarbonate, phosphate, cholesterol, and uric acid 
Other: Urine drug screening (cocaine, barbiturates, amphetamines, opiates, benzodiazepine, 
alcohol, and cannabinoids) (Screening Visit only). Clinical significance of a positive urine drug 
screen will be assessed by the investigator; positive results for cocaine, barbiturates, and 
cannabinoids are exclusionary. 


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Pregnancy test: 
Serum human chorionic gonadotropin pregnancy test (for women of 
childbearing potential only) should be conducted at the Screening Visit and Week 16/EOT Visit. 
A negative urine pregnancy test must be documented at the Randomization Visit and the Week 
12/ETP Visit for the patient to be eligible for randomization and dosing with study drug. Positive 
results on the pregnancy test will exclude a patient from participating or continuing in the trial. 


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6.0 
STATISTICAL METHODS 
6.1 
GENERAL METHODS 
Efficacy outcomes from the Treatment Period will be based on the ITT Population and will be 
summarized by treatment group assigned at the Randomization Visit. Efficacy outcomes from 
the RW Period only or from the Combined Treatment and RW Period will be based on the RW 
Population and will be summarized by treatment sequence determined at the Week 12/ETP Visit. 
Treatment periods will be summarized for safety in the same manner as efficacy; however, safety 
summaries (Safety Population) will be based on the actual treatment received. 
Descriptive statistics including the number of patients, mean, minimum and maximum, and 
standard deviation (SD) will be calculated for continuous variables. Frequencies and percentages 
for each category will be calculated for categorical variables. Percentages will be based on the 
total number of non-missing values. The number missing will be presented, but without a 
percentage. All hypothesis tests will be two-sided with a 5% significance level, and 95% 
confidence intervals (CIs) will be used, unless stated otherwise. 
All statistical analyses will be performed using SAS Version 9.3 (or later) for Windows. 
6.2 
ADJUSTING FOR COVARIATES 
As a general approach, the baseline values will be included in the mixed model for repeated 
measures (MMRM) and analysis of covariance (ANCOVA) as a covariate  when the 
postbaseline or change scores are analyzed. Heterogeneity of slopes will be explored (e.g., 
review of residuals, inclusion of an interaction term, comparison of group differences at the 25th 
and 75th percentiles). 
6.3 
HANDLING OF DROPOUTS/MISSING DATA IMPUTATION METHOD 
For responder endpoints, a patient will be deemed a weekly non-responder for all weeks 
following the patient’s discontinuation from the study. The responder definition will be applied 
to the week the patient discontinues. Unless stated otherwise, missing data will not be imputed. 
6.4 
INTERIM ANALYSIS AND DATA MONITORING 
No formal interim analyses are planned to compare treatment groups with respect to efficacy or 
safety prior to formal completion of the trial. 
6.5 
MULTICENTER STUDIES 
This study is being conducted in approximately 80 centers.  Due to the potential of small 
numbers of patients per center, data will be pooled into the following 5 geographic regions (as 
listed in Section 9.3): Northeast, Southeast, Midwest, Southwest, and West. 
All analyses using trial center will use this 5-category geographic region variable. 


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6.6 
MULTIPLE COMPARISONS/MULTIPLICITY 
The overall family-wise Type I error rate for the primary and secondary efficacy analyses will be 
controlled at the α=0.05 level by employing a fixed-sequence procedure as described below. 
Following the fixed-sequence procedure, if the primary hypothesis between the placebo group 
and the linaclotide 290 µg group is statistically significant (α=0.05) in the ITT Population, then 
the primary objective of the trial will have been achieved and the next hypothesis can be tested; 
otherwise, testing will stop. The testing of each sequential hypothesis is conditional on all the 
previous hypotheses being rejected at the 0.05 level of significance. If a hypothesis is not 
rejected at the 0.05 level of significance, then all remaining hypotheses are deemed not 
statistically significant. All hypothesis testing will be two-sided. 
1. Linaclotide vs. placebo – Change from Baseline in Abdominal Score  
2. Linaclotide vs. placebo – Change from Baseline in 12-week Abdominal Score (CDF) 
3. Linaclotide vs. placebo – 6/12 Week Abdominal Score Responder 
4. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 12 
5. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 10 
6. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 8 
7. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 6 
8. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 4 
9. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 2 
10. Linaclotide vs. placebo – Change from Baseline in Abdominal Score at Week 1 
 
6.7 
USE OF AN EFFICACY SUBSET 
Not applicable 
6.8 
ACTIVE CONTROL TO SHOW EQUIVALENCE 
Not applicable. 
6.9 
EXAMINATION OF SUBGROUPS 
Subgroup analyses will be performed on the primary and secondary efficacy endpoints, as well 
as treatment emergent adverse events by preferred term using the subgroups defined in 
Table 6.9-1. 


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Table 6.9-1 
Subgroup Variables 
Subgroup Variable 
Subgroups 
Age 
(1) <65; ≥65 
(2) <65; ≥65 to <75; ≥75 
Sex 
Female; Male 
Race 
Caucasian; Black/African American; Other  
Ethnic Origin 
Hispanic; Non-Hispanic 
Body Mass Index (BMI) 
<30 kg/m2; ≥30 kg/m2 
 


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7.0 
ANALYSIS METHODS 
7.1 
PATIENT POPULATIONS 
7.1.1 
Screened Population 
The Screened Population consists of all patients who signed informed consent and received a 
patient identification (PID) number. 
7.1.2 
Safety Population 
The Safety Population consists of all patients who received at least one dose of study drug. 
7.1.3 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population consists of all randomized patients. Efficacy analysis will 
be based on the ITT population, in which patients are evaluated according to the treatment group 
to which they were assigned at randomization. 
7.1.4 
Randomized Withdrawal Population 
The RW Population consists of all patients who were re-randomized or allocated to study drug 
upon completion of the Treatment Period. For the RW Period, there are 3 treatment sequences as 
follows: 
1. 290 µg-290 µg (290 µg linaclotide administered in the Treatment Period, followed by 
290 µg linaclotide in the RW Period) 
2. 290 µg-Placebo (290 µg linaclotide administered in the Treatment Period, followed by 
placebo in the RW Period) 
3. Placebo-290 µg (placebo administered in the Treatment Period, followed by 290 µg 
linaclotide in the RW Period) 
Randomized Withdrawal Safety Population 
The RW Safety Population consists of all patients who were re-randomized to or assigned to 
double-blind RW treatment and received at least one dose of RW treatment. 
7.2 
PROTOCOL DEVIATIONS 
Protocol deviations and Important Protocol Deviations (IPD) will be identified and documented 
for all randomized patients prior to unblinding through programmatic checks of the study data 
and select individual data reviews. IPDs will be determined based on review of all protocol 
deviations and protocol deviation categories (i.e., Use of Disallowed Medication); this review 
will be performed by members of the Ironwood Clinical Trials team, including but not limited to 
the Clinical Medical Researcher and study Biostatistician. IPD categories include, but are not 
limited to: 
• those who entered the study even though they did not satisfy the entry criteria 
• those who developed withdrawal criteria during the study but were not withdrawn 
• those who received the wrong treatment or incorrect dose 


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• those who received an excluded concomitant treatment 
 
The number and percentage of subjects with IPDs will be presented by study treatment and IPD 
category. Protocol deviations and IPDs will be provided by patient in data listings. 
7.3 
PATIENT DISPOSITION 
The number and percentage of patients included in each of the Safety, and ITT populations will 
be summarized overall and by treatment group for each trial center within each geographic 
region. The number of patients in the Screened Population will be summarized by geographic 
region (See Section 9.3 for definition of geographic region) and by study center. 
The number and percentage of screen failure patients (i.e., patients who entered the Screening 
Period but not the Pretreatment Period) and the number and percentage of pretreatment failures 
(i.e., patients who entered the Pretreatment Period but were not randomized), along with the 
associated reasons for failure, will be tabulated overall for the Screened Population. Patients who 
initially failed screening and were re-screened will only be counted once, that is, the PID used 
for the rescreened subject will be summarized and listed for patient disposition.  
The number and percentage of ITT patients, the number and percentage of patients who 
completed the Treatment Period, as well as the number and percentage of patients who 
prematurely discontinued treatment will be presented for each treatment group and pooled across 
treatment groups. The reasons for premature discontinuation from the Treatment Period as 
recorded on the trial completion forms of the electronic case report forms (eCRFs) will be 
summarized (number and percentage) by treatment group for the Randomized Population. The 
number and percentage of patients who prematurely discontinued treatment will be summarized 
for each treatment group by time of discontinuation, defined as the number of days from first 
dose of study drug to the date of last dose during the Treatment Period, categorized into weeks 
(Week 1 through Week 12). All patients who prematurely discontinue during the Treatment 
Period will be listed by discontinuation reason for the Randomized Population.  
Similar to the Treatment Period, the number and percentage of patients who are re-randomized 
into the RW Period, complete the RW Period, and prematurely discontinue from the RW Period 
will be presented overall and by treatment sequence. The reason for premature discontinuation 
from the RW Period as recorded on the trial completion forms of the eCRFs will be summarized 
(number and percentage) by treatment sequence and overall. 
7.4 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographic parameters (age, age group, race, ethnicity, sex), and baseline characteristics 
(weight; height; and body mass index, calculated as weight in kg/[height in m]2) will be 
summarized descriptively for the Safety and ITT Populations. Baseline efficacy parameters 
(including the abdominal score, abdominal bloating, abdominal discomfort, abdominal pain, 
SBM frequency, CSBM frequency, BSFS score, stool consistency, and straining) will be 
summarized descriptively for the ITT Population. 


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Abnormalities in patients’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 21.0. The number and percentage of 
patients with abnormalities in medical and surgical histories in each system organ class (SOC) 
and preferred term will be summarized by treatment group for the Safety Population. 
7.5 
MEASUREMENT OF TREATMENT COMPLIANCE 
Dosing compliance for a specified period is defined as the total number of capsules taken by a 
patient during that period divided by the number of capsules that were expected to be taken 
during the same period, multiplied by 100. The total number of capsules taken will be calculated 
based on the following equation: total number of capsules dispensed – (number of capsules 
returned + number of capsules lost). The total number of capsules expected to be taken during a 
specified period equals the number of days in the period. 
Descriptive statistics for study drug compliance for the Treatment Period overall, and for each of 
the 3 consecutive 4-week periods (weeks 1-4, 5-8, 9-12) in the Treatment Period (consistent with 
study drug dispensing) will be presented for the Safety Population. Similarly, descriptive 
statistics for the RW Period (RW weeks 1-4) will be presented for the RW Population. 
7.6 
EXTENT OF EXPOSURE 
Exposure to study drug will be calculated as the number of days from the date of first dose taken 
to the date of last dose taken. 
Exposure to study drug for the Safety Population during the double-blind treatment period will 
be summarized descriptively by treatment group. Overall treatment duration will also be 
categorized as 1 Day; >1 Day to ≤ 7 Days; >7 Days to ≤30 Days; >30 Days to ≤90 Days; and 
>90 Days and the number and percent of patients in each category will be summarized. In 
addition, a cumulative distribution graph of exposure to study drug by treatment will be 
provided. 
Patient-years, defined as exposure to the study drug in years, will be summarized by treatment 
group for the Safety Population. 
Similar summaries will be provided by treatment sequence for the RW period with the Overall 
treatment duration categorized as 1 Day; >1 Day to ≤7 Days; >7 Days to ≤21 Days; >21 Days to 
≤28 Days, and >28 Days. 
7.7 
PRIOR AND CONCOMITANT MEDICATION 
Prior medication is defined as any medication taken before the date of the first dose of double-
blind study drug. Concomitant medicines are defined as any medicines taken on or after the date 
of first dose of study drug during the defined period (Treatment/RW). Any medicines started 
after the date of last dose of study drug for the defined period (Treatment/RW) will be excluded 
from the summaries related to concomitant medicines for that period. 


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Both prior and concomitant medications will be coded by drug name and therapeutic class using 
WHO Drug B2 March 2018 version or above. The use of prior and concomitant medications will 
be summarized for the Safety Population by the number and percentage of patients in each 
treatment group and for the RW Population by treatment sequence receiving each medication 
within each therapeutic class. If a patient took a specific medication multiple times or took 
multiple medications in the same category (based on Anatomical-Therapeutic-Chemical 
classification), that patient would be counted only once for the coded drug name or therapeutic 
class. The use of per-protocol rescue medicines is collected separately in the eDiary and will be 
summarized as described in Section 7.9.3. 
7.8 
EDIARY COMPLIANCE 
Patients are required to enter their evening diary assessments into the eDiary each evening during 
the pretreatment, treatment, and RW periods. An evening assessment is considered complete if 
all questions, excluding the weekly assessments, are answered. 
eDiary compliance will be calculated for baseline (pretreatment period), the treatment period 
(weeks 1-12), RW period (RW weeks 1-4), and for each week. For each time period, eDiary 
percent compliance will be calculated as 100* the number of completed evening assessments 
divided by the expected number of days in the period. Percent compliance will also be 
dichotomized as ≥80% and <80% for each period, as well as the number and percentage of 
patients with ≥4 / <4 complete eDiary entries each week. Descriptive statistics (number of 
patients, mean, SD, median, minimum, and maximum) for eDiary compliance will be presented 
for the ITT population by treatment; n and percent will be presented for the dichotomous 
categories. 
7.9 
EFFICACY ANALYSIS 
All efficacy analyses will be based on the ITT Population for the Treatment Period and based on 
the RW Population for the RW Period. 
Baseline values for efficacy parameters will be derived from the eDiary daily data collected in 
the Pretreatment Period, specifically the period of time from 14 days prior to randomization up to 
the time of randomization. 
A patient’s daily abdominal score is calculated as the average of the daily abdominal pain, 
abdominal bloating, and abdominal discomfort assessments. If two or more of these individual 
daily abdominal symptoms are missing, then the Abdominal Score for that day will be missing. 
Baseline values for patient symptom severity parameters (e.g., abdominal score, abdominal 
discomfort, abdominal bloating, abdominal pain, and constipation severity) will be the average 
of the non-missing severity scores reported during this period. 
An SBM is defined as a BM that occurs in the absence of laxative, enema, or suppository use on 
either the calendar day of the BM or the calendar day before the BM. CSBM is defined as an 
SBM associated with a sense of complete evacuation. 
The baseline CSBM and SBM weekly rates will be derived based on the number of CSBMs and 
SBMs a patient had during this period. 


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Baseline stool consistency and straining will be calculated as the average of the non-missing 
values from the SBMs reported by the patient during this period. A patient’s baseline Stool 
Consistency and straining cannot be assessed if the patient does not have at least one SBM 
during the Pretreatment Period. Patients with missing baseline Stool Consistency will be 
excluded from Stool Consistency analyses that involve change from baseline. Similarly, patients 
with missing baseline straining will be excluded from straining analyses that involve change 
from baseline. 
For weekly responder parameters based on daily eDiary assessments, a patient with less than 4 
complete evening reports during an analysis week will not be considered a responder for that 
week. 
Trial centers will be pooled by geographic region (details provided in Section 9.3). In lieu of trial 
center, geographic region will be used in analyses adjusting for center-to-center variability. 
All hypotheses will be tested at a two-sided 0.05 significance level (Section 6.6). All confidence 
intervals will be 2-sided 95% confidence intervals, unless stated otherwise. 
7.9.1 
Primary Endpoint 
The primary endpoint is the Change from Baseline in Abdominal Score at Each Week during the 
Treatment Period. The weekly Abdominal Score is the average of the non-missing daily 
Abdominal Scores during in a week. Change from baseline will be calculated as the weekly score 
minus the baseline score. 
7.9.1.1 
Analyses of the Primary Endpoint 
Inferential testing between the linaclotide 290 µg and placebo groups with regard to the change 
from baseline in abdominal score over the Treatment Period will be evaluated employing a 
mixed model with repeated measures (MMRM) framework with week (categorical), treatment, 
geographic region, and week-by-treatment fixed effects, patient as the random effect, and 
baseline value as a covariate. An unstructured covariance structure will be utilized to model the 
covariance matrix. Descriptive statistics based on the MMRM model will include least-squares 
(LS) mean change from baseline for each treatment, the LS mean difference between linaclotide 
290 µg and placebo, corresponding 95% CIs, and the p-value associated with the comparison. 
7.9.1.2 
Sensitivity Analyses of the Key Efficacy Parameters 
If warranted, for the primary efficacy and secondary endpoints/analyses (defined in Section 
7.9.2), the potential impact of missing data on the estimates of treatment effect will be assessed 
using a sensitivity analysis approach based on multiple imputations (MI). 
In order to characterize the extent of missing data associated with the key efficacy parameter, the 
number and percentage of patients with <4 completed evening diaries will be presented by 
treatment group for the ITT Population for each week of the Treatment Period (Please refer to 
Section 7.8 for additional details). 


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Weekly data for a patient with <4 complete evening diaries in a week will be classified as 
missing for that week. Sensitivity analyses will utilize a pattern-mixture model using a placebo-
based method (3). 
The placebo-based MI imputes missing data after dropout (monotonic) based on the placebo 
group data using multiple imputation methodology for all subjects (including active treatment 
subjects). 
The steps to implement placebo-based MI are as follows: 
1. Create a Monotonic Dataset:  One-thousand (1000) datasets will be generated where 
missing outcome data at intermittent week (s) (non-monotonic ) will be first imputed for 
each treatment using non-missing data from all subjects within the treatment group by a 
Monte Carlo Markov Chain (MCMC) imputation model with treatment, baseline score, 
geographic region and weekly score. The MCMC statement (mcmc chain=multiple 
impute=monotone ) in the SAS PROC MI procedure will be used. As a result, each of the 
1000 datasets will only have missing ending data, or a monotone missing data pattern. 
2. For each of the 1000 datasets with monotonic missing data, the monotonic missing 
weekly data will be imputed one week at a time by a sequence of MIs, as follows.  
Imputation will utilize data from all Placebo subjects and Active treatment with the week 
of interest (week currently being imputed) missing. 
a. For week 1, create two datasets:  one containing all placebo patients and active 
patients with the week 1 value - missing, referred to as Mono_imp1; one 
containing all other patients, referred to as Mono_rest1. 
b. For Mono_imp1, impute the missing values at week 1 utilizing Proc MI: 
 
PROC MI data=mono_imp1 out=reg_imp1 nimpute=1 seed=XXXX; 
    By imputation;  /*note 1000 imputation performed in step 1*/ 
    Var base siteid change1 ; 
    Monotone Regression (change1); 
Run; 
 
c. Set Mono_rest1 and reg_imp1  Call this dataset IMP1. 
d. Repeat Steps 2a-2c for weeks 2 through 12, respectively  
Note: for Week i, i>1,  
PROC MI data=mono_impi out=reg_impi nimpute=1 seed=XXXX; 
    By imputation;  /*note 1000 imputation performed in step 1*/ 
    Var base siteid change1 change2 . . . change(i-1) change(i); 
    Monotone regression (change(i)); 
Run; 
3. Analyze each of the 1000 imputed complete datasets. 
a. For continuous endpoints, perform same statistical analyses (MMRM) as described in 
Section 7.9.1.1 for observed case.  
b. For responder endpoint: 
a. Using the abdominal score data imputed above, recalculate the responder 


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b. For each imputed dataset, perform Cochran-Mantel-Haenszel (CMH) analyses 
as described in Section 7.9.2.1. 
4. Estimation and Inference of the MI datasets will be performed using Rubin’s combination 
rules (4) as implemented through the MIANALYZE procedure in SAS. 
7.9.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Change from Baseline in 12-week Abdominal Score 
The 12-week Abdominal Score is the average of the non-missing Abdominal Scores 
reported over the course of the Treatment Period. Change from baseline will be 
calculated as the 12-week score minus the baseline score. 
• 6/12 Week Abdominal Score Responder 
A 6/12 Week Abdominal Score Responder is a patient who meets the Weekly Abdominal 
Score Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For 
each week in the Treatment Period, a Weekly Abdominal Score Responder is a patient 
who has an improvement from baseline of at least 2 points (ie, a -2 change from baseline) 
in the respective weekly abdominal score. 
7.9.2.1 
Secondary Efficacy Analysis 
The cumulative distribution functions (CDFs) for linaclotide 290 µg and placebo will be 
estimated for the Change from Baseline in 12-week Abdominal Score endpoint. The CDFs will 
be compared using the Wilcoxon rank sum test with Hodges-Lehmann estimator for the median 
difference. 
For the secondary responder endpoint, the proportion of responders in the linaclotide 290 µg 
group will be compared to the proportion of responders in the placebo group using a Cochran-
Mantel-Haenszel (CMH) test controlling for geographic region. The number and percent of 
responders, the difference in responder rates between the linaclotide 290 µg and placebo groups, 
the odds ratio relative to placebo controlling for geographic region, all corresponding 95% CIs, 
and the p-value associated with the CMH test will be presented. The 95% CIs for responder rates 
will be obtained using exact Clopper-Pearson method; 95% CIs for differences in responder rates 
will be obtained using the normal approximation to the binomial distribution.  
A secondary time-course analysis of the Change from Baseline in Abdominal Score (see primary 
endpoint definition in Section 7.9.1.1) will also be conducted. Using the MMRM framework 
defined in the primary analyses, treatment difference between linaclotide 290 µg and placebo 
will be assessed at each individual week. For each week, descriptive statistics based on the 
MMRM model will include the LS mean change from baseline for each treatment, the LS mean 
difference between linaclotide 290 µg and placebo, corresponding 95% CIs, and the p-value 
associated with the treatment comparison. Only weeks 12, 10, 8, 6, 4, 2, and 1 are secondary 
analyses controlled for multiplicity. 


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7.9.3 
Additional Efficacy Endpoints 
Additional efficacy endpoints will be explored outside of the formal testing procedures and not 
controlled for multiplicity. These endpoints will include: 
• 6/12 Week Abdominal Pain and Constipation (APC) +1 Responder 
A 6/12 Week APC +1 Responder is a patient who meets the Weekly APC +1 Responder criteria 
for at least 6 out of the 12 weeks of the Treatment Period. For each week in the Treatment 
Period, a Weekly APC +1 Responder is a patient who has an increase from baseline of at least 1 
in the respective CSBM weekly rate and has a decrease from baseline of at least 30% in the 
respective weekly abdominal pain score. If a patient did not enter information into the eDiary on 
at least 4 days for a particular Treatment Period week, the patient will not be considered a 
responder for that week. 
• Change from Baseline in Abdominal Pain at Each Week 
Abdominal pain is measured daily using an 11-point NRS. For each week on treatment, the 
weekly abdominal pain score is the mean of the non-missing daily values. 
• Change from Baseline in CSBM Frequency Rate at Each Week 
A patient’s weekly CSBM frequency rate is the CSBM rate (CSBMs/week) calculated for that 
week. 
• Change from Baseline in SBM Frequency Rate at Each Week 
A patient’s weekly SBM frequency rate is the SBM rate (SBMs/week) calculated for that week. 
• Change from Baseline in BSFS (Stool Consistency) at Each Week 
Stool consistency is measured using the 7-point BSFS. The patient’s BSFS score for each week 
on treatment is the mean of the non-missing BSFS scores from the SBMs reported by the patient 
during the week. 
• Change from Baseline in Stool Consistency at Each Week 
Stool consistency is measured using a 5-point ordinal scale. The patient’s stool consistency score 
for each week on treatment is the mean of the non-missing stool consistency scores from the 
SBMs reported by the patient during the week. 
• Change from Baseline in Straining at Each Week 
Straining is measured using a 5-point ordinal scale. The patient’s straining score for each week 
on treatment is the mean of the non-missing straining scores from the SBMs reported by the 
patient during the week. 


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• Change from Baseline in Abdominal Discomfort at Each Week 
Abdominal discomfort is measured daily using an 11-point NRS. For each week on treatment, 
the weekly abdominal discomfort score is the mean of the non-missing daily values. 
• Change from Baseline in Abdominal Bloating at Each Week 
Abdominal bloating is measured daily using an 11-point NRS. For each week on treatment, the 
weekly abdominal bloating score is the mean of the non-missing daily values. 
• Percent Change from Baseline in Abdominal Pain at Each Week 
Percent change will be calculated as 100 * the Change from Baseline in Abdominal Pain at 
Worst at each week divided by the baseline abdominal pain score. 
• Change from Baseline in Percent of Days with Use of Rescue Medicine over the 
Treatment Period 
The percent of days using per-protocol rescue medicine or any other laxative, suppository, or 
enema during each week will be calculated as 100 * the number of days rescue medicine was 
used during the week divided by the total number of days on treatment. 
• SBM Within 24 Hours After First Dose Responder 
A patient meets the SBM Within 24 Hours After First Dose Responder criteria if the amount of 
time between the randomization date and time and the time of first reported SBM is less than or 
equal to 24 hours.  For patients who did not take their first dose of study medication on the 
randomization visit, then the first reported SBM must occur on the same study day as the first 
dose study day.  Randomization date and time is utilized as a surrogate for the date and time of 
first dose because only first dose date, not time, is captured. 
• 6/12 Week Abdominal Pain 30% Responder 
A 6/12 Week Abdominal Pain 30% Responder is a patient who meets the Weekly Abdominal 
Pain 30% Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For each 
week in the Treatment Period, a Weekly Abdominal Pain 30% Responder is a patient who has a 
decrease from baseline of at least 30% in the respective weekly abdominal pain score. If a patient 
did not enter information into the eDiary on at least 4 days for a particular Treatment Period 
week, the patient will not be considered a Weekly Abdominal Pain 30% Responder for that 
week. 
• 6/12 Week Abdominal Pain Responder 


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A 6/12 Week Abdominal Pain Responder is a patient who meets the Weekly Abdominal Pain 
Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For each week in 
the Treatment Period, a Weekly Abdominal Pain Responder is a patient who has an improvement 
from baseline of at least 2 points (ie, a -2 change from baseline) in the respective weekly 
abdominal pain score. If a patient did not enter information into the eDiary on at least 4 days for 
a particular Treatment Period week, the patient will not be considered a Weekly Abdominal Pain 
Responder for that week. 
• 6/12 Week Abdominal Discomfort Responder 
A 6/12 Week Abdominal Discomfort Responder is a patient who meets the Weekly Abdominal 
Discomfort Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For 
each week in the Treatment Period, a Weekly Abdominal Discomfort Responder is a patient who 
has an improvement from baseline of at least 2 points (ie, a -2 change from baseline) in the 
respective weekly abdominal discomfort score. If a patient did not enter information into the 
eDiary on at least 4 days for a particular Treatment Period week, the patient will not be 
considered a Weekly Abdominal Discomfort Responder for that week. 
• 6/12 Week Abdominal Bloating Responder 
A 6/12 Week Abdominal Bloating Responder is a patient who meets the Weekly Abdominal 
Bloating Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For each 
week in the Treatment Period, a Weekly Abdominal Bloating Responder is a patient who has an 
improvement from baseline of at least 2 points (ie, a -2 change from baseline) in the respective 
weekly abdominal bloating score. If a patient did not enter information into the eDiary on at least 
4 days for a particular Treatment Period week, the patient will not be considered a Weekly 
Abdominal Bloating Responder for that week. 
• 6/12 Week CSBM Responder 
A 6/12 Week CSBM Responder is a patient who meets the Weekly CSBM Responder criteria for 
at least 6 out of the 12 weeks of the Treatment Period. For each week in the Treatment Period, a 
Weekly CSBM Responder is a patient who has an increase from baseline of at least 1 in the 
respective CSBM weekly rate. If a patient did not enter information into the eDiary on at least 4 
days for a particular Treatment Period week, the patient will not be considered a Weekly CSBM 
Responder for that week. 
• Treatment Satisfaction 
Treatment satisfaction is measured on a 5-point ordinal scale. Treatment satisfaction will be 
analyzed separately for each Treatment Period week. 
• Adequate Relief 
Assessment of adequate relief during the previous 7 days is measured on a binary scale (yes/no). 
Assessment of adequate relief will be analyzed separately for each Treatment Period week. 
• 6/12 Week Adequate Relief Responder 


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A 6/12 Week Adequate Relief Responder is a patient who reports Adequate Relief for at least 6 
out of the 12 weeks of the Treatment Period. 
• Change from Baseline in Constipation Severity 
Constipation severity is measured weekly using a 5-point ordinal scale. Change from baseline 
will be calculated at each week. 
• Change from Baseline in IBS Symptom Severity 
IBS symptom severity is measured weekly on a 5-point ordinal scale. Change from baseline will 
be calculated at each week. 
7.9.3.1 
Analyses of Additional Efficacy Endpoints 
All categorical responder parameters (e.g., 6/12 Week CSBM Responder) and SBM within 24 
Hours After First Dose, will be analyzed utilizing the same methods defined in Section 7.9.2.1. 
All continuous change-from-baseline at each week endpoints and Treatment Satisfaction will be 
analyzed and summarized using the MMRM approach described in Section 7.9.1.1. 
7.9.4 
Randomized Withdrawal Period Endpoints 
For the RW Period, statistical analyses will be presented by treatment sequence (treatment 
sequences defined in Section 7.1.4). 
The following endpoints will be calculated for the RW Period following the methods described 
for the primary and additional endpoints in Sections 7.9.1 and 7.9.3: 
• Change from Baseline in Abdominal Score at Each Week 
• Change from Baseline in Abdominal Bloating at Each Week 
• Change from Baseline in Abdominal Discomfort at Each Week 
• Change from Baseline in Abdominal Pain at Each Week 
• Change from Baseline in CSBM Frequency Rate at Each Week 
• Change from Baseline in SBM Frequency Rate at Each Week 
• Change from Baseline in BSFS (Stool Consistency) at Each Week 
• Change from Baseline in Stool Consistency at Each Week 
• Change from Baseline in Percent of Days with Use of Rescue Medicine over the RW 
Period 
 


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7.9.4.1 
Randomized Withdrawal Period Analyses 
All RW Period endpoints will be summarized for the RW Period only and for the Combined 
Treatment and RW Period using descriptive statistics and 95% CIs for each treatment sequence. 
No statistical inference will be performed. 
7.10 
POSITIVE CONTROL 
Not applicable. 
7.11 
SAFETY ANALYSIS 
For the Treatment Period, all safety analyses will be based on the Safety Population. For the RW 
Period and the combined 16-week Treatment-RW Period, the safety analyses will be performed 
using the RW Safety Population. The safety parameters will comprise adverse events (AEs), 
clinical laboratory parameters, and vital signs. For each safety parameter, the last nonmissing 
assessment made before randomization will be used as the baseline for all analyses of that safety 
parameter. 
Treatment assignment for Safety summaries is based on the treatment the patient actually 
received. The ‘treatment actually received’ for patients who received treatment(s) other than 
their randomized treatment during the course of the trial will be defined as the treatment group in 
which the patient actually took the greatest number of doses. 
Continuous variables will be summarized by number of patients and mean, SD, median, 
minimum, and maximum values. Categorical variables will be summarized by number and 
percentage of patients. 
7.11.1 
Adverse Events 
Adverse events will be coded by system organ class and preferred term using the MedDRA 
dictionary, version 21.0. 
An AE that occurs during the Treatment Period will be considered a treatment-emergent adverse 
event (TEAE) if it was not present prior to the date of the first dose of double-blind study drug or 
was present prior to the date of the first dose but increased in severity during the Treatment 
Period. If more than 1 AE was reported before the first dose of double-blind study drug and 
coded to the same preferred term, the AE with the greatest severity will be used as the 
benchmark for comparison with the AEs occurring during the Treatment Period that were also 
coded to that preferred term.  
An AE that occurs on or after the date of the first dose of the double-blind study drug for the RW 
Period will be considered a TEAE for the RW Period (RW TEAE) if it was not present prior to 
the date of the first dose of double-blind study drug of the Treatment Period or was present prior 
to the date of the first dose of double-blind study drug for the Treatment Period but increased in 
severity on or after the date of the first dose of the double-blind study drug for the RW Period. 
An AE that occurs more than 1 day after the last dose of study drug in the RW Period will not be 
considered a RW TEAE. 


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An AE that occurs on or after the date of the first dose of the double-blind study drug for the RW 
Period will be considered a newly emergent adverse event (NEAE) for the RW Period if it was 
not present prior to the date of the first dose of the double-blind study drug for the RW Period or 
was present prior but increased in severity after receiving RW period double-blind study drug. 
An AE that occurs more than 1 day after the last dose of double-blind study drug will not be 
counted as an NEAE. 
The period in which a serious adverse event (SAE) occurred will follow the methods defined 
above for TEAEs, RW TEAEs, and NEAEs. Table 7.11-1 summarizes the classification of AEs. 
Table 7.11-1 Adverse Event Classification 
Type of AE 
Reference Period 
for Baseline  
Starting Point of Period 
Ending Point 
TEAE 
Screening+ 
pretreatment 
First dose during 
treatment period 
Earlier of day after last dose of Trt 
period & day before first dose of 
RW period 
RW TEAE 
Screening+ 
pretreatment 
First dose during RW 
period 
Day after date of last dose of RW trt 
NEAE 
Screening+ 
pretreatment+ 
treatment 
First dose during RW 
period 
Day after date of last dose of RW trt 
 
The number and percentage of patients in each treatment group who experience TEAEs will be 
summarized. For the Treatment Period, TEAEs will be summarized for each treatment group by 
system organ class and preferred term; by system organ class, preferred term, and severity; and 
by system organ class, preferred term, and relationship to study drug. The same summaries will 
be provided for each treatment sequence for the RW Period (RW TEAEs and NEAEs). For the 
Treatment-RW Period, TEAEs will be summarized for each treatment sequence by system organ 
class and preferred term only. If a patient has more than 1 AE coded to the same preferred term, 
the patient will be counted only once for that preferred term by identifying those TEAEs with the 
greatest severity and the closest relationship to study drug for the summarization by severity and 
by relationship to the study drug, respectively. 
For the Treatment Period, the incidence of common (≥2% of patients in any treatment group) 
TEAEs, on-therapy serious adverse events (SAEs), and AEs leading to premature 
discontinuation of study drug will be summarized by preferred term and treatment group, sorted 
in decreasing frequency. The above summaries will also be provided for the RW Period by 
treatment sequence. In addition, the incidence of on-therapy SAEs that led to death will be 
summarized. 
For the Screened Population, listings will be presented for patients who died, patients with SAEs, 
and patients with AEs leading to premature discontinuation, if any. 


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7.11.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values (in SI units) and changes from the baseline 
values at each assessment time point will be presented by treatment group for Treatment Period 
and by treatment sequence for the RW Period. The End of Treatment is the last non-missing 
postbaseline value in the Treatment Period; End of study is the last non-missing postbaseline 
value. The hematology and chemistry laboratory parameters listed in Section 5.4.5 will be 
summarized. 
Clinical laboratory test values will be potentially clinically significant (PCS) if they meet either 
the low or high PCS criteria listed in Table 7.11-2. The number and percentage of patients with 
postbaseline PCS clinical laboratory values will be tabulated by treatment group for the 
Treatment Period and by treatment sequence for the RW and Treatment-RW Periods. The 
percentages will be calculated relative to the number of patients with non-PCS baseline values 
and at least 1 assessment in the corresponding postbaseline period. A supportive listing of 
patients with postbaseline PCS values will be provided, including the PID number, trial center, 
and baseline and postbaseline values. A listing of all AEs for patients with PCS clinical 
laboratory values will also be provided. The PCS flags will be derived flags (not from the 
clinically significant laboratory tests reported as AEs by trial centers).  
Table 7.11-2 Criteria for Potentially Clinically Significant Laboratory Results 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Albumin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Alanine aminotransferase 
U/L 
— 
≥ 3 × ULN 
Alkaline phosphatase 
U/L 
— 
≥ 3 × ULN 
Aspartate aminotransferase 
U/L 
— 
≥ 3 × ULN 
Bicarbonate 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Bilirubin, total 
μmol/L 
— 
> 1.5 × ULN 
Calcium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Chloride 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Cholesterol, total 
mmol/L 
— 
> 1.6 × ULN 
Creatinine 
μmol/L 
— 
> 1.3 × ULN 
Glucose 
mmol/L 
< 0.8 × LLN 
> 1.4 × ULN 
Magnesium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Phosphate 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Potassium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Protein, total  
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Sodium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Urea nitrogen 
mmol/L 
— 
> 1.2 × ULN 
Uric acid  
μmol/L 
< 0.9 × LLN 
> 1.1 × ULN 


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Parameter 
SI Unit 
Lower Limit 
Higher Limit 
HEMATOLOGY 
Basophils, absolute cell 
count 
109/L 
— 
> 3 × ULN 
Eosinophils, absolute cell 
count 
109/L 
— 
> 3 × ULN 
Hematocrit 
Ratio 
< 0.9 × LLN 
> 1.1 × ULN 
Hemoglobin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Lymphocytes, absolute cell 
count 
109/L 
< 0.8 × LLN 
> 1.5 × ULN 
Mean corpuscular 
hemoglobin 
pg 
— 
> 3 × ULN 
Mean corpuscular 
hemoglobin concentration 
g/L 
— 
> 3 × ULN 
Mean corpuscular volume 
fL 
< 0.9 × LLN 
> 1.1 × ULN 
Monocytes, absolute cell 
count 
109/L 
— 
> 3 × ULN 
Neutrophils, absolute cell 
count 
109/L 
< 0.8 × LLN 
> 1.5 × ULN 
Platelet count 
109/L 
< 0.5 × LLN 
> 1.5 × ULN 
Red blood cell count 
1012/L 
< 0.9 × LLN 
> 1.1 × ULN 
White blood cell count 
109/L 
< 0.7 × LLN 
> 1.5 × ULN 
LLN = lower limit of normal value provided by the laboratory; SI = Le Système International d’Unités (International System of 
Units); ULN = upper limit of normal value provided by the laboratory. 
 
7.11.3 
Vital Signs 
Descriptive statistics for body weight and vital signs (oral temperature, respiratory rate, systolic 
and diastolic blood pressure, and pulse rate) and changes from baseline values at each visit will 
be presented by treatment group for the Treatment Period and by treatment sequence for the 
Treatment-RW period. The End of Treatment is the last non-missing postbaseline value in the 
Treatment Period; End of study is the last non-missing postbaseline value. 
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 7.11-3. The number and percentage of patients with 
postbaseline PCS vital signs will be tabulated by treatment group for the Treatment Period and 
by treatment sequence for the RW Period and the Treatment-RW Period. The percentages will be 
calculated relative to the number of patients with nonmissing baseline values and at least 1 
assessment in the corresponding postbaseline period. A supportive listing of patients with 
postbaseline PCS values will be provided, including the PID number, trial center, and baseline 
and postbaseline values. 
A listing of all AEs for patients with PCS vital sign values will also be provided. 


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Table 7.11-3 Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteriaa 
Observed Value 
Change From Baseline 
Sitting systolic blood 
pressure, mm Hg 
High 
≥ 180 
Increase of ≥ 20 
Low 
≤ 90 
Decrease of ≥ 20 
Sitting diastolic blood 
pressure, mm Hg 
High 
≥ 105 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Sitting pulse rate, bpm 
High 
≥ 120 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Weight, kg 
High 
— 
Increase of ≥ 7% 
Low 
— 
Decrease of ≥ 7% 
a 
A post-baseline value is considered potentially clinically significant if it meets both the observed-value and the 
change-from-baseline criteria. 
bpm = beats per minute. 
 
7.11.4 
Other Safety Parameters 
7.11.4.1 
Physical Examination 
Any physical examination abnormality that the investigator considers to be potentially clinically 
significant and changed from the baseline will be reported as an AE. No separate analysis for 
Physical Examinations is planned. 
7.12 
HEALTH OUTCOMES ANALYSIS 
Health outcome analyses will be performed on the ITT population for the Treatment Period and 
on the RW Population for the RW Period. 
7.12.1 
Irritable Bowel Syndrome–Quality of Life Assessment (IBS-QOL) 
The IBS-QOL parameters consist of the overall average score and eight subscale scores (ie, 
dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, 
sexual, and relationships). For the Week 12/ETP Visit and the Week 16/EOT Visit, change from 
baseline in the IBS-QOL overall average score and the subscale scores will be analyzed using an 
ANCOVA model with fixed effect terms for treatment group and geographic region and the 
corresponding baseline IBS-QOL score as a covariate. 


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Table 7.12-1 Irritable Bowel Syndrome–Quality of Life Questionnaire 
Endpoint (Subscale) 
Items 
 
 
Dysphoria (DY) 
1, 6, 7, 9, 10, 13, 16, 30 
 
 
Interference with activity (IN) 
3, 18, 19, 22, 27, 29, 31 
 
 
Body image (BI) 
5, 21, 25, 26 
 
 
Health worry (HW) 
4, 15, 32 
 
 
Food avoidance (FA) 
11, 23, 28 
 
 
Social reaction (SR) 
2, 14, 17, 34 
 
 
Sexual (SX) 
12, 20 
 
 
Relationships (RL) 
8, 24, 33 
 
 
Overall (OV) 
All items 
 
 
 
Subscales are scored through simple summative scaling. All items are negatively framed (on a 1-
5 point scale), with the highest response scale equaling the worst quality of life. When scored, all 
items are reversed so that, as IBS-QOL scores increase, quality of life increases. All final raw 
scores are transformed to a 0-to-100 scale using the following formula: 
 
Scale Score = Sum of the items −lowest possible score
possible raw score range
× 100 
 
This transformation converts the lowest and highest possible scores to 0 and 100, respectively. 
Scores between these values represent the percentage of the total possible score achieved. 
If a patient is missing any item in the derivation of a subscale, that subscale is considered 
missing. If any item is missing, the total score is considered missing. However, the subscales 
with nonmissing items can still be calculated. 
7.12.2 
CDC Healthy Days Core Module (CDC HRQOL-4) 
The CDC HRQOL-4 (the Healthy Days Core Module) consists of 4 questions. Self-rated general 
health, physically unhealthy days, mentally unhealthy days, and poor physical/mental days are 
collected. Unhealthy days is defined as: 
Unhealthy days = minimum of (physically unhealthy days + mentally unhealthy days, or 30) 
Descriptive summaries for the derived unhealthy days and the change from baseline will be 
summarized descriptively at each visit. For the Week 12/ETP Visit and the Week 16/EOT Visit, 
treatment difference between the change from baseline score will be performed using ANCOVA 
model with fixed effect terms for treatment group and geographic region and the corresponding 
baseline measure as a covariate. 


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8.0 
CHANGES FROM ANALYSES PLANNED IN THE PROTOCOL 
 


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9.0 
DATA HANDLING CONVENTIONS 
9.1 
VISIT TIME WINDOWS FOR SAFETY ANALYSIS 
Table 9.1-1 below presents the visits assigned for the safety analysis corresponding to the range 
of trial days (window) during which an actual visit may have occurred. 
Table 9.1-1 
Visit Time Windows for Safety Analysis 
Derived Visit 
Scheduled Test / Visit Daya 
Window 
Baseline 
Day 1 
Days ≤ 1 
Week 4 (Day 29) Visit 
Day 29 
Days [2, 43] 
Week 8 (Day 57) Visit 
Day 57 
Days [44, 71] 
Week 12 (Day 85) Visit 
Day 85 
Days > 72 but prior to RW Day 1 
End of Treatment Periodb 
End of Treatment Period Visit 
Week 16 (RW Day 29) Visit 
RW Day 29 
Days > RW Day 1 
End of Trial 
End of Trial Visit 
a 
Relative to the date of randomization or first RW dose; Day 1 = the day of randomization; RW Day 1 = the day of first 
RW dose. 
b 
“End of Treatment Period/End of Trial” will be presented in analysis tables for safety parameters, including ECG, clinical 
laboratory, and vital signs. 
Test/Visit Day will be calculated as follows: test/visit date – date of randomization or date of 
first RW dose + 1. 
If there are multiple values available for the same Visit, the data with the latest date for that visit 
will be utilized for summary. 
9.2 
VISIT TIME WINDOWS FOR EFFICACY ANALYSIS 
Table 9.2-1 presents the analysis weeks assigned for the efficacy analysis of the patient diary 
data related to BM characteristics. These analysis weeks will be used in the calculations for all 
week-based parameters (e.g., Abdominal Score, SBM weekly frequency rate, BSFS weekly 
scores). 


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Table 9.2-1 
Analysis Time Windows for Efficacy Analysis 
Period 
Analysis Week 
Beginsa 
Endsa 
Pretreatment 
(Baselineb) 
Week –2  
Day –14  
Day –8 
Week –1  
Day –7 
Day 1 (time of 
randomization) 
Treatment 
Week 1  
Day 1 (time of randomization) 
Day 7 
Week 2  
Day 8 
Day 14 
Week 3  
Day 15  
Day 21 
Week 4  
Day 22 
Day 28  
Week 5  
Day 29 
Day 35 
Week 6  
Day 36  
Day 42 
Week 7  
Day 43 
Day 49  
Week 8  
Day 50 
Day 56 
Week 9  
Day 57  
Day 63 
Week 10 
Day 64 
Day 70  
Week 11  
Day 71 
Day 77  
Week 12 
Day 78 
Day of last treatment 
period dose dayc 
(usually Day 85) 
RW 
Week 1 
RW Day 1 
RW Day 7 
Week 2 
RW Day 8 
RW Day14 
Week 3 
RW Day15 
RW Day 21 
Week 4 
RW Day 22 
Day of last RW dose 
(usually day 28) 
Note: There is no Day 0 or Week 0. For eDiary assessments in which a patient is asked to report if an event occurred 
“yesterday” or “today” (e.g., a bowel movement or rescue medication use), these windows pertain to when the event 
occurred, not to when the event is reported. For example, if a patient reports in eDiary on Day 78 a bowel movement 
occurring “yesterday,” that bowel movement (and subsequent stool consistency and straining scores) would be 
included in Analysis Week 11, not Analysis Week 12.  
a 
Relative to the date of randomization or first RW dose; Day 1 = the day of randomization; RW Day 1 = the day 
of first RW dose. For the calculation of rates (eg, stool frequency rates) in which the duration of a week or the 
overall period is calculated to the nearest hour, a day begins and ends at midnight. 
b 
Baseline values for efficacy parameters will be derived from the daily eDiary and eCRF data collected in the 
Pretreatment Period, specifically the period from 14 days before randomization up to the time of 
randomization. 
c 
For patients who fail to provide the date of last dose at the last visit, the later date of the last known dose (drug 
dispense eCRF) or the last eDiary date will be used to impute the last dose date. 
 
For the Treatment Period or RW Period, diary day is calculated as diary date – date of 
randomization or date of first RW dose + 1. For the Pretreatment Period, diary day is calculated 
as diary date - date of randomization. However, the day of randomization is always trial Day 1. 
Patients will complete their diary entries once a day, with the exception of Day 1 of entry into 
the Treatment Period, during which 2 diary data sets will be collected. On Day 1, daily questions 
will be entered before and after the randomization, whereas weekly questions will be entered 
before but not after randomization. 


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If a patient withdraws during the Treatment Period or RW Period, the patient’s Treatment Period 
or RW Period shall end on the day of the last dose. The affected Treatment Period or RW Period 
week shall be shortened to the end of the withdrawn patient’s Treatment Period or RW Period, 
and all subsequent Treatment Period or RW Period weeks will be missing for that patient. 
Table 9.2-2 presents the analysis weeks assigned for the efficacy analysis of the patient diary 
data related to Weekly Questions (e.g., Weekly Patient Assessment of Constipation Severity, 
Weekly Patient Assessment of IBS Symptom Severity, Weekly Patient and Assessment of 
Adequate Relief, and Weekly Patient Assessment of Treatment Satisfaction). 
Table 9.2-2 
Analysis Time Windows for Efficacy Analysis – Weekly Assessments 
Period 
Analysis Week 
Begins 
Ends 
Pretreatment 
(Baselineb) 
Week –2  
Day –11  
Day –5 
Week –1  
Day –4 
Day 1 (time of 
randomization) 
Treatment 
Week 1  
Day 7 
Day 10 
Week 2  
Day 11 
Day 17 
Week 3  
Day 18 
Day 24 
Week 4  
Day 25 
Day 31 
Week 5  
Day 32 
Day 38 
Week 6  
Day 39 
Day 45 
Week 7  
Day 46 
Day 52 
Week 8  
Day 53 
Day 59 
Week 9  
Day 60 
Day 65 
Week 10 
Day 66 
Day 72 
Week 11  
Day 73 
Day 79 
Week 12 
Day 80 
Day of last treatment 
period weekly dose 
day (usually Day 
84)* 
RW 
Week 1 
RW Day 7 
RW Day 10 
Week 2 
RW Day 11 
RW Day17 
Week 3 
RW Day18 
RW Day 24 
Week 4 
RW Day 25 
Day of last RW dose 
(28+3 Days) 
*For patients completing the treatment period, but not entering the RW period, Day 87 defines the End 
study day for Week 12 assignment. 
 
In general, weekly questions will be assigned only to the analysis week for which the question 
covers at least 4 days of that week. 
If a weekly question covers days from different study phases, the answers will be discarded.  For 
example, a weekly question answered on study day 2 would cover part of 1 day from the 
treatment phase & 6 days from the pre-treatment phase, so these data would be discarded.  
 


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If patients answer the weekly questions multiple times for a week, for each question, the average 
of the respective answers will be assigned as the weekly value. 
For time periods covering more than a week, the value will be calculated as the average of the 
weekly values. Thus, for pre-treatment, the value will be calculated as the average of week -2 
and week -1. 
9.3 
POOLING OF TRIAL CENTERS 
Because of the potential of many trial centers to have a small number of patients, the centers will 
be pooled by the following 5 geographic regions (as listed in Table 9.3-1): Northeast, Southeast, 
Midwest, Southwest, and West. All analyses using trial center will use this 5-category center 
variable. 
Table 9.3-1 
Definition of Geographic Regions 
Northeast 
Southeast 
Midwest 
Southwest 
West 
CT 
AL 
IA 
AZ 
CA 
DE 
AR 
IL 
NM 
CO 
MA 
FL 
IN 
OK 
ID 
MD 
GA 
KS 
TX 
MT 
ME 
KY 
MI 
 
NV 
NH 
LA 
MN 
 
OR 
NJ 
MS 
MO 
 
UT 
NY 
NC 
ND 
 
WA 
PA 
SC 
NE 
 
WY 
RI 
TN 
OH 
 
 
VT 
VA 
SD 
 
 
 
WV 
WI 
 
 
 
9.4 
DERIVED EFFICACY VARIABLES 
9.4.1 
Patient Recall for eDiary Data 
Bowel Habits 
The eDiary is designed to allow patients to enter Daily Bowel Habits through a spontaneous 
report or the evening report. 
The spontaneous report allows the patient to report BMs, occurring between evening reports, at 
any time. If the previous evening report was not completed, then the patient can report BM 
information occurring between 7:00 PM of the previous night and the current spontaneous report. 
These BM information reporting rules were put into place to reduce recall bias. 


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Rescue Medicine (RM) 
The spontaneous report allows the patient to report RM information, occurring between evening 
reports, at any time. If the previous evening report was not completed, then the patient can report 
RM information between 7:00 PM of the previous night and the current spontaneous report. 
These RM information reporting rules were put into place to reduce recall bias. 
Abdominal Symptom Severity 
During the Evening Diary Report, the eDiary will capture separately the rating of abdominal 
pain, abdominal bloating, and abdominal discomfort experienced by the patient during the past 
24 hours. 
9.4.2 
Handling of Missing eDiary Data  
In the eDiary, for each BM and rescue medicine use reported, the patient will be asked whether 
the BM or rescue medicine use occurred “today” or “yesterday.” The following conventions will 
be followed in the event of missing data: 
Gaps in the eDiary Data 
If a patient does not complete either a spontaneous or evening report every day, there will be 
gaps in the data.  
There will be no adjustments for these gaps in the eDiary data for the efficacy data analyses 
using an OC approach. Effectively, this means that analyses will assume that no rescue medicine 
use or BMs occurred during these gaps. 
Missing “Today” or “Yesterday” Information for Rescue Medicine 
When a patient uses rescue medicine and the exact date of use is known, there will be a 2-day 
window during which any BMs will not be assessed as SBMs: (1) the day when the rescue 
medicine was administered and (2) the day after. If, in the daily diary, a patient has reported 
taking a rescue medicine but the corresponding date is missing, the rescue medicine use must 
have occurred either on the day of the diary entry or on the day before the diary entry. The rescue 
medicine window in this missing-date scenario will be 3 days, covering the day before the 
eDiary report, the day of the eDiary report, and the day after the eDiary report. This window will 
be used to determine if a BM should be considered an SBM. 
For the analysis of rescue medicines, the missing date will be imputed as the date in which the 
rescue medicine was reported. 
Missing “Today” or “Yesterday” Information for Bowel Movements 
If a patient reports having had a BM but does not provide the exact date, the BM must have 
occurred either on the day of the report or on the day before the report. For determining whether 
a BM is an SBM, this 2-day BM window will be used in conjunction with the rescue medicine 
window. If there is any overlap between the 2-day BM window and the patient’s rescue medicine 
window (which could be either 2-day window or 3-day window), the BM will not be considered 
an SBM. 


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Many analyses require specific dates for each BM. If a BM date is missing, it will be imputed as 
the date/time stamp of the eDiary report in which the BM was reported. However, the following 
exception applies to this imputation rule: 
When the first day of the BM window is the last day of a rescue medicine window and the 
second day of the BM window is not also a day of a rescue medicine window, the missing BM 
date will be imputed as the first day of the BM window (i.e., the day before the eDiary report in 
which the BM was recorded). This rule of exception is designed to minimize the risk of 
mischaracterizing a non-spontaneous BM as an SBM. 
Missing Stool Consistency Questions 
No imputation will be performed for a missing BSFS score or the stool consistency 5-point 
ordinal measure. 
Missing Completeness of Evacuation Response 
If the completeness of evacuation response (Question #12) is missing, an SBM will not be 
considered complete. 
Missing Daily Abdominal Symptoms 
No imputation will be performed for missing daily abdominal symptoms (Abdominal Pain, 
Abdominal Discomfort, Abdominal Bloating). 
9.4.3 
Weekly Stool Frequency Rates  
The components for calculating a patient’s stool frequency rates (BM, SBM, and CSBM weekly 
rates) for a given analysis week are as follows: 
• The number of BMs that occurred during that analysis week 
• The number of those BMs that were SBMs 
• The number of those SBMs that were CSBMs 
• The length of time of the analysis week 
The determination of the length of time of an analysis week is provided in Section 9.4.3.1. 
9.4.3.1 
Length of an Analysis Week 
With respect to a patient’s scheduled analysis weeks, the term duration is used. In regard to the 
duration of a week, it is expected that 1 or more of a patient’s “weeks” may not be exactly 7×24 
hours in duration (e.g., a patient may withdraw or discontinue early from the trial). Deviations 
from the 7×24–hour norm are structural in nature; and, as such, the calculations of the weekly 
rates of SBMs or CSBMs will incorporate the actual duration of the week. 
Following an observed-cases approach, no adjustment to the duration of a week will be made for 
missing eDiary data absent because of missed reports. 


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9.4.3.2 
Weekly Stool Frequency Rate Calculations 
The weekly frequency rate for SBMs (CSBMs) will be based on the number of SBMs (CSBMs) 
occurring during that week, adjusting for differences in the duration of the week versus the 
7×24–hour norm. A description of the corresponding formula is provided below. 
Weekly stool frequency rates for each analysis week will be calculated as follows: 
Weekly Frequency Rate (Analysis Weeki) = (7 × 24) × Ci/Di 
Where: 
i is an indicator of analysis week number (e.g., i = –2, –1, 1, …, 12), 
Ci is the number of events (SBMs or CSBMs) reported during analysis week i, and 
Di is the duration (in hours) of analysis week i, from beginning to end (Table 9.2-1). 
9.4.3.3 
Overall Weekly Stool Frequency Rate Calculations for Each Analysis Period 
For each of the analysis periods (Pretreatment [Baseline] and Treatment Period), the overall 
weekly stool frequency rates will be calculated in a manner similar to that for an individual 
week. The corresponding formulas are provided below. 
Overall weekly stool frequency rates for each analysis period will be calculated as follows: 
Weekly Frequency Rate (Analysis Periodj) = (7 × 24) × Cj/Dj 
Where: 
j is an indicator of analysis period number (e.g., j = 1 [pretreatment], 2 [treatment]), 
Cj is the number of events (SBMs or CSBMs) reported during analysis period j, and 
Dj is the duration (in hours) of analysis period j, from beginning to end (Table 9.2-1). 
9.4.4 
Other Weekly Scores Derivation  
For the abdominal score, first the daily average of Abdominal Pain, Abdominal Bloating and 
Abdominal Discomfort will be calculated. If more than 1 of the symptom scores is missing on a 
day, that daily abdominal score will be missing. Weekly scores will be based on the average of 
the non-missing daily abdominal scores. 
For Abdominal Score, Pain, Bloating, and Discomfort, the patient’s weekly average will be the 
average of the non-missing daily scores reported by the patient during each week. 


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For stool consistency questions, the patient’s weekly score will be the average of the non-
missing daily scores from the SBMs reported by the patient during each week. 
For straining, the patient’s weekly straining score will be the average of the non-missing daily 
straining scores from the SBMs reported by the patient during each week. 
9.5 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS 
If a patient has repeated assessments prior to the start of double-blind study drug, then the results 
from the final non-missing assessment made prior to the start of the double-blind study drug will 
be used as baseline. If end-of-trial assessments are repeated or if unscheduled visits occur, the 
last non-missing post baseline assessment will be used as the end-of-trial assessment for 
generating summary statistics. However, all post-baseline assessments will be used for PCS 
value determination as described above and all assessments will be presented in the data listings. 
9.6 
MISSING DATE OF THE LAST DOSE OF STUDY DRUG 
When the date of the last dose of double-blind study drug is missing for a patient in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all efforts 
are made it is still missing, the latest date reported from eDiary entry or from the Study Drug 
Dispensation eCRF question ‘Date of most recent dose’ will be used as the last dose date.  
9.7 
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS 
If severity is missing for an AE that started prior to the first double-blind study drug, all efforts 
should be made to obtain the severity from the investigator. If it is still missing after all efforts, 
then a severity of “Mild” will be assigned. If the severity is missing for an AE that started on or 
after the date of the first dose of double-blind study drug, then a severity of “Severe” will be 
assigned. The imputed values for the missing severity assessment will be used for the incidence 
summary, while the actual missing values will be presented in data listings. 
9.8 
MISSING RELATIONSHIP TO STUDY DRUG FOR ADVERSE EVENTS 
If the relationship to study drug is missing for an AE started on or after the date of the first dose 
of double-blind study drug, all efforts should be made to obtain the date from the investigator. If 
it is still missing after all efforts, a causality of “Related” will be assigned in the corresponding 
analysis derived data set. The imputed values for the missing relationship to double-blind study 
drug will be used only for incidence summary, while the actual missing values will be presented 
in data listings. 
9.9 
MISSING DATE INFORMATION FOR ADVERSE EVENTS 
The following imputation rules apply to cases in which the start date is incomplete  for adverse 
events. 


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a. If AEs occurred during the Screening or Pretreatment Period (i.e., the Screening or 
Pretreatment Period is identified AE eCRF) 
Missing day, month and year 
• If the entire AE start date is missing, then the start date of the Period identified on the AE 
eCRF page will be assigned to the missing fields. 
Missing day and month 
• If the year is the same as the year of the date of informed consent, then the day and month of 
the date of informed consent will be assigned to the missing fields. 
• If the year is prior to the year of the date of informed consent, then December 31 will be 
assigned to the missing fields. 
• If the year is after the year of the date of informed consent, then January 1 will be assigned to 
the missing fields. 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
Missing day only  
• If the month and year are the same as the month and year of the date of informed consent, 
then the date of informed consent will be assigned to the missing day. 
• If either the year is before the year of the date of informed consent or if both years are the 
same but the month is before the month of the date of informed consent, then the last day of 
the month will be assigned to the missing day. 
• If either the year is after the year of the date of informed consent or if both years are the same 
but the month is after the month of the date of informed consent, then the first day of the 
month will be assigned to the missing day. 
If the stop date is complete and it is before the date of randomization and the imputed start date 
as above is after the stop date, the start date will be imputed by the stop date. If the stop date is 
complete and it is on or after the date of randomization and the imputed start date as above is 
after the stop date, the start date will be imputed by the date immediately before the date of 
randomization. 
If the start date is completely missing, then the date of informed consent will be used to impute 
the start date. 


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b. If AEs occurred during the Treatment Period (i.e., the Treatment Period is identified on the 
AE eCRF) 
Missing day, month and year 
• If the entire AE start date is missing, then the start date of the Period identified on the AE 
eCRF page will be assigned to the missing fields 
Missing day and month 
• If the year is the same as the year of the date of the first dose of double-blind study drug, then 
the day and month of the date of the first dose of double-blind study drug will be assigned to 
the missing fields. 
• If the year is prior to the year of the date of the first dose of double-blind study drug, then 
December 31 will be assigned to the missing fields. 
• If the year is after the year of the date of the first dose of double-blind study drug, then 
January 1 will be assigned to the missing fields. 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
Missing day only 
• If the month and year are the same as the month and year of the date of the first dose of 
double-blind study drug, then the date of the first dose of double-blind study drug will be 
assigned to the missing day. 
• If either the year is before the year of the date of the first dose of double-blind study drug or 
if both years are the same but the month is before the month of the date of the first dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day. 
• If either the year is after the year of the date of the first dose of double-blind study drug or if 
both years are the same but the month is after the month of the date of the first dose of 
double-blind study drug, then the first day of the month will be assigned to the missing day. 
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, then the following algorithm 
is used to impute the start date: 
• If the stop date is after the date of the first dose of double-blind study drug, the date of the 
first dose of double-blind study drug will be assigned to the missing start date. 
• If the stop date is before the date of the first dose of double-blind study drug, the stop date 
will be assigned to the missing start date.  


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c. If AEs occurred during the RW Period (ie, the RW Period is checked on the AE eCRF) 
Missing day, month and year 
• If the entire AE start date is missing, then the start date of the Period identified on the AE 
eCRF page will be assigned to the missing fields. 
Missing day and month 
• If the year is the same as the year of the date of the first dose of double-blind study drug in 
the RW Period, the day and month of the date of the first dose of double-blind study drug in 
the RW Period will be assigned to the missing fields. 
• If the year is prior to the year of the date of the first dose of double-blind study drug in the 
RW Period, December 31 will be assigned to the missing fields. 
• If the year is after the year of the date of the first dose of double-blind study drug in the RW 
Period, January 1 will be assigned to the missing fields. 
9.10 
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS 
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or stop 
date will be imputed. When the start date and the stop date are both incomplete for a patient, 
impute the start date first. 
9.10.1 
Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day, month and year 
• If the start date is completely missing, then the date of the screening visit will be assigned to 
the missing field. 
Missing day and month 
• If the year of the incomplete start date is the same as the year of the date of the first dose of 
double-blind study drug, then the day and month of the date of the first dose will be assigned 
to the missing fields. 
• If the year of the incomplete start date is prior to the year of the date of the first dose of 
double-blind study drug, then December 31 will be assigned to the missing fields. 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 


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Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of double-blind study drug, then the day of the date of the first dose will 
be assigned to the missing day. 
• If either the year is before the year of the date of the first dose of double-blind study drug or 
if both years are the same but the month is before the month of the date of the first dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day. 
• If either the year is after the year of the date of the first dose of double-blind study drug or if 
both years are the same but the month is after the month of the date of the first dose of 
double-blind study drug, then the first day of the month will be assigned to the missing day. 
9.10.2 
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of double-blind study drug is missing, replace it with the last diary call date. If the imputed 
stop date is before the start date (imputed or non-imputed start date), then the imputed stop date 
will be equal to the start date. 
Missing day, month and year 
• If the stop date is completely missing, then the end of trial date will be assigned. 
Missing day and month 
• If the year of the incomplete stop date is prior to the year of the date of the last dose of 
double-blind study drug, then December 31 will be assigned to the missing fields. 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
Missing day only 
• If either the year is before the year of the date of the last dose of double-blind study drug or if 
both years are the same but the month is before the month of the date of the last dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day. 
9.11 
CHARACTER VALUES OF CLINICAL LABORATORY PARAMETERS 
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table, for example, due to it being a character string rather than a numerical type, a coded value 
needs to be appropriately determined and used in the statistical analyses. However, the actual 
values as reported in the database will be presented in data listings. 
Table 9.11-1 shows examples of how some possible laboratory results should be coded for the 
analysis. 


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Table 9.11-1 Examples of Coding Special Character Values for Clinical Laboratory 
Parameters 
Laboratory Test, 
SI Unit 
Possible Laboratory Results 
Coded Value for Analysis 
CHEMISTRY 
ALT, U/L 
< 5 
0 
AST, U/L 
< 5 
0 
Bilirubin, total, μmol/L 
< 2 
0 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités (International 
System of Units). 
 


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10.0 
REFERENCES 
 
1. Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons 
with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 
1998;43(2):400-11. 
2. Prevention CfDCa. Measuring Healthy Days: Population Assessment of Health-Related 
Quality of Life. Centers for Disease Control and Prevention [Internet]. 2000. Available from: 
https://www.cdc.gov/hrqol/pdfs/mhd.pdf. 
3. Ratitch, B., O'Kelly, M. and Tosiello, R. (2013), Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharmaceut. Statist., 
12: 337–347. doi: 10.1002/pst.1549  
4. Rubin DB (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons Ltd., 
New York. 
 
 


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APPENDIX 1:
BRISTOL STOOL FORM SCALE 
Type 1 - Separate hard lumps like nuts (difficult to pass) 
 
Type 2 - Like a sausage but lumpy 
Type 3 - Like a sausage but with cracks on the surface 
 
Type 4 - Like a sausage or snake, smooth and soft 
Type 5 - Soft pieces with clear-cut edges (easy to pass) 
 
Type 6 - Fluffy pieces with ragged edges, a mushy stool 
 
Type 7 - Watery, no solid pieces (entirely liquid) 
 


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APPENDIX 2: 
IBS-QOL 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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APPENDIX 3: 
CDC HRQOL-4 
Healthy Days Core Module (CDC HRQOL– 4) 
1. Would you say that in general your health is 
 
 
 
 
 
 
 
 
2. Now thinking about your physical health, which includes physical illness and injury, for how many 
days during the past 30 days was your physical health not good? 
 
 
 
 
 
3. Now thinking about your mental health, which includes stress, depression, and problems with 
emotions, for how many days during the past 30 days was your mental health not good? 
 
 
 
 
 
Please Read 
a. Excellent 1 
b. Very good 2 
c. Good 
3 
d. Fair 
4 
or 
e. Poor 
5 
 
Do not read these responses 
Don’t know/Not sure 
7 
Refused 
9 
 a. Number of Days _ _ 
 b. None 
8 8 
 Don’t know/Not sure 7 7 
Refused 
9 9 
 a. Number of Days _ _  
b. None 
8 8 
If both Q2 AND Q3 = “None,” skip next question 
 Don’t know/Not sure 7 7 
Refused 
9 9 


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4. During the past 30 days, for about how many days did poor physical or mental health keep you 
from doing your usual activities, such as self-care, work, or recreation? 
 
 
 
 
 
 
 a. Number of Days _ _ 
b. None 
8 8 
 Don’t know/Not sure 7 7 
Refused 
9 9