A Phase 2b, Randomized, Double-blind, Double-dummy, Placebo-controlled, Parallel-group, Dose-range-finding Study of Two Delayed Release Formulations of Linaclotide Administered Orally for 12 Weeks to Patients With Irritable Bowel Syndrome With Constipation
Phase: PHASE2
Conditions: Irritable Bowel Syndrome With Constipation
Sponsor: Ironwood Pharmaceuticals, Inc.

 
 
 
Clinical Study Protocol: MCP-103-204-P-03 
Final Version, 09 October 2015 
Study Title: 
A Phase 2b, Randomized, Double-blind, Double-dummy, Placebo-
controlled, Parallel-group, Dose-range-finding Study of Two Delayed 
Release Formulations of Linaclotide Administered Orally for 12 Weeks 
to Patients with Irritable Bowel Syndrome with Constipation 
Study Number: 
MCP-103-204 
Study Phase: 
2b 
Product Name: 
Linaclotide Delayed Release 
Indication: 
Irritable Bowel Syndrome with Constipation 
Sponsor: 
Ironwood Pharmaceuticals, Inc. 
301 Binney Street 
Cambridge, MA 02142 
Sponsor Contact: 
Nick Omniewski, MPH 
Clinical Study Manager 
Ironwood Pharmaceuticals, Inc. 
Phone:  (617) 621-8454 
e-mail:  nomniewski@ironwoodpharma.com 
 
 
Date 
Original Protocol: 
20 July 2015 
Amendment #1: 
17 August 2015 
Amendment #2: 
09 October 2015 
 
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 
Study Number: 
MCP-103-204 
Study Title: 
A Phase 2b, Randomized, Double-blind, Double-dummy, Placebo-controlled, Parallel-group, 
Dose-range-finding Study of Two Delayed Release Formulations of Linaclotide Administered 
Orally for 12 Weeks to Patients with Irritable Bowel Syndrome with Constipation  
Study Centers: 
Approximately 80 in the United States 
Development Phase: 2b 
Objective(s):  
The objectives of this study are to evaluate the safety, efficacy, and dose response of two 
different delayed release formulations of linaclotide (DR; DR formulation 1 is DR1; DR 
formulation 2 is DR2) administered orally to patients with irritable bowel syndrome with 
constipation (IBS-C). 
 
 
Methodology: 
This is a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-
group, multiple-dose, 12-week study, consisting of 3 distinct periods, as illustrated in the figure 
below. The study will enroll patients who have IBS-C diagnosed using Rome III criteria. Eligible 
patients will be randomized in equal proportions to one of 8 treatments: 30 µg, 100 µg, or 300 µg 
of the linaclotide DR1 formulation; 30 µg, 100 µg, or 300 µg of the linaclotide DR2 formulation; 
290 µg of the IR formulation of linaclotide (stated as linaclotide IR throughout); or placebo. 
Linaclotide IR is being included in the study as a positive control, against which the safety and 
efficacy of the various doses of the two test formulations can be compared. 
 
 
 
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Overview of Study Design
Study Periods
1. Screening Period: The Screening Period starts with the signature of the informed consent 
form (ICF; Appendix I) 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. 
2. Pretreatment Period: The Pretreatment Period is defined as the 14 to 21 calendar 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 a daily evening report
-
Weekly Patient Assessment of Constipation Severity
-
Weekly Patient Assessment of IBS Symptom Severity
-
Weekly Patient Assessment of Adequate Relief
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 12/
End-of-Treatment 
Period Visit**
(Day 85 + 3)
100 µg Linaclotide DR1 tablet and Placebo capsule
Placebo tablet and Placebo capsule
No Treatment
Note: there is no Day 0.
*Applicable to a subset of patients (See 
Follow-up Phone Call Section)
**This visit represents the end of the study
30 µg Linaclotide DR1 tablet and Placebo capsule
300 µg Linaclotide DR1 tablet and Placebo capsule
100 µg Linaclotide DR2 tablet and Placebo capsule
290 µg Linaclotide IR capsule and Placebo tablet
300 µg Linaclotide DR2 tablet and Placebo capsule
30 µg Linaclotide DR2 tablet and Placebo capsule
Follow-up
Call*
(Day 3)
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-
Use of Per-protocol Rescue Medicine or Any Other Laxatives, Suppositories, or 
Enemas on an event-driven basis
Patients who satisfy all of the 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 one of 8 treatments: 30 µg, 100 µg, or 
300 µg of linaclotide DR1; 30 µg, 100 µg, or 300 µg of linaclotide DR2; 290 µg of 
linaclotide IR; or placebo. 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 (Daily BM-related Symptom-severity Assessments on an event-
driven basis, and Daily Abdominal Symptom-severity Assessments in a daily evening 
report), weekly assessments (Weekly Patient Assessment of Constipation Severity,
Weekly Patient Assessment of IBS Symptom Severity, and Weekly Patient Assessment 
of Adequate Relief), and Use of Per-protocol Rescue Medicine or Any Other Laxatives, 
Suppositories, or Enemas on an event-driven basis. Quality-of-life and patient-outcome 
assessments will be performed at study visits throughout the Treatment Period. A list of 
these assessments and the visits when they will be performed is provided in the Study 
Procedures section below. Patients will complete a Week 4 Visit, Week 8 Visit, and 
Week 12/End of Treatment Visit during the Treatment Period. (See Schedule of 
Evaluations) Appropriate site personnel will complete a follow-up phone call to patients 
within 48 hours following initial study drug administration to assess for developing AEs. 
The Sponsor will perform a blinded review of the safety information obtained from the 
first 40 follow-up phone calls, and determine whether follow-up phone calls to patients 
should continue or be discontinued. (See Follow-up Phone Call Section)
Study Procedures
During the Pretreatment and Treatment 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:
•
Daily BM-related Symptom-severity Assessments
-
The following information will be entered by the patient for each BM on an event-driven 
basis:
◦
BM day and time
◦
Association with a sense of a complete evacuation
◦
Stool consistency on the Bristol Stool Form Scale (BSFS) 
◦
Straining on a 5-point ordinal scale
◦
Stool consistency on a 5-point ordinal scale
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•
Daily Abdominal Symptom-severity Assessments
-
The following information will be entered by the patient in a daily evening report:
◦
Rating of abdominal pain at its worst during the previous 24 hours on a 0-to-10 point 
NRS 
◦
Rating of abdominal discomfort at its worst during the previous 24 hours on a 0-to-10 
point NRS
◦
Rating of abdominal bloating at its worst during the previous 24 hours on a 0-to-10 
point numerical rating scale (NRS)
•
Use of Per-protocol Rescue Medicine or Any Other Laxatives, Suppositories, or Enemas on 
an event-driven basis
Weekly Assessments: The following information will be entered by the patient into the eDiary 
each week at the same time as the daily evening report:
•
Weekly Patient Assessment of Constipation Severity
•
Weekly Patient Assessment of IBS Symptom Severity
•
Weekly Patient Assessment of Adequate Relief
Study Visit Assessments: The following information will be captured on the eDiary at visits 
during the Treatment Period: 
•
Short Form-12 Health Survey version 2 (SF-12v2, captured at the Randomization Visit 
before the first dose of study drug and at all subsequent study visits)
•
EuroQol-5 Dimension (EQ-5D, captured at the Randomization Visit before the first dose of 
study drug and all subsequent study visits)
•
Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2, captured at the Randomization Visit 
before the first dose of study drug and at all subsequent study visits)
•
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS, captured at the 
Randomization Visit before the first dose of study drug and at the Week 4 Visit)
•
Treatment Satisfaction Assessment (captured at the Week 4 Visit and all subsequent study 
visits)
Concomitant Medicine
•
Rescue Medicine: During the Pretreatment and Treatment 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 
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symptoms become intolerable. In order to qualify for randomization into the Treatment 
Period, patients must not have used Rescue Medicine on the calendar 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 calendar day after randomization.
•
Prohibited Medicine: Medicines that are not permitted during the Pretreatment and Treatment 
Periods are listed in Appendix II.
Number of Patients:
Approximately 520 IBS-C patients (65 patients per treatment group) will be randomized into the 
Treatment Period.
Diagnosis and Main Criteria for Inclusion:
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
1. Patient has signed an ICF.
2. Patient is ambulatory and community-dwelling (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. Sexually active female patients of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a bilateral oophorectomy, hysterectomy, or tubal 
ligation) 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 (i.e., oral contraceptive, contraceptive implant, or injectable 
hormonal contraceptive)
b. Double-barrier birth control (e.g., condom plus intrauterine device, diaphragm plus 
spermicide, etc.)
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 defined by the American Gastroenterological 
Association guidelines and described in Appendix III. (Note: Patients are eligible to enter 
the Pretreatment Period on the fifth calendar day after a colonoscopy.)
6. Patient has no clinically significant concurrent illness or findings on a physical examination 
and 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: 
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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 study, could represent a safety 
concern if the patient participates in the study, or could confound the study-specified 
assessments of safety or efficacy.)
7. 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.
Relieved 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 or lubiprostone.
8. 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.
9. 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, 
lubiprostone, polyethylene glycol 3350, or any laxative.
10. 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 calendar days before 
the Randomization Visit and the calendar day of Randomization up to the time when the 
data entry into the eDiary is made in clinic.
11. Patient reports ≤6 complete spontaneous BMs (CSBMs) and ≤ 10 spontaneous BMs 
(SBMs) in the eDiary over the 14 calendar days before the Randomization Visit and the 
calendar day of Randomization up to the time when the data entry into the eDiary is made 
in clinic. (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 concomitant medicine use via the eDiary.)
12. Patient is compliant (as defined in the study procedures section below) with eDiary 
completion by adequately responding to eDiary questions on 10 or more of the 14 calendar 
days before the Randomization Visit.
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13. Patient is willing to discontinue any laxatives used before the Pretreatment Visit in favor of 
the protocol-defined Rescue Medicine (bisacodyl tablets or suppositories).
14. Patient is fluent in English or Spanish.
15. Patient is able to operate the eDiary adequately.
16. Patient agrees to refrain from making any new, major life-style changes that may affect 
IBS-C symptoms (e.g., starting a new diet or changing his or her exercise pattern) from the 
time of signature of the ICF to the last study visit.
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the study:
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 II) for > 
25% of BMs during the 12 weeks before the Screening Visit.
2. Patient has a structural abnormality of the gastrointestinal (GI) tract or a disease or 
condition that can affect GI motility.
3. Patient has ever had a diagnosis or family history of familial adenomatous polyposis, 
hereditary nonpolyposis colorectal cancer, or any other form of familial colorectal cancer.
4. Patient has ever had a diagnosis of inflammatory bowel disease (IBD).
5. Patient currently has unexplained and clinically significant alarm symptoms (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 (i.e., disease that is not adequately treated 
or stable with therapy).
7. Patient has a history of diverticulitis or any chronic condition (e.g., chronic pancreatitis, 
polycystic kidney disease, ovarian cysts, endometriosis) that can be associated with 
abdominal pain or discomfort and could confound the assessments in this study, unless the 
patient is considered to have been cured of the condition.
8. Patient has a potential central nervous system cause of constipation (e.g., 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).
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11. 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
12. 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 provided that 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.)
13. Patient has a history of diabetic neuropathy.
14. 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.
15. 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 as long as they 
have exhibited no actual abuse during the 12 months before the Randomization Visit.)
16. Patient reports a BSFS score of 6 (loose, mushy stools) for > 1 SBM or a BSFS score of 7 
(watery stools) with any SBM over the 14 calendar days before the Randomization Visit
and the calendar day of Randomization up to the time when data is entered into the eDiary 
in the clinic.
17. Patient used Rescue Medicine (bisacodyl tablet or suppository) or any other laxative, 
suppository, or enema, on the calendar day before or the calendar day of the 
Randomization Visit.
18. 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 II. (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 study.)
19. Patient has been hospitalized for a psychiatric condition or has made a suicide attempt 
during the two years before the Randomization Visit.
20. Patient has taken commercially available linaclotide or participated in a linaclotide, 
plecanatide, or SP-333 clinical study during the 30 days before the Screening Visit.
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21. Patient has received an investigational drug during the 30 days before the Screening Visit 
or is planning to receive an investigational drug (other than that administered during this 
study) or use an investigational device at any time during the study.
22. 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 study.
23. Patient has previously entered the Pretreatment Period of this study.
24. Patient is directly or indirectly involved in the conduct and administration of this study as 
an investigator, subinvestigator, study coordinator, other study staff member, or employee 
of Ironwood Pharmaceuticals, Forest Laboratories, Actavis, Inc., or Allergan, Inc.; 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 study; or the patient is enrolled in 
this study at another clinical study site.
Test Products, Dosage, and Mode of Administration:
Test products will be administered in a double-dummy manner as follows:
•
30 µg linaclotide DR1 oral tablet and a placebo oral capsule (matching the 290 µg 
linaclotide IR oral capsule) administered once daily in the morning at least 30 minutes 
before breakfast
•
100 µg linaclotide DR1 oral tablet and a placebo oral capsule administered once daily in 
the morning at least 30 minutes before breakfast
•
300 µg linaclotide DR1 oral tablet and a placebo oral capsule administered once daily in 
the morning at least 30 minutes before breakfast
•
30 µg linaclotide DR2 oral tablet and a placebo oral capsule administered once daily in the 
morning at least 30 minutes before breakfast
•
100 µg linaclotide DR2 oral tablet and a placebo oral capsule administered once daily in 
the morning at least 30 minutes before breakfast
•
300 µg linaclotide DR2 oral tablet and a placebo oral capsule administered once daily in 
the morning at least 30 minutes before breakfast
Reference Therapy, Dosage, and Mode of Administration:
The reference therapy will be administered in a double-dummy manner as follows:
•
290 µg linaclotide IR oral capsule and a placebo oral tablet (matching the DR1 and DR2 
oral tablet) administered once daily in the morning at least 30 minutes before breakfast
•
Placebo oral capsule and a placebo oral tablet administered once daily in the morning at 
least 30 minutes before breakfast
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Duration of Treatment:
The test product and reference therapy will be administered for 12 weeks. Total patient 
participation is expected to last for up to 130 days.
Criteria for Evaluation:
Key Efficacy Assessments
The following efficacy assessments based on the eDiary questions are used to determine the key 
efficacy parameters: number of BMs and whether the BM is an SBM or CSBM, and daily patient 
assessment of abdominal pain over the last 24 hours (11-point NRS).
Other Efficacy Assessments
Other efficacy assessments are based on stool consistency as measured by the BSFS scale and on 
a 5-point ordinal scale; straining as measured on a 5-point ordinal scale (1 = Not at all, 5 = An 
extreme amount); and daily patient assessments of abdominal discomfort and abdominal 
bloating, each on an 11-point NRS. In addition, the Weekly Patient Assessment of Constipation 
Severity, the Weekly Patient Assessment of IBS Symptom Severity, and the Weekly Patient 
Assessment of Adequate Relief will be evaluated.
Safety Measure(s):
AE recording (each visit), clinical laboratory measures (chemistry and hematology: Screening, 
Randomization, and End-of-Treatment Period Visits), vital sign parameters (each visit).  Note: 
Urinalysis and electrocardiograms will not be obtained in this study.
Statistical Methods:
Analysis Populations
The Intent-to-Treat (ITT) Population consists of all randomized patients who received at least 
one dose of study drug. The Safety Population is defined identically to the ITT Population.
General Methods
Efficacy analyses will be performed on the ITT Population. Unless otherwise specified, all 
confidence intervals will be two-sided and with a confidence level of 95%. No adjustments will 
be made for multiplicity in the conduct of comparisons among the linaclotide DR doses for the 
key efficacy parameters, or in the testing of the other efficacy parameters.
For analysis of continuous parameters (e.g., change from baseline), descriptive statistics (n, 
mean, standard deviation, median, and range) will be calculated and presented for each treatment 
group. For categorical parameters (e.g., responder vs. non-responder), the number and 
percentage of each category will be calculated and presented for each treatment group.
Key Efficacy Parameters
•
The Weekly Change from Baseline in Abdominal Pain
•
The Weekly Change from Baseline CSBM Frequency
•
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. The Weekly APC +1 
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Responder criteria are defined below.
Key Efficacy Analysis
For each continuous weekly change-from-baseline measure defined above, inferential testing of 
the change from baseline will be evaluated employing a mixed model with repeated measures 
(MMRM) framework with week (categorical), treatment, and week-by-treatment fixed effects, 
patient as the random effect, and baseline value as a covariate. The initial covariance structure 
will be compound symmetry but exploratory analyses with unstructured and autoregressive (1) 
structures will also be considered, primarily for planning purposes.
Corresponding with the primary efficacy objective of the study, which is to study the dose 
response of a range of oral doses within the linaclotide DR1 and DR2 formulations, the efficacy 
analysis of weekly change from baseline will be conducted by employing an overall trend test 
(i.e., linear contrast) for each formulation to test for a monotonically increasing dose response. 
Within a formulation, if the overall trend test reaches statistical significance (α = 0.05), then that 
linaclotide DR formulation will be considered efficacious and the nature of the dose response 
will be explored among the individual linaclotide DR doses within the formulation. 
 
 
The efficacy analysis of 6/12 Week APC+1 Responder rate will be confirmatory of the above 
and conducted by employing an overall trend test (i.e., Cochran-Mantel-Haenszel [CMH] 
correlation statistic) for each formulation (excluding the Active Control [linaclotide IR]) to test 
for a monotonically increasing dose response within the formulation. If the overall CMH statistic 
reaches statistical significance (α = 0.05), the tested formulation will be considered efficacious 
and the nature of the dose response will be explored among the individual linaclotide DR doses 
within the formulation. 
Other Efficacy Parameters
•
6/12 Week CSBM +1 Responder: A 6/12 Week CSBM +1 Responder is a patient who 
meets the Weekly CSBM +1 Responder criteria for at least 6 out of the 12 weeks of the 
Treatment Period. The Weekly CSBM +1 Responder criteria are defined below.
•
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. The Weekly Abdominal Pain Responder criteria are 
defined below.
•
Weekly CSBM +1 Responder: For each week in the Treatment Period, a Weekly CSBM 
+1 Responder is a patient who has an increase from baseline of at least 1 in the CSBM 
weekly rate for that week. 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 +1 Responder for that week.
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•
Weekly Abdominal Pain Responder: For each week in the Treatment Period, a Weekly 
Abdominal Pain Responder is a patient who has a decrease from baseline of at least 30% in 
the mean abdominal pain score for that week. 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.
•
Weekly APC +1 Responder: For each week in the Treatment Period, a Weekly APC +1 
Responder is a patient who meets the criteria to be a Weekly CSBM +1 Responder and a 
Weekly Abdominal Pain Responder. 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 APC +1 Responder for that week.
•
Change from Baseline in 12-week Abdominal Pain
•
Change from Baseline in 12-week CSBM Frequency Rate 
•
Change from Baseline in 12-week SBM Frequency Rate
•
Change from Baseline in 12-week Stool Consistency
•
Change from Baseline in 12-week Straining
•
Change from Baseline in 12-week Abdominal Discomfort
•
Change from Baseline in 12-week Abdominal Bloating
•
Change from Baseline in 12-week Constipation Severity
•
Change from Baseline in 12-week Abdominal Symptom Score
•
Change from Baseline in 12-week IBS Symptom Severity
Other Efficacy Analysis
All categorical responder parameters (e.g., Weekly CSBM +1 Responder) will be analyzed 
utilizing the same methods defined above for the key efficacy measure 6/12 Week APC +1 
Responder.
All continuous change-from-baseline in 12-week efficacy parameters will be evaluated by 
comparing each DR1 and DR2 dose with the placebo group using an analysis of covariance 
(ANCOVA) model with treatment group and geographic region as fixed-effect terms and 
baseline value as a covariate. Least-squares means for each treatment group, least-squares mean 
differences between each DR1 and DR2 dose and the placebo group and their corresponding 
confidence intervals, and p-values for the pairwise comparisons versus placebo will be presented. 
Safety Analysis
All safety parameters will be analyzed descriptively in accordance with the General Methods.
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Sample Size
The sample size per treatment group was determined based on a one-way design and includes 
8 treatments: placebo; 30 µg, 100 µg, or 300 µg of the linaclotide DR1 formulation; 30 µg, 
100 µg, or 300 µg of the linaclotide DR2 formulation; and the approved 290 µg dose of the 
linaclotide IR formulation. Previous trials with linaclotide IR demonstrated treatment differences 
with respect to Change from Baseline in 12-week Abdominal Pain of 0.78 (-1.196 vs. -1.975 for 
placebo and linaclotide IR, respectively), and a standard deviations of 1.73 (based on the root 
mean squared error from an ANCOVA adjusting for baseline pain). Based on these historical 
values, it was estimated that, within each formulation, the highest two active treatment groups 
(DR1 100 µg and 300 µg; DR2 100 µg and 300 µg) would reflect the previously observed 
treatment difference (-1.975), the lowest active treatment groups with each formulation (DR1 
30 µg; DR2 30 µg) would reflect 50% of the observed treatment difference (-1.586), and placebo 
would reflect the previously observed difference (-1.196). Under these assumptions, a study with 
65 patients per treatment group (520 total patients) will have 81% power based on a 2-sided 
linear trends test within each formulation (linear contrast: -3 (placebo) -1 (30 µg) 1 (100 µg) 3 
(300 µg); IR formulation not included) at an alpha level of 0.05. In addition, subsequent pairwise 
comparison between placebo and the active treatment groups reflecting the previously observed 
treatment difference will have 73% statistical power (two-sided, α = 0.05).
Date of Original Protocol: 20 July 2015
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Schedule of Evaluations MCP-103-204
Screening 
Period
(Up to 21 
days)
Pretreatment 
Period
(14 to 21 
days)
Treatment Period
(12 weeks)
Visit Days →
Screening 
Visit
(Day -42 
through 
Day -15)
Pretreatment 
Visit
(Day -21 to 
Day -14)
Randomization 
Visit
(Day 1)
Follow-up 
Call
(Day 3)
Week 4 Visit
(Day 29±3)
Week 8 Visit
(Day 57±3)
Week 12/End-of-
Treatment Period Visit o
(Day 85+3)
Visit Numbers →
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Study Procedure ↓
Signature of ICF
X
Inclusion and Exclusion 
Criteria Verification
X
X
X
IWRS Registration a
X
X
X
X
X
X
Medical History
X
Physical Examination b
X
X
Body Weight and Height c
X
X
X
X
X
X
Seated Vital Signs d
X
X
X
X
X
X
Prior and Concomitant 
Medicines e
X
X
X
X
X
X
Clinical Laboratory Tests f
X
X
X
Pregnancy Test g
X
X
X
Laxative/Suppository/Enema 
Washout Instructions h
X
AE Evaluations i
X
X
X
X
X
X
eDiary Registration and 
Training j
X
X
X
X
X
Daily and Weekly 
Assessments k
X
X
X
X
X
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Schedule of Evaluations MCP-103-204
Screening 
Period
(Up to 21 
days)
Pretreatment 
Period
(14 to 21 
days)
Treatment Period
(12 weeks)
Visit Days →
Screening 
Visit
(Day -42 
through 
Day -15)
Pretreatment 
Visit
(Day -21 to 
Day -14)
Randomization 
Visit
(Day 1)
Follow-up 
Call
(Day 3)
Week 4 Visit
(Day 29±3)
Week 8 Visit
(Day 57±3)
Week 12/End-of-
Treatment Period Visit o
(Day 85+3)
Visit Numbers →
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Study Procedure ↓
eDiary Compliance 
Verification and Reminder l
X
X
X
X
Rescue Medicine Dispensed m
X
X
X
X
Patient eDiary Entry, in Clinic
X
X
X
X
Randomization
X
SF-12v2
X
X
X
X
EQ-5D
X
X
X
X
SF-MPQ-2
X
X
X
X
IBS-SSS
X
X
Treatment Satisfaction 
Assessment
X
X
X
Study Drug Dispensed
X
X
X
Study Drug Administration n
X
Study Drug Accountability
X
X
X
a.
Site personnel will interact with IWRS to register the patient visit. Refer to the IWRS User Manual.
b.
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 
Screening Period on all patients who do not require a colonoscopy (refer to Appendix III). 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.
c.
Height is measured only at the Screening Visit.
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d.
Vital signs must be obtained in the seated position and include oral temperature, respiratory rate, blood pressure, and pulse.
e.
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 history of 
using particular treatments for IBS-C and CIC (see Section 5.4.7 Concomitant Medicines).
f.
Chemistry, CBC, and drug screen. The urine drug screen will be performed at the Screening Visit only.
g.
To be eligible to continue in the study, a negative serum pregnancy test must be documented at the Screening Visit. A negative urine pregnancy test must be 
documented at the Randomization Visit (prior to dosing), and a negative serum pregnancy test must be documented at the Week 12/End-of-Treatment Period 
(EOT) Visit.
h.
Study coordinator will instruct patients about the use of laxatives, suppositories, and enemas (refer to Appendix II).
i.
All AEs occurring after the patient signs the ICF will be captured. Appropriate site personnel will complete a follow-up phone call to patients within 48 
hours following initial study drug administration to assess for developing AEs. The Sponsor will perform a blinded review of the safety information obtained 
from the first 40 follow-up phone calls, and determine whether follow-up phone calls to patients should continue or be discontinued. (See Follow-up Phone 
Call Section)
j.
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.
k.
An eDiary will be used for recording Daily BM-related Symptom Severity Assessments, Daily abdominal Symptom-severity Assessments, Weekly 
Assessments, EQ-5D, Treatment Satisfaction, Assessment, SF-MPQ-2, SF-12-v2, IBS-SSS, and any use of rescue medicine. Patients will enter BMs and 
rescue medicine in the eDiary on an event-driven basis, and will complete an evening entry each day to record daily assessments.
l.
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 EOT visit). (eDiary questions may be found in the eDiary User Manual.)
m. 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.
n.
Study drug will be administered in the clinic at the Randomization Visit (study drug does not need to be taken in the morning before breakfast). 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.
o.
Patients who are randomized but do not complete the Treatment Period (withdraw consent or are discontinued before they have completed 12 weeks of 
treatment), will be considered Treatment Period withdrawals and should complete the procedures required at the EOT Visit (even if out of window).
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STUDY IDENTIFICATION
Sponsor
Ironwood Pharmaceuticals, Inc.
301 Binney Street
Cambridge, MA 02142
(617) 621-7722 (Main Telephone)
(617) 494-0908 (Main Fax)
http://www.ironwoodpharma.com
Medical Monitor
B. Joseph Lavins, MD
Senior Director, Clinical Research
Ironwood Pharmaceuticals, Inc.
Phone:  (617) 621-8431
Mobile:  (617) 909-6508
e-mail:  bjlavins@ironwoodpharma.com
Safety Officer
Karel Van Loon, MD
Senior Director, Clinical Safety & Pharmacovigilance
Ironwood Pharmaceuticals, Inc.
Phone:  (617) 374-3909
Mobile:  (510) 364-7010
e-mail:  kvanloon@ironwoodpharma.com
Contract Research 
Organization (CRO) 
Contact
Pamalar Lewis
Project Manager
PPD
980 Harvest Drive, Suite 130
Blue Bell, PA 19422-1955
Phone:  (910) 558-1955
Mobile:  (609) 922-8231
Fax:  (856) 457-4753
e-mail:  Pamalar.Lewis@ppdi.com
Clinical Laboratory(ies) 
Denise Elliot
Associate Project Manager
PPD Global Central Labs
2 Tesseneer Drive
Highland Heights, KY  41076
Phone:  (859) 815-6224
Mobile:  (859) 490-9741
e-mail:  Denise.Elliot@ppdi.com
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Ironwood Contact 
Nick Omniewski, MPH
Clinical Study Manager
Ironwood Pharmaceuticals, Inc.
Phone:  (617) 621-8454
e-mail:  nomniewski@ironwoodpharma.com
Serious Adverse Event 
(SAE) Email
Wilsafety@ppdi.com
Dedicated SAE Facsimile 
Number
1 888 488 9697
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TABLE OF CONTENTS
SYNOPSIS .................................................................................................................................2
LIST OF ABBREVIATIONS....................................................................................................26
1.
ETHICAL CONSIDERATIONS.......................................................................................28
1.1
INSTITUTIONAL REVIEW BOARD.....................................................................28
1.2
PATIENT INFORMATION AND CONSENT ........................................................28
2.
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE...........................29
3.
INTRODUCTION.............................................................................................................30
4.
STUDY OBJECTIVES .....................................................................................................34
5.
INVESTIGATIONAL PLAN............................................................................................35
5.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION..................................35
5.1.1
Study Periods.................................................................................................37
5.1.1.1
Screening Period...................................................................................37
5.1.1.2
Pretreatment Period ..............................................................................37
5.1.1.3
Treatment Period..................................................................................38
5.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS..............................................................................................38
5.3
SELECTION OF STUDY POPULATION ..............................................................39
5.3.1
Inclusion Criteria............................................................................................39
5.3.2
Exclusion Criteria ..........................................................................................41
5.3.3
Removal of Patients From Therapy or Assessment.........................................43
5.3.4
Replacement Procedures ................................................................................44
5.4
TREATMENTS.......................................................................................................44
5.4.1
Treatments Administered ...............................................................................44
5.4.2
Identity of Investigational Product..................................................................45
5.4.3
Method of Assigning Patients to Treatment Groups........................................46
5.4.4
Selection of Dosage in the Study....................................................................47
5.4.5
Selection and Timing of Dose for Each Patient...............................................47
5.4.6
Blinding .........................................................................................................48
5.4.7
Concomitant Medicines..................................................................................48
5.4.8
Treatment Compliance ...................................................................................49
5.5
EFFICACY AND SAFETY VARIABLES ..............................................................49
5.5.1
Schedule of Evaluations .................................................................................49
5.5.2
Efficacy Measurements ..................................................................................61
5.5.2.1
Key Efficacy Assessments....................................................................61
5.5.2.2
Other Efficacy Assessments..................................................................62
5.5.2.3
Health Outcomes Assessments..............................................................67
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5.5.3
Safety Assessments ........................................................................................68
5.5.3.1
Adverse Events.....................................................................................68
5.5.3.2
Serious Adverse Events ........................................................................70
5.5.3.3
Clinical Laboratory Determinations......................................................73
5.5.3.4
Vital Signs............................................................................................74
5.5.3.5
Other Safety Assessments.....................................................................75
5.6
DATA QUALITY ASSURANCE............................................................................75
5.6.1
Data Monitoring.............................................................................................75
5.6.2
Data Recording and Documentation...............................................................76
5.7
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........76
5.7.1
Analysis Populations......................................................................................76
5.7.1.1
ITT Population .....................................................................................76
5.7.1.2
Safety Population .................................................................................76
5.7.2
General Methods............................................................................................77
5.7.3
Patient Disposition .........................................................................................77
5.7.4
Demographics and Other Baseline Characteristics..........................................77
5.7.5
Prior and Concomitant Medicines...................................................................78
5.7.6
Extent of Exposure and Treatment Compliance..............................................78
5.7.6.1
Exposure to Study Drug........................................................................78
5.7.6.2
Measurement of Treatment Compliance................................................78
5.7.6.3
eDiary Compliance...............................................................................79
5.7.7
Efficacy Analyses ..........................................................................................79
5.7.7.1
Key Efficacy Parameters ......................................................................80
5.7.7.2
Key Efficacy Analysis ..........................................................................81
5.7.7.3
Other Efficacy Parameters ....................................................................82
5.7.7.4
Other Efficacy Analyses .......................................................................84
5.7.8
Health Outcomes Analyses.............................................................................85
5.7.8.1
SF-12v2................................................................................................85
5.7.8.2
EQ-5D..................................................................................................85
5.7.8.3
SF-MPQ-2............................................................................................85
5.7.8.4
Irritable Bowel Syndrome-Symptom Severity Scale .............................86
5.7.9
Safety Analyses..............................................................................................86
5.7.9.1
Adverse Events.....................................................................................86
5.7.9.2
Clinical Laboratory Parameters.............................................................87
5.7.9.3
Vital Signs............................................................................................87
5.7.10
Interim Analysis.............................................................................................88
5.7.11
Development of Scoring and Psychometric Analysis......................................88
5.7.12
Determination of Sample Size ........................................................................89
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5.8
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES...89
6.
STUDY SPONSORSHIP ..................................................................................................90
6.1
STUDY TERMINATION........................................................................................90
6.2
REPORTING AND PUBLICATION.......................................................................90
7.
INVESTIGATOR OBLIGATIONS...................................................................................91
7.1
DOCUMENTATION ..............................................................................................91
7.2
PERFORMANCE....................................................................................................91
7.3
USE OF INVESTIGATIONAL MATERIALS ........................................................92
7.4
CASE REPORT FORMS.........................................................................................92
7.5
RETENTION AND REVIEW OF RECORDS.........................................................92
7.6
PATIENT CONFIDENTIALITY.............................................................................93
8.
SPONSOR SIGNATURES................................................................................................94
9.
INVESTIGATOR’S STATEMENT ..................................................................................95
10. APPENDICES ..................................................................................................................96
11. LITERATURE CITED....................................................................................................116
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LIST OF IN-TEXT TABLES
Table 1.
Schedule of Evaluations.................................................................................50
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LIST OF IN-TEXT FIGURES
Figure 1.
Overview of Study Design .............................................................................36
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LIST OF APPENDICES
Appendix I
Elements of Informed Consent .......................................................................97
Appendix II
Concomitant and Prohibited Medicines ..........................................................99
Appendix III
Summary of American Gastroenterological Association Guidelines .............102
Appendix IV
Bristol Stool Form Scale ..............................................................................103
Appendix V
Key efficacy assessments .............................................................................104
Appendix VI       Other efficacy assessments...........................................................................105
Appendix VII
SF-12v2 .......................................................................................................108
Appendix VIII
EQ-5D Questionnaire...................................................................................111
Appendix IX
Short-Form McGill Pain Questionnaire-2.....................................................113
Appendix X
Irritable Bowel Syndrome-Symptom Severity Scale.....................................114
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LIST OF ABBREVIATIONS
AE
adverse event/experience
ANCOVA
analysis of covariance
ANOVA
analysis of variance
APC
Abdominal Pain and Constipation
BM
bowel movement
BP
blood pressure
BSFS
Bristol Stool Form Scale
CIC
chronic idiopathic constipation
CBC
complete blood count
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
DR1
delayed release formulation 1
DR2
delayed release formulation 2
eCRF
electronic case report form
EDC
electronic data capture
eDiary
electronic diary
EOT
End of Treatment Period
EQ-5D
EuroQol-5 Dimension
FDA
Food and Drug Administration
GC-C
guanylate cyclase-C
GCP
good clinical practice
GI
gastrointestinal
HEENT
head, ears, eyes, nose, and throat
HIPAA
Health Insurance Portability and Accountability Act
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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
IBS-SSS
irritable bowel syndrome – symptom severity scale
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
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model with repeated measures
NDA
New Drug Application
NRS
numerical rating scale
PCS
potentially clinically significant
PID
patient identification
QOL
quality of life
SAE
serious adverse event
SAP
statistical analysis plan
SBM
spontaneous bowel movement
SD
standard deviation
SF-12v2
Short Form-12 Health Survey version 2
SOC
system organ class
TEAE
treatment-emergent adverse event
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1.
ETHICAL CONSIDERATIONS
This clinical study is designed to comply with the International Conference on Harmonisation 
(ICH) Guidance on General Considerations for Clinical Trials (62 Code of Federal Regulations 
[CFR] 66113, December 17, 1997) and Good Clinical Practice (GCP): Consolidated Guidance 
(62 CFR 25692, May 9, 1997). The study 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 and 21 CFR § 312.120.
1.1
INSTITUTIONAL REVIEW BOARD
Obtaining approval by the Institutional Review Board (IRB) prior to the start of the study 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 study, the investigator will provide timely and 
accurate reports to the IRB on the progress of the study, 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 study protocol (and any amendments), Informed 
Consent Form (ICF; Appendix I), and associated documentation will be approved by the IRB 
prior to study initiation, in compliance with CFR, Title 21, Part 56.
1.2
PATIENT INFORMATION AND CONSENT
Before entry into the study, patients will be provided with a written explanation of the study 
describing the nature of the study, as well as its purpose, expected duration, and the benefits and 
risks involved in study participation. Patients will then be given the opportunity to ask questions 
and will be informed of their right to withdraw from the study without prejudice. After this 
explanation and before entering the study, 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 study, the ICF will be revised. 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 study will be performed at approximately 80 study centers in the US. The investigator at the 
study center will be responsible for ensuring that the study 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 study, which 
will consist of completing all protocol assessments, maintaining the study file and the patient 
records, drug accountability, corresponding with the IRB, and completing the electronic case 
report forms (eCRFs).
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3.
INTRODUCTION
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 III guidelines. 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)
Patients with IBS have increased visceral hypersensitivity and disregulated intestinal peristalsis. 
Abdominal pain in IBS is most often reported as lower left quadrant pain.(8) Patients with IBS 
have also demonstrated increased rectal hypersensitivity to balloon distension.(9) Therefore, it is 
hypothesized that abdominal pain in IBS patients originates, at least in part, in the colon and 
rectum.
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. It is the first approved GC-C agonist. 
As a GC-C agonist, linaclotide and its active metabolite improve bowel symptoms and 
abdominal pain via localized effects of cyclic guanosine monophosphate (cGMP) on the 
intestinal mucosa. Linaclotide induces fluid secretion in two ways: 1) by increasing intracellular 
cGMP leading to cystic fibrosis transmembrane conductance regulator (CFTR) channels and 
chloride secretion that results in net sodium and water movement into the intestinal lumen;(10)
and 2) by inhibiting sodium reabsorption in the colon.(11) 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 pain in animal models and in patients with IBS-C.(12) 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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The FDA-approved linaclotide immediate release (IR) formulation (LINZESS®) is a rapidly 
dissolving capsule, and dissolution tests suggest that it is released primarily in the stomach. 
Although GC-C is found throughout the GI tract, LINZESS® IR and its active metabolite likely 
have their greatest activity in the proximal region of the small intestine, as experiments 
conducted with rodent intestinal fluid have shown that both linaclotide and its metabolite are 
degraded into smaller peptide fragments and amino acids in the reducing environment of the 
small intestine.(13) Some linaclotide or its active metabolite can traverse the entire GI tract; in a 
Phase 1 clinical study with LINZESS®, up to 5% of the oral dose was recovered in the feces of 
healthy volunteers, in the form of the active metabolite. However, the amount of linaclotide 
and/or its metabolite reaching different regions of the GI tract following oral administration of 
LINZESS® is not known. A delayed release (DR) formulation that could avoid being degraded 
in the proximal small intestine may allow linaclotide to be delivered directly to the lower 
intestine, bypassing the GC-C receptors higher up in the GI tract.
Ironwood Pharmaceuticals and Forest Laboratories, LLC (an affiliate of Actavis, Inc.) are 
developing a DR formulation of linaclotide for patients who have IBS-C or CIC with the 
hypothesis that delivery of linaclotide to these regions will limit fluid secretion while preserving 
the inhibition of fluid reabsorption in the colon and enhancing the nociceptive effects of the drug 
by enabling higher concentrations of linaclotide to interact with GC-C in the colon. Two 
different DR tablet formulations have been developed:
•
DR1 
 
•
DR2 
 
 
 
 
 It is anticipated that delivery of linaclotide to the lower intestine will limit 
CFTR-mediated fluid secretion while preserving the inhibition of fluid reabsorption in the colon, 
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and will enable the delivery of higher concentrations of linaclotide directly to interact with GC-C 
in the proximal region of the small intestine, the hypothesized source of pain in IBS-C.
This is the first clinical study of linaclotide using a delayed release formulation. 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.(14,15) These 
trials evaluated the safety and efficacy of linaclotide IR 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 of their 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, 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. (14,15) 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 two 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. Human studies have not been 
conducted with the DR formulations of linaclotide. As the IR and DR formulations have the 
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same active ingredient, similar gastrointestinal side effects (diarrhea, abdominal pain, abdominal 
distension, and flatulence) may be expected. However, the frequency and severity of these 
effects remain to be determined.
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 and its relevance to the delayed release 
formulations.
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4.
STUDY OBJECTIVES
The objectives of this study are to evaluate the safety, efficacy, and dose response of two 
different delayed release formulations of linaclotide (DR; DR formulation 1 is DR1; DR 
formulation 2 is DR2) administered orally to patients with irritable bowel syndrome with 
constipation (IBS-C). 
 
 
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5.
INVESTIGATIONAL PLAN
5.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
This is a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-
group, multiple-dose, 12-week study, consisting of 3 distinct periods, as illustrated in Figure 1
below. The study will enroll patients who have IBS-C diagnosed using Rome III criteria. Eligible 
patients will be randomized in equal proportions to one of 8 treatments: 30 µg, 100 µg, or 300 µg 
of the linaclotide DR1 formulation; 30 µg, 100 µg, or 300 µg of the linaclotide DR2 formulation; 
290 µg (the approved dose) of the linaclotide IR formulation; or placebo. Linaclotide IR is being 
included in the study as a positive control, against which the safety and efficacy of the various 
doses of the two test formulations can be compared. 
 
 
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Figure 1.
Overview of Study Design
The study will consist of up to 21 days of screening, 14 to 21 days of pretreatment, and 12 weeks 
of double-blind treatment. At the end of the Pretreatment Period, during which patients will 
provide qualifying Bowel Movement (BM)-related and Abdominal Symptom-severity 
Assessments, and Rescue Medicine information, patients meeting the entry criteria for this study 
will be randomized in equal proportions to one of the 8 double-blind treatment groups.
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 12/
End-of-Treatment 
Period Visit**
(Day 85 + 3)
100 µg Linaclotide DR1 tablet and Placebo capsule
Placebo tablet and Placebo capsule
No Treatment
Note: there is no Day 0.
*Applicable to a subset of patients (See 
Follow-up Phone Call Section)
**This visit represents the end of the study
30 µg Linaclotide DR1 tablet and Placebo capsule
300 µg Linaclotide DR1 tablet and Placebo capsule
100 µg Linaclotide DR2 tablet and Placebo capsule
290 µg Linaclotide IR capsule and Placebo tablet
300 µg Linaclotide DR2 tablet and Placebo capsule
30 µg Linaclotide DR2 tablet and Placebo capsule
Follow-up
Call*
(Day 3)
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5.1.1
Study Periods
5.1.1.1
Screening Period
The Screening Period starts with signature of the ICF 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. Any over-the-counter or 
prescription laxatives, suppositories, or enemas used to treat IBS-C must not be taken during the 
calendar day before the Pretreatment Visit through the end of the Treatment period; whereas
other prohibited medicines must not be taken during the 14 calendar days before the Pretreatment 
Visit through the end of the Treatment period (refer to Appendix II).
5.1.1.2
Pretreatment Period
The Pretreatment Period is defined as the 14 to 21 calendar days immediately before the 
Randomization Visit. During this period, patients will provide the following information in a 
handheld electronic diary (eDiary):
•
Daily BM-related Symptom-severity Assessments on an event-driven basis
•
Daily Abdominal Symptom-severity Assessments in a daily evening report
•
Weekly Patient Assessment of Constipation Severity
•
Weekly Patient Assessment of IBS Symptom Severity
•
Weekly Patient Assessment of Adequate Relief
•
Use of Per-protocol Rescue Medicine or any other Laxatives, Suppositories, or Enemas on an 
event-driven basis
Patients who satisfy all of the entry criteria will enter the Treatment Period.
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5.1.1.3
Treatment Period
The Treatment Period begins with treatment assignment and lasts for 12 weeks. Patients will be 
randomly assigned to one of 8 treatments: 30 µg, 100 µg, or 300 µg of linaclotide DR1; 30 µg, 
100 µg, or 300 µg of linaclotide DR2; 290 µg of linaclotide IR; or placebo. Study drug will be 
taken once daily in the morning at least 30 minutes before breakfast. (Note: Patients will take 
their initial dose of study drug at the clinic during the Randomization Visit.) At the 
Randomization Visit, patients must have fasted for at least 2 hours prior to arriving at the clinic 
for their visit. Patients will continue to use the handheld eDiary to provide their daily 
assessments (Daily BM-related Symptom-severity Assessments on an event-driven basis, and 
Daily Abdominal Symptom-severity Assessments in a daily evening report), weekly assessments 
(Weekly Patient Assessment of Constipation Severity, Weekly Patient Assessment of IBS 
Symptom Severity, and Weekly Patient Assessment of Adequate Relief), and the use of per-
protocol Rescue Medicine and any other Laxatives, Suppositories, or Enemas on an event-driven 
basis. Quality-of-life and patient-outcome assessments will be performed at study visits 
throughout the Treatment Period. A list of these assessments and the visits when they are 
performed is provided in the Schedule of Evaluations (Table 1). Patients will complete a Week 4 
Visit, Week 8 Visit, and Week 12/End of Treatment Visit during the Treatment Period. (See 
Schedule of Evaluations) Appropriate site personnel will complete a follow-up phone call to 
patients within 48 hours following initial study drug administration to assess for developing AEs. 
In doing this, patients will be asked the same nonleading question that is asked at the study visits. 
(See Section 5.5.3.2.1)
5.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE 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. Linaclotide IR at the 290 µg dose (the FDA-approved dose for IBS-C) is being included in 
the study as a positive control, against which the safety and efficacy of the various doses of the 
two test (DR) formulations can be compared; to maintain the blind (linaclotide IR is supplied as 
a capsule and both linaclotide DR formulations are supplied as tablets), a double-dummy design 
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was employed. 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., eDiary), and a 12-
week Treatment Period to compare the test treatment to the placebo control and active control.
5.3
SELECTION OF STUDY POPULATION
5.3.1
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
1. Patient has signed an ICF.
2. Patient is ambulatory and community-dwelling (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. Sexually active female patients of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a bilateral oophorectomy, hysterectomy, or tubal 
ligation) 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 (i.e., oral contraceptive, contraceptive implant, or injectable 
hormonal contraceptive)
b. Double-barrier birth control (e.g., condom plus intrauterine device, diaphragm plus 
spermicide, etc.)
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 defined by the American Gastroenterological 
Association guidelines and described in Appendix III. (Note: Patients are eligible to enter 
the Pretreatment Period on the fifth calendar day after a colonoscopy.)
6. Patient has no clinically significant concurrent illness or findings on a physical 
examination and 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 study, 
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could represent a safety concern if the patient participates in the study, or could confound 
the study-specified assessments of safety or efficacy.)
7. 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.
Relieved 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 or lubiprostone.
8. 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.
9. 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, 
lubiprostone, polyethylene glycol 3350, or any laxative.
10. 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 calendar days 
before the Randomization Visit and the calendar day of Randomization up to the time 
when the data entry into the eDiary is made in clinic.
11. Patient reports ≤6 complete spontaneous BMs (CSBMs) and ≤ 10 spontaneous BMs 
(SBMs) in the eDiary over the 14 calendar days before the Randomization Visit and the 
calendar day of Randomization up to the time when the data entry into the eDiary is made 
in clinic. (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 concomitant medicine use via the eDiary.)
12. Patient is compliant (as defined in the study procedures section below) with eDiary 
completion by adequately responding to eDiary questions on 10 or more of the 14 
calendar days before the Randomization Visit.
13. Patient is willing to discontinue any laxatives used before the Pretreatment Visit in favor 
of the protocol-defined Rescue Medicine (bisacodyl tablets or suppositories).
14. Patient is fluent in English or Spanish.
15. Patient is able to operate the eDiary adequately.
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16. Patient agrees to refrain from making any new, major life-style changes that may affect 
IBS-C symptoms (e.g., starting a new diet or changing his or her exercise pattern) from 
the time of signature of the ICF to the last study visit.
5.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the study:
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 II) 
for > 25% of BMs during the 12 weeks before the Screening Visit.
2. Patient has a structural abnormality of the gastrointestinal (GI) tract or a disease or 
condition that can affect GI motility.
3. Patient has ever had a diagnosis or family history of familial adenomatous polyposis, 
hereditary nonpolyposis colorectal cancer, or any other form of familial colorectal cancer.
4. Patient has ever had a diagnosis of inflammatory bowel disease (IBD).
5. Patient currently has unexplained and clinically significant alarm symptoms (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 (i.e., disease that is not adequately treated 
or stable with therapy).
7. Patient has a history of diverticulitis or any chronic condition (e.g., chronic pancreatitis, 
polycystic kidney disease, ovarian cysts, endometriosis) that can be associated with 
abdominal pain or discomfort and could confound the assessments in this study, unless 
the patient is considered to have been cured of the condition.
8. Patient has a potential central nervous system cause of constipation (e.g., 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 had surgery that meets any of the following criteria:
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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
12. 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 provided that 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.)
13. Patient has a history of diabetic neuropathy.
14. 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.
15. 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 as 
long as they have exhibited no actual abuse during the 12 months before the 
Randomization Visit.)
16. Patient reports a BSFS score of 6 (loose, mushy stools) for > 1 SBM or a BSFS score of 7 
(watery stools) with any SBM over the 14 calendar days before the Randomization Visit
and the calendar day of Randomization up to the time when data is entered into the 
eDiary in the clinic.
17. Patient used Rescue Medicine (bisacodyl tablet or suppository) or any other laxative, 
suppository, or enema, on the calendar day before or the calendar day of the start of the 
Randomization Visit.
18. 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 II. (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 study.)
19. Patient has been hospitalized for a psychiatric condition or has made a suicide attempt 
during the two years before the Randomization Visit.
20. Patient has taken commercially available linaclotide or participated in a linaclotide, 
plecanatide, or SP-333 clinical study during the 30 days before the Screening Visit.
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21. Patient has received an investigational drug during the 30 days before the Screening Visit 
or is planning to receive an investigational drug (other than that administered during this 
study) or use an investigational device at any time during the study.
22. 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 study.
23. Patient has previously entered the Pretreatment Period of this study.
24. Patient is directly or indirectly involved in the conduct and administration of this study as 
an investigator, subinvestigator, study coordinator, other study staff member, or 
employee of Ironwood Pharmaceuticals, Forest Laboratories, Actavis, Inc., or Allergan, 
Inc.; 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 study; or the patient is 
enrolled in this study at another clinical study site.
5.3.3
Removal of Patients From Therapy or Assessment
A premature discontinuation will occur when a patient who signed the ICF ceases participation 
in the study, regardless of circumstances, before the completion of the protocol. Patients can 
prematurely discontinue or be prematurely discontinued by the investigator or sponsor from the 
study at any time for any reason including the following:
•
Failure to meet Inclusion/Exclusion Criteria (Screen 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)
•
Study termination by Sponsor
•
Pregnancy
•
Other, such as administrative reasons
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Patients who are randomized but do not complete the Treatment Period (withdraw consent or are 
discontinued before they have completed visits up to and including the Week 12/ End-of-
Treatment Period (EOT) Visit, will be considered Treatment Period withdrawals and should 
complete the procedures required at the EOT Visit (even if out of window) at the time of their 
discontinuation. The reasons for premature discontinuation from the study 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 study 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 study 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 three 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 study.
5.3.4
Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
5.4
TREATMENTS
5.4.1
Treatments Administered
Study drug in the form of oral tablets and oral capsules will be provided by Ironwood or 
designee. For the double-blind Treatment Period, study drug will be administered in a double-
dummy manner as follows:
•
30 µg linaclotide DR1 oral tablet and a placebo oral capsule (matching the 290 µg linaclotide 
IR oral capsule) administered once daily in the morning at least 30 minutes before breakfast
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•
100 µg linaclotide DR1 oral tablet and a placebo oral capsule administered once daily in the 
morning at least 30 minutes before breakfast
•
300 µg linaclotide DR1 oral tablet and a placebo oral capsule administered once daily in the 
morning at least 30 minutes before breakfast
•
30 µg linaclotide DR2 oral tablet and a placebo oral capsule administered once daily in the 
morning at least 30 minutes before breakfast
•
100 µg linaclotide DR2 oral tablet and a placebo oral capsule administered once daily in the 
morning at least 30 minutes before breakfast
•
300 µg linaclotide DR2 oral tablet and a placebo oral capsule administered once daily in the 
morning at least 30 minutes before breakfast
•
290 µg linaclotide IR oral capsule and a placebo oral tablet (matching the DR1 and DR2 oral 
tablet) administered once daily in the morning at least 30 minutes before breakfast
•
Placebo oral capsule and a placebo oral tablet administered once daily in the morning at least 
30 minutes before breakfast
5.4.2
Identity of Investigational Product
All study drug will be supplied in bottles containing thirty five (35) tablets of linaclotide DR1 
(30 µg, 100 µg, or 300 µg), linaclotide DR2 (30 µg, 100 µg, or 300 µg), or matching placebo 
tablets; or thirty five (35) capsules of linaclotide IR (290 µg) or matching placebo capsules. 
Bottles 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 IR (290 µg) and matching 
placebo capsules will be stored at the study center in an appropriate secure, temperature 
controlled area at 77°F (25°C), excursions permitted to 59-86°F (15-30°C). Linaclotide DR1 
(30 µg, 100 µg, or 300 µg), linaclotide DR2 (30 µg, 100 µg, or 300 µg), and matching placebo 
tablets will be stored refrigerated at the study center in an appropriate secure, temperature 
controlled area at 36-46°F (2-8°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.
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The investigator must ensure that the receipt and use of all study drug supplied is recorded and 
supervise the storage and allocation of these supplies. All study medication supplies must be 
retained in a locked room that may only be accessed by the investigator, or other duly designated 
persons. Study medication must not be used outside the context of this protocol and under no 
circumstances should the investigator or study center personnel allow the supplies to be used 
other than as directed by this protocol without prior authorization from Ironwood. All unused 
study drug must be returned to Ironwood’s designee. Whenever study drug is returned (excluding 
Sponsor-supplied per-protocol Rescue Medicine), unit counts must be performed by study center 
staff and verified by a site monitor to ensure reliable drug accountability. Drug unit counts are 
documented on the appropriate eCRF form. Prior to the end of the study, instructions for the 
return of all unused tablets/capsules and study drug bottles will be provided. 
5.4.3
Method of Assigning Patients to Treatment Groups
The patient identification (PID) number will consist of seven digits; the first three digits 
represent the study center number, followed by a one-digit study indicator (‘4’) and a three-digit 
patient number assigned in an ascending sequential order, beginning with 001, 002, etc. The 
patient will retain the same PID number (which is also the Screening Number) throughout the 
Treatment Period.
Patients who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized into the study at the Randomization Visit on Day 1. Approximately 520 patients will 
be randomized in equal proportions to one of eight treatments (as described in Section 5.4.1). 
Randomization numbers will be assigned by interactive web response system (IWRS).
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5.4.4
Selection of Dosage in the Study
This protocol is intended to evaluate the safety, efficacy, and dose response of the DR1 and DR2 
formulations of linaclotide, compared with each other and with the linaclotide IR formulation. 
The linaclotide IR formulation has been included as a positive control at the dose level (290 µg) 
approved by FDA for the treatment of IBS-C in adults. As this is a dose-range-finding study, 
three dose levels of each DR formulation will be evaluated; in order to facilitate comparison of 
the DR1 and DR2 formulations, the same doses (30 µg, 100 µg, and 300 µg) will be used for 
each. The 300 µg dose approximates the 290 µg dose of linaclotide IR (the FDA-approved dose 
for IBS-C), allowing for direct comparison of the DR formulations with the IR formulation. The 
30 µg dose represents approximately 1/10 of the 290 µg dose of linaclotide IR. In a Phase 1 
food-effect study (MCP-103-103) in patients administered the FDA-approved IR formulation, 
active peptide recovery in stool samples from fed and fasted subjects following once-daily 
administration of linaclotide IR 290 µg for 7 days averaged 3-5%; therefore, the 30 µg dose is 
approximately 2-fold greater than the amount of linaclotide entering the large intestine with the 
IR formulation. The 100 µg dose was selected because it represents a ½ log difference from the 
30 µg dose and the 300 µg dose.
5.4.5
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 at the Randomization 
Visit (randomization number assigned by IWRS) and dispensed two bottles, one containing 
35 tablets and one containing 35 capsules. Additional bottles will be dispensed at subsequent 
visits per the Schedule of Evaluations (Table 1). Patients will be instructed to take one tablet and 
one capsule in the morning at least 30 minutes before breakfast. Patients will take their initial 
dose of study drug (one tablet and one capsule, as described in Section 5.4.1) at the study 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 be instructed to return all unused study drug and bottles to 
the study center at the visits defined in the Schedule of Evaluations (Table 1).
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5.4.6
Blinding
This study is a double-blind, double-dummy study.
A list of patient randomization codes will be generated by Actavis, and implemented by the 
IWRS vendor (an electronic version will be stored on a secure server). This list will identify each 
patient by randomization number and include the patient’s corresponding treatment assignment. 
The medication code list will be supplied by Almac Clinical Services to the IWRS contract 
research organization.
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 
study 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 study center will disqualify the patient from further participation 
in the study.
5.4.7
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 II. During the Pretreatment and Treatment 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 calendar day before the Randomization Visit and 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 
calendar day after randomization.
At the Screening Visit, all ongoing medicines or investigational products taken by the patient, 
and past use of certain IBS-C or CIC (approved or unapproved) prescription medications 
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(including tegaserod [Zelnorm®], prucalopride, plecanatide, linaclotide [Linzess®] and 
lubiprostone [Amitiza®]), even if not ongoing at the time of the Screening Visit, will be recorded. 
Any over-the-counter or prescription laxatives, suppositories, or enemas used to treat IBS-C may 
not be used during the Pretreatment and Treatment Periods and may not be used on the calendar 
day before the Pretreatment Visit. Other prohibited medicines may not be used during the 
Pretreatment and Treatment Periods and may not be used during the 14 calendar days before the 
Pretreatment Visit (refer to Appendix II). 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 study. Rescue Medicine will be documented by the patient via 
eDiary.
5.4.8
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, study drug will be taken by the patient once daily in 
the morning at least 30 minutes before breakfast. Study drug compliance by the patient will be 
closely monitored during the Treatment Period by counting the number of tablets/capsules 
returned and recording that information on the eCRF. Every effort will be made to collect all 
unused study drug.
5.5
EFFICACY AND SAFETY VARIABLES
5.5.1
Schedule of Evaluations
The schedule of study procedures and assessments is presented by visit in the Schedule of 
Evaluations in Table 1. The descriptions of the procedures to be performed at each visit are 
provided below. Following randomization, all visits should adhere to a window of ± 3 days 
during the Treatment Period, except for the EOT Visit, which cannot occur before Day 85.
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Table 1.
Schedule of Evaluations
Schedule of Evaluations MCP-103-204
Screening 
Period
(Up to 21 
days)
Pretreatment 
Period
(14 to 21 
days)
Treatment Period
(12 weeks)
Visit Days →
Screening 
Visit
(Day -42 
through 
Day -15)
Pretreatment 
Visit
(Day -21 to 
Day -14)
Randomization 
Visit
(Day 1)
Follow-up 
Call
(Day 3)
Week 4 Visit
(Day 29±3)
Week 8 Visit
(Day 57±3)
Week 12/End-of-
Treatment Period Visit o
(Day 85+3)
Visit Numbers →
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Study Procedure ↓
Signature of ICF
X
Inclusion and Exclusion 
Criteria Verification
X
X
X
IWRS Registration a
X
X
X
X
X
X
Medical History
X
Physical Examination b
X
X
Body Weight and Height c
X
X
X
X
X
X
Seated Vital Signs d
X
X
X
X
X
X
Prior and Concomitant 
Medicines e
X
X
X
X
X
X
Clinical Laboratory Tests f
X
X
X
Pregnancy Test g
X
X
X
Laxative/Suppository/Enema 
Washout Instructions h
X
AE Evaluations i
X
X
X
X
X
X
eDiary Registration and 
Training j
X
X
X
X
X
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Table 1.
Schedule of Evaluations
Schedule of Evaluations MCP-103-204
Screening 
Period
(Up to 21 
days)
Pretreatment 
Period
(14 to 21 
days)
Treatment Period
(12 weeks)
Visit Days →
Screening 
Visit
(Day -42 
through 
Day -15)
Pretreatment 
Visit
(Day -21 to 
Day -14)
Randomization 
Visit
(Day 1)
Follow-up 
Call
(Day 3)
Week 4 Visit
(Day 29±3)
Week 8 Visit
(Day 57±3)
Week 12/End-of-
Treatment Period Visit o
(Day 85+3)
Visit Numbers →
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Study Procedure ↓
Daily and Weekly 
Assessments k
X
X
X
X
X
eDiary Compliance 
Verification and Reminder l
X
X
X
X
Rescue Medicine Dispensed m
X
X
X
X
Patient eDiary Entry, in Clinic
X
X
X
X
Randomization
X
SF-12v2
X
X
X
X
EQ-5D
X
X
X
X
SF-MPQ-2
X
X
X
X
IBS-SSS
X
X
Treatment Satisfaction 
Assessment
X
X
X
Study Drug Dispensed
X
X
X
Study Drug Administration n
X
Study Drug Accountability
X
X
X
a.
Site personnel will interact with IWRS to register the patient visit. Refer to the IWRS User Manual.
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b.
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 
Screening Period on all patients who do not require a colonoscopy (refer to Appendix III). 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.
c.
Height is measured only at the Screening Visit.
d.
Vital signs must be obtained in the seated position and include oral temperature, respiratory rate, blood pressure, and pulse.
e.
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 history of 
using particular treatments for IBS-C and CIC (see Section 5.4.7 Concomitant Medicines).
f.
Chemistry, CBC, and drug screen. The urine drug screen will be performed at the Screening Visit only.
g.
To be eligible to continue in the study, a negative serum pregnancy test must be documented at the Screening Visit. A negative urine pregnancy test must be 
documented at the Randomization Visit (prior to dosing), and a negative serum pregnancy test must be documented at the Week 12/End-of-Treatment Period 
(EOT) Visit.
h.
Study coordinator will instruct patients about the use of laxatives, suppositories, and enemas (refer to Appendix II).
i.
All AEs occurring after the patient signs the ICF will be captured. Appropriate site personnel will complete a follow-up phone call to patients within 48 
hours following initial study drug administration to assess for developing AEs. The Sponsor will perform a blinded review of the safety information obtained 
from the first 40 follow-up phone calls, and determine whether follow-up phone calls to patients should continue or be discontinued. (See Follow-up Phone 
Call Section)
j.
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.
k.
An eDiary will be used for recording Daily BM-related Symptom Severity Assessments, Daily abdominal Symptom-severity Assessments, Weekly 
Assessments, EQ-5D, Treatment Satisfaction, Assessment, SF-MPQ-2, SF-12-v2, IBS-SSS, and any use of rescue medicine. Patients will enter BMs and 
rescue medicine in the eDiary on an event-driven basis, and will complete an evening entry each day to record daily assessments.
l.
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 EOT visit). (eDiary questions may be found in the eDiary User Manual.)
m. 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.
n.
Study drug will be administered in the clinic at the Randomization Visit (study drug does not need to be taken in the morning before breakfast). 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.
o.
Patients who are randomized but do not complete the Treatment Period (withdraw consent or are discontinued before they have completed 12 weeks of 
treatment), will be considered Treatment Period withdrawals and should complete the procedures required at the EOT Visit (even if out of window).
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Screening Visit (Visit 1)
At the Screening Visit, a review of Inclusion and Exclusion Criteria will be conducted to 
determine the patient’s eligibility for progression to the Pretreatment Period. Overall eligibility 
should be determined by the investigator or an appropriately trained health professional listed on 
Form FDA 1572. Study procedures will be reviewed with the patient, the caregiver, and the 
patient’s legally authorized representative (LAR: if different from the caregiver); and 
documentation of informed consent will be obtained. After the patient signs the ICF, the study 
coordinator will access IWRS to register the patient’s Screening Visit, and the patient will then 
be assigned a unique PID number in sequential order. The following procedures will be 
performed thereafter:
•
Medical history
•
Physical examination
-
A physical examination should include all assessments (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 Screening Period in all patients who 
do not require a colonoscopy (refer to Appendix III). After the Screening Period, the 
rectal examination is optional and may be performed at the discretion of the investigator.
-
The breast and genitourinary examinations are optional at the discretion of the 
investigator.
•
Body weight and height
•
Seated vital signs
•
Documentation of prior and concomitant medicines, including investigational products and 
past use of tegaserod (Zelnorm®), prucalopride, plecanatide, linaclotide (Linzess®), and 
lubiprostone (Amitiza®)
•
Collection of blood and urine samples for clinical laboratory determinations
-
Clinical chemistry
-
Complete blood count (CBC)
-
Urine drug screen
•
Serum pregnancy test (result must be confirmed as negative in order to qualify for study 
participation)
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•
Instructions given for patients to discontinue the use of all laxatives, suppositories and/or 
enemas at least one calendar day before the first day of the Pretreatment Period, and all other 
prohibited medicines (as defined in Appendix II) at least 14 calendar days before the first day 
of the Pretreatment Period.
•
Patient reminder (schedule patient’s next visit and remind the patient to refrain from using 
prohibited medicines as described in Appendix II)
Pretreatment Visit (Visit 2)
The Pretreatment Period will occur between 14 and 21 days immediately before the 
Randomization Visit. The purposes of this period are to collect Pretreatment Period data to 
determine whether the patient is eligible to continue into the Treatment Period of the study, to 
provide the patient with experience using the data collection methods employed during the study 
(i.e., eDiary), and for comparison with data collected during the Treatment Period.
The study coordinator will access IWRS to register the patient’s Pretreatment Visit. At the 
Pretreatment Visit, which will occur between Day -21 and Day -14 (inclusive), the Inclusion and 
Exclusion Criteria will again be reviewed, study procedures will be explained to the patient, and 
the following will be performed:
•
Verification that Inclusion and Exclusion Criteria continue to be met
•
Body weight
•
Seated vital signs
•
Documentation of concomitant medicines
•
Review of AEs, from the signing of the ICF to Visit 2
•
Register visit in eDiary
•
eDiary training (patients will be instructed on the use of eDiary) and the assessments that will
be collected as listed below:
-
Daily BM-related Symptom-severity Assessments on an event-driven basis (frequency, 
consistency, straining and completeness)
-
Daily Abdominal Symptom-severity Assessments in a daily evening report (abdominal 
bloating, abdominal discomfort, and abdominal pain)
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-
Use of Per-protocol Rescue Medicine or any other Laxatives, Suppositories, and Enemas
on an event-driven basis
-
Weekly Patient Assessment of Constipation Severity
-
Weekly Patient Assessment of IBS Symptom Severity
-
Weekly Patient Assessment of Adequate Relief
•
Dispensing of Rescue Medicine; review with patient how Rescue Medicine should be used
•
Patient reminder (schedule patient’s next visit and remind the patient to refrain from using 
prohibited medicines and to refrain from using Rescue Medicine the calendar day before and 
day of the Randomization Visit)
Randomization Visit (Visit 3)
At the Randomization Visit, the Inclusion and Exclusion Criteria will again be reviewed to 
confirm the patient’s eligibility. At this visit, the study coordinator will register the 
Randomization Visit on the patient’s eDiary, and the patient will respond to the required 
assessments on the eDiary in the clinic. After the patient completes the eDiary entry, the study 
coordinator will access the eDiary website to confirm the patient’s eligibility. If the patient’s 
eligibility is confirmed in the eDiary website and all Inclusion and Exclusion criteria are met 
(reference below bulleted procedures to be completed prior to randomization), the study 
coordinator will confirm on the eDiary that the patient is randomized. The study coordinator will 
then register the Randomization Visit in IWRS, and the IWRS will assign a randomization 
number. Once the necessary procedures are completed (reference below bulleted procedures to 
be completed after randomization but prior to first dose), each eligible patient will be 
administered study drug (initial doses) in the clinic. The patient will be dispensed two bottles 
containing double-blind study drug (one bottle containing tablets and one bottle containing 
capsules) for the first four weeks of the Treatment Period. The study coordinator will perform the 
appropriate procedures after study drug administration, including review of the study procedures 
with the patient and instruct the patient to continue to complete the eDiary daily.
The following procedures will be performed before randomization and administration of the first 
dose of study drug at the study center:
•
Verification that Inclusion and Exclusion Criteria continue to be met
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•
Body weight
•
Seated vital signs
•
Documentation of concomitant medicines
•
Collection of blood for clinical laboratory determinations
-
Clinical chemistry
-
CBC
•
Urine pregnancy test (result must be confirmed as negative before randomization and the 
administration of the first dose of study drug)
•
Review of AEs
•
eDiary compliance verification (study coordinator will verify the patient’s compliance with 
the daily entry requirement) and eDiary entry in the clinic, including the following 
assessments:
-
Daily BM-related Symptom-severity Assessments on an event-driven basis
-
Daily Abdominal Symptom-severity Assessments in a daily evening report
-
Use of Per-protocol Rescue Medicine or any other Laxatives, Suppositories, and Enemas
on an event-driven basis
-
Weekly Patient Assessment of Constipation Severity
-
Weekly Patient Assessment of IBS Symptom Severity
-
Weekly Patient Assessment of Adequate Relief
In addition, the study coordinator will verify the patient’s compliance with the eDiary entry 
requirement during the Pretreatment Period and remind the patient to complete his or her eDiary 
entry each day.
The following procedures will be performed after randomization (prior to first dose):
•
SF-12v2 (Short Form-12 Health Survey version 2 [self-administered by the patient; 
Appendix VII])
•
EQ-5D (EuroQoL-5 Dimension [self-administered by the patient; Appendix VIII])
•
SF-MPQ-2 (Short-Form McGill Pain Questionnaire-2 [self-administered by the patient; 
Appendix IX])
•
IBS-SSS (Irritable Bowel Syndrome-Symptom Severity Scale [self-administered by the 
patient; Appendix X])
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•
Study drug (initial doses) administered in the clinic
The following procedures will be performed after study drug administration:
•
Dispensing of study drug - one bottle containing 34 tablets (one bottle = 35 tablets less the 
initial dose) and one bottle containing 34 capsules (one bottle = 35 capsules less the initial 
dose)
•
eDiary entry reminder (patients will be instructed to complete eDiary throughout the day of 
the Randomization Visit and reminded to complete eDiary entry each day thereafter)
•
Dispensing of Rescue Medicine, as needed; review with patient how Rescue Medicine should 
be used
•
Patient reminders (schedule patient’s next visit and remind the patient to refrain from using 
prohibited medicines and to refrain from using Rescue Medicine for the remainder of the day 
of randomization and for the calendar day after randomization)
Follow-up Phone Call (Day 3)
Appropriate site personnel will complete a follow-up phone call to patients within 48 hours 
following initial study drug administration to assess for developing AEs. In doing this, patients 
will be asked the same nonleading question that is asked at the study visits. (See Section 
5.5.3.2.1) Any AE reported during the phone call will be captured on the eCRF. Patients who 
report AEs during the follow-up phone call will be provided with instructions on the appropriate 
follow-up care. The Sponsor will perform a blinded review of the safety information obtained 
from the first 40 follow-up phone calls. If the safety information from the phone calls is 
consistent with the known safety profile of the IR formulation of linaclotide (LINZESS® 290 µg 
in IBS-C), then no further follow-up phone calls will be made to patients. The Sponsor will 
communicate accordingly to the clinical sites to indicate whether follow-up phone calls to 
patients should continue or be discontinued.
Week 4 Visit (Visit 4)
The following procedures will be performed:
•
Register visit in IWRS
•
Body weight
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•
Seated vital signs
•
Documentation of concomitant medicines
•
Review of AEs 
•
Register visit in eDiary and eDiary compliance verification (study coordinator will verify the 
patient’s compliance with the daily entry requirement); after determining the patient’s 
compliance, the study coordinator will remind the patient to complete eDiary entry to provide 
the following information:
-
Daily BM-related Symptom-severity Assessments on an event-driven basis
-
Daily Abdominal Symptom-severity Assessments in a daily evening report
-
Use of Per-protocol Rescue Medicine or any other Laxatives, Suppositories, and Enemas
on an event-driven basis
-
Weekly Patient Assessment of Constipation Severity
-
Weekly Patient Assessment of IBS Symptom Severity
-
Weekly Patient Assessment of Adequate Relief
•
Dispensing of Rescue Medicine, as needed; review with patient how Rescue Medicine should 
be used
•
SF-12v2 (self-administered by the patient; Appendix VII)
•
EQ-5D (self-administered by the patient; Appendix VIII)
•
SF-MPQ-2 (self-administered by the patient; Appendix IX)
•
IBS-SSS (Irritable Bowel Syndrome-Symptom Severity Scale [self-administered by the 
patient; Appendix X])
•
Treatment Satisfaction Assessment (self-administered by the patient)
•
Dispensing of study drug (one bottle containing 35 tablets and one bottle containing 35 
capsules)
•
Study drug accountability
•
Patient reminders (schedule patient’s next visit and remind the patient to refrain from using 
prohibited medicines and to return any unused study drug at the next visit)
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Week 8 Visit (Visit 5)
The following procedures will be performed:
•
Register visit in IWRS
•
Body weight
•
Seated vital signs
•
Documentation of concomitant medicines
•
Review of AEs
•
Register visit in eDiary and eDiary compliance verification (study coordinator will verify the 
patient’s compliance with the daily entry requirement); after determining the patient’s 
compliance, the study coordinator will remind the patient to complete eDiary entry to provide 
the following information:
-
Daily BM-related Symptom-severity Assessments on an event-driven basis
-
Daily Abdominal Symptom-severity Assessments in a daily evening report
-
Use of Per-protocol Rescue Medicine or any other Laxatives, Suppositories, and Enemas
on an event-driven basis
-
Weekly Patient Assessment of Constipation Severity
-
Weekly Patient Assessment of IBS Symptom Severity
-
Weekly Patient Assessment of Adequate Relief
•
Dispensing of Rescue Medicine, as needed; review with patient how Rescue Medicine should 
be used
•
SF-12v2 (self-administered by the patient; Appendix VII)
•
EQ-5D (self-administered by the patient; Appendix VIII)
•
SF-MPQ-2 (self-administered by the patient; Appendix IX)
•
Treatment Satisfaction Assessment (self-administered by the patient)
•
Dispensing of study drug (one bottle containing 35 tablets and one bottle containing 35 
capsules)
•
Study drug accountability
•
Patient reminders (schedule patient’s next visit and remind the patient to refrain from using 
prohibited medicines and to return any unused study drug at the next visit)
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Week 12/End-of-Treatment Period Visit (Visit 6)
Patients who are randomized but do not complete the Treatment Period (withdraw consent or are 
discontinued before they have completed 12 weeks of treatment), will be considered Treatment 
Period withdrawals and should complete the procedures required at the EOT Visit (even if out of 
window). Any clinical findings obtained during the final examination or at premature 
discontinuation for any reason, including clinically significant laboratory abnormalities, will be 
followed until the condition returns to screening status, has resolved or stabilized, or can be 
explained as being unrelated to study drug.
The following procedures will be performed:
•
Register visit in IWRS
•
Physical examination (rectal, breast, and genitourinary examinations are optional at the 
discretion of the investigator)
•
Body weight
•
Seated vital signs
•
Documentation of concomitant medicines
•
Collection of blood for clinical laboratory determinations:
-
Clinical chemistry
-
CBC
•
Serum pregnancy test
•
Review of AEs
•
Register visit in eDiary and eDiary compliance verification (study coordinator will verify the 
patient’s compliance with the daily entry requirement); eDiary entry in the clinic, including 
the following assessments:
-
Daily BM-related Symptom-severity Assessments on an event-driven basis
-
Daily Abdominal Symptom-severity Assessments in a daily evening report
-
Use of Per-protocol Rescue Medicine or any other Laxatives, Suppositories, and Enemas
on an event-driven basis
-
Weekly Patient Assessment of Constipation Severity
-
Weekly Patient Assessment of IBS Symptom Severity
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-
Weekly Patient Assessment of Adequate Relief
•
SF-12v2 (self-administered by the patient; Appendix VII)
•
EQ-5D (self-administered by the patient; Appendix VIII)
•
SF-MPQ-2 (self-administered by the patient; Appendix IX)
•
Treatment Satisfaction Assessment (self-administered by the patient)
•
Study drug accountability
•
Register visit in IWRS (study coordinator will confirm in IWRS that the patient has 
completed participation in the study)
5.5.2
Efficacy Measurements
5.5.2.1
Key Efficacy Assessments
The key efficacy assessments that will be used to determine the key efficacy parameters 
(Section 5.7.7.1) are the eDiary questions that determine whether a BM is a CSBM and the daily 
patient assessment of Abdominal Pain at its Worst:
Complete Spontaneous Bowel Movement
•
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 Rescue Medicine Use. Patients will report rescue medicine use on an event-
driven basis. An evening report will ask whether the patient entered all rescue medicine use 
for that day, and collect rescue medicine not previously entered for that day.  
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Each day of the Pretreatment and Treatment 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 in Section 5.5.2.2.) The patient will also complete eDiary entries 
on an event-driven basis to report use of Rescue Medicines (e.g., oral bisacodyl; bisacodyl 
suppository) to treat their symptoms. Patients will complete a daily evening report to enter any 
BMs and Rescue Medicine usage not previously reported by the patient for that day.  
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”>
5.5.2.2
Other Efficacy Assessments
In addition to the key efficacy assessments, the following efficacy assessments are used in 
determining the other efficacy parameters.
Spontaneous Bowel Movement
The SBM assessment is based on the eDiary questions that determine whether a BM is an SBM:
•
BM day and time
•
Day of any Rescue Medicine Use
Refer to Section 5.5.2.1 for the questions.
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Stool Consistency
Patient assessment of stool consistency will be collected using two questions by daily eDiary 
entry on an event-driven basis. For each BM, the patient assesses his/her stool using the BSFS 
(Appendix IV) 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.(16) The 7-point ordinal BSFS scale 
is provided below:
“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)
Second, the patient assesses his/her stool using a 5 point ordinal scale:
“How would you describe the consistency of your stool?”

Very hard

Hard

Neither too hard nor too soft

Loose but not watery

Very loose and watery
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Straining
Patient assessment of straining will be collected daily by eDiary entry. 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)
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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Abdominal Symptom Score Scale
A patient’s Abdominal Symtom Score Scale will be a composite measure based on combined 
scores from the Daily Patient Assessment of Abdominal Pain at its Worst, Daily Patient 
Assessment of Abdominal Discomfort at its Worst, and Patient Assessment of Abdominal 
Bloating at its Worst.
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
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3=Moderate
4=Severe
5=Very severe
Weekly Patient Assessment of Adequate Relief
Patient assessment of adequate relief of IBS symptoms will be reported weekly by eDiary entry. 
The rating of the 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
Treatment Satisfaction Assessment
A treatment satisfaction assessment will be performed at the Week 4 Visit and all subsequent 
study visits by eDiary entry. 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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5.5.2.3
Health Outcomes Assessments
SF-12v2 
The SF-12v2 Health Survey is a widely used generic measure of health status (Appendix 
VII)(17). The SF-12v2 measures eight concepts commonly represented in widely used surveys: 
physical functioning, role limitations due to physical health problems, bodily pain, general 
health, vitality (energy/fatigue), social functioning, role limitations due to emotional problems, 
and mental health (psychological distress and psychological well-being). These eight scales are 
aggregated into two summary measures: the Physical and Mental Component Summary Scores. 
The SF-12v2 will be self-administered at the Randomization Visit prior to the patient receiving 
study drug and at all subsequent study visits. Treatment Period withdrawals should complete the 
self-administration of the SF-12v2 at the EOT Visit (even if out of window).
EQ-5D 
The EQ-5D is a generic measure of health status that is widely used in Europe (Appendix 
VIII)(18). The descriptive system consists of five questions assessing the following dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses to the 
five questions define a health state for which a utility index can be derived from published 
algorithms.(19) The second component of the EQ-5D is a visual analogue scale, asking patients 
to rate their health from 0 to 100 (0 represents worst imaginable health state and 100 represents 
best imaginable health state). The EQ-5D will be self-administered at the Randomization Visit 
prior to the patient receiving study drug and at all subsequent study visits. Treatment Period 
withdrawals should complete the self-administration of the EQ-5D at the EOT Visit (even if out 
of window).
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SF-MPQ-2
The SF-MPQ-2 is a measure that provides a comprehensive evaluation of both neuropathic and 
non-neuropathic pain through assessment of 22 words describing different qualities of pain and 
related symptoms (Appendix IX) (20). It will be self-administered at the Randomization Visit 
prior to the patient receiving study drug and at all subsequent study visits. Treatment Period 
withdrawals should complete the self-administration of the SF-MPQ-2 at the EOT Visit (even if 
out of window). The SF-MPQ-2 consists of a total pain score and four summary scales: (1) 
continuous descriptors, (2) intermittent descriptors, (3) neuropathic descriptors, and (4) affective 
descriptors.
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS)
The Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS) (21) contains seven questions 
that ask patients to rate the severity and frequency of their abdominal pain and distention, 
dissatisfaction with bowel habits, and the extent to which the patient’s bowel habits interfere 
with life in general. The IBS-SSS (Appendix X) also includes queries related to stool passage 
and bowel functioning which are not included in the IBS-SSS total score (e.g., stool consistency, 
BM frequency, urgency, straining, incomplete evacuation, and passing mucus or blood in the 
stool). The IBS-SSS will be self-administered at the Randomization Visit prior to the patient 
receiving study drug and at the Week 4 Visit.
5.5.3
Safety Assessments
Patients must be seen by a physician or an appropriately trained health professional listed on 
Form FDA 1572 at every visit, and the AE evaluation must be documented. The procedures in 
this section will be performed at the designated visits.
5.5.3.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment (ICH, E2A).
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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 (ICH, E2A). An AE 
includes, but is not limited to, the following:
•
Any unfavorable changes in general condition
•
Any clinically significant worsening of a preexisting condition
•
Any intercurrent diseases and accidents
Note: A procedure is not an AE, but the reason for a procedure may be an AE.
Laboratory abnormalities, changes in vital signs, and physical examination findings should be 
considered AEs and reported on the AE reporting form of the patient's eCRF if they are deemed 
to be clinically significant, necessitate intervention and/or the investigator considers them to be 
AEs.
5.5.3.1.1
Causality Assessment
For all AEs, the investigator must provide an assessment of causal relationship to study drug. 
The causality assessment must be recorded on the appropriate AE reporting form of the patient’s 
eCRF. Causal relationship must be assessed according to the following:
Related: 
An event where there is a reasonable possibility of a causal relationship between 
the event and the study drug
Unrelated:
Any other event
5.5.3.1.2
Severity Assessment
The investigator will provide an assessment of the severity of each AE by recording a severity 
rating on the appropriate AE reporting form 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:
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Mild:
The AE was an annoyance to the patient but did not further hinder baseline 
functioning; the AE may have been intermittent or continuous.
Moderate:
The AE caused the patient to experience some discomfort or some interference 
with normal activities but was not hazardous to health; prescription drug therapy 
may have been employed to treat the AE.
Severe:
The AE caused the patient to experience severe discomfort or severely limited or 
prevented normal activities and represented a definite hazard to health; 
prescription drug therapy and/or hospitalization may have been employed to treat 
the AE.
5.5.3.2
Serious Adverse Events
According to ICH guidelines, an SAE is any AE occurring at any dose that meets one or more of 
the following criteria/outcomes:
•
Results in death
•
Is life-threatening
•
Requires inpatient hospitalization or prolongation of an existing hospitalization
•
Results in persistent or significant disability or incapacity
•
Results in a congenital anomaly or birth defect
•
Is another important medical event that may not result in death, be life-threatening, or require 
hospitalization; such an event may be considered serious when, based on appropriate medical 
judgment, it 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.
Emergency room visits that do not result in admission to the hospital should be evaluated for one 
of the other serious outcomes (e.g., life-threatening, other serious [medically important] event).
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5.5.3.2.1
Reporting Adverse Events and Serious Adverse Events
General Reporting Requirements
It is Ironwood policy to collect and record all AEs (i.e., any untoward medical occurrences or 
unfavorable and unintended signs, symptoms, or diseases) that occur in patients after the time the 
patients sign the ICF for the study. 
At each visit following the first visit and at the follow-up phone call within 48 hours following 
initial study drug administration (when applicable), patients are to be queried regarding any AEs 
that have occurred since the previous visit. Patients will be asked to volunteer information 
concerning AEs with a nonleading question such as, “How have you been since your last visit?”
Study center personnel will then record all pertinent information verbatim (as reported by the 
patient) in the patient’s source documentation and subsequently into the eCRF.
Patients who report AEs during the follow-up phone call will be provided with instructions on 
the appropriate follow-up care. The Sponsor will perform a blinded review of the safety 
information obtained from the first 40 follow-up phone calls. If the safety information from the 
phone calls is consistent with the known safety profile of the IR formulation of linaclotide 
(LINZESS® 290 µg in IBS-C), then no further follow-up phone calls will be made to patients.
The Sponsor will communicate accordingly to the clinical sites to indicate whether follow-up 
phone calls to patients should continue or be discontinued.
All AEs must be recorded in the patient’s source documentation and subsequently on the 
appropriate AE reporting page of the patient’s eCRF whether or not they are considered causally 
related to study drug.
For every AE, the investigator must:
•
Provide instructions to the patient on the appropriate follow-up care, if necessary;
•
Provide an assessment of the severity, causal relationship to study drug, and seriousness of 
the event;
•
Document all actions taken with regard to study drug (i.e., no action taken, treatment 
temporarily interrupted or treatment discontinued). The investigator may allow a patient to 
temporarily interrupt study drug for up to three days should an AE occur. If the investigator 
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believes that the patient is unable to resume dosing or requires a suspension of dosing on 
more than one occasion, then the investigator should contact the Medical Monitor to discuss 
the patient’s continued participation in the study; and
•
Detail any other treatment measures taken for the AE
SPECIAL SITUATION: EXPOSURE TO STUDY DRUG DURING PREGNANCY
1. A patient who reports pregnancy prior to study drug randomization must be withdrawn 
from the study. The pregnancy is recorded as a reason for screen failure. Since there has 
been no exposure to study drug, there is no need to notify Ironwood Drug Safety of the 
pregnancy.
2. A patient who reports pregnancy after randomization, must discontinue study drug at 
once. The site must notify Ironwood Drug Safety of the pregnancy (within 24 hours), 
using the standard Pregnancy Notification Form. The site makes reasonable efforts to 
follow the pregnancy to term and notifies Ironwood Drug Safety of the pregnancy 
outcome (within 24 hours of being informed), using the standard Pregnancy Outcome 
Form.
Adverse Event Reporting Period
At each study visit following the first visit, at the follow-up phone call within 48 hours following 
initial study drug administration (when applicable), and during any communication with a patient 
or patient representative occurring outside a defined study visit, all AEs reported by the patient 
or patient representative or observed or otherwise identified by the investigator or other study 
personnel must be documented. For all AEs, the reporting period begins at the signature of the 
ICF and continues until the patient is lost to follow-up or until completion of study participation 
(e.g., early termination or EOT Visit.)
Serious Adverse Event Reporting Period
Upon learning of an AE considered serious as described in Section 5.5.3.2, the investigator or 
other study personnel must inform Ironwood or designee of the event as soon as possible (not 
later than 24 hours from learning of the event). Reporting will not be delayed pending a 
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resolution or an outcome of the event. If an outcome of an SAE is not available at the time of the 
initial report, Ironwood expects follow-up to proceed until such time as an outcome is known. 
The starting point for the collection of SAEs will be from the time the patient signs the ICF. An 
SAE will be defined as an on-therapy SAE if it occurred on or after the date of the first dose of 
double-blind study drug and within 30 days of the date of the last dose of double-blind study 
drug.
5.5.3.2.2
Follow-Up Procedures for Serious Adverse Events
Ironwood or designee will promptly investigate all safety information received. Follow-up 
information to a safety report will be submitted as soon as the relevant information is available 
(21 CFR § 312.32 [d]).
Relevant information such as discharge summaries, autopsy reports, and medical consultations 
will be reviewed in detail by the investigator. The investigator will comment on any event, 
abnormal laboratory result, or any other finding, noting whether it will be considered adverse or 
part of the patient’s natural disease history and, if adverse, whether it will be considered a serious 
or nonserious AE. In addition, the investigator will report on an SAE form all subsequent events 
or other findings determined to be relevant and will state for each event or finding whether it is 
related to study drug. All events determined to be nonserious will be reported on the relevant 
eCRF form.
5.5.3.3
Clinical Laboratory Determinations
Blood and urine samples will be collected for clinical laboratory tests (according to the study 
specific manual) at the Screening Visit and other visits defined in the Schedule of Evaluations 
(Table 1). At the Screening Visit, the investigator will assess the clinical significance of any 
values outside the reference ranges provided by the central laboratory, and patients with 
abnormalities judged to be clinically significant will be excluded from the study.
Clinical laboratory tests will be performed according to directives in the Schedule of Evaluations 
(Table 1).
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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, and cholesterol
•
Other:
Urine drug screening (cocaine, barbiturates, amphetamines, opiates, 
benzodiazepine, alcohol, and cannabinoids) (screening only). Clinical 
significance of a positive urine drug screen will be assessed by the 
investigator; positive results for cocaine, barbiturates, and cannabinoids 
are exclusionary.
•
Pregnancy test:
Serum human chorionic gonadotropin pregnancy test (for women of 
childbearing potential only) should be conducted at the Screening Visit 
and other visits specified in the Schedule of Evaluations (Table 1). A 
negative urine pregnancy test must be documented at the Randomization 
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 study.
A central laboratory will be used to evaluate all urine and blood samples (except for the urine 
pregnancy test), which will be collected, processed, and stored according to the instructions 
provided by the laboratory.
5.5.3.4
Vital Signs
At every study visit, vital sign measurements will be performed (with the patients in the seated 
position) and documented. The parameters are oral temperature, pulse rate, respiratory rate, and 
systolic and diastolic blood pressure (BP). Pulse and BP readings will be taken after the patient 
has been sitting for five minutes.
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5.5.3.5
Other Safety Assessments
5.5.3.5.1
Physical Examination
A complete physical examination will be performed at the Screening Visit and EOT Visit, as 
defined in the Schedule of Evaluations (Table 1), 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 rectal examination should be performed during the Screening Period in 
all patients who do not require a colonoscopy (refer to Appendix III). 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.
5.5.3.5.2
Medical History
A complete medical history will be provided by the patient at the Screening Visit.
5.6
DATA QUALITY ASSURANCE
5.6.1
Data Monitoring
Before any patient enters the study, 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 study 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 study 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.
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5.6.2
Data Recording and Documentation
All data collected in the context of this study 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. Study records (e.g., essential documents [commonly called regulatory 
documents], correspondence) will be retained at the study center, along with adequate source 
documentation, according to FDA and ICH requirements. All study records must be available for 
inspection by Ironwood, its authorized designee, and the FDA.
Data collection will involve the use of the Medidata RAVE 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 study 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.
5.7
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
5.7.1
Analysis Populations
5.7.1.1
ITT Population
The Intent-to-Treat (ITT) Population consists of all randomized patients who received at least 
one dose of study drug. 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.
5.7.1.2
Safety Population
The Safety Population consists of all randomized patients who received at least one dose of study 
drug. Safety analysis will be based on the Safety population, in which patients are evaluated 
according to the treatment they actually received.
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5.7.2
General Methods
Descriptive statistics (n, mean, standard deviation [SD], minimum, median, and maximum) will 
be calculated to summarize continuous variables. Frequency and percentage of patients in each 
category will be calculated to summarize categorical variables.
Unless otherwise specified, all confidence intervals will be two-sided with a confidence level of 
95%. No adjustments will be made for multiplicity in the conduct of comparisons among the 
linaclotide DR dose for the key efficacy parameters, or in the testing of the other efficacy 
parameters.
Statistical analyses will be performed using Version 9.3 (or newer) of SAS for Windows.
5.7.3
Patient Disposition
The number of screen failures (i.e., patients who entered the Screening Period but not the 
Pretreatment Period) and the number of pretreatment failures (i.e., patients who entered the 
Pretreatment Period but were not randomized) will be tabulated by reason for failure.
The number of randomized patients and the number of patients in the ITT Population will be 
presented by treatment group for each study center within each geographic region.
The number and percentage of randomized patients who are in the ITT Population will be 
presented by treatment group. The number and percentage of randomized patients who complete 
the Treatment Period and those who prematurely discontinue treatment will also be presented by 
treatment group. Furthermore, the number and percentage of randomized patients who 
prematurely discontinue from the Treatment Period will be presented for each treatment group 
by reason for premature discontinuation as recorded on the study completion form of the eCRFs. 
5.7.4
Demographics and Other Baseline Characteristics
Demographic parameters (age; age group; race; ethnicity; sex) and baseline characterisitics 
(weight; height; and body mass index, calculated as weight [kg]/(height [m])2) will be 
summarized descriptively by treatment group for the Safety and ITT populations. Baseline 
efficacy parameters (including SBM frequency, CSBM frequency, stool consistency, straining, 
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abdominal discomfort, abdominal pain, and abdominal bloating) will be summarized 
descriptively by treatment group for the ITT population.
Protocol deviations and important protocol deviations will be identified through blinded data 
review.  
5.7.5
Prior and Concomitant Medicines
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 Treatment Period. Any medicines taken after the date of last dose of study 
drug will be excluded from the summaries related to concomitant medicines.
Both prior and concomitant medicine use will be summarized by the number and percentage of 
patients in each treatment group receiving each medicine within each therapeutic class for the 
ITT Population. Multiple medicines used by a patient in the same category (based on 
Anatomical-Therapeutic-Chemical classification) will be counted only once.
5.7.6
Extent of Exposure and Treatment Compliance
5.7.6.1
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, inclusive, will be summarized by treatment group for the Safety 
Population.
5.7.6.2
Measurement of Treatment Compliance
Dosing compliance for the Treatment Period is defined as the total number of tablets/capsules 
actually taken by a patient during the Treatment Period divided by the number of tablets/capsules 
that were expected to be taken during the Treatment Period multiplied by 100. The total number 
of tablets/capsules actually taken will be calculated by subtracting the total number of 
tablets/capsules returned from the total number of tablets/capsules dispensed. The total number 
of tablets/capsules expected to be taken during the Treatment Period is the number of days 
between the date of first dose taken and the date of last dose taken, inclusive.
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Descriptive statistics for study drug compliance on the Safety Population will be calculated by 
treatment group for the Treatment Period as a whole and for each of the three consecutive 4-
week periods comprising the Treatment Period (consistent with study drug dispensing).
5.7.6.3
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 (number of patients, mean, standard deviation [SD], median, minimum, and 
maximum) for eDiary compliance will be presented for the ITT population by treatment group.
The number and percentage of patients with complete entries ≥ 80% / < 80% of the time during 
the Pretreatment and Treatment Period, as well as the number and percentage of patients with > 4 
/ < 4 complete calls each week will be presented by treatment group for the ITT Population.
5.7.7
Efficacy Analyses
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. 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 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. Baseline values for patient symptom severity 
parameters (e.g., abdominal pain, constipation severity) will be the average of the non-missing 
severity scores reported during this period.
Study centers will be pooled together by geographic region (details to be provided in the 
Statistical Analysis Plan [SAP]). In lieu of study center, geographic region will be used in 
analyses adjusting for center-to-center variability.
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An observed-case approach to missing data will be applied.  Sensitivity analyses of the key 
endpoints will include, but are not limited to, a multiple imputation approach and a last 
observation carried forward (LOCF) 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.
Further sensitivity analyses will be performed employing a modified responder definition that 
emphasizes the end of treatment (namely, 12-week CSBM Sustained Responder, defined as a 
patient who is a CSBM Weekly Responder for at least 9 of the 12 weeks and at least 3 of the last 
4 weeks of the Treatment Period). Details for these analyses will be provided in the SAP.
All hypothesis testing will be performed at a two-sided 0.05 significance level.  No adjustment 
for multiplicity will be applied.
5.7.7.1
Key Efficacy Parameters
There are 3 key efficacy parameters: 1) Weekly Change from Baseline in Abdominal Pain, 
2) Weekly Change from Baseline in CSBM Frequency, and 3) 6/12 Week Abdominal Pain and 
Constipation (APC) +1 Responder. The criteria for each of the 3 primary efficacy parameters are 
provided below:
1. Weekly Change from Baseline in Abdominal Pain
Abdominal pain is measured daily using an 11-point NRS. A patient’s weekly abdominal 
pain score is the average of the nonmissing abdominal pain scores reported by the patient 
during each week.
2. Weekly Change from Baseline in CSBM Frequency
A patient’s weekly CSBM frequency rate is the CSBM rate (CSBMs/week) calculated 
over that week.
3. 6/12 Week 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. The Weekly APC +1 
Responder criteria are defined in Section 5.7.7.3.
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5.7.7.2
Key Efficacy Analysis
For each continuous weekly change-from-baseline measure defined above, inferential testing of 
the change from baseline will be evaluated employing a MMRM framework with week 
(categorical), treatment, and week-by-treatment fixed effects, patient as the random effect, and 
baseline value as a covariate. The initial covariance structure will be compound symmetry but 
exploratory analyses with unstructured and autoregressive (1) structures will also be considered, 
primarily for planning purposes.
Corresponding with the primary efficacy objective of the study, which is to study the dose 
response of a range of oral doses within the linaclotide DR1 and DR2 formulations, the efficacy 
analysis of weekly change from baseline will be conducted by employing an overall trend test 
(i.e., linear contrast) for each formulation to test for a monotonically increasing dose response. 
Within a formulation, if the overall trend test reaches statistical significance (α = 0.05), then that 
linaclotide DR formulation will be considered efficacious and the nature of the dose response 
will be explored among the individual linaclotide DR doses within the formulation. 
 
 
 The treatment-by-week 
interaction will be assessed and, if significant, appropriate trend analyses will be performed at 
each week.
The efficacy analysis of 6/12 Week APC+1 Responder rate will be confirmatory of the above 
and conducted by employing an overall trend test (i.e., Cochran-Mantel-Haenszel [CMH] 
correlation statistic) for each formulation (excluding the Active Control [linaclotide IR]) to test 
for a monotonically increasing dose response within the formulation. If the overall CMH statistic 
reaches statistical significance (α = 0.05), the tested formulation will be considered efficacious 
and the nature of the dose response will be explored among the individual linaclotide DR doses 
within the formulation. 
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5.7.7.3
Other Efficacy Parameters
The other efficacy parameters are as follows:
•
6/12 Week CSBM +1 Responder
A 6/12 Week CSBM +1 Responder is a patient who meets the Weekly CSBM +1 Responder 
criteria for at least 6 out of the 12 weeks of the Treatment Period. The Weekly CSBM +1 
Responder criteria are defined below.
•
9/12 Week CSBM +1 Responder
A 9/12 Week CSBM +1 Responder is a patient who meets the Weekly CSBM +1 Responder 
criteria for at least 9 out of the 12 weeks of the Treatment Period. The Weekly CSBM +1 
Responder criteria are defined below.
•
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. The Weekly 
Abdominal Pain Responder criteria are defined below.
•
9/12 Week Abdominal Pain Responder
A 9/12 Week Abdominal Pain Responder is a patient who meets the Weekly Abdominal Pain 
Responder criteria for at least 9 out of the 12 weeks of the Treatment Period. The Weekly 
Abdominal Pain Responder criteria are defined below.
•
Weekly CSBM +1 Responder
For each week in the Treatment Period, a Weekly CSBM +1 Responder is a patient who has 
an increase from baseline of at least 1 in the CSBM weekly rate for that week. 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 +1 Responder for that week.
•
Weekly Abdominal Pain Responder
For each week in the Treatment Period, a Weekly Abdominal Pain Responder is a patient 
who has a decrease from baseline of at least 30% in the mean abdominal pain score for that 
week. 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.
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•
Weekly APC +1 Responder
For each week in the Treatment Period, a Weekly APC +1 Responder is a patient who meets 
the criteria to be a Weekly CSBM +1 Responder and a Weekly Abdominal Pain Responder. 
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 APC +1 Responder for 
that week.
•
Change from Baseline in 12-week Abdominal Pain
Abdominal pain is measured daily using an 11-point NRS. The patient’s abdominal pain 
score for the Treatment Period is the average of the non-missing daily worst abdominal pain 
scores reported by the patient during the 12-week Treatment Period.
•
Change from Baseline in 12-week CSBM Frequency Rate
A patient’s 12-week CSBM frequency rate will be the CSBM rate (CSBMs/week) calculated 
over the 12 weeks of the Treatment Period.
•
Change from Baseline in 12-week SBM Frequency Rate
A patient’s 12-week SBM frequency rate will be the SBM rate (SBMs/week) calculated over 
the 12 weeks of the Treatment Period.
•
Change from Baseline in 12-week Stool Consistency
Stool consistency is measured using the 7-point BSFS. The patient’s BSFS score for the 
Treatment Period is the average of the non-missing BSFS scores from the SBMs reported by 
the patient during the 12-week Treatment Period.
•
Change from Baseline in 12-week Straining
Straining is measured using a 5-point ordinal scale. The patient’s straining score for the 
Treatment Period is the average of the non-missing straining scores from the SBMs reported 
by the patient during the 12-week Treatment Period.
•
Change from Baseline in 12-week Abdominal Discomfort
Abdominal discomfort is measured daily using an 11-point NRS. The patient’s abdominal 
discomfort score for the Treatment Period is the average of the non-missing daily abdominal 
discomfort scores reported by the patient during the 12-week Treatment Period.
•
Change from Baseline in 12-week Abdominal Bloating
Abdominal bloating is measured daily using an 11-point NRS. The patient’s abdominal 
bloating score for the Treatment Period is the average of the non-missing daily abdominal 
bloating scores reported by the patient during the 12-week Treatment Period.
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•
Change from Baseline in 12-Week Abdominal Symptom Score
The patient’s abdominal symptom score for the Treatment Period is the average of the non-
missing daily abdominal symptom scores reported by the patient during the 12-week 
Treatment Period.
•
Change from Baseline in 12-Week Constipation Severity
Constipation severity is measured weekly using a 5-point ordinal scale. The patient’s 
constipation severity score for the Treatment Period is the average of the non-missing weekly 
constipation severity scores reported by the patient during the 12-week Treatment Period.
•
Change from Baseline in 12-week IBS Symptom Severity
IBS symptom severity is measured weekly on a 5-point ordinal scale. The patient’s IBS 
symptom severity score for the Treatment Period is the average of the non-missing weekly 
IBS symptom severity scores reported by the patient during the 12-week Treatment Period.
•
Change from Baseline in 12-Week Percent of Days with Use of Per-Protocol Rescue 
Medicine
The percent of days using per protocol rescue medicine or any other laxative, suppository, or 
enema during the Treatment Period will be calculated as the 100 * number of days rescue 
medicine was used during the Treatment Period divided by the total number of days on 
treatment.
•
Treatment Satisfaction
Treatment satisfaction is measured on a 5-point ordinal scale. Treatment satisfaction will be 
analyzed separately at each post-dose visit.
•
Assessment of 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 at each post-dose visit.
5.7.7.4
Other Efficacy Analyses
All categorical responder parameters (e.g., Weekly CSBM +1 Responder) will be analyzed 
utilizing the same methods defined above for the key efficacy measure 6/12 Week APC +1 
Responder.
All continuous change-from-baseline in 12-week efficacy parameters will be evaluated by 
comparing each DR1 and DR2 dose with the placebo group using an ANCOVA model with 
treatment group and geographic region as fixed-effect terms and baseline value as a covariate. 
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Least-squares means for each treatment group, least-squares mean differences between each DR1 
and DR2 dose and the placebo group and their corresponding confidence intervals, and p-values 
for the pairwise comparisons versus placebo will be presented. 
 
 
For Treatment Satisfaction, inferential testing will be evaluated employing a MMRM framework 
with week (categorical), treatment, and week-by-treatment fixed effects, and patient as the 
random effect. The covariance structure will be unstructured.
5.7.8
Health Outcomes Analyses
Health outcomes analysis will be based on the ITT Population.
5.7.8.1
SF-12v2
Descriptive statistics (n, mean, SD, median, minimum, and maximum) will be presented for the 
absolute and change-from-baseline Physical Component Summary and Mental Component 
Summary scores at Randomization, Week 4, Week 8, and EOT. Treatment differences for the 
change from baseline at each post-dose visit will be analyzed using an ANCOVA with treatment 
and geographic region as fixed effects and baseline summary score as a covariate.
5.7.8.2
EQ-5D
Patient responses to the descriptive system (i.e., health state) will be converted to the 
corresponding utility score and the descriptive statistics (n, mean, SD, median, minimum and 
maximum) will be presented for utility index score by treatment group. The same statistics will 
be calculated for the visual analog scale of patient’s health rating. Results will be presented for 
the following study visits: Randomization, Week 4, Week 8, and EOT.
5.7.8.3
SF-MPQ-2
At each assessment of the SF-MPQ-2, total pain score and the 4 subscales (Continuous pain, 
Intermittent pain, Neuropathic pain, and Affective pain) will be calculated. Descriptive statistics 
and the change from baseline will be presented for each score. Treatment differences with 
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respect to change from baseline will be assessed using an ANCOVA with treatment and 
geographic region as fixed effects and baseline value as a covariate.
5.7.8.4
Irritable Bowel Syndrome-Symptom Severity Scale
At each assessment of the IBS-SSS, the severity scores will be calculated. Descriptive statistics 
will be presented for the severity score and the other IBS items related to bowel habit (4 items) 
and site of pain (2 items).  
5.7.9
Safety Analyses
All safety parameters will be analyzed descriptively in accordance with the general methods 
described in Section 5.7.2.
5.7.9.1
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 study. A treatment-emergent AE (TEAE) is an 
AE that occurs during the Treatment Period (up to one day after the last dose of double-blind 
study drug) and was not present prior to the date of the first dose, or was present prior to the date 
of the first dose but increased in severity during the Treatment 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 Period that were also coded to that 
preferred term. An AE that occurs more than one day after the last dose of double-blind study 
drug will not be counted as a TEAE.
For the Treatment Period, the number and percentage of patients reporting TEAEs in each 
treatment group 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.
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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.
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. In addition, the incidence of fatal SAEs (i.e., events that caused death), if any, 
will be summarized separately by treatment group and preferred term for the Treatment Period.
Listings will be presented for patients with SAEs, patients with AEs leading to discontinuation, 
and patients who die (if any).
5.7.9.2
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 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. 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 one 
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 one 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, study center, and baseline and post-baseline values. A 
listing of all AEs for patients with PCS laboratory values will also be provided.
5.7.9.3
Vital Signs
Descriptive statistics for vital signs (i.e., 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 study 
will be presented by treatment group for the Treatment Period.
The number and percentage of patients with PCS post-baseline vital signs will be tabulated by 
treatment group for the Treatment Period. A vital sign value will be considered PCS if it meets 
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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 one 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 one 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, study center, and baseline and post-baseline values. A listing of all AEs for patients with 
PCS vital sign values will also be provided.
5.7.10
Interim Analysis
No interim analysis is planned for this study.
5.7.11
Development of Scoring and Psychometric Analysis
The daily completed IBS-C bowel functioning and abdominal symptoms items will be examined 
for the purpose of determining their measurement property and performance as outcomes in this 
sample. If deemed appropriate based on item level performance, scoring algorithms will be 
developed and tested. These analyses will utilize blinded data pooled across treatment and dosing 
groups. If appropriate, factor analysis and/or item response theory (IRT) or Rasch analysis will 
also be performed (to be determined during the development of the SAP). A stand alone 
psychometric statistical analysis plan (SAP) will be developed pror to database lock. The 
psychometric SAP will detail assessments of reliability (test-retest reliability and, where 
appropriate, internal consistency), construct validity (including possible factor analysis, possible 
IRT/Rasch analysis, concurrent/convergent validity and known groups validity), and ability to 
detect change over time. In addition, analyses will be performed to provide guidance for 
interpretation of changes in scores.
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5.7.12
Determination of Sample Size
The sample size per treatment group was determined based on a one-way design and includes 8 
treatments: placebo; 30 µg, 100 µg, or 300 µg of the linaclotide DR1 formulation; 30 µg, 100 µg, 
or 300 µg of the linaclotide DR2 formulation; and the 290 µg dose of the linaclotide IR 
formulation (the FDA-approved dose for IBS-C). Previous trials with linaclotide IR 
demonstrated treatment differences with respect to Change from Baseline in 12-Week 
Abdominal Pain of 0.78 (-1.196 vs. -1.975 for placebo and linaclotide IR, respectively), and a 
standard deviations of 1.73 (based on the root mean squared error from an ANCOVA adjusting 
for baseline pain). Based on these historical values, it was estimated that, within each 
formulation, the highest two active treatment arms (DR1 100 µg and 300 µg; DR2 100 µg and 
300 µg) would reflect the previously observed treatment difference (-1.975), the lowest active 
treatment arms with each formulation (DR1 30 µg; DR2 30 µg) would reflect 50% of the 
observed treatment difference (-1.586), and placebo would reflect the previously observed 
difference (-1.196). Under these assumptions, a study with 65 patients per treatment arm 
(520 total patients) will have 81% power based on a 2-sided linear trends test within each 
formulation (linear contrast: -3 (placebo) -1 (30 µg) 1 (100 µg) 3 (300 µg); IR formulation not 
included) at an alpha level of 0.05. In addition, subsequent pairwise comparison between placebo 
and the active treatment groups reflecting the previously observed treatment difference will have 
73% statistical power (two-sided, α = 0.05).
5.8
CHANGES IN THE CONDUCT OF THE STUDY 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 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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6.
STUDY SPONSORSHIP
6.1
STUDY TERMINATION
Ironwood reserves the right to terminate the study in its entirety or at a specific center at any 
time.
6.2
REPORTING AND PUBLICATION
All data generated in this study will be the property of Ironwood and Forest Laboratories, LLC 
(an affiliate of Actavis, Inc.). An integrated clinical and statistical report will be prepared at the 
completion of the study.
Publication of the results by the investigator will be subject to mutual agreement between the 
investigator and Ironwood.
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7.
INVESTIGATOR OBLIGATIONS
7.1
DOCUMENTATION
The investigator must provide the following to Ironwood or designee prior to the start of the 
study in accordance with ICH E6:
•
A completed and signed Form FDA 1572. If, during the course of the study, 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 original IRB approval for conducting the study. If the study is ongoing, 
renewals must be submitted at yearly intervals. All subsequent 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
•
A financial disclosure agreement completed and signed by the investigator and all 
subinvestigators listed on Form FDA 1572. If applicable, the investigator will provide an 
updated financial disclosure agreement to the Sponsor one year after the completion of the 
study
7.2
PERFORMANCE
The investigator must demonstrate reasonable efforts to obtain qualified patients for the study.
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7.3
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 
subinvestigators 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 study supplies. Ironwood or designee will supply forms on which to 
record the date the study drug was received, the lot number and expiration date of the study drug, 
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.
7.4
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.
7.5
RETENTION AND REVIEW OF RECORDS
The investigator must maintain the documentation relating to this study. If Ironwood or the FDA 
wishes to review any documentation relating to the study, 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 study (e.g., ICFs, clinical laboratory reports, source documents, study 
drug dispensing records) for whichever of the following is the shortest:
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•
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
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 study 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.
7.6
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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9. 
INVESTIGATOR’S STATEMENT 
Study Title: 
A Phase 2b, Randomized, Double-blind, Double-dummy, Placebo-
controlled, Parallel-group, Dose-range-finding Study of Two 
Delayed Release Formulations of Linaclotide Administered Orally 
for 12 Weeks to Patients with Irritable Bowel Syndrome with 
Constipation 
Study Number: 
MCP-103-204 
Final Date: 
09 October 2015 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
 
 
Signed: 
 
 
Date:  
 
<Investigator Name> 
 
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10.
APPENDICES
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APPENDIX I
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 study or from the patient’s LAR. 
This consent must include the following items:
•
A statement that the study 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 study, 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 study
•
A statement of consent (e.g., “I agree to participate . . .”)
•
A place for the patient’s signature and date of signing
A copy of the signed consent form should be given to the patient.
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APPENDIX II
CONCOMITANT AND PROHIBITED MEDICINES 
Rescue Medicine
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 and Treatment 
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 calendar day 
before the Randomization Visit and 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 calendar day after the Randomization 
Visit.
Prohibited Medicine
All medicine listed in the sections below (“1-day Washout” and “14-day Washout”) are excluded 
during the Pretreatment and Treatment Periods. A 1-day washout means that the particular 
medicine is not allowed during the calendar day before the Pretreatment Visit; a 14-day washout 
means that the particular medicine is not allowed during the 14 calendar days before the 
Pretreatment Visit.
1-DAY WASHOUT (no medicine during the calendar day before the Pretreatment Visit)
1. Any over-the-counter or prescription laxative, suppository, or enema (e.g., 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 study.
2. Any medicine used to treat diarrhea (e.g., bismuth subsalicylate, kaolin).
3. NSAIDs if taken for abdominal pain or discomfort.
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14-DAY WASHOUT (no medicine during the 14 calendar days before the Pretreatment Visit)
1. Drugs with known pharmacological activity at 5-hydroxytryptophan (HT)4, 5-HT2b or 
5-HT3 receptors (e.g., 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 participated in a linaclotide or 
plecanatide clinical study during the 30 days before the Screening Visit.
3. Prokinetic agents (e.g., metoclopramide, itopride, prucalopride, and domperidone).
4. Anti-cholinergic agents (e.g., dicyclomine, flavoxate, scopolamine, hyoscyamine, 
propantheline, oxybutynin, tolterodine, solefenacin, darifenacin, and trospium). Note: 
inhaled ipratropium and tiotropium are permitted.
5. Bile acid sequestrants (e.g., cholestyramine and colestipol).
6. Cholinomimetic agents (e.g., bethanechol, pyridostigmine, tacrine, and physostigmine). 
Note: intraocular cholinomimetic agents (e.g., pilocarpine) are permitted.
7. Antipsychotic agents (e.g., 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 (e.g., amitriptyline, imipramine, and nortriptyline);
-
Monoamine oxidase inhibitors (e.g., furazolidone, isocarboxazid, pargyline, 
phenelzine, and selegiline tranylcypromine);
-
Selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine, and 
citalopram);
-
Serotonin and norepinephrine reuptake inhibitors (e.g., venlafaxine and desvenlafaxine 
succinate)
-
Others (e.g., 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 (e.g., nifedipine, diltiazem, amlodipine, 
felodipine, nicardipine, nimodipine, nisoldipine, etc.) are permitted and may be used 
without restriction.
10. Oral and parenteral antibiotics (However, a standard regimen [up to 10 days] of oral 
antibiotics is permitted.)
11. Any investigational or imported drugs that have not been approved for human use by the 
US FDA.
12. All narcotics either alone or in combination (e.g., tramadol, codeine, morphine, 
propoxyphene, loperamide, diphenoxylate, and paregoric). Note: narcotics used as 
anesthesia for a colonoscopy require a 5 calendar day wash-out prior to the patient entering 
into the Pretreatment Period.
13. Any medicine taken for the purpose of losing weight (e.g., orlistat, phentermine, 
phendimetrazine, diethylpropion, benzphetamine, and sibutramine).
14. Any medicine that is known to cause diarrhea (e.g., acarbose).
15. Proton pump inhibitors (e.g., 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 (e.g., butalbital and phenobarbital) and chronic oral or parenteral 
glucocorticoids (which must be discontinued at least three months before the Screening 
Visit; however, one 10-day course of oral or one injection of parenteral glucocorticoids is 
permitted during the Pretreatment or Treatment 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 study.
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APPENDIX III
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 two or fewer small (< 1 
cm) tubular adenomas without appreciable villous tissue or high-grade dysplasia and 
provided the colonoscopy was performed during the five 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 two first-degree relatives with colorectal cancer diagnosed at 
any age must have had a colonoscopy with negative findings during the five 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 two 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 five 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. 
Because narcotics are used as anesthesia for a colonoscopy, patients are eligible to enter the 
Pretreatment Period on the fifth calendar day after a colonoscopy. 
Source: Winawer, et al, (2003)
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APPENDIX IV
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 V
KEY EFFICACY ASSESSMENTS
Complete Spontaneous Bowel Movement
Did you feel like you completely emptied your bowels after your bowel movement?
1 = Yes
2 = No
Daily Patient Assessment of Abdominal Pain at its Worst
How would you rate your worst abdominal pain in the past 24 hours?

0

1

2

3

4

5

6

7

8

9

10
No abdominal
pain
Worst possible 
abdominal pain
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APPENDIX VI
OTHER EFFICACY ASSESSMENTS
Stool Consistency
[BSFS]
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)
[Note: This item (BSFS) will be administered with pictures.]
[5 Point Ordinal Scale]
How would you describe the consistency of your stool? 
Very hard
Hard
Neither too hard nor too soft
Loose but not watery
Very loose and watery
Straining
How much did you strain during your bowel movement?
Not at all
A little (mild straining)
A fair amount (moderate straining)
A large amount (severe straining)
An extreme amount (extremely severe straining)
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Daily Patient Assessment of Abdominal Discomfort at its Worst
How would you rate your worst abdominal discomfort in the past 24 hours?

0

1

2

3

4

5

6

7

8

9

10
No abdominal 
discomfort
Worst possible 
abdominal 
discomfort
Daily Patient Assessment of Abdominal Bloating at its Worst
How would you rate your worst abdominal bloating in the past 24 hours?

0

1

2

3

4

5

6

7

8

9

10
No abdominal 
bloating
Worst possible 
abdominal 
bloating
Weekly Patient Assessment of Constipation Severity
On average, how would you rate your constipation during the past 7 days?
1=None
2=Mild
3=Moderate
4=Severe
5=Very severe
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Weekly Patient Assessment of IBS Symptom Severity
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
Weekly Patient Assessment of Adequate Relief
Overall, have you had adequate relief from your IBS symptoms during the past 7 days?
1 = Yes
2 = No
Treatment Satisfaction Assessment
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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APPENDIX VII SF-12V2
 
Your Health and Well-Being 
  
This survey asks for your views about your health. This information will help 
keep track of how you feel and how well you are able to do your usual activities. 
Thank you for completing this survey! 
 
For each of the following questions, please mark an 
 in the one box that best 
describes your answer. 
 
1. In general, would you say your health is: 
2. The following questions are about activities you might do during a typical 
day.  Does your health now limit you in these activities?  If so, how much? 
 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
 
  
 
a Moderate activities, such as moving a table, pushing  
a vacuum cleaner, bowling, or playing golf ............................. 
 1 ..............
 2 ............. 
 3
 
b Climbing several flights of stairs ............................................. 
 1 ..............
 2 ............. 
 3
Excellent 
Very good 
Good 
Fair 
Poor 
 



 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
SF-12v2® Health Survey © 1994, 2002 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-12® is a registered trademark of Medical Outcomes Trust. 
 
(SF-12v2® Health Survey Acute, United States (English)) 
 
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SF-12v2® Health Survey © 1994, 2002 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-12® is a registered trademark of Medical Outcomes Trust. 
 
(SF-12v2® Health Survey Acute, United States (English)) 
3. During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health?  
4. During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)? 
5. During the past week, how much did pain interfere with your normal work 
(including both work outside the home and housework)?  
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2
 
3
 
4
  
 5 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
 
a 
Accomplished less than you  
 
 
would like ......................................
 1 ............. 
 2 ..............
 3 .............. 
 4 .............
 5 
 
b 
Were limited in the kind of  
 
 
work or other activities ..................
 1 ............. 
 2 ..............
 3 .............. 
 4 .............
 5
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
 
a 
Accomplished less than you  
 
 
would like ......................................
 1 ............. 
 2 ..............
 3 .............. 
 4 .............
 5 
 
b 
Did work or other activities 
 
 
less carefully than usual ................
 1 ............. 
 2 ..............
 3 .............. 
 4 .............
 5
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SF-12v2® Health Survey © 1994, 2002 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-12® is a registered trademark of Medical Outcomes Trust. 
 
(SF-12v2® Health Survey Acute, United States (English)) 
6. These questions are about how you feel and how things have been with you 
during the past week.  For each question, please give the one answer that 
comes closest to the way you have been feeling.  How much of the time 
during the past week… 
7. During the past week, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)? 
 
 
 
 
 
 
 
Thank you for completing these questions! 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
 
a 
Have you felt calm and   
peaceful? ........................................
 1 .............. 
 2 ..............
 3 .............. 
 4 ..............
 5
 
b 
Did you have a lot of energy? .......
 1 .............. 
 2 ..............
 3 .............. 
 4 ..............
 5
 
c 
Have you felt downhearted   
and depressed? ...............................
 1 .............. 
 2 ..............
 3 .............. 
 4 ..............
 5
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
 
 
 
 
  
 1 
  
 2
 
3
 
4
  
 5 
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APPENDIX VIII EQ-5D QUESTIONNAIRE 
By placing a checkmark in one box in each group below, please indicate which statements best 
describe your own health state today.
Mobility
I have no problems in walking about
I have some problems in walking about
I am confined to bed
Self-Care
I have no problems with self-care
I have some problems washing or dressing myself
I am unable to wash or dress myself
Usual Activities (e.g., work, study, housework, family, or leisure activities)
I have no problems with performing my usual activities 
I have some problems with performing my usual activities
I am unable to perform my usual activities
Pain/Discomfort
I have no pain or discomfort
I have moderate pain or discomfort
I have extreme pain or discomfort
Anxiety/Depression
I am not anxious or depressed
I am moderately anxious or depressed
I am extremely anxious or depressed
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To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the 
worst state is marked 0.
We would like you to indicate on this scale how good or 
bad your own health is today, in your opinion.  Please do 
this by drawing a line from the box below to whichever 
point on the scale indicates how good or bad your health 
state is today.
Your own
health state
today
9 0
8 0
7 0
6 0
5 0
4 0
3 0
2 0
1 0
100
Worst
imaginable
health state
0
Best 
imaginable
health state
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APPENDIX IX
SHORT-FORM MCGILL PAIN QUESTIONNAIRE-2
 
This questionnaire provides you with a list of words that describe some of the different qualities of pain 
and related symptoms. Please put an X through the numbers that best describe the intensity of each 
of the pain and related symptoms you felt during the past week. Use 0 if the word does not describe 
your pain or related symptoms.
Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2)
1. Throbbing pain
2. Shooting pain
3. Stabbing pain
4. Sharp pain
5. Cramping pain
6. Gnawing pain
7. Hot-burning pain
8. Aching pain
9. Heavy pain
10. Tender
11. Splitting pain
12. Tiring-exhausting
13. Sickening
14. Fearful
15. Punishing-cruel
16. Electric-shock pain
17. Cold-freezing pain
18. Piercing
19. Pain caused by
light touch
20. Itching
21. Tingling or ‘pins
and needles’
22. Numbness
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
1
2
3
4
5
6
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8
9
10
none
worst possible
0
1
2
3
4
5
6
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8
9
10
none
worst possible
0
1
2
3
4
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6
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9
10
none
worst possible
0
1
2
3
4
5
6
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9
10
none
worst possible
0
1
2
3
4
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10
none
worst possible
0
1
2
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5
6
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9
10
none
worst possible
0
1
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none
worst possible
0
1
2
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10
none
worst possible
0
1
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10
none
worst possible
0
1
2
3
4
5
6
7
8
9
10
none
worst possible
0
©R. Melzack and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). 
Information regarding permission to reproduce the SF-MPQ-2 can be obtained at www.immpact.org.
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APPENDIX X
IRRITABLE BOWEL SYNDROME-SYMPTOM 
                         SEVERITY SCALE 
IBS-SSS Questionnaire
1.
A.  Do you currently (in the last month) suffer from abdominal (tummy) pain?
  Yes
  No
B.  If yes, how severe is your abdominal (tummy) pain?  Please indicate a number from 0 
to 10, with 0 meaning “ no pain” and 10 meaning “very severe.”
no pain
0 1 2 3 4 5 6 7 8 9 10
very severe
C.  Please enter the number of times that you get the pain every 10 days.  For example, if 
you choose 4 it means that you get pain 4 out of 10 days.  If you get pain every day 
enter 10.
no days with pain
0 1 2 3 4 5 6 7 8 9 10
10 days with pain
2.         A.  Do you currently suffer from abdominal distention* (bloating, swollen or tight     
tummy)?  *Women, please ignore distention related to your period.
  Yes
  No
B.  If yes, how severe is your abdominal distention/tightness?  Please indicate a number 
from 0 to 10, with 0 meaning “no distention” and 10 meaning “very severe.”
no distention
0 1 2 3 4 5 6 7 8 9 10
very severe
3.
How dissatisfied are you with your bowel habits?  Please indicate a number from 0 to 10, 
with 0 meaning “very happy” and 10 meaning “very unhappy.”
very happy
0 1 2 3 4 5 6 7 8 9 10
very unhappy
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4.
Please indicate how much abdominal pain or discomfort or altered bowel habits are 
affecting or interfering with your life in general.  Please indicate a number from 0 to 10, 
with o meaning “not at all” and 10 meaning “completely.”
not at all 
0 1 2 3 4 5 6 7 8 9 10
completely
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11.
LITERATURE CITED
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15. Rao S, Lembo AJ, Shiff SJ, Lavins BJ, Currie MG, Jia XD, et al. A 12-week, randomized, 
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Linaclotide Delayed Release 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-204-P-03 
 
09 October 2015 
 
Document Date: 09-Oct-2015 11:10