Conditions: Irritable Bowel Syndrome With Constipation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 759
Healthy volunteers: no

Brief summary:
The objectives of this study are to evaluate the safety, efficacy, and dose response of two 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). Additional objectives include understanding how the two DR formulations compare with each other and with the FDA-approved 290 μg LINZESS® (the immediate release \[IR\] formulation of linaclotide).

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None

Interventions: intervention 1: Linaclotide intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Oral, once daily intervention 2: Oral, once daily

Protocol document:
Prot_001.pdf: 
 
 
 
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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Clinical Study Protocol: MCP-103-204-P-03 
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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
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
©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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Clinical Study Protocol: MCP-103-204-P-03 
 
09 October 2015 
 
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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
Linaclotide Delayed Release 
 
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Clinical Study Protocol: MCP-103-204-P-03 
 
09 October 2015 
 
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Page 115 of 117
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
Linaclotide Delayed Release 
 
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Clinical Study Protocol: MCP-103-204-P-03 
 
09 October 2015 
 
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Page 116 of 117
11.
LITERATURE CITED
1. Drossman DA, Corazziari E, Delvaux N, Spiller R, Talley NJ, Thompson CA, et al. Rome 
III:  The functional gastrointestinal disorders. 3 ed. McLean, VA: Degnon Associates; 2006.
2. Sandler RS, Jordan MC, Shelton BJ. Demographic and dietary determinants of constipation 
in the US population. Am J Public Health 1990 Feb;80(2):185-9.
3. Camilleri M, Prather CM. The irritable bowel syndrome: mechanisms and a practical 
approach to management. Ann Intern Med 1992 Jun 15;116(12 Pt 1):1001-8.
4. Thompson WG. Irritable bowel syndrome: pathogenesis and management. Lancet 1993 Jun 
19;341(8860):1569-72.
5. Lynn RB, Friedman LS. Irritable bowel syndrome. N Engl J Med 1993 Dec 
23;329(26):1940-5.
6. Zighelboim J, Talley NJ. What are functional bowel disorders? Gastroenterology 1993 
Apr;104(4):1196-201.
7. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable 
bowel syndrome. Gastroenterology 2002 Dec;123(6):2108-31.
8. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterology 2006;130:1480-91.
9. Kanazawa M, Palsson OS, Thiwan SI, Turner MJ, van Tilburg MA, Gangarosa LM, et al. 
Contributions of pain sensitivity and colonic motility to IBS symptom severity and 
predominant bowel habits. Am J Gastroenterol 2008 Oct;103(10):2550-61.
10. Forte LR. Guanylin regulatory peptides: structures, biological activities mediated by cyclic 
GMP and pathobiology. Regul Pept 1999;81(1-3):25-39.
11. Sindic A. Cellular Effects of Guanylin and Uroguanylin. J Am Soc Nephrol 2005.
12. Castro J, Harrington AM, Hughes PA, Martin CM, Ge P, Shea CM, et al. Linaclotide Inhibits 
Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and 
Extracellular Cyclic GMP. Gastroenterology 2013 Dec;145(6):1334-46.e1-11.
13. Busby RW, Kessler MM, Bartolini WP, Bryant AP, Hannig G, Higgins CS, et al. 
Pharmacological Properties, Metabolism and Disposition of Linaclotide, a Novel Therapeutic 
Peptide Approved for the Treatment of Irritable Bowel Syndrome with Constipation and 
Chronic Idiopathic Constipation. J Pharmacol Exp Ther 2013;344:196-206.
14. Chey WD, Lembo AJ, Lavins BJ, Shiff SJ, Kurtz CB, Currie MG, et al. Linaclotide for 
irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-
controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012 Sep 18;107:1702-
12.
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Clinical Study Protocol: MCP-103-204-P-03 
 
09 October 2015 
 
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Page 117 of 117
15. Rao S, Lembo AJ, Shiff SJ, Lavins BJ, Currie MG, Jia XD, et al. A 12-week, randomized, 
controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and 
safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012 
Sep 18;107:1714-25.
16. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol 1997 Sep;32(9):920-4.
17. Ware John E.Jr., Kosinski M. A 12-Item Short-Form Health Survey: Construction of Scales 
and Preliminary Tests of Reliability and Validity. Med Care 1996;34:220-33.
18. EuroQol--a new facility for the measurement of health-related quality of life. The EuroQol 
Group. Health Policy 1990 Dec;16(3):199-208.
19. Shaw JW, Johnson JA, Coons SJ. U.S. valuation of the EQ-5D health states: development 
and testing of the D1 valuation model. Med Care 2005;43:203-20.
20. Dworkin RH, Turk DC, Revicki DA, Harding G, Coyne KS, Peirce-Sandner S, et al. 
Development and initial validation of an expanded and revised version of the Short-form 
McGill Pain Questionnaire (SF-MPQ-2). Pain 2009 Jul;144(1-2):35-42.
21. Francis C, Morris J, Whorwell P: The irritable bowel severity scoring system: a simple 
method of monitoring irritable bowel syndrome and its progress.  Aliment Pharmacol 
Ther 1997, 11:395-402.
Linaclotide Delayed Release 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-204-P-03 
 
09 October 2015 
 
Document Date: 09-Oct-2015 11:10

SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN: MCP-103-204-SAP-01
Final Version 1.0, 04 October 2016
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
Product Name:
linaclotide
Sponsor:
Ironwood Pharmaceuticals, Inc
301 Binney Street
Cambridge, MA 02142
Final Date:
04 October 2016
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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Statistical Analysis Plan: MCP-103-204-SAP-01
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS......................................................................................................8
1.
INTRODUCTION.............................................................................................................10
2.
STUDY OBJECTIVES .....................................................................................................11
3.
STUDY DESIGN..............................................................................................................12
3.1
GENERAL DESCRIPTION ....................................................................................12
3.2
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL 
GROUPS.................................................................................................................12
3.3
TREATMENTS ADMINISTERED.........................................................................13
3.4
METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ................14
3.5
BLINDING..............................................................................................................14
4.
DETERMINATION OF SAMPLE SIZE...........................................................................15
5.
PHARMACOKINETICS, EFFICACY AND SAFETY ASSESSMENTS .........................16
5.1
STUDY SCHEMATIC AND SCHEDULE OF ASSESSMENT ..............................16
5.2
PHARMACOKINETIC ASSESSMENTS ...............................................................20
5.3
EFFICACY ASSESSMENTS..................................................................................20
5.3.1
Key Efficacy Assessments..............................................................................20
5.3.2
Other Efficacy Assessments ...........................................................................21
5.3.3
Health Outcomes Assessments .......................................................................25
5.3.3.1
Short Form-12 Health Survey Version 2 (SF-12v2) ..............................25
5.3.3.2
EuroQoL-5 Dimension (EQ-5D-3L) .....................................................25
5.3.3.3
Short Form McGill Pain Questionnaire-2 (SF-MPQ-2).........................26
5.3.3.4
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS) ............26
5.4
SAFETY ASSESSMENTS......................................................................................26
5.4.1
Adverse Events ..............................................................................................26
5.4.1.1
Causality Assessment ...........................................................................27
5.4.1.2
Severity Assessment.............................................................................27
5.4.1.3
Serious Adverse Events ........................................................................27
5.4.2
Medical History .............................................................................................27
5.4.3
Physical Examination.....................................................................................27
5.4.4
Vital Signs .....................................................................................................28
5.4.5
Clinical Laboratory Data................................................................................28
6.
STATISTICAL METHODS..............................................................................................29
6.1
GENERAL METHODS...........................................................................................29
6.2
ADJUSTING FOR COVARIATES .........................................................................29
6.3
HANDLING OF DROPOUTS/MISSING DATA IMPUTATION METHOD..........29
6.4
INTERIM ANALYSIS AND DATA MONITORING .............................................30
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6.5
MULTICENTER STUDIES ....................................................................................30
6.6
MULTIPLE COMPARISONS/MULTIPLICITY.....................................................30
6.7
USE OF AN EFFICACY SUBSET..........................................................................30
6.8
ACTIVE CONTROL TO SHOW EQUIVALENCE ................................................30
6.9
EXAMINATION OF SUBGROUPS .......................................................................30
7.
ANALYSIS METHODS ...................................................................................................31
7.1
PATIENT POPULATIONS.....................................................................................31
7.1.1
Screened Population.......................................................................................31
7.1.2
Randomized Population .................................................................................31
7.1.3
Safety Population...........................................................................................31
7.1.4
Intent-to-Treat Population ..............................................................................31
7.2
PROTOCOL DEVIATIONS....................................................................................31
7.3
PATIENT DISPOSITION .......................................................................................32
7.4
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...................33
7.5
MEASUREMENT OF TREATMENT COMPLIANCE...........................................33
7.6
EXTENT OF EXPOSURE ......................................................................................34
7.7
PRIOR AND CONCOMITANT MEDICATION.....................................................35
7.8
EDIARY COMPLIANCE........................................................................................35
7.9
EFFICACY ANALYSIS..........................................................................................36
7.9.1
Key Efficacy Parameter(s)..............................................................................37
7.9.1.1
Analyses of the Key Efficacy Parameters..............................................38
7.9.1.2
Sensitivity Analyses of the Key Efficacy Parameters ............................39
7.9.2
Other Efficacy parameter(s) ...........................................................................40
7.9.2.1
Sustained Responders ...........................................................................43
7.9.2.2
Analyses of Other Efficacy Parameters.................................................44
7.10
POSITIVE CONTROL............................................................................................45
7.11
SAFETY ANALYSIS..............................................................................................45
7.11.1
Adverse Events ..............................................................................................45
7.11.2
Clinical Laboratory Parameters ......................................................................47
7.11.3
Vital Signs .....................................................................................................49
7.11.4
Other Safety Parameters.................................................................................50
7.11.4.1
Physical Examination ...........................................................................50
7.12
HEALTH OUTCOMES ANALYSIS.......................................................................50
7.12.1
Short Form-12 Health Survey Version 2.........................................................50
7.12.2
EuroQol-5 Dimension (EQ-5D-3L)................................................................51
7.12.3
Short Form McGill Pain Questionnaire - 2 (SF-MPQ-2).................................51
7.12.4
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS)......................51
8.
CHANGES FROM ANALYSES PLANNED IN THE PROTOCOL.................................52
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9.
DATA HANDLING CONVENTIONS..............................................................................54
9.1
VISIT TIME WINDOWS FOR SAFETY ANALYSIS............................................54
9.2
VISIT TIME WINDOWS FOR EFFICACY ANALYSIS........................................54
9.3
POOLING OF TRIAL CENTERS...........................................................................56
9.4
DERIVED EFFICACY VARIABLES .....................................................................56
9.4.1
Patient Recall for eDiary Data........................................................................56
9.4.2
Handling of Missing eDiary Data...................................................................58
9.4.3
Weekly Stool Frequency Rates.......................................................................60
9.4.3.1
Length of an Analysis Week.................................................................60
9.4.3.2
Weekly Stool Frequency Rate Calculations ..........................................60
9.4.3.3
Overall Weekly Stool Frequency Rate Calculations for Each Analysis 
Period...................................................................................................61
9.4.4
Other Weekly Scores Derivation ....................................................................61
9.5
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS.......................................................................................................62
9.6
MISSING DATE OF THE LAST DOSE OF STUDY DRUG..................................62
9.7
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS ........................62
9.8
MISSING RELATIONSHIP TO STUDY DRUG FOR ADVERSE EVENTS .........63
9.9
MISSING DATE INFORMATION FOR ADVERSE EVENTS ..............................63
9.10
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS......................................................................................................65
9.10.1
Incomplete Start Date.....................................................................................66
9.10.2
Incomplete Stop Date.....................................................................................66
9.11
CHARACTER VALUES OF CLINICAL LABORATORY PARAMETERS ..........67
9.12
HEALTH OUTCOME PARAMETERS ..................................................................68
9.12.1
Short Form 12 Health Survey Version 2.........................................................68
9.12.2
EuroQol-5 dimension (EQ-5D-3L).................................................................71
9.12.3
Short Form McGill Pain Questionnaire - 2 (SF-MPQ-2).................................72
9.12.4
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS)......................73
10. REFERENCES..................................................................................................................74
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Statistical Analysis Plan: MCP-103-204-SAP-01
04 October 2016
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LIST OF IN-TEXT TABLES
Table 1.
Treatments Administered ...............................................................................14
Table 2.
Schedule of Evaluations MCP-103-204..........................................................17
Table 3.
Criteria for Potentially Clinically Significant Laboratory Results ...................48
Table 4.
Criteria for Potentially Clinically Significant Vital Signs................................50
Table 5.
Visit Time Windows for Safety Analysis........................................................54
Table 6.
Analysis Time Windows for Efficacy Analysis ..............................................55
Table 7.
Definition of Geographic Regions..................................................................56
Table 8.
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters .....................................................................................................68
Table 9.
Summary of Formulas for Scoring and Transforming Scales..........................69
Table 10.
1998 General US Population Means and Standard Deviations Used to 
Derive Short Form-12 Health Survey, Version 2.0, z-Scores—Acute Form....70
Table 11.
1990 Factor Score Coefficients Used to Derive Physical Component 
Summary and Mental Component Summary Scale Scores—Standard and 
Acute Forms ..................................................................................................70
Table 12.
EuroQol Quality-of-Life Questionnaire Utility Index .....................................72
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LIST OF IN-TEXT FIGURES
Figure 1.
Overview of Study Design .............................................................................13
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04 October 2016
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LIST OF APPENDICES
Appendix I.
Bristol Stool Form Scale ................................................................................75
Appendix II.
SF-12v2 .........................................................................................................76
Appendix III.
EQ-5D-3L Questionnaire ...............................................................................79
Appendix IV.
Short-Form McGill Pain Questionnaire-2.......................................................81
Appendix V.
Irritable Bowel Syndrome-Symptom Severity Scale.......................................82
Appendix VI.
Mixed Model for Repeated Measures.............................................................84
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Statistical Analysis Plan: MCP-103-204-SAP-01
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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APC
Abdominal Pain and Constipation
AST
aspartate aminotransferase
BM
bowel movement
BP
blood pressure
bpm
beats per minute
BSFS
Bristol Stool Form Scale
CBC
complete blood count
CIC
chronic idiopathic constipation
CMH
Cochran-Mantel-Haenszel
CSBM
complete spontaneous bowel movement
DR
delayed release
DR1
delayed release formulation 1 – targeted to release in ileal region
DR2
delayed release formulation 2 – targeted to release in the late ileum to 
ascending colon 
eCRF
electronic case report form
eDiary
electronic diary
EOT
End-of-Treatment Period
EQ-5D-3L
EuroQol-5 Dimension
HEENT
head, ears, eyes, nose, throat
IBS-C
Irritable Bowel Syndrome with Constipation
IBS-SSS
Irritable Bowel Syndrome – Symptom Severity Scale
ICF
informed consent form
IPD
Important Protocol Deviations
IR
immediate release
ITT
Intent-to-Treat
IWRS
interactive web response system
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LLN
lower limit of normal
LOCF
last observation carried forward
LS
least-squares
MCMC
Monte-Carlo Markov chain
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MMRM
Mixed Model Repeated Measures
NRS
numerical rating scale
OC
observed case
PCS
potentially clinically significant
PID
patient identification number
RM
rescue medication
SAE
serious adverse event
SAP
statistical analysis plan
SBM
spontaneous bowel movement 
SD
standard deviation
SF-12-v2
Short Form-12 Health Survey Version 2
SF-MPQ-2
Short Form McGill Pain Questionnaire - 2
SI
Le Système International d’Unités (International System of Units)
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
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1.
INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and/or specified in the amended 
protocol of Study MCP-103-204-P-03 (dated 09 October 2015). Specifications for the tables, 
figures, and data listings are contained in a separate document. 
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2.
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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3.
STUDY DESIGN
3.1
GENERAL DESCRIPTION
The MCP-103-204 study is a multicenter, randomized, double-blind, double-dummy, placebo-
controlled, parallel group, multiple-dose, 12-week study, consisting of 3 distinct periods
(Screening, Pretreatment, and Treatment). The study will enroll patients who have IBS-C 
diagnosed using Rome III criteria. Approximately 520 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.
 
 
 
 
The length of this trial is 14-18 weeks, with 3 distinct periods, including up to 21 days of 
Screening, 14 to 21 days of Pretreatment, and 12 weeks of double-blind treatment. Signed 
informed consent from the patient or the patient’s legally authorized representative will be 
obtained before any study-related procedures begin. During the Pretreatment Period, patients will 
provide daily information on bowel habits, symptom severity, and use of Rescue Medicine. 
Patients meeting all of the entry criteria for this trial at the end of the Pretreatment Period will 
enter the Treatment Period.
3.2
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF 
CONTROL GROUPS
A double-blind, placebo-controlled, parallel-group study design was chosen in accordance with 
the concepts in ICH E10, Choice of Control Groups and Related Issues in Clinical Trials, in 
order to provide comparable treatment groups and minimal chance of selection or investigator 
bias. 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 
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a capsule and both linaclotide DR formulations are supplied as tablets), a double-dummy design 
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., electronic diary 
[eDiary]), and a 12-week Treatment Period to compare the test treatment to the placebo control 
and the active control, Linaclotide IR 290 ug (See Figure 1).
Figure 1.
Overview of Study Design
Note: there is no Day 0.
*Applicable to a subset of patients
**This visit represents the end of the study
3.3
TREATMENTS ADMINISTERED
Patients will be instructed to take one tablet and one capsule in the morning at least 30 minutes 
before breakfast. 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 described in Table 1:
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04 October 2016
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Table 1.
Treatments Administered
Treatment Group
Capsule
Tablet
30 μg linaclotide DR1
Placebo
30 μg linaclotide DR1
100 μg linaclotide DR1
Placebo
100 μg linaclotide DR1
300 μg linaclotide DR1
Placebo
300 μg linaclotide DR1
30 μg linaclotide DR2
Placebo
30 μg linaclotide DR2
100 μg linaclotide DR2
Placebo
100 μg linaclotide DR2
300 μg linaclotide DR2
Placebo
300 μg linaclotide DR2
290 μg linaclotide IR
290 μg linaclotide IR
Placebo
Placebo
Placebo
Placebo
Oral capsule and oral tablet both administered once daily in the morning at least 30 minutes before 
breakfast
3.4
METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
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 (described in Section 3.3). 
Randomization numbers will be assigned by interactive web response system (IWRS).
3.5
BLINDING
This study is a double-blind, double-dummy study.
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4.
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 deviation 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 Change from Baseline (-1.975), the lowest active 
treatment arms within each formulation (DR1 30 µg; DR2 30 µg) would achieve a Change from 
Baseline of -1.586 reflecting 50% of the observed prior treatment difference (-0.39), and placebo 
would reflect the previously observed Change from Baseline (-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).
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5.
PHARMACOKINETICS, EFFICACY AND SAFETY 
ASSESSMENTS
5.1
STUDY SCHEMATIC AND SCHEDULE OF ASSESSMENT
The schedule of evaluations for Study MCP-103-204 is presented in Table 2.  The double-blind 
treatment period starts with the first dose of double-blind study drug and ends with the last 
assessment.
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Table 2.
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 2.
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-3L
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
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AE = adverse event; BM = bowel movement; CIC = chronic idiopathic constipation; CBC = complete blood count; EQ-5D-3L = EuroQoL-5 Dimension; IBS-
SSS = Irritable Bowel Syndrome – Symptom Severity Scale; ICF = informed consent form; SF-12-v2 = Short Form-12 Health Survey version 2; SF-MPQ-2 = 
Short Form McGill Pain Questionnaire-2
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. 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.
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.
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. 
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-3L, 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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5.2
PHARMACOKINETIC ASSESSMENTS
There are no pharmacokinetic assessments planned for this study.
5.3
EFFICACY ASSESSMENTS
5.3.1
Key Efficacy Assessments
The key efficacy assessments that will be used to determine the key efficacy parameters are the 
eDiary questions that determine whether a bowel movement (BM) is a complete spontaneous 
BM (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.  
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.) The patient will also complete eDiary entries on an event-driven basis to report use of
Rescue Medicines (e.g., oral bisacodyl; bisacodyl suppository), laxatives, suppositories, or 
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enemas 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 
numerical rating scale (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”>
5.3.2
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 (SBM)
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
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 Bristol 
Stool Form Scale (BSFS; Appendix I) which depicts the stool consistency characteristics along 
with descriptions for each of them. The patient assigns a corresponding score for each BM. 
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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
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)
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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”>
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
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Weekly Patient Assessment of IBS Symptom Severity
Patient assessment of IBS symptom severity will be reported weekly by eDiary entry. The rating 
of IBS symptom severity during the previous 7 days on a 5-point ordinal scale will be provided 
by the patient answering the following question: 
“On average, how would you rate your IBS symptoms during the past 7 days?”
1=None
2=Mild
3=Moderate
4=Severe
5=Very severe
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
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2=A little satisfied
3=Moderately satisfied
4=Quite satisfied
5=Very satisfied
5.3.3
Health Outcomes Assessments
5.3.3.1
Short Form-12 Health Survey Version 2 (SF-12v2)
The SF-12v2 Health Survey (1) is a widely used generic measure of health status (Appendix II). 
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).
5.3.3.2
EuroQoL-5 Dimension (EQ-5D-3L)
The EQ-5D-3L is a generic measure of health status that is widely used in Europe (Appendix 
III)(2). 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.(3) The second component of the EQ-5D-3L 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-3L 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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5.3.3.3
Short Form McGill Pain Questionnaire-2 (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 IV) (4). 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.
5.3.3.4
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS)
The Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS, Appendix V) (5) contains 
seven questions that ask patients to rate the severity and frequency of their abdominal pain, the 
severity of their abdominal distention, the dissatisfaction with their bowel habits, and how much 
abdominal pain or discomfort or altered bowel habits interfere with their life in general. The IBS-
SSS will be self-administered at the Randomization Visit prior to the patient receiving study drug 
and at the Week 4 Visit.
5.4
SAFETY ASSESSMENTS
The safety parameters will include adverse events (AEs), clinical laboratory and vital sign 
parameters, and physical examination.
5.4.1
Adverse Events
The AE assessment (interview) will be collected from the time the patient signed the informed 
consent form until 30 days after the patient’s last study visit.
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5.4.1.1 
Causality Assessment 
Causal relationship must be assessed according to the following scale: 
• Related 
An event where there is a reasonable possibility of a causal relationship 
between the event and the study drug 
• Unrelated 
Any other event 
 
5.4.1.2 
Severity Assessment 
Severity will be assessed according to the following scale: 
• Mild 
The AE was an annoyance to the patient but did not further hinder baseline 
functioning 
• 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 
 
5.4.1.3 
Serious Adverse Events 
All adverse events will be categorized as Serious (as defined in the MCP-103-204 Protocol, 
Section 5.5.3.2) or Non-Serious. 
5.4.2 
Medical History 
A complete medical history will be performed as defined in the Schedule of Assessments 
(Table 2). 
5.4.3 
Physical Examination 
A complete physical examination will be performed as defined in the Schedule of Events 
(Table 2). A physical examination will include the following assessments: general appearance; 
head, ears, eyes, nose, and throat (HEENT); neck; cardiovascular; thorax/lungs; abdomen; 
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musculoskeletal; lymph nodes; skin; neurologic; and mental status. Breast, genitourinary, and 
rectal examinations (if required).
5.4.4
Vital Signs
Vital sign measurements will be performed as defined in the Schedule of Events (Table 2). Vital 
sign measurements include oral temperature (°C), respiratory rate, systolic and diastolic blood 
pressure (BP), and pulse. Respiratory rate, pulse, and BP readings will be taken after the patient 
has been seated for at least 5 minutes.
5.4.5
Clinical Laboratory Data
Fasted blood and urine samples for clinical laboratory tests will be collected at the days and 
times defined in the Schedule of Events (Table 2). A central laboratory will be used to evaluate 
all blood and urine samples (except the urine pregnancy test). 
The following clinical laboratory tests will be performed:
•
Hematology: Absolute and differential white blood cell count, erythrocyte count, 
hemoglobin, hematocrit, platelet count, and red blood cell indices (mean corpuscular volume, 
mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration)
•
Chemistry: Sodium, magnesium, potassium, calcium, chloride, glucose, blood urea nitrogen, 
creatinine, total protein, alkaline phosphatase, albumin, total bilirubin, aspartate 
aminotransferase, alanine aminotransferase, bicarbonate, phosphate, 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. 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.
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6.
STATISTICAL METHODS
6.1
GENERAL METHODS
All summaries will be presented by treatment unless specified otherwise. Descriptive statistics 
including the number of patients, mean, standard deviation (SD), median, minimum, and 
maximum will be calculated for continuous variables. Frequencies and percentages for each 
category will be calculated for categorical variables. Percentages will be based on the total 
number of non-missing values. The number missing will be presented, but without a percentage. 
All hypothesis tests will be two-sided with a 5% significance level, and 95% confidence intervals 
will be used, unless stated otherwise.  There is no adjustment for multiplicity; p-values will be 
reported as nominal.  
All statistical analyses will be performed using SAS Version 9.3 (or later) for Windows.
6.2
ADJUSTING FOR COVARIATES
As a general approach, the baseline values will be included in the mixed model repeated 
measures (MMRM) or analysis of covariance (ANCOVA) when the absolute or change score are 
analyzed.  Heterogeneity of slopes will be explored (e.g., review of residuals, inclusion of an 
interaction term, comparison of group differences at the 25th and 75th percentiles) and, if any 
changes to planned analyses are needed, the change will be documented in the clinical study 
report.
6.3
HANDLING OF DROPOUTS/MISSING DATA IMPUTATION METHOD
For responder endpoints, a patient will be deemed a weekly non-responder for all weeks 
following the patient’s discontinuation from the study. The responder definition will be applied 
to the week the patient discontinues.   Unless stated otherwise, missing data will not be imputed.
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6.4
INTERIM ANALYSIS AND DATA MONITORING
No formal interim analyses are planned to compare treatment groups with respect to efficacy or 
safety prior to formal completion of the trial.
6.5
MULTICENTER STUDIES
This study is being conducted in approximately 80 centers.  Due to the potential of small 
numbers of patients per center, data will be pooled by center into the following 5 geographic
regions (as listed in Table 7): Northeast, Southeast, Midwest, Southwest, and West. 
All analyses using trial center will use this 5-category geographic region variable.
6.6
MULTIPLE COMPARISONS/MULTIPLICITY
No multiple comparison adjustments are planned for this study.
6.7
USE OF AN EFFICACY SUBSET
Not applicable
6.8
ACTIVE CONTROL TO SHOW EQUIVALENCE
Not applicable
6.9
EXAMINATION OF SUBGROUPS
No subgroup analyses are planned for this study.
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7.
ANALYSIS METHODS
7.1
PATIENT POPULATIONS
7.1.1
Screened Population
The Screened Population consists of all patients who signed informed consent and received a 
patient identification (PID) number.
7.1.2
Randomized Population
The Randomized Population consists of all patients in the Screened Population who were 
randomized to a treatment group in the study.
7.1.3
Safety Population
The Safety Population consists of all patients who received at least one dose of study drug, in 
which patients are evaluated according to the treatment they actually received.  The ‘treatment 
actually received’ for patients who received treatment(s) other than their randomized treatment 
during the course of the trial will be defined as the treatment group in which the patient actually 
took the greatest number of doses.  All safety analyses will be based on the Safety population.
7.1.4
Intent-to-Treat 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.
7.2
PROTOCOL DEVIATIONS
Protocol deviations and Important Protocol Deviations (IPD) will be identified and documented 
for all randomized patients prior to unblinding through programmatic checks of the study data 
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and select individual data reviews. IPDs will be determined based on review of all protocol 
deviations and protocol deviation categories (i.e., Use of Disallowed Medication) performed by 
members of the Ironwood Clinical Trials team, including but not limited to the Clinical Medical 
Researcher and study Biostatistician. Deviations to be reviewed include, but are not limited to:
•
those who entered the study even though they did not satisfy the entry criteria; 
•
those who developed withdrawal criteria during the study but were not withdrawn; 
•
those who received the wrong treatment or incorrect dose; 
•
those who received an excluded concomitant treatment. 
The number and percentage of subjects with IPDs will be presented by study treatment and IPD 
category. Protocol deviations and IPDs will be provided by patient in data listings.
7.3
PATIENT DISPOSITION
The number and percentage of patients included in each of the Randomized, Safety, and ITT
populations will be summarized overall and by treatment group for each trial center within each 
geographic region. The number of patients in the Screened Population will be summarized 
overall only by study center within geographic region (See Section 9.3 for definition of 
geographic region).
The number and percentage of screen failure patients (i.e., patients who entered the Screening 
Period but not the Pretreatment Period) and the number and percentage of pretreatment failures
(i.e., patients who entered the Pretreatment Period but were not randomly assigned to treatment), 
along with the associated reasons for failure, will be tabulated overall for the Screened 
Population. Patients who initially failed screening and were re-screened will only be counted 
once, that is, the PID used for the rescreened subject will be summarized and listed for patient 
disposition. 
The number and percentage of randomized patients who are in the ITT population, the number 
and percentage of patients who completed the Treatment Period, as well as the number and 
percentage of patients who prematurely discontinued treatment will be presented for each 
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treatment group and pooled across treatment groups for the Randomized Population. The reasons
for premature discontinuation from the Treatment Period as recorded on the trial completion 
forms of the electronic case report forms (eCRFs) will be summarized (number and percentage) 
by treatment group for the Randomized Population. The number and percentage of patients who 
prematurely discontinued treatment will be summarized for each treatment group by time of 
discontinuation, defined as the number of days from first dose of study drug to the date of last 
dose during the Treatment Period, categorized into weeks (Week 1 through Week 12). All
patients who prematurely discontinue during the Treatment Period will be listed by 
discontinuation reason for the Randomized Population.
7.4
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic parameters (age; age group; race; ethnicity; sex; 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, abdominal pain, abdominal bloating, abdominal discomfort, 
abdominal symptom composite score [consisting of abdominal pain, abdominal bloating, 
abdominal discomfort], stool consistency, and straining) will be summarized descriptively by 
treatment group for the ITT population. Continuous variables will be summarized by number of 
patients and mean, SD, median, minimum, and maximum values. Categorical variables will be 
summarized by number and percentage of patients.
Abnormalities in patients’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 18.0. The number and percentage of
patients with abnormalities in medical and surgical histories in each system organ class (SOC)
and preferred term will be summarized by treatment group for the Safety Population.
7.5
MEASUREMENT OF TREATMENT COMPLIANCE
Patients will take their initial dose of study drug at the trial center during the Randomization 
Visit (Visit 3). For all days in the Treatment Period, patients are instructed to take study drug 
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once daily in the morning at least 30 minutes before breakfast.  The double-dummy dosing 
requires all patients to take one capsule and one tablet for each dose.
Dosing compliance for the Treatment Period is defined as the number of capsules and tablets 
(Total number of capsules + Total number of tablets) actually taken by a patient during the 
Treatment Period divided by the number of capsules and tablets that were expected to be taken 
during the Treatment Period multiplied by 100. The total number of capsules actually taken will 
be calculated as total number of capsules dispensed minus total number capsules returned minus 
total number of capsules lost.  The same calculation will be applied for the calculation of total 
tablets taken.  The total number of capsules and tablets 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, multiplied by 2.  Patients will be included in the period summary only for 
the periods they were on study (i.e., the periods that are prior to or contain the last dose date).
This information will be obtained from Study Drug Accountability Record of the patient’s eCRF.
Descriptive statistics for study drug compliance will be presented for the Safety Population by 
treatment group for the Treatment Period as a whole and for each of the three consecutive drug 
dispensed/drug return periods (approximately 4-weeks) comprising the Treatment Period.    
7.6
EXTENT OF EXPOSURE
Exposure to study drug for the Safety Population during the double-blind treatment period will 
be summarized by treatment group in terms of treatment duration and calculated as the number 
of days from the date of the first dose of double-blind study drug to the date of the last dose of 
double-blind study drug, inclusive. Overall treatment duration will also be categorized as 1 Day; 
>1 Day to ≤ 7 Days; >7 Days to ≤ 30 Days; >30 Day to ≤90 Days; and ≥90 Days.  
Patient-years, defined as exposure to the study drug in years, will be summarized by treatment
group for the Safety Population.
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7.7 
PRIOR AND CONCOMITANT MEDICATION 
Prior medication is defined as any medication taken before the date of the first dose of double-
blind study drug. Concomitant medication is defined as any medication taken on or after the date 
of the first dose of double-blind study drug during the Treatment Period. Medications started 
after the date of the last dose of double-blind study drug will not be considered concomitant 
medications. 
Both prior and concomitant medications will be coded by drug name and therapeutic class using 
WHO Drug Dictionary version B2 March 2015.  The use of prior and concomitant medications 
will be summarized for the Safety Population by the number and percentage of patients in each 
treatment group receiving each medication within each therapeutic class. If a patient took a 
specific medication multiple times or took multiple medications in the same category (based on 
Anatomical-Therapeutic-Chemical classification), that patient would be counted only once for 
the coded drug name or therapeutic class. The use of per-protocol rescue medicines is collected 
separately the eDiary and will be summarized as described in Section 7.9.2. 
7.8 
EDIARY COMPLIANCE 
Patients are required to enter their evening diary assessments into the eDiary each evening during 
the pretreatment and treatment period.  An evening assessment is considered complete if all 
questions, excluding the weekly assessments, are answered. 
eDiary compliance will be calculated for baseline (pretreatment period), the treatment period, 
and weekly. For each time period, eDiary percent compliance will be calculated as 100* the 
number of completed evening reports divided by the expected number of days in the period.  
Percent compliance will also be dichotomized as ≥80% and <80% for each period, as well as the 
number and percentage of patients with > 4 / < 4 complete eDairy entries each week; these will 
be presented by treatment group for the ITT Population.  Descriptive statistics (number of 
patients, mean, SD, median, minimum, and maximum) for eDiary compliance will be presented 
for the ITT population by treatment; n and percent will be presented for the dichotomous 
categories. 
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7.9
EFFICACY ANALYSIS
All efficacy analyses will be based on the ITT Population for key efficacy parameters. 
Daily eDiary assessments collect information on BMs, including whether a BM is an SBM. SBM
is defined as a BM that occurs in the absence of a laxative, enema, or suppository use on either 
the calendar day of the BM or the calendar day before the BM. CSBM is defined as an SBM 
associated with a sense of complete evacuation.
Baseline values for efficacy parameters will be derived from the eDiary daily data collected in 
the Pretreatment Period, specifically the period of time from 14 days prior to the day of 
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 from the SBMs reported by the patient during this period. A patient’s baseline Stool 
Consistency and straining cannot be assessed if the patient does not have at least one SBM 
during the Pretreatment Period.  Patients with missing baseline Stool Consistency will be 
excluded from Stool Consistency analyses that involve change from baseline.  Similarly, patients 
with missing baseline straining will be excluded from straining analyses that involve change 
from baseline.
Baseline values for patient symptom severity parameters (e.g., abdominal discomfort, abdominal 
bloating, abdominal pain, abdominal symptom score [details provided in Section 7.9.2], and 
constipation severity) will be the average of the non-missing severity scores reported during this 
period.
For weekly responder parameters based on daily eDiary assessments, a patient with less than 4 
complete evening reports during an analysis week will not be considered a responder for that 
week.
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Trial centers will be pooled by geographic region (details provided in Section 9.3). In lieu of trial 
center, geographic region will be used in analyses adjusting for center-to- center variability.
All hypotheses will be tested at a two-sided 0.05 significance level (Section 7.9.2). All 
confidence intervals will be 2-sided 95% confidence intervals, unless stated otherwise.
7.9.1
Key Efficacy Parameter(s)
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:
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.
Weekly Change from Baseline in CSBM Frequency
A patient’s weekly CSBM frequency rate is the CSBM rate (CSBMs/week) calculated over that 
week.
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. 
•
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.
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•
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.
•
A Weekly Abdominal Pain Responder is a patient who has a decrease in the weekly average 
of the abdominal pain score of at least 30% compared with the baseline average.  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.
7.9.1.1
Analyses of the Key Efficacy Parameters
All analyses of the key primary efficacy endpoints will be performed on the ITT Population.
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, geographical region, and week-by-treatment fixed effects, and baseline 
value as a covariate. A compound symmetry covariance structure will be used to model the 
covariance of within-patient results. Exploratory analyses with unstructured and autoregressive 
(1) covariance structures will also be considered for planning purposes.
The overall dose response within each DR formulation will be conducted by employing an 
overall trend test (i.e., linear contrast, see Appendix VI) for each formulation to test for a 
monotonically increasing dose response within the MMRM. Overall treatment effect pairwise 
comparisons will be performed between each linaclotide treatment and placebo.  
 
 
  
Pairwise treatment comparisons with placebo will be performed at each week utilizing the same 
MMRM models.  
The efficacy analysis of 6/12 Week APC+1 Responder rate will be performed by using a CMH 
test controlling for geographic region for each DR formulation (i.e., 1. DR1 and Placebo; 2. DR2 
and Placebo).  The overall trend test will be assessed via the CMH correlation statistics to test for 
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a monotonically increasing dose response within the formulation. Pairwise comparisons between 
each linaclotide dose and placebo will be performed.
7.9.1.2
Sensitivity Analyses of the Key Efficacy Parameters
If warranted, for selected efficacy endpoints, the potential impact of missing data on the 
estimates of treatment effect will be assessed using alternative statistical methods. The following 
sensitivity analysis approach based on multiple imputations (MI) will be utilized.
In order to characterize the extent of missing data associated with the key efficacy parameter, the 
number and percentage of patients with < 4 completed evening diaries will be presented by 
treatment group for the Intent-to-treat (ITT) Population for each week of the Treatment Period 
(Please refer to Section 7.8 for additional details).  
Weekly data for a patient with less than 4 complete evening diaries will be classified as missing 
for that week.  A pattern-mixture model using a placebo-based multiple imputation method (6) 
will be used as sensitivity analyses to explore the effects of missing data on the key efficacy 
endpoints and select other endpoints for the ITT Population.  
The placebo-based MI imputes missing data after dropout (monotonic) based on the placebo 
group data using multiple imputation methodology for all subjects (including active treatment 
subjects).
The steps to implement Control-based MI are as follows:
1. Create a Monotonic Dataset:  One-thousand (1000) datasets will be generated where 
missing outcome data at intermittent week (s) (non-monotonic) will be first imputed for 
each treatment using non-missing data from all subjects within the treatment group by a 
Monte Carlo Markov Chain (MCMC) imputation model with treatment, baseline score, 
geographic region and weekly score. The MCMC statement (mcmc chain=multiple 
impute=monotone) in the SAS PROC MI procedure will be used. As a result, each of the 
1000 datasets will only have missing ending data, or a monotone missing data pattern.
2. For each of the 1000 datasets with monotonic missing data, the monotonic missing 
weekly data will be imputed one week at a time by a sequence of MIs, as follows.  
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Imputation will utilize data from all Placebo subjects and Active treatment with the week 
of interest (week currently being imputed) missing.
a.
For week 1, create two datasets:  one containing all placebo patients and active 
patients with the week 1 value - missing, referred to as Mono_imp1; one containing 
all other patients, referred to as Mono_rest1.
b. For Mono_imp1, impute the missing values at week 1 utilizing Proc MI:
PROC MI data=mono_imp1 out=reg_imp1 nimpute=1 seed=XXXX;
   By imputation;  /*note 1000 imputation performed in step 1*/
    Var base siteid change1 ;
Run;
c.
Set Mono_rest1 and reg_imp1  Call this dataset IMP1.
d. Repeat Steps 2a-2c for weeks 2 – 12, respectively 
Note: for Week i, i>1, 
PROC MI data=mono_impi out=reg_impi nimpute=1 seed=XXXX;
    By imputation;  /*note 1000 imputation performed in step 1*/
    Var base siteid change1 change2 . . . change(i-1) change(i);
Run;
3. Analyze each of the 1000 imputed complete datasets.
a.
For continuous endpoints, perform same statistical analyses (MMRM or ANCOVA) 
as described for observed case. 
b. For responder endpoint:
a.
Using the CSBM and Abdominal Pain data imputed above, recalculate the 
responder
b. For each imputed dataset, perform Cochran-Mantel-Haenszel (CMH) analyses 
as described above.
4. Estimation and Inference of the MI datasets will be performed using Rubin’s combination 
rules (7) as implemented through the MIANALYZE procedure in SAS.
7.9.2
Other Efficacy parameter(s)
The other efficacy parameters are as follows:
•
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 
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4 days for a particular Treatment Period week, the patient will not be considered a Weekly 
CSBM +1 Responder for that week.
•
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. 
•
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. 
•
CSBM (SBM) within 24 Hours of Receiving the First Dose of Study Drug: Date and time 
of first dose and date and time of first CSBM (SBM) is used to determine whether a CSBM 
(SBM) is occurred within 24 hours after the patient took the first dose of study drug.
•
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.
•
Weekly Abdominal Pain Responder: A Weekly Abdominal Pain Responder is a patient 
who has a decrease in the weekly average of the abdominal pain score of at least 30% 
compared with the baseline average.  If a patient did not enter information into the eDiary on 
at least 4 days for a particular Treatment Period week, the patient will not be considered a 
Weekly Abdominal Pain Responder for that week.
•
6/12 Week Abdominal 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.
•
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. 
•
Weekly Abdominal Symptom Score Responder: A Weekly Abdominal Symptom Score
Responder is a patient who has a decrease in the weekly average of the Abdominal Symptom 
Score of at least 30% compared with the baseline average.  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 Symptom Score Responder for that 
week.
•
6/12 Week Abdominal Symptom Score Responder: A 6/12 Week Abdominal Symptom 
Score Responder is a patient who meets the Weekly Abdominal Symptom Score Responder 
criteria for at least 6 out of the 12 weeks of the Treatment Period.
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•
9/12 Week Abdominal Symptom Score Responder: A 9/12 Week Abdominal Symptom 
Score Responder is a patient who meets the Weekly Abdominal Symptom Score Responder 
criteria for at least 9 out of the 12 weeks of the Treatment Period.
•
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.
•
Percent Change from Baseline in 12-week Abdominal Pain: Percent change will be 
calculated as the 100 * the Change from Baseline in Abdominal Pain divided by the baseline 
Abdominal Pain score.
•
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.
•
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.  A patient’s
daily abdominal symptom score is calculated as the average of the daily abdominal pain, 
abdominal bloating, and abdominal discomfort.   If two or more of the individual daily 
abdominal symptoms are missing, then the Abdominal Symptom Score for that day will be 
missing.
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•
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 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 100 * the 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.
•
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.
•
6/12 Week Adequate Relief Responder:  A 6/12 Week Adequate Relief Responder is a 
patient who reports Adequate Relief for at least 6 out of the 12 weeks of the Treatment 
Period.
•
9/12 Week Adequate Relief Responder:  A 9/12 Week Adequate Relief Responder is a 
patient who reports Adequate Relief for at least 9 out of the 12 weeks of the Treatment 
Period.
7.9.2.1
Sustained Responders
Select 9/12 Week and 6/12 Week responder parameter will also be assessed for as sustained 
response to determine if the treatment effect is maintained during weeks 9 to 12 of the treatment 
period.  A 9/12 Week Sustained Responders is a patient meeting the 9/12 Week Responder 
definition, plus are weekly responders for 3 of the last 4 weeks (weeks 9-12) of the treatment 
period.  A 6/12 Week Sustained Responders is a patient meeting the 6/12 Week Responder 
definition, plus are weekly responders for 2 of the last 4 weeks (weeks 9-12) of the treatment 
period.  The Sustained Responder definition will be applied to the following response endpoints:
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•
APC+1 Responder
•
CSBM+1 Responder
•
Abdominal Pain Responder
7.9.2.2
Analyses of Other Efficacy Parameters
All categorical responder parameters (e.g., Weekly CSBM +1 Responder) and CSBM (SBM) 
with 24-hours of first dose, 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 using an 
ANCOVA model with treatment group and geographic region as fixed-effect terms and baseline 
value as a covariate. Least-squares (LS) means for each treatment group, LS mean differences 
between each linaclotide dose and placebo 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. Pairwise comparisons between 
each treatment group and placebo will be performed overall and at each visit.  Associated 
LSMeans, LSMeans differences and confidence intervals will be presented.
For Change from Baseline in 12-Week CSBM, SBM, Stool Consistency (BSFS and 5 point 
ordinal score), Abdominal Pain, Abdominal Discomfort, Abdominal Bloating, and the 
Abdominal Symptom Composite Score, sensitivity analyses will be performed by applying the 
same ANCOVA model to the rank-transformed data. Change and baseline values will be ranked 
based on the normalization method of Blom with ties set to the mean.  If the results of the 
sensitivity analysis show consistency with those obtained from the original analysis, only results 
from the original ANCOVA will be reported.
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For Change from Baseline in weekly SBM, Stool Consistency (BSFS and 5 point ordinal score),
Abdominal Discomfort, Abdominal Bloating, and the Abdominal Symptom Composite Score, an 
ANCOVA with treatment and geographic region as fixed effects and baseline as a covariate will 
be fit.  All pairwise comparisons performed for the 12-week analyses will be performed for each 
week.
7.10
POSITIVE CONTROL
The 290 µg linaclotide dose is FDA-approved for the treatment of IBS-C (Linzess®) and is 
included in the current trial to evaluate assay sensitivity and to provide comparative data for the 
patient population treated with 290 µg linaclotide within the linaclotide program. Linaclotide 
290 µg will be compared to placebo utilizing the same method described for pairwise 
comparison described in Section 7.9.
7.11
SAFETY ANALYSIS
The safety analysis will be performed using the Safety Population. The safety parameters will 
include AEs, clinical laboratory and vital sign parameters, and physical examination. For each of 
the clinical laboratory and vital sign parameters, the last non-missing safety assessment before 
the first dose of double-blind drug will be used as the baseline for all analyses of that safety 
parameter. 
Continuous variables will be summarized by number of patients and mean, SD, median, 
minimum, and maximum values. Categorical variables will be summarized by number and 
percentage of patients.
7.11.1
Adverse Events
Adverse events will be coded by system organ class and preferred term using the MedDRA
dictionary, version 18.
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An AE that occurs during the Treatment Period will be considered a treatment-emergent adverse 
event (TEAE) if it started after the first dose of double-blind study drug or was present prior to 
the date of the first dose of double-blind study drug but increased in severity after the first dose 
of double-blind study drug. If more than 1 AE was reported before the first dose of double-blind 
study drug and coded to the same preferred term, the AE with the greatest severity will be used 
as the benchmark for comparison with the AEs occurring during the Treatment Period. An AE 
that occurs more than one day after the date of the last dose of double-blind study drug will not 
be considered as a TEAE.
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by system organ class (SOC) and preferred term and further categorized by severity
and relationship to the study drug. If a patient has more than 1 AE coded to the same preferred 
term, the patient will be counted only once for that preferred term using the highest severity and 
closest relationship to study drug for the summarization by severity and relationship to study 
drug, respectively. 
The incidence of common (≥2% of patients in any treatment group) TEAEs will be summarized 
by preferred term and treatment group for the Treatment Period. 
A serious adverse event (SAE) that occurred between the date of the first dose of double-blind 
study drug and 30 days after the date of the last dose of double-blind study drug, inclusive, will 
be considered an on-therapy SAE. The number and percentage of patients who have on-therapy 
SAEs will be summarized by preferred term and treatment group. In addition, the incidence of 
on-therapy SAEs that led to death will be summarized separately by preferred term for each 
treatment group.
The number and percentage of patients in the Safety Population who have AEs leading to 
premature discontinuation of the study drug will be summarized by preferred term and treatment.
For patients experiencing a TEAE coded as diarrhea, the number of days from first dose of study 
drug for the Treatment Period to the onset date of the first occurrence of treatment-emergent 
diarrhea during the Treatment Period will be summarized by treatment group using descriptive 
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statistics.  In addition, the incidence of treatment-emergent diarrhea by time of first onset for the 
Treatment Period will be calculated for each treatment group.
For the Screened Population, listings will be presented for patients who died, patients with SAEs, 
and patients with AEs leading to premature discontinuation, if any.
7.11.2
Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) and changes from the baseline 
values at each assessment time point will be presented by treatment group for the following 
laboratory parameters:
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
Clinical laboratory test values will be considered potentially clinically significant (PCS) if they 
meet either the lower-limit or higher-limit PCS criteria listed in Table 3. The number and 
percentage of patients who have PCS post-baseline clinical laboratory values will be tabulated by 
treatment group for the Treatment Period. The percentages will be calculated relative to the 
number of patients with available non-PCS baseline values and at least 1 assessment in the 
corresponding post-baseline period. The numerator will be the total number of patients with 
available non-PCS baseline values and at least 1 PCS value in the corresponding post-baseline 
period. A supportive listing of patients with PCS post-baseline values will be provided, including 
the PID number, trial center, baseline and all post-baseline (including non-PCS) values. A listing 
of all AEs for patients with post-baseline PCS laboratory values will also be provided.
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Table 3. 
Criteria for Potentially Clinically Significant Laboratory Results 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Albumin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Alanine aminotransferase 
U/L 
— 
≥ 3 × ULN 
Alkaline phosphatase 
U/L 
— 
≥ 3 × ULN 
Aspartate aminotransferase 
U/L 
— 
≥ 3 × ULN 
Bicarbonate 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Bilirubin, total 
μmol/L 
— 
> 1.5 × ULN 
Calcium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Chloride 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Cholesterol, total 
mmol/L 
— 
> 1.6 × ULN 
Creatinine 
μmol/L 
— 
> 1.3 × ULN 
Glucose 
mmol/L 
< 0.8 × LLN 
> 1.4 × ULN 
Magnesium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Phosphate 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Potassium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Protein, total  
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Sodium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Urea nitrogen 
mmol/L 
— 
> 1.2 × ULN 
Uric acid  
μmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
HEMATOLOGY 
Basophils, absolute cell 
count 
109/L 
— 
> 3 × ULN 
Eosinophils, absolute cell 
count 
109/L 
— 
> 3 × ULN 
Hematocrit 
Ratio 
< 0.9 × LLN 
> 1.1 × ULN 
Hemoglobin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Lymphocytes, absolute cell 
count 
109/L 
< 0.8 × LLN 
> 1.5 × ULN 
Mean corpuscular 
hemoglobin 
pg 
— 
> 3 × ULN 
Mean corpuscular 
hemoglobin concentration 
g/L 
— 
> 3 × ULN 
Mean corpuscular volume 
fL 
< 0.9 × LLN 
> 1.1 × ULN 
Monocytes, absolute cell 
109/L 
— 
> 3 × ULN 
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Table 3.
Criteria for Potentially Clinically Significant Laboratory Results
Parameter
SI Unit
Lower Limit
Higher Limit
count
Neutrophils, absolute cell 
count
109/L
< 0.8 × LLN
> 1.5 × ULN
Platelet count
109/L
< 0.5 × LLN
> 1.5 × ULN
Red blood cell count
1012/L
< 0.9 × LLN
> 1.1 × ULN
White blood cell count
109/L
< 0.7 × LLN
> 1.5 × ULN
LLN = lower limit of normal value provided by the laboratory; SI = Le Système International d’Unités (International 
System of Units); ULN = upper limit of normal value provided by the laboratory.
7.11.3
Vital Signs
Descriptive statistics for vital signs (systolic and diastolic blood pressures, pulse rate, respiratory 
rate, temperature, and weight) and changes from baseline values at each visit and at the end of 
study will be presented by treatment group for the Treatment Period.
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 4. The number and percentage of patients with PCS 
post-baseline values will be tabulated by treatment group for the Treatment Period. The 
percentages will be calculated relative to the number of patients with baseline values and at least 
1 post-baseline assessment for the Treatment Period. The numerator will be the total number of 
patients with available baseline values and at least 1 PCS post-baseline value for the Treatment 
Period. A supportive listing of patients with PCS post-baseline values will be provided, including 
the PID number, trial center, baseline and all post-baseline (including non-PCS) values.
In addition, a listing of all AEs that occurred in patients who had PCS post-baseline vital sign 
values will be provided.
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Table 4.
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteriaa
Observed Value
Change From Baseline
Sitting systolic blood 
pressure, mm Hg
High
≥ 180
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Sitting diastolic blood 
pressure, mm Hg
High
≥ 105
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Sitting pulse rate, bpm
High
≥ 120
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 7%
Low
—
Decrease of ≥7%
a.
A post-baseline value is considered potentially clinically significant if it meets both the observed-value and the 
change-from-baseline criteria.
bpm = beats per minute.
7.11.4
Other Safety Parameters
7.11.4.1
Physical Examination
Any physical examination abnormality that the investigator considers to be potentially clinically 
significant and changed from the baseline will be reported as an AE. No separate analysis for 
Physical Examinations is planned.
7.12
HEALTH OUTCOMES ANALYSIS
Health outcome analyses will be performed on the ITT population.  
7.12.1
Short Form-12 Health Survey Version 2 
The higher-order norm-based scores, Physical Component Summary (PCS-12) and Mental 
Component Summary (MCS-12), will be computed at Randomization, Week 4, Week 8, and 
EOT. Descriptive statistics (n, mean, SD, median, minimum, and maximum) will be presented 
for the absolute and change-from-baseline by visit. Treatment differences for the change from 
baseline at each post-dose visit will be analyzed using an ANCOVA with treatment and 
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geographic region as fixed effects and baseline summary score as a covariate. (See Section 
9.12.1 for scale scoring)
7.12.2
EuroQol-5 Dimension (EQ-5D-3L)
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 score by treatment group.  The same statistics will be 
calculated for the analog scale reflecting the patient’s preference for their health state.  Results 
will be presented at baseline and at each post-baseline week using both observed case (OC) and 
last observation carried forward (LOCF) approaches to missing post-baseline data. (See Section 
9.12.2 for scale scoring)
7.12.3
Short Form McGill Pain Questionnaire - 2 (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 
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. (See Section 9.12.3 for scale 
scoring)
7.12.4
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS)
At each assessment of the IBS-SSS, the IBS-SSS Total score will be calculated. Descriptive 
statistics will be presented for the IBS-SSS Total score and each severity score.  (See Section 
9.12.4 for scale scoring)
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8.
CHANGES FROM ANALYSES PLANNED IN THE 
PROTOCOL
a.
For the key efficacy parameters Weekly Change from Baseline in Abdominal Pain and 
Weekly Change from Baseline in CSBM Frequency, the protocol states:
Additional exploratory comparisons between the linaclotide doses (DR1, DR2) and 
linaclotide IR, 
 
 
 All other comparisons between linaclotide dose (DR1, DR2, and IR) 
will be performed descriptively.
b. For 6/12 Week APC+1 Responder rate, the protocol states:
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. 
 
The SAP clarifies statistical inference compares Placebo to each DR1 and DR2 doses only, 
regardless of the overall trend significance.  All other treatment comparisons will be 
descriptive in nature.
c.
For each 6/12 Week and 9/12 Week responder endpoint defined in the protocol, a 
corresponding “Sustained Responder” was added.  Each new ‘Sustained Responder’ 
parameter will be presented and analyzed as described in Sections 7.9.1.1 and 7.9.1.2
d. For the analyses of the 12-week Change from baseline, the protocol states:
 
 
 All other comparisons between linaclotide dose (DR1, DR2, and IR) 
will be performed descriptively.
e.
For all responders in the “Other Efficacy Endpoint” section, the protocol states:
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.
The SAP clarifies statistical inference compares Placebo to each DR1 and DR2 doses only.  
All other treatment comparisons will be descriptive in nature.
f.
For patients experiencing a TEAE coded as diarrhea, analyses of the number of days from 
first dose of study drug for the Treatment Period to the onset date of the first occurrence of 
treatment-emergent diarrhea during the Treatment Period listed in the SAP were not 
identified in the protocol.
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g. The endpoints and analyses of 6/12 and 9/12 Week Adequate Relief were not specified in the 
protocol.
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9.
DATA HANDLING CONVENTIONS
9.1
VISIT TIME WINDOWS FOR SAFETY ANALYSIS
Table 5 below presents the visits assigned for the safety analysis corresponding to the range of 
trial days (window) during which an actual visit may have occurred.
Table 5.
Visit Time Windows for Safety Analysis
Derived Visit
Scheduled Test / Visit Daya
Window
Baseline
Day 1
Days ≤ 1
Day 29 Visit
Day 29
Days [2, 43]
Day 57 Visit
Day 57
Days [44, 71]
Day 85 Visit
Day 85
Days [72, 99]
End of Trialb
Final or termination visit
a.
Relative to the date of randomization; Day 1 = the day of randomization.
b.
“End of Trial” will be presented in analysis tables for safety parameters, including clinical laboratory and vital 
signs.
Test/Visit Day will be calculated as follows: test/visit date – date of randomization.
9.2
VISIT TIME WINDOWS FOR EFFICACY ANALYSIS
Table 6 presents the analysis weeks assigned for the efficacy analysis of the patient diary data 
related to BM characteristics. These analysis weeks will be used in the calculations for all week-
based parameters (e.g., SBM weekly frequency rate, BSFS weekly scores).
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Table 6.
Analysis Time Windows for Efficacy Analysis
Period
Analysis Week
Beginsa
Endsa
Pretreatment 
(Baselineb)
Week –2 
Day –14 
Day –8
Week –1 
Day –7
Day 1 (time of 
randomization)
Treatment
Week 1 
Day 1 (time of randomization)
Day 7
Week 2 
Day 8
Day 14
Week 3 
Day 15 
Day 21
Week 4 
Day 22
Day 28 
Week 5 
Day 29
Day 35
Week 6 
Day 36 
Day 42
Week 7 
Day 43
Day 49 
Week 8 
Day 50
Day 56
Week 9 
Day 57 
Day 63
Week 10
Day 64
Day 70 
Week 11 
Day 71
Day 77 
Week 12
Day 78
last dose dayc (usually 
Day 85)
Note: There is no Day 0 or Week 0. For eDiary assessments in which a patient is asked to report if an event occurred 
“yesterday” or “today” (e.g., a bowel movement or rescue medication use), these windows pertain to when the event 
occurred, not to when the event is reported. For example, if a patient reports in eDiary on Day 78 a bowel movement 
occurring “yesterday,” that bowel movement (and subsequent stool consistency and straining scores) would be 
included in Analysis Week 11, not Analysis Week 12. 
a.
Relative to the date of randomization; Day 1 = the day of randomization. For the calculation of rates (e.g., stool 
frequency rates) in which the duration of a week or the overall period is calculated to the nearest hour, a day 
begins and ends at midnight. 
b.
Baseline values for efficacy parameters will be derived from the daily eDiary and eCRF data collected in the 
Pretreatment Period, specifically the period from 14 days before randomization up to the time of randomization.
c.
For patients who fail to provide the date of last dose at the last visit, the last eDiary date will be used to impute 
the last dose date.
For the Treatment Period, diary day is calculated as diary date – date of randomization + 1. For 
the Pretreatment Period, diary day is calculated as diary date - date of randomization. However, 
the day of randomization is always trial Day 1. Patients will complete their diary entries once a 
day, with the exception of Day 1 of entry into the Treatment Period during which 2 diary data 
sets will be collected. On Day 1, daily questions will be entered before and after the 
randomization, whereas weekly questions will be entered before but not after randomization.
If a patient withdraws during the Treatment Period, the patient’s Treatment Period shall end on
the day of the last dose. The affected Treatment Period week shall be shortened to the end of the 
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withdrawn patient’s Treatment Period, and all subsequent Treatment Period weeks will be 
missing for that patient.
9.3
POOLING OF TRIAL CENTERS
Because of the potential of many trial centers to have a small number of patients, the centers will 
be pooled by the following 5 geographic regions (as listed in Table 7): Northeast, Southeast, 
Midwest, Southwest, and West. All analyses using trial center will use this 5-category center 
variable.
Table 7.
Definition of Geographic Regions
Northeast
Southeast
Midwest
Southwest
West
CT
AL
IA
AZ
CA
DE
AR
IL
NM
CO
MA
FL
IN
OK
ID
MD
GA
KS
TX
MT
ME
KY
MI
NV
NH
LA
MN
OR
NJ
MS
MO
UT
NY
NC
ND
WA
PA
SC
NE
WY
RI
TN
OH
VT
VA
SD
WV
WI
9.4
DERIVED EFFICACY VARIABLES
9.4.1
Patient Recall for eDiary Data
Bowel Habits
The eDiary is designed to allow patients to enter Daily Bowel Habits through a spontaneous 
report or the evening report.  
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The spontaneous report allows the patient to report BMs, occurring between evening reports, at 
any time.  If the previous evening report was not completed, then the patient can report BM 
information occurring between 7:00 PM of the previous night and the current spontaneous report.
The evening report allows the patient to report BM information between the time of the previous 
evening report and the current evening report (~24-hour recall).  If the previous evening report 
was not completed, then the patient can report BM information within the evening report 
occurring between 7:00 PM of the previous night and the current evening report.
These BM information reporting rules were put into place to reduce recall bias.
Rescue Medicine (RM)
The spontaneous report allows the patient to report RM information, occurring between evening 
reports, at any time. If the previous evening report was not completed, then the patient can 
report RM information between 7:00 PM of the previous night and the current spontaneous 
report.
The evening report allows the patient to report RM information between the time of the previous 
evening report and the current evening report (~24-hour recall).  If the previous evening report 
was not completed, then the patient can report RM information within the evening report 
occurring between 7:00 PM of the previous night and the current evening report.
These RM information reporting rules were put into place to reduce recall bias.
Abdominal Symptom Severity
During the Evening Diary Report, the eDiary will capture separately the rating of abdominal
pain, bloating, and discomfort experienced by the patient during the past 24 hours.
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9.4.2
Handling of Missing eDiary Data 
In the eDiary, for each BM and rescue medicine use reported, the patient will be asked whether 
the BM or rescue medicine use occurred “today” or “yesterday.” The following conventions will 
be followed in the event of missing data:
Gaps in the eDiary Data
If a patient does not complete either a spontaneous or evening report every day, there will be 
gaps in the data. 
There will be no adjustments for these gaps in the eDiary data for the efficacy data analyses 
using an OC approach. Effectively, this means that analyses will assume that no rescue medicine
use or BMs occurred during these gaps.
Missing “Today” or “Yesterday” Information for Rescue Medicine
When a patient uses rescue medicine and the exact date of use is known, there will be a 2-day 
window during which any BMs will not be assessed as SBMs: (1) the day when the rescue 
medicine was administered and (2) the day after. If, in the daily diary, a patient has reported
taking a rescue medicine but the corresponding date is missing, the rescue medicine use must 
have occurred either on the day of the diary entry or on the day before the diary entry. The rescue 
medicine window in this missing-date scenario will be 3 days, covering the day before the 
eDiary report, the day of the eDiary report, and the day after the eDiary report. This window will 
be used to determine if a BM should be considered an SBM.
For the analysis of rescue medicines, the missing date will be imputed as the date in which the 
rescue medicine was reported.
Missing “Today” or “Yesterday” Information for Bowel Movements
If a patient reports having had a BM but does not provide the exact date, the BM must have 
occurred either on the day of the report or on the day before the report. For determining whether 
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a BM is an SBM, this 2-day window will be used in conjunction with the rescue medicine
window. If there is any overlap between the BM window and the patient’s rescue medicine
window, the BM will not be considered an SBM.
Many analyses require specific dates for each BM. If a BM date is missing, it will be imputed as 
the date/time stamp of the eDiary report in which the BM was reported. However, the following 
exception applies to this imputation rule:
When the first day of the BM window is the last day of a rescue medicine window and the 
second day of the BM window is not also a day of a rescue medicine window, the missing BM 
date will be imputed as the first day of the BM window (i.e., the day before the eDiary report in 
which the BM was recorded). This rule of exception is designed to minimize the risk of 
mischaracterizing a non-spontaneous BM as an SBM.
Missing Stool Consistency Questions
No imputation will be performed for a missing BSFS score or the stool consistency 5 point 
ordinal measure.
Missing Completeness of Evacuation Response 
If the completeness of evacuation response (Question #12) is missing, an SBM will not be 
considered complete.
Missing Daily Abdominal Symptoms
No imputation will be performed for missing daily symptoms (Abdominal Pain, Abdominal 
Discomfort, Abdominal Bloating).
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9.4.3 
Weekly Stool Frequency Rates  
The components for calculating a patient’s stool frequency rates (BM, SBM, and CSBM weekly 
rates) for a given analysis week are as follows: 
• The number of BMs that occurred during that analysis week 
• The number of those BMs that were SBMs 
• The number of those SBMs that were CSBMs 
• The length of time of the analysis week 
• The determination of the length of time of an analysis week is provided in Section 9.4.3.1. 
 
9.4.3.1 
Length of an Analysis Week 
With respect to a patient’s scheduled analysis weeks, the term duration is used. In regard to the 
duration of a week, it is expected that 1 or more of a patient’s “weeks” may not be exactly 7×24 
hours in duration (e.g., a patient may withdraw or discontinue early from the trial). Deviations 
from the 7×24–hour norm are structural in nature; and, as such, the calculations of the weekly 
rates of SBMs or CSBMs will incorporate the actual duration of the week. 
Following an observed-cases approach, no adjustment to the duration of a week will be made for 
missing eDiary data absent because of missed reports. 
9.4.3.2 
Weekly Stool Frequency Rate Calculations 
The weekly frequency rate for SBMs (CSBMs) will be based on the number of SBMs (CSBMs) 
occurring during that week, adjusting for differences in the duration of the week versus the 
7×24–hour norm. A description of the corresponding formula is provided below. 
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Weekly stool frequency rates for each analysis week will be calculated as follows:
Weekly Frequency Rate (Analysis Weeki) = (7 × 24) × Ci/Di
Where:
i is an indicator of analysis week number (e.g., i = –2, –1, 1, …, 12),
C
i is the number of events (SBMs or CSBMs) reported during analysis week i, and
D
i is the duration (in hours) of analysis week i, from beginning to end (Table 6).
9.4.3.3
Overall Weekly Stool Frequency Rate Calculations for Each Analysis 
Period
For each of the 2 analysis periods (Pretreatment and Treatment), the overall weekly stool 
frequency rates will be calculated in a manner similar to that for an individual week. The 
corresponding formulas are provided below.
Overall weekly stool frequency rates for each analysis period will be calculated as follows:
Weekly Frequency Rate (Analysis Periodj) = (7 × 24) × Cj/Dj
Where:
j is an indicator of analysis period number (e.g., j = 1 [pretreatment], 2 [treatment]),
C
j is the number of events (SBMs or CSBMs) reported during analysis period j, and
D
j is the duration (in hours) of analysis period j, from beginning to end (Table 6).
9.4.4
Other Weekly Scores Derivation 
For Abdominal Pain, Bloating, and Discomfort, the patient’s weekly average will be the average 
of the non-missing daily scores reported by the patient during each week.
For stool consistency questions, the patient’s weekly score will be the average of the non-
missing daily scores from the SBMs reported by the patient during each week. 
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For straining, the patient’s weekly straining score will be the average of the non-missing daily 
straining scores from the SBMs reported by the patient during each week. 
For the abdominal symptom composite score, first the daily average of Abdominal Pain, 
Abdominal Bloating and Abdominal Discomfort will be calculated.  If more than 1 of the 
symptom scores is missing on a day, that daily abdominal symptom composite score will be 
missing.  Weekly scores will be based on the average of the non-missing abdominal symptom 
composite scores.
9.5
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
If a patient has repeated assessments prior to the start of double-blind study drug, then the results 
from the final non-missing assessment made prior to the start of the double-blind study drug will 
be used as baseline. If end-of-study assessments are repeated or if unscheduled visits occur, the 
last non-missing post baseline assessment will be used as the end-of-study assessment for 
generating summary statistics. However, all post-baseline assessments will be used for PCS 
value determination as described above and all assessments will be presented in the data listings.
9.6
MISSING DATE OF THE LAST DOSE OF STUDY DRUG
When the date of the last dose of double-blind study drug is missing for a patient in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all efforts 
are made it is still missing, the last eDiary entry will be used as the last dose date. 
9.7
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE started prior to the first double blind study drug, all efforts 
should be made to obtain the severity from the investigator. If it is still missing after all efforts, 
then a severity of “Mild” will be assigned. If the severity is missing for an AE started on or after 
the date of the first dose of double-blind study drug, then a severity of “Severe” will be assigned. 
The imputed values for the missing severity assessment will be used for the incidence summary, 
while the actual missing values will be presented in data listings.
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9.8
MISSING RELATIONSHIP TO STUDY DRUG FOR ADVERSE 
EVENTS
If the relationship to study drug is missing for an AE started on or after the date of the first dose 
of double-blind study drug, all efforts should be made to obtain the date from the investigator. If 
it is still missing after all efforts, a causality of “Related” will be assigned in the corresponding 
analysis derived data set. The imputed values for the missing relationship to double-blind study 
drug will be used only for incidence summary, while the actual missing values will be presented 
in data listings.
9.9
MISSING DATE INFORMATION FOR ADVERSE EVENTS
The following imputation rules apply to cases in which the start date is incomplete (i.e., partial 
missing) for adverse events.
a.
If AEs occurred during the Screening or Pretreatment Period (i.e., the Screening or 
Pretreatment Period is checked on the AE eCRF)
Missing day and month
•
If the year is the same as the year of the date of informed consent, then the day and month of 
the date of informed consent will be assigned to the missing fields.
•
If the year is prior to the year of the date of informed consent, then December 31 will be 
assigned to the missing fields.
•
If the year is after the year of the date of informed consent, then January 1 will be assigned to 
the missing fields.
Missing month only
•
The day will be treated as missing and both month and day will be replaced according to the 
above procedure.
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Missing day only 
•
If the month and year are the same as the month and year of the date of informed consent, 
then the date of informed consent will be assigned to the missing day.
•
If either the year is before the year of the date of informed consent or if both years are the 
same but the month is before the month of the date of informed consent, then the last day of 
the month will be assigned to the missing day.
•
If either the year is after the year of the date of informed consent or if both years are the same 
but the month is after the month of the date of informed consent, then the first day of the 
month will be assigned to the missing day.
If the stop date is complete and it is before the date of randomization and the imputed start date 
as above is after the stop date, the start date will be imputed by the stop date. If the stop date is 
complete and it is on or after the date of randomization and the imputed start date as above is 
after the stop date, the start date will be imputed by the date immediately before the date of 
randomization.
If the start date is completely missing, then the date of informed consent will be used to impute 
the start date.
b. If AEs occurred during the Treatment Period (i.e., the Treatment Period is checked on 
the AE eCRF)
Missing day and month
•
If the year is the same as the year of the date of the first dose of double-blind study drug, then 
the day and month of the date of the first dose of double-blind study drug will be assigned to 
the missing fields.
•
If the year is prior to the year of the date of the first dose of double-blind study drug, then 
December 31 will be assigned to the missing fields.
•
If the year is after the year of the date of the first dose of double-blind study drug, then 
January 1 will be assigned to the missing fields.
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Missing month only
•
The day will be treated as missing and both month and day will be replaced according to the 
above procedure.
Missing day only
•
If the month and year are the same as the month and year of the date of the first dose of 
double-blind study drug, then the date of the first dose of double-blind study drug will be 
assigned to the missing day.
•
If either the year is before the year of the date of the first dose of double-blind study drug or 
if both years are the same but the month is before the month of the date of the first dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day.
•
If either the year is after the year of the date of the first dose of double-blind study drug or if 
both years are the same but the month is after the month of the date of the first dose of 
double-blind study drug, then the first day of the month will be assigned to the missing day.
•
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date.
•
If the start date is completely missing and the stop date is complete, then the following 
algorithm is used to impute the start date:
•
If the stop date is after the date of the first dose of double-blind study drug, the date of the 
first dose of double-blind study drug will be assigned to the missing start date.
•
If the stop date is before the date of the first dose of double-blind study drug, the stop date 
will be assigned to the missing start date. 
9.10
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or stop 
date will be imputed. When the start date and the stop date are both incomplete for a patient, 
impute the start date first.
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9.10.1
Incomplete Start Date
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date.
Missing day and month
•
If the year of the incomplete start date is the same as the year of the date of the first dose of 
double-blind study drug, then the day and month of the date of the first dose will be assigned 
to the missing fields.
•
If the year of the incomplete start date is prior to the year of the date of the first dose of 
double-blind study drug, then December 31 will be assigned to the missing fields.
Missing month only
•
The day will be treated as missing and both month and day will be replaced according to the 
above procedure.
Missing day only
•
If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of double-blind study drug, then the day of the date of the first dose will 
be assigned to the missing day.
•
If either the year is before the year of the date of the first dose of double-blind study drug or 
if both years are the same but the month is before the month of the date of the first dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day.
•
If either the year is after the year of the date of the first dose of double-blind study drug or if 
both years are the same but the month is after the month of the date of the first dose of 
double-blind study drug, then the first day of the month will be assigned to the missing day.
9.10.2
Incomplete Stop Date
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of double-blind study drug is missing, replace it with the last diary call date. If the imputed 
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stop date is before the start date (imputed or non-imputed start date), then the imputed stop date 
will be equal to the start date.
Missing day and month
•
If the year of the incomplete stop date is prior to the year of the date of the last dose of 
double-blind study drug, then December 31 will be assigned to the missing fields.
Missing month only
•
The day will be treated as missing and both month and day will be replaced according to the 
above procedure.
Missing day only
•
If either the year is before the year of the date of the last dose of double-blind study drug or if 
both years are the same but the month is before the month of the date of the last dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day.
9.11
CHARACTER VALUES OF CLINICAL LABORATORY PARAMETERS
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table due, for example, to it being a character string rather than a numerical type, a coded value 
needs to be appropriately determined and used in the statistical analyses. However, the actual 
values as reported in the database will be presented in data listings.
Table 8 shows examples of how some possible laboratory results should be coded for the 
analysis.
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Table 8.
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters
Laboratory Test,
SI Unit
Possible Laboratory Results
Coded Value for Analysis
CHEMISTRY
ALT, U/L
< 5
0
AST, U/L
< 5
0
Bilirubin, total, μmol/L
< 2
0
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités
(International System of Units).
9.12
HEALTH OUTCOME PARAMETERS
9.12.1
Short Form 12 Health Survey Version 2
The SF-12 is a multipurpose, short-form health survey consisting of 12 questions designed for 
use in clinical practice and research, health policy evaluations, and general population surveys. 
The SF-12, Version 2.0, contains 12 items that, when scored, yield an 8-scale profile of 
functional health and well-being, as well as physical and mental summary measures. 
The 8 scales (also known as domains) are as follows: Physical Functioning (PF), Role Physical 
(RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role 
Emotional (RE), and Mental Health (MH). A norm-based score will be computed for each of the 
8 scales using standard scoring rules. These rules generate a standardized score (with a mean of 
50 and an SD of 10 in the general U.S. Population) for each of the scales such that higher scores 
represent better health condition. 
In addition, scores from these 8 scales will be aggregated in 2 distinct, higher-order summary 
norm-based scores: Physical Component Summary (PCS-12) and Mental Component Summary 
(MCS-12) scores. These 2 summary scores will also be standardized to have a mean of 50 and an
SD of 10 in the general US Population. 
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The steps involved in scoring SF-12 can be found at Ware et al (1995) (1); they are briefly 
described as follows:
Item Recoding
Reverse score items 1, 5, 6a, and 6b so that, for all scales, higher scores indicate better health 
condition. The scores 1, 2, 3, 4, and 5 of items 5, 6a, and 6b will be reversed to 5, 4, 3, 2, and 1. 
For item 1, the scores 1, 2, 3, 4, and 5 will be reversed to 5, 4.4, 3.4, 2.0, and 1.0.
Aggregate and Transform Scale Scores
A transformed scale score for each scale will be computed by subtracting the lowest possible 
derived score from the actual derived score, dividing the difference by the corresponding 
possible derived score range, and multiplying the ratio by 100. Table 9 summarizes the process.
Table 9.
Summary of Formulas for Scoring and Transforming Scales
Scale
Sum Final Item 
Values (After 
Recoding)
Lowest and Highest 
Possible Derived 
Scores
Possible Derived 
Score Range
Physical Functioning 
(PF)
2a + 2b
2, 6
4
Role-Physical (RP)
3a + 3b
2, 10
8
Bodily Pain (BP)
5
1, 5
4
General Health (GH)
1
1, 5
4
Vitality (VT)
6b
1, 5
4
Social Functioning 
(SF)
7
1, 5
4
Role-Emotional (RE)
4a + 4b
2, 10
8
Mental Health (MH)
6a + 6c
2, 10
8
Compute Standardized Values (z-Scores) for the Short Form-12 Health Survey, Version 
2.0, Scales
A z-score for each scale is computed by subtracting the 1998 general US population mean for 
each SF-12 scale and dividing the difference by the corresponding scale SD from the 1998 
general US population (Table 10).
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Table 10.
1998 General US Population Means and Standard Deviations Used 
to Derive Short Form-12 Health Survey, Version 2.0, z-Scores—
Acute Form
SF-12 Scale
Meana
SDa
Physical Functioning (PF)
80.64733
29.71224
Role-Physical (RP)
80.61635
27.84366
Bodily Pain (BP)
83.42495
24.34172
General Health (GH)
71.96134
23.53406
Vitality (VT)
55.11847
25.63085
Social Functioning (SF)
84.58234
25.21668
Role-Emotional (RE)
86.79996
22.64927
Mental Health (MH)
71.38235
20.54864
a.
The means and SDs for each scale of the Short Form-12 Health Survey, Version 2.0, are based on the 
0-100 scoring.
Compute Aggregate Summary Scores
An aggregate physical and mental summary score will be computed by multiplying the z-score of 
each SF-12 scale by its respective factor score coefficient (Table 11) and summing the 8 
products for each summary score.
Table 11.
1990 Factor Score Coefficients Used to Derive Physical Component 
Summary and Mental Component Summary Scale Scores—
Standard and Acute Forms
SF-12 Scale
Standard and Acute Form Factor Score 
Coefficients
PCS
MCS
Physical Functioning (PF)
0.42402
-0.22999
Role-Physical (RP)
0.35119
-0.12329
Bodily Pain (BP)
0.31754
-0.09731
General Health (GH)
0.24954
-0.01571
Vitality (VT)
0.02877
0.23534
Social Functioning (SF)
–0.00753
0.26876
Role-Emotional (RE)
–0.19206
0.43407
Mental Health (MH)
–0.22069
0.48581
MCS = Mental Component Summary; PCS = Physical Component Summary; SF-12 = Short Form-12 
Health Survey.
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Compute Norm-Based Summary Scores
This step involves transforming the aggregate physical and mental summary scores to the norm-
based (50, 10) scoring (mean = 50 and SD = 10 in the general 1998 US population) by 
multiplying the respective aggregate summary score by 10 and adding 50. See Ware et al (1) for 
details of the standard scoring rules.
If any item is missing in SF-12, then the PCS-12 and MCS-12 scores will not be calculated and 
will be set to missing.
9.12.2
EuroQol-5 dimension (EQ-5D-3L)
The 5-item responses of the EQ-5D-3L define a health state that can be converted into a single 
summary utility index that assigns weights (ie, value) to each level. Different weights are 
available. For this study, the US TTO (time trade-off) weights will be used (3).
The EQ-5D-3L index is computed according to the following equation as: 
EQindex = 1 - {0.146016 × m1 + 0.557685 × m2 + 0.1753425 × s1 + 0.4711896 × s2 + 
0.1397295 × u1 + 0.3742594 × u2 + 0.1728907 × p1 + 0.5371011 × p2 + 0.156223 × a1 + 
0.4501876 × a2 + -0.1395949 × d1 + 0.0106868 ×* i22 + -0.1215579 × i3 + -0.0147963 × i32}
where the variables m1, s1, u1, p1, a1, m2, s2, u2, p2, a2 , i2, i22, i3, i32 and d1 are given in Table 12.
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Table 12.
EuroQol Quality-of-Life Questionnaire Utility Index
EuroQoL
Level 2
Level 3
Mobility
m1 = 1 if Level 2 
selected
0 otherwise
m2 = 1 if Level 3 
selected
0 otherwise
m0 = 1 if m1 = 0 & 
m2 = 0
0 otherwise
Self-care
s1 = 1 if Level 2 
selected
0 otherwise
s2 = 1 if Level 3 
selected
0 otherwise
s0 = 1 if s1 = 0 & s2 = 0
0 otherwise
Usual activity
u1 = 1 if Level 2 
selected
0 otherwise
u2 = 1 if Level 3 
selected
0 otherwise
u0 = 1 if u1 = 0 & u2 = 
0
0 otherwise
Pain/discomfort
p1 = 1 if Level 2 
selected
0 otherwise
p2 = 1 if Level 3 
selected
0 otherwise
p0 = 1 if p1 = 0 & p2 = 
0
0 otherwise
Anxiety/depression
a1 = 1 if Level 2 
selected
0 otherwise
a2 = 1 if Level 3 
selected
0 otherwise
a0 = 1 if a1 = 0 & a2 = 
0
0 otherwise
Interaction terms
i2 = max {0, (m1 + s1 + u1 + p1 +a1) – 1}
i22 = i2 × i2
i3 = max {0, (m2 + s2 + u2 + p2 + a2) – 1}
i32 = i3 × i3
d1 = max {0, 4 – (m0 + s0 + u0 + p0 + a0)}
If any dimension is missing in the EQ-5D-3L, the EQ-5D-3L index will not be calculated and 
will be set to missing.
9.12.3
Short Form McGill Pain Questionnaire - 2 (SF-MPQ-2)
The SF-MPQ-2 is composed of 22 items investigating 4 dimensions.
Dimension of Pain
(Subscales)
Number of items
Cluster of items
Direction of Score
Continuous
6
1, 5-6, 8-10
Lower score = Lower 
pain
Intermittent
6
2-4, 11, 16, 18
Neuropathic
6
7, 17, 19-22
Affective Descriptor
4
12-15
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Subscale score: For each of the scales, scores are calculated by taking the mean of the item 
ratings included in the scale. 
Total score: mean of all SF-MPQ-2 item ratings 
Interpretation and Analysis of missing data: - No correction is necessary for missing data if the 
subject has omitted a few items. Mean scores should be calculated on the available items. 
9.12.4 
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS) 
The IBS-SSS has 2 severity questions each with a 0-10 point rating scale where a higher score 
represents greater severity or poorer quality of life (see Appendix V), one frequency of pain (0-
10) over the last 10 days question, one dissatisfaction score with a 0-10 point rating where a 
higher score represents greater dissatisfaction, and one indication of how much pain, discomfort 
or altered bowel interfere with general life score with a 0-10 scale where a higher score 
representing greater interference.  The IBS-SSS total score will be the average of the 5 non-
missing scores described above. 
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10.
REFERENCES
1. Ware John E.Jr., Kosinski M. A 12-Item Short-Form Health Survey: Construction of Scales 
and Preliminary Tests of Reliability and Validity. Med Care 1996;34:220-33.
2. EuroQol--a new facility for the measurement of health-related quality of life. The EuroQol 
Group. Health Policy 1990 Dec;16(3):199-208.
3. Shaw JW, Johnson JA, Coons SJ. U.S. valuation of the EQ-5D health states: development 
and testing of the D1 valuation model. Med Care 2005;43:203-20.
4. Dworkin RH, Turk DC, Revicki DA, Harding G, Coyne KS, Peirce-Sandner S, et al. 
Development and initial validation of an expanded and revised version of the Short-form 
McGill Pain Questionnaire (SF-MPQ-2). Pain 2009 Jul;144(1-2):35-42.
5. Francis C, Morris J, Whorwell P: The irritable bowel severity scoring system: a simple 
method of monitoring irritable bowel syndrome and its progress.  Aliment Pharmacol 
Ther 1997, 11:395-402.
6. Ratitch, B., O'Kelly, M. and Tosiello, R. (2013), Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharmaceut. Statist., 
12: 337–347. doi: 10.1002/pst.1549
7. Rubin DB (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons Ltd., 
New York.
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APPENDIX I.
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 II.
SF-12V2
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APPENDIX III.
EQ-5D-3L 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 IV.
SHORT-FORM MCGILL PAIN QUESTIONNAIRE-2
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APPENDIX V.
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.”
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very happy
0 1 2 3 4 5 6 7 8 9 10
very unhappy
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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Ironwood Pharmaceuticals, Inc.
Statistical Analysis Plan: MCP-103-204-SAP-01
04 October 2016
Confidential
Page 84 of 86
 
 
 
 
 
: 19-Oct-2016 15:05
Document Date: 


linaclotide
Ironwood Pharmaceuticals, Inc
Statistical Analysis Plan: MCP-103-204-SAP-01
04 October 2016
Confidential
Page 85 of 86
 
 
 
 
 
 
 
     
     
 
     
: 19-Oct-2016 15:05


linaclotide
Ironwood Pharmaceuticals, Inc
Statistical Analysis Plan: MCP-103-204-SAP-01
04 October 2016
Confidential
Page 86 of 86
 
 
 
: 19-Oct-2016 15:05
Document Date: