Clinical trial NCT03931785
Conditions: Irritable Bowel Syndrome With Diarrhea (IBS-D)
Keywords: Abdominal pain Diarrhea Irritable Bowel Syndrome
Sponsor: Ironwood Pharmaceuticals, Inc.
Start date: 2019-05-01; Completion date: 2020-03-11
Enrollment: 515 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety and tolerability, treatment effect on abdominal pain, and dose response of MD-7246 administered orally to patients with diarrhea-predominant irritable bowel syndrome (IBS-D).

Detailed description:

Arms: arm 1: 1 MD-7246 300-μg oral tablet and 3 matching placebo oral tablets arm 2: 2 MD-7246 300-μg oral tablets and 2 matching placebo oral tablets arm 3: 4 MD-7246 300-μg oral tablets arm 4: 4 matching placebo oral tablets
Interventions: intervention 1: MD-7246 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet intervention 2: Matching oral tablet

Protocol documents:
Prot_000.pdf: 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 2 of 118 
SAE Reporting Fax Number/Email: 
Organization 
Email 
Safety Hotline Fax 
Safety Hotline Phone 
PPD 
 
 
 
Note: The preferred method of SAE reporting is via the electronic data capture (EDC) system; reporting should be 
done via fax/email if the EDC system is not available. 
 
Sponsor Signatory: 
 
 
Refer to the final page of this protocol for electronic signature and date of approval. 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 3 of 118 
SYNOPSIS 
Study Number: 
MCP-103-205 
Study Title: 
A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-range-
finding Study of MD-7246 Administered Orally for 12 Weeks to Treat Abdominal Pain in 
Patients with Diarrhea-predominant Irritable Bowel Syndrome 
Study Centers: 
Approximately 80 in the United States 
Development Phase: 2 
Objective(s): 
The objectives of this study are to evaluate the safety and tolerability, treatment effect on 
abdominal pain, and dose response of MD-7246 administered orally to patients with diarrhea-
predominant irritable bowel syndrome (IBS-D). An exploratory objective of the study is to 
assess bowel function changes with MD-7246 in patients with IBS-D. 
Methodology: 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
dose-range-finding, 12-week study, consisting of 4 distinct periods, as illustrated in the figure 
below. The study will enroll patients who have IBS-D diagnosed using Rome IV criteria. 
Eligible patients will be randomized in equal proportions to 1 of 4 treatments: 300, 600, or 
1200 µg of MD-7246, or matching placebo, administered once daily. MD-7246 is a delayed 
release (DR) tablet formulation of linaclotide designed to release linaclotide in the distal ileum 
near the ileocecal junction, to target guanylate cyclase C (GC-C) receptors in the colon and 
minimize secretory effects in the gastrointestinal (GI) tract. 




MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 5 of 118 
- 
Daily Assessments: 
◦ 
Daily Abdominal Symptom Assessments in a daily evening report 
◦ 
Bowel Movement (BM)-related Assessments on an event-driven basis (meaning 
these are assessments made for each event at the time the event occurs [or during 
the daily evening report for any events not previously entered for that day]) 
- 
Weekly Assessments 
◦ 
Weekly Patient Assessment of Degree of Relief of IBS Symptoms 
◦ 
Weekly Patient Assessment of Adequate Relief of IBS Pain 
◦ 
Weekly Patient Assessment of BM-related Symptom Severity (patient global 
impression of severity [PGI-S]) 
◦ 
Weekly Patient Assessment of BM-related Symptom Change (patient global 
impression of change [PGI-C]) 
- 
Use of Loperamide for Diarrhea on an event-driven basis 
Patients who satisfy all entry criteria will enter the Treatment Period. 
3. Treatment Period: The Treatment Period begins with treatment assignment and lasts for 
12 weeks. Patients will be randomized in equal proportions to 1 of 4 treatments: 300, 600, 
or 1200 µg of MD-7246, or matching placebo. Patients will take their initial dose of study 
drug at the study center during the Randomization Visit. On all other days, study drug will 
be taken once daily at approximately the same time of day without regard to food (patients 
will be instructed to choose a time that is convenient for them and continue daily dosing at 
that time throughout the Treatment Period). Patients will continue to use the handheld 
eDiary to provide their: 
- 
Daily Assessments: 
◦ 
Daily Abdominal Symptom Assessments in a daily evening report 
◦ 
BM-related Assessments on an event-driven basis (meaning these are assessments 
made for each event at the time the event occurs [or during the daily evening report 
for any events not previously entered for that day]) 
- 
Weekly Assessments 
◦ 
Weekly Patient Assessment of Degree of Relief of IBS Symptoms 
◦ 
Weekly Patient Assessment of Adequate Relief of IBS Pain 
◦ 
Weekly Patient Assessment of Treatment Satisfaction 
◦ 
Weekly Patient Assessment of BM-related Symptom Severity (PGI-S) 
◦ 
Weekly Patient Assessment of BM-related Symptom Change (PGI-C) 
- 
Use of Loperamide for Diarrhea on an event-driven basis 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 6 of 118 
- 
Health-related quality-of-life and patient-outcome assessments will be performed at the 
Randomization Visit and at study visits throughout the Treatment Period. A list of 
these assessments and the visits when they will be performed is provided under Study 
Visit Assessments in the Study Procedures section below 
Patients will complete a Week 2 Phone Call, and Week 4, Week 8, and Week 12/End of 
Treatment (EOT) Visits during the Treatment Period (see Schedule of Evaluations). 
4. Posttreatment Period: The Posttreatment Period starts on the day following the last day of 
dosing (Week 12/EOT Visit) and finishes 2 weeks later at the End of Study (EOS) Follow-
up Phone Call. During the call, patients will be asked to report any AEs and medicines 
taken since the Week 12/EOT Visit and detail any other symptoms or comments they may 
have (at the discretion of the investigator, patients may be requested to return to the study 
center for their EOS Follow-up). 
 
Overall Study Stopping Criteria and Data Monitoring Committee (DMC) 
The Sponsor may stop enrollment prematurely because of low recruitment rates. The Sponsor 
may suspend or terminate the study prematurely because of a change in opinion of the 
Institutional Review Board, DMC, or a regulatory authority decision. 
An independent DMC will regularly review safety data during the conduct of the study. 
Periodic safety review meetings will be scheduled when approximately 1/3 and 2/3 of patients 
have been randomized. The committee will review accumulated safety data, and may request 
unblinding of the treatment groups, in order to make any recommendations regarding the 
acceptability of continuing the study based on AEs reported. 
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 by the patient into the eDiary 
each day: 
• Diary of IBS Symptoms - Diarrhea (DIBSS-D; Appendix 4) 
- 
Daily Abdominal Symptom Assessments (entered by the patient in a daily evening 
report): 
◦ 
Rating of abdominal bloating at its worst during the previous 24 hours on an 
11-point numerical rating scale (NRS) 
◦ 
Rating of abdominal discomfort at its worst during the previous 24 hours on an 
11-point NRS 
◦ 
Rating of abdominal pain at its worst during the previous 24 hours on an 11-point 
NRS 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 7 of 118 
◦ 
Rating of abdominal cramping at its worst during the previous 24 hours on an 
11-point NRS 
- 
Daily BM-related Assessments (entered by the patient for each BM on an event-driven 
basis): 
◦ 
BM date and time 
◦ 
Stool consistency on a 5-point ordinal scale 
◦ 
Stool consistency on the 7-point Bristol Stool Form Scale (BSFS) 
◦ 
BM urgency on a binary (Yes/No) scale 
• Use of Loperamide for Diarrhea on an event-driven basis 
 
Weekly Assessments: The following information will be entered by the patient into the eDiary 
once per week at the same time as the daily evening report: 
• Patient Assessment of Degree of Relief of IBS Symptoms on a 7-point balanced scale 
• Patient Assessment of Adequate Relief of IBS Pain on a binary scale (Yes/No) 
• Patient Assessment of Treatment Satisfaction on a 5-point ordinal scale (assessed at each 
week of the Treatment Period after the Randomization Visit) 
• Patient Assessment of BM-related Symptom Severity on a 5-point ordinal scale 
• Patient Assessment of BM-related Symptom Change on a 7-point ordinal scale 
 
Study Visit Assessments:  
• The following information will be captured in the eDiary at the Pretreatment Visit: 
- 
Pain Catastrophizing Scale 
• The following information will be captured in the eDiary at the Randomization Visit 
before the first dose of study drug and at all subsequent study visits: 
- 
Short Form-12 Health Survey version 2 (SF-12v2) 
- 
EuroQol-5 Dimension (EQ-5D-3L) 
- 
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS) 
 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 8 of 118 
Protocol-permitted OTC Medication for Diarrhea 
• Throughout the study (Screening Period through Posttreatment Period), patients will be 
allowed to use loperamide (Imodium®) to assist in the management of their diarrhea. 
Loperamide will be provided to the patient at study visits to use as needed (at the patient’s 
discretion) to stabilize their diarrhea throughout the study. Beginning at the Pretreatment 
Visit (when the patients receive the eDiary) through the Week 12/EOT Visit, the day 
(yesterday/today) and dose will be entered by the patient for each use of loperamide for 
diarrhea on an event-driven basis. 
• Prescription medications for the treatment of diarrhea or IBS are not permitted during the 
study, from 4 weeks (28 days) before the Pretreatment Visit (or 3 months before the 
Pretreatment Visit for rifaximin) through the EOS Follow-up Phone Call (see Appendix 2). 
 
Number of Patients: 
Approximately 368 IBS-D patients (approximately 92 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 all of the following criteria: 
1. Patient has given consent by signing an ICF. 
2. Patient is an ambulatory male or female aged 18 years or older at the Screening Visit. 
3. Female patients are not pregnant and lactating females must agree not to breastfeed. 
4. Female patients of childbearing potential (ie, women who are not postmenopausal or who 
have not had a bilateral oophorectomy, hysterectomy, or tubal ligation) who are sexually 
active with a male partner must agree to use one of the following methods of birth control 
from the date they sign the ICF until the End of Study Visit: 
a. Hormonal contraception (ie, oral contraceptive, contraceptive implant, or injectable 
hormonal contraceptive) 
b. Double-barrier birth control (eg, condom plus intrauterine device, diaphragm plus 
spermicide) 
c. Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy 
5. 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. 
 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 9 of 118 
6. Patient meets the colonoscopy requirements as defined by the American 
Gastroenterological Association guidelines and described in Appendix 3. (Note: Patients 
who receive narcotic anesthesia for a colonoscopy are eligible to enter the Pretreatment 
Period only on the fifth day or later after the colonoscopy.) 
7. Patient meets Rome IV criteria for IBS (1): reports recurrent abdominal pain, on average at 
least 1 day/week during the 3 months before the diagnosis, with the onset at least 6 months 
before the diagnosis, associated with 2 or more of the following features: 
a. Related to defecation 
b. Associated with a change in frequency of stool 
c. Associated with a change in form (appearance) of stool 
Note: the diagnosis can be made at the Screening Visit or can be based on patient recall of 
symptoms that the patient had before starting chronic treatment with FDA-approved 
medications to treat IBS-D (eg, alosetron, rifaximin, or eluxadoline). 
8. Patient meets the Rome IV criteria for IBS-D (1), based on stool form on days with at least 
1 abnormal BM: >25% of BMs with BSFS score of 6 or 7 and <25% of BMs with BSFS 
score of 1 or 2. 
Note: IBS-D diagnosis should be based on the patient’s BM abnormalities when the patient 
is not taking medications to treat his/her BM abnormalities. 
9. Patient has an average score for abdominal pain at its worst of ≥4.0 and ≤9.0, as reported 
in the eDiary using an 11-point NRS during the 14 days before the Randomization Visit 
and including the eDiary entry made in clinic at the Randomization Visit prior to 
randomization. 
10. Patient is compliant (as defined in the study procedures section below) with eDiary 
completion by adequately responding to eDiary questions (ie, completing the daily evening 
report) on 10 or more of the 14 days before the Randomization Visit. 
11. Patient is able to swallow solid, oral dosage forms whole with the aid of liquid (patient 
may not chew, divide, crush, or dissolve the study drug). 
12. Patient is fluent in English or Spanish. 
13. Patient agrees to refrain from making any new, major lifestyle changes that may affect IBS 
symptoms (eg, starting a new diet or changing his or her exercise pattern) from the time of 
signature of the ICF to the last study visit. 
 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 10 of 118 
Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible to participate in the study: 
1. Patient has a known or suspected structural abnormality of the gastrointestinal (GI) tract 
(eg, mechanical gastrointestinal obstruction) or a disease or condition that can affect GI 
motility. 
2. Patient has clinically significant concurrent illness or findings on a physical examination 
or clinical laboratory tests (clinical chemistry panel, complete blood count [CBC]) after 
signing the ICF but before receiving the first dose of study drug. (Note: The investigator 
will determine if a finding is clinically significant. In making this determination, the 
investigator will consider whether the finding could prevent the patient from performing 
any of the protocol-specified assessments, represent a condition that would exclude the 
patient from the study, represent a safety concern if the patient participates in the study, or 
confound the study-specified assessments of safety or efficacy.) 
3. Patient has a positive drug or alcohol screen, including testing positive for marijuana or 
other drugs that target the endocannabinoid system, such as dronabinol. 
4. Patient has been diagnosed with or has a family history of familial adenomatous polyposis, 
hereditary nonpolyposis colorectal cancer, or any other form of familial colorectal cancer. 
5. Patient has a history of inflammatory or immune-mediated GI disorders, including 
inflammatory bowel disease (IBD) and symptomatic biopsy- or serology-positive celiac 
disease. 
6. Patient has symptomatic lactose intolerance, symptomatic non-celiac gluten sensitivity, or 
other malabsorption syndrome. 
7. Patient currently has clinically significant symptoms such as lower GI bleeding (rectal 
bleeding or heme-positive stool), iron-deficiency anemia, weight loss, or systemic signs of 
infection or colitis. 
8. Patient has any chronic condition with ongoing symptoms that can be associated with 
abdominal pain or discomfort and could confound the assessments in this study (eg, 
diverticulitis, ileus, active peptic ulcer disease, uncontrolled gastroesophageal reflux 
disease, gastroparesis, chronic pancreatitis, polycystic kidney disease, ovarian cysts, 
endometriosis, urological pain). 
9. Patient has a history of intestinal obstruction, toxic megacolon, megarectum, descending 
perineum syndrome, solitary rectal ulcer syndrome, systemic sclerosis, multiple sclerosis, 
Parkinson’s disease, spinal cord injury. 
10. Patient has ever had a fecal impaction that required hospitalization or emergency room 
treatment, or has a history of cathartic colon, ischemic colitis, or pelvic floor dysfunction 
(unless successful treatment has been documented by a normal balloon expulsion test). 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 11 of 118 
11. Patient has currently documented positive stool tests for enteric pathogens, ova or 
parasites. 
12. Patient has a history of a microbiologically documented lower GI infection (eg, 
Clostridium difficile colitis) or received treatment for a microbiologically documented 
lower GI infection during the 3 months before the Screening Visit. 
13. Patient has a history of hypersensitivity to linaclotide, any of the excipients contained in 
the study drug (MD-7246 or placebo) as described in Section 7.1, or loperamide. 
14. 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 (including cholecystectomy), pelvis, or retroperitoneal 
structures during the 6 months before the Screening Visit, or during the 3 months 
before the Screening Visit for laparoscopic surgery 
c. Other major surgery, including appendectomy, during the 3 months before the 
Screening Visit 
15. Patient has a history of cancer other than treated basal cell or squamous cell carcinoma of 
the skin. (Note: Patients with a history of cancer are allowed if the malignancy has been in 
a complete remission for at least 3 years before the Randomization Visit. A complete 
remission is defined as the disappearance of all signs of cancer in response to treatment.) 
16. Patient has a history of diabetic neuropathy. 
17. Patient has a history of human immunodeficiency virus infection. 
18. 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. 
19. Patient has a recent history (during the 12 months before the Randomization Visit) of drug 
or alcohol abuse. (Note: Patients with a history of drug or alcohol abuse that was 
diagnosed greater than 12 months before the Randomization Visit may be enrolled if they 
have exhibited no actual abuse during the 12 months before the Randomization Visit.) 
20. Patient has a history or current evidence of laxative or opioid abuse. 
21. Patient has been hospitalized for a major psychiatric condition or has made a suicide 
attempt during the 2 years before the Randomization Visit. 
22. Patient has received an investigational drug during the 30 days before the Screening Visit. 
23. Patient reported using a Prohibited Medicine during the Screening or Pretreatment Period, 
does not meet all the Prohibited Medicine criteria, or is not willing or able to abide by the 
restrictions regarding use of Prohibited Medicines, as detailed in Appendix 2. 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 12 of 118 
24. 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. 
25. Patient has previously entered the Pretreatment Period of this study. 
26. Patient is directly or indirectly involved in the conduct and administration of this study as 
an investigator, sub-investigator, study coordinator, other study staff member, or employee 
of Ironwood Pharmaceuticals or Allergan; or the patient is a first-degree family member, 
significant other, or relative residing with one of the above persons involved directly or 
indirectly in the study; or the patient is enrolled in this study at another clinical study site. 
 
Test Product, Dosage, and Mode of Administration: 
MD-7246 (formerly known as linaclotide DR2) at 3 dose levels (300, 600, or 1200 µg) 
administered as oral tablets in a double-blind manner once daily at approximately the same 
time of day without regard to food. 
Reference Therapy, Dosage, and Mode of Administration: 
Placebo oral tablets matching the test product in size and appearance administered in a double-
blind manner once daily at approximately the same time of day without regard to food. 
Duration of Treatment:  
The test product and reference therapy will be administered for 12 weeks. Total patient 
participation will be up to 151 days, including the Screening, Pretreatment, Treatment, and 
Posttreatment Periods. 
Criteria for Evaluation: 
Key Efficacy Assessment 
The following efficacy assessment based on the eDiary question is used to determine the key 
efficacy endpoints: 
• Daily patient assessment of abdominal pain at its worst over the last 24 hours on an 
11-point NRS 
 
Additional Efficacy Assessments 
Additional efficacy assessments are based on the following eDiary questions: 
• Daily patient assessments of abdominal bloating, abdominal discomfort, and abdominal 
cramping at their worst over the last 24 hours, each on an 11-point NRS 
• Weekly patient assessment of degree of relief of IBS symptoms on a 7-point balanced 
scale 
• Weekly patient assessment of adequate relief of IBS pain on a binary scale 
• Weekly patient assessment of treatment satisfaction on a 5-point ordinal scale 
 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 13 of 118 
Exploratory Assessments 
Exploratory assessments are based on the following eDiary BM-related questions; these non-
efficacy assessments will inform evaluation of whether MD-7246 affects bowel function: 
• BM frequency (date and time) 
• Stool consistency on a 5-point ordinal scale 
• Stool consistency on the 7-point BSFS 
• BM urgency on a binary scale 
• Use of loperamide for diarrhea 
• Weekly patient assessment of BM-related symptom severity on a 5-point ordinal scale 
• Weekly patient assessment of BM-related symptom change on a 7-point ordinal scale 
 
Safety Measures: 
Adverse event (AE) recording (each visit), clinical laboratory measures (chemistry and 
hematology: Screening, Randomization, Week 4, Week 8, and Week 12/EOT Visits), body 
weight (each visit), vital sign parameters (each visit). 
Statistical Methods: 
Analysis Populations 
The Screened Population consists of all patients who had a Screening Visit (Visit 1) and were 
assigned a patient identification (PID) number. 
The Intent-to-Treat (ITT) Population consists of all randomized patients. 
The Safety Population consists of all patients who received at least 1 dose of study drug. 
General Methods 
Efficacy analyses will be performed on the ITT Population for all outcomes reported during 
the Treatment Period using treatment group assigned at the Randomization Visit. Unless 
otherwise specified, all confidence intervals (CIs) will be 2-sided and with a confidence level 
of 95%. No adjustments will be made for multiplicity in the conduct of comparisons among 
the MD-7246 doses relative to placebo for the key efficacy endpoints, or in the analysis of the 
additional efficacy endpoints or exploratory endpoints. Safety analyses will be performed 
using descriptive summaries based on the Safety Population and on actual treatment received. 
For analysis of continuous parameters (eg, change from baseline), descriptive statistics (n, 
mean, standard deviation, median, and range) will be calculated and presented for each 
treatment group. For categorical parameters (eg, responder vs. non-responder), the number and 
percentage of each category will be calculated and presented for each treatment group. 
Percentages will be based on the total number of non-missing values; the number missing will 
be presented, but without a percentage. 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 14 of 118 
Key Efficacy Endpoints 
• Change from Baseline in Abdominal Pain at its Worst at Each Week 
The weekly abdominal pain at its worst score is the average of the non-missing abdominal 
pain scores during each week (Weeks 1-12) in the study. The baseline abdominal pain 
score is the average of the non-missing abdominal pain scores during the last 14 days of 
the Pretreatment Period and the day of the Randomization Visit reported prior to 
randomization. Change from baseline will be calculated for each week as the weekly score 
minus the baseline score. 
• 6/12 Week Abdominal Pain 30% Responder 
A 6/12 Week Abdominal Pain 30% Responder is a patient who meets the Weekly 
Abdominal Pain 30% Responder criteria for at least 6 out of the 12 weeks of the Treatment 
Period. A Weekly Abdominal Pain 30% Responder is a patient who has a decrease from 
baseline of at least 30% in the mean abdominal pain at its worst 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 30% 
Responder for that week. 
 
Key Efficacy Analysis 
Comparisons between the MD-7246 dose groups and placebo with regard to the change from 
baseline in abdominal pain over the Treatment Period will be evaluated employing a mixed 
model with repeated measures (MMRM) framework with week (categorical), treatment, 
geographic region, and week-by-treatment fixed effects, patient as the random effect, and 
baseline value as a covariate. An unstructured covariance structure will be utilized. 
Descriptive statistics, for the overall Treatment Period effect, based on the MMRM model will 
include least-squares (LS) mean change from baseline for each treatment, the LS mean 
difference between each MD-7246 dose and placebo, corresponding 95% CIs, and the p-value 
associated with the comparison. In addition, weekly treatment differences between each MD-
7246 dose group and placebo will be provided using the same MMRM model defined above. 
For the 6/12 Week Abdominal Pain 30% Responder endpoint, the proportion of responders in 
each MD-7246 group will be compared to the proportion of responders in the placebo group 
using a Cochran-Mantel-Haenszel (CMH) test controlling for geographic region. The number 
and percent of responders, the difference in responder rates between each MD-7246 group and 
the placebo group, the odds ratio relative to placebo, all corresponding 95% CIs, and the p-
value associated with the CMH test will be presented. 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 15 of 118 
Additional Efficacy Endpoints 
• 6/12 Week Abdominal Pain 50% Responder 
≥50% decrease from baseline in abdominal pain for ≥6 of 12 weeks 
• 6/12 Week Abdominal Discomfort 30% Responder 
≥30% decrease from baseline in abdominal discomfort for ≥6 of 12 weeks 
• 6/12 Week Abdominal Bloating 30% Responder 
≥30% decrease from baseline in abdominal bloating for ≥6 of 12 weeks 
• 6/12 Week Abdominal Cramping 30% Responder 
≥30% decrease from baseline in abdominal cramping for ≥6 of 12 weeks 
• 6/12 Week Degree of Relief Responder 
Score of ≤2 (“completely” or “considerably” relieved) for ≥6 of 12 weeks 
• 6/12 Week Adequate Relief of IBS Pain Responder 
Patient reports adequate relief of IBS pain (“yes”) for ≥6 of 12 weeks 
• Treatment Satisfaction 
• Change from Baseline in Percent of Abdominal Pain-free Days at Each Week 
• Change from Baseline in Abdominal Discomfort at its Worst at Each Week 
• Change from Baseline in Abdominal Bloating at its Worst at Each Week 
• Change from Baseline in Abdominal Cramping at its Worst at Each Week 
 
Additional Efficacy Analysis 
The additional categorical responder (eg, 6/12 Week Abdominal Bloating 30% Responder) 
and continuous change-from-baseline endpoints will be analyzed utilizing the same methods 
defined above for the key efficacy endpoints. 
Treatment Satisfaction will be analyzed utilizing an MMRM framework with week 
(categorical), treatment, geographic region, and week-by-treatment fixed effects, and patient 
as the random effect. An unstructured covariance structure will be utilized. Pairwise 
comparisons between each treatment group and placebo will be performed for the overall 
Treatment Period effect. MMRM-associated statistics, as defined above for the key efficacy 
change-from-baseline endpoint, will be presented. 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 16 of 118 
Exploratory Endpoints 
Exploratory endpoints related to bowel function will be studied to address the exploratory 
objective of the study. These non-efficacy endpoints will include: 
• Change from Baseline in BM Frequency Rate at Each Week 
• Change from Baseline in BSFS (Stool Consistency) at Each Week 
• Change from Baseline in Urgent BM Frequency Rate at Each Week 
• Change from Baseline in the Percent of Days Experiencing an Episode of Diarrhea per 
Week 
An episode of diarrhea is defined as a sequence of ≥2 loose/watery BMs (BSFS 6 or 7) that 
are never separated by >1 non-loose/watery stool or by a day without a BM. 
• Change from Baseline in the Percent of Days Experiencing No Episodes of Diarrhea per 
Week 
• Change from Baseline in BM-related Symptom Severity at Each Week 
• BM-related Symptom Change 
• Change from Baseline in Percent of Days with Use of Loperamide for Diarrhea at Each 
Week 
 
Exploratory Analysis 
Exploratory change-from-baseline endpoints will be analyzed utilizing the same methods as 
described above for the key efficacy analysis. BM-related Symptom Change will be analyzed 
for the Treatment Period overall utilizing the same methods as described above for the 
additional efficacy analysis of Treatment Satisfaction. 
Safety Analysis 
All safety parameters will be analyzed descriptively in accordance with the General Methods. 
Sample Size 
In a previously conducted Phase 2b trial utilizing MD-7246 (formerly known as linaclotide 
DR2), MCP-103-204, the standard deviation for the change from baseline to Week 12 in 
abdominal pain at its worst ranged from 2.32 to 2.88. Assuming a clinically meaningful 
treatment difference between MD-7246 and placebo of 1.0 for the mean change from baseline 
to Week 12 in abdominal pain, a standard deviation of 2.4, and 92 patients per treatment group 
(368 total), the estimated power is approximately 80% to detect a difference between each 
MD-7246 dose and placebo at a 2-sided significance level of 0.05 using a 2-sample t-test. 
Final Date: 29 January 2019 
 


MD-7246 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
Confidential 
Page 17 of 118 
SCHEDULE OF EVALUATIONS 
Schedule of Evaluations MCP-103-205 
Study Period → 
Screening 
Period 
(Up to 28 days) 
Pretreatment 
Period 
(14 to 21 days) 
Treatment Period 
(12 weeks) 
Posttreatment 
Period 
(2 weeks) 
Visit Days → 
Screening 
Visit 
(Day -49 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -14) 
Random-
ization 
Visit 
(Day 1) 
Week 2 
Phone Call 
(Day 15±3) 
Week 4 
Visit 
(Day 29±3) 
Week 8 
Visit 
(Day 57±3) 
Week 12/ End-
of-Treatment 
Visit p 
(Day 85+3) 
End-of-Study 
Follow-up 
Phone Call 
(Day 99+3) 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Telephone 
Call 
Visit 4 
Visit 5 
Visit 6 
Telephone 
Call 
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 
X 
X 
Clinical Laboratory Tests f 
X 
 
X* 
 
X 
X 
X 
 
Pregnancy Test g 
X 
 
X* 
 
 
 
X 
 
Prohibited Medications Washout 
Instructions 
X 
 
 
 
 
 
 
 
Loperamide for Diarrhea Dispensed h 
X 
X 
X 
 
X 
X 
X 
 
AE Evaluations i 
 
X 
X* 
X 
X 
X 
X 
X 
eDiary Registration and Training j 
 
X 
X* 
 
X 
X 
X 
 
Pain Catastrophizing Scale 
 
X 
 
 
 
 
 
 
Daily and Weekly Assessments k 
 
X 
 
Patient eDiary Entry, in Clinic 
 
X 
X* 
 
X 
X 
X 
 


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Schedule of Evaluations MCP-103-205 
Study Period → 
Screening 
Period 
(Up to 28 days) 
Pretreatment 
Period 
(14 to 21 days) 
Treatment Period 
(12 weeks) 
Posttreatment 
Period 
(2 weeks) 
Visit Days → 
Screening 
Visit 
(Day -49 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -14) 
Random-
ization 
Visit 
(Day 1) 
Week 2 
Phone Call 
(Day 15±3) 
Week 4 
Visit 
(Day 29±3) 
Week 8 
Visit 
(Day 57±3) 
Week 12/ End-
of-Treatment 
Visit p 
(Day 85+3) 
End-of-Study 
Follow-up 
Phone Call 
(Day 99+3) 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Telephone 
Call 
Visit 4 
Visit 5 
Visit 6 
Telephone 
Call 
Study Procedure ↓ 
 
 
 
 
 
 
 
 
eDiary Compliance Verification and 
Reminder l 
 
 
X* 
X 
X 
X 
X 
 
Randomization 
 
 
X† 
 
 
 
 
 
SF-12v2 
 
 
X† 
 
X 
X 
X 
 
EQ-5D-3L 
 
 
X† 
 
X 
X 
X 
 
IBS-SSS 
 
 
X† 
 
X 
X 
X 
 
Study Drug Dispensed 
 
 
X 
 
X 
X 
 
 
Study Drug Administration m 
 
 
X 
 
 
 
 
 
Safety Phone Call n 
 
 
 
X 
 
 
 
X 
Study Drug Accountability 
 
 
 
 
X 
X 
X 
 
Investigator Consultation with 
Patient o 
 
X (Activity Triggered by eDiary Alert) 
 
AE=adverse event; BM=bowel movement; CBC=complete blood count; eDiary=electronic diary; EOS=End-of-Study; EOT=End-of-Treatment; 
EQ-5D-3L=EuroQol-5 Dimension 3-level; IBS=irritable bowel syndrome; IBS-SSS= Irritable Bowel Syndrome-Symptom Severity Scale; ICF=informed consent 
form; IWRS=interactive web response system; SF-12v2=Short Form-12 Health Survey version 2. 
* Assessment done prior to randomization; † Assessment done predose 
a. 
Site personnel will interact with IWRS to register the patient visit. Refer to the IWRS User Manual. 
b. A physical examination includes, at minimum, the following: general appearance, HEENT (head, ears, eyes, nose, and throat), cardiac, respiratory, 
gastrointestinal, musculoskeletal, neurological, and dermatological systems. Rectal examinations should be performed at the discretion of the investigator; 
the purpose of the rectal examination is to rule out pathologies that might be caused by obstruction. Breast and genitourinary examinations are not required. 
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. Pulse and blood pressure 
readings will be taken after the patient has been sitting for 5 minutes. 
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 (approved or unapproved). 


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f. 
Chemistry and CBC. Urine drug screen will be performed at the Screening Visit only. 
g. Required for females of childbearing potential only. 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 serum pregnancy test results must be 
documented at the Week 12/EOT Visit. 
h. Protocol-permitted loperamide for diarrhea will be supplied to patients at the Screening Visit and, if needed, at the Pretreatment Visit, subsequent study drug 
dispensing visits, and the Week 12/EOT Visit. 
i. 
All AEs occurring after the patient signs the ICF will be captured. 
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 Abdominal Symptom Assessments, BM-related Assessments, Weekly Assessments, Pain Catastrophizing Scale 
(Pretreatment Visit only), SF-12v2, EQ-5D, IBS-SSS, and any use of loperamide for diarrhea. Patients will enter BMs and loperamide use in the eDiary on 
an event-driven basis, and will complete an evening entry each day to record daily assessments, including any BMs and/or loperamide use not previously 
recorded for that day, and weekly assessments. At the Randomization Visit, eDiary assessments will be completed in clinic prior to randomization. 
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 compliance reminder will also occur during the Week 2 Phone Call. 
m. Study drug will be administered in the clinic at the Randomization Visit. On all other days, study drug will be taken once daily at approximately the same 
time of day without regard to food. 
n. Appropriate site personnel will contact patients by phone to assess for AEs, record concomitant medicines, and (at Week 2 only) remind patients to comply 
with study drug and eDiary completion. Any AE or concomitant medicine reported during the phone call will be captured on the eCRF. Patients who report 
AEs during the call will be provided with instructions on the appropriate follow-up care. At the discretion of the investigator, patients may be requested to 
return to the clinic for this contact or an unscheduled visit may be conducted following the phone call. 
o. Throughout the Pretreatment and Treatment Periods, the eDiary will send automated alerts to the investigator if patients experience episodes of constipation 
with excessive use of loperamide or diarrhea that is not well managed with the use of loperamide (as defined in Section 8.2.6). In the event of an alert, the 
investigator must review with the patient their use of loperamide and their pattern of constipation or diarrhea. 
p. 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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TABLE OF CONTENTS 
SYNOPSIS .......................................................................................................................................3 
SCHEDULE OF EVALUATIONS ...............................................................................................17 
LIST OF ABBREVIATIONS ........................................................................................................26 
1. 
ETHICAL CONSIDERATIONS ...........................................................................................29 
1.1 
INSTITUTIONAL REVIEW BOARD........................................................................29 
1.2 
PATIENT INFORMATION AND CONSENT ...........................................................29 
2. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ............................30 
3. 
INTRODUCTION .................................................................................................................31 
3.1 
IRRITABLE BOWEL SYNDROME (IBS) ................................................................31 
3.2 
MD-7246 ......................................................................................................................32 
3.3 
MD-7246 CLINICAL DEVELOPMENT....................................................................34 
4. 
STUDY OBJECTIVES ..........................................................................................................38 
5. 
INVESTIGATIONAL PLAN ................................................................................................39 
5.1 
OVERALL STUDY DESIGN AND PLAN ................................................................39 
5.1.1 
Study Periods .....................................................................................................40 
5.1.1.1 
Screening Period ......................................................................................40 
5.1.1.2 
Pretreatment Period ..................................................................................40 
5.1.1.3 
Treatment Period ......................................................................................41 
5.1.1.4 
Posttreatment Period ................................................................................42 
5.1.2 
Stopping Criteria and Data Monitoring Committee (DMC) ..............................42 
5.1.2.1 
Study Drug Discontinuation Criteria for Individual Patients ..................42 
5.1.2.2 
Overall Study Stopping Criteria...............................................................42 
5.1.2.3 
Data Monitoring Committee ....................................................................43 
5.2 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUP ............................43 
5.3 
STUDY DURATION ..................................................................................................43 
6. 
SELECTION OF STUDY POPULATION ...........................................................................44 
6.1 
INCLUSION CRITERIA.............................................................................................44 
6.2 
EXCLUSION CRITERIA ...........................................................................................45 
6.3 
DISCONTINUATION OF PATIENTS FROM THERAPY OR ASSESSMENT ......48 
6.4 
REPLACEMENT PROCEDURES .............................................................................49 
7. 
TREATMENTS .....................................................................................................................50 
7.1 
TREATMENTS ADMINISTERED ............................................................................50 
7.2 
IDENTITY AND STORAGE OF INVESTIGATIONAL PRODUCT .......................51 
7.3 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS....................51 
7.4 
SELECTION OF DOSAGE IN THE STUDY ............................................................52 
7.5 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT ...............................53 


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7.6 
BLINDING ..................................................................................................................53 
7.7 
CONCOMITANT MEDICINES .................................................................................54 
7.8 
TREATMENT COMPLIANCE ..................................................................................55 
8. 
STUDY PROCEDURES AND ASSESSMENTS .................................................................56 
8.1 
EFFICACY ASSESSMENTS .....................................................................................56 
8.1.1 
Key Efficacy Assessment ..................................................................................56 
8.1.2 
Additional Efficacy Assessments ......................................................................56 
8.1.3 
Exploratory Assessments ...................................................................................59 
8.1.4 
Health Economics and Outcomes Research Assessments .................................63 
8.1.5 
Completion of eDiary Assessments ...................................................................64 
8.2 
SAFETY ASSESSMENTS ..........................................................................................65 
8.2.1 
Adverse Events ..................................................................................................65 
8.2.1.1 
Definitions................................................................................................65 
8.2.1.2 
Classification of an Adverse Event ..........................................................66 
8.2.1.3 
Procedures for Recording Adverse Events ..............................................69 
8.2.1.4 
Procedures for Collecting and Reporting Serious Adverse Events .........70 
8.2.2 
Clinical Laboratory Determinations ..................................................................72 
8.2.3 
Vital Signs ..........................................................................................................73 
8.2.4 
Physical Examination.........................................................................................74 
8.2.5 
Medical History .................................................................................................74 
8.2.6 
Required Investigator Consultation with the Patient .........................................75 
9. 
DATA QUALITY ASSURANCE .........................................................................................76 
9.1 
DATA MONITORING ................................................................................................76 
9.2 
DATA RECORDING AND DOCUMENTATION ....................................................76 
10. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ......................78 
10.1 
ANALYSIS POPULATIONS .....................................................................................78 
10.1.1 
Screened Population...........................................................................................78 
10.1.2 
Intent-to-Treat Population ..................................................................................78 
10.1.3 
Safety Population ...............................................................................................78 
10.2 
GENERAL METHODS...............................................................................................78 
10.2.1 
Patient Disposition .............................................................................................79 
10.2.2 
Demographics and Baseline Characteristics ......................................................79 
10.2.3 
Protocol Deviations ............................................................................................79 
10.2.4 
Prior and Concomitant Medicines .....................................................................80 
10.3 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................80 
10.3.1 
Exposure to Study Drug .....................................................................................80 
10.3.2 
Measurement of Treatment Compliance ............................................................80 
10.3.3 
eDiary Compliance ............................................................................................81 


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10.4 
EFFICACY ANALYSES ............................................................................................81 
10.4.1 
Key Efficacy Endpoints .....................................................................................82 
10.4.2 
Key Efficacy Analysis .......................................................................................82 
10.4.3 
Additional Efficacy Endpoints ...........................................................................83 
10.4.4 
Additional Efficacy Analysis .............................................................................85 
10.4.5 
Exploratory Endpoints .......................................................................................85 
10.4.6 
Exploratory Analysis .........................................................................................87 
10.5 
HEALTH ECONOMICS AND OUTCOMES RESEARCH ANALYSES ................87 
10.5.1 
Pain Catastrophizing Scale ................................................................................87 
10.5.2 
SF-12v2 ..............................................................................................................87 
10.5.3 
EQ-5D-3L ..........................................................................................................88 
10.5.4 
IBS-SSS .............................................................................................................88 
10.6 
SAFETY ANALYSES.................................................................................................88 
10.6.1 
Adverse Events ..................................................................................................88 
10.6.2 
Clinical Laboratory Parameters .........................................................................89 
10.6.3 
Vital Signs ..........................................................................................................90 
10.7 
INTERIM ANALYSIS ................................................................................................90 
10.8 
DETERMINATION OF SAMPLE SIZE ....................................................................91 
11. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES .............92 
12. STUDY SPONSORSHIP ......................................................................................................93 
12.1 
STUDY TERMINATION ...........................................................................................93 
12.2 
REPORTING AND PUBLICATION ..........................................................................93 
13. INVESTIGATOR OBLIGATIONS ......................................................................................94 
13.1 
DOCUMENTATION ..................................................................................................94 
13.2 
PERFORMANCE ........................................................................................................94 
13.3 
USE OF INVESTIGATIONAL MATERIALS ...........................................................95 
13.4 
CASE REPORT FORMS ............................................................................................95 
13.5 
RETENTION AND REVIEW OF RECORDS ...........................................................95 
13.6 
PATIENT CONFIDENTIALITY ................................................................................96 
14. APPENDICES .......................................................................................................................97 
15. REFERENCE LIST .............................................................................................................117 
 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
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LIST OF IN-TEXT TABLES 
Table 1. 
Adverse Event Causality ....................................................................................68 
 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
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LIST OF IN-TEXT FIGURES 
Figure 1. 
Overview of Study Design .................................................................................39 
 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
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LIST OF APPENDICES 
Appendix 1 
Elements of Informed Consent ..........................................................................98 
Appendix 2 
Concomitant and Prohibited Medications........................................................100 
Appendix 3 
Summary of American Gastroenterological Association Guidelines ..............104 
Appendix 4 
DIBSS-D ..........................................................................................................105 
Appendix 5 
Bristol Stool Form Scale ..................................................................................107 
Appendix 6 
Pain Catastrophizing Scale ..............................................................................108 
Appendix 7 
SF-12v2 ............................................................................................................109 
Appendix 8 
EQ-5D-3L ........................................................................................................112 
Appendix 9 
IBS-SSS ...........................................................................................................114 
Appendix 10 
Investigator’s Signature ...................................................................................116 
 
 


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BM 
bowel movement 
BP 
blood pressure 
BSFS 
Bristol Stool Form Scale 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
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 
DIBSS-M 
Diary of IBS Symptoms – Mixed 
DMC 
data monitoring committee 
DR 
delayed release 
 
 
 
 
EC50 
half maximal effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EOS 
End of Study 
EOT 
End of Treatment 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
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EQ-5D-3L 
EuroQol-5 Dimension 3-level 
FDA 
Food and Drug Administration 
GC-C 
guanylate cyclase-C 
GCP 
good clinical practice 
GI 
gastrointestinal 
GPS 
Global Patient Safety 
HEENT 
head, ears, eyes, nose, and throat 
HEOR 
health economics and outcomes research 
HIPAA 
Health Insurance Portability and Accountability Act 
HT 
hydroxytryptophan 
IBD 
inflammatory bowel disease 
IBS 
irritable bowel syndrome 
IBS-C 
irritable bowel syndrome with constipation 
IBS-D 
irritable bowel syndrome with diarrhea 
IBS-M 
irritable bowel syndrome mixed 
IBS-SSS 
Irritable Bowel Syndrome – Symptom Severity Scale 
IBS-U 
unclassified irritable bowel syndrome 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IPD 
important protocol deviation 
IR 
immediate release 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
Ki 
inhibitory constant 
LLOQ 
lower limit of quantitation 
LS 
least squares 
MAOI 
monoamine oxidase inhibitor 


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model with repeated measures 
NDA 
New Drug Application 
NRS 
numerical rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over-the-counter 
PCS 
potentially clinically significant 
PD 
pharmacodynamic(s) 
PEG 
polyethylene glycol 
PGI-C 
patient global impression of change 
PGI-S 
patient global impression of severity 
PID 
patient identification 
PK 
pharmacokinetic(s) 
QOL 
quality of life 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SF-12v2 
Short Form-12 Health Survey version 2 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SOC 
system organ class 
SSRI 
selective serotonin reuptake inhibitor 
TCA 
tricyclic antidepressant 
TEAE 
treatment-emergent adverse event 
US 
United States 
 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
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1. 
ETHICAL CONSIDERATIONS 
This clinical study is designed to comply with the International Council on Harmonisation (ICH) 
Guidance on General Considerations for Clinical Trials, ICH E8 (published in the US Federal 
Register Volume 62, page 66113, December 17, 1997) and Good Clinical Practice (GCP): 
Consolidated Guidance, ICH E6 (published in the US Federal Register, Volume 62, page 25692, 
May 9, 1997). The 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. 
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 1), and associated documentation will be approved by the IRB 
prior to study initiation, in compliance with 21 CFR 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 per 21 CFR Part 50. Patients will then be given the 
opportunity to ask questions and will be informed of their right to withdraw from the 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 and any currently enrolled patient 
will be made aware of the new information and asked if he/she wishes to continue in the study. 
The revised consent form will be submitted to the IRB for review and approval prior to its use. 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
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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). 
Ironwood Pharmaceuticals, Inc. and Allergan Sales, LLC are development partners for this 
study. 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
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3. 
INTRODUCTION 
3.1 
IRRITABLE BOWEL SYNDROME (IBS) 
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal (GI) disorder 
characterized by recurrent abdominal pain associated with defecation and/or a change in stool 
frequency or form. In addition to the characteristic abdominal pain, IBS is often associated with 
abdominal distension and bloating.(1-6) 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 based on predominant stool form as IBS with diarrhea (IBS-D), IBS with 
constipation (IBS-C), or IBS mixed (IBS-M; mixed constipation and diarrhea), according to the 
Rome diagnostic criteria. IBS patients who rarely or never have abnormal stools or do not fit into 
1 of the 3 main IBS subtypes are subtyped as unclassified IBS (IBS-U).(8) 


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3.2 
MD-7246 
MD-7246 is currently being developed for the treatment of abdominal pain associated with 
IBS-D. MD-7246 is an orally administered, delayed release (DR) tablet formulation of 
linaclotide designed to target guanylate cyclase C (GC-C) receptors in the colon and minimize 
secretory effects. 
Linaclotide is a minimally absorbed 14-amino acid synthetic peptide agonist of GC-C. 
Linaclotide and its active metabolite bind to and activate GC-C on the luminal surface of the 
intestinal epithelial cells. As a GC-C agonist, linaclotide (and its active metabolite) improves 
bowel symptoms and abdominal pain via agonism of cyclic guanosine monophosphate (cGMP) 
on the intestinal mucosa. Activation of GC-C results in an increase in concentrations of cGMP, 
both extracellularly and intracellularly. Orally administered linaclotide has also been shown to 
reduce visceral hypersensitivity in animal models and abdominal pain in patients with IBS-C.(9) 
Extracellular cGMP in the serosal space is believed to modulate the activity of local afferent 
(sensory) nerve fibers. Increases in cGMP within the intestinal epithelial cells triggers a signal 
transduction cascade, leading to activation of the cystic fibrosis transmembrane conductance 
regulator (CFTR) ion channels. This activation causes secretion of chloride and bicarbonate into 
the intestinal lumen, resulting in increased luminal fluid secretion and acceleration of intestinal 
transit.(10) These effects on fluid dynamics within the GI tract are believed to play a role in 
accelerating intestinal transit and increasing stool water, which in turn results in softer stools. 
LINZESS® is an orally administered, immediate release (IR) capsule formulation of linaclotide 
approved by the US FDA in 2012 at two dosage strengths: 290 µg for the treatment of IBS-C in 
adults, and 145 µg for the treatment of chronic idiopathic constipation (CIC) in adults. In 2017, 
US FDA also approved linaclotide (LINZESS®) 72 µg IR capsules for the treatment of CIC. The 
FDA-approved linaclotide IR formulation is a rapidly dissolving capsule, and dissolution tests 
suggest that it is released primarily in the stomach. 
DR tablet formulations of linaclotide were developed with the hypothesis that delayed delivery 
of linaclotide will limit fluid secretion in the small intestine and maintain the nociceptive effects 
of the drug by enabling higher concentrations of linaclotide to interact with GC-C in the colon. 
 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
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• 
 
 
• DR formulation 2 (DR2), also referred to as MD-7246, was designed to target the distal 
ileum near the ileocecal junction to relieve pain and minimize secretory effects in the GI 
tract. 
 
Although GC-C is found throughout the GI tract, when administered as LINZESS®, linaclotide 
and its active metabolite are likely to have the greatest activity in the proximal region of the 
small intestine, due to metabolism within the GI tract. Preclinical experiments 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.(11) This degradation may reduce the amount 
of linaclotide available to engage GC-C receptors in the distal ileum and colon when 
administered as LINZESS®. Some linaclotide or its active metabolite can traverse the entire GI 
tract; in a Phase 1 clinical study with LINZESS®, approximately 5% of the oral dose was 
recovered in the feces of healthy volunteers, primarily in the form of the active metabolite. 
However, linaclotide is not expected to reliably reach the colon at high concentrations following 
oral administration of LINZESS®. MD-7246 (the DR2 formulation) may allow higher 
concentrations of linaclotide to be delivered to the colon, bypassing the GC-C receptors in the 
duodenum, jejunum, and proximal ileum (where the effects of increased luminal fluid secretion 
are more pronounced than in the colon, which has a higher re-absorptive capability), and 
avoiding degradation in the proximal small intestine. 
The MD-7246 tablets consist of linaclotide tablet cores coated with pH-dependent enteric 
polymers that dissolve at the pH levels encountered in the distal small intestine. Once the 
functional delayed-release coat dissolves, the linaclotide tablet core dissolves 
 
 It is anticipated that delivery of linaclotide to the lower intestine will limit CFTR-mediated 
fluid secretion, thus having little impact on bowel function and stool form, and will enable the 
delivery of higher concentrations of linaclotide directly to interact with GC-C in the large 
intestine, the hypothesized source of pain for patients with IBS. 




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The Phase 2b study (MCP-103-204) was a multicenter, randomized, double-blind, double-
dummy, placebo-controlled, parallel-group, dose-range-finding study evaluating the two DR 
tablet formulations of linaclotide administered once daily for 12 weeks. A total of 532 patients 
with IBS-C (Rome III criteria) were randomized in equal proportions to 1 of 8 treatment groups: 
• Linaclotide DR1 (30 µg, 100 µg, or 300 µg) 
• Linaclotide DR2 (30 µg, 100 µg, or 300 µg) 
• LINZESS® (Linaclotide IR) 290 µg 
• Placebo 
 
All patients randomized to treatment (Intent-to-treat [ITT] Population) took at least 1 dose of 
study drug (Safety Population). Patients were instructed to take the study drug in the morning, 
under fasted conditions. Demographics and baseline clinical characteristics were generally 
similar across the treatment groups, which each included 66-67 patients. Efficacy results for the 
linaclotide DR2 and placebo groups and safety results for the linaclotide DR2, linaclotide IR, and 
placebo groups are summarized below. 
As hypothesized, the linaclotide DR2 formulation had minimal effects on bowel function 
(frequency and stool form) but showed a signal of benefit on abdominal pain relief. Mean 
reductions and percent reductions from baseline in abdominal pain for all linaclotide DR2 groups 
were numerically greater than for the placebo group over the entire Treatment Period and at each 
week. All linaclotide DR2 groups showed numerically higher responder rates than the placebo 
group for the following abdominal pain responder endpoints: 6/12 Week Abdominal Pain 
Sustained Responder and 9/12 Week Abdominal Pain Responder and Sustained Responder. For 
change in complete spontaneous bowel movement (CSBM) frequency over the entire Treatment 
Period, the linaclotide DR2 groups showed no dose response, with only the lowest dose group 
having a numerically higher CSBM frequency compared with the placebo group. There was no 
dose response for any CSBM +1 responder rate for linaclotide DR2. Overall, the linaclotide DR2 
formulation showed an abdominal pain relief signal with minimal to no secretory effects. 


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The linaclotide DR2 formulation was well tolerated and did not identify any new safety signals 
relative to the linaclotide IR formulation. There were no deaths reported in the study. Two 
patients (1 each in the placebo and linaclotide IR groups) reported a total of 3 on-therapy SAEs, 
(pneumonia, sepsis, and gastroenteritis) that were considered by the investigator to be unrelated 
to study drug. TEAEs occurred in 30.3% of placebo-treated patients, 40.9% of linaclotide IR-
treated patients, and 22.4-30.3% of linaclotide DR2 patients. No TEAE was reported by ≥5% of 
patients in any of the linaclotide DR2 groups. Diarrhea was the most common TEAE in the 
study, but was reported infrequently in the placebo (1.5%) and linaclotide DR2 groups 
(0.0-3.0%) compared with the linaclotide IR group (13.6%). All diarrhea TEAEs were mild to 
moderate in severity. Diarrhea resulted in the discontinuation of 4 patients in the linaclotide IR 
group; no patient in the placebo or linaclotide DR2 groups discontinued due to diarrhea. 
In the Phase 1 multiple-dose study (MCP-103-105) of the linaclotide DR2 formulation, 3 cohorts 
of 8 subjects each were randomized to receive linaclotide DR2 (6 subjects) or placebo 
(2 subjects) for 7 days. In total, 6 subjects each were randomized to linaclotide DR2 300, 1200, 
or 3000 µg or placebo. Linaclotide and its metabolite were not quantifiable in any plasma 
samples from this study (LLOQ of 0.100 ng/mL for both analytes) and PK parameters could not 
be calculated, indicating negligible systemic exposure following 7 days of oral administration of 
the linaclotide DR2 formulation at doses up to 3000 µg/day under fed conditions. 
There were no SAEs, deaths, or AEs leading to discontinuation in this Phase 1 multiple-dose 
study. All AEs were mild in severity. TEAEs were reported by 16.7%, 16.7%, and 33.3% of 
subjects in the linaclotide DR2 300, 1200, and 3000 µg groups, respectively, and 50.0% of 
subjects in the placebo group. No TEAE was reported by >1 subject. TEAEs were most 
frequently reported in the GI disorders system organ class (SOC); 16.7% of linaclotide DR2 
3000 µg subjects and 50.0% of placebo subjects reported TEAEs in the GI disorders SOC. No 
diarrhea TEAEs were reported. 
The linaclotide DR2 formulation (hereafter referred to as MD-7246) will be evaluated in this 
study for the treatment of abdominal pain associated with IBS-D. This is the first study of 
linaclotide in IBS-D patients. 


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Refer to the Investigator’s Brochure for a more detailed description of the chemistry, 
pharmacology, efficacy, and safety of the IR and DR formulations of linaclotide, based on 
studies conducted in animals, healthy volunteers, and in patients with IBS-C and CIC. 


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4. 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the safety and tolerability, treatment effect on 
abdominal pain, and dose response of MD-7246 administered orally to patients with diarrhea-
predominant irritable bowel syndrome (IBS-D). An exploratory objective of the study is to assess 
bowel function changes with MD-7246 in patients with IBS-D. 




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5.1.1 
Study Periods 
5.1.1.1 
Screening Period 
The Screening Period starts with the signing of the ICF (Appendix 1) and may last for up to 
28 days. During this period, patient eligibility for entry into the Pretreatment Period will be 
determined. Loperamide, a protocol-permitted OTC medication for diarrhea, will be distributed 
to eligible patients beginning at the Screening Visit. The end of the Screening Period coincides 
with the start of the Pretreatment Period. If the patient meets the entry criteria assessed at the 
Screening Visit and does not require a washout of prohibited medicines (see Appendix 2), the 
Screening Visit and Pretreatment Visit may be combined into one visit. 
5.1.1.2 
Pretreatment Period 
The Pretreatment Period is defined as the 14 to 21 days immediately before the Randomization 
Visit. During this period, patients will provide the following information in a handheld electronic 
diary (eDiary): 
• Daily Assessments 
- 
Daily Abdominal Symptom Assessments in a daily evening report 
- 
Bowel Movement (BM)-related Assessments on an event-driven basis (meaning these are 
assessments made for each event at the time the event occurs [or during the daily evening 
report for any events not previously entered for that day]) 
• Weekly Assessments 
- 
Weekly Patient Assessment of Degree of Relief of IBS Symptoms 
- 
Weekly Patient Assessment of Adequate Relief of IBS Pain 
- 
Weekly Patient Assessment of BM-related Symptom Severity (patient global impression 
of severity [PGI-S]) 
- 
Weekly Patient Assessment of BM-related Symptom Change (patient global impression 
of change [PGI-C]) 
• Use of Loperamide for Diarrhea on an event-driven basis 
 
Patients who satisfy all 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 
randomized in equal proportions to 1 of 4 treatments: 300, 600, or 1200 µg of MD-7246 or 
matching placebo. Patients will take their initial dose of study drug at the study center during the 
Randomization Visit. On all other days, study drug will be taken once daily at approximately the 
same time of day without regard to food (patients will be instructed to choose a time that is 
convenient for them and continue daily dosing at that time throughout the Treatment Period). 
Patients will continue to use the handheld eDiary to provide their: 
• Daily Assessments 
- 
Daily Abdominal Symptom Assessments in a daily evening report 
- 
BM-related Assessments on an event-driven basis (meaning these are assessments made 
for each event at the time the event occurs [or during the daily evening report for any 
events not previously entered for that day]) 
• Weekly Assessments 
- 
Weekly Patient Assessment of Degree of Relief of IBS Symptoms 
- 
Weekly Patient Assessment of Adequate Relief of IBS Pain 
- 
Weekly Patient Assessment of Treatment Satisfaction 
- 
Weekly Patient Assessment of BM-related Symptom Severity (PGI-S) 
- 
Weekly Patient Assessment of BM-related Symptom Change (PGI-C) 
• Use of Loperamide for Diarrhea on an event-driven basis 
• Health-related quality-of-life and patient-outcome assessments (ie, Short Form-12 Health 
Survey version 2 [SF-12v2], EuroQol-5 Dimension [EQ-5D-3L], and Irritable Bowel 
Syndrome-Symptom Severity Scale [IBS-SSS]) will be performed at the Randomization 
Visit and at study visits throughout the Treatment Period. A list of these assessments and the 
visits when they will be performed is provided in the Schedule of Evaluations. 
 
Patients will complete a Week 2 Phone Call, and Week 4, Week 8, and Week 12/End of 
Treatment (EOT) Visits during the Treatment Period (see Schedule of Evaluations). 


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5.1.1.4 
Posttreatment Period 
The Posttreatment Period starts on the day following the last day of dosing (Week 12/EOT Visit) 
and finishes 2 weeks later at the End of Study (EOS) Follow-up Phone Call. During the call, 
patients will be asked to report any AEs and medicines taken since the Week 12/EOT Visit and 
detail any other symptoms or comments they may have (at the discretion of the investigator, 
patients may be requested to return to the study center for their EOS Follow-up). 
5.1.2 
Stopping Criteria and Data Monitoring Committee (DMC) 
5.1.2.1 
Study Drug Discontinuation Criteria for Individual Patients 
A patient will be discontinued from study drug dosing in the event of a confirmed pregnancy (see 
Section 8.2.1.4.2). 
Dosing of study drug for an individual patient will be suspended for up to 5 days and a patient 
may be discontinued from study drug dosing for the following reasons: 
• An SAE considered by the investigator or Sponsor to be related to study drug (per causality 
definitions in Section 8.2.1.2.2 and SAE definition in Section 8.2.1.1) 
• Evidence of significant volume depletion and/or significant electrolyte abnormalities that are 
considered by the investigator or Sponsor to be associated with diarrhea related to study drug 
• A vital sign and/or laboratory abnormality judged to be clinically significant by the 
investigator and that, in the opinion of the investigator or Sponsor, is related to study drug 
• The occurrence of any other AE that, in the opinion of the investigator or Sponsor, is related 
to study drug and represents a clinically significant safety risk to the patient 
 
The investigator will determine if the patient can continue in the study based on seriousness and 
severity of the AE and the patient's history. Procedures required for discontinued patients are 
detailed in Section 6.3. 
5.1.2.2 
Overall Study Stopping Criteria 
The Sponsor may stop enrollment prematurely because of low recruitment rates. 
The Sponsor may suspend or terminate the study prematurely because of a change in opinion of 
the IRB, DMC (as detailed in Section 5.1.2.3), or a regulatory authority decision. 


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5.1.2.3 
Data Monitoring Committee 
An independent DMC will regularly review safety data during the conduct of the study. Periodic 
safety review meetings will be scheduled when approximately 1/3 and 2/3 of patients have been 
randomized. The committee will review accumulated safety data, and may request unblinding of 
the treatment groups, in order to make any recommendations regarding the acceptability of 
continuing the study based on AEs reported. Details of the DMC membership, standard 
operational procedures for data monitoring/review, frequency of review, and other pertinent 
details will be provided in a separate DMC Charter. 
5.2 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUP 
A double-blind, placebo-controlled, parallel-group study design was chosen in accordance with 
the concepts in ICH E10, Choice of Control Groups and Related Issues in Clinical Trials, in 
order to provide comparable treatment groups and minimal chance of selection or investigator 
bias. The study has a 14-21 day Pretreatment Period to establish a baseline without study drug 
and to familiarize patients with data collection methodology (ie, eDiary), a 12-week Treatment 
Period to compare the test treatment to a placebo control, and a 2-week Posttreatment Period to 
assess safety after MD-7246 treatment has been withdrawn. 
The study will evaluate the effect of the test treatment on abdominal pain in IBS-D patients. 
Because the test treatment is not expected to significantly affect bowel function, loperamide will 
be provided beginning at the Screening Visit for patients to use as needed, at the patients’ 
discretion, to stabilize their diarrhea throughout the study; utilization of loperamide for diarrhea 
will be recorded on an event-driven basis. 
5.3 
STUDY DURATION 
The test product and reference therapy will be administered for 12 weeks. Total patient 
participation will be up to 151 days, including the Screening, Pretreatment, Treatment, and 
Posttreatment Periods. 


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6. 
SELECTION OF STUDY POPULATION 
6.1 
INCLUSION CRITERIA 
To be eligible to participate in the study, patients must meet the following criteria: 
1. Patient has given consent by signing an ICF. 
2. Patient is an ambulatory male or female aged 18 years or older at the Screening Visit. 
3. Female patients are not pregnant and lactating females must agree not to breastfeed. 
4. Female patients of childbearing potential (ie, women who are not postmenopausal or who 
have not had a bilateral oophorectomy, hysterectomy, or tubal ligation) who are sexually 
active with a male partner must agree to use one of the following methods of birth control 
from the date they sign the ICF until the End of Study Visit: 
a. Hormonal contraception (ie, oral contraceptive, contraceptive implant, or injectable 
hormonal contraceptive) 
b. Double-barrier birth control (eg, condom plus intrauterine device, diaphragm plus 
spermicide) 
c. Maintenance of a monogamous relationship with a male partner who has been surgically 
sterilized by vasectomy 
5. 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. 
6. Patient meets the colonoscopy requirements as defined by the American Gastroenterological 
Association guidelines and described in Appendix 3. (Note: Patients who receive narcotic 
anesthesia for a colonoscopy are eligible to enter the Pretreatment Period only on the fifth 
day or later after the colonoscopy.) 
7. Patient meets Rome IV criteria for IBS (1): reports recurrent abdominal pain, on average at 
least 1 day/week during the 3 months before the diagnosis, with the onset at least 6 months 
before the diagnosis, associated with 2 or more of the following features: 
a. Related to defecation 
b. Associated with a change in frequency of stool 
c. Associated with a change in form (appearance) of stool 
Note: the diagnosis can be made at the Screening Visit or can be based on patient recall of 
symptoms that the patient had before starting chronic treatment with FDA-approved 
medications to treat IBS (eg, alosetron, rifaximin, or eluxadoline). 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
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8. Patient meets the Rome IV criteria for IBS-D (1), based on stool form on days with at least 1 
abnormal BM: >25% of BMs with BSFS score of 6 or 7 and <25% of BMs with BSFS score 
of 1 or 2. 
Note: IBS-D diagnosis should be based on the patient’s BM abnormalities when the patient is 
not taking medications to treat his/her BM abnormalities. 
9. Patient has an average score for abdominal pain at its worst of ≥4.0 and ≤9.0, as reported in 
the eDiary using an 11-point numerical rating scale (NRS) during the 14 days before the 
Randomization Visit and including the eDiary entry made in clinic at the Randomization 
Visit prior to randomization. 
10. Patient is compliant (as defined in the study procedures section below) with eDiary 
completion by adequately responding to eDiary questions (ie, completing the daily evening 
report) on 10 or more of the 14 days before the Randomization Visit. 
11. Patient is able to swallow solid, oral dosage forms whole with the aid of liquid (patient may 
not chew, divide, crush, or dissolve the study drug). 
12. Patient is fluent in English or Spanish. 
13. Patient agrees to refrain from making any new, major lifestyle changes that may affect IBS 
symptoms (eg, starting a new diet or changing his or her exercise pattern) from the time of 
signature of the ICF to the last study visit. 
 
6.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will not be eligible to participate in the study. 
1. Patient has a known or suspected structural abnormality of the gastrointestinal (GI) tract (eg, 
mechanical gastrointestinal obstruction) or a disease or condition that can affect GI motility. 
2. Patient has clinically significant concurrent illness or findings on a physical examination or 
clinical laboratory tests (clinical chemistry panel, complete blood count [CBC]) after signing 
the ICF but before receiving the first dose of study drug. (Note: The investigator will 
determine if a finding is clinically significant. In making this determination, the investigator 
will consider whether the finding could prevent the patient from performing any of the 
protocol-specified assessments, represent a condition that would exclude the patient from the 
study, represent a safety concern if the patient participates in the study, or confound the 
study-specified assessments of safety or efficacy.) 
3. Patient has a positive drug or alcohol screen, including testing positive for marijuana or other 
drugs that target the endocannabinoid system, such as dronabinol. 
4. Patient has been diagnosed with or has a family history of familial adenomatous polyposis, 
hereditary nonpolyposis colorectal cancer, or any other form of familial colorectal cancer. 


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5. Patient has a history of inflammatory or immune-mediated GI disorders, including 
inflammatory bowel disease (IBD) and symptomatic biopsy- or serology-positive celiac 
disease. 
6. Patient has symptomatic lactose intolerance, symptomatic non-celiac gluten sensitivity, or 
other malabsorption syndrome. 
7. Patient currently has clinically significant symptoms such as lower GI bleeding (rectal 
bleeding or heme-positive stool), iron-deficiency anemia, weight loss, or systemic signs of 
infection or colitis. 
8. Patient has any chronic condition with ongoing symptoms that can be associated with 
abdominal pain or discomfort and could confound the assessments in this study (eg, 
diverticulitis, ileus, active peptic ulcer disease, uncontrolled gastroesophageal reflux disease, 
gastroparesis, chronic pancreatitis, polycystic kidney disease, ovarian cysts, endometriosis, 
urological pain). 
9. Patient has a history of intestinal obstruction, toxic megacolon, megarectum, descending 
perineum syndrome, solitary rectal ulcer syndrome, systemic sclerosis, multiple sclerosis, 
Parkinson’s disease, spinal cord injury. 
10. Patient has ever had a fecal impaction that required hospitalization or emergency room 
treatment, or has a history of cathartic colon, ischemic colitis, or pelvic floor dysfunction 
(unless successful treatment has been documented by a normal balloon expulsion test). 
11. Patient has currently documented positive stool tests for enteric pathogens, ova or parasites. 
12. Patient has a history of a microbiologically documented lower GI infection (eg, Clostridium 
difficile colitis) or received treatment for a microbiologically documented lower GI infection 
during the 3 months before the Screening Visit. 
13. Patient has a history of hypersensitivity to linaclotide, any of the excipients contained in the 
study drug (MD-7246 or placebo) as described in Section 7.1, or loperamide. 
14. 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 (including cholecystectomy), pelvis, or retroperitoneal structures 
during the 6 months before the Screening Visit, or during the 3 months before the 
Screening Visit for laparoscopic surgery 
c. Other major surgery, including appendectomy, during the 3 months before the Screening 
Visit 
15. Patient has a history of cancer other than treated basal cell or squamous cell carcinoma of the 
skin. (Note: Patients with a history of cancer are allowed if the malignancy has been in a 


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Clinical Study Protocol: MCP-103-205 Amendment 1 
29 January 2019 
 
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complete remission for at least 3 years before the Randomization Visit. A complete remission 
is defined as the disappearance of all signs of cancer in response to treatment.) 
16. Patient has a history of diabetic neuropathy. 
17. Patient has a history of human immunodeficiency virus infection. 
18. 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. 
19. Patient has a recent history (during the 12 months before the Randomization Visit) of drug or 
alcohol abuse. (Note: Patients with a history of drug or alcohol abuse that was diagnosed 
greater than 12 months before the Randomization Visit may be enrolled if they have 
exhibited no actual abuse during the 12 months before the Randomization Visit.) 
20. Patient has a history or current evidence of laxative or opioid abuse. 
21. Patient has been hospitalized for a major psychiatric condition or has made a suicide attempt 
during the 2 years before the Randomization Visit. 
22. Patient has received an investigational drug during the 30 days before the Screening Visit. 
23. Patient reported using a Prohibited Medicine during the Screening or Pretreatment Period, 
does not meet all the Prohibited Medicine criteria, or is not willing or able to abide by the 
restrictions regarding use of Prohibited Medicines, as detailed in Appendix 2. 
24. 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. 
25. Patient has previously entered the Pretreatment Period of this study. 
26. Patient is directly or indirectly involved in the conduct and administration of this study as an 
investigator, sub-investigator, study coordinator, other study staff member, or employee of 
Ironwood Pharmaceuticals or Allergan; or the patient is a first-degree family member, 
significant other, or relative residing with one of the above persons involved directly or 
indirectly in the study; or the patient is enrolled in this study at another clinical study site. 
 


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6.3 
DISCONTINUATION OF PATIENTS FROM THERAPY OR 
ASSESSMENT 
A premature discontinuation will occur when a patient who signed the ICF ceases participation 
in the study, regardless of circumstances, before the completion of the protocol. In addition to the 
individual discontinuation criteria detailed in Section 5.1.2.1, 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 (Screening or Pretreatment Failure) 
• 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 
• Other, such as administrative reasons 
 
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) 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. 


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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 5 days should an 
intolerable AE occur. If the investigator believes that the patient is unable to resume dosing or 
requires a temporary suspension of dosing on more than 1 occasion, the investigator should 
contact the Medical Monitor to discuss the patient’s continued participation in the study. 
6.4 
REPLACEMENT PROCEDURES 
Patients in this study who prematurely discontinue treatment will not be replaced. 


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7. 
TREATMENTS 
7.1 
TREATMENTS ADMINISTERED 
Study drug in the form of oral tablets will be provided by
 on behalf of 
Ironwood Pharmaceuticals. For the double-blind Treatment Period, patients will be supplied with 
identically appearing tablets containing MD-7246 (linaclotide DR2; 300 µg) and/or placebo 
(packaged as described in Section 7.2), to be administered once daily in a double-blind manner 
as follows: 
• MD-7246 300 µg group: 1 MD-7246 (linaclotide DR2) 300-µg oral tablet and 3 matching 
placebo oral tablets 
• MD-7246 600 µg group: 2 MD-7246 (linaclotide DR2) 300-µg oral tablets and 2 matching 
placebo oral tablets 
• MD-7246 1200 µg group: 4 MD-7246 (linaclotide DR2) 300-µg oral tablets 
• Placebo group: 4 matching placebo oral tablets 
 
 
 
 
 
 
 
 
 


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7.2 
IDENTITY AND STORAGE OF INVESTIGATIONAL PRODUCT 
All study drug will be supplied in blinded cartons containing five 4x7 blister cards, a total of 
thirty-five (35) days of study drug doses per carton. Each blister card will contain 7 days of study 
drug doses (a total of 28 tablets of MD-7246 [labeled as linaclotide DR2] 300 µg and/or 
matching placebo, as described in Section 7.1); patients will take 1 row of tablets (4 tablets) each 
day, as clearly marked on the blister card. Blister strips will be manufactured using Dessiflex® 
desiccated film and assembled into cardstock for the blister cards. Blister cards and cartons will 
be uniquely numbered and labeled in a double-blind fashion that conforms to regulatory 
requirements. 
All study drug will be provided by
 on behalf of Ironwood 
Pharmaceuticals. MD-7246 (labeled as linaclotide DR2) and matching placebo tablets will be 
stored at refrigerated conditions at the study center in an appropriate secure, temperature-
controlled area at 36-46°F (2-8°C), with excursions permitted up to 77°F (25°C) for up to 
24 hours. 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. 
Patients will be instructed to store study drug at room temperature (68-77°F [20-25°C]). 
7.3 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS 
The patient identification (PID) number will consist of 7 digits; the first 3 digits represent the 
study center number, followed by a 1-digit study indicator (‘5’) and a 3-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 and 
Posttreatment Periods. 
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 368 patients will 
be randomized to 1 of 4 treatments: MD-7246 300, 600, or 1200 µg or placebo (1:1:1:1), as 
described in Section 7.1. Randomization numbers will be assigned by IWRS. 


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7.4 
SELECTION OF DOSAGE IN THE STUDY 
This protocol is intended to evaluate the safety and tolerability, treatment effect on abdominal 
pain, and dose response of MD-7246 (previously referred to as linaclotide DR2) in IBS-D 
patients. The doses of MD-7246 were selected based on safety and tolerability results from prior 
clinical experience with this DR formulation of linaclotide and nonclinical pharmacology models 
of visceral pain. 
In the Phase 1 PK/pharmacodynamic (PD) study MCP-103-105, linaclotide DR2 was well 
tolerated by 18 healthy subjects when administered for 7 days at doses of 300, 1200, and 
3000 µg per day (6 subjects at each dose); AEs for linaclotide DR2 subjects were similar to 
placebo and all AEs were mild in severity. The 300-µg dose was also well tolerated in 2 prior 
clinical studies: as a single dose in 16 healthy subjects in the Phase 1 PK and food effect study 
MCP-103-104, and as chronic dosing (once daily for 12 weeks) in 66 IBS-C patients in the Phase 
2b study MCP-103-204. 
Linaclotide binds the GC-C receptor on human intestinal epithelial cell lines (T84 cells) at both 
high-affinity (Ki1 of 1.23 nM) and low-affinity (Ki2 of 156 nM) sites with high specificity. 
Binding of linaclotide to human intestinal (T84) cells stimulates cGMP production in a 
concentration-dependent manner, with a half maximal effective concentration (EC50) of about 
100 nM. A dose of 300 µg of linaclotide administered to the colon in humans will result in 
localized concentrations 2- to 10-fold the EC50 of linaclotide. Efficacy was observed on non-
clinical models of visceral hypersensitivity at doses of 2.5 µg/kg, which is a human equivalent of 
approximately 300 µg. 
The 600-µg and 1200-µg doses of MD-7246 were selected as incremental steps from the 300-µg 
dose to allow for evaluation of dose response in efficacy. Based on the safety and tolerability at 
doses up to 3000 µg in healthy subjects, the planned MD-7246 doses of 300, 600, and 1200 µg 
are expected to be safe and well tolerated in IBS-D patients. 


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7.5 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT 
All study drug will be administered orally once daily. Patients who meet all eligibility criteria at 
the Screening, Pretreatment, and Randomization Visits will be randomized to treatment at the 
Randomization Visit (as described in Section 7.3; randomization number assigned by IWRS) and 
dispensed a carton with 5 blister cards, each containing 28 tablets (140 tablets total). Additional 
blister cards will be dispensed at subsequent visits per the Schedule of Evaluations. Patients will 
take their initial dose of study drug (1 row of tablets from the blister card; 4 tablets) at the study 
center during the Randomization Visit. For the remainder of the Treatment Period, patients will 
be instructed to take 1 row of tablets (4 tablets) from the blister card each day, at approximately 
the same time of day without regard to food (patients will be instructed to choose a time that is 
convenient for them and continue once-daily dosing at that time throughout the Treatment 
Period). Patients will be instructed to return all unused study drug and blister cards to the study 
center at the visits defined in the Schedule of Evaluations. 
The investigator may allow a patient to stop taking study drug for up to 5 days should an 
intolerable AE occur, as described in Section 6.3. 
7.6 
BLINDING 
The Sponsor study personnel, the investigator and all other site study personnel, and the patient 
will remain blinded to individual patient treatment assignments throughout the study. Specific 
designated personnel in the Global Patient Safety (GPS) group at Ironwood may be unblinded to 
the treatment assignment of individual patients for regulatory reporting purposes. 
Patient randomization codes for the Treatment Period will be generated by Allergan and 
implemented by the IWRS vendor (an electronic version will be stored on a secure server). The 
randomization list will identify each patient by randomization number and include the patient’s 
corresponding treatment assignment. The medication code list will be supplied by 
 
 to the IWRS vendor. 


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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 Sponsor immediately. An explanation for breaking the blind will be 
recorded on the relevant eCRF. Breaking the blind at the study center will disqualify the patient 
from further participation in the study (refer to Section 6.3 for details regarding procedures and 
follow-up for patients who are discontinued from therapy). 
7.7 
CONCOMITANT MEDICINES 
A complete list of drugs that are conditionally allowed and drugs that are not allowed as 
concomitant medicines for either episodic or chronic use is provided in Appendix 2. Throughout 
the study (Screening Period through Posttreatment Period), patients will be allowed to use 
loperamide to assist in managing their diarrhea. Loperamide 2-mg caplets will be provided to the 
patient at study visits to use as needed (at the patient’s discretion) to manage their diarrhea 
throughout the study. Patient dosing of loperamide should not exceed 16 mg/day (8 unit doses), 
consistent with the product label. Beginning at the Pretreatment Visit (when the patients receive 
the eDiary) through the Week 12/EOT Visit, the day and dose will be entered by the patient for 
each use of loperamide on an event-driven basis. 
At the Screening Visit, all ongoing medicines or investigational products taken by the patient 
will be recorded. Past use of certain prescription medications (approved or unapproved) to 
manage IBS symptoms (including alosetron [Lotronex®], rifaximin [Xifaxan®], and eluxadoline 
[Viberzi®]), even if not ongoing at the time of the Screening Visit, will be recorded at the 
Screening Visit. 


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Prescription medications used to treat IBS-D may not be used during the 4 weeks (28 days) 
before the Pretreatment Visit (or during the 3 months before the Pretreatment Visit for 
rifaximin). OTC medications used to treat IBS-D, other than loperamide, may not be used during 
the study (from the time of the Screening Visit through the EOS Follow-up Phone Call). Other 
prohibited medicines may not be used during the Pretreatment, Treatment, and Posttreatment 
Periods, and may not be used during some or all of the Screening Period (refer to Appendix 2). 
Any changes in concomitant medicines or new medicines added after the Screening Visit will be 
recorded on the eCRF. Concomitant medicines will be recorded at study visits throughout the 
entire study. Use of loperamide for diarrhea will be documented by the patient via eDiary. 
7.8 
TREATMENT COMPLIANCE 
Study drug will be administered to the patient by study center staff at the Randomization Visit. 
For all other days in the Treatment Period, study drug will be taken by the patient once daily at 
approximately the same time of day without regard to food. 
Study drug accountability will be closely monitored during the Treatment Period by counting the 
number of tablets returned and recording that information on the eCRF. Every effort will be 
made to collect all unused study drug. Additionally, patients will be asked about the number of 
tablets lost and that information will be recorded on the eCRF. 


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8. 
STUDY PROCEDURES AND ASSESSMENTS 
8.1 
EFFICACY ASSESSMENTS 
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. Event-driven and daily assessments of 
abdominal and bowel symptoms will be collected using the Diary of IBS Symptoms - Diarrhea 
(DIBSS-D; Appendix 4). 
8.1.1 
Key Efficacy Assessment 
The efficacy assessment that will be used to determine the key efficacy endpoints (Section 
10.4.1) is the daily patient assessment of abdominal pain at its worst. 
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”> 
8.1.2 
Additional Efficacy Assessments 
The efficacy assessments that will be used to determine the additional efficacy endpoints are the 
daily patient assessments of abdominal pain at its worst (as described in Section 8.1.1), and 
abdominal bloating, abdominal discomfort, and abdominal cramping at their worst; and weekly 
patient assessments of degree of relief of IBS symptoms, adequate relief of IBS pain, and 
treatment satisfaction. 


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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”> 
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 Cramping at its Worst 
Patient assessment of abdominal cramping at its worst will be collected via a daily evening 
report in the eDiary. The rating of abdominal cramping 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 cramping in the past 24 hours?” 
<eDiary presents NRS where 0 is anchored with “No abdominal cramping” and 10 is anchored 
with “Worst possible abdominal cramping”> 


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Weekly Patient Assessment of Degree of Relief of IBS Symptoms 
Patient assessment of degree of relief of IBS symptoms will be reported weekly by eDiary entry. 
The rating of degree of relief during the previous 7 days on a 7-point balanced scale will be 
provided by the patient answering the following question: 
“Compared to before you started the study, how would you rate your IBS symptoms during the 
past 7 days?” 
1=Significantly relieved 
2=Moderately relieved 
3=Somewhat relieved 
4=Unchanged 
5=Somewhat worse 
6=Moderately worse 
7=Significantly worse 
 
Weekly Patient Assessment of Adequate Relief of IBS Pain 
Patient assessment of adequate relief of IBS pain will be reported weekly by eDiary entry. The 
rating of adequate relief during the previous 7 days on a binary scale will be provided by the 
patient answering the following question: 
“Overall, have you had adequate relief from your IBS pain during the past 7 days?” 
1=Yes 
2=No 
 


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Weekly Patient Assessment of Treatment Satisfaction 
Patient assessment of treatment satisfaction will be reported weekly by eDiary entry each week 
of the Treatment Period after the Randomization Visit. Patients will answer the following 
question on a 5-point ordinal scale: 
“Overall, how satisfied are you with the study medication’s ability to relieve your IBS 
symptoms?” 
1=Not at all satisfied 
2=A little satisfied 
3=Moderately satisfied 
4=Quite satisfied 
5=Very satisfied 
 
8.1.3 
Exploratory Assessments 
In addition to the key/additional efficacy assessments, the following non-efficacy exploratory 
assessments are used in determining the exploratory endpoints. 
Each day of the Pretreatment and Treatment Periods, the patient will complete eDiary entries on 
an event-driven basis to report BMs. (The patient is also asked to provide assessments of stool 
consistency and urgency, which are described below.) The patient will also complete eDiary 
entries on an event-driven basis to report use of loperamide for diarrhea. Patients will complete a 
daily evening report to enter any BMs and loperamide usage not previously reported by the 
patient for that day (recall is limited to 24 hours or to the time of the previous evening’s report). 
Bowel Movement Frequency 
The assessment of BM frequency is based on the eDiary questions that record BM date 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. 


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Stool Consistency (5-point ordinal scale) 
Patient assessment of stool consistency will be collected using 2 questions by eDiary entry on an 
event-driven basis (ie, for each BM reported in the eDiary). 
For each BM, patients will assess stool consistency by daily eDiary entry on an event-driven 
basis using a 5-point ordinal scale: 
“How would you describe the consistency of your stool?” 
1=Very hard 
2=Hard 
3=Neither too hard nor too soft 
4=Loose but not watery 
5=Very loose and watery 
 
The patient also assesses his/her stool consistency using the 7-point BSFS described below. 
Stool Consistency (BSFS) 
In addition to the patient assessment of stool consistency using the 5-point ordinal scale 
(described above), the patient assesses the stool consistency of each BM by daily eDiary entry on 
an event-driven basis using the BSFS (Appendix 5), 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.(12) The 7-point ordinal BSFS is provided below (see Appendix 5 for full scale 
including pictures): 


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“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) 
 
BM Urgency 
Patient assessment of BM urgency will be collected by eDiary entry on an event-driven basis (ie, 
for each BM reported in the eDiary). For each BM, urgency will be assessed by the patient using 
a binary scale: 
“Did you feel the need to rush to the toilet in order to avoid an accident before your bowel 
movement?” 
1=Yes 
2=No 
 
Use of Loperamide for Diarrhea 
Patients will report use of loperamide (Imodium®) for diarrhea on an event-driven basis (ie, for 
each use of the medication). An evening report will ask whether the patient entered all 
loperamide use for that day and collect all loperamide use not previously entered for that day 
(recall is limited to 24 hours or to the time of the previous evening’s report). 
“Did you use Imodium® (loperamide) for diarrhea that you have not yet reported in the Diary?” 
1=Yes 
2=No 


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“Was the Imodium® (loperamide) taken yesterday or today?” 
1=Yesterday 
2=Today 
“How many Imodium® (loperamide) pills did you take?” 
__ pill(s) 
 
Weekly Patient Assessment of Bowel Movement-related Symptom Severity 
Patient global impression of severity (PGI-S) of BM-related symptoms will be reported weekly 
by eDiary entry. The rating of BM-related symptom severity during the previous 7 days on a 
5-point ordinal scale will be provided by the patient answering the following question: 
“How would you rate your bowel movement-related symptoms during the past 7 days?” 
1=None 
2=Mild 
3=Moderate 
4=Severe 
5=Very severe 
 
Weekly Patient Assessment of Bowel Movement-related Symptom Change 
Patient global impression of change (PGI-C) of BM-related symptoms will be reported weekly 
by eDiary entry. The rating of BM-related symptom change during the previous 7 days on a 
7-point ordinal scale will be provided by the patient answering the following question: 
“Compared to before you started the study, please rate the overall change in your bowel 
movement-related symptoms during the past 7 days.” 


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1=Very much better 
2=Moderately better 
3=A little better 
4=No change 
5=A little worse 
6=Moderately worse 
7=Very much worse 
 
8.1.4 
Health Economics and Outcomes Research Assessments 
Pain Catastrophizing Scale 
The Pain Catastrophizing Scale is an instrument for assessing catastrophic thinking related to 
pain and consists of 13 questions assessing the following 3 dimensions: rumination, 
magnification, and helplessness (Appendix 6).(13) The Pain Catastrophizing Scale will be 
completed at the Pretreatment Visit as specified in the Schedule of Evaluations; the assessment 
will be triggered by site personnel on the patient’s eDiary for the questionnaire to be self-
administered by the patient. 
Short Form-12 Health Survey version 2 (SF-12v2) 
The SF-12v2 is a widely used generic measure of health status (Appendix 7).(14) The SF-12v2 
measures 8 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 8 scales are aggregated into 2 summary measures: 
the Physical and Mental Component Summary Scores. The SF-12v2 will be completed at the 
Randomization Visit prior to the patient receiving study drug and at subsequent visits as 
specified in the Schedule of Evaluations. At each of the designated visits, the assessment will be 
triggered by site personnel on the patient’s eDiary for the questionnaire to be self-administered 
by the patient. 


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EuroQol-5 Dimension 3-level (EQ-5D-3L) 
The EQ-5D-3L is a generic measure of health status that is widely used in Europe (Appendix 
8).(15) The descriptive system consists of 5 questions assessing the following dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses to the 
5 questions define a health state for which a utility index can be derived from published 
algorithms.(16) 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 completed at the Randomization 
Visit prior to the patient receiving study drug and at subsequent visits as specified in the 
Schedule of Evaluations. At each of the designated visits, the assessment will be triggered by site 
personnel on the patient’s eDiary for the questionnaire to be self-administered by the patient. 
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS) 
The IBS-SSS contains 7 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 (Appendix 9).(17) The IBS-SSS will be 
completed at the Randomization Visit prior to the patient receiving study drug and at subsequent 
visits as specified in the Schedule of Evaluations. At each of the designated visits, the assessment 
will be triggered by site personnel on the patient’s eDiary for the questionnaire to be self-
administered by the patient. 
8.1.5 
Completion of eDiary Assessments 
To ensure patient compliance with the completion of the evening eDiary report, alarms occurring 
at 7, 8, 9, 10, and 11 PM will be programmed to alert the patient that he/she has not completed 
the evening eDiary report. Upon completion of the evening eDiary report, the alarm will no 
longer be active for the remainder of that day. If the patient does not complete the evening report 
prior to midnight, that day’s evening report will no longer be available for reporting by the 
patient and all evening assessments for that day will be considered missing. 
Patient compliance with the daily eDiary completion requirement will be verified by site staff as 
specified in the Schedule of Evaluations. 


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


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• Persistent or significant disability or incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly or birth defect 
• Is considered to be an important medical event: Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Treatment-emergent Adverse Event 
A TEAE is an event that emerges, or a preexisting event that worsens, any time after 
administration of the first dose of study drug (Day 1). 
8.2.1.2 
Classification of an Adverse Event 
8.2.1.2.1 
Severity 
The investigator or delegated physician will provide an assessment of the severity of each AE by 
recording a severity rating in the patient’s source documentation and on the AE page of the 
patient’s eCRF. Severity, which is a description of the intensity of manifestation of the AE, is 
distinct from seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality. Severity will be assessed according to the 
following scale: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant. 


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Severe: 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
AEs should be recorded using the maximum intensity of the event (eg, if a patient reported 
nausea lasting 3 days, 1 start date and 1 stop date should be recorded along with the maximum 
intensity experienced for that event over that 3-day timeframe). 
8.2.1.2.2 
Relationship to Study Drug 
For all AEs, the investigator must provide an assessment of causal relationship to study drug. 
The investigator must assess the relationship of each AE (including SAEs) to the use of a study 
drug using a 2-category scale (not related or related) based on clinical judgment and using all 
available information, and may include consideration of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, preexisting 
conditions, concomitant use of other drugs, and presence of environmental or genetic factors 
• The temporal association between drug exposure and onset of the AE 
• Whether the manifestations of the AE are consistent with known actions or toxicity of the 
investigational product 
• Whether the AE resolved or improved with stopping use of the study drug; judgment should 
be used if multiple products are discontinued at the same time 
 
The causality assessment must be recorded in the patient’s source documentation and on the AE 
page of the patient’s eCRF. The causal relationship between study drug and the AE will be 
assessed using the categories shown in Table 1. 


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Table 1. 
Adverse Event Causality 
Category 
Definition 
Not related 
An AE is not associated with study medication if: 
- 
Lack of a temporal relationship to study drug administration makes a 
causal relationship improbable (eg, the event did not occur within a 
reasonable time frame following administration of the study 
medication); and/or 
- 
Other causative factor(s) (eg, a preexisting clinical condition, other 
concomitant treatments) more likely explain the occurrence of the 
event, and 
- 
The event did not improve with stopping of the investigational 
product, and/or 
- 
The event did not recur upon re-exposure with investigational product 
Related 
An AE is attributed to the study medication if: 
- 
A temporal relationship to study drug administration makes a causal 
relationship plausible (eg, the event occurred within a reasonable time 
frame following administration of study medication); and/or 
- 
Other causative factor(s) (eg, the patient’s clinical condition, other 
concomitant treatments) either do not explain the event or are less 
equally likely to have led to the occurrence of the event, or 
- 
The event improved with stopping of the investigational product, 
and/or 
- 
The event recurred upon re-exposure with investigational product 
 
8.2.1.2.3 
Laboratory and Vital Sign Abnormalities 
The investigator will review clinical laboratory and vital sign values for significance and 
consideration as an AE. An abnormality should be captured as an AE if it meets any of the 
following criteria: 
• Meets criteria for an SAE 
• Results in discontinuation or temporary dose suspension 
• Requires the patient to receive specific corrective therapy 
• Is considered by the investigator to be clinically significant 
 


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Ongoing abnormal laboratory/vital sign values or conditions that are being treated at baseline 
will be captured as an AE if the condition increases in severity and/or frequency during the 
course of the study or if the condition requires more frequent treatment. If a patient is treated for 
an abnormal laboratory/vital sign value just before the Screening Visit, then the medical history 
should reflect the severity of the condition before treatment. 
8.2.1.3 
Procedures for Recording Adverse Events 
The investigator will record all AEs from the time informed consent is obtained until completion 
of study participation (eg, early termination or EOS Follow-up Phone Call). At each study visit, 
the investigator will inquire about the occurrence of AEs/SAEs since the last visit. 
The occurrence of an AE or SAE may come to the attention of study center personnel during 
study visits and interviews of a study patient presenting for medical care, or upon review by a 
site monitor. All AEs including SAEs will be captured on the appropriate eCRF. Information to 
be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study drug (assessed only by those with the training and authority to make a 
diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study 
must be documented appropriately regardless of relationship. All SAEs will be followed to 
adequate resolution or stabilization for up to a maximum of 30 days after last dose. 
Any medical condition that is present at the time that the patient is screened and does not 
deteriorate (worsen in severity and/or frequency) should be recorded as Medical History and not 
as an AE. However, if the patient’s condition deteriorates at any time during the study, it will be 
recorded as an AE. AEs characterized as intermittent require documentation of onset and 
duration of each episode. 
Pretreatment AEs will be collected and captured in the patient’s source documentation from the 
time the patient signs the ICF until the patient receives study drug. Pretreatment AEs in 
randomized patients will additionally be entered on the AE page of the patient’s eCRF. 
Laboratory abnormalities, changes in vital signs, and physical examination findings should be 
considered AEs and reported on the AE page of the patient's eCRF only if the investigator 
considers them clinically significant and/or they necessitate intervention. 


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8.2.1.4 
Procedures for Collecting and Reporting Serious Adverse Events 
The investigator or designee is to report any SAE to PPD within 24 hours of becoming aware of 
the event that occurred during the reporting period. 
All SAEs will be submitted within the EDC system. The system will prompt the Investigator or 
designee to provide as much information as possible, including the following: 
• SAE term 
• Serious criteria 
• Severity 
• Causality assessment 
• Action taken with study drug 
• Narrative explaining the context of the SAE outcome 
 
If all SAE information is not available at the time of the initial report, follow-up SAE reports will 
be completed and submitted within the same reporting timelines as initial reports using the EDC 
system. If the EDC system is not available, the investigator or designee will complete the hard-
copy SAE form, including all of the required information noted above. The completed form 
should then be provided to PPD using the contact information below: 
 
 
 
 
The investigator or designee should receive email confirmation from PPD that the SAE 
information was received within 24 hours after its submission (whether submitted via EDC or 
hard-copy form). In the event this receipt confirmation is not received, the investigator or 
designee will alert PPD. 
The investigator or designee is required to follow SAEs until resolution or stabilization for up to 
a maximum of 30 days after last dose. Resolution is defined as: 
• Resolved with or without residual effects (sequelae) 


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• A return to baseline for a preexisting condition 
• The investigator does not expect any further improvement or worsening of the event 
• Fatal outcome: If an autopsy is performed on a deceased patient, the autopsy report and death 
certificate must be provided to PPD as soon as it is available. 
 
8.2.1.4.1 
Reporting of SAEs to the IRB 
The investigator will receive prompt notification of SAEs, with the use of the study product, that 
are both unexpected and related, or any finding that suggests a significant risk for patients. The 
investigator will promptly inform the IRB of the notification and insert the notification in the 
Investigator’s Regulatory Binder in accordance with local regulations. 
All applicable expedited safety reports will be forwarded, by Ironwood, to the investigator. 
The investigator will inform Ironwood of any local regulatory or IRB requirements not covered 
by the procedures in this or the prior section. 
8.2.1.4.2 
Reporting of Pregnancy 
Any female patient who becomes pregnant while participating in the study will be withdrawn 
from the study. 
Information on any pregnancies in female patients, or the female partner of a male patient, will 
be collected from the Screening Visit until the completion of the EOS Follow-up Phone Call. 
If the patient or the female partner of a male patient becomes pregnant after receiving study drug 
during the course of study, the investigator will collect and record the pregnancy information on 
the Pregnancy Reporting Form and submit it to PPD within 24 hours of learning of the 
pregnancy. (Note: If the female partner of a male patient becomes pregnant, the investigator must 
attempt to obtain consent to collect pregnancy information [including status of the newborn, if 
applicable] before reporting information to Ironwood). If not all information on the Pregnancy 
Reporting Form is available at the time of the initial report, follow-up Pregnancy Reporting 
Forms will be completed and submitted within 24 hours of becoming aware of new information. 


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The investigator is required to attempt follow-up on the pregnancy until the completion of the 
pregnancy. Information on the status of the mother and newborn will be forwarded to PPD 
within 24 hours of the investigator becoming aware. Generally, follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be an SAE and reported as such. A 
spontaneous abortion is always considered to be an SAE and will be reported as such. 
Furthermore, any SAE occurring as a result of a post-study pregnancy and considered reasonably 
related to the investigational product by the investigator, will be reported to PPD using the hard-
copy SAE form as described in Section 8.2.1.4. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
8.2.2 
Clinical Laboratory Determinations 
See below for the list of clinical laboratory tests to be performed and refer to the Schedule of 
Evaluations for the timing and frequency. All protocol-required laboratory assessments, as 
defined below, must be conducted in accordance with the laboratory manual and the Schedule of 
Evaluations. 
The tests detailed below will be performed (additional tests may be performed at any time during 
the study as determined necessary by the investigator or as required by local regulations): 
• Hematology: 
Absolute and differential white blood cell count, erythrocyte count, 
hemoglobin, hematocrit, platelet count, and red blood cell indices (mean 
corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular 
hemoglobin concentration) 
• Chemistry: 
Sodium, magnesium, potassium, calcium, chloride, glucose, blood urea 
nitrogen, creatinine, total protein, alkaline phosphatase, albumin, total 
bilirubin, aspartate aminotransferase, alanine aminotransferase, 
bicarbonate, phosphate, cholesterol, and uric acid 


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


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8.2.4 
Physical Examination 
A complete physical examination will be performed as outlined in the Schedule of Evaluations, 
by the investigator or a licensed health professional listed on Form FDA 1572. Any physical 
examination abnormality that the investigator considers to be potentially clinically significant 
and changed from the baseline will be reported as an AE. A complete physical examination will 
include, at a minimum, assessment of the general appearance of the patient and the HEENT 
(head, eyes, ears, nose, and throat), cardiac, respiratory, gastrointestinal, musculoskeletal, 
neurological, and dermatological systems. Height (only at screening) and weight will also be 
measured and recorded. 
Rectal examinations should be performed at the discretion of the investigator; the purpose of the 
rectal examination is to rule out pathologies that might be caused by obstruction. For all physical 
examinations, the breast and genitourinary examinations are not required. 
8.2.5 
Medical History 
A complete medical history, including disease-specific history, will be provided by the patient at 
the Screening Visit. 
As part of their disease-specific history, patients will be asked about any prior IBS diagnosis. 
Patients will be enrolled based on the Rome IV criteria for IBS-D, as detailed in Section 6.1 and 
described below. 
Patient reports recurrent abdominal pain, on average at least 1 day/week during the 3 months 
before the diagnosis, with the onset at least 6 months before the diagnosis, associated with 2 or 
more of the following features: 
a. Related to defecation 
b. Associated with a change in frequency of stool 
c. Associated with a change in form (appearance) of stool 
 


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According to the Rome IV criteria, patients are subtyped as IBS-D if they have >25% of BMs 
with BSFS score of 6 or 7 and <25% of BMs with BSFS score of 1 or 2, based on stool form on 
days with at least 1 abnormal BM. 
8.2.6 
Required Investigator Consultation with the Patient 
Patients will be allowed use of loperamide on an as-needed basis to control their diarrhea. 
Throughout the Pretreatment and Treatment Periods, the eDiary will send automated alerts to the 
investigator if patients experience constipation with excessive use of loperamide or diarrhea that 
is not well managed with the use of loperamide, as described below. 
If a patient reports no BMs for ≥3 consecutive days with daily use of loperamide, the investigator 
must review the use of loperamide and pattern of constipation with the patient. An unscheduled 
visit to further evaluate the patient should be arranged if deemed necessary by the investigator. 
The decision to continue, interrupt, or permanently discontinue study drug will be left to the 
discretion of the investigator on a patient-by-patient basis. 
If the eDiary alert indicates that a patient took ≥8 unit doses (≥16 mg) of loperamide in a 24-hour 
period for ≥5 consecutive days, the investigator must review the use of loperamide and pattern of 
diarrhea with the patient. An unscheduled visit to further evaluate the patient should be arranged 
if deemed necessary by the investigator. The decision to continue, interrupt, or permanently 
discontinue study drug due to excessive use of loperamide will be left to the discretion of the 
investigator on a patient-by-patient basis. 


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9. 
DATA QUALITY ASSURANCE 
9.1 
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 and his/her staff will be 
responsible for reviewing eCRFs, resolving data queries generated by the site monitor via the 
system, providing missing or corrected data, approving all changes performed on his/her data, 
and endorsing the patient data within the EDC system. This approval method will include 
applying an electronic signature, which is a uniquely assigned username and password that 
together will represent a traditional handwritten signature. 
9.2 
DATA RECORDING AND DOCUMENTATION 
All data collected in the context of this 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 (eg, 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. 


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Data collection will involve the use of the 
, 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. 


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10. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
10.1 
ANALYSIS POPULATIONS 
10.1.1 
Screened Population 
The Screened Population consists of all patients who had a Screening Visit (Visit 1) and were 
assigned a PID number. 
10.1.2 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population consists of all randomized patients. 
10.1.3 
Safety Population 
The Safety Population consists of all patients who received at least one dose of study drug. 
10.2 
GENERAL METHODS 
Efficacy analyses will be performed on the ITT Population for all outcomes reported during the 
Treatment Period using treatment group assigned at the Randomization Visit. Unless otherwise 
specified, all confidence intervals (CIs) will be 2-sided and with a confidence level of 95%. No 
adjustments will be made for multiplicity in the conduct of comparisons among the MD-7246 
doses relative to placebo for the key efficacy endpoints, or in the analysis of the additional 
efficacy endpoints or exploratory endpoints. Safety analyses will be performed using descriptive 
summaries based on the Safety Population and on actual treatment received. 
For analysis of continuous parameters (eg, change from baseline), descriptive statistics (n, mean, 
standard deviation [SD], median, and range) will be calculated and presented for each treatment 
group. For categorical parameters (eg, responder vs. non-responder), the number and percentage 
of each category will be calculated and presented for each treatment group. Percentages will be 
based on the total number of non-missing values; the number missing will be presented, but 
without a percentage. 


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


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10.2.4 
Prior and Concomitant Medicines 
Prior and concomitant medicines will be classified using the most current version of the WHO 
Drug Dictionary available at the start of the study (or newer). 
Prior medicines are defined as any medicines taken prior to the date of first dose of study drug. 
Concomitant medicines are defined as any medicines taken on or after the date of first dose of 
study drug during the Treatment Period. Posttreatment medicines are defined as any medicines 
started after the date of last dose of study drug for the Treatment Period. 
Both prior and concomitant medicine use, classified by therapeutic class, will be summarized by 
treatment group 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. 
Posttreatment medicines will be presented in data listings. 
10.3 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
10.3.1 
Exposure to Study Drug 
Exposure to study drug, calculated as the number of days from the date of first dose taken to the 
date of last dose taken, will be summarized by treatment group for the Safety Population. 
10.3.2 
Measurement of Treatment Compliance 
Dosing compliance for a specified period is defined as the total number of tablets actually taken 
by a patient during that period divided by the number of tablets that were expected to be taken 
during the same period, multiplied by 100. The total number of tablets actually taken will be 
calculated based on the following equation: total number of tablets dispensed – (number of 
tablets returned + number of tablets lost). The total number of tablets expected to be taken during 
a specified period equals the number of days in the period, multiplied by 4. 
Descriptive statistics for study drug compliance for the Treatment Period overall, and for each of 
the 3 consecutive 4-week periods in the Treatment Period (consistent with study drug 
dispensing) will be presented for the Safety Population. 


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10.3.3 
eDiary Compliance 
eDiary compliance will be based on the percentage of complete eDiary entries made by a patient. 
A complete eDiary entry is defined as one in which the patient responds to every eDiary question 
asked in the evening report on that day. The questions that are asked weekly will not be included 
in the determination of a complete entry. The percentage of complete eDiary entries will be 
calculated as 100 times the number of completed evening reports divided by the total number of 
days in the study period (Pretreatment and Treatment). 
Descriptive statistics for eDiary compliance (%) and the patients with ≥80%/<80% complete 
eDiary entries during the Pretreatment and Treatment Periods will be presented. 
10.4 
EFFICACY ANALYSES 
All efficacy analyses to address the objectives of the study will be based on the ITT Population. 
Exploratory analyses to address the exploratory objective of the study also will be based on the 
ITT Population. 
Baseline values for efficacy and exploratory parameters are derived from the eDiary and eCRF 
data collected in the Pretreatment Period, specifically, the period of time from 14 days prior to 
randomization up to the time of randomization. Baseline values for patient symptom severity 
parameters (eg, abdominal symptoms [pain, bloating, discomfort, cramping]) will be the average 
of the non-missing severity scores reported during this period. The baseline BM and urgent BM 
weekly rates will be derived based on the number of BMs and urgent BMs a patient had during 
this period. Baseline BSFS score and stool consistency will be calculated as the average of the 
non-missing values reported by the patient 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. 
Sensitivity analyses of the key endpoints will include, but are not limited to, a multiple 
imputation approach. If the normality assumption of the errors is violated for the key mixed 
model with repeated measures (MMRM) or analysis of covariance (ANCOVA) analyses, ranked 
or other appropriate analyses will be applied. 


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All hypothesis testing will be performed at a 2-sided 0.05 significance level. No adjustment for 
multiplicity will be applied. 
10.4.1 
Key Efficacy Endpoints 
The 2 key efficacy endpoints are: 
• Change from Baseline in Abdominal Pain at its Worst at Each Week 
The weekly abdominal pain at its worst score is the average of the non-missing abdominal 
pain scores during each week (Weeks 1-12) in the study. The baseline abdominal pain score 
is the average of the non-missing abdominal pain scores during the last 14 days of the 
Pretreatment Period and the day of the Randomization Visit reported prior to randomization. 
Change from baseline will be calculated for each week as the weekly score minus the 
baseline score. 
• 6/12 Week Abdominal Pain 30% Responder 
A 6/12 Week Abdominal Pain 30% Responder is a patient who meets the Weekly Abdominal 
Pain 30% Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. A 
Weekly Abdominal Pain 30% Responder is a patient who has a decrease from baseline of at 
least 30% in the mean abdominal pain at its worst 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 30% Responder for that week. 
 
10.4.2 
Key Efficacy Analysis 
Comparisons between the MD-7246 dose groups and placebo with regard to the change from 
baseline in abdominal pain over the Treatment Period will be evaluated employing a MMRM 
framework with week (categorical), treatment, geographic region, and week-by-treatment fixed 
effects, patient as the random effect, and baseline value as a covariate. An unstructured 
covariance structure will be utilized. Descriptive statistics, for the overall Treatment Period 
effect, based on the MMRM model will include least-squares (LS) mean change from baseline 
for each treatment, the LS mean difference between each MD-7246 dose and placebo, 
corresponding 95% CIs, and the p-value associated with the comparison. In addition, weekly 
treatment differences between each MD-7246 group and placebo will be provided using the same 
MMRM model defined above. 


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For the 6/12 Week Abdominal Pain 30% Responder endpoint, the proportion of responders in 
each MD-7246 group will be compared to the proportion of responders in the placebo group 
using a Cochran-Mantel-Haenszel (CMH) test controlling for geographic region. The number 
and percent of responders, the difference in responder rates between each MD-7246 group and 
the placebo group, the odds ratio relative to placebo, all corresponding 95% CIs, and the p-value 
associated with the CMH test will be presented. 
10.4.3 
Additional Efficacy Endpoints 
The additional efficacy endpoints are: 
• 6/12 Week Abdominal Pain 50% Responder 
A 6/12 Week Abdominal Pain 50% Responder is a patient who meets the Weekly Abdominal 
Pain 50% Responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For 
each week in the Treatment Period, a Weekly Abdominal Pain 50% Responder is a patient 
who has a decrease from baseline of at least 50% in the mean abdominal pain at its worst 
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 50% Responder for that week. 
• 6/12 Week Abdominal Discomfort 30% Responder 
A 6/12 Week Abdominal Discomfort 30% Responder is a patient who meets the Weekly 
Abdominal Discomfort 30% Responder criteria for at least 6 out of the 12 weeks of the 
Treatment Period. The Weekly Abdominal Discomfort 30% Responder criteria are defined 
the same as the Weekly Abdominal Pain 30% Responder criteria above. 
• 6/12 Week Abdominal Bloating 30% Responder 
A 6/12 Week Abdominal Bloating 30% Responder is a patient who meets the Weekly 
Abdominal Bloating 30% Responder criteria for at least 6 out of the 12 weeks of the 
Treatment Period. The Weekly Abdominal Bloating 30% Responder criteria are defined the 
same as the Weekly Abdominal Pain 30% Responder criteria above. 
• 6/12 Week Abdominal Cramping 30% Responder 
A 6/12 Week Abdominal Cramping 30% Responder is a patient who meets the Weekly 
Abdominal Cramping 30% Responder criteria for at least 6 out of the 12 weeks of the 
Treatment Period. The Weekly Abdominal Cramping 30% Responder criteria are defined the 
same as the Weekly Abdominal Pain 30% Responder criteria above. 


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• 6/12 Week Degree of Relief Responder 
A 6/12 Week Degree of Relief Responder is a patient who scores ≤2 (“completely” or 
“considerably” relieved) for at least 6 out of the 12 weeks of the Treatment Period. 
• 6/12 Week Adequate Relief of IBS Pain Responder 
A 6/12 Week Adequate Relief of IBS Pain Responder is a patient who reports adequate relief 
of IBS pain (“yes”) for at least 6 out of the 12 weeks of the Treatment Period. 
• Treatment Satisfaction 
For each week of the Treatment Period, patients will rate their satisfaction with the study 
medication’s ability to relieve their IBS symptoms on a 5-point ordinal scale. 
• Change from Baseline in Percent of Abdominal Pain-free Days at Each Week 
Abdominal pain is measured daily using an 11-point NRS. Abdominal pain-free days will be 
those days where the patient reports a score of 0 for abdominal pain at its worst. The percent 
of abdominal pain-free days will be calculated as the number of Abdominal Pain-free Days 
during a particular week, divided by the total number of days with non-missing daily 
abdominal pain at its worst assessments for that week, multiplied by 100. Due to the potential 
of this data to not meet parametric normality assumptions, the baseline percent abdominal 
pain-free days and change from baseline in percent abdominal pain-free days will be ranked 
first, respectively, and then transformed to the expected values of the order statistics of the 
standard normal distribution (ie, normal scores). 
• Change from Baseline in Abdominal Discomfort at its Worst at Each Week 
Abdominal discomfort is measured daily using an 11-point NRS. For each week on 
treatment, the weekly abdominal discomfort score is the mean of the non-missing daily 
values. 
• Change from Baseline in Abdominal Bloating at its Worst at Each Week 
Abdominal bloating is measured daily using an 11-point NRS. For each week on treatment, 
the weekly abdominal bloating score is the mean of the non-missing daily values. 
• Change from Baseline in Abdominal Cramping at its Worst at Each Week 
Abdominal cramping is measured daily using an 11-point NRS. For each week on treatment, 
the weekly abdominal cramping score is the mean of the non-missing daily values. 
 


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10.4.4 
Additional Efficacy Analysis 
The additional categorical responder (eg, 6/12 Week Abdominal Bloating 30% Responder) and 
continuous change-from-baseline endpoints will be analyzed utilizing the same methods defined 
for the key efficacy endpoints in Section 10.4.2. Treatment Satisfaction will be analyzed utilizing 
an MMRM framework with week (categorical), treatment, geographic region, and week-by-
treatment fixed effects, and patient as the random effect. An unstructured covariance structure 
will be utilized. Pairwise comparisons between each treatment group and placebo will be 
performed for the overall Treatment Period effect. MMRM-associated statistics, as defined in 
Section 10.4.2 for the key efficacy change-from-baseline endpoint, will be presented. 
10.4.5 
Exploratory Endpoints 
Exploratory endpoints related to bowel function will be studied to address the exploratory 
objective of the study. These non-efficacy endpoints will include: 
• Change from Baseline in BM Frequency Rate at Each Week 
A patient’s weekly BM frequency rate is the BM rate (BMs/week) calculated for that week. 
• Change from Baseline in BSFS (Stool Consistency) at Each Week 
Stool consistency is measured using the 7-point BSFS. The patient’s BSFS score for each 
week on treatment is the mean of the non-missing BSFS scores from the BMs reported by the 
patient during the week. 
• Change from Baseline in Urgent BM Frequency Rate at Each Week 
An urgent BM is a BM that is associated with urgency (ie, the need to rush to the toilet to 
avoid an accident). A patient’s weekly urgent BM frequency rate is the urgent BM rate 
(urgent BMs/week) calculated for that week. 


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• Change from Baseline in the Percent of Days Experiencing an Episode of Diarrhea per Week 
An episode of diarrhea is defined as a sequence of 2 or more loose/watery BMs (BSFS 6 or 
7) that are never separated by >1 non-loose/watery stool or by a day without a BM. The 
Treatment Period percent of days experiencing an episode of diarrhea will be calculated as 
100 times the number of days with a diarrhea episode at each week divided by 7. For 
baseline, the number of days with a diarrhea episode will be determined for the last 14 days 
of the Pretreatment Period. The baseline percent of days experiencing an episode of diarrhea 
will be calculated as 100 times the number of days experiencing an episode during the 
baseline period divided by the length in days of the baseline period (typically 14 days). The 
change from baseline will be calculated for each week as the weekly percent minus the 
baseline percent. 
• Change from Baseline in the Percent of Days Experiencing No Episodes of Diarrhea per 
Week 
Episodes of diarrhea are described above. The percent of days experiencing no episodes of 
diarrhea per week will be calculated using the same method as described above for episodes 
of diarrhea. 
• Change from Baseline in BM-related Symptom Severity at Each Week 
BM-related Symptom severity is measured weekly using a 5-point ordinal scale comparing 
the severity for the past 7 days. 
• BM-related Symptom Change 
BM-related symptom change is measured weekly using a 7-point ordinal scale comparing the 
severity for the past 7 days to the severity before starting the study. 
• Change from Baseline in Percent of Days with Use of Loperamide for Diarrhea at Each 
Week 
The percent of days using loperamide for diarrhea at each week will be calculated as 100 
times the number of days loperamide was used during the week divided by 7. 
 


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10.4.6 
Exploratory Analysis 
Exploratory change-from-baseline endpoints will be analyzed utilizing the same methods as 
described in Section 10.4.2 for the key efficacy analysis. BM-related Symptom Change will be 
analyzed utilizing an MMRM framework with week (categorical), treatment, geographic region, 
and week-by-treatment fixed effects, and patient as the random effect. An unstructured 
covariance structure will be utilized. Pairwise comparisons between each treatment group and 
placebo will be performed for the overall Treatment Period effect. MMRM-associated statistics, 
as defined in Section 10.4.2 for the key efficacy change-from-baseline endpoint, will be 
presented. 
10.5 
HEALTH ECONOMICS AND OUTCOMES RESEARCH ANALYSES 
Health economics and outcomes research (HEOR) analyses will be based on the ITT Population. 
10.5.1 
Pain Catastrophizing Scale 
The Pain Catastrophizing Scale is a 13-item instrument that asks patients to reflect on their 
thoughts and feelings of past painful experiences. The patient responds to each statement using a 
5-point scale (0=None at all to 4=All the time). The total Pain Catastrophizing Scale score plus 
the 3 subscale scores (Rumination, Magnification, and Helplessness) will be derived and 
summarized by treatment for the Pretreatment Visit. 
10.5.2 
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 for all visits at which the SF-12v2 is completed. Treatment differences for the 
change from baseline at each post-dose visit will be analyzed using MMRM as described in 
Section 10.4.2 for the key efficacy change-from-baseline endpoint. 


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10.5.3 
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 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 
each visit. 
10.5.4 
IBS-SSS 
The IBS-SSS parameters consist of 5 individual items and the IBS-SSS total score. The 
5 individual items (severity of abdominal pain, frequency of abdominal pain, severity of 
abdominal distension, dissatisfaction with bowel habits, and interference of IBS with life in 
general) are based on a 0-100 scale (10 times the original scale) and the IBS-SSS total score 
parameter is the sum of the 5 IBS-SSS individual item scores (0-500 scale). 
For each post-baseline visit, change from baseline in the IBS-SSS total score and individual 
items will be analyzed using an ANCOVA model with fixed effect terms for treatment group and 
geographic region and the corresponding baseline IBS-SSS score as a covariate. 
10.6 
SAFETY ANALYSES 
All safety parameters will be analyzed descriptively in accordance with the general methods 
described in Section 10.2. 
10.6.1 
Adverse Events 
Adverse Event Verbatim Terms will be coded in the EDC system against the most current 
version of the Medical Dictionary for Regulatory Activities (MedDRA) available at the start of 
the study (or newer). 
An AE that occurs during the Treatment Period (up to 1 day after the last dose of double-blind 
study drug) will be considered a TEAE for the Treatment Period if it was not present prior to the 
date of the first dose of double-blind study drug, or was present prior to the date of the first dose 
but increased in severity during the Treatment Period. 


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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 1 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.  
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 (ie, events with an outcome of 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 died (if any). 
10.6.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values (in standard units) and changes from the 
baseline values at each assessment time point will be presented by treatment group for the 
Treatment Period, for each clinical laboratory parameter. 


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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 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, study center, and baseline and post-baseline values. A 
listing of all AEs for patients with PCS laboratory values will also be provided. 
10.6.3 
Vital Signs 
Descriptive statistics for vital signs (ie, pulse rate, systolic and diastolic BP, respiratory rate, 
temperature, and body weight) and changes from baseline at each visit and at the end of the 
period/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 
both the observed value criterion and the change from baseline value criterion. The criteria for 
PCS vital sign values will be detailed in the SAP. The percentages will be calculated relative to 
the number of patients with baseline values and at least 1 assessment in the corresponding post-
baseline period. The numerator will be the total number of patients with available non-PCS 
baseline values and at least 1 PCS value in the corresponding post-baseline period. A supportive 
listing of patients with PCS post-baseline values will be provided, including the PID number, 
study center, and baseline and post-baseline values. A listing of all AEs for patients with PCS 
vital sign values will also be provided. 
10.7 
INTERIM ANALYSIS 
An optional interim analysis of unblinded safety and efficacy data may be performed to assess 
futility. If it is decided to perform such an interim futility analysis, details regarding the interim 
futility analysis (eg, alpha spending and statistical boundaries) will be included in the SAP, along 
with updates to the data management plan as necessary. 


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10.8 
DETERMINATION OF SAMPLE SIZE 
In a previously conducted Phase 2b trial utilizing MD-7246 (MCP-103-204), the SD for the 
change from baseline to Week 12 in abdominal pain at its worst ranged from 2.32 to 2.88. 
Assuming a clinically meaningful treatment difference between MD-7246 and placebo of 1.0 for 
the mean change from baseline to Week 12 in abdominal pain, an SD of 2.4, and 92 patients per 
treatment group (368 patients total), the estimated power is approximately 80% to detect a 
difference between each MD-7246 dose and placebo at a 2-sided significance level of 0.05 using 
a 2-sample t-test. 


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11. 
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, 
submitted by the Sponsor to the FDA, and the signature page, signed by the investigator, has 
been received by Ironwood or designee. If the protocol is amended to eliminate or reduce the risk 
to patients, the amendment may be implemented before IRB review and approval. However, the 
IRB must be informed in writing of such an amendment, and approval must be obtained within 
reasonable time limits. Deviating from the protocol is permitted only if absolutely necessary for 
the safety of the patients and must immediately be reported to Ironwood or designee. 


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12. 
STUDY SPONSORSHIP 
12.1 
STUDY TERMINATION 
Ironwood reserves the right to terminate the study in its entirety or at a specific center at any 
time. 
12.2 
REPORTING AND PUBLICATION 
All data generated in this study will be the property of Ironwood and its partner, Allergan Sales, 
LLC. 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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13. 
INVESTIGATOR OBLIGATIONS 
13.1 
DOCUMENTATION 
The investigator must provide the following to Ironwood or designee prior to the start of the 
study in accordance with ICH E6 and FDA regulations: 
• 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 initial IRB approval for conducting the study. If the study is ongoing, renewals 
must be submitted at yearly intervals. All amendments to the protocol must be submitted and 
approved by the IRB, as stated in Section 1.1. 
• A copy of the IRB-approved ICF 
• A copy of the IRB-approved Health Insurance Portability and Accountability Act (HIPAA) 
authorization form 
• A list of the IRB members or the Department of Health and Human Services (DHHS) 
general assurance number 
• A copy of the laboratory reference ranges 
• The Investigator’s Statement page in this protocol signed and dated by the investigator 
• Financial disclosure agreements completed and signed by the investigator and each sub-
investigator listed on Form FDA 1572. If there are any relevant changes, the investigator 
(and any sub-investigator) will provide an updated financial disclosure agreement to the 
Sponsor at the time of the change, and up to 1 year after the completion of the study 
 
13.2 
PERFORMANCE 
The investigator must demonstrate reasonable efforts to obtain qualified patients for the study. 


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


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If the investigation does not result in the submission of the data in support of, or as part of, an 
NDA, records must be retained for 2 years following notification by Ironwood that the entire 
clinical investigation (not merely the investigator’s portion) is completed, terminated, or 
discontinued or for 2 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. 
13.6 
PATIENT CONFIDENTIALITY 
All patient records will only be identified by initials and PID number. Patients’ names are not to 
be transmitted to Ironwood or its authorized designee. The investigator will keep a Master 
Patient List on which the PID number and the full name, address, and telephone number of each 
patient is listed. 


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14. 
APPENDICES 


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APPENDIX 1 
ELEMENTS OF INFORMED CONSENT 
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained from each patient participating in a clinical research study. 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 contract research organization (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 (eg, “I agree to participate...”) 
• A place for the patient’s signature and date of signing 
• A statement that a description of this clinical study will be available on 
http://www.ClinicalTrials.gov  
 
A copy of the signed consent form will be given to the patient. 


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APPENDIX 2 
CONCOMITANT AND PROHIBITED MEDICATIONS 
Protocol-permitted OTC Medication for Diarrhea 
Protocol-permitted over-the-counter (OTC) medication for diarrhea, loperamide (Imodium®), 
will be dispensed to patients. Throughout the study (Screening Period through Posttreatment 
Period), patients will be allowed to use loperamide to assist in the management of their diarrhea. 
Loperamide will be provided to the patient at study visits to use as needed (at the patient’s 
discretion) to manage their diarrhea throughout the study. Patient dosing of loperamide should 
not exceed 16 mg/day (8 unit doses), consistent with the product label. Beginning at the 
Pretreatment Visit through the Week 12/EOT Visit, patients will report loperamide use in the 
eDiary on an event-driven basis. In order to be eligible for the study, patients must discontinue 
use of other OTC and prescription medications for the treatment of IBS (as detailed below). 
Prohibited Medicine 
All medicines listed in the sections below are excluded during the Pretreatment, Treatment, and 
Posttreatment Periods. Washout periods in relation to the Screening and/or Pretreatment Visits 
are detailed below. 
PRESCREEN WASHOUT (medicines must have been stopped prior to the Screening Visit, 
unless otherwise specified) 
No medicine during the 3 months before the Screening Visit: 
1. Chronic oral or parenteral glucocorticoids (however, one 10-day course of oral or one 
injection of parenteral glucocorticoids is permitted during the Pretreatment, Treatment, or 
Posttreatment Periods) 
No medicine during the 3 months before the Pretreatment Visit: 
1. Rifaximin 


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No medicine during the 30 days before the Screening Visit: 
1. Any investigational or imported drugs that have not been approved for human use by the 
US FDA 
2. Cannabinoid drugs (eg, medical marijuana, dronabinol, nabilone) 
3. The following antidepressants, if used daily for treatment of IBS symptoms (Note: Other 
use of these medications will be allowed 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.) 
a. Tricyclic antidepressants (TCAs; eg, amitriptyline, imipramine, nortriptyline) 
b. Selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, sertraline, paroxetine, 
citalopram) 
c. Serotonin-norepinephrine reuptake inhibitors (SNRIs; eg, venlafaxine, desvenlafaxine 
succinate) 
4. Phenergan and ondansetron if used daily for treatment of IBS symptoms (Note: Will be 
allowed for occasional use as needed for the treatment of nausea/vomiting.) 
 
SCREENING PERIOD WASHOUT (medicines must be stopped beginning at the Screening 
Visit, unless otherwise specified, with minimum washouts prior to the Pretreatment Visit as 
specified below) 
1. Alosetron or eluxadoline (prescription medications for IBS-D) during the 28 days before 
the Pretreatment Visit 
2. Barbiturates (eg, butalbital, phenobarbital, Fioricet®) during the 28 days before the 
Pretreatment Visit 
3. Any medication used to treat abdominal pain/discomfort or diarrhea (eg, antispasmodics, 
peppermint oil, narcotics, bismuth subsalicylate, kaolin), and any herbal or natural agent 
that a person might take for abdominal pain/discomfort or diarrhea; all of these 
medications must be stopped beginning at the Screening Visit, and the following 
washouts are required prior to the Pretreatment Visit: 
◦ 
No washout required for loperamide (protocol-permitted) 
◦ 
14-day washout (ie, no medication during the 14 days before the Pretreatment Visit): 
- 
Prokinetic agents (eg, metoclopramide, itopride, prucalopride, domperidone) 
- 
Antispasmodic/anticholinergic agents (eg, dicyclomine, flavoxate, scopolamine, 
hyoscyamine, propantheline, oxybutynin, tolterodine, solefenacin, darifenacin, 
trospium). Note: Inhaled ipratropium and tiotropium are permitted. 


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- 
All narcotics either alone or in combination (eg, propoxyphene, diphenoxylate, 
paregoric). Note: narcotics used as anesthesia for a colonoscopy require a 5-day 
wash-out prior to the Pretreatment Visit. 
◦ 
3-day washout (ie, no medication during the 3 days before the Pretreatment Visit) 
- 
Peppermint oil, bismuth subsalicylate, kaolin, and herbal or natural agents 
(Note: The use of fiber, probiotics, or stool softeners [such as docusate] is acceptable.) 
4. Opioid and centrally acting (eg, tramadol, codeine, gabapentin, pregabalin) analgesic 
medications beginning at the Screening Visit, with a required 14-day washout (ie, no 
medication during the 14 days before the Pretreatment Visit) (Note: Acetaminophen will 
be allowed for occasional use as needed for the treatment of mild non-IBS pain. 
Gabapentin and pregabalin are acceptable if not prescribed for IBS symptoms, and 
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.) 
5. Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin or aspirin-containing 
medications, if used daily for treatment of IBS symptoms, beginning at the Screening 
Visit, with a required 14-day washout (ie, no medication during the 14 days before the 
Pretreatment Visit) (Note: NSAIDs will be allowed for occasional use as needed for the 
treatment of mild non-IBS pain; low-dose aspirin (81 mg) is acceptable for daily use.) 
6. Any other drugs affecting GI motility (known to cause constipation or diarrhea) during 
the 14 days before the Pretreatment Visit. 
 
14-DAY WASHOUT (no medicine during the 14 days before the Pretreatment Visit, unless 
otherwise specified, but allowed earlier in the Screening Period if applicable) 
1. Drugs with known pharmacological activity at 5-hydroxytryptophan (HT)4, 5-HT2b or 
5-HT3 receptors (eg, cisapride, tropisetron, granisetron, dolasetron, mirtazapine) 
2. Bile acid sequestrants (eg, cholestyramine and colestipol) 
3. Cholinomimetic agents (eg, bethanechol, pyridostigmine, tacrine, and physostigmine). 
Note: intraocular cholinomimetic agents (eg, pilocarpine) are permitted. 
4. Antipsychotic agents (eg, risperidone, haloperidol, droperidol, chlorpromazine, 
perphenazine, all phenothiazines, quetiapine, olanzapine, and clozapine) unless the 
patient has been on a stable dose for 30 days before the Screening Visit and plans to 
continue on a stable dose throughout the study. Note: paliperidone is permitted without 
restriction. 


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5. Monoamine oxidase inhibitors (MAOIs; eg, furazolidone, isocarboxazid, pargyline, 
phenelzine, selegiline tranylcypromine) or other antidepressants (eg, trazodone, 
bupropion), unless the patient has been on a stable dose for 30 days before the Screening 
Visit and plans to continue on a stable dose throughout the study. Note: TCAs, SSRIs, 
and SNRIs require a longer (prescreen) washout as discussed above. 
6. Calcium channel blocker verapamil unless the patient has been on a stable dose for 
30 days before the Screening Visit and plans to continue on a stable dose throughout the 
study. Note: all other calcium channel blockers (eg, nifedipine, diltiazem, amlodipine, 
felodipine, nicardipine, nimodipine, nisoldipine) are permitted and may be used without 
restriction. 
7. Oral and parenteral antibiotics (however, 1 standard regimen [up to 10 days] of oral 
antibiotics is permitted during the Treatment or Posttreatment Periods, with the exception 
of erythromycin). 
8. Any medicine taken for the purpose of losing weight (eg, orlistat, phentermine, 
phendimetrazine, diethylpropion, benzphetamine, and sibutramine). 
9. Proton pump inhibitors (eg, omeprazole, lansoprazole, esomeprazole, pantoprazole, 
rabeprazole) unless the patient has been on a stable dose for 30 days before the Screening 
Visit and plans to continue on a stable dose throughout the study. 
10. 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 on a stable dose throughout the study. 
 


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


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APPENDIX 4 
DIBSS-D 
Diary of Irritable Bowel Syndrome Symptoms – D (DIBSS-D) v0.1 


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Diary of Irritable Bowel Syndrome Symptoms – D (DIBSS-D) v0.1 


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








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APPENDIX 8 
EQ-5D-3L 




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APPENDIX 9 
IBS-SSS 
IBS-SSS Questionnaire 
1. 
A.  Do you currently (in the last month) suffer from abdominal (tummy) pain? 
  Yes 
  No 
B.  If yes, how severe is your abdominal (tummy) pain?  Please indicate a number from 0 
to 10, with 0 meaning “ no pain” and 10 meaning “very severe.” 
no pain 
0 1 2 3 4 5 6 7 8 9 10 
very severe 
C.  Please enter the number of times that you get the pain every 10 days.  For example, if 
you choose 4 it means that you get pain 4 out of 10 days.  If you get pain every day 
enter 10. 
no days with pain 
0 1 2 3 4 5 6 7 8 9 10 
10 days with pain 
 
2.         A.  Do you currently suffer from abdominal distention* (bloating, swollen or tight      
tummy)?  *Women, please ignore distention related to your period. 
  Yes 
  No 
B.  If yes, how severe is your abdominal distention/tightness?  Please indicate a number 
from 0 to 10, with 0 meaning “no distention” and 10 meaning “very severe.” 
no distention 
0 1 2 3 4 5 6 7 8 9 10 
very severe 
 
3. 
How dissatisfied are you with your bowel habits?  Please indicate a number from 0 to 10, 
with 0 meaning “very happy” and 10 meaning “very unhappy.” 
very happy 
0 1 2 3 4 5 6 7 8 9 10 
very unhappy 


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29 January 2019 
 
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4. 
Please indicate how much abdominal pain or discomfort or altered bowel habits are 
affecting or interfering with your life in general.  Please indicate a number from 0 to 10, 
with o meaning “not at all” and 10 meaning “completely.” 
not at all  
0 1 2 3 4 5 6 7 8 9 10 
completely 
 


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APPENDIX 10 
INVESTIGATOR’S SIGNATURE 
Study Title: 
A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-
group, Dose-range-finding Study of MD-7246 Administered Orally 
for 12 Weeks to Treat Abdominal Pain in Patients with Diarrhea-
predominant Irritable Bowel Syndrome 
Study Number: 
MCP-103-205 
Final Date: 
29 January 2019 
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:  
 
 
 
Print Name: 
 
 


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29 January 2019 
 
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15. 
REFERENCE LIST 
1. Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, et al. Bowel Disorders. 
Gastroenterology. 2016;150:1393-407. 
2. Sandler RS, Jordan MC, Shelton BJ. Demographic and dietary determinants of constipation 
in the US population. Am J Public Health. 1990;80(2):185-9. 
3. Camilleri M, Prather CM. The irritable bowel syndrome: mechanisms and a practical 
approach to management. Ann Intern Med. 1992;116(12 Pt 1):1001-8. 
4. Thompson WG. Irritable bowel syndrome: pathogenesis and management. Lancet. 
1993;341(8860):1569-72. 
5. Lynn RB, Friedman LS. Irritable bowel syndrome. N Engl J Med. 1993;329(26):1940-5. 
6. Zighelboim J, Talley NJ. What are functional bowel disorders? Gastroenterology. 
1993;104(4):1196-201. 
7. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable 
bowel syndrome. Gastroenterology. 2002;123(6):2108-31. 
8. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterology. 2006;130:1480-91. 
9. Castro J, Harrington AM, Hughes PA, Martin CM, Ge P, Shea CM, et al. Linaclotide Inhibits 
Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and 
Extracellular Cyclic GMP. Gastroenterology. 2013;145(6):1334-46. 
10. Forte LR. Guanylin regulatory peptides: structures, biological activities mediated by cyclic 
GMP and pathobiology. Regul Pept. 1999;81(1-3):25-39. 
11. 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(1):196-206. 
12. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997;32(9):920-4. 
13. Sullivan MJ, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and 
validation. Psychological Assessment. 1995;7:524-32. 
14. Ware J, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales 
and preliminary tests of reliability and validity. Med Care. 1996;34(3):220-33. 
15. EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. 
The EuroQol Group. Health Policy. 1990;16:199-208. 


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16. Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and 
testing of the D1 valuation model. Med Care. 2005;43(3):203-20. 
17. Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple 
method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther. 
1997;11(2):395-402. 
 






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Summary of Changes for Protocol Amendment 1: MCP-103-205 
29 January 2019 
 
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SPONSOR SIGNATURE 
 
 
Ironwood Pharmaceuticals, Inc. 
Refer to the final page of this document for electronic signature and date of approval. 
 


MD-7246 
 
Ironwood Pharmaceuticals, Inc. 
Summary of Changes for Protocol Amendment 1: MCP-103-205 
29 January 2019 
 
Confidential 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2 
1. 
SUMMARY OF THE PROTOCOL AMENDMENT .............................................................4 
 


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Summary of Changes for Protocol Amendment 1: MCP-103-205 
29 January 2019 
 
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1. 
SUMMARY OF THE PROTOCOL AMENDMENT 
The major changes from clinical protocol MCP-103-205 Original Protocol to MCP-103-205 
Protocol Amendment 1 are summarized below. 
The following changes were made to the protocol: 
• The indication was changed from irritable bowel syndrome (IBS) to abdominal pain in 
diarrhea-predominant IBS (IBS-D); constipation and mixed subtypes were removed from the 
study. 
- 
The study title, objectives, introduction, and other sections as described below, were 
updated to reflect this change. 
• The contact information for SAE reporting was changed from Ironwood to PPD 
(
 
). 
• The Rome IV questionnaire was removed for diagnosis and subtyping (Rome IV criteria are 
still used, as detailed in the inclusion criteria).  
- 
Rome IV diagnostic questionnaire IBS Module was removed from the appendices. 
• Stratification by IBS subtype and minimum enrollment for each subtype were removed from 
descriptions of randomization and enrollment. 
• The Pretreatment Period was shortened from 21-28 days to 14-21 days. 
- 
Timing of the Screening and Pretreatment Visits, and total duration of patient 
participation in the study, were adjusted accordingly: Screening Visit (Day -49 to 
Day -15), Pretreatment Visit (Day -21 to Day -14), and duration (up to 151 days). 
• The Week 2 and Week 14/EOS Visits were changed to phone calls collecting only adverse 
events (AEs) and concomitant medicines, and an eDiary compliance reminder was added at 
Week 2. 
- 
Other assessments at these timepoints were removed: IWRS registration, body weight 
and height, vital signs, eDiary registration, patient eDiary entry in clinic, eDiary 
compliance verification and reminder (removed at EOS only), EQ-5D-3L, and IBS-SSS 
- 
Because the last visit to the clinic will now be the Week 12/End-of-Treatment (EOT) 
Visit, eDiary entry (including daily, weekly, and study visit assessments) was removed 
during the Posttreatment Period; statistical analyses related to the Posttreatment Period 
were updated accordingly. 
- 
Details regarding the Week 2 and Week 14/EOS calls were added in the Schedule of 
Evaluation footnotes and in the descriptions of the study periods. 


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• Protocol-permitted over-the-counter (OTC) medications for constipation and diarrhea 
(MiraLAX® [polyethylene glycol 3350], Ex-Lax® [sennosides], and Imodium® [loperamide]) 
were changed to loperamide for diarrhea to reflect the indication change to IBS-D only. 
- 
The assessment of use of these medications on an event-driven basis, corresponding 
eDiary questions and exploratory endpoints, and concomitant and prohibited medicines 
were updated accordingly. 
• The Diary of IBS Symptoms – Mixed (DIBSS-M) was changed to the DIBSS – Diarrhea 
(DIBSS-D) for daily abdominal symptom and BM-related assessments, to reflect the 
indication change to IBS-D only. 
- 
Assessments of straining and completeness of evacuation (and corresponding eDiary 
questions and exploratory endpoints) were removed to reflect the components of the 
DIBSS-D. 
• The IBS-QOL and HADS were removed from the study visit assessments. 
- 
Corresponding statistical analyses and appendices were also removed. 
• The number of patients was reduced from approximately 400 IBS patients (approximately 
100 patients per treatment group) to approximately 368 IBS-D patients (approximately 
92 patients per treatment group). 
- 
Sample size determination was updated to reflect this change. 
• Inclusion criteria were updated as follows: 
- 
#7 and 8 (related to Rome IV diagnosis and subtyping, respectively) were updated to 
reflect the indication change to IBS-D only, by removing medications and criteria 
specific to IBS-C and IBS-M. 
- 
#11 was added to ensure patients are able to swallow the study drug whole, as study drug 
may not be chewed, divided, crushed, or dissolved. 
• Exclusion criteria were updated as follows: 
- 
#5-7 in the original protocol were consolidated into #5-6 in the amended protocol 
- 
#12 was broadened to exclude patients with a history of a microbiologically documented 
lower GI infection, or received treatment for a microbiologically documented lower GI 
infection during the 3 months before Screening; Clostridium difficile colitis was given as 
an example of such an infection, rather than the only such infection excluded 
- 
#13 was updated to exclude patients with a history of hypersensitivity to loperamide, in 
addition to linaclotide or any of the excipients in the study drug (MD-7246 or placebo) 
- 
#14b was updated to add details regarding laparoscopic surgery of the abdomen, pelvis, 
or retroperitoneal structures (excluded during the 3 months before Screening) 


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- 
#15 was updated to allow patients whose cancer had been complete remission for 3 years 
before Randomization (reduced from 5 years) 
- 
#17 was added to exclude patients with a history of human immunodeficiency virus 
infection 
- 
#20 was added to exclude patients with a history or current evidence of laxative or opiod 
abuse 
- 
#23 in the original protocol was removed because it was specific to IBS-C 
- 
Minor revisions for structure, clarity, and to reduce redundancy were made to #2, 9, and 
10 
• Efficacy and exploratory statistical analyses were updated to remove IBS subtype and 
treatment-by-IBS-subtype from fixed effects and to remove by-subtype analyses. 
• The exploratory endpoints were updated to reflect the changes in indication and protocol-
permitted OTC medications, and the change from DIBSS-M to DIBSS-D: 
- 
Removed Change from Baseline in Straining at Each Week and Change from Baseline in 
the Proportion of Days Experiencing an Episode of Constipation per Week 
- 
Removed constipation from Change from Baseline in the Proportion of Days 
Experiencing No Episodes or Constipation or Diarrhea per Week 
- 
Updated Change from Baseline in Percent of Days with Use of Protocol-permitted OTC 
Medications for Constipation and Diarrhea to reflect the change to Loperamide for 
Diarrhea 
• The rectal examination as part of the physical examination was changed to be at the 
discretion of the investigator, rather than required at Screening for all patients not requiring 
colonoscopy and not required at subsequent visits. 
• Overall study stopping criteria were updated to remove text related to stopping enrollment 
after the required number of patients have been enrolled (considered self-evident based on 
target enrollment) and reference to IBS subtypes. 
• The rationale for study design was updated to reflect the study design changes described 
above, including the shortened Pretreatment Period, removal of Posttreatment Period eDiary 
assessment, indication change to IBS-D only, removal of stratification by IBS subtype, and 
changes to protocol-permitted OTC medications. 
• Prohibited medicines were refined to be more specific to IBS-D and to clarify washout 
periods and exceptions. 
- 
Opioids and centrally acting analgesic medications were moved from Prescreen Washout 
to Screening Period Washout and clarifications regarding washout exceptions were added 
- 
Cannabinoid drugs were added to the Prescreen Washout (30 days before Screening) 


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29 January 2019 
 
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- 
Prescription medications for IBS-C were removed 
- 
Barbiturates were moved to the Screening Period Washout (28 days before Pretreatment), 
from 14-day Washout 
- 
Medications used to treat constipation or diarrhea were updated to remove medications 
for constipation (eg, osmotic and stimulant laxatives, prokinetics), prohibit medications 
used to treat abdominal pain/discomfort, and clarify washout periods and exceptions 
- 
Clarified that erythromycin is not allowed, even as part of a standard regimen of oral 
antibiotics 
• The section describing the criteria for reporting laboratory abnormalities as AEs was 
expanded to include vital signs. 
• The procedures for recording AEs were corrected for consistency with the Safety 
Management Plan to state that all SAEs will be followed to adequate resolution or 
stabilization for up to a maximum of 30 days after last dose (changed to SAEs from AEs and 
specified maximum follow-up). 
• The procedures for collecting and reporting SAEs were revised to detail reporting via the 
electronic data capture (EDC) system, back-up reporting with the hard-copy SAE form, and 
confirmation of receipt of SAE information; to update contact information from Ironwood to 
PPD; and to require SAE follow-up until resolution or stabilization for up to a maximum of 
30 days after last dose. 
• The procedures for reporting pregnancy and pregnancy-related SAEs were revised to update 
the contact information from 
 and specify that SAEs occurring as a result of 
post-study pregnancy are to be reported using the hard-copy SAE form. 
• The required investigator consultation with the patient was updated to reflect the indication 
and protocol-permitted OTC medications changes, and to refine the thresholds that trigger 
eDiary alerts (ie, no BMs for ≥3 consecutive days with daily use of loperamide; ≥8 unit doses 
(≥16 mg) of loperamide in a 24-hour period for ≥5 consecutive days). 
• Minor administrative changes and revisions (ie, grammar, formatting, style, and sentence 
structure) were also made throughout the document to improve clarity, consistency, and 
succinctness. 
 



SAP_001.pdf: 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OBJECTIVES ................................................................................................9 
3. 
STUDY DESIGN .......................................................................................................10 
3.1. 
General Description ....................................................................................................10 
3.2. 
Discussion of Study Design, Including Choice of Control Group .............................12 
3.3. 
Treatments Administered ............................................................................................13 
3.4. 
Methods of Assigning Subjects to Treatment Groups ................................................13 
3.5. 
Blinding ......................................................................................................................13 
4. 
DETERMINATION OF SAMPLE SIZE ...................................................................14 
5. 
PHARMACOKINETICS, EFFICACY, AND SAFETY ASSESSMENTS...............15 
5.1. 
Study Schematic and Schedule of Assessments .........................................................15 
5.2. 
Pharmacokinetic Assessments ....................................................................................19 
5.3. 
Efficacy Assessments .................................................................................................19 
5.3.1. 
Key Efficacy Assessment ...........................................................................................19 
5.3.2. 
Additional Efficacy Assessments ...............................................................................19 
5.3.3. 
Exploratory Assessments ............................................................................................21 
5.4. 
Health Outcomes Assessments ...................................................................................23 
5.5. 
Completion of eDiary Assessments ............................................................................24 
5.6. 
Safety Assessments .....................................................................................................25 
5.6.1. 
Adverse Events ...........................................................................................................25 
5.6.1.1. 
Causality Assessment .................................................................................................25 
5.6.1.2. 
Classification of Adverse Event Severity ...................................................................26 
5.6.1.3. 
Serious Adverse Events ..............................................................................................27 
5.6.2. 
Clinical Laboratory Data ............................................................................................27 
5.6.3. 
Vital Signs ..................................................................................................................28 
5.6.4. 
Physical Examination .................................................................................................29 
5.6.5. 
Medical History ..........................................................................................................29 
6. 
DATA QUALITY ASSURANCE ..............................................................................30 
6.1. 
Data Monitoring ..........................................................................................................30 


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6.2. 
Data Recording and Documentation ...........................................................................30 
7. 
STATISTICAL METHODS .......................................................................................31 
7.1. 
General Methods .........................................................................................................31 
7.2. 
Adjusting for Covariates .............................................................................................31 
7.3. 
Handling of Dropouts/Missing Data Imputation Method ...........................................31 
7.4. 
Interim Analysis and Data Monitoring .......................................................................31 
7.5. 
Multicenter Studies .....................................................................................................32 
7.6. 
Multiple Comparisons/Multiplicity ............................................................................32 
7.7. 
Examination of Subgroups .........................................................................................32 
7.8. 
Analysis Methods .......................................................................................................32 
7.8.1. 
Patient Populations .....................................................................................................32 
7.8.1.1. 
Analysis Periods .........................................................................................................32 
7.8.2. 
Patient Disposition ......................................................................................................33 
7.8.3. 
Protocol Deviations ....................................................................................................33 
7.8.4. 
Demographics and Other Baselines Characteristics ...................................................33 
7.8.5. 
Measurement of Treatment Compliance ....................................................................34 
7.8.6. 
Extent of Exposure .....................................................................................................34 
7.8.7. 
Prior and Concomitant Medication .............................................................................34 
7.8.8. 
eDiary Compliance .....................................................................................................34 
7.8.9. 
Efficacy Endpoints and Analyses ...............................................................................35 
7.8.9.1. 
Key Efficacy Endpoints ..............................................................................................35 
7.8.9.2. 
Analyses of the Key Efficacy Endpoints ....................................................................36 
7.8.9.3. 
Sensitivity Analyses of the Key Efficacy Endpoints ..................................................37 
7.8.9.4. 
Additional Efficacy Endpoints and Analyses .............................................................37 
7.8.10. 
Exploratory Endpoints and Analyses..........................................................................40 
7.8.11. 
Safety Analysis ...........................................................................................................41 
7.8.11.1. 
Adverse Events ...........................................................................................................41 
7.8.11.2. 
Clinical Laboratory Parameters ..................................................................................42 
7.8.11.3. 
Vital Signs ..................................................................................................................43 
7.8.11.4. 
Physical Examination .................................................................................................44 
7.8.12. 
Health Outcomes Analysis .........................................................................................44 
8. 
REFERENCES ...........................................................................................................46 


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APPENDIX 1. CHANGES FROM ANALYSES PLANNED IN THE PROTOCOL ...............47 
APPENDIX 2. VISIT TIME WINDOWS FOR SAFETY ANALYSIS .....................................49 
APPENDIX 3. VISIT TIME WINDOWS FOR EFFICACY ANALYSIS ................................50 
APPENDIX 4. BRISTOL STOOL FORM SCALE ...................................................................52 
 
 
 


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LIST OF TABLES 
Table 1: 
Schedule of Evaluations .............................................................................................16 
Table 2: 
Criteria for Potentially Clinically Significant Laboratory Results .............................42 
Table 3: 
Criteria for Potentially Clinically Significant Vital Signs ..........................................44 
 
 
 
LIST OF FIGURES 
Figure 1: 
Overview of Study Design ..........................................................................................12 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
APC 
Abdominal Pain and Constipation 
AST 
aspartate aminotransferase 
BM 
bowel movement 
BP 
blood pressure 
BPM 
beats per minute 
BSFS 
Bristol Stool Form Scale 
CBC 
complete blood count 
CDC HRQOL-4 CDC Healthy Days Core Module 
CIC 
chronic idiopathic constipation 
CMH 
Cochran Mantel-Haenszel 
CSBM 
complete spontaneous bowel movement 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EOT 
End-of-Treatment 
HEENT 
head, ears, eyes, nose, throat 
IBS-D 
irritable bowel syndrome with diarrhea 
IBS-SSS 
Irritable Bowel Syndrome – Symptom Severity Scale 
ICF 
informed consent form 
IPD 
Important Protocol Deviations 
ITT 
Intent-to-treat 
IWRS 
interactive web response system 
LLN 
lower limit of normal 
LS 
least-squares 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MI 
multiple imputation 
MMRM 
Mixed Model Repeated Measures 


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NRS 
numerical rating scale 
PCS 
potentially clinically significant 
PID 
patient identification number 
Pg 
picogram 
PGI-C 
patient global impression of change 
PGI-S 
patient global impression of severity 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SF-12v2 
Short Form-12 Health Survey version 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 
US 
United States 
 


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1. 
INTRODUCTION 
The MCP-103-205 study is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, dose-range-finding, 12-week study, consisting of 4 distinct periods: up to 2 weeks 
Screening, 2-3 weeks Pretreatment, 12 weeks Treatment, and 2 weeks Posttreatment. The study 
will enroll approximately 368 patients who have IBS-D diagnosed using Rome IV criteria. 
Eligible patients will be randomized in equal proportions to 1 of 4 treatments: 300, 600, or 
1200 μg of MD-7246, or matching placebo, administered once daily. MD-7246 is a delayed 
release (DR) tablet formulation of linaclotide designed to release linaclotide in the distal ileum 
near the ileocecal junction, to target guanylate cyclase C (GC-C) receptors in the colon and 
minimize secretory effects in the gastrointestinal (GI) tract. 
This statistical analysis plan (SAP) describes the statistical analysis methods for the analysis of 
efficacy and safety data collected according to the following documents: 
• Study Protocol MCP-103-205 Amendment 1, dated 29 January 2019 
• Case Report Form (CRF) version 3.0, dated 26 November 2019 
Data presentation details for the analyses included in this SAP will be specified in a separate data 
presentation plan for the format of Tables, Figures and Listings. 


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2. 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the safety and tolerability, treatment effect on 
abdominal pain, and dose response of MD-7246 administered orally to patients with diarrhea-
predominant irritable bowel syndrome (IBS-D). An exploratory objective of the study is to assess 
bowel function changes with MD-7246 in patients with IBS-D. 


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3. 
STUDY DESIGN 
3.1. 
General Description 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-range-
finding, 12-week study, consisting of 4 distinct periods, as illustrated in Figure 1 below. The 
study will enroll patients who have IBS-D diagnosed using Rome IV criteria. Eligible patients 
will be randomized in equal proportions to 1 of 4 treatments: 300, 600, or 1200 µg of MD-7246, 
or matching placebo, administered once daily. MD-7246 is a delayed release (DR) tablet 
formulation of linaclotide designed to release linaclotide in the distal ileum near the ileocecal 
junction, to target guanylate cyclase C (GC-C) receptors in the colon and minimize secretory 
effects in the gastrointestinal (GI) tract. 
Study Periods 
Screening Period: The Screening Period starts with the signing of the informed consent form 
(ICF; Appendix 1) and may last for up to 28 days. During this period, patient eligibility for entry 
into the Pretreatment Period will be determined. Loperamide, a protocol-permitted over-the-
counter (OTC) medication for diarrhea, will be distributed to eligible patients beginning at the 
Screening Visit. The end of the Screening Period coincides with the start of the Pretreatment 
Period. If the patient meets the entry criteria assessed at the Screening Visit and does not require 
a washout of prohibited medicines, the Screening Visit and Pretreatment Visit may be combined 
into one visit.  
Pretreatment Period: The Pretreatment Period is defined as the 14 to 21 days immediately 
before the Randomization Visit. During this period, patients will provide the following 
information in a handheld electronic diary (eDiary): 
• Daily Assessments: 
− Daily Abdominal Symptom Assessments in a daily evening report 
− Bowel Movement (BM)-related Assessments on an event-driven basis (meaning 
these are assessments made for each event at the time the event occurs [or during 
the daily evening report for any events not previously entered for that day]) 
• Weekly Assessments: 
− Weekly Patient Assessment of Degree of Relief of IBS Symptoms 
− Weekly Patient Assessment of Adequate Relief of IBS Pain 
− Weekly Patient Assessment of BM-related Symptom Severity (patient global 
impression of severity [PGI-S]) 
− Weekly Patient Assessment of BM-related Symptom Change (patient global 
impression of change [PGI-C]) 
• Use of Loperamide for Diarrhea on an event-driven basis  
Patients who satisfy all entry criteria will enter the Treatment Period. 


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Treatment Period: The Treatment Period begins with treatment assignment and lasts for 
12 weeks. Patients will be randomized in equal proportions to 1 of 4 treatments: 300, 600, or 
1200 µg of MD-7246, or matching placebo. Patients will take their initial dose of study drug at 
the study center during the Randomization Visit. On all other days, study drug will be taken once 
daily at approximately the same time of day without regard to food (patients will be instructed to 
choose a time that is convenient for them and continue daily dosing at that time throughout the 
Treatment Period). Patients will continue to use the handheld eDiary to provide their:  
• Daily Assessments: 
− Daily Abdominal Symptom Assessments in a daily evening report 
− BM-related Assessments on an event-driven basis 
• Weekly Assessments: 
− Weekly Patient Assessment of Degree of Relief of IBS Symptoms 
− Weekly Patient Assessment of Adequate Relief of IBS Pain 
− Weekly Patient Assessment of Treatment Satisfaction 
− Weekly Patient Assessment of BM-related Symptom Severity (PGI-S) 
− Weekly Patient Assessment of BM-related Symptom Change (PGI-C) 
• Use of Loperamide for Diarrhea on an event-driven basis 
Health-related quality-of-life and patient-outcome assessments will be performed at the 
Randomization Visit and at study visits throughout the Treatment Period. A list of these 
assessments and the visits when they will be performed is provided in the Schedule of 
Evaluations. 
Patients will complete a Week 2 Phone Call, and Week 4, Week 8, and Week 12/End of 
Treatment (EOT) Visits during the Treatment Period (see Schedule of Evaluations). 
Posttreatment Period: The Posttreatment Period starts on the day following the last day of 
dosing (Week 12/EOT Visit) and finishes 2 weeks later at the End of Study (EOS) Follow-up 
Phone Call. During the call, patients will be asked to report any AEs and medicines taken since 
the Week 12/EOT Visit and detail any other symptoms or comments they may have (at the 
discretion of the investigator, patients may be requested to return to the study center for their 
EOS Follow-up). 
Overall Study Stopping Criteria and Data Monitoring Committee 
The Sponsor may stop enrollment prematurely because of low recruitment rates. The Sponsor 
may suspend or terminate the study prematurely because of a change in opinion of the 
Institutional Review Board, Data Monitoring Committee (DMC), or a regulatory authority 
decision. 


Ironwood Pharmaceuticals, Inc. 
Statistical Analysis Plan: MCP-103-205 
MD-7246
14 April 2020 
An independent DMC will regularly review safety data dming the conduct of the study. Periodic 
safety review meetings will be scheduled when approximately 1/3 and 2/3 of patients have been 
randomized. The committee will review accumulated safety data, and may request unblinding of 
the ti·eatment groups, in order to make any recommendations regarding the acceptability of 
continuing the study based on AEs repo1ted. 
Figure 1: 
Overview of Study Design 
•
II
3.2. 
Discussion of Study Design, Including Choice of Control Group 
A double-blind, placebo-conti·olled, parallel-group study design was chosen in accordance with 
the concepts in ICH EIO, Choice of Conti·ol Groups and Related Issues in Clinical Trials, in 
order to provide comparable u-eatment groups and minimal chance of selection or investigator 
bias. The study has a 14-21 day Preti·eatment Period to establish patient baseline values without 
study diug and to familiarize patients with data collection methodology (ie, eDia1y), a 12-week 
Treatment Period to compare the test ti·eatment to a placebo conti·ol, and a 2-week Postti·eatment 
Period to assess safety after MD-7246 u-eatment has been withdi·awn. 
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The study will evaluate the effect of the test treatment on abdominal pain in IBS-D patients. 
Because the test treatment is not expected to significantly affect bowel function, loperamide will 
be provided beginning at the Screening Visit for patients to use as needed, at the patients’ 
discretion, to stabilize their diarrhea throughout the study; utilization of loperamide for diarrhea 
will be recorded on an event-driven basis. 
Three doses of MD-7246 were selected to assess the relationship between dose and response. 
3.3. 
Treatments Administered 
The Treatment Period begins with treatment assignment and lasts for 12 weeks. Patients will be 
randomized in equal proportions to 1 of 4 treatments: 300, 600, or 1200 µg of MD-7246 or 
matching placebo. Patients will take their initial dose of study drug at the study center during the 
Randomization Visit. On all other days, study drug will be taken once daily at approximately the 
same time of day without regard to food (patients will be instructed to choose a time that is 
convenient for them and continue daily dosing at that time throughout the Treatment Period). 
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 368 patients will 
be randomized to 1 of 4 treatments: MD-7246 300 µg, 600 µg, or 1200 µg or placebo (1:1:1:1). 
Randomization numbers will be assigned by interactive web response system (IWRS). 
3.5. 
Blinding 
This is a double-blind study. The Sponsor study personnel, the investigator, all other site study 
personnel, and the patient will remain blinded to individual patient treatment assignments 
throughout the study. Specifically designated personnel in the Global Patient Safety (GPS) group 
at Ironwood may be unblinded to the treatment assignment of individual patients for regulatory 
reporting purposes. 
Patient randomization codes for the Treatment Period will be generated by Allergan and 
implemented by the IWRS vendor (an electronic version will be stored on a secure server). The 
randomization list will identify each patient by randomization number and include the patient’s 
corresponding treatment assignment. The medication code list will be supplied by 
 
 to the IWRS vendor. 
In case of an emergency, the IWRS will be accessed to obtain the study drug assignment of a 
patient. Accessing the IWRS for emergency unblinding should be done only in an emergency 
that necessitates identifying the treatment assignment 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 Sponsor immediately. An explanation for breaking the 
blind will be recorded on the relevant eCRF. Breaking the blind at the study center will 
disqualify the patient from further participation in the study (refer to Protocol Section 6.3 for 
details regarding procedures and follow-up for patients who are discontinued from therapy). 


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4. 
DETERMINATION OF SAMPLE SIZE 
In a previously conducted Phase 2b trial utilizing MD-7246 (ie, Study MCP-103-204), the 
observed sample standard deviation (SD) for the change from baseline to Week 12 in abdominal 
pain at its worst ranged from 2.32 to 2.88. Assuming a clinically meaningful treatment difference 
between MD-7246 and placebo of 1.0 for the mean change from baseline to Week 12 in 
abdominal pain at its worst, an SD of 2.4, and 92 patients per treatment group (368 patients 
total), the estimated power is approximately 80% to detect a difference between each MD-7246 
dose and placebo at a 2-sided significance level of 0.05 using a 2-sample t-test. 


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5. 
PHARMACOKINETICS, EFFICACY, AND SAFETY 
ASSESSMENTS 
5.1. 
Study Schematic and Schedule of Assessments 
The schedule of evaluations for Study MCP-103-205 is presented in Table 1. 
 


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Table 1: 
Schedule of Evaluations 
MCP-103-205 
Study Period → 
Screening 
Period 
(Up to 28 days) 
Pretreatment 
Period 
(14 to 21 days) 
Treatment Period 
(12 weeks) 
Posttreatment 
Period 
(2 weeks) 
Visit Days → 
Screening 
Visit 
(Day -49 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -14) 
Random-
ization 
Visit 
(Day 1) 
Week 2 
Phone Call 
(Day 15±3) 
Week 4 
Visit 
(Day 29±3) 
Week 8 
Visit 
(Day 57±3) 
Week 12/ End-
of-Treatment 
Visit p 
(Day 85+3) 
End-of-Study 
Follow-up 
Phone Call 
(Day 99+3) 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Telephone 
Call 
Visit 4 
Visit 5 
Visit 6 
Telephone 
Call 
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 
X 
X 
Clinical Laboratory Tests f 
X 
 
X* 
 
X 
X 
X 
 
Pregnancy Test g 
X 
 
X* 
 
 
 
X 
 
Prohibited Medications Washout 
Instructions 
X 
 
 
 
 
 
 
 
Loperamide for Diarrhea Dispensed h 
X 
X 
X 
 
X 
X 
X 
 
AE Evaluations i 
 
X 
X* 
X 
X 
X 
X 
X 
eDiary Registration and Training j 
 
X 
X* 
 
X 
X 
X 
 
Pain Catastrophizing Scale 
 
X 
 
 
 
 
 
 
Daily and Weekly Assessments k 
 
X 
 
Patient eDiary Entry, in Clinic 
 
X 
X* 
 
X 
X 
X 
 
eDiary Compliance Verification and 
Reminder l 
 
 
X* 
X 
X 
X 
X 
 


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MCP-103-205 
Study Period → 
Screening 
Period 
(Up to 28 days) 
Pretreatment 
Period 
(14 to 21 days) 
Treatment Period 
(12 weeks) 
Posttreatment 
Period 
(2 weeks) 
Visit Days → 
Screening 
Visit 
(Day -49 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -14) 
Random-
ization 
Visit 
(Day 1) 
Week 2 
Phone Call 
(Day 15±3) 
Week 4 
Visit 
(Day 29±3) 
Week 8 
Visit 
(Day 57±3) 
Week 12/ End-
of-Treatment 
Visit p 
(Day 85+3) 
End-of-Study 
Follow-up 
Phone Call 
(Day 99+3) 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Telephone 
Call 
Visit 4 
Visit 5 
Visit 6 
Telephone 
Call 
Study Procedure ↓ 
 
 
 
 
 
 
 
 
Randomization 
 
 
X† 
 
 
 
 
 
SF-12v2 
 
 
X† 
 
X 
X 
X 
 
EQ-5D-3L 
 
 
X† 
 
X 
X 
X 
 
IBS-SSS 
 
 
X† 
 
X 
X 
X 
 
Study Drug Dispensed 
 
 
X 
 
X 
X 
 
 
Study Drug Administration m 
 
 
X 
 
 
 
 
 
Safety Phone Call n 
 
 
 
X 
 
 
 
X 
Study Drug Accountability 
 
 
 
 
X 
X 
X 
 
Investigator Consultation with 
Patient o 
 
X (Activity Triggered by eDiary Alert) 
 
AE=adverse event; BM=bowel movement; CBC=complete blood count; eDiary=electronic diary; EOS=End-of-Study; EOT=End-of-Treatment; 
EQ-5D-3L=EuroQol-5 Dimension 3-level; IBS=irritable bowel syndrome; IBS-SSS= Irritable Bowel Syndrome-Symptom Severity Scale; ICF=informed consent 
form; IWRS=interactive web response system; SF-12v2=Short Form-12 Health Survey version 2. 
* Assessment done prior to randomization; † Assessment done predose 
a. 
Site personnel will interact with IWRS to register the patient visit. Refer to the IWRS User Manual. 
b. A physical examination includes, at minimum, the following: general appearance, HEENT (head, ears, eyes, nose, and throat), cardiac, respiratory, 
gastrointestinal, musculoskeletal, neurological, and dermatological systems. Rectal examinations should be performed at the discretion of the investigator; 
the purpose of the rectal examination is to rule out pathologies that might be caused by obstruction. Breast and genitourinary examinations are not required. 
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. Pulse and blood pressure 
readings will be taken after the patient has been sitting for 5 minutes. 
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 (approved or unapproved). 
f. 
Chemistry and CBC. Urine drug screen will be performed at the Screening Visit only. 


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g. Required for females of childbearing potential only. 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 serum pregnancy test results must be 
documented at the Week 12/EOT Visit. 
h. Protocol-permitted loperamide for diarrhea will be supplied to patients at the Screening Visit and, if needed, at the Pretreatment Visit, subsequent study drug 
dispensing visits, and the Week 12/EOT Visit. 
i. 
All AEs occurring after the patient signs the ICF will be captured. 
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 Abdominal Symptom Assessments, BM-related Assessments, Weekly Assessments, Pain Catastrophizing Scale 
(Pretreatment Visit only), SF-12v2, EQ-5D, IBS-SSS, and any use of loperamide for diarrhea. Patients will enter BMs and loperamide use in the eDiary on 
an event-driven basis, and will complete an evening entry each day to record daily assessments, including any BMs and/or loperamide use not previously 
recorded for that day, and weekly assessments. At the Randomization Visit, eDiary assessments will be completed in clinic prior to randomization. 
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 compliance reminder will also occur during the Week 2 Phone Call. 
m. Study drug will be administered in the clinic at the Randomization Visit. On all other days, study drug will be taken once daily at approximately the same 
time of day without regard to food. 
n. Appropriate site personnel will contact patients by phone to assess for AEs, record concomitant medicines, and (at Week 2 only) remind patients to comply 
with study drug and eDiary completion. Any AE or concomitant medicine reported during the phone call will be captured on the eCRF. Patients who report 
AEs during the call will be provided with instructions on the appropriate follow-up care. At the discretion of the investigator, patients may be requested to 
return to the clinic for this contact or an unscheduled visit may be conducted following the phone call. 
o. Throughout the Pretreatment and Treatment Periods, the eDiary will send automated alerts to the investigator if patients experience episodes of constipation 
with excessive use of loperamide or diarrhea that is not well managed with the use of loperamide (as defined in Protocol Section 8.2.6). In the event of an 
alert, the investigator must review with the patient their use of loperamide and their pattern of constipation or diarrhea. 
p. 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 
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. Event-driven and daily assessments of 
abdominal and bowel symptoms will be collected using the Diary of IBS Symptoms – Diarrhea 
(DIBSS-D; Protocol Appendix 4). 
5.3.1. 
Key Efficacy Assessment 
The efficacy assessment that will be used to determine the key efficacy endpoints is the daily 
patient assessment of abdominal pain at its worst. 
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. 
Additional Efficacy Assessments 
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”> 
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”> 


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Daily Patient Assessment of Abdominal Cramping at its Worst 
Patient assessment of abdominal cramping at its worst will be collected via a daily evening 
report in the eDiary. The rating of abdominal cramping 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 cramping in the past 24 hours?” 
<eDiary presents NRS where 0 is anchored with “No abdominal cramping” and 10 is anchored 
with “Worst possible abdominal cramping”> 
Weekly Patient Assessment of Degree of Relief of IBS Symptoms 
Patient assessment of degree of relief of IBS symptoms will be reported weekly by eDiary entry. 
The rating of degree of relief during the previous 7 days on a 7-point balanced scale will be 
provided by the patient answering the following question: 
“Compared to before you started the study, how would you rate your IBS symptoms during the 
past 7 days?” 
1=Significantly relieved 
2=Moderately relieved 
3=Somewhat relieved 
4=Unchanged 
5=Somewhat worse 
6=Moderately worse 
7=Significantly worse 
Weekly Patient Assessment of Adequate Relief of IBS Pain 
Patient assessment of adequate relief of IBS pain will be reported weekly by eDiary entry. The 
rating of adequate relief during the previous 7 days on a binary scale will be provided by the 
patient answering the following question: 
“Overall, have you had adequate relief from your IBS pain during the past 7 days?” 
1=Yes 
2=No 
Weekly Patient Assessment of Treatment Satisfaction 
Patient assessment of treatment satisfaction will be reported weekly by eDiary entry each week 
of the Treatment Period after the Randomization Visit. Patients will answer the following 
question on a 5-point ordinal scale: 


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“Overall, how satisfied are you with the study medication’s ability to relieve your IBS 
symptoms?” 
1=Not at all satisfied 
2=A little satisfied 
3=Moderately satisfied 
4=Quite satisfied 
5=Very satisfied 
5.3.3. 
Exploratory Assessments 
In addition to the key/additional efficacy assessments, the following non-efficacy exploratory 
assessments are used in determining the exploratory endpoints. 
Each day of the Pretreatment and Treatment Periods, the patient will complete eDiary entries on 
an event-driven basis to report BMs. The patient is also asked to provide assessments of stool 
consistency and urgency, which are described below. Additionally, the patient will complete 
eDiary entries on an event-driven basis to report use of loperamide for diarrhea. Patients will 
complete a daily evening report to enter any BMs and/or loperamide usage not previously 
reported by the patient for that day (recall is limited to the period of time following the patient’s 
completion of the previous night’s Evening Report [ie for an Evening Report completed 
yesterday at 10:00pm, no events can be recorded today with a time preceding 10:00pm 
yesterday], or time following 7:00pm the previous day in instances where the previous night’s 
Evening Report was missed by the patient). 
Bowel Movement Frequency 
The assessment of BM frequency is based on the eDiary questions that record BM date 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. 
Stool Consistency (5-point ordinal scale) 
Patient assessment of stool consistency will be collected using two eDiary questions recorded on 
an event-driven basis (ie, for each BM reported in the eDiary). For each BM, patients will assess 
stool consistency by daily eDiary entry using a 5-point ordinal scale: 
“How would you describe the consistency of your stool?” 
1=Very hard 
2=Hard 
3=Neither too hard nor too soft 
4=Loose but not watery 
5=Very loose and watery 
The patient also assesses his/her stool consistency using the 7-point Bristol Stool Form Scale 
(BSFS) described below. 


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Stool Consistency (BSFS) 
In addition to the patient assessment of stool consistency using the 5-point ordinal scale 
(described above), the stool consistency of each BM will be recorded by the patient by daily 
eDiary entry for each BM on an event-driven basis using the BSFS (Protocol Appendix 5), 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. The 7-point ordinal BSFS is provided below (see Protocol 
Appendix 5 for full scale including pictures): 
“Please describe the form of your stool using the following scale where:” 
1=Separate hard lumps like nuts (hard to pass) 
2=Sausage-shaped but lumpy 
3=Like a sausage but with cracks on the surface 
4=Like a sausage or snake, smooth and soft 
5=Soft blobs with clear-cut edges (passed easily) 
6=Fluffy pieces with ragged edges, a mushy stool 
7=Watery, no solid pieces, entirely liquid 
BM Urgency 
Patient assessment of BM urgency will be collected by eDiary entry on an event-driven basis (ie, 
for each BM reported in the eDiary). For each BM, urgency will be assessed by the patient using 
a binary scale: 
“Did you feel the need to rush to the toilet in order to avoid an accident before your bowel 
movement?” 
1=Yes 
2=No 
Use of Loperamide for Diarrhea 
Patients will report use of loperamide (Imodium®) for diarrhea on an event-driven basis (ie, for 
each use of the medication). An evening report will ask whether the patient entered all 
loperamide use for that day and collect all loperamide use not previously entered for that day 
(recall is limited to the period of time following the patient’s completion of the previous night’s 
Evening Report [ie for an Evening Report completed yesterday at 10:00pm, no events can be 
recorded today with a time preceding 10:00pm yesterday], or time following 7:00pm the 
previous day in instances where the previous night’s Evening Report was missed by the patient). 
“Did you use Imodium® (loperamide) for diarrhea that you have not yet reported in the Diary?” 
1=Yes 
2=No 


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“Was the Imodium® (loperamide) taken yesterday or today?” 
1=Yesterday 
2=Today 
“How many Imodium® (loperamide) pills did you take?” 
__ pill(s) 
Weekly Patient Assessment of Bowel Movement-related Symptom Severity 
Patient global impression of severity (PGI-S) of BM-related symptoms will be reported weekly 
by eDiary entry. The rating of BM-related symptom severity during the previous 7 days on a 
5-point ordinal scale will be provided by the patient answering the following question: 
“How would you rate your bowel movement-related symptoms during the past 7 days?” 
1=None 
2=Mild 
3=Moderate 
4=Severe 
5=Very severe 
Weekly Patient Assessment of Bowel Movement-related Symptom Change 
Patient global impression of change (PGI-C) of BM-related symptoms will be reported weekly 
by eDiary entry. The rating of BM-related symptom change during the previous 7 days on a 
7-point ordinal scale will be provided by the patient answering the following question: 
“Compared to before you started the study, please rate the overall change in your bowel 
movement-related symptoms during the past 7 days.” 
1=Very much better 
2=Moderately better 
3=A little better 
4=No change 
5=A little worse 
6=Moderately worse 
7=Very much worse 
5.4. 
Health Outcomes Assessments 
Pain Catastrophizing Scale 
The Pain Catastrophizing Scale is an instrument for assessing catastrophic thinking related to 
pain and consists of 13 questions assessing the following 3 dimensions: rumination, 
magnification, and helplessness (Protocol Appendix 6). The Pain Catastrophizing Scale will be 
completed at the Pretreatment Visit as specified in the Schedule of Evaluations; the assessment 


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will be triggered by site personnel on the patient’s eDiary for the questionnaire to be self-
administered by the patient. 
Short Form-12 Health Survey version 2 (SF-12v2) 
The SF-12v2 is a widely used generic measure of health status (Protocol Appendix 7). The SF-
12v2 measures 8 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 8 scales are aggregated into 
2 summary measures: the Physical and Mental Component Summary Scores. The SF-12v2 will 
be completed at the Randomization Visit prior to the patient receiving study drug and at 
subsequent visits as specified in the Schedule of Evaluations. At each of the designated visits, the 
assessment will be triggered by site personnel on the patient’s eDiary for the questionnaire to be 
self-administered by the patient. 
EuroQol-5 Dimension 3-level (EQ-5D-3L) 
The EQ-5D-3L is a generic measure of health status that is widely used in Europe (protocol 
Appendix 8). The descriptive system consists of 5 questions assessing the following dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses to the 5 
questions define a health state for which a utility index can be derived from published 
algorithms. 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 completed at the Randomization Visit prior 
to the patient receiving study drug and at subsequent visits as specified in the Schedule of 
Evaluations. At each of the designated visits, the assessment will be triggered by site personnel 
on the patient’s eDiary for the questionnaire to be self-administered by the patient. 
Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS) 
The IBS-SSS contains 7 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 (Protocol Appendix 9). The IBS-SSS will be 
completed at the Randomization Visit prior to the patient receiving study drug and at subsequent 
visits as specified in the Schedule of Evaluations. At each of the designated visits, the assessment 
will be triggered by site personnel on the patient’s eDiary for the questionnaire to be self-
administered by the patient. 
5.5. 
Completion of eDiary Assessments 
To ensure patient compliance with the completion of the evening eDiary report, alarms occurring 
at 7, 8, 9, 10, and 11 PM will be programmed to alert the patient that he/she has not completed 
the evening eDiary report. Upon completion of the evening eDiary report, the alarm will no 
longer be active for the remainder of that day. If the patient does not complete the evening report 
prior to midnight, that day’s evening report will no longer be available for reporting by the 
patient, and all evening assessments for that day will be considered missing. 
Patient compliance with the daily eDiary completion requirement will be verified by site staff as 
specified in the Schedule of Evaluations. 


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5.6. 
Safety Assessments 
Safety will be evaluated by AE reports (discussed herein), standard clinical laboratory 
assessments, vital signs, physical examinations, and medical history. Planned timepoints for all 
safety assessments are provided in the Schedule of Evaluations. 
5.6.1. 
Adverse Events 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug-related. 
An AE, therefore, can be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
Treatment-emergent Adverse Event 
A TEAE is an event that emerges, or a preexisting event that worsens (with a new start date), any 
time after administration of the first dose of study drug (Day 1) during the treatment emergent 
period, which is defined as the date of the first treatment to the date on or before 1 day after the 
date of the last treatment. The Investigator will provide an assessment of the AE relationship to 
study drug and AE severity for each AE.   
5.6.1.1. 
Causality Assessment 
For all AEs, the investigator must provide an assessment of causal relationship to study drug. 
The investigator must assess the relationship of each AE (including SAEs) to the use of a study 
drug using a 2-category scale (not related or related) based on clinical judgment and using all 
available information, and may include consideration of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, 
preexisting conditions, concomitant use of other drugs, and presence of 
environmental or genetic factors 
• The temporal association between drug exposure and onset of the AE 
• Whether the manifestations of the AE are consistent with known actions or toxicity of 
the investigational product 
• Whether the AE resolved or improved with stopping use of the study drug; judgment 
should be used if multiple products are discontinued at the same time 


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The causality assessment must be recorded in the patient’s source documentation and on the AE 
page of the patient’s eCRF. The causal relationship between study drug and the AE will be 
assessed using the categories shown in the following table: 
Category 
Definition 
Not related 
An AE is not associated with study medication if: 
- 
Lack of a temporal relationship to study drug administration makes a 
causal relationship improbable (eg, the event did not occur within a 
reasonable time frame following administration of the study 
medication); and/or 
- 
Other causative factor(s) (eg, a preexisting clinical condition, other 
concomitant treatments) more likely explain the occurrence of the 
event, and 
- 
The event did not improve with stopping of the investigational 
product, and/or 
- 
The event did not recur upon re-exposure with investigational product 
Related 
An AE is attributed to the study medication if: 
- 
A temporal relationship to study drug administration makes a causal 
relationship plausible (eg, the event occurred within a reasonable time 
frame following administration of study medication); and/or 
- 
Other causative factor(s) (eg, the patient’s clinical condition, other 
concomitant treatments) either do not explain the event or are less 
equally likely to have led to the occurrence of the event, or 
- 
The event improved with stopping of the investigational product, 
and/or 
- 
The event recurred upon re-exposure with investigational product 
 
5.6.1.2. 
Classification of Adverse Event Severity 
The investigator or delegated physician will provide an assessment of the severity of each AE by 
recording a severity rating in the patient’s source documentation and on the AE page of the 
patient’s eCRF. Severity, which is a description of the intensity of manifestation of the AE, is 
distinct from seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality. Severity will be assessed according to the 
following scale: 
• Mild: A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 


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• Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant. 
• Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
AEs should be recorded using the maximum intensity of the event (eg, if a patient reported 
nausea lasting 3 days, 1 start date and 1 stop date should be recorded along with the maximum 
intensity experienced for that event over that 3-day timeframe). 
5.6.1.3. 
Serious Adverse Events 
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results in 
any of the following outcomes: 
• Death 
• Life-threatening experience: An AE is considered "life-threatening" if, in the view of 
either the investigator or Sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death. 
• Inpatient hospitalization or prolongation of an existing hospitalization: AEs requiring 
hospital admissions that are less than 24 hours in duration do not meet this criterion. 
A scheduled hospitalization for a preexisting condition that has not worsened during 
participation in the study does not meet this criterion. Preplanned hospitalizations for 
an elective medical/surgical procedure or routine check-ups do not meet this criterion. 
• Persistent or significant disability or incapacity or substantial disruption of the ability 
to conduct normal life functions 
• A congenital anomaly or birth defect 
• Is considered to be an important medical event: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the 
patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
5.6.2. 
Clinical Laboratory Data 
See below for the list of clinical laboratory tests to be performed and refer to the Schedule of 
Evaluations for the timing and frequency. All protocol-required laboratory assessments, as 
defined below, must be conducted in accordance with the laboratory manual and the Schedule of 
Evaluations. 


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The tests detailed below will be performed (additional tests may be performed at any time during 
the study as determined necessary by the investigator or as required by local regulations): 
• Hematology: Absolute and differential white blood cell count, erythrocyte count, 
hemoglobin, hematocrit, platelet count, and red blood cell indices (mean corpuscular 
volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration) 
• Chemistry: Sodium, magnesium, potassium, calcium, chloride, glucose, blood urea 
nitrogen, creatinine, total protein, alkaline phosphatase, albumin, total bilirubin, 
aspartate aminotransferase, alanine aminotransferase, bicarbonate, phosphate, 
cholesterol, and uric acid 
• Other: Urine drug screening (cocaine, barbiturates, amphetamines, opiates, 
benzodiazepine, alcohol, and cannabinoids) (Screening Visit only). By definition, a 
positive drug screen (including testing positive for marijuana in states where 
marijuana is legalized) is clinically significant and, therefore, exclusionary. 
• Pregnancy test: Serum human chorionic gonadotropin pregnancy test (for women of 
childbearing potential only) should be conducted at the Screening Visit and 
Week 12/EOT Visit. A negative urine pregnancy test must be documented at the 
Randomization Visit for women of childbearing potential 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. 
The investigator must review each laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. All laboratory tests with abnormal 
values considered clinically significant during participation in the study should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
investigator or Medical Monitor. If such values do not return to normal/baseline within a period 
of time judged reasonable by the investigator, the etiology should be identified and the Sponsor 
notified. If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in patient management or are considered 
clinically significant by the investigator (eg, SAE or AE or study drug discontinuation), the 
results must be recorded in the eCRF. 
5.6.3. 
Vital Signs 
Vital sign measurements will be performed as outlined in the Schedule of Evaluations. Oral 
temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure (BP) will be 
assessed with the patient in a seated position. BP and pulse measurements will be assessed with a 
completely automated device; manual techniques will be used only if an automated device is not 
available. 
BP and pulse measurements should be preceded by at least 5 minutes of rest for the patient in a 
quiet setting without distractions (eg, television, cell phones). 


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5.6.4. 
Physical Examination 
A complete physical examination will be performed as outlined in the Schedule of Evaluations, 
by the investigator or a licensed health professional listed on Form FDA 1572. Any physical 
examination abnormality that the investigator considers to be potentially clinically significant 
and changed from the baseline will be reported as an AE. A complete physical examination will 
include, at a minimum, assessment of the general appearance of the patient and the HEENT 
(head, eyes, ears, nose, and throat), cardiac, respiratory, gastrointestinal, musculoskeletal, 
neurological, and dermatological systems. Height (only at screening) and weight will also be 
measured and recorded. 
Rectal examinations should be performed at the discretion of the investigator; the purpose of the 
rectal examination is to rule out pathologies that might be caused by obstruction. For all physical 
examinations, the breast and genitourinary examinations are not required. 
5.6.5. 
Medical History 
A complete medical history, including disease-specific history, will be provided by the patient at 
the Screening Visit. As part of their disease-specific history, patients will be asked about any 
prior IBS diagnosis. Patients will be enrolled based on the Rome IV criteria for IBS-D, as 
detailed in protocol Section 6.1 and described below. 
Patient reports recurrent abdominal pain, on average at least 1 day/week during the 3 months 
before the diagnosis, with the onset at least 6 months before the diagnosis, associated with 2 or 
more of the following features: 
a. Related to defecation 
b. Associated with a change in frequency of stool 
c. Associated with a change in form (appearance) of stool 
According to the Rome IV criteria, patients are subtyped as IBS-D if they have >25% of BMs 
with BSFS score of 6 or 7 and <25% of BMs with BSFS score of 1 or 2, based on stool form on 
days with at least 1 abnormal BM. 


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6. 
DATA QUALITY ASSURANCE 
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 
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. 
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 (eg, 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 
, 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. 


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7. 
STATISTICAL METHODS 
7.1. 
General Methods 
In general, efficacy analyses will be performed for all efficacy outcomes reported during the 
Treatment Period based on the treatment group assigned at the randomization visit. Unless 
otherwise specified, all confidence intervals (CIs) will be 2-sided and with a confidence level of 
95%. No adjustments will be made for multiplicity in the conduct of comparisons among the 
MD-7246 doses relative to placebo for all efficacy endpoints, unless otherwise specified. Safety 
analyses will be performed using descriptive summaries based on the Safety Population and on 
actual treatment received. 
For analysis of continuous parameters (eg, change from baseline), descriptive statistics (n, mean, 
standard deviation [SD], median, and range) will be calculated and presented for each treatment 
group. For categorical parameters (eg, responder vs. non-responder), the number and percentage 
of each category will be calculated and presented for each treatment group. Percentages will be 
based on the total number of non-missing values; the number missing will be presented, but 
without a percentage. 
All statistical analyses will be performed using SAS Version 9.4 (or later) for Windows. 
7.2. 
Adjusting for Covariates 
As a general approach, the baseline value will be included in the mixed model for repeated 
measures (MMRM), Poisson regression model, and/or analysis of covariance (ANCOVA) as a 
covariate when the postbaseline or change from baseline are analyzed. 
7.3. 
Handling of Dropouts/Missing Data Imputation Method 
For weekly responder endpoints based on daily eDiary entries (eg, Weekly Abdominal Pain 30% 
Responder), a patient who reported daily assess for fewer than 4 days during a week within the 
Treatment Period will be considered a non-responder for that week. A patient will be deemed a 
weekly non-responder for all weeks following the patient’s discontinuation from the study 
treatment. 
Similarly, the weekly symptom score that is calculated using daily eDiary symptom assessments 
will be the average of available daily assessment records for at least 4/7 records during the 
relevant week. The weekly symptom score will be set to missing for weeks with fewer than 
4 days of daily assessments. For patients who prematurely discontinues the treatment prior to 
Week 12, the weekly symptom scores will be considered missing for all weeks after the 
treatment discontinuation. 
Unless stated otherwise, missing data will not be imputed. 
7.4. 
Interim Analysis and Data Monitoring 
No interim analysis of unblinded efficacy data will be performed. A DMC will be reviewing the 
safety data at defined time points (see DMC Charter). During the process, the data review will be 
handled by an independent clinical research organization (CRO). No sponsors’ team members 
will be exposed to any data in unblinded fashion. 


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7.5. 
Multicenter Studies 
This study is being conducted in approximately 80 centers in the US. Due to the potential of 
small numbers of patients per center, study centers may be pooled into the following 
geographical regions as necessary for the purposes of subgrouping: Northeast, Southeast, 
Midwest, Southwest, and West, for the relevant analyses such as the summary of disposition. 
7.6. 
Multiple Comparisons/Multiplicity 
No multiplicity adjustments will be used. 
7.7. 
Examination of Subgroups 
No subgroup analysis is planned; however, specific subgroup analyses may be performed for 
selected efficacy parameters if data warrants. 
7.8. 
Analysis Methods 
7.8.1. 
Patient Populations 
Screened Population 
The Screened Population consists of all patients who had a Screening Visit (Visit 1) and were 
assigned a patient identification (PID) number. 
Safety Population 
The Safety Population consists of all patients who received at least one dose of study drug. All 
safety analyses will be based on Safety Population, unless otherwise specified. Patients in Safety 
Population will be grouped based on the first treatment they receive. 
Modified Intent-to-treat Population 
The Intent-to-Treat (ITT) Population consists of all randomized patients. The modified ITT 
population (mITT) consists of all patients within ITT and have at least 1 dose of study drug. All 
efficacy analyses will be performed on the mITT Population for all outcomes reported during the 
Treatment Period using treatment group assigned at randomization, unless otherwise specified. 
7.8.1.1. 
Analysis Periods 
For the purpose of analyses, three analysis periods are defined and will be used for different 
analyses. 
The Pretreatment period is defined as the 14 days immediately prior to the date of the first dose 
of study drug. 
The Treatment Period is defined as the period from the date of the first dose of study drug to the 
date of the last dose of study drug. This will be used as the primary efficacy analysis period 
unless otherwise specified.  
The Treatment Emergent Period (TE Period) is defined as the period from the date of the first 
dose of study drug to 1 day after the date of the last dose. For analysis purposes, AEs and 
required medications will be considered treatment emergent if they occur within this period. TE 
period will be the primary analysis period for AEs and medications. 


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7.8.2. 
Patient Disposition 
The number and percentage of patients included in the Safety and mITT populations will be 
summarized overall and by treatment group for each trial center within each geographic region. 
The number of patients in the Screened Population will be summarized by geographic region 
(See Section 7.5 for definition of geographic region) and within each region by study center. 
The number and percentage of screen failure patients (ie, patients who entered the Screening 
Period but not the Pretreatment Period) and the number and percentage of pretreatment failures 
(i.e., patients who entered the Pretreatment Period but were not randomized), along with the 
associated reasons for failure, will be tabulated overall for the Screened Population. Patients who 
initially failed screening and were re-screened will only be counted once; that is, the PID number 
used for the rescreened subject will be summarized and listed for patient disposition. 
The number and percentage of mITT patients, the number and percentage of patients who 
completed the Treatment Period, as well as the number and percentage of patients who 
prematurely discontinued treatment will be presented for each treatment group and overall. The 
reason for premature discontinuation from treatment as recorded on the trial completion forms of 
the electronic case report forms (eCRFs) will also be presented. All patients who prematurely 
discontinue treatment will be listed by discontinuation reason for the ITT Population.  
Similarly, the numbers and percentages of patients who completed study (ie, completed the 
Treatment Period and 2-week Posttreatment Period), and who prematurely discontinue from the 
study will be summarized with reasons for discontinuation by treatment as recorded on the study 
completion form. 
7.8.3. 
Protocol Deviations 
Protocol deviations and Important Protocol Deviations (IPD) will be identified and documented 
by the study team for all mITT patients prior to unblinding. IPDs will be determined based on 
blinded review of all protocol deviations and protocol deviation categories. IPD categories 
include, but are not limited to: 
• 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. All protocol deviations regardless of significance will be listed. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion page of the 
eCRF. 
7.8.4. 
Demographics and Other Baselines Characteristics 
Demographic parameters (age, age group, race, ethnicity, sex), and baseline characteristics 
(weight; height; and body mass index, calculated as weight in kg/[height in m]2) will be 
summarized descriptively for the Safety and mITT Populations. Baseline efficacy and bowel 


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parameters (including abdominal pain, abdominal bloating, abdominal discomfort, abdominal 
cramping, BM frequency, urgent BM frequency, BSFS score, stool consistency) will be 
summarized descriptively for the mITT Population. 
7.8.5. 
Measurement of Treatment Compliance 
Dosing compliance for a specified period is defined as the total number of tablets taken by a 
patient during that period divided by the number of tablets that were expected to be taken during 
the same period, multiplied by 100. The total number of tablets taken will be calculated based on 
the following equation: total number of tablets dispensed – (number of tablets returned + number 
of tablets lost). The total number of tablets expected to be taken during a specified period equals 
the number of days in the period, multiplied by 4 (ie, the daily number of tablets to be taken).  
Descriptive statistics for study drug compliance for the Treatment Period overall, and for each of 
the 3 consecutive 4-week periods in the Treatment Period (consistent with study drug 
dispensing) will be presented for the Safety Population. 
7.8.6. 
Extent of Exposure 
Duration of 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, regardless of the detailed dosing information for 
individual days in between, will be summarized by treatment group for the Safety Population. 
Summary statistics including n, mean, standard deviation, median, minimum and maximum will 
be tabulated. The numbers and percentages of patients completing certain duration periods will 
also be included for the following: ≥1 week; ≥4 weeks; ≥8 weeks; 12 weeks (including more 
than 12 weeks). 
7.8.7. 
Prior and Concomitant Medication 
Prior and concomitant medicines will be classified using WHO Drug Dictionary version B3 
March 2019. Prior medicines are defined as any medicines with a start date prior to the date of 
first dose of study drug. Concomitant medicines are defined as any medicines with an end date 
on or after the date of first dose of study drug during the TE Period. Posttreatment medicines are 
defined as any medicines started after the TE Period (ie, >24h after the last dose of study drug). 
A medication started prior to the first dose of the study drug and ended on or after the date of the 
first dose of the study drug will be considered as both prior and concomitant medications. 
Both prior and concomitant medicine use, classified by therapeutic class, will be summarized by 
treatment group and by Anatomical-Therapeutic-Chemical (ATC) classification for the Safety 
Population. Multiple medicines used by a patient in the same ATC category will be counted only 
once. 
Posttreatment medicines will be presented in data listings only. 
7.8.8. 
eDiary Compliance 
eDiary compliance will be based on the percentage of complete daily eDiary entries made by a 
patient and analyzed base on mITT population. A complete daily eDiary entry is defined as one 
in which the patient responds to every eDiary question asked in the evening report on a day 
(namely, a complete eDiary entry day). The questions that are asked weekly will not be included 


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in the determination of a complete entry. The percentage of complete eDiary entries will be 
calculated as 100 times the number of completed evening reports divided by the total number of 
days in the study period (respectively for Pretreatment Period and Treatment Period). 
Descriptive statistics for eDiary compliance (%) will be summarized during Pretreatment and 
Treatment Period, at each week and overall. The patients with ≥80%/<80% complete eDiary 
entries during the Pretreatment and Treatment Periods will be tabulated by treatment. Numbers 
and percentages of patients completing at least 4 eDiary evening reports will be summarize at 
each week during Treatment Period and Pretreatment Period. 
7.8.9. 
Efficacy Endpoints and Analyses 
All efficacy analyses will be based on the mITT Population, unless otherwise specified. All 
hypothesis testing will be performed pairwise without adjustment for multiplicity, unless 
otherwise specified. 
Baseline values for efficacy and exploratory 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 Visit and up to the time of the first dose of study drug. 
• For patient symptom parameters (eg, abdominal symptoms [pain, bloating, 
discomfort, cramping]), the baseline value will be the average of the non-missing 
severity scores reported during the 14-day prior to the first dose during Pretreatment 
period and up to time of first dose of study drug.  
• The baseline BM and urgent BM weekly rates will be derived based on the number of 
BMs and urgent BMs a patient had during the 14-day prior to the first dose in 
Pretreatment Period and up to time of first dose of study drug.  
• Baseline BSFS score and stool consistency will be calculated as the average of the 
non-missing values reported by the patient during the 14-day prior to the first dose in 
Pretreatment Period and up to time of first dose of study drug. 
7.8.9.1. 
Key Efficacy Endpoints 
Change from Baseline in Abdominal Pain Through the Treatment Period 
The Change from Baseline in Abdominal Pain Through the Treatment Period is defined as the 
overall change from baseline in the Abdominal Pain through the Treatment Period, which is 
estimated based on each weekly change from baseline in the abdominal pain score (based on the 
daily abdominal pain at its worst score) minus the baseline abdominal pain score for patients in 
the mITT population. 
The postbaseline weekly abdominal pain score is the average of the non-missing daily abdominal 
pain at its worst scores during a week (Weeks 1-12) if there are at least 4 daily scores entered 
into the eDairy during the week, or will be considered as missing if there are less than 4 daily 
scores in the week. Weekly change from baseline will be calculated for each week as the weekly 
score minus the baseline score. 


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6/12 Week Abdominal Pain 30% Responder  
The 6/12 Week Abdominal Pain 30% Responder is defined for patients in the mITT population 
and is a patient who meets the Weekly Abdominal Pain 30% Responder criteria for at least 6 out 
of the 12 weeks of the Treatment Period. A Weekly Abdominal Pain 30% Responder is a patient 
who has a decrease from baseline of at least 30% in the weekly abdominal pain for that week. If 
a patient did not have an abdominal pain score for at least 4 days in a particular week during the 
Treatment Period, the patient will not be considered a Weekly Abdominal Pain 30% Responder 
for that week. For all weeks after the treatment discontinuation, the patient will be considered as 
non-responder. A patient in mITT population who did not have any post baseline assessment for 
abdominal pain at its worst will be considered a weekly non-responder for all post baseline 
weeks, subsequently, will not be a 6/12 week abdominal pain responder. 
7.8.9.2. 
Analyses of the Key Efficacy Endpoints 
Change from Baseline in Abdominal Pain Through the Treatment Period 
The overall treatment effect will be evaluated via the comparison between the MD-7246 dose 
groups and placebo with regard to the weekly change from baseline (CFB) in abdominal pain 
using a MMRM model, including the weekly CFB score in abdominal pain as dependent variable 
and treatment, visit week (categorical), and treatment-by-week as fixed effects, patient as a 
random effect, and the baseline value as a continuous covariate. An unstructured covariance 
matrix will be used for the MMRM analysis, unless the model does not converge, in which case 
the compound symmetry will be used. 
In this MMRM, a patient in mITT population without any postbaseline abdominal pain score at 
its worse will be considered missing. For patients with postbaseline abdominal pain scores, at 
any particular week, if there are fewer than 4 daily scores available, the weekly change from 
baseline will be considered as missing. Weeks after the treatment discontinuation will be 
considered as missing. 
Descriptive statistics for the overall treatment effect based on the MMRM model will include the 
least-squares (LS) mean difference between each MD-7246 dose and placebo, LS mean change 
from baseline for each treatment, their corresponding 95% CIs, and the p-values associated with 
the comparisons to placebo. In addition, LS Means for the weekly treatment differences between 
each MD-7246 group and placebo will also be provided with the same set of statistics derived 
from the same MMRM model defined above and will be plotted based on the MMRM estimates. 
Additionally, the non-model based descriptive statistics for the corresponding change from 
baseline (overall or weekly) will be provided by treatment group in the same tables for the 
MMRM estimates. Among them, the overall change from baseline is defined as the average of 
all non-missing post baseline daily scores during the Treatment Period minus the baseline 
abdominal pain score. The cumulative distribution for the overall change from baseline during 
the entire treatment period will be summarized and plotted by treatment group. 
6/12 Week Abdominal Pain 30% Responder 
For the 6/12 Week Abdominal Pain 30% Responder endpoint, the proportion of responders in 
each MD-7246 treatment group will be summarized and compared to the proportion of 
responders in the placebo group using a CMH test. The number and percentage of responders, 


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the differences in responder rates between each MD-7246 dose group and the placebo group, the 
odds ratio relative to placebo, the corresponding 95% CIs, and the associated p-values will be 
presented.  
A bar plot for the percentage of 6/12 week 30% responders will be provided by treatment group 
based on the summary statistics. A forest plot for the odds ratios between active treatment arms 
and placebo will be provided with corresponding 95% confidence intervals. 
Regarding the weekly 30% responders, the number and percentage of responders will be 
summarized for each week within Treatment Period, based on the mITT population. A bar plot 
by treatment group and by week (for Week 1 and Week 12 only) will be provided. 
For any week, a patient with fewer than 4 daily scores available will be considered non-
responder for that week. 
7.8.9.3. 
Sensitivity Analyses of the Key Efficacy Endpoints 
No sensitivity analysis analyses for the two key efficacy endpoints will be performed. 
7.8.9.4. 
Additional Efficacy Endpoints and Analyses 
The following endpoints are defined similarly to the Change from Baseline in Abdominal pain, 
for its overall and weekly. They will be analyzed using similar MMRM model and the non-
model based summary statistics for the Change from Baseline in Abdominal Pain (through the 
Treatment Period and at each week): 
• Change from Baseline in Abdominal Discomfort through the Treatment Period and at 
each week 
• Change from Baseline in Abdominal Bloating through the Treatment Period and at 
each week 
• Change from Baseline in Abdominal Cramping through the Treatment Period and at 
each week 
• Treatment Satisfaction through Treatment period and at each week will be 
summarized and analyzed using MMRM model (without baseline in the model). 
Treatment Satisfaction is scored weekly on a 5-point scale during the Treatment 
Period only and no change from baseline is defined for this assessment. 
The following 6/12 week responder endpoints are defined in the same manner as the 6/12 Week 
Abdominal Pain 30% Responder based on their relevant weekly responders. For each week in 
the Treatment Period, a weekly responder is a patient who satisfies the responder criteria in the 
change from baseline for that week. If a patient did not enter information into the eDiary on at 
least 4 days for a particular week during the Treatment Period, the patient will not be considered 
a weekly responder for that week. A patient who did not have any relevant post baseline 
assessment will be considered a weekly non-responder for all post baseline weeks, subsequently, 
will not be a 6/12 week responder. For all weeks after the treatment discontinuation, the patient 
will be considered as non-responder. 


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These responder endpoints will be summarized by treatment and the comparison between the 
active treatment group and placebo will be analyzed using a CMH test. The relevant number and 
percentage of weekly responders will be summarized by treatment at each week. 
• 6/12 Week Abdominal Pain 40% Responder 
A 6/12 Week Abdominal Pain 40% Responder is a patient who meets the Weekly 
Abdominal Pain 40% Responder criteria for at least 6 out of the 12 weeks of the 
Treatment Period. 
• 6/12 Week Abdominal Pain 50% Responder 
A 6/12 Week Abdominal Pain 50% Responder is a patient who meets the Weekly 
Abdominal Pain 50% Responder criteria for at least 6 out of the 12 weeks of the 
Treatment Period. 
• 9/12 Week Abdominal Pain 30% Sustained Responder 
A 9/12 Week Abdominal Pain Sustained Responder is a patient who meets the 
Weekly Abdominal Pain 30% Responder criteria for at least 9 out of the 12 weeks of 
the Treatment Period. 
• 9/12 Week Abdominal Pain 50% Sustained Responder 
A 9/12 Week Abdominal Pain Sustained Responder is a patient who meets the 
Weekly Abdominal Pain 50% Responder criteria for at least 9 out of the 12 weeks of 
the Treatment Period. 
• 6/12 Week Abdominal Discomfort 30% Responder 
A 6/12 Week Abdominal Discomfort 30% Responder is a patient who meets the 
Weekly Abdominal Discomfort 30% Responder criteria for at least 6 out of the 
12 weeks of the Treatment Period. 
• 6/12 Week Abdominal Bloating 30% Responder 
A 6/12 Week Abdominal Bloating 30% Responder is a patient who meets the Weekly 
Abdominal Bloating 30% Responder criteria for at least 6 out of the 12 weeks of the 
Treatment Period. 
• 6/12 Week Abdominal Cramping 30% Responder 
A 6/12 Week Abdominal Cramping 30% Responder is a patient who meets the 
Weekly Abdominal Cramping 30% Responder criteria for at least 6 out of the 
12 weeks of the Treatment Period. 
• 6/12 Week Degree of Relief Responder 
A 6/12 Week Degree of Relief Responder is a patient who scores ≤2 for at least 6 out 
of the 12 weeks of the Treatment Period. 
• 6/12 Week Adequate Relief of IBS Pain Responder 


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A 6/12 Week Adequate Relief of IBS Pain Responder is a patient who reports 
adequate relief of IBS pain (“yes”) for at least 6 out of the 12 weeks of the Treatment 
Period. 
The following responder endpoints are defined based on whether a patient satisfies certain 
criteria for the change from baseline in daily abdominal pain at its worst on at least 50% of 
protocol defined treatment days (84 days). If a patient did not enter information into the eDiary 
on at least 42 days during Treatment Period, the patient will not be considered a responder for 
any of the following responder endpoints. Numbers and percentages of patients satisfying these 
responder definitions will be summarized by treatment and the comparison between each active 
treatment group and placebo will be analyzed using a CMH test. 
• 50% of Days Daily Abdominal Pain 30% Responder 
A 50% of days Daily Abdominal Pain 30% Responder is defined as a patient who 
achieves at least 30% decrease from baseline in daily abdominal pain score at its 
worst for at least 50% of days in the 12-week Treatment Period, which is at least 
42 days. These 50% days with at least 30% decrease don’t have to be consecutive 
during treatment period. 
• 50% of Days Daily Abdominal Pain 40% Responder 
A 50% of days Daily Abdominal Pain 40% Responder is defined as a patient who 
achieves at least 40% decrease from baseline in daily abdominal pain score at its 
worst for at least 50% of days in the 12-week Treatment Period, which is at least 
42 days. These 50% days with at least 40% decrease don’t have to be consecutive 
during the Treatment Period. 
• 50% of Days Daily Abdominal Pain 50% Responder 
A 50% of days Daily Abdominal Pain 50% Responder is defined as a patient who 
achieves at least 50% decrease from baseline in daily abdominal pain score at its 
worst for at least 50% of days in the 12-week Treatment Period, which is at least 
42 days. These 50% days with at least 50% decrease don’t have to be consecutive 
during the Treatment Period. 
Additionally, the cumulative distribution of patients satisfying 50% of days daily abdominal pain 
response based on the percent change from baseline will be plotted and tabulated by treatment 
group and by percent change from baseline in the daily abdominal pain at its worst. 
Abdominal pain is measured daily using an 11-point NRS. Abdominal pain-free days will be 
those days where the patient reports a score of 0 for abdominal pain at its worst. The post 
baseline number of abdominal pain-free days per week will be calculated as the number of 
Abdominal Pain-free Days during the Treatment Period (from the first to the last dose), divided 
by the total number of days within Treatment Period times 7. The baseline percent number of 
abdominal pain-free days per week will be calculated as the number of Abdominal Pain-free 
Days during the Pretreatment Period (per defined Pretreatment Period), divided by the total 
number of days within the Pretreatment Period times 7. The descriptive statistics (n, mean, SD, 
median, minimum and maximum) for the baseline and post-baseline abdominal pain-free days 


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per week and the count of abdominal pain-free days during the Treatment Period will be 
tabulated by treatment group. 
Assuming the count for the abdominal pain free days follows a Poisson distribution, the post-
baseline abdominal pain-free days will be analyzed using a Poisson regression with treatment 
and baseline number of abdominal-pain free days as the covariates along with an offset variable 
of treatment duration (in weeks). In the case of overdispersion, the negative binomial model 
instead of Poisson regression will be implemented. Model estimates for weekly abdominal pain 
free days will be presented by treatment along with corresponding 95% confidence intervals. In 
the same table, the difference between the weekly rates for MD-7246 treatment arms and placebo 
will be represented with corresponding 95% confidence intervals and p-values associated with 
the comparisons to placebo.  
7.8.10. 
Exploratory Endpoints and Analyses 
The following endpoints will be summarized and analyzed via a similar MMRM for the Change 
from Baseline in Abdominal Pain through the Treatment Period and at each week: 
• Change from Baseline in BM Frequency Rate through the Treatment Period and at 
each week 
For each period of interest (Pretreatment Period, Treatment Period, or a particular 
week), the BM frequency rate is a weekly rate, which is calculated as the total 
number of BM within the period divided by the total number of days during the 
period multiplied by 7. The change from baseline in BM frequency rate is the 
postbaseline frequency rate minus the baseline frequency rate. For weeks after the 
treatment discontinuation, this rate will be missing. 
• Change from Baseline in BSFS (Stool Consistency) through the Treatment Period and 
at each week.  
For each period of interest (Pretreatment Period, Treatment Period, or a particular 
week), the BSFS is the average of all available BSFS scores the period. The change 
from baseline in BSFS is the postbaseline BSFS score minus the baseline score. For 
weeks after the treatment discontinuation, this score will be missing. 
• Change from Baseline in the Percent of Days Experiencing an Episode of Diarrhea 
through the Treatment Period and at each week 
An episode of diarrhea is defined as a sequence of 2 or more loose/watery BMs 
(BSFS 6 or 7) that are never separated by >1 non-loose/watery stool or by a day 
without a BM. For each period of interest (Treatment Period, or a particular week), 
the percent of days experiencing an episode of diarrhea will be calculated as 100 
times the number of days with a diarrhea episode divided by the total number of days 
with study treatment in the period. For baseline, the number of days with a diarrhea 
episode will be determined for the last 14 days of the Pretreatment Period. The 
baseline percent of days experiencing an episode of diarrhea will be calculated as 100 
times the number of days experiencing an episode during the baseline period divided 
by the length in days of the baseline period (typically 14 days). The change from 


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baseline will be calculated for each week as the weekly percent minus the baseline 
percent. For weeks after the treatment discontinuation, this percent will be missing. 
• Change from Baseline in the Percent of Days Experiencing No Episodes of Diarrhea 
through the Treatment Period and at each week  
For each period of interest, the Percent of Days experiencing no episode of diarrhea 
will be 100% minus the percent of days experiencing episode of diarrhea. 
• Change from Baseline in BM-related Symptom Severity through the Treatment 
Period  
Patient global impression of severity (PGI-S) of BM-related symptom severity on a 5-
point scale will be reported weekly by eDiary entry. Weekly PGI-S will be 
summarized weekly and analyzed via MMRM. 
• BM-related Symptom Change 
Patient global impression of change (PGI-C) of BM-related symptoms is measured 
weekly using a 7-point ordinal scale comparing the severity for the past 7 days to the 
severity before starting the study. The postbaseline weekly PGI-C score will be 
analyzed via MMRM (without baseline). 
Urgent BM Frequency Rate and Number of Days with Use of Loperamide for Diarrhea per week 
will be defined similarly as Number of Abdominal Pain-free days per week and will be 
calculated as the total number of events within the entire Treatment Period (or Pretreatment 
Period for baseline) divided by the total number of days within the Treatment Period, then 
multiplied by 7. Similar to Number of Abdominal Pain-free Days per week, these endpoints will 
be summarized by treatment group and the relevant count data during the entire treatment period 
will be analyzed by Poisson regression for the comparison between any active treatment group 
and placebo. If the data is skewed to 0 (overdispersed), the Negative binomial model will be 
used. 
7.8.11. 
Safety Analysis 
All safety analyses will be performed using the Safety Population. 
7.8.11.1. Adverse Events 
Adverse event verbatim terms will be coded in the EDC system against Medical Dictionary for 
Regulatory Activities (MedDRA) version 22.0. 
During the TE Period, an AE that has a start date during the TE Period (from the date of the first 
dose to 1 day after the last dose of double-blind study drug) will be considered a TEAE. For the 
TE Period, the number and percentage of patients reporting TEAEs in each treatment group will 
be tabulated: 
• By system organ class (SOC) and preferred term (PT) 
• By SOC, PT, and severity 
• By SOC, PT, and relationship to study drug 


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If a patient has more than one TEAE coded to the same PT or SOC, the patient will be counted 
only once for that PT or SOC by identifying those TEAEs with the highest severity and the 
closest relationship to study drug. 
The incidence of the following TEAEs will be summarized by PT: 
• Common (≥2% of patients in any treatment group) TEAEs 
• Treatment-emergent SAEs 
• TEAEs leading to premature discontinuation of study drug 
In addition, the incidence of SAEs, fatal SAEs (ie, events with an outcome of death), if any, will 
be summarized separately by treatment group and PT within the period from the first dose to 
30 days after the last dose of study drug.  
AE Listings will be presented for all patients with AEs, screened patients with SAEs, patients 
with AEs leading to discontinuation, and patients who died (if any), respectively. 
7.8.11.2. 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 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 TE period. The criteria for 
PCS laboratory values are described in Table 2. 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 TE 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, study center, and baseline and post-baseline values. A listing of all AEs for 
patients with PCS laboratory values will also be provided. 
Table 2: 
Criteria for Potentially Clinically Significant Laboratory Results 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Albumin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Alanine aminotransferase 
U/L 
— 
≥ 3 × ULN 
Alkaline phosphatase 
U/L 
— 
≥ 3 × ULN 
Aspartate aminotransferase 
U/L 
— 
≥ 3 × ULN 
Bicarbonate 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Bilirubin, total 
μmol/L 
— 
> 1.5 × ULN 
Calcium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Chloride 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Cholesterol, total 
mmol/L 
— 
> 1.6 × ULN 


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Parameter 
SI Unit 
Lower Limit 
Higher Limit 
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 
count 
109/L 
— 
> 3 × ULN 
Neutrophils, absolute cell 
count 
109/L 
< 0.8 × LLN 
> 1.5 × ULN 
Platelet count 
109/L 
< 0.5 × LLN 
> 1.5 × ULN 
Red blood cell count 
1012/L 
< 0.9 × LLN 
> 1.1 × ULN 
White blood cell count 
109/L 
< 0.7 × LLN 
> 1.5 × ULN 
LLN=lower limit of normal value provided by the laboratory; SI=Le Système International d’Unités (International System of 
Units); ULN=upper limit of normal value provided by the laboratory. 
7.8.11.3. Vital Signs 
Descriptive statistics for vital signs (ie, pulse rate, systolic and diastolic BP, respiratory rate, 
temperature, and body weight) and changes from baseline at each visit and at the end of the 
period/study will be presented by treatment group. 


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The number and percentage of patients with PCS post-baseline vital signs will be tabulated by 
treatment group for the Treatment Emergent Period. A vital sign value will be considered PCS if 
it meets both the observed value criterion and the change from baseline value criterion. The 
criteria for PCS vital sign values is detailed in Table 3. 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 postbaseline period. The numerator will be the total number of 
patients with available 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, study center, and baseline and post-baseline values. A listing of all 
AEs for patients with PCS vital sign values will also be provided. 
Table 3: 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteriaa 
Observed Value 
Change from Baseline 
Sitting systolic blood 
pressure, mmHg 
High 
≥ 180 
Increase of ≥ 20 
Low 
≤ 90 
Decrease of ≥ 20 
Sitting diastolic blood 
pressure, mmHg 
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. 
 
7.8.11.4. 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. 
7.8.12. 
Health Outcomes Analysis 
Pain Catastrophizing Scale 
The Pain Catastrophizing Scale is a 13-item instrument that asks patients to reflect on their 
thoughts and feelings of past painful experiences. The patient responds to each statement using a 
5-point scale (0=None at all to 4=All the time). The total Pain Catastrophizing Scale score plus 
the 3 subscale scores (Rumination, Magnification, and Helplessness) will be derived and 
summarized by treatment for the Pretreatment Visit based on mITT population. 


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IBS-SSS 
The IBS-SSS parameters consist of 5 individual items and the IBS-SSS total score. The 
5 individual items (severity of abdominal pain, frequency of abdominal pain, severity of 
abdominal distension, dissatisfaction with bowel habits, and interference of IBS with life in 
general) are based on a 0-100 scale (10 times the original scale) and the IBS-SSS total score 
parameter is the sum of the 5 IBS-SSS individual item scores (0-500 scale). 
For each post-baseline visit, change from baseline in the IBS-SSS total score and individual 
items will be summarized analyzed using an MMRM model similar to that for the change from 
baseline in abdominal pain.  
SF-12v2 and EQ-5D-3L 
SF-12v2 and EQ-5D-3L analyses will not be included in this statistical analysis plan, but will be 
discussed in a separate analysis plan. 


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8. 
REFERENCES 
1. Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons 
with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 
1998;43(2):400-11. 
2. Prevention CfDCa. Measuring Healthy Days: Population Assessment of Health-Related 
Quality of Life. Centers for Disease Control and Prevention [Internet]. 2000. Available from: 
https://www.cdc.gov/hrqol/pdfs/mhd.pdf. 
3. Ratitch, B., O'Kelly, M. and Tosiello, R. (2013), Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharmaceut. Statist., 
12: 337–347. doi: 10.1002/pst.1549  
 


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APPENDIX 1. 
CHANGES FROM ANALYSES PLANNED IN THE PROTOCOL 
Type 
Protocol 
SAP 
Justifications 
Language 
Clarification 
Change from baseline at Each Week in various 
efficacy assessments 
Change from baseline through the 
Treatment Period and at Each Week 
To differentiate 
• 
Change through the entire 
Treatment Period.  
• 
Individual weekly changes 
 
Treatment Period was used for 2 periods: 
• 
From the day of the first dose to 1 day after 
the last dose 
• 
From the day of the first dose to the day of 
the last dose 
Clearly distinguish different periods: 
• 
From the day of the first dose to 1 day 
after the last dose is defined as 
Treatment Emergent Period. 
• 
From the day of the first dose to the day 
of the last dose is defined as Treatment 
Period. 
Clarification  
Operational 
Adjustment 
• 
An optional interim analysis of unblinded 
safety and efficacy data may be performed 
to assess futility.  
• 
Sensitivity analyses planned for the change 
from baseline in abdominal pain score 
• 
Analyses for Health outcome parameters 
SF-12v2 and EQ-5D-3L were included. 
• 
No interim analysis performed 
• 
No sensitivity analysis performed 
• 
Analyses for Health outcome 
parameters SF-12v2 and EQ-5D-3L will 
be in a separate analysis plan. 
• 
Faster enrollment won’t leave 
time for an interim analysis. 
• 
In a hypothesis generating 
phase 2 study, the sensitivity 
analysis is unnecessary. 
• 
HEOR parameters will be 
detailed out in relevant 
analysis plan 


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Type 
Protocol 
SAP 
Justifications 
Methodologic 
Changes 
• 
MMRM analysis for the abdominal pain 
change from baseline included geographic 
region. 
• 
Estimation, terminology and analysis for  
o Percent of Abdominal Pain Free 
Days 
o Urgent BM Frequency Rate  
o Percent of Days with Use of 
Loperamide for Diarrhea 
• 
The quantities were estimated for each 
week, and analyzed by MMRM 
• 
Analysis for IBS-SSS total score and sub-
scores was based on ANCOVA model. 
• 
MMRMs did not adjust for geographic 
region. 
• 
New Terms 
o Abdominal Pain Free Days per 
week 
o Urgent BM Frequency Rate  
o Number of Days with Use of 
Loperamide for Diarrhea 
• 
Quantities are estimated for the 
Treatment period and from Poisson 
regression model using the relevant 
count data 
• 
IBS-SSS total score and sub-scores was 
based on MMRM model 
• 
Sample size limited number of 
covariates in the MMRM 
model. 
• 
Relatively rare events for 
patients in IBS-D lead to 
different statistical distribution 
for the count data 
• 
Multiple visits in IBS-SSS 
support repeated measure 
analysis 
Addition 
The following endpoints and relevant analyses 
were not included: 
• 
6/12 week abdominal pain at its worst 40% 
responder  
• 
9/12 week abdominal pain at its worst 30, 
50% sustained responders 
• 
50% days 30%, 40%, 50% responders  
The following endpoints and relevant 
analyses are included: 
• 
6/12 week abdominal pain at its worst 
40% responder  
• 
9/12 week abdominal pain at its worst 
30, 50% sustained responders 
• 
50% days 30%, 40%, 50% responders 
Added for exploratory purposes. 


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APPENDIX 2. 
VISIT TIME WINDOWS FOR SAFETY ANALYSIS 
Appendix Table 2-1 below presents the visits assigned for the safety analysis corresponding to 
the range of trial days (window) during which an actual visit may have occurred. 
Appendix Table 2-1: Visit Time Windows for Safety Analysis 
Derived Visit 
Scheduled Test / Visit Daya 
Window 
Baseline 
Day 1 
Days ≤ 1 
Week 4 (Day 29) Visit 
Day 29 (+/- 3 days) 
Days [2, 43] 
Week 8 (Day 57) Visit 
Day 57 (+/- 3 days) 
Days [44, 71] 
Week 12 (Day 85) Visit 
Day 85 (+ 3 days) 
Days > 72 
End of Treatment 
Day of Last Study Treatment based on End of Treatment CRF form 
End of Study 
Study Day for the End of Study Follow-Up Phone Call 
a 
Relative to the date of first dose (Day 1). 
b 
“End of Treatment/End of Study” will be presented in analysis tables for safety parameters, including ECG, 
clinical laboratory, and vital signs. 
 
Test/Visit Day will be calculated as follows: test/visit date – date of first dose + 1. 
If there are multiple values available for the same Visit, the data with the latest date for that visit 
will be utilized for summary. 


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APPENDIX 3. 
VISIT TIME WINDOWS FOR EFFICACY ANALYSIS 
Appendix Table 3-1 presents the analysis weeks assigned for the efficacy analysis of the patient 
diary data related to BM characteristics. These analysis weeks will be used in the calculations for 
all week-based parameters (eg, abdominal pain, BSFS weekly scores). 
Appendix Table 3-1: Analysis Time Windows for Efficacy Analysis 
Period 
Analysis Week 
Beginsa 
Endsa 
Pretreatment 
(Baselineb) 
Week –2  
Day –14  
Day –8 
Week –1  
Day –7 
Day 1 (time of first dose) 
Treatment 
Week 1  
Day 1 (time of first dose) 
Day 7 
Week 2  
Day 8 
Day 14 
Week 3  
Day 15  
Day 21 
Week 4  
Day 22 
Day 28  
Week 5  
Day 29 
Day 35 
Week 6  
Day 36  
Day 42 
Week 7  
Day 43 
Day 49  
Week 8  
Day 50 
Day 56 
Week 9  
Day 57  
Day 63 
Week 10 
Day 64 
Day 70  
Week 11  
Day 71 
Day 77  
Week 12 
Day 78 
Day of last study treatment 
dosec (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), 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) would be included in Analysis Week 11, 
not Analysis Week 12.  
a 
Relative to the date of first dose; Day 1 = the day of first dose. For the calculation of 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 Visit up to the time of first 
dose. 
c 
For patients who fail to provide the date of last dose n the End of Treatment CRF form, the later date of the 
last known dose (drug dispense eCRF) or the last eDiary date will be used to impute the last dose date. 
For the Treatment Period, diary day is calculated as diary date – date of first dose + 1. For the 
Pretreatment Period, diary day is calculated as diary date - date of first dose. However, the day of 
first dose is always trial Day 1. 
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 shall be shortened to the end of the 
withdrawn patient’s Treatment Period, and all subsequent weeks will be missing for that patient. 


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Appendix Table 3-2 presents the analysis weeks assigned for the efficacy analysis of the patient 
diary data related to Weekly Questions (eg, Weekly Patient Assessment of Degree of Relief of 
IBS Symptoms, Weekly Patient Assessment of Adequate Relief of IBS Pain, and Weekly Patient 
Assessment of Treatment Satisfaction). 
Appendix Table 3-2: Analysis Time Windows for Efficacy Analysis – Weekly Assessments 
Period 
Analysis Week 
Beginsa 
Endsa 
Pretreatment 
(Baselineb) 
Week –2  
Day –11  
Day –5 
Week –1  
Day –4 
Day 1 (time of first dose) 
Treatment 
Week 1  
Day 7 
Day 10 
Week 2  
Day 11 
Day 17 
Week 3  
Day 18 
Day 24 
Week 4  
Day 25 
Day 31 
Week 5  
Day 32 
Day 38 
Week 6  
Day 39 
Day 45 
Week 7  
Day 46 
Day 52 
Week 8  
Day 53 
Day 59 
Week 9  
Day 60 
Day 65 
Week 10 
Day 66 
Day 72 
Week 11  
Day 73 
Day 79 
Week 12 
Day 80 
3 Days after last study treatment 
dose (usually Day 84)* 
a 
Relative to the date of first dose; Day 1 = the day of first dose. For the calculation of 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 weekly eDiary and eCRF data collected in the 
Pretreatment Period. 
In general, weekly questions will be assigned only to the analysis week for which the question 
covers at least 4 days of that week. 
If a weekly question covers days from different study phases, the answers will be discarded. For 
example, a weekly question answered on study day 2 would cover part of 1 day from the 
Treatment Period and 6 days from the Pretreatment Period, so these data would be discarded. 
If patients answer the weekly questions multiple times for a week, for each question, the average 
of the respective answers will be assigned as the weekly value. 
For time periods covering more than a week, the value will be calculated as the average of the 
weekly values. Thus, for Pretreatment, the value will be calculated as the average of week -2 and 
week -1. 


Ironwood Pharmaceuticals, Inc. 
 
MD-7246 
Statistical Analysis Plan: MCP-103-205 
 
14 April 2020 
 
Confidential 
Page 52 of 52 
 
APPENDIX 4. 
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)