Clinical trial NCT02637557
Conditions: Gastroesophageal Reflux Disease
Sponsor: Ironwood Pharmaceuticals, Inc.
Start date: 2016-03-01; Completion date: 2017-04-26
Enrollment: 282 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are to evaluate the safety, efficacy, and dose-response relationship of IW-3718 administered orally to participants who have GERD and continue to experience GERD symptoms while receiving once-daily (QD), standard-dose proton pump inhibitors (PPIs).

Detailed description:

Arms: arm 1: Matching placebo twice daily arm 2: 500 mg IW-3718 twice daily arm 3: 1000 mg IW-3718 twice daily arm 4: 1500 mg IW-3718 twice daily
Interventions: intervention 1: IW-3718 intervention 2: Matching Placebo intervention 3: PPI
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: All participants were taking a standard dose QD PPI (dexlansoprazole, esomeprazole, esomeprazole magnesium, lansoprazole, omeprazole, pantoprazole, pantoprazole sodium sesquihydrate, rabeprazole or rabeprazole sodium) during the study.

Protocol documents:
Prot_001.pdf: 
 
 
 
Clinical Study Protocol: ICP-3718-202-P-03 
Final Version, 27 July 2016 
__________________________________________________________________ 
Study Title: 
A Phase 2b, Randomized, Double-blind, Placebo-controlled, 
Parallel-group, Dose-range-finding Trial of IW-3718 
Administered Orally for 8 Weeks to Patients with Symptomatic 
Gastroesophageal Reflux Disease Not Completely Responsive to 
Proton Pump Inhibitors 
Study Number: 
ICP-3718-202 
Study Phase: 
2b 
Product Name: 
IW-3718 
Indication: 
Gastroesophageal reflux disease (GERD) not completely 
responsive to proton pump inhibitor (PPI) therapy 
Sponsor: 
Ironwood Pharmaceuticals, Inc. 
301 Binney Street 
Cambridge, MA 02142, USA 
Sponsor Contact: 
Lara Lane, Clinical Study Manager  
Medical Monitor: 
Robert Mittleman, MD, MS, FACC 
 
 
Date 
Original Protocol: 
09 November 2015 (v1.0) 
Amendment 1 
05 April 2016 (v2.0) 
Amendment 2 
27 July 2016 (v3.0) 
 
Confidentiality Statement 
The contents of this document are confidential and belong to Ironwood Pharmaceuticals, Inc. 
Except as may be otherwise agreed to in writing, by accepting or reviewing these materials, 
you (including any colleagues or subordinates) agree to hold such information in confidence 
and not to disclose it to others (except where required by applicable law), nor to use it for 
unauthorized purposes. In the event of actual or suspected breach of this obligation, 
Ironwood should be promptly notified. 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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SYNOPSIS 
Study Number: ICP-3718-202 
Study Title: A Phase 2b, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Dose-range-finding Trial of IW-3718 Administered Orally for 8 Weeks to Patients with 
Symptomatic Gastroesophageal Reflux Disease Not Completely Responsive to Proton Pump 
Inhibitors 
Study Centers: Approximately 60-80 centers in the United States 
Development Phase: 2b 
Objectives: The objectives of this study are to evaluate the safety, efficacy, and dose-response 
relationship of IW-3718 administered orally to patients who have GERD and continue to 
experience GERD symptoms while receiving once-daily (QD), optimized, standard-dose PPIs. 
Methodology: This is a multicenter, randomized, double-blind, placebo-controlled, parallel-
group, 8-week study, consisting of 3 distinct periods as illustrated in the figure below. The 
study will enroll patients who have GERD and continue to experience GERD symptoms while 
receiving QD, standard-dose PPI therapy that in the investigator’s opinion has been optimized. 
Eligible patients will continue to take their PPI and will be randomized to placebo or to 
500 mg IW-3718 twice daily (BID), 1000 mg IW-3718 BID, or 1500 mg IW-3718 BID. 
 
Overview of Study Design 
 
Screening Period: The Screening Period starts with the signature of the informed consent form 
(ICF) and may last for up to 28 days. During this period, patient eligibility for entry into the 
Pretreatment Period will be determined. Two procedures will be required during the Screening 
* This visit represents the end of the study
Screening
Period
Pretreatment
Period
Treatment Period
Day 1 to Day 57
14 to 21 days
Up to 28 days
Screening
Visit
(Day -49 to
Day -15)
Pretreatment
Visit
(Day -21 to
Day -14)
Randomization
Visit
(Day 1)
Week 2 Visit
(Day 15 ± 3)
Week 4 Visit
(Day 29 ± 3)
Week 8 / 
End of Trial
Visit*
(Day 57 + 3)
No Treatment
500 mg IW-3718 twice daily
1000 mg IW-3718 twice daily
1500 mg IW-3718 twice daily
Placebo twice daily
Note:  There is no Day 0
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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Period in all patients; a third procedure (Bilitec® testing) will be optional for all patients at 
selected sites (all will be done while patients continue to take their PPI):  
• An esophagogastroduodenoscopy (EGD)  
• Approximately 48 to 96 hours of pH testing with the Bravo® device. If for some reason 96 
hours of testing is not possible, then approximately 48 hours of testing is acceptable 
(Please refer to section 3.5.1.10 for further instruction) 
• Approximately 24 hours of bilirubin detection using the Bilitec® monitoring system 
(optional at selected sites) 
Histamine-2 receptor antagonists (H2RAs) should be stopped at least 5 calendar days prior to 
the EGD and Bravo pH monitoring; antacids should be stopped at least 1 calendar day prior to 
the EGD and Bravo pH monitoring. The EGD must be performed during the Screening Period 
and at least 7 days before the start of the Pretreatment Period to allow time for pH collection 
and allow the patient to stabilize following these procedures. Upon completion of the Bravo 
testing, patients will continue to refrain from using H2RAs, but may continue to use antacids if 
needed until 1 day prior to entering the Pretreatment Period. During the Pretreatment Period, 
patients may use protocol-defined rescue medication per protocol requirements.  Patients will 
continue to use their current PPI throughout the entire Screening Period. The end of the 
Screening Period coincides with the start of the Pretreatment Period. 
At selected sites, patients who are screened for the study with EGD and Bravo testing will also 
be given the option of having a Bilitec monitor inserted at that time. The Bilitec procedure is 
being completed in a subset of patients to collect information about whether bilirubin is 
present in the duodenogastric refluxate. Previous Bilitec 2000 studies have shown associations 
between total bile acid concentrations and Bilitec 2000 absorbance.  Patients participating in 
the Bilitec procedure will agree to comply with a “white diet” (see Appendix 8 for example 
“white diet”) and return approximately 24 hours later for removal of the probe. The results of 
the Bilitec monitoring will not affect qualification for enrollment and during participation in 
the study, patients will be blinded of their Bilitec testing results. 
Pretreatment Period: The Pretreatment Period is defined as the 14 to 21 calendar days 
immediately before the Randomization Visit. During this period, patients will continue to use 
their PPI and will refrain from using other anti-reflux medications, including antacids and 
H2RAs, except for the antacid that is dispensed as rescue medicine. They will also provide the 
following information in a handheld electronic diary (eDiary); they will perform at least 2 
weeks of symptom assessments during which they will be required to complete daily 
assessments for at least 5 days each week during the last 14 calendar days before the 
Randomization Visit and weekly assessments at least once during the last 7 calendar days 
before the Randomization Visit in order to be eligible for randomization: 
• GERD symptoms assessed once daily in the evening in the modified Reflux Symptom 
Questionnaire Electronic Diary (mRESQ-eD; Appendix 1) (Note: any patient who 
completed the Pretreatment Visit under the original RESQ-eD, protocol version ICP-3718-
202-P-01 dated November 9, 2015 will continue completing daily e-diary assessments for 
the remainder of the study under the original RESQ-eD; patients completing the 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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Pretreatment Visit under subsequent versions of the protocol will complete the mRESQ-eD 
for the duration of the study.) 
• Dyspepsia symptoms assessed once daily in the evening using Daily Dyspepsia Symptoms 
(Appendix 2) 
• Assessment of sleep assessed once daily in the morning using Daily Assessment of Sleep 
(Appendix 3) 
• Use of per-protocol rescue medicine assessed twice daily. 
• Symptom relief and bothersomeness assessed once a week in the evening 
Patients will be instructed to take their PPI approximately 30-60 minutes before breakfast each 
day, even on study visit days. Patients who satisfy all of the entry criteria will enter the 
Treatment Period. 
Treatment Period: The Treatment Period begins with treatment assignment and lasts for 8 
weeks. Patients will be stratified by whether they have, or do not have, erosive esophagitis on 
the screening EGD and randomly assigned to 1 of 4 treatments (1:1:1:1) within each stratum: 
placebo or 500 mg IW-3718 BID, 1000 mg IW-3718 BID, or 1500 mg IW-3718 BID. The 
treatment schedule will be managed by a central vendor. Enrollment will be monitored to 
ensure that no single center contributes > 15% of the targeted study enrollment, unless 
otherwise approved by the Medical Monitor. Study drug will be taken immediately after the 
morning and evening meals. Patients will continue to take their PPI approximately 30-60 
minutes before breakfast each day and to use the eDiary to provide their daily assessments 
(GERD symptoms, dyspepsia symptoms, assessment of sleep), weekly assessments (weekly 
symptom bothersomeness and degree of relief questions; Appendix 6), and use of per-protocol 
rescue medicine. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria  
To be eligible to participate in the study, patients must meet the following criteria: 
1. Patient has signed an ICF before any study-specific procedures are performed. 
2. Patient is an ambulatory, community-dwelling male or nonpregnant female and is at least 
18 years old at the Screening Visit. Lactating females must agree not to breastfeed.  
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Study Population:  The study population will consist of adult patients with GERD who are 
not completely responsive to QD PPI therapy.  Patients must be receiving optimized PPI 
therapy for 8 weeks or longer, for which no further adjustments to the patient’s PPI therapy 
would be beneficial to the patient, per the investigator’s opinion. PPI dosing must be 
consistent with current labeling (Appendix 11).  Approximately 260 patients (65 patients per 
treatment arm) will be randomized into the Treatment Period. Patients will be randomized 
through central randomization in a 1:1:1:1 ratio to receive either 500 mg IW-3718 BID, 1000 
mg IW-3718 BID, 1500 mg IW-3718 BID, or placebo BID. Patients will be stratified by 
whether they have or do not have erosive esophagitis on the screening EGD. 


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3. Patient has a diagnosis of GERD and reports experiencing GERD symptoms (heartburn or 
regurgitation) on ≥ 4 days per week during the 8 weeks before the Screening Visit while 
taking standard QD PPI therapy. 
4. Patient has been receiving individually optimized, standard-labeled dose, QD, PPI therapy 
(treatment that, according to the Investigator’s judgment, could not be further improved by 
changing the brand or timing of PPI administration) for a minimum of 8 weeks before the 
Screening Visit. Patients should be on a PPI dose and schedule that is consistent with the 
approved labeling (Appendix 11). Patients who have their PPI modified during the 
Screening Period may be re-screened after 8 weeks of optimized, standard-labeled dose, 
QD, PPI therapy provided they have not previously entered the Pretreatment Period. 
5. An EGD with approximately 48 to 96 hours of pH monitoring (with a Bravo® device) 
during the Screening Period (while the patient continues taking their PPI) demonstrates 1 
or more of the following: 
a. Erosive esophagitis (Grade A or greater based on the Los Angeles classification of 
esophagitis; Appendix 5) on EGD  
b. Evidence of pathological acid reflux (pH is < 4 for ≥ 4.2% of the recording time) 
during at least 1 of the 24-hour time intervals of pH testing with the Bravo device 
6. Patient reports heartburn severity (HS, Item #1 on mRESQ-eD) ≥ 3 (moderate) on at least 
2 days and has an average HS of ≥ 2 (mild) during the last 7 days before randomization. 
7. Sexually active female patients of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a bilateral oophorectomy, hysterectomy, or tubal 
ligation) must agree to use 1 of the following methods of birth control from the date they 
sign the ICF until 24 hours after their final dose of study drug: 
a. Hormonal contraception (i.e., contraceptive implant or injectable hormonal 
contraceptive) 
b. Double-barrier birth control (e.g., condom plus intrauterine device, diaphragm plus 
spermicide, etc.); Patients may continue taking oral contraceptives while using one or 
more barrier methods. 
c. Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy 
8. 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.  
9. Patient agrees not to make any changes to their usual diet during the study, except those 
patients participating in Bilitec testing, who must agree to a “white diet” during Bilitec 
testing only. 
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10. Patient is compliant with eDiary completion; that is, they have adequately completed the 
eDiary questions on at least 5 days each week during the 14 calendar days before the start 
of the Treatment Period. 
11. Patient is compliant with QD PPI dosing during the 14 calendar days before the start of the 
Treatment Period. Patients are considered compliant if, as reported in the eDiary, they take 
their PPI on at least 5 days each week. 
12. Patient is fluent and literate in English or Spanish. 
13. Patient is able to operate the eDiary adequately and agrees to adhere to the study 
requirements. 
14. For patients who are receiving supplementation of a fat-soluble vitamin in order to correct 
or avoid a fat-soluble vitamin deficiency, the patient is willing to take the vitamin 
supplement at least 4 hours before taking study medication. 
Exclusion Criteria  
Patients who meet any of the following criteria will not be eligible to participate in the study: 
1. Patient has a history of complete lack of GERD symptom response to PPIs in the past. 
2. Patient reports epigastric pain or burning as his or her predominant symptom at the 
Screening Visit. 
3. Patient has a history of gastroparesis, bowel obstruction, or is at risk for a bowel 
obstruction (e.g., patient has an organic gastrointestinal [GI] motility disorders or a history 
of major GI surgery).  
4. Patient has a history of serum triglycerides concentrations > 500 mg/dL on a fasting 
specimen, or has serum triglycerides concentrations > 500 mg/dL on a fasting specimen at 
Screening or any time during the Pretreatment Period.  
5. Patient has a history of hypertriglyceridemia-induced pancreatitis.  
6. In the Investigator's opinion, patient is susceptible to a deficiency of fat-soluble vitamins 
(especially vitamin D deficiency; e.g., the patient is African American or Hispanic or has 
osteoporosis, osteomalacia, etc.) and will be put at risk by receiving colesevelam for 8 
weeks. 
7. Patient has an active swallowing disorder that would prevent them from being able to 
swallow the study medication.  
8. Patient has any alarm symptoms including but not limited to GI bleeding, anemia, 
vomiting, or unexpected weight loss any time during the Screening or Pretreatment Periods
9. Patient has undergone surgery that meets any of the following criteria:  
a. Surgery of the GI tract (including gastric banding) other than an appendectomy, 
cholecystectomy, minor oral or rectal surgery (e.g., tonsillectomy, hemorrhoidectomy, 
rectocele repair) at any time before the Screening Visit 
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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
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b. An appendectomy during the 3 months before the Screening Visit or a 
cholecystectomy during the 6 months before the Screening Visit or minor oral or rectal 
surgery during the 30 days before the Screening Visit 
c. Non-GI surgery of the abdomen, pelvis, or retroperitoneal structures during the 
6 months before the Screening Visit 
d. Thoracic surgery during the 6 months before the Screening Visit 
e. Other major non-GI surgery during the 30 days before the Screening Visit 
10. Patient has previously undergone thoracic or abdominal radiotherapy 
11. EGD, conducted during the Screening Period, reveals that the patient has long-segment 
Barrett’s esophagus (greater than 3 centimeters) or definite dysplastic changes in the 
esophagus, peptic ulcer disease, active GI bleeding, presence of symptomatic esophageal 
strictures, presence of esophageal or fundic varices, erosive gastritis, or eosinophilic, 
herpetic or Candida esophagitis.  
12. Patient has Gilbert’s disease, Crohn’s disease, diabetes mellitus, Zollinger-Ellison 
syndrome, pancreatitis, cholecystitis, or systemic sclerosis. 
13. Patient has elevated (defined as > 1.5 times the upper limit of normal by the laboratory) 
levels of serum bilirubin at Screening or any time during the Pretreatment Period. 
14. Patient has a history of clinically significant hypersensitivity or allergies to any of the 
excipients contained in the study medication (active or placebo).  
15. Patient has a history of cancer (resected basal cell or squamous cell carcinoma is 
acceptable). Note: patients with a history of cancer are allowed provided that the 
malignancy has been in complete remission for at least 5 years before the Screening Visit. 
A complete remission is defined as the disappearance of all signs of cancer in response to 
treatment. 
16. Patient has history of active alcoholism, drug addiction, or illicit drug use (including 
marijuana) during the 12 months before the Screening Visit. 
17. Patient has any clinically significant finding on a physical exam, 12-lead 
electrocardiogram (ECG), or clinical laboratory test after signing the ICF but before 
receiving the first dose of study medication. (Note: The Investigator will determine if a 
particular finding is clinically significant. In making this determination, the Investigator 
will consider whether the particular finding could prevent the patient from performing any 
of the protocol-specified assessments, could represent a condition that would exclude the 
patient from the study, could represent a safety concern if the patient participates in the 
study, or could confound the study-specified assessments of safety or efficacy.)  
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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18. Patient reports using a prohibited medication during the Screening or Pretreatment Periods, 
or is not willing or able to abide by the restrictions regarding use of prohibited medications 
as defined in Appendix 4. 
19. Patient has received an investigational drug during the 30 days before the Screening Visit, 
or is planning to receive another investigational drug or use an investigational device at 
any time during the study.  
20. 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. 
21. Patient has previously entered the Treatment Period of a study in which IW-3718 is a 
treatment. 
22. Patient has previously entered the Pretreatment Period of this study. 
23. Patient is enrolled in this study at another clinical study site; is an employee of the 
Institution or Ironwood Pharmaceuticals; or is a first-degree family member, significant 
other, or relative residing with an employee of the Institution or Ironwood 
Pharmaceuticals. 
Test Product, Dose and Mode of Administration:   
Test product will be administered as follows: 
• 500 mg IW-3718 BID: One 500 mg IW-3718 oral tablet plus 2 placebo oral tablets 
(3 tablets total) administered BID, immediately after the morning and evening meals 
• 1000 mg IW-3718 BID: Two 500 mg IW-3718 oral tablets plus 1 placebo oral tablet 
(3 tablets total) administered BID, immediately after the morning and evening meals 
• 1500 mg IW-3718 BID: Three 500 mg IW-3718 oral tablets administered BID, 
immediately after the morning and evening meals 
Reference Therapy, Dosage, and Mode of Administration:  
Matching placebo:  Three oral placebo tablets administered BID immediately after the 
morning and evening meals 
Duration of Treatment:  
Study medication will be administered orally BID for 8 weeks; total patient participation is 
expected to last up to 109 days, including the Screening Period. 
Total participation for patients who qualify for a one-week screening extension could last up 
to 116 days. 
Criteria for Evaluation: 
Key Efficacy Assessments 
The daily patient assessments used to determine the key efficacy parameters are the once-daily 
assessment of heartburn symptoms and regurgitation symptoms obtained from the 
mRESQ-eD.  
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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The items in the mRESQ-eD used to score heartburn severity will be the 3 items in the 
Heartburn Domain assessed on a 0-to-5 ordinal severity scale: 
• Heartburn 
• A burning feeling behind the breastbone or in the center of the upper stomach 
• Pain behind the breastbone or in the center of the upper stomach 
The items in the mRESQ-eD used to score regurgitation frequency will be the 2 items in the 
Regurgitation Domain assessed on a 0-to-4 ordinal frequency scale: 
• Regurgitation (liquid or food moving upwards towards your throat or mouth) 
• An acid or bitter taste in the mouth 
Other Efficacy Assessments 
The daily patient assessments used to determine the other efficacy parameters are as follows:  
• Once-daily assessment of hoarseness, cough, and difficulty swallowing, all assessed on a 
0-to-5 ordinal severity scale  
• Once-daily assessment of burping, assessed on a 0-4 frequency scale 
• Once-daily assessment of sleep: number of awakenings, sleep time, overall sleep quality 
assessed on a 5 point verbal rating scale 
• Once-daily assessment of dyspepsia: nausea, stomach fullness after eating, difficulty 
finishing meals, abdominal pain; all assessed at their worst on a 0-to-10 numerical rating 
scale 
Safety Assessments: 
Adverse event (AE) recording, clinical laboratory measures (clinical chemistry, hematology, 
and urinalysis), vital sign measurements, ECGs, physical examinations, and EGDs. 
Statistical Methods: 
Sample Size Determination 
The sample size per arm was determined by estimating the overall power of a trend test in a 
one-way design that included placebo and all the active treatment arms (500 mg BID, 1000 mg 
BID, and 1500 mg BID of IW-3718 BID). The efficacy parameter of interest in the previous 
Phase 2a study (ICP-3718-201) was change from baseline in daytime heartburn defined as the 
presence of heartburn since the patient awoke that morning (assessed in the evening) and 
assessed with an 11-point (0 to 10) NRS, where 0=none and 10=very severe. In that study, 
IW-3718 demonstrated treatment differences near 0.70 points for change over the treatment 
period (e.g., -0.73 vs. -1.38 for placebo and IW-3718, respectively), and standard deviations 
near 1.35 for the least-squares means (LSMs). Employing these historical values, it is expected 
that a study with 58 patients per arm (the expected number of patients at Week 8 given an 
enrollment of 260 patients) will have statistical power of at least 80% for the overall trend test 
(i.e., linear contrast) for the mRESQ-eD parameter of weekly heartburn severity score 
(WHSS), defined as the average of DHSS in a particular week, where the highest active 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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treatment arm reflects 110% of the previously observed treatment difference and the lowest 
2 active treatment arms reflect 55% of the same (two-sided, =0.05). At the proposed sample 
size, a subsequent pairwise comparison between placebo and an active treatment arm 
reflecting the previously observed treatment difference will have 80% statistical power (two-
sided, =0.05). 
Analysis Populations 
The Screened Population consists of all patients who consented to participate in the study. The 
modified Intent-to-treat (mITT) Population consists of all randomized patients who received at 
least 1 dose of study treatment. The Per-Protocol Population (PP) is defined as those patients 
in the mITT Population who have a minimum of 6 weeks of eDiary data for the heartburn and 
regurgitation severity scores and > 80% compliance with study treatment for the available 
Treatment Period days. The Safety Population is defined identically to the mITT Population. 
General Methods 
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, and range). Categorical variables will be summarized using the count and 
proportion of patients in each category. Unless otherwise specified, all confidence intervals 
will be two-sided and with a confidence level of 95%. No adjustments will be made for 
multiplicity. Details of the data handling methods will be specified in the Statistical Analysis 
Plan. If not otherwise specified, the baseline value is defined as the last non-missing value 
measured before administration of study treatment on Day 1. All statistical analyses will be 
performed using SAS® Version 9.3 (or later) for Windows. 
Primary Efficacy Parameter 
Percent change from baseline in WHSS at Week 8  
Secondary Efficacy Parameters 
1. Percent change from baseline in WHSS at Week 4. 
2. Change from baseline in WHSS at (a) Week 4 and (b) Week 8. 
3. Proportion of patients who are overall heartburn responders  
a. Weekly heartburn responder: patient with a decrease from baseline of ≥ 30% in WHSS 
b. Overall heartburn responder: patient who is a weekly heartburn responder for at least 1 
of the final 2 weeks and for ≥ 50% of the treatment weeks 
4. Proportion of patients with a daily heartburn severity score (DHSS) of no more than very 
mild (≤ 1) on any day during (a) Week 4 and (b) Week 8. 
5. The number of days per week where DHSS was no more than very mild (≤ 1) at (a) Week 
4 and (b) Week 8.  
6. Change from baseline in each mRESQ-eD item by week. 
7. Proportion of heartburn free days in Week 4 and Week 8. 
Note: DHSS is defined as the maximum of the 3 items in the heartburn assessments of a 
particular day, collected with the mRESQ-eD instrument. Further, WHSS is defined as the 
average of DHSS in a particular week. 
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Heartburn-free days will be calculated by 2 approaches. The first will employ the single 
heartburn item in the heartburn domain (Item #1 from mRESQ-eD: Heartburn) which is 
similar to the heartburn rating scale(s) used in the PPI literature. The second will employ all 3 
items in the heartburn domain (Items #1 through #3 from mRESQ-eD: Heartburn; Burning 
feeling behind the breastbone or in the center of the upper stomach; Pain behind the 
breastbone or in the center of the upper stomach. In the first approach, the heartburn item 
needs to be assessed at 0 (Did not have) while in the second approach all 3 heartburn domain 
items need to be assessed at 0 (Did not have). 
Efficacy Analyses for the Primary and Secondary Efficacy Parameters 
For the analysis of continuous parameters (e.g., absolute change from baseline and percent 
change from baseline), descriptive statistics (patient number [n], mean, standard deviation, 
median, and range) will be presented for each treatment group. Each IW-3718 group will be 
compared with the placebo group using an analysis of covariance (ANCOVA) model with 
treatment group and esophagitis stratum as fixed effect terms and the corresponding baseline 
efficacy value as a covariate. Least-squares means for each treatment group, a linear contrast 
among the LSMs to test the overall ordinal dose response, LSMs differences between each 
IW-3718 group and the placebo group and their corresponding confidence intervals, and p-
values for the pairwise comparisons versus placebo will be presented. The treatment by 
esophagitis stratum interaction term will be explored to evaluate whether quantitative or 
qualitative interaction(s) are present, and treatment comparisons within each stratum will be 
conducted, as warranted.  
The cumulative distribution function (CDF) of change from baseline for key efficacy 
parameters will be plotted by treatment group. To aid in the interpretation of the graphical 
representation of the CDF across treatments, a two-sample Kolmogorov-Smirnov test will be 
conducted (22). A p-value ≤ 0.05 indicates that the 2 treatment samples are unlikely to have 
been drawn from the same continuous distribution by chance alone. 
For the analysis of responder parameters (i.e., responder vs. non-responder), the counts and 
proportions of responders will be calculated for each treatment group. The proportions of 
responders between each IW-3718 group and the placebo group will be compared using a 
Cochran-Mantel-Haenszel (CMH) test controlling esophagitis stratum. The CMH test is the 
primary analysis for responder parameters. The difference in the proportion of responders 
between each IW-3718 group and the placebo group as well as the CMH estimates of the odds 
ratio (IW-3718 over placebo) and the corresponding 95% confidence intervals will also be 
presented.  
Safety Analysis 
All safety parameters will be analyzed with descriptive statistics. Safety analyses will be 
performed on the Safety Population. The safety parameters will include AEs, treatment-
emergent AEs (TEAEs), clinical laboratory evaluations, vital signs, ECG, and physical 
examination. For each safety parameter, the last non-missing assessment made before 
randomization will be used as the baseline for all analyses of that safety parameter. 
 
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Schedule of Events 
 
 
Screening 
Period 
(Up to 4 
weeks)w 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-up 
Visit Days → 
Screening 
Visit  (Day -
49 to Day -
15) 
Pretreatment 
Visit 
(Day -21 to 
Day -1) 
Randomization 
Visit 
(Day 1) 
Week 2 
Visit 
(Day 15 
± 3) 
Week 4 
Visit 
(Day 29 
± 3) 
 
EOT 
+ 7 days 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Study Procedure ↓ 
 
 
 
 
 
 
 
Inclusion and Exclusion Criteria 
Verification 
X 
X 
X 
 
 
 
 
Signing of ICF 
X 
 
 
 
 
 
 
IWRS Registration (a) 
X 
X 
X 
X 
X 
X 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination (b) 
X 
 
 
 
 
X 
 
Body Weight and Height (c)  
X 
X 
X 
X 
X 
X 
 
H2RA/Antacid Washout (d) 
X 
 
 
 
 
 
 
Bilitec Monitoring (e) 
X 
 
 
 
 
 
 
EGD (f) 
X 
 
 
 
 
X 
 
48 to 96 Hours of pH Testing 
with Bravo Device (g) 
X 
 
 
 
 
 
 
Seated Vital Signs (h)  
X 
X 
X 
X 
X 
X 
 
12-Lead ECG (i) 
X 
 
X 
 
 
X 
 
Prior and Concomitant 
Medications (j) 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory Tests (k) 
X 
 
X 
 
X 
X 
 
Serum Pregnancy Test (l) 
X 
 
 
 
 
X 
 
Document Date: 05-Aug-2016 09:10
Week 8 / 
End-of-treatment 
Visit  
(Day 57 + 3) 


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Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
Page 13 of 173 
Schedule of Events 
 
 
Screening 
Period 
(Up to 4 
weeks)w 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-up 
Visit Days → 
Screening 
Visit  (Day -
49 to Day -
15) 
Pretreatment 
Visit 
(Day -21 to 
Day -1) 
Randomization 
Visit 
(Day 1) 
Week 2 
Visit 
(Day 15 
± 3) 
Week 4 
Visit 
(Day 29 
± 3) 
 
EOT 
+ 7 days 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Study Procedure ↓ 
 
 
 
 
 
 
 
Urine Pregnancy Test (l) 
 
 
X 
 
X 
 
 
Drug and Alcohol Screen (m) 
X 
 
 
 
 
 
 
AE Evaluations (n) 
X 
X 
X 
X 
X 
X 
 
Rescue Medicine Dispensed (o) 
 
X 
X 
X 
X 
 
 
PDA Training and Dispensation 
 
X 
 
 
 
 
 
Saliva Collection (p) 
X 
X 
X 
 
X 
X 
 
eDiary (q) 
 
X 
X 
X 
X 
X 
 
Weekly Symptom and Treatment 
Assessments (r) 
 
X 
X 
X 
X 
X 
 
GSRS-Self 
 
 
X 
 
X 
X 
 
QIDS-SR-16 
 
 
X 
 
 
 
 
SF-12V2 
 
 
X 
 
X 
X 
 
EQ-5D-3L 
 
 
X 
 
X 
X 
 
Randomization 
 
 
X 
 
 
 
 
Study Medication Dispensed (s) 
 
 
X 
X 
X 
 
 
Study Medication Return (t) 
 
 
 
X 
X 
X 
 
PDA Return 
 
 
 
 
 
X 
 
mRESQ-eD Debrief Interview (x) 
 
X (x) 
 
 
X (x) 
 
 
End of Treatment Question (u) 
 
 
 
 
 
X 
 
Document Date: 05-Aug-2016 09:10
Week 8 / 
End-of-treatment 
Visit  
(Day 57 + 3) 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
Page 14 of 173 
Schedule of Events 
 
 
Screening 
Period 
(Up to 4 
weeks)w 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-up 
Visit Days → 
Screening 
Visit  (Day -
49 to Day -
15) 
Pretreatment 
Visit 
(Day -21 to 
Day -1) 
Randomization 
Visit 
(Day 1) 
Week 2 
Visit 
(Day 15 
± 3) 
Week 4 
Visit 
(Day 29 
± 3) 
 
EOT 
+ 7 days 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Study Procedure ↓ 
 
 
 
 
 
 
 
Safety Follow-up Call (v) 
 
 
 
 
 
 
X 
 
Abbreviations: AE = adverse event; BP = blood pressure; CBC = complete blood count; ECG = electrocardiogram; EGD = esophagogastroduodenoscopy; 
EOT = End-of-treatment; EQ = EuroQol; GSRS = Gastrointestinal Symptoms Rating Scale; H2RA = histamine-2 receptor antagonist; HEENT = head, eyes, ears, 
nose, and throat; ICF = informed consent form; IWRS = interactive web response system; PDA = personal digital assistant; PPI = proton pump inhibitor; 
QID = Quick Inventory of Depressive Symptomology; mRESQ-eD = modified Reflux Symptom Questionnaire Electronic Diary; SAE = serious adverse event; 
SF = short form 
 
a. 
Site personnel will interact with IWRS to register the patient visit and transition the patient to the next appropriate study period. 
b. A physical examination should include the following assessments: general appearance; HEENT; neck; cardiovascular; respiratory; abdomen/liver/spleen; 
musculoskeletal; lymph nodes; skin; neurologic; nervous system, and mental status. Breast, genitourinary, and rectal examinations are optional and may be 
performed at the discretion of the Investigator. 
c. 
Height will be measured only at the Screening Visit.  
d. During the Screening Period, patients will begin to washout H2RAs and antacids. H2RAs should be stopped 5 calendar days prior to the EGD and Bravo pH 
monitoring and antacids should be stopped 1 calendar day prior to the EGD and Bravo pH monitoring. Patients may resume antacid use upon completion of 
the Bravo testing, but must refrain from H2RA use for the remainder of the study.  During the Pretreatment Period, patients will refrain from using any anti-
reflux medications, antacids, and H2RAs, except for the antacids that are provided as rescue medicine). Patients will continue to use their current PPI during 
the Pretreatment Period. 
e. 
At selected sites, selected patients who are screened for the study with EGD and Bravo testing will also be given the option of having a Bilitec monitor 
inserted during the same procedure. These patients will return 24 hours later for removal of the probe. The results of the Bilitec test will not affect 
qualification for enrollment.  The Bilitec device and Bravo recorder internal clocks must be synchronized, and both devices should be activated concurrently; 
however, if it is not possible to simultaneously activate both devices, the Bravo recorder should be activated first, with the Bilitec device activation 
immediately (within 5 minutes) after the Bravo pH recorder activation. 
f. 
All patients will be required to undergo an EGD during the Screening Period. There must be a minimum of 7 days between the EGD and the start of the 
Pretreatment Period to allow for pH testing and patient stabilization. An EGD will be performed at the Week 8 / EOT Visit in all patients who have Grade C 
or D esophagitis (based on the Los Angeles classification of esophagitis, see Appendix 5) on the EGD obtained during the Screening Period.  
Document Date: 05-Aug-2016 09:10
Week 8 / 
End-of-treatment 
Visit  
(Day 57 + 3) 


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
Page 15 of 173 
g. Approximately 48 to 96 hours of pH testing with the Bravo device. If for some reason 96 hours of testing is not possible, then approximately 48 hours of 
testing is acceptable. During the entire period of Bravo pH monitoring (approximately 48-96 hours), patients will record ingestion of anything other than 
water by depressing the ‘meal’ button on the Bravo recorder upon the beginning and completion of the meal, snack, or drink.  Patients will also record any 
periods during which they are lying down by depressing the ‘supine’ button on the Bravo recorder at the beginning and upon completion of the supine 
period.  In addition, for the entire 48-96 hour Bravo pH monitoring period, patients will complete a paper diary (see Appendix 9), recording at a minimum all 
instances of meals, snacks, drinks, and/or resting in the supine position. 
h. Vital sign measurements include oral temperature (°C), respiratory rate, systolic and diastolic BP, and pulse. Respiratory rate, BP, and pulse measurements 
must be obtained after the patient has been seated for at least 5 minutes. 
i. 
12-Lead ECGs should be obtained after the patient has been supine for at least 5 minutes. 
j. 
Prior medications will be collected at the Screening Visit as follows: all medicines taken by the patient during the 30 days before the Screening Visit, most 
recent use of an H2RA, and most recent use of an antacid. 
k. Clinical laboratory tests include clinical chemistry, hematology (CBC), coagulation, and urinalysis.  If the triglyceride value exceeds the protocol-specified 
criteria and the patient was not under fasted conditions, the patient may return to complete a fasted lipid panel. 
l. 
For all female patients of childbearing potential, a negative serum pregnancy test must be documented at the Screening Visit, and a negative urine pregnancy 
test must be documented at the Randomization Visit (before dosing) in order for the patient to be randomized into the study. A urine pregnancy test will be 
obtained at the Week 4 Visit; a serum pregnancy test will be conducted at the EOT Visit. 
m. Patients must undergo a urine drug screen for selected drugs of abuse (cocaine, barbiturates, amphetamines, opiates, benzodiazepines, and cannabinoids) and 
a serum alcohol screen at the Screening Visit. 
n. All AEs will be captured from the time the patient signs the ICF through the EOT Visit. 
o. Rescue medicine will be supplied to patients at the Pretreatment Visit, and if needed, at subsequent visits. 
p. At each of the indicated visits, patients will provide approximately 1 mL of saliva for future use (bile acids will be quantified in the saliva, and the quantity 
of bile acid may be used to define potential responders to IW-3718). At the time of saliva collection, study site staff will collect the following information: 
time of day, time of patient’s last meal, and time of last study medication administration. During the Randomization Visit, study site staff will collect the 
saliva sample immediately following the light snack but prior to study drug administration. 
q. The eDiary will be dispensed at the Pretreatment Visit and patients must complete at least 5 days each week during the 14 days before the Treatment Period 
in order to be eligible for randomization. Patients should bring their eDiary to each visit. The eDiary will collect daily PPI administration, rescue medication 
use, mRESQ-eD (Appendix 1; daily), Daily Assessment of Sleep (Appendix 3; daily), Daily Dyspepsia Symptoms (Appendix 2; daily).  
r. 
Symptom bothersomeness and symptom relief items (Appendix 6; weekly); Treatment satisfaction (Appendix 6; weekly). 
s. 
The first dose of study medication will be administered in the clinic with liquid and a snack at the Randomization Visit. At all other visits, patients will take 
their study medication prior to arriving at the clinic, but will be dispensed additional doses needed until the next study visit. 
t. 
Treatment compliance with study drug will be assessed based on return of unused tablets. 
u. All patients will be asked an EOT question regarding the difficulty of swallowing the IW-3718 or placebo tablets (Appendix 6). 
v. Study site will contact each patient via telephone 7 days after the EOT Visit to collect information pertaining to ongoing AEs/SAEs and information 
concerning any new AEs/SAEs since the EOT Visit. 
w. Ironwood may grant a one-week extension of the screening period window if needed for logistical delays (e.g., subject travel, scheduling issues, delays in 
test results, equipment malfunction, etc.).  Approval should be requested from Ironwood prior to each extension. 
x. Patients participating in the optional mRESQ-eD Cognitive Debriefing interviews will be assigned to one of three interview groups.  Interviews will take 
place at different timepoints depending on the patient’s group assignment.  (see Appendix 10)
Document Date: 05-Aug-2016 09:10


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 16 of 173 
STUDY IDENTIFICATION 
Sponsor 
Ironwood Pharmaceuticals, Inc. 
301 Binney Street 
Cambridge, MA 02142  
(617) 621-7722 (Main Telephone) 
(617) 494-0908 (Main Fax) 
http://www.ironwoodpharma.com 
Drug Safety Specialist 
(Serious Adverse Event 
[SAE] Reporting) 
Patricia O’Donnell 
Ironwood Pharmaceuticals, Inc. 
(617) 374-5159 (Telephone) 
Email: podonnell@ironwoodpharma.com 
Medical Monitor 
Robert Mittleman, MD, MS, FACC 
Ironwood Pharmaceuticals, Inc. 
(617) 768-2605 
Protocol Inquiries and 
Contract Research 
Organization (CRO) 
Medical Monitor 
Jean Telusma 
PPD 
1-800-201-8725 
https://epip.ppdi.com 
Clinical Laboratory 
PPD 
2 Tesseneer Drive 
Highland Heights, KY 41076 
CRO  
PPD 
929 North Front Street 
Wilmington, NC 28401 
(910) 251-0081 
Fax: (910) 762-5820 
Ironwood Contact 
Lara Lane  
Ironwood Pharmaceuticals, Inc. 
(617) 768-2621  
Dedicated SAE Telephone, 
Facsimile, and Email 
Facsimile: (888) 488-9697 
Email: Wilsafety@ppdi.com 
VP Drug Safety 
Pharmacovigilance 
 
Karel Van Loon, MD 
Ironwood Pharmaceuticals, Inc. 
(617) 374-3909 
Email: kvanloon@ironwoodpharma.com 
 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
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Page 17 of 173 
TABLE OF CONTENTS 
SYNOPSIS .......................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................23 
1. 
INTRODUCTION .................................................................................................................25 
1.1 
BILE ACIDS AND GERD ..........................................................................................25 
1.2 
IW-3718 .......................................................................................................................26 
2. 
STUDY OBJECTIVES ..........................................................................................................29 
3. 
INVESTIGATIONAL PLAN ................................................................................................30 
3.1 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ....................................30 
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS ..................................................................................................33 
3.3 
SELECTION OF STUDY POPULATION .................................................................33 
3.3.1 
Eligibility Criteria ..............................................................................................33 
3.3.1.1 
Inclusion Criteria .....................................................................................33 
3.3.1.2 
Exclusion Criteria ....................................................................................35 
3.3.2 
Removal of Patients from Therapy or Assessment ............................................37 
3.3.3 
Replacement Procedures ....................................................................................38 
3.4 
STUDY TREATMENTS .............................................................................................38 
3.4.1 
Investigational Product ......................................................................................38 
3.4.1.1 
IW-3718 ...................................................................................................38 
3.4.1.2 
Placebo .....................................................................................................39 
3.4.1.3 
Rescue Medicine ......................................................................................39 
3.4.1.4 
Treatment Compliance .............................................................................40 
3.4.2 
Packaging and Labeling .....................................................................................40 
3.4.3 
Storage and Stability ..........................................................................................40 
3.4.4 
Method of Assigning Patients to Treatment Groups ..........................................41 
3.4.5 
Selection of Dosage in the Study .......................................................................41 
3.4.6 
Selection and Timing of Dose for Each Patient .................................................41 
3.4.7 
Blinding..............................................................................................................42 
3.4.8 
Prior and Concomitant Medications ..................................................................43 
3.4.8.1 
Rescue Medication ...................................................................................43 
3.4.8.2 
Prohibited Medicines ...............................................................................43 
3.4.9 
Dietary Requirements ........................................................................................43 
3.5 
SAFETY AND EFFICACY ASSESSMENTS ............................................................43 
3.5.1 
Safety Assessments ............................................................................................44 
3.5.1.1 
Adverse Events ........................................................................................44 
3.5.1.2 
Serious Adverse Events ...........................................................................45 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
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3.5.1.3 
Reporting Adverse Events and Serious Adverse Events and 
Pregnancy .................................................................................................46 
3.5.1.4 
Medical History .......................................................................................48 
3.5.1.5 
Physical Examination, Body Weight, and Height ...................................49 
3.5.1.6 
Electrocardiograms ..................................................................................49 
3.5.1.7 
Vital Signs ................................................................................................49 
3.5.1.8 
Clinical Laboratory Determinations ........................................................49 
3.5.1.9 
Esophagogastroduodenoscopy .................................................................51 
3.5.1.10 
Bravo ........................................................................................................51 
3.5.1.11 
Bilitec .......................................................................................................51 
3.5.2 
Efficacy Assessments .........................................................................................52 
3.5.2.1 
Symptom Severity Assessment ................................................................52 
3.5.2.2 
GSRS-Self ................................................................................................55 
3.5.2.3 
QIDS-SR-16 .............................................................................................55 
3.5.2.4 
SF-12V2 Health Survey ...........................................................................55 
3.5.2.5 
EQ-5D-3L ................................................................................................56 
3.5.2.6 
End-of-treatment Question .......................................................................56 
3.5.2.7 
mRESQ Cognitive Debriefing Interviews ...............................................56 
3.6 
SCHEDULE OF EVENTS ..........................................................................................57 
3.6.1 
Screening Period (Day –49 to Day -15) .............................................................62 
3.6.1.1 
Screening Visit (Visit 1) Procedures........................................................62 
3.6.1.2 
Extension of Screening Period .................................................................63 
3.6.1.3 
Pretreatment Visit (Visit 2) Procedures ...................................................63 
3.6.2 
Treatment Period (Day 1 to Day 57) ..................................................................63 
3.6.2.1 
Randomization Visit (Visit 3) Procedures ...............................................64 
3.6.2.2 
Week 2 Visit (Visit 4) Procedures ...........................................................65 
3.6.2.3 
Week 4 (Visit 5) Procedures ....................................................................65 
3.6.2.4 
Week 8/End-of-treatment (Visit 6) Procedures .......................................66 
3.6.3 
Follow-up ...........................................................................................................67 
3.6.4 
Early Termination Procedures ...........................................................................67 
3.7 
STATISTICAL METHODS ........................................................................................67 
3.7.1 
Analysis Populations ..........................................................................................67 
3.7.2 
General Methods ................................................................................................67 
3.7.3 
Patient Disposition, Demographics, and Baseline Characteristics ....................68 
3.7.4 
Efficacy Analyses ..............................................................................................68 
3.7.4.1 
Primary and Secondary Efficacy Parameters ...........................................69 
3.7.4.2 
Other Efficacy Parameters .......................................................................71 
3.7.5 
Safety Analyses ..................................................................................................72 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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3.7.5.1 
Adverse Events ........................................................................................72 
3.7.5.2 
ECGs, Vital Signs, and Clinical Laboratory Tests ..................................73 
3.7.6 
Interim Analysis .................................................................................................73 
3.7.7 
Determination of Sample Size ...........................................................................73 
3.8 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ...74 
4. 
ETHICAL CONSIDERATIONS ...........................................................................................75 
4.1 
INSTITUTIONAL REVIEW BOARD ........................................................................75 
4.2 
PATIENT INFORMATION AND INFORMED CONSENT .....................................76 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ............................77 
5.1 
GENERATION OF STUDY RECORDS ....................................................................77 
5.2 
DATA QUALITY ASSURANCE ...............................................................................78 
5.3 
ELECTRONIC CASE REPORT FORMS AND DATA MANAGEMENT ...............78 
5.4 
STUDY MONITORING .............................................................................................78 
6. 
STUDY SPONSORSHIP.......................................................................................................80 
6.1 
INVESTIGATOR AND STUDY TERMINATION ...................................................80 
6.2 
REPORTING AND PUBLICATION ..........................................................................80 
7. 
INVESTIGATOR OBLIGATIONS ......................................................................................81 
7.1 
DOCUMENTATION ..................................................................................................81 
7.2 
PERFORMANCE ........................................................................................................83 
7.3 
USE OF INVESTIGATIONAL MATERIALS ...........................................................83 
7.4 
RETENTION AND REVIEW OF RECORDS ...........................................................83 
7.5 
PATIENT CONFIDENTIALITY ................................................................................84 
8. 
REFERENCE LIST ...............................................................................................................85 
9. 
SPONSOR SIGNATURES ....................................................................................................87 
10.  INVESTIGATOR’S STATEMENT ......................................................................................88 
11.  APPENDICES .......................................................................................................................89 
 
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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
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Page 20 of 173 
LIST OF IN-TEXT TABLES 
Table 1. 
Clinical Laboratory Tests ...................................................................................50 
Table 2. 
Schedule of Events .............................................................................................58 
Table 3. 
Analysis Time Windows for Efficacy Analysis ................................................69 
 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 21 of 173 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Overview of Study Design .................................................................................30 
 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 22 of 173 
LIST OF APPENDICES 
Appendix 1 
mRESQ-eD ........................................................................................................90 
Appendix 2 
DAILY DYSPEPSIA SYMPTOMS ..................................................................91 
Appendix 3 
DAILY ASSESSMENT OF SLEEP ..................................................................92 
Appendix 4 
PROHIBITED MEDICATIONS .......................................................................93 
Appendix 5 
LOS ANGELES CLASSIFICATION OF ESOPHAGITIS ..............................95 
Appendix 6 
WEEKLY AND END OF TREATMENT ASSESSMENTS ............................96 
Appendix 7 
IN-CLINIC ASSESSMENTS ............................................................................98 
Appendix 8 
EXAMPLE “WHITE DIET” ...........................................................................112 
Appendix 9 
BRAVO PH RECORDER INSTRUCTIONS AND PATIENT DIARY ........113 
Appendix 10 
COGNITIVE DEBRIEFING INTERVIEWS TO EVALUATE THE 
CONTENT VALIDITY OF THE MODIFIED REFLUX SYMPTOM 
QUESTIONNAIRE (mRESQ-eD) STUDY MANUAL .................................116 
Appendix 11 
PPI DOSE LEVELS DURING STUDY PARTICIPATION ..........................173 
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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 23 of 173 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BAS 
bile acid sequestrant 
BID 
twice daily 
BP 
blood pressure 
CBC 
complete blood count 
CDF 
cumulative distribution function 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
DGER 
duodenogastroesophageal reflux 
DHSS 
daily heartburn severity score 
DRFS 
daily regurgitation frequency score 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EGD 
esophagogastroduodenoscopy 
EOT 
End-of-treatment 
EQ 
EuroQol 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
GI 
Gastrointestinal 
GSRS 
Gastrointestinal Symptoms Rating Scale 
H2RA 
histamine-2 receptor antagonist 
HCl 
Hydrochloride 
HS 
heartburn severity 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
Document Date: 05-Aug-2016 09:10


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
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Page 24 of 173 
IWRS 
interactive web response system 
LDL-C 
low-density lipoprotein cholesterol 
LSM 
least-square mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
mRESQ-eD 
modified Reflux Symptom Questionnaire Electronic Diary 
NRS 
numerical rating scale 
PDA 
personal digital assistant 
PID 
patient identification 
PP 
Per-Protocol 
PPI 
proton pump inhibitor 
QD 
once daily 
QIDS-SR-16 
Quick Inventory of Depressive Symptomatology (16 Item) Self Report  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF 
short form 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
US 
United States 
WHSS 
weekly heartburn severity score 
WRFS 
weekly regurgitation frequency score 
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IW-3718 
 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
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Page 25 of 173 
1. 
INTRODUCTION 
1.1 
BILE ACIDS AND GERD 
Bile acids play an important role in the digestive process; however, data from nonclinical and 
mechanistic studies suggest that the prolonged presence or excess of bile acids in the stomach 
and esophagus can result in toxic effects on regional tissues (1,2,3,4). Duodenogastroesophageal 
reflux (DGER), which contains bile acids, is thought to produce symptoms such as retrosternal 
pain, heartburn, nausea, and vomiting (5,6), and is associated with more severe esophageal 
pathology in patients with gastroesophageal reflux disease (GERD) and Barrett’s esophagus, a 
precancerous change in the esophagus (4,7). 
Gastroesophageal reflux disease is a chronic and common medical disorder with a prevalence 
estimated at approximately 20% to 40% in Western countries (8), and is associated with rising 
healthcare utilization and cost (9). Currently, proton pump inhibitors (PPIs) are the standard of 
care for GERD; however, it is estimated that approximately 10% to 40% of GERD patients 
remain symptomatic on standard-dose PPI therapy (10). DGER is hypothesized to be a potential 
cause of incomplete symptom response in patients who continue to experience bothersome 
GERD symptoms despite treatment with PPIs (11). 
There is significant evidence to support DGER as a putative mechanism for persistent GERD 
symptoms. Pathological bile acid reflux occurs in approximately 65% of patients who continue 
to experience bothersome GERD symptoms despite treatment with PPIs and is hypothesized to 
be a cause of their incomplete symptom response (11).  There is considerable clinical and 
nonclinical evidence that bile acid can cause esophageal damage both in conjunction with 
stomach acid as well as independently (1,2,5). 
There is currently no widely used diagnostic technique for evaluating the role of bile acid salts in 
the presence of GERD that is refractory to standard dose PPIs. In this study we require patients 
to have esophageal erosions demonstrated by EGD or to have acid reflux confirmed by the use of 
the Bravo device inserted at the time of the EGD.  
The Bilitec® device can be placed in the esophagus and uses the spectrophotometric analysis of 
the presence of bilirubin as a marker for the presence of bile acid salts that might be contributing 
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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 26 of 173 
to reflux. It was demonstrated that bilirubin content detected by this device correlates with the 
concentrations of pancreatic enzymes in aspirated refluxate, suggesting that bilirubin is a good 
tracer for DGER (12). Therefore it is reasonable to correlate the results of Bilitec testing with the 
response to IW-3718 in a subgroup of patients selected to have this testing, along with the other 
procedures outlined in this protocol. 
1.2 
IW-3718 
Ironwood is developing IW-3718 for the treatment of symptomatic GERD not completely 
responsive to PPIs and for and other gastrointestinal (GI) disorders. IW-3718 is colesevelam 
hydrochloride (HCl), a bile acid sequestrant (BAS). 
Colesevelam HCl (hereafter referred to as colesevelam) is an orally administered, nonabsorbed, 
nondigestible polymer that binds bile acids in the GI tract. Colesevelam was approved in 2000 in 
the United States (US) as the active ingredient in Welchol™, and is indicated as an adjunct to 
diet and exercise for reduction of elevated low-density lipoprotein cholesterol (LDL-C) in adults 
with primary hyperlipidemia. Colesevelam is currently available as an immediate-release 
formulation only. 
IW-3718 tablets are formulated as a controlled-release, solid oral dosage form intended to extend 
the release of the drug substance, colesevelam, into the stomach. The released colesevelam is 
expected to bind bile acids that are refluxed into the stomach and upper duodenum, forming a 
bile acid-colesevelam complex and preventing the free bile acids from entering the esophagus. 
The bile acid-colesevelam complex will travel down the GI tract and be excreted without being 
absorbed. 
The controlled-release formulation in IW-3718 tablets is based on Depomed’s Acuform® 
technology which utilizes swelling polymers to allow the tablet to be retained in the stomach for 
approximately 9 hours when dosed in the fed state, during which time the tablet slowly releases 
the active ingredient in the stomach and upper GI tract. The tablet’s active ingredient is steadily 
delivered to the stomach and upper GI tract in a near zero-order manner. The technology is used 
in the formulation of 5 Food and Drug Administration (FDA)-approved drugs: Glumetza® 
(metformin HCl, extended release), Janumet® XR (sitagliptin and metformin HCl extended-
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release), Proquin® XR (ciprofloxacin HCl monohydrate, extended release), NUCYNTA® ER 
(tapentadol extended-release tablets), and once-daily Gralise™ (gabapentin) tablets. 
Colesevelam is not systemically absorbed and does not interfere with systemic drug metabolizing 
enzymes. Distribution of colesevelam is limited to the GI tract and elimination occurs through 
fecal excretion. 
Colesevelam reduces serum LDL-C concentrations by binding bile acids in the intestine, 
impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, 
cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile 
acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual 
effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA 
reductase, and increasing the number of hepatic LDL receptors. These compensatory effects 
result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C 
concentrations. Serum triglyceride concentrations may increase or remain unchanged. The 
mechanism by which colesevelam improves glycemic control is unknown. However, increasing 
evidence suggests that colesevelam, as a BAS, may function by signaling molecules in the liver 
and GI tract for lipid and glucose metabolism (13,14,15,16). The mechanism by which 
colesevelam is expected to reduce symptoms in GERD is by binding bile acids that are refluxed 
into the stomach and preventing the free bile acids from entering the esophagus and reacting with 
the esophageal mucosa. 
There are no reported clinical efficacy studies with colesevelam in patients with GERD, or other 
upper GI disorders. 
Colesevelam (as Welchol) has been evaluated for safety in clinical studies and via post-
marketing pharmacovigilance. In general, colesevelam was safe and well-tolerated in adults with 
hyperlipidemia or type 2 diabetes mellitus, and in adolescents with familial 
hypercholesterolemia. Due to the large doses required for lipid lowering, and its local effects in 
the GI tract, most of the adverse events (AEs) related to colesevelam are GI in nature 
(constipation, flatulence, and dyspepsia). Most of these AEs were of mild or moderate intensity. 
In clinical lipid-lowering studies, the incidence of dyspepsia was greater at the higher doses (3.8 
and 4.5 g/day). 
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IW-3718 has been evaluated in a Phase 2a study. This study was a 4-week, randomized, double-
blind, placebo-controlled, proof-of-concept study in patients with GERD not completely 
responsive to QD PPI therapy. In this study patients were randomized in a 1:1 fashion to either 
IW-3718 1000 mg bid or placebo. A Bilitec procedure was performed as an optional procedure. 
Esophageal duodenogastroscopy and pH monitoring were not required, but results were collected 
if these procedures were performed prior to randomization or in the recent past. Symptoms were 
assessed over the four week period to determine severity of heartburn-related symptoms. 
Safety and efficacy data are available for 93 patients, 46 of whom received 1000 mg IW-3718 
BID. IW-3718 was well tolerated among patients with GERD. There were no deaths or study 
medication-related serious adverse events (SAEs). Common TEAEs (>5% of patients) among 
patients who received IW 3718 or placebo included constipation (13% vs 0%) and abdominal 
pain (7% vs 2%).  
In this study, among all patients (Intent-to-treat [ITT] Population), severity of daytime heartburn 
showed a trend toward being numerically reduced in IW-3718 patients compared to placebo 
(p=0.124). The largest differences between IW-3718 and placebo for this parameter were seen in 
patients who underwent Bilitec monitoring. Improvements were also observed for nighttime 
heartburn severity at Week 4. A greater percentage of IW-3718-treated patients (9 patients, 
19.6%) reported an absence of heartburn during Week 4 compared with those receiving placebo 
(5 patients, 10.6%). 
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2. 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the safety, efficacy, and dose-response relationship of 
IW-3718 administered orally to patients who have GERD and continue to experience GERD 
symptoms while receiving once-daily (QD), standard-dose PPIs. 
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3. 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 8-week 
study, consisting of 3 distinct periods as illustrated in Figure 1. The study will enroll patients 
who have GERD and continue to experience GERD symptoms while receiving QD, standard-
dose PPI therapy. Eligible patients will continue to take their PPI and will be randomized to 
placebo or to 500 mg IW-3718 twice daily (BID), 1000 mg IW-3718 BID, or 1500 mg IW-3718 
BID. Randomization will be stratified by whether they have, or do not have, erosive esophagitis 
on the screening esophagogastroduodenoscopy (EGD). 
Figure 1. Overview of Study Design 
 
All patients will take their current PPI approximately 30-60 minutes before breakfast each day 
during the Screening, Pretreatment, and Treatment Periods. During the Treatment Period, all 
patients will take IW-3718 or matching placebo immediately upon completion of the morning 
and evening meal each day. 
Screening Period: The Screening Period starts with the signature of the informed consent form 
(ICF) and is expected to last for up to 28 days. During this period, patient eligibility for entry 
into the Pretreatment Period will be determined. Two procedures will be required during the 
* This visit represents the end of the study
Screening
Period
Pretreatment
Period
Treatment Period
Day 1 to Day 57
14 to 21 days
Up to 28 days
Screening
Visit
(Day -49 to
Day -15)
Pretreatment
Visit
(Day -21 to
Day -14)
Randomization
Visit
(Day 1)
Week 2 Visit
(Day 15 ± 3)
Week 4 Visit
(Day 29 ± 3)
Week 8 / 
End of Trial
Visit*
(Day 57 + 3)
No Treatment
500 mg IW-3718 twice daily
1000 mg IW-3718 twice daily
1500 mg IW-3718 twice daily
Placebo twice daily
Note:  There is no Day 0
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Screening Period in all patients; a third procedure Bilitec® testing will be optional for all patients 
at selected sites (all will be done while patients continue to take their PPI):  
• An EGD  
• Approximately 48 to 96 hours of pH testing with the Bravo® device. If for some reason 96 
hours of testing is not possible, then approximately 48 hours of testing is acceptable (Please 
refer to section 3.5.1.10 for further instruction)  
• Approximately 24 hours of bilirubin detection using the Bilitec monitoring system (optional 
at selected sites) 
Histamine-2 receptor antagonists (H2RAs) should be stopped 5 calendar days prior to the EGD 
and Bravo pH monitoring and antacids should be stopped 1 calendar day prior to the EGD and 
Bravo pH monitoring. The EGD must be performed during the Screening Period and at least 7 
days before the start of the Pretreatment Period to allow time for pH collection and allow the 
patient to stabilize following these procedures. Upon completion of the Bravo testing, patients 
will refrain from using H2RAs, but may continue to use antacids if needed. Patients will 
continue to use their current PPI throughout the Screening Period. The end of the Screening 
Period coincides with the start of the Pretreatment Period 
At selected sites, patients who are screened for the study with EGD and Bravo testing will also 
be given the option of having a Bilitec monitor inserted at that time. The Bilitec procedure is 
being completed in a subset of patients to collect information about whether bilirubin is present 
in the duodenogastric refluxate. Previous Bilitec 2000 studies have shown associations between 
total bile acid concentrations and Bilitec 2000 absorbance.  Patients participating in the Bilitec 
procedure will agree to comply with a “white diet” (see Appendix 8 for example “white diet”) 
and return approximately 24 hours later for removal of the probe. The results of the Bilitec 
monitoring will not affect qualification for enrollment and during participation in the study, 
patients will be blinded of their Bilitec testing results. 
Ironwood may grant a one-week extension of the screening period window if needed for 
logistical delays, as described in Section 3.6.1.2.   
 
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Pretreatment Period: The Pretreatment Period is defined as the 14 to 21 calendar days 
immediately before the Randomization Visit. During this period, patients will continue to use 
their PPI and will refrain from using other anti-reflux medications, including antacids and 
H2RAs, except for the antacid that is dispensed as rescue medicine. They will also provide the 
following information in a handheld eDiary; they will perform at least 2 weeks of symptom 
assessments during which they will be required to complete daily assessments for at least 5 days 
each week during the 14 calendar days before the start of the Treatment Period and weekly 
assessments at least once during the 7 calendar days before the start of the Treatment Period in 
order to be eligible for randomization: 
• GERD symptoms assessed once daily in the evening in the modified Reflux Symptom 
Questionnaire eDiary (mRESQ-eD; Appendix 1) 
• Dyspepsia symptoms assessed once daily in the evening using Daily Dyspepsia Symptoms 
(Appendix 2) 
• Assessment of sleep assessed once daily in the morning using Daily Assessment of Sleep 
(Appendix 3) 
• Use of per-protocol rescue medicine assessed twice daily 
• Symptom relief and bothersomeness assessed once a week in the evening 
Patients will be instructed to take their PPI at least approximately 30-60 minutes before breakfast 
each day, even on study visit days. Patients who satisfy all of the entry criteria will enter the 
Treatment Period. 
Treatment Period: The Treatment Period begins with treatment assignment and lasts for 
8 weeks. Patients will be stratified by whether they have, or do not have, erosive esophagitis on 
the screening EGD and randomly assigned to 1 of 4 treatments (1:1:1:1) within each stratum: 
placebo or 500 mg IW-3718 BID, 1000 mg IW-3718 BID, or 1500 mg IW-3718 BID. The 
treatment schedule will be managed by a central vendor. Enrollment will be monitored to ensure 
that no single center contributes > 15% of the targeted study enrollment, unless otherwise 
approved by the Medical Monitor. Study drug will be taken immediately after the morning and 
evening meals. Patients will continue to take their PPI approximately 30-60 minutes before 
breakfast each day and to use the eDiary to provide their daily assessments (GERD symptoms, 
dyspepsia symptoms, assessment of sleep), weekly assessments (weekly symptom 
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bothersomeness and degree of relief questions; Appendix 6), PPI compliance, and use of per-
protocol rescue medicine. 
For details regarding the assessments during each study period, see the Schedule of Events 
(Table 2). 
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS 
A double-blind, placebo-controlled, parallel-group study design was chosen in accordance with 
the concepts in International Conference on Harmonisation (ICH) E10, Choice of Control 
Groups and Related Issues in Clinical Trials (International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use, 2001), in order to 
provide comparable treatment groups and minimal chance of selection or Investigator bias.  
This study has a 14- to 21-day Pretreatment Period to establish a baseline without therapy and to 
familiarize patients with data collection methodology (i.e., personal digital assistants [PDAs]), 
and an 8-week Treatment Period to compare the test treatment with a placebo control. 
3.3 
SELECTION OF STUDY POPULATION 
This study will be conducted in patients with GERD not completely responsive to QD PPI 
therapy. Approximately 260 patients will be randomized (approximately 65 patients per 
treatment group). The study will be conducted at approximately 60-80 study centers in the US. 
Optional Bilitec testing will be done at a selected number of sites participating in the protocol. 
The goal at these sites will be to enroll a minimum of 60 patients with Bilitec testing who are 
randomized to treatment with IW-3718 or placebo. 
Study medication will be administered orally BID for 8 weeks; total patient participation is 
expected to last up to 109 days, including the Screening Period. 
3.3.1 
Eligibility Criteria 
3.3.1.1 
Inclusion Criteria 
Each patient must meet all of the following criteria to be eligible for enrollment in this study: 
1. Patient has signed an ICF before any study-specific procedures are performed.  
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2. Patient is an ambulatory, community-dwelling male or nonpregnant female and is at least 
18 years old at the Screening Visit. Lactating females must agree not to breastfeed.  
3. Patient has a diagnosis of GERD and reports experiencing GERD symptoms (heartburn or 
regurgitation) on ≥ 4 days per week during the 8 weeks before the Screening Visit while 
taking standard QD PPI therapy. 
4. Patient has been receiving individually optimized, standard-labeled dose, QD, PPI therapy 
(treatment that, according to the Investigator’s judgment, could not be further improved by 
changing the brand or timing of PPI administration) for a minimum of 8 weeks before the 
Screening Visit. Patients should be on a PPI dose and schedule that is consistent with the 
approved labeling (Appendix 11). Patients who have their PPI modified during the Screening 
Period may be re-screened after 8 weeks of optimized, standard-labeled dose, QD, PPI 
therapy provided they have not previously entered the Pretreatment Period. 
5. An EGD with approximately 48 to 96 hours of pH monitoring (with a Bravo device) during 
the Screening Period (while the patient continues taking their PPIs) demonstrates 1 or more 
of the following: 
a. Erosive esophagitis (Grade A or greater based on the Los Angeles classification of 
esophagitis; Appendix 5) on EGD  
b. Evidence of pathological acid reflux (pH is < 4 for ≥ 4.2% of the recording time) during 
at least 1 of the 24-hour time intervals of pH testing with the Bravo device  
6. Patient reports heartburn severity (HS, Item #1 on mRESQ-eD) ≥ 3 (moderate) on at least 
2 days and has an average HS of ≥ 2 (mild) during the last 7 days before randomization.  
7. Sexually active female patients of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a bilateral oophorectomy, hysterectomy, or tubal 
ligation) must agree to use 1 of the following methods of birth control from the date they sign 
the ICF until 24 hours after their final dose of study drug: 
a. Hormonal contraception (i.e., contraceptive implant or injectable hormonal 
contraceptive) 
b. Double-barrier birth control (e.g., condom plus intrauterine device, diaphragm plus 
spermicide, etc.) Patients may continue taking oral contraceptives while using one or 
more barrier methods. 
c. Maintenance of a monogamous relationship with a male partner who has been surgically 
sterilized by vasectomy 
8. 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. 
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9. Patient agrees not to make any changes to their usual diet during the study, except those 
patients participating in Bilitec testing, who must agree to a “white diet” during Bilitec 
testing only. 
10. Patient is compliant with eDiary completion; that is, they have adequately completed the 
eDiary questions on at least 5 days each week during the 14 calendar days before the start of 
the Treatment Period. 
11. Patient is compliant with QD PPI dosing during the 14 calendar days before the start of the 
Treatment Period. Patients are considered compliant if, as reported in the eDiary, they take 
their PPI on at least 5 days each week. 
12. Patient is fluent and literate in English or Spanish. 
13. Patient is able to operate the eDiary adequately and agrees to adhere to the study 
requirements. 
14. For patients who are receiving supplementation of a fat-soluble vitamin in order to correct or 
avoid a fat-soluble vitamin deficiency, the patient is willing to take the vitamin supplement at 
least 4 hours before taking study medication.  
3.3.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible to participate in the study: 
1. Patient has a history of complete lack of GERD symptom response to PPIs in the past. 
2. Patient reports epigastric pain or burning as his or her predominant symptom at the Screening 
Visit. 
3. Patient has a history of gastroparesis, bowel obstruction, or is at risk for a bowel obstruction 
(e.g., patient has an organic GI motility disorder or a history of major GI surgery).  
4. Patient has a history of serum triglycerides concentrations > 500 mg/dL on a fasting 
specimen, or has serum triglycerides concentrations > 500 mg/dL on a fasting specimen at 
Screening or any time during the Pretreatment Period.  
5. Patient has a history of hypertriglyceridemia-induced pancreatitis.  
6. In the Investigator's opinion, patient is susceptible to a deficiency of fat-soluble vitamins 
(especially vitamin D deficiency; e.g., the patient is African American or Hispanic or has 
osteoporosis, osteomalacia, etc.) and will be put at risk by receiving colesevelam for 8 weeks. 
7. Patient has an active swallowing disorder that would prevent them from being able to 
swallow the study medication.  
8. Patient has any alarm symptoms including but not limited to GI bleeding, anemia, vomiting, 
or unexpected weight loss any time during the Screening or Pretreatment Periods. 
9. Patient has undergone surgery that meets any of the following criteria:  
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a. Surgery of the GI tract (including gastric banding) other than an appendectomy,  
holecystectomy, minor oral or rectal surgery (e.g., tonsillectomy, hemorrhoidectomy, 
rectocele repair) at any time before the Screening Visit 
b. An appendectomy during the 3 months before the Screening Visit or a cholecystectomy 
during the 6 months before the Screening Visit or minor oral or rectal surgery during the 
30 days before the Screening Visit 
c. Non-GI surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months 
before the Screening Visit 
d. Thoracic surgery during the 6 months before the Screening Visit 
e. Other major non-GI surgery during the 30 days before the Screening Visit 
10. Patient has previously undergone thoracic or abdominal radiotherapy. 
11. EGD, conducted during the Screening Period, reveals that the patient has long-segment 
Barrett’s esophagus (greater than 3 centimeters) or definite dysplastic changes in the 
esophagus, peptic ulcer disease, active GI bleeding, presence of symptomatic esophageal 
strictures, presence of esophageal or fundic varices, erosive gastritis, or eosinophilic, herpetic 
or candida esophagitis.  
12. Patient has Gilbert’s disease, Crohn’s disease, diabetes mellitus, Zollinger-Ellison syndrome, 
pancreatitis, cholecystitis, or systemic sclerosis. 
13. Patient has elevated (defined as > 1.5 times the upper limit of normal by the laboratory) 
levels of serum bilirubin at Screening or anytime during the Pretreatment Period. 
14. Patient has a history of clinically significant hypersensitivity or allergies to any of the 
excipients contained in the study medication (active or placebo).  
15. Patient has a history of cancer (resected basal cell or squamous cell carcinoma is acceptable). 
Note: patients with a history of cancer are allowed provided that the malignancy has been in 
complete remission for at least 5 years before the Screening Visit. A complete remission is 
defined as the disappearance of all signs of cancer in response to treatment. 
16. Patient has history of active alcoholism, drug addiction, or illicit drug use (including 
marijuana) during the 12 months before the Screening Visit. 
17. Patient has any clinically significant finding on a physical exam, 12-lead electrocardiogram 
(ECG), or clinical laboratory test after signing the ICF but before receiving the first dose of 
study medication. (Note: The Investigator will determine if a particular finding is clinically 
significant. In making this determination, the Investigator will consider whether the 
particular finding could prevent the patient from performing any of the protocol-specified 
assessments, could represent a condition that would exclude the patient from the study, could 
represent a safety concern if the patient participates in the study, or could confound the 
study-specified assessments of safety or efficacy.)  
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18. Patient reports using a prohibited medication during the Screening or Pretreatment Periods, 
or is not willing or able to abide by the restrictions regarding use of prohibited medications as 
defined in Appendix 4.  
19. Patient has received an investigational drug during the 30 days before the Screening Visit, or 
is planning to receive another investigational drug or use an investigational device at any 
time during the study.  
20. 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. 
21. Patient has previously entered the Treatment Period of study in which IW-3718 is a 
treatment. 
22. Patient has previously entered the Pretreatment Period of this study. 
23. Patient is enrolled in this study at another clinical study site; is an employee of the Institution 
or Ironwood Pharmaceuticals; or is a first-degree family member, significant other, or 
relative residing with an employee of the Institution or Ironwood Pharmaceuticals. 
3.3.2 
Removal of Patients from Therapy or Assessment 
A premature discontinuation will occur when a patient who has signed the ICF ceases 
participation in the study, regardless of circumstances, before completion of the Treatment 
Period. 
A patient will be considered to have completed the study after receiving 8 weeks of treatment 
and completing the End-of-treatment (EOT) Visit at Day 57. A window of +3 days will be 
allowed for the EOT visit; if a patient completes the EOT Visit prior to Day 57, this will be 
considered a protocol deviation. 
Patients will be informed that they are free to withdraw from the study at any time and for any 
reason. The Investigator may remove a patient from the study if, in the Investigator’s opinion, it 
is not in the best interest of the patient to continue the study. Patients may also be discontinued 
from the study by the Investigator or the Sponsor at any time for any reason, including the 
following: 
• Failure to meet an inclusion/exclusion criterion that is clinically relevant and affects patient 
safety 
• Adverse event(s) 
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• Protocol violation, including lack of compliance 
• Insufficient therapeutic response (lack of efficacy) 
• Lost to follow-up (every effort must be made to contact the patient; a certified letter must be 
sent) 
• Withdrawal of consent (attempts should be made to determine the reason for the patient 
withdrawing consent if possible) 
• Study termination by the Sponsor 
• Other reasons (e.g., administrative reasons or pregnancy) 
 
The date the patient is withdrawn from the study and the reason for discontinuation will be 
recorded on the study termination form of the electronic case report form (eCRF). Patients who 
discontinue from the study for any reason should complete the assessments required at the EOT 
Visit at the time of their discontinuation. Patients who discontinue from the study will be 
followed until resolution of all of their AEs or until the unresolved AEs are judged by the 
Investigator to have stabilized. Study centers should make a reasonable effort to follow any 
pregnant patients until delivery or end of the pregnancy. 
If a patient does not return for a scheduled visit, the study center should contact the patient. An 
effort must 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. 
3.3.3 
Replacement Procedures 
Patients in this study who prematurely discontinue treatment will not be replaced. 
3.4 
STUDY TREATMENTS 
3.4.1 
Investigational Product 
3.4.1.1 
IW-3718 
Study medication will be provided as 500 mg IW-3718 tablets which are white to off-white, oval 
shaped, film-coated tablets intended for oral administration. In addition to the active drug 
substance, colesevelam, 500 mg IW-3718 tablets contain the following inactive ingredients: 
microcrystalline cellulose, polyethylene oxide, colloidal silicon oxide, butylated hydroxyl 
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toluene, magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium dioxide, and talc. 
Tablets should be taken whole and never broken, crushed, or chewed.  
Patients randomized to receive IW-3718 will administer the test product as follows: 
• 500 mg IW-3718 BID: One 500 mg IW-3718 oral tablet plus 2 placebo oral tablets (3 tablets 
total) administered BID, immediately after the morning and evening meals 
• 1000 mg IW-3718 BID: Two 500 mg IW-3718 oral tablets plus 1 placebo oral tablet 
(3 tablets total) administered BID, immediately after the morning and evening meals 
• 1500 mg IW-3718 BID: Three 500 mg IW-3718 oral tablets administered BID, immediately 
after the morning and evening meals 
 
3.4.1.2 
Placebo 
Placebo to match 500 mg IW-3718 tablets will be provided as white to off-white, oval shaped, 
film-coated, oral tablets containing microcrystalline cellulose, polyethylene oxide, colloidal 
silicon oxide, butylated hydroxyl toluene, magnesium stearate, polyvinyl alcohol, polyethylene 
glycol, titanium dioxide, and talc. Tablets should be taken whole and never broken, crushed, or 
chewed. 
Patients randomized to receive placebo will administer the test product as follows: 
• Three oral placebo tablets will be administered BID immediately after the morning and 
evening meals. 
 
3.4.1.3 
Rescue Medicine 
Antacid rescue medicine will be provided to the clinical site as a bottled liquid (magnesium 
hydroxide 200 mg/aluminum hydroxide 200 mg per 5 mL). 
During completion of the PDA daytime and nighttime diary questions, patients will be asked 
about their rescue medicine use by responding to the following questions: 
• “How many times did you use your rescue medicine (liquid antacid) from the time you got 
out of bed this morning until now?” (Daytime assessment, completed at night before going to 
bed) 
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• “How many times did you use your rescue medicine (liquid antacid) last night?” (Nighttime 
assessment, completed in the morning) 
 
3.4.1.4 
Treatment Compliance 
Patients will be dispensed the appropriate number of Sponsor-packaged, labeled blister wallets 
needed until the next study visit (see Section 3.6). Patients will be asked to return all blister 
wallets (including unused tablets) at each study visit for assessment of compliance with the 
dosing regimen. 
Patients will record their PPI administration each day (once daily) in their eDiary. 
3.4.2 
Packaging and Labeling 
Study medication (IW-3718 and placebo tablets) will be provided by Ironwood as 60 count 
blisters in wallets, indicating morning and evening doses. Study medication will be uniquely 
numbered and labeled in a double-blind fashion that conforms to regulatory requirements. 
3.4.3 
Storage and Stability 
Study medication (IW-3718 and placebo tablets) will be shipped at refrigerated temperatures 
between 2°C and 8°C (36°F and 46°F) and must be stored at refrigerated temperatures between 
2°C and 8°C (36°F and 46°F). Antacid rescue medicine will be shipped at room temperature 
between 20°C and 25°C (68°F and 77°F) and must be stored at room temperature between 20°C 
and 25°C (68°F and 77°F). Any deviation from these 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. 
The Investigator must ensure that the receipt and use of all study medication supplied is recorded 
and must supervise the storage and allocation of these supplies. All study medication supplies 
must be retained in a locked room that may only be accessed by the Investigator, or other duly 
designated persons. Study medication must not be used outside the context of this protocol, and 
under no circumstances should the Investigator or study center personnel allow the supplies to be 
used other than as directed by this protocol without prior authorization from Ironwood. 
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3.4.4 
Method of Assigning Patients to Treatment Groups 
Patients who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized into the study on Day 1. Patients will be stratified by whether they have or do not 
have erosive esophagitis on the screening EGD then randomized through central randomization 
in a 1:1:1:1 ratio to receive either 500 mg IW-3718 BID, 1000 mg IW-3718 BID, 1500 mg 
IW-3718 BID, or placebo BID.  
The computer-generated randomization schedule will be prepared by an independent statistician 
not otherwise associated with the study. 
3.4.5 
Selection of Dosage in the Study 
During this study, oral doses of IW-3718 at 500 mg BID (total daily dose of 1000 mg/day), 
1000 mg BID (total daily dose of 2000 mg/day), and 1500 mg BID (total daily dose of 
3000 mg/day) given as an adjunct to QD PPI for 56 days will be studied in order to evaluate the 
dose-response relationship for IW-3718 in a placebo-controlled study. The 1000 mg BID dose 
was used in a previous Phase 2a study (Study ICP-3718-201) and provided a reasonable level of 
efficacy with an acceptable safety and tolerability profile. The highest dose level (1500 mg BID) 
was chosen to determine whether it can provide a higher level of efficacy with an acceptable 
safety profile. The lowest dose level (500 mg BID) will be included since it may demonstrate 
efficacy, and will allow for a more accurate assessment of the dose-response relationship for 
IW-3718. This could support the proof-of-concept for efficacy and support further evaluation of 
IW-3718 in Phase 3 studies with any of the 3 dose levels. In addition to assessing efficacy for 
each dose group, the safety profile at all 3 doses will also be evaluated. 
3.4.6 
Selection and Timing of Dose for Each Patient 
Patients will be randomized to receive 500 mg IW-3718 BID, 1000 mg IW-3718 BID, 1500 mg 
IW-3718 BID, or placebo BID. The first dose of study medication will be taken with liquid and a 
snack in clinic at the Randomization Visit (on Day 1). Patients should take their second dose that 
evening immediately upon completion of dinner, ensuring that at least 8 hours have elapsed since 
the first dose in clinic. 
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During the Treatment Period, patients will take study medication BID at home, in the morning 
(immediately upon completion of breakfast) and in the evening (immediately upon completion of 
dinner), even on study visit days. The last dose of study medication will be taken the morning of 
the EOT Visit.  
Additionally, all patients will take their current PPI during the Pretreatment, Randomization, and 
Treatment Periods (i.e., Day -21 through Day 57 [+ 3 days]). The PPI will be taken each day, 
approximately 30-60 minutes before breakfast. 
During completion of the PDA daily diary questions, patients will be asked to confirm daily 
dosing of their PPI by responding to the following question: 
• “Did you take your PPI this morning?” 
3.4.7 
Blinding 
This study is double-blind and placebo-controlled. The Sponsor, Investigator, and study center 
staff will be blinded to treatment assignments.  
Unblinding of a patient’s treatment assignment is restricted to emergency situations and should 
only be used under circumstances where knowledge of the treatment is necessary for the proper 
handling of the patient. Except in a medical emergency, the Investigator and blinded study center 
staff will remain blinded during the conduct of the study and until such time that all 
discrepancies in the clinical database are resolved (i.e., at the time of the database lock). 
Individual patient treatment assignment unblinding is available to the Investigator through the 
interactive web response system (IWRS) in the event of an emergency. The Investigator should 
make all reasonable efforts to notify and discuss the circumstances requiring unblinding with the 
Medical Monitor or designee in advance of breaking the blind. If the treatment blind is broken, 
the reason and the date should be recorded and signed by the Investigator and information 
regarding the unblinding should be submitted as soon as possible to the Sponsor. The patient will 
be immediately withdrawn from the study if the code is broken. 
The Sponsor may also break the blind in circumstances where unblinding is necessary for the 
safety of the patients. 
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3.4.8 
Prior and Concomitant Medications 
At the Screening Visit, the following information will be recorded for each patient: 
• All medications the patient is taking (ongoing) 
• All prior medications taken during the 30 days before the Screening Visit 
• Most recent use of an H2RA  
• Most recent use of an antacid  
 
Any medication taken by a patient during the course of the study (beginning at the Screening 
Visit), including any new medications added or changes in medications previously reported, and 
the reason for its use will be documented in the source documents and the eCRF. 
3.4.8.1 
Rescue Medication 
During the Pretreatment and Treatment Periods, patients may use dispensed, protocol-permitted 
antacid (magnesium hydroxide 200 mg/aluminum hydroxide 200 mg per 5 mL; 15 mL up to 
4 times/day) as rescue medicine when their heartburn becomes intolerable. Each day, patients 
will record in their eDiary the number of times that rescue medication was used. 
3.4.8.2 
Prohibited Medicines 
Medicines that are not permitted during the Pretreatment and Treatment Periods are provided in 
Appendix 4. 
3.4.9 
Dietary Requirements 
Per the inclusion criteria, patients must agree not to make any changes to their usual diet during 
the study, except as required for study-specific procedures (e.g., Bilitec). 
3.5 
SAFETY AND EFFICACY ASSESSMENTS 
The timing of safety and efficacy assessments is presented in Section 3.6. 
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3.5.1 
Safety Assessments 
3.5.1.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  
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. 
An AE includes, but is not limited to, the following: 
• Any unfavorable changes in general condition 
• Any clinically significant worsening of a pre-existing condition 
• Any intercurrent diseases and accidents 
 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
3.5.1.1.1 
Causality Assessment 
For all AEs, the Investigator must provide an assessment of causal relationship to study 
medication. The causality assessment must be recorded in the patient’s source documentation 
and on the AE page of the patient’s eCRF. Causal relationship must be assessed according to the 
following: 
 Related: 
An AE where there is a reasonable possibility of a causal relationship 
between the event and the study medication 
 Unrelated: Any other AE 
3.5.1.1.2 
Severity Assessment 
The Investigator 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 
will be assessed according to the following scale: 
 Mild: 
The AE was an annoyance to the patient but did not further hinder baseline 
functioning 
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 Moderate: 
The AE caused the patient to experience some discomfort or some 
interference with normal activities but was not hazardous to health; 
prescription drug therapy may have been employed to treat the AE 
 Severe: 
The AE caused the patient to experience severe discomfort or severely 
limited or prevented normal activities and represented a definite hazard to 
health; prescription drug therapy and/or hospitalization may have been 
employed to treat the AE 
 
3.5.1.2 
Serious Adverse Events 
A serious AE (SAE) is defined as any AE occurring at any dose that results in any of the 
following outcomes: 
• Death 
• Life-threatening: the patient was at immediate risk of death from the reaction as it occurred 
(i.e., it does not include a reaction that hypothetically might have caused death had it 
occurred in a more severe form) 
• Hospitalization or prolongation of an existing hospitalization 
• Persistent or significant disability or incapacity: a substantial disruption of a person’s ability 
to conduct normal daily functions 
• Congenital anomaly or birth defect 
• Important medical events: events that may not result in death, be life-threatening, or require 
hospitalization. Such an event may be considered serious when, based on appropriate medical 
judgment, it may jeopardize the subject and may require medical or surgical intervention to 
prevent 1 of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency department or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Emergency room visits that do not result in admission to the hospital should be evaluated for 1 of 
the other serious outcomes (e.g., life-threatening, other serious [medically important] event). 
 
 
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3.5.1.3 
Reporting Adverse Events and Serious Adverse Events and Pregnancy 
SPECIAL SITUATION: EXPOSURE TO STUDY DRUG DURING PREGNANCY 
1. A patient who reports pregnancy prior to study drug randomization must be withdrawn from 
the study.  The pregnancy is recorded as a reason for screen failure. Since there has been no 
exposure to study drug, there is no need to notify Ironwood Drug Safety of the pregnancy. 
2. A patient who reports pregnancy after randomization, must discontinue study drug at once. 
The site must notify Ironwood Drug Safety via PPD PVG email: Wilsafety@ppdi.com; fax: 
1-888-488-9697 of the pregnancy (within 24 hours), using the standard Pregnancy 
Notification Form. The site makes reasonable efforts to follow the pregnancy to term and 
notifies PPD PVG email: Wilsafety@ppdi.com; fax: 1-888-488-9697 of the pregnancy 
outcome (within 24 hours of being informed), using the standard Pregnancy Outcome Form. 
General Reporting Requirements 
Adverse events will be collected and recorded from the time the patient signs the ICF at the 
Screening Visit until 7 days after the EOT Visit. The study site will make contact with the patient 
via telephone 7 days following the EOT visit to collect information pertaining to ongoing AEs 
and information concerning new AEs. All AEs, regardless of the assumption of a causal 
relationship with study procedures or study medication, must be recorded in the patient’s source 
documentation and subsequently on the appropriate AE page of the patient’s eCRF. This record 
includes AEs the patient reports spontaneously, those observed by the Investigator, and those 
elicited by the Investigator in response to open-ended questions during the study, such as “Have 
you had any health problems since your last visit?” 
For every AE, the Investigator must 
• Provide an assessment of the severity, causal relationship to the study medication, and 
seriousness of the event; 
• Document all actions taken with regard to the study medication (i.e., no action taken, 
treatment temporarily interrupted, or treatment discontinued); and 
• Detail any other treatment measures taken for the AE, including concomitant medications 
and/or procedures. 
 
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Pretreatment AEs will be collected from the time the patient signs the ICF until the patient 
receives study medication. Pretreatment AEs will be captured in the patient’s source 
documentation, but will only be entered for randomized patients on the AE page of the patient’s 
eCRF. 
Laboratory abnormalities and changes in vital signs, physical examination findings, and 12-lead 
ECG parameters should be considered AEs and reported on the AE page of the patient’s eCRF if 
the Investigator considers them clinically significant and/or they necessitate intervention. 
Any medical condition that is present when a patient is screened and does not worsen in severity 
and/or frequency should be reported as Medical History and not as an AE. However, if the 
condition does deteriorate in severity and/or frequency at any time during the study, it should be 
reported as an AE. 
Serious Adverse Event Reporting Requirements 
An AE that meets any of the serious criteria as described in Section 3.5.1.2 must be reported to 
Ironwood within 24 hours from the time that site personnel first learn of the event, using the SAE 
Report Form provided for the study. Regardless of causality, all SAEs must be reported and will 
be collected and recorded from the time the patient signs the ICF at the Screening Visit until 
7 days after the EOT Visit. The study site will make contact with the patient via telephone 7 days 
following the EOT visit to collect information pertaining to ongoing SAEs and information 
concerning new SAEs. Any SAE that occurs at any time after that 7-day time period, and which 
the Investigator considers to be related to study medication, should be reported to Ironwood 
immediately. All SAEs must also be recorded in the patient’s source documentation and on the 
AE page of the patient’s eCRF. 
The initial report should include at least the following information: 
• Patient identification number 
• Description and onset of the event 
• Serious criteria 
• Causality assessment to study medication 
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All SAE Report Forms should be faxed or emailed to: 
PPD PVG 
Fax: 1-888-488-9697 
Email: Wilsafety@ppdi.com 
If follow-up is obtained, or requested by Ironwood, the additional information should be faxed or 
emailed on an SAE Report Form to Ironwood in a timely manner according to the procedures 
outlined above. Copies of discharge summaries, consultant reports, autopsy reports, and any 
other relevant documents may also be requested. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE. These measures and the patient’s response to these measures should 
be recorded. All SAEs regardless of relationship to study medication, will be followed by the 
Investigator until satisfactory resolution, the Investigator deems the SAE to be chronic or stable, 
or until the patient is lost to follow-up. Clinical, laboratory, and diagnostic measures should be 
employed by the Investigator as needed to adequately determine the etiology of the event. 
The Investigator will be responsible for reporting all SAEs to the Institutional Review Board 
(IRB). Ironwood will be responsible for reporting to the regulatory authorities.  
All SAEs will be followed until resolution, until the event has stabilized, or until the patient is 
lost to follow-up. 
3.5.1.4 
Medical History 
A complete medical history will be performed as defined in the Schedule of Events (Table 2). 
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3.5.1.5 
Physical Examination, Body Weight, and Height 
A complete physical examination will be performed as defined in the Schedule of Events 
(Table 2). The physical examination of each patient should include examination and assessment 
of the following: 
General appearance 
Head, eyes, ears, nose, and throat 
Cardiovascular system 
Neck 
Respiratory system 
Musculoskeletal system 
Abdomen/liver/spleen 
Nervous system 
Lymph nodes 
Skin 
Neurologic status 
Mental status 
 
Breast, genitourinary, and rectal examinations are optional and may be performed at the 
discretion of the Investigator. Any new, clinically significant abnormal findings from the 
physical examination will be reported as an AE. 
Each patient’s weight will be recorded at every study visit; height will only be recorded at the 
Screening Visit. 
3.5.1.6 
Electrocardiograms 
A 12-lead ECG will be performed as defined in the Schedule of Events (Table 2) and 
documented on the eCRF. Electrocardiograms should be obtained after the patient has been 
supine for at least 5 minutes. 
3.5.1.7 
Vital Signs 
Vital sign measurements will be performed as defined in the Schedule of Events (Table 2) and 
documented on the eCRF. Vital sign measurements include oral temperature (°C), respiratory 
rate, systolic and diastolic blood pressure (BP), and pulse. Respiratory rate, pulse, and BP 
readings will be taken after the patient has been seated for at least 5 minutes. 
3.5.1.8 
Clinical Laboratory Determinations 
Blood and urine samples for clinical laboratory tests will be collected at the visits defined in the 
Schedule of Events (Table 2). The clinical laboratory evaluations will include the clinical 
chemistry, hematology, coagulation, and urinalysis parameters presented in Table 1. 
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Table 1. 
Clinical Laboratory Tests 
Clinical Chemistry 
Hematology (CBC) 
Complete Urinalysis 
A1C 
Hematocrit 
pH and specific gravity 
Albumin 
Hemoglobin 
Bilirubin 
Alkaline phosphatase 
Platelet count 
Glucose 
ALT 
MPV 
Ketones 
AST 
RBC count 
Leukocytes 
Bicarbonate 
WBC count 
Nitrites 
BUN 
WBC differential 
Occult blood 
Calcium 
(% and absolute) 
Protein 
Chloride 
Basophils 
Urobilinogen 
Total cholesterol 
Eosinophils 
 
HDL cholesterol 
Lymphocytes 
 
LDL cholesterol  
Monocytes 
 
Creatinine 
Neutrophils 
 
GGT 
RBC indices 
 
Glucose 
MCH 
 
Iron 
MCHC 
 
LDH 
MCV 
 
Magnesium 
RDW 
 
Phosphorus 
Coagulation 
 
Potassium 
aPTT 
 
Sodium 
PT 
 
Total bilirubin 
 
 
Total protein 
 
 
Triglycerides 
 
 
Uric acid 
 
 
Abbreviations: A1C = glycated hemoglobin; ALT = alanine aminotransferase; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; 
GGT = gamma glutamyl transferase; HDL = high-density lipoprotein; LDH = lactate dehydrogenase; LDL = low-
density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume; MPV = mean platelet volume; PT = prothrombin time; RBC = red blood cell; 
RDW = red cell distribution width; WBC = white blood cell 
 
A blood sample for serum pregnancy testing will be collected from all female patients of 
childbearing potential (i.e., women who are not postmenopausal or who have not had a bilateral 
oophorectomy, hysterectomy, or tubal ligation) at the Screening and EOT Visits, and a urine 
sample will be collected at the Randomization Visit (prior to dosing) and the Week 4 Visit. 
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These pregnancy test results must be negative for patient eligibility. Ironwood may perform non-
genetic analyses on existing plasma or serum samples for research purposes (e.g., bile in serum). 
A urine screen for selected drugs of abuse (cocaine, barbiturates, amphetamines, opiates, 
benzodiazepines, and cannabinoids) and a serum alcohol screen will be performed at the 
Screening Visit. 
3.5.1.9 
Esophagogastroduodenoscopy 
At all sites, an EGD will be performed on all patients at the screening visit.  An additional EGD 
will be performed at the Week 8/EOT Visit in all patients who had an EGD during the Screening 
Period that demonstrated Grade C or D esophagitis (based on the Los Angeles classification of 
esophagitis; Appendix 5).  
3.5.1.10 
Bravo 
At all sites, all patients will undergo 48 to 96 hours of pH testing with the Bravo device. If for 
some reason 96 hours of testing is not possible, then approximately 48 hours of testing is 
acceptable. During the entire period of Bravo pH monitoring (approximately 48-96 hours), 
patients will record ingestion of anything other than water by depressing the ‘meal’ button on the 
Bravo device upon the beginning and completion of the event.  Patients will also record any 
periods during which they are lying down by depressing the ‘supine’ button on the Bravo device 
at the beginning and upon completion of the supine period.  In addition, for the entire 48-96 hour 
Bravo pH monitoring period, patients will also complete a paper diary (see Appendix 9), 
recording at a minimum all instances of meals, snacks, drinks, and/or resting in the supine 
position. All patients will return to the site with their Bravo pH monitor and patient diary after 
approximately 96 hours (or 48 hours where applicable) to return the recording device. Please 
refer to the Bravo Site Manual for specific instructions. 
3.5.1.11 
Bilitec 
At certain participating sites, selected patients who are screened with EGD and Bravo testing 
will also receive insertion of a Bilitec device during the same procedure. The patient selection 
will be dependent on Investigator selection and patient consent. All such patients will return to 
the site approximately 24 hours after the procedure for removal of the device. All patients 
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participating in the Bilitec testing will also have to follow very specific procedures including a 
“white diet” (see Appendix 8 for a sample “white diet”) during this 24 hour period. Please refer 
to the Bilitec Site Manual for specific instructions.  Notes for patients who are participating in 
Bilitec testing: the internal clocks for the Bravo pH recorder and Bilitec device should be 
synchronized, and both devices should be activated and begin recording simultaneously; if it is 
not possible to simultaneously activate both devices, the Bravo recorder should be activated first, 
with the Bilitec device activated immediately (within 5 minutes) after the Bravo pH recorder 
activation. 
3.5.2 
Efficacy Assessments 
The daily patient assessments used to determine the key efficacy parameters are the daily 
assessment of heartburn symptoms (assessed on a 0-to-5 ordinal severity scale) and regurgitation 
symptoms (assessed on a 0-to-4 ordinal frequency scale) obtained from the mRESQ-eD. 
Additional assessments will also be used to determine the other efficacy parameters, as described 
in the sections that follow. 
3.5.2.1 
Symptom Severity Assessment 
3.5.2.1.1 
Daily Assessments 
During the Pretreatment and Treatment Periods, patients will enter information into their eDiary 
at approximately the same time each day.  
• GERD symptoms (mRESQ-eD, Appendix 1) completed once daily before going to bed each 
night.  
 
Note: The following items are assessed on a 0-5 severity scale: 0=Did not have, 1=Very 
mild, 2=Mild, 3=Moderate, 4=Moderately severe, 5=Severe 
 
o Heartburn 
o Burning feeling behind breastbone or in the center of the upper stomach 
o Pain behind the breastbone or in the center of the upper stomach 
o Difficulty swallowing 
o Hoarseness 
o Cough 
 
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Note: The following items are assessed on a 0-4 frequency scale: 0=Never, 1= Rarely, 
2=Sometimes, 3=Often, 4=Very often 
 
o Regurgitation (liquid or food) moving upwards toward your throat or mouth 
o An acid or bitter taste in the mouth 
o Burping 
o Coughing 
 
 Dyspepsia symptoms (Daily Dyspepsia Symptoms, Appendix 2) completed once daily before 
going to bed each night.  
 
Note: All items are assessed on a 0-to-10 numerical rating scale (NRS) with 0=not having the 
symptom and 10=having the worst possible level of the symptom 
 
o Worst nausea (feeling like you might throw up) 
o Worst stomach fullness after you finished eating 
o Difficulty you had finishing your meals because you felt full too quickly 
o Worst abdominal pain 
 
 Assessment of sleep (Daily Assessment of Sleep, Appendix 3) completed once daily upon 
getting up each morning (5:00 a.m. to 12:00 p.m.) 
 
o Last night, did you wake up during the night after falling asleep? Y/N 
o [If yes], how many times did you wake up last night after falling asleep?  
o How long did you sleep last night? Do not count any time you lay in bed, but did 
not sleep.  
o Please rate the overall quality of your sleep last night. 1=very poor, 2=poor, 3=fair, 
4=good, 5=very good 
 
• Use of per-protocol rescue medicine (antacids) 
 
 
 
 
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3.5.2.1.2 
Weekly Assessments 
The following information will be entered into the eDiary each week at about the same time as 
the evening daily assessment (see Appendix 6): 
• Degree of relief questions  
Note: all items are assessed on a 7-point balanced ordinal scale: 1=Significantly relieved, 
2=Moderately relieved, 3=Somewhat relieved, 4=Unchanged, 5=Somewhat worse, 
6=Moderately worse, 7=Significantly worse 
 
o How would you rate your heartburn (a burning sensation in your chest, behind the 
breastbone) over the past 7 days? 
o How would you rate your regurgitation (the feeling of stomach contents, either 
liquid or food, moving upwards to your throat or mouth) over the past 7 days? 
o Compared to before you started this study, how would you rate your overall 
GERD symptoms over the past 7 days? 
 
• Global Treatment Satisfaction Assessment  
Note: the following items will be assessed on a 5-point ordinal scale: 1=Very dissatisfied, 
2=Dissatisfied, 3=Neither satisfied nor dissatisfied, 4=Satisfied, 5=Very satisfied 
 
o How would you rate your satisfaction with the study treatment? 
 
• Bothersomeness Assessment.  
Note: the following items will be assessed on a 5-point ordinal scale: 1=Not at all, 2=A little 
bit, 3=A moderate amount, 4=A great deal, 5=An extreme amount 
 
o How much were you bothered by heartburn (a burning sensation in your chest, 
behind the breastbone) over the past week? 
o How much were you bothered by regurgitation (the feeling of stomach contents, 
either liquid or food, moving upwards to your throat or mouth) over the past 
week? 
 
Weekly items assessing symptom bothersomeness and symptom relief will be used to explore 
responder definitions and treatment benefit analysis. 
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3.5.2.2 
GSRS-Self 
The Gastrointestinal Symptoms Rating Scale (GSRS)-Self is a self-administered 15-item 
questionnaire that uses a 7-point Likert scale for discomfort: 
1 = None 
2 = Minor 
3 = Mild 
4 = Moderate 
5 = Moderately severe 
6 = Severe 
7 = Very severe 
The items can then be grouped into 5 domains: abdominal pain (3 items), reflux syndrome 
(2 items), indigestion (4 items), diarrhea (3 items), and constipation (3 items) (17). Patients will 
complete the GSRS-Self at the Randomization Visit, the Week 4 Visit, and at the EOT Visit; 
responses will be recorded in an electronic diary via a portable PDA device. 
3.5.2.3 
QIDS-SR-16 
The Quick Inventory of Depressive Symptomatology (QIDS)-SR-16 is a self completed 
questionnaire designed to assess the severity of 9 clinically defined symptoms of depression on a 
scale from 0 (no symptom impact) to 3 (severe impact) (18). The tool can be used to screen for 
depression or as a measure of symptom severity. Patients will complete the QIDS-SR-16 at the 
Randomization Visit. Responses will be recorded in an electronic diary via a portable PDA 
device. 
3.5.2.4 
SF-12V2 Health Survey 
The SF-12V2 is a widely used generic measure of health status and measures 8 concepts of 
health: 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 component and mental 
component summary scores (19). Patients will complete the SF-12V2 at the Randomization 
Visit, the Week 4 Visit, and at the EOT Visit; responses will be recorded in an electronic diary 
via a portable PDA device. 
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3.5.2.5 
EQ-5D-3L 
The EuroQol (EQ)-5D-3L is a generic measure of health widely used in Europe (20). The first 
component 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 (21). The second 
component of the EQ-5D is a visual analogue scale, asking patients to rate their health from 0 to 
100 (0 represents worst imaginable health state and 100 represents best imaginable health state). 
Patients will complete the EQ-5D-3L at the Randomization Visit, the Week 4 Visit, and at the 
EOT Visit; responses will be recorded in an electronic diary via a portable PDA device. 
3.5.2.6 
End-of-treatment Question 
Patients will be asked a single item at their final visit (EOT), asking about the difficulty of 
swallowing the treatment medication (see Appendix 6). The item will ask “How difficult were 
the tablets to swallow?” and be rated on a 4 point ordinal scale: 
1 = Not at all difficult 
2 = A little difficult 
3 = Moderately difficult 
4 = Extremely difficult 
 
3.5.2.7 
mRESQ Cognitive Debriefing Interviews 
Cognitive debriefing interviews will be conducted to support the modified mRESQ as fit for 
purpose in the context of a clinical trial.  The original RESQ-eD was modified including 
instructions, removal of redundant items, and inclusion of alternate response scales for selected 
symptoms.  Guidance on instrument development emphasizes the need for adequate empirical 
evidence in the patient population targeted for enrollment in the clinical trials to support content 
validity for the desired claim. To that end, a sample of patients at selected sites will be asked to 
participate in an optional symptom diary interview, either via phone or face to face.  
Approximately 30 subjects will be interviewed from participating sites; 5 screen failures, 5 pre-
treatment and 20 active treatment subjects will be interviewed.  During the one time interview, 
patients will be asked to respond to open-ended questions intended to assess content validity of 
the mRESQ-eD instrument.  See Appendix 10 for further details.  
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3.6 
SCHEDULE OF EVENTS 
The schedule of study procedures and assessments is presented by visit in the Schedule of Events 
in Table 2. 
 
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Table 2. 
Schedule of Events 
 
Screening 
Period 
(Up to 4 
weeks)w 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-up
Visit Days → 
Screening 
Visit (Day 
-49 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -1) 
Randomization 
Visit 
(Day 1) 
Week 2 
Visit 
(Day 15 ± 3)
Week 4 
Visit 
(Day 29 ± 3)
Week 8 / 
End-of-treatment 
Visit  
(Day 57 +3) 
EOT 
+ 7 days 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Study Procedure ↓ 
 
 
 
 
 
 
 
Inclusion and Exclusion Criteria 
Verification 
X 
X 
X 
 
 
 
 
Signing of ICF 
X 
 
 
 
 
 
 
IWRS Registration (a) 
X 
X 
X 
X 
X 
X 
 
Medical History 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Physical Examination (b) 
X 
 
 
 
 
X 
 
Body Weight and Height (c)  
X 
X 
X 
X 
X 
X 
 
H2RA/Antacid Washout (d) 
X 
 
 
 
 
 
 
Bilitec Monitoring (e) 
X 
 
 
 
 
 
 
EGD (f) 
X 
 
 
 
 
X 
 
48 to 96 Hours of pH Testing 
with Bravo Device (g) 
X 
 
 
 
 
 
 
Seated Vital Signs (h)  
X 
X 
X 
X 
X 
X 
 
12-Lead ECG (i) 
X 
 
X 
 
 
X 
 
Prior and Concomitant 
Medications (j) 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory Tests(k) 
X 
 
X 
 
X 
X 
 
Serum Pregnancy Test (l) 
X 
 
 
 
 
X 
 
Urine Pregnancy Test (l) 
 
 
X 
 
X 
 
 
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Table 2. 
Schedule of Events 
 
Screening 
Period 
(Up to 4 
weeks)w 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-up
Visit Days → 
Screening 
Visit (Day 
-49 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -1) 
Randomization 
Visit 
(Day 1) 
Week 2 
Visit 
(Day 15 ± 3)
Week 4 
Visit 
(Day 29 ± 3)
Week 8 / 
End-of-treatment 
Visit  
(Day 57 +3) 
EOT 
+ 7 days 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Study Procedure ↓ 
 
 
 
 
 
 
 
Drug and Alcohol Screen (m) 
X 
 
 
 
 
 
 
AE Evaluations (n) 
X 
X 
X 
X 
X 
X 
 
Rescue Medicine Dispensed (o) 
 
X 
X 
X 
X 
 
 
PDA Training and Dispensation 
 
X 
 
 
 
 
 
Saliva Collection (p) 
X 
X 
X 
 
X 
X 
 
eDiary (q) 
 
X 
X 
X 
X 
X 
 
Weekly Symptom and Treatment 
Assessments (r) 
 
X 
X 
X 
X 
X 
 
GSRS-Self 
 
 
X 
 
X 
X 
 
QIDS-SR-16 
 
 
X 
 
 
 
 
SF-12V2 
 
 
X 
 
X 
X 
 
EQ-5D-3L 
 
 
X 
 
X 
X 
 
Randomization 
 
 
X 
 
 
 
 
Study Medication Dispensed (s) 
 
 
X 
X 
X 
 
 
Study Medication Return (t) 
 
 
 
X 
X 
X 
 
PDA Return 
 
 
 
 
 
X 
 
mRESQ Debrief Interview (x) 
 
X (x) 
 
 
X (x) 
 
 
End-of-treatment Question (u) 
 
 
 
 
 
X 
 
Safety Follow-up Call (v) 
 
 
 
 
 
 
X 
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Abbreviations: AE = adverse event; BP = blood pressure; CBC = complete blood count; ECG = electrocardiogram; EGD = esophagogastroduodenoscopy; 
EOT = End-of-treatment; EQ = EuroQol; GSRS = Gastrointestinal Symptoms Rating Scale; H2RA = histamine-2 receptor antagonist; HEENT = head, eyes, ears, 
nose, and throat; ICF = informed consent form; IWRS = interactive web response system; PDA = personal digital assistant; PPI = proton pump inhibitor; 
QID = Quick Inventory of Depressive Symptomology; mRESQ-eD = modified Reflux Symptom Questionnaire Electronic Diary; SAE = serious adverse event; 
SF = short form 
a. 
Site personnel will interact with IWRS to register the patient visit and transition the patient to the next appropriate study period. 
b. A physical examination should include the following assessments: general appearance; HEENT; neck; cardiovascular; respiratory; abdomen/liver/spleen; 
musculoskeletal; lymph nodes; skin; neurologic; nervous system, and mental status. Breast, genitourinary, and rectal examinations are optional and may be 
performed at the discretion of the Investigator. 
c. 
Height will be measured only at the Screening Visit.  
d. During the Screening Period, patients will begin to washout H2RAs and antacids. H2RAs should be stopped 5 calendar days prior to the EGD and Bravo pH 
monitoring and antacids should be stopped 1 calendar day prior to the EGD and Bravo pH monitoring. Patients may resume antacid use upon completion of 
the Bravo testing, but must refrain from H2RA use for the remainder of the study.  During the Pretreatment Period, patients will refrain from using any anti-
reflux medications, antacids, and H2RAs, except for the antacids that are provided as rescue medicine). Patients will continue to use their current PPI during 
the Pretreatment Period. 
e. 
At selected sites, selected patients who are screened for the study with EGD and Bravo testing will also be given the option of having a Bilitec monitor 
inserted during the same procedure. These patients will return 24 hours later for removal of the probe. The results of the Bilitec test will not affect 
qualification for enrollment. The Bilitec device and Bravo recorder internal clocks must be synchronized, and both devices should be activated concurrently; 
however, if it is not possible to simultaneously activate both devices, the Bravo recorder should be activated first, with the Bilitec device activated 
immediately (within 5 minutes) after the Bravo pH recorder activation. 
f. 
All patients will be required to undergo an EGD during the Screening Period. There must be a minimum of 7 days between the EGD and the start of the 
Pretreatment Period. An EGD will be performed at the Week 8/EOT Visit in all patients who have Grade C or D esophagitis (based on the Los Angeles 
classification of esophagitis; see Appendix 5) on the EGD obtained during the Screening Period.  
g. Approximately 48 to 96 hours of pH testing with the Bravo device. If for some reason 96 hours of testing is not possible, then approximately 48 hours of 
testing is acceptable. During the entire period of Bravo pH monitoring (approximately 48-96 hours), patients will record ingestion of all meals, snacks, and 
drinks by depressing the ‘meal’ button on the Bravo recorder upon the beginning and completion of the meal, snack, or drink.  Patients will also record any 
periods during which they are lying down by depressing the ‘supine’ button on the Bravo recorder at the beginning and upon completion of the supine 
period.  In addition, for the entire 48-96 hour Bravo pH monitoring period, patients will also complete a paper diary (see Appendix 9), recording at a 
minimum, all instances of meals, snacks, drinks, and/or resting in the supine position. 
h. Vital sign measurements include oral temperature (°C), respiratory rate, systolic and diastolic BP, and pulse. Respiratory rate, BP, and pulse measurements 
must be obtained after the patient has been seated for at least 5 minutes. 
i. 
12-lead ECGs should be obtained after the patient has been supine for at least 5 minutes. 
j. 
Prior medications will be collected at the Screening Visit as follows: all medicines taken by the patient during the 30 days before the Screening Visit, most 
recent use of an H2RA, and most recent use of an antacid. 
k. Clinical laboratory tests include clinical chemistry, hematology (CBC), coagulation, and urinalysis. If the triglyceride value exceeds the protocol-specified 
criteria and the patient was not under fasted conditions, the patient may return to completed a fasted lipid panel. 
l. 
For all female patients of childbearing potential, a negative serum pregnancy test must be documented at the Screening Visit, and a negative urine pregnancy 
test must be documented at the Randomization Visit (before dosing) in order for the patient to be randomized into the study. A urine pregnancy test will be 
obtained at the Week 4 Visit; serum pregnancy test will be conducted at the EOT Visit. 
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m. Patients must undergo a urine drug screen for selected drugs of abuse (cocaine, barbiturates, amphetamines, opiates, benzodiazepines, and cannabinoids) and 
a serum alcohol screen at the Screening Visit. 
n. All AEs will be captured from the time the patient signs the ICF through the EOT Visit. 
o. Rescue medicine will be supplied to patients at the Pretreatment Visit, and if needed, at subsequent visits. 
p. At each of the indicated visits, patients will provide approximately 1 mL of saliva for future use (bile acids will be quantified in the saliva, and the quantity 
of bile acid may be used to define potential responders to IW-3718). At the time of saliva collection, study site staff will collect the following information: 
time of day, time of patient’s last meal, and time of last study medication administration. During the Randomization Visit, study site staff will collect the 
saliva sample immediately following the light snack but prior to study drug administration. 
q. The eDiary will be dispensed at the Pretreatment Visit and patients must complete 5 days each week during the 14 calendar days before the Treatment Period 
in order to be eligible for randomization. Patients should bring their eDiary to each visit. The eDiary will collect daily PPI administration, rescue medication 
use, mRESQ-eD (Appendix 1; daily), Daily Assessment of Sleep (Appendix 3; daily), Daily Dyspepsia Symptoms (Appendix 2; daily). 
r. 
Symptom bothersomeness and relief items (Appendix 6; weekly); Treatment satisfaction item (Appendix 6; weekly). 
s. 
The first dose of study medication will be administered in the clinic with liquid and a snack at the Randomization Visit. At all other visits, patients will take 
their study medication prior to arriving at the clinic, but will be dispensed additional doses needed until the next study visit. 
t. 
Treatment compliance with study drug will be assessed based on return of unused tablets. 
u. All patients will be asked an EOT question regarding the difficulty of swallowing the IW-3718 or placebo tablets (Appendix 6). 
v. Study site will contact each patient via telephone 7 days after the EOT Visit to collect information pertaining to ongoing AEs/SAEs and information 
concerning any new AEs/SAEs since the EOT Visit 
w. Ironwood may grant a one-week extension of the screening period window if needed for logistical delays (e.g., subject travel, scheduling issues, delays in 
test results, equipment malfunction, etc.).  Approval should be requested from Ironwood prior to each extension. 
 
 
 
 
 
 
 
 
 
x. Patients participating in the optional mRESQ-eD Cognitive Debriefing interviews will be assigned to one of three interview groups.  Interviews will take 
place at different timepoints depending on the patient’s group assignment.  (see Appendix 10)
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3.6.1 
Screening Period (Day –49 to Day -15) 
3.6.1.1 
Screening Visit (Visit 1) Procedures 
• Signing of ICF 
• Register visit in IWRS 
• Review of inclusion and exclusion criteria 
• Demographics 
• Medical history 
• Physical examination 
• Body weight and height 
• Begin H2RA and antacid washout (for 5 calendar days before the EGD and Bravo pH 
monitoring [H2RA] and 1 calendar day before the EGD and Bravo pH monitoring [antacids]) 
• EGD 
• Approximately 48 to 96 hours of pH testing with a Bravo device (if 96 hours of testing is not 
possible, then approximately 48 hours of testing is acceptable) 
• Optional 24 hours of measurements of bilirubin using the Bilitec device (for patients 
undergoing the Bilitec procedure – device removed after 24 hours) 
• Seated vital signs 
• 12-lead ECG 
• Prior medications (all medicines taken during the 30 days before the Screening Visit, most 
recent use of an H2RA, and most recent use of an antacid) 
• Collection of blood and urine samples for clinical laboratory test, including: 
 
-  Clinical chemistry 
 
-  Hematology (complete blood count [CBC]) 
 
-  Coagulation 
 
-  Urinalysis 
• Serum pregnancy test for all female patients of childbearing potential (must be confirmed 
negative) 
• AE evaluation (throughout the Screening Period) 
• Saliva collection 
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3.6.1.2 
Extension of Screening Period 
Ironwood may grant a one-week extension of the screening period window if needed for 
logistical delays (e.g., subject travel, scheduling issues, delays in test results, equipment 
malfunction, etc.).  Approval should be requested from Ironwood prior to each extension. 
If an extension of greater than one week is needed for logistical delays, subjects will be 
considered screen failures and will need to re-screen.  If these subjects had already completed the 
EGD/Bravo (and Bilitec, if applicable) assessments during the original screening period, they 
will not need to repeat these tests as long as they enter Pre-Treatment within 35 days of the 
assessments.  All other study assessments should be repeated during re-screening. Pretreatment 
Period (Day –21 to Day -1). 
3.6.1.3 
Pretreatment Visit (Visit 2) Procedures 
• Register visit in IWRS 
• Review of inclusion and exclusion criteria 
• Body weight 
• Seated vital signs 
• Prior and concomitant medications 
• AE evaluation (throughout the Pretreatment Period) 
• Antacid rescue medicine dispensation 
• PDA training 
• PDA is dispensed (for recording daily and weekly evaluations throughout the Pretreatment 
and Treatment Periods in the eDiary) 
• Saliva collection 
• A subset of patients participating in the optional Cognitive Debriefing Interview at selected 
sites will undergo the interview at this visit. 
3.6.2 
Treatment Period (Day 1 to Day 57) 
For all visits during the Treatment Period, patients will take their PPI and study medication 
(except for the Randomization Visit) prior to reporting to the study site. 
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3.6.2.1 
Randomization Visit (Visit 3) Procedures 
• Register visit in IWRS 
• Review of inclusion and exclusion criteria 
• Body weight 
• Seated vital signs 
• 12-lead ECG 
• Concomitant medications 
• Collection of blood and urine samples for clinical laboratory tests, including: 
 
-  Clinical chemistry 
 
-  Hematology (CBC) 
 
-  Coagulation 
 
-  Urinalysis 
• Urine pregnancy test for all females of childbearing potential (must be confirmed negative 
prior to dosing) 
• AE evaluation (throughout the Treatment Period) 
• Antacid rescue medicine dispensation (if needed) 
• Saliva collection 
• Collect PDA and review eDiary 
• GSRS-Self 
• QIDS-SR-16 
• SF-12V2 
• EQ-5D-3L 
• Randomization 
• Study medication dispensed 
• Study medication administration (first dose of study medication taken in clinic with liquid 
and a snack. Patients should take their second dose that evening, with liquid, immediately 
upon completion of dinner and ensure that at least 8 hours have elapsed since the first dose in 
clinic).  
 
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3.6.2.2 
Week 2 Visit (Visit 4) Procedures 
• Register visit in IWRS 
• Body weight 
• Seated vital signs 
• Concomitant medications 
• AE evaluation (throughout the Treatment Period) 
• Antacid rescue medicine dispensation (if needed) 
• Collect PDA and review eDiary 
• Return of all unused study medication  
• Additional study medication dispensed 
 
3.6.2.3 
Week 4 (Visit 5) Procedures 
• Register visit in IWRS 
• Body weight 
• Seated vital signs 
• Concomitant medications 
• Collection of blood and urine samples for clinical laboratory tests, including: 
 
-  Clinical chemistry 
 
-  Hematology (CBC) 
 
-  Coagulation 
 
-  Urinalysis 
• Urine pregnancy test for all females of childbearing potential 
• AE evaluation (throughout the Treatment Period) 
• Antacid rescue medicine dispensation (if needed) 
• Saliva collection 
• Collect PDA and review eDiary 
• GSRS-Self 
• SF-12V2 
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• EQ-5D-3L 
• Study medication dispensed 
• Return of all unused study medication  
• A subset of patients participating in the optional Cognitive Debriefing Interview at selected 
sites will undergo the interview at this visit. 
 
3.6.2.4 
Week 8/End-of-treatment (Visit 6) Procedures 
• Register visit in IWRS 
• Physical examination 
• Body weight 
• EGD 
• Seated vital signs 
• 12-lead ECG 
• Concomitant medications 
• Collection of blood and urine samples for clinical laboratory tests, including: 
 
-  Clinical chemistry 
 
-  Hematology (CBC) 
 
-  Coagulation 
 
-  Urinalysis 
• Serum pregnancy test for all female patients of childbearing potential  
• AE evaluation (throughout the Treatment Period) 
• Saliva collection 
• Review eDiary 
• GSRS-Self 
• SF-12V2 
• EQ-5D-3L 
• Return of all unused study medication  
• Return PDA device 
• End of treatment question 
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3.6.3 
Follow-up 
The study site will contact all patients via telephone 7 days following the EOT Visit in order to 
collect information regarding ongoing AEs and/or SAEs and any new AEs and/or SAEs since the 
EOT Visit (Section 3.5.1.3). 
3.6.4 
Early Termination Procedures 
Patients who discontinue from the study for any reason should complete the assessments 
required at the EOT Visit (Section 3.6.2.4) at the time of their discontinuation. 
3.7 
STATISTICAL METHODS 
Additional details regarding the statistical methods will be provided in the Statistical Analysis 
Plan (SAP), to be finalized prior to unblinding of the study. 
3.7.1 
Analysis Populations 
• The Screened Population consists of all patients who consented to participate in the study.  
• The modified Intent-to-Treat (mITT) Population consists of all randomized patients who 
received at least 1 dose of study treatment.  
• The Per-Protocol Population (PP) is defined as those patients in the mITT Population who 
have a minimum of 6 weeks of eDiary data for the heartburn severity and regurgitation 
frequency scores and > 80% compliance with study treatment for the available Treatment 
Period days.  
• The Safety Population is defined as all randomized patients who received at least 1 dose of 
study treatment. 
3.7.2 
General Methods 
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, and range). Categorical variables will be summarized using the subject count 
and proportions of patients in each category. Unless otherwise specified, all confidence intervals 
will be two-sided and with a confidence level of 95%. Due to the exploratory nature of the trial, 
no adjustments will be made for multiplicity. Details of the data handling methods will be 
specified in the SAP. If not otherwise specified, the baseline value is defined as the last non-
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missing value measured before administration of study treatment on Day 1. All statistical 
analyses will be performed using SAS® Version 9.3 (or later) for Windows. 
3.7.3 
Patient Disposition, Demographics, and Baseline Characteristics 
The count and proportion of patients included in the mITT, PP, and Safety Populations will be 
presented overall and by treatment group. The number of patients in the Screened Population 
will be presented overall. 
The count and proportion of screen failures (i.e., patients who enter the Screening Period but not 
the Pretreatment Period) and patients ineligible for randomization (i.e., patients who enter the 
Pretreatment Period but are not randomized), along with the associated reasons for failure or 
ineligibility, will be tabulated overall for the Screened Population. 
The count and proportion of patients who complete treatment, who complete the study, and who 
prematurely discontinue will be presented for each treatment group and overall for the mITT 
Population. The reason for premature discontinuation as recorded on the study completion forms 
of the eCRFs will be summarized by treatment group and overall for the mITT Population. 
Demographic parameters (e.g., age, sex, race, weight, height, and body mass index) and other 
baseline characteristics (including heartburn severity, regurgitation frequency, and weekly 
assessments) will be summarized by treatment group. 
3.7.4 
Efficacy Analyses 
Table 3 provides the analysis time windows allowed for the efficacy analyses in the Pretreatment 
and Treatment Periods. 
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Table 3. 
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 (Day before first 
dose) 
Treatment 
Week 1  
Day 1 (Day 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 
a. 
Relative to the date of first dose (Day 1). 
b. Baseline values for efficacy parameters will be derived from the daily eDiary and eCRF data collected in the 
Pretreatment Period Week -2 and Week -1. 
 
3.7.4.1 
Primary and Secondary Efficacy Parameters 
The primary efficacy parameter is the percent change from baseline (i.e., Pretreatment) in weekly 
heartburn severity score (WHSS) at Week 8. 
Daily heartburn severity score (DHSS) is defined as the maximum of the 3 items measuring 
heartburn from a particular day collected with the mRESQ-eD instrument; WHSS is defined as 
the average of available DHSS in a particular week. 
The secondary efficacy parameters include the following: 
1. Percent change from baseline in WHSS at Week 4 
2. Change from baseline in WHSS at (a) Week 4 and (b) Week 8 
3. Proportion of patients who are overall heartburn responders 
a. Weekly Heartburn Responder: patient with a decrease from baseline of ≥ 30% in WHSS 
b. Overall heartburn responder: patient who is a weekly heartburn responder for at least 1 of 
the final 2 weeks and for ≥ 50% of the treatment weeks 
4. Proportion of patients with a DHSS of no more than very mild (≤ 1) on any day during (a) 
Week 4 and (b) Week 8 
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5. The number of days per week where DHSS was no more than very mild (≤ 1) at (a) Week 4 
and (b) Week 8.  
6. Change from baseline in each mRESQ-eD item by week. 
7. Proportion of heartburn free days in Week 4 and Week 8 
Note: DHSS is defined as the maximum of the 3 items in the heartburn assessments of a 
particular day, collected with the mRESQ-eD instrument. Further, WHSS is defined as the 
average of DHSS in a particular week. 
Heartburn-free days will be calculated by 2 approaches.  The first will employ the single 
heartburn item in the heartburn domain (Item #1 from mRESQ-eD: Heartburn) which is similar 
to the heartburn rating scale(s) used in the PPI literature.  The second will employ all 3 items in 
the heartburn domain (Items #1 through #3 from mRESQ-eD: Heartburn; Burning feeling behind 
the breastbone or in the center of the upper stomach; Pain behind the breastbone or in the center 
of the upper stomach.  In the first approach, the heartburn item needs to be assessed at 0 (Did not 
have) while in the second approach all 3 heartburn domain items need to be assessed at 0 (Did 
not have). 
For the analysis of continuous parameters (e.g., absolute change from baseline and percent 
change from baseline), descriptive statistics (patient number [n], mean, standard deviation, 
median, and range) will be presented for each treatment group. Each IW-3718 group will be 
compared with the placebo group using an analysis of covariance (ANCOVA) model with 
treatment group, and esophagitis stratum as fixed effect terms and the corresponding baseline 
efficacy parameter value as a covariate. Least-squares means (LSMs) for each treatment group, a 
linear contrast among the LSMs to test the overall ordinal dose response, LSMs differences 
between each IW-3718 group and the placebo group and their corresponding confidence 
intervals, and p-values for the pairwise comparisons versus placebo will be presented. The 
treatment by esophagitis stratum interaction term will be explored to evaluate whether 
quantitative or qualitative interaction(s) are present, and treatment comparisons within each 
stratum will be conducted, as warranted. 
The cumulative distribution function (CDF) of change from baseline for key efficacy parameters 
will be plotted by treatment group. To aid in the interpretation of the graphical representation of 
the CDF across treatments, a two-sample Kolmogorov-Smirnov test will be conducted (22). A 
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p-value ≤ 0.05 indicates that the 2 treatment samples are unlikely to have been drawn from the 
same continuous distribution by chance alone. 
For the analysis of responder parameters (i.e., responder vs. non-responder), the counts and 
proportion of responders will be calculated for each treatment group. The proportions of 
responders between each IW-3718 group and the placebo group will be compared using a 
Cochran-Mantel-Haenszel (CMH) test controlling for esophagitis stratum. The CMH test is the 
primary analysis for responder parameters. The difference in the proportion of responders 
between each IW-3718 group and the placebo group as well as the CMH estimates of the odds 
ratio (IW-3718 over placebo) and the corresponding 95% confidence intervals will also be 
presented. 
3.7.4.2 
Other Efficacy Parameters 
Other efficacy parameters include the following: 
1. Percent change from baseline in weekly regurgitation frequency scores (WRFS) to (a) 
Week 4 and (b) Week 8 in patients with a mean baseline regurgitation frequency of ≥ 2 
(sometimes).  
2. Change from baseline in WRFS to (a) Week 4 and (b) Week 8 
3. Proportion of patients who are overall regurgitation responders (of patients with a baseline 
regurgitation frequency of ≥ 2 [sometimes]) 
a. Weekly regurgitation responder: patient with a decrease from baseline of ≥ 30% in 
WRFS  
b. Overall regurgitation responder: patient who is a weekly responder for at least 1 of the 
final 2 weeks and for ≥ 50% of the treatment weeks 
4. Proportion of patients with regurgitation frequency of no more than rarely (daily 
regurgitation frequence score [DRFS] ≤ 1) on any day during (a) Week 4 and (b) Week 8 
5. Change from baseline to (a) Week 4 and (b) Week 8 in the number of days per week where 
DRFS was no more than rarely (≤ 1) 
6. Change from baseline to Week 8 in weekly means for each of the daily symptom assessments 
Note: DRFS is the maximum of the 2 items in the regurgitation domain scores of a particular 
day, collected with the mRESQ-eD instrument. Similarly, WRFS is defined as the average of 
DRFS in a particular week. A DRFS of zero is considered Regurgitation Free for a particular 
day. 
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7. Weekly means for daily sleep assessments (number of awakenings, hours of sleep, sleep 
quality) 
8. Weekly means for weekly symptom bothersomeness assessments, symptom relief 
assessments, and treatment satisfaction assessment  
9. Exploratory non-efficacy parameters and analysis:  
a. Summarize patient baseline disease characteristics and key efficacy differences for 
patients with or without Bilitec monitoring performed during the Screening Period 
b. Compare patient baseline disease characteristics and key efficacy parameters between 
bile acid positive versus bile acid negative patients (on the subgroup of patients with 
Bilitec monitoring during the Screening Period). 
c. Assess sensitivity and specificity (i.e., receiver operating characteristic [ROC] curve) of 
bile acid levels measured in saliva as a test for bile acid pathophysiology with Bilitec test 
findings as the reference standard (on the subgroup of patients with Bilitec monitoring 
during the Screening Period) 
d. Utilize bile acid levels in saliva as a predictor of response to treatment 
 
For analysis of continuous parameters, descriptive statistics (n, mean, standard deviation, 
median, and range) will be presented for each treatment group. Each IW-3718 group will be 
compared with the placebo group using an ANCOVA model with treatment group and 
esophagitis stratum as fixed effect terms and corresponding baseline efficacy parameter value as 
a covariate.  
3.7.5 
Safety Analyses 
All safety parameters will be analyzed with descriptive statistics. Safety analyses will be 
performed on the Safety Population. The safety parameters will include AEs, treatment-emergent 
AEs (TEAEs), clinical laboratory evaluations, vital signs, ECGs, and physical examination. For 
each safety parameter, the last non-missing assessment made before randomization will be used 
as the baseline for all analyses of that safety parameter. 
3.7.5.1 
Adverse Events 
Adverse event verbatim terms will be coded using the most current version of Medical 
Dictionary for Regulatory Activities (MedDRA) available at the start of the study. An AE 
(classified by preferred term) will be considered a TEAE if the AE onset date was after initial 
study medication administration and within 1 day of the last dose of study medication. The 
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number and percentage of patients reporting TEAEs will be tabulated by system organ class 
(SOC), preferred term, and treatment group. The number and percentage of patients reporting 
TEAEs will also be tabulated by SOC, preferred term, severity, and treatment group. Listings 
will be provided for deaths (if any), severe AEs, drug-related AEs, SAEs, and AEs leading to 
study discontinuation. 
If a patient has more than 1 TEAE coded to the same preferred term, the patient will be counted 
only once for that preferred term. For the analysis of TEAEs by severity, the patient’s highest 
severity TEAE within a preferred term will be used. 
3.7.5.2 
ECGs, Vital Signs, and Clinical Laboratory Tests 
Descriptive statistics will be calculated on ECGs, vital signs, and clinical laboratory test results 
at each assessment time point, by treatment group. The change from baseline at each post-
baseline time point also will be summarized by treatment group. 
3.7.6 
Interim Analysis 
An interim analysis is not planned for this study. 
3.7.7 
Determination of Sample Size 
The sample size per arm was determined by estimating the overall power of a linear trend test in 
a one-way design that included placebo and all the active treatment arms (500 mg BID, 1000 mg 
BID, and1500 mg BID of IW-3718). The efficacy endpoint of interest in the previous Phase 2a 
study (ICP-3718-201) was change from baseline in daytime heartburn defined as the presence of 
heartburn since the patient awoke that morning (assessed in the evening) and assessed with an 
11-point [0 to 10] NRS, where 0=none and 10=very severe. In that study, IW-3718 demonstrated 
treatment differences near 0.70 points for change over the treatment period (e.g., -0.73 vs. -1.38 
for placebo and IW-3718, respectively), and standard deviations near 1.35 for the LSMs. 
Employing these historical values, a study with 58 patients per arm (the expected number of 
patients at Week 8 given an enrollment of 260 patients) will have statistical power of at least 
80% for the overall trend test (i.e., linear contrast) where the highest active treatment arm reflects 
110% of the previously observed treatment difference and the lowest 2 active treatment arms 
reflect 55% of the same (two-sided, α=0.05). At the proposed sample size, a subsequent pairwise 
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comparison between placebo and an active treatment arm reflecting the previously observed 
treatment difference will have 80% statistical power (two-sided, α=0.05). 
3.8 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES  
Any amendment to this protocol will be provided to the Investigator in writing by Ironwood or 
its designee. Prior to implementation, any protocol amendment regarding reportable deviations 
(as defined by the IRB) must be approved by the IRB and the signature page must be signed by 
the Investigator and received by Ironwood or its designee, with the following exception: 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 its designee. 
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4. 
ETHICAL CONSIDERATIONS 
This study will be performed in accordance with the Declaration of Helsinki (i.e., the 
recommendations guiding physicians in biomedical research involving human subjects adopted 
by the 18th World Medical Assembly, Helsinki, Finland, 1964, and later revisions), ICH E6 Good 
Clinical Practice (GCP) guidelines, and applicable regulatory documents. 
4.1 
INSTITUTIONAL REVIEW BOARD 
Prior to the study onset, the protocol, any protocol amendments, ICFs, advertisements to be used 
for patient recruitment, and any other written information regarding this study to be provided to a 
patient or patient’s legal guardian must be approved by the IRB. 
All IRB approvals must be dated and signed by the IRB Chairman or his or her designee and 
must identify the IRB by name and address, the clinical protocol by title and/or protocol number, 
and the date upon which approval or favorable opinion was granted for the clinical research. 
Copies of IRB approvals should be forwarded to Ironwood. All correspondence with the IRB 
should be maintained in the Investigator File. 
No drug will be released to the site to dose a patient until written IRB authorization has been 
received by Ironwood. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB. The Investigator must supply Ironwood with 
written documentation of the approval of the continued clinical research. 
The IRB must be constituted in accordance with Federal and ICH GCP guidelines and any 
relevant and applicable local regulations. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by Ironwood and by the IRB that approved the study. 
Amendments to the protocol must be submitted in writing to the Investigator’s IRB for approval 
prior to patients being enrolled into the amended protocol. 
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4.2 
PATIENT INFORMATION AND INFORMED CONSENT 
Informed consent procedures will comply with the Code of Federal Regulations (CFR) 21 CFR, 
Parts 50 and 312. 
The written ICF must be approved by the IRB for the purposes of obtaining and documenting 
consent. 
Before entry into the study, each patient will be provided with a written explanation of the study. 
It is the responsibility of the Investigator or appropriately trained health professional to give each 
patient full and adequate information regarding the objectives and procedures of the study and 
the possible risks involved. Patients will then be given the opportunity to ask questions and the 
Investigator will be available to answer questions as needed. Patients will be informed of their 
right to withdraw from the study at any time without prejudice. After this explanation and before 
entering the study, the patient will voluntarily sign an ICF. The patient should receive a copy of 
the signed and dated ICF. The Investigator must retain each patient’s original signed ICF. 
If new information becomes available that may be relevant to the patient’s consent and 
willingness to participate in the study, the ICF will be revised. The revised ICF must be 
submitted to the IRB for review and approval prior to its use. 
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5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE 
This study will be performed at approximately 60-80 study centers in the US. The Investigator at 
each 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 eCRFs. 
5.1 
GENERATION OF STUDY RECORDS 
Ironwood or its designated representative will conduct a study center visit to verify the 
qualifications of each Investigator, inspect study center facilities, and inform the Investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study patient. 
All information recorded in the eCRFs for this study must be consistent with the patient’s source 
documentation. 
During the course of the study, the Clinical Site Monitor will make study center visits to review 
protocol compliance, compare eCRFs and individual patient’s medical records, assess drug 
accountability (in a blinded manner), and ensure that the study is being conducted according to 
pertinent regulatory requirements. All eCRFs will be verified with source documentation. The 
review of medical records will be performed in a manner that ensures patient confidentiality is 
maintained. 
The Clinical Site Monitor will discuss instances of missing or uninterpretable data with the 
Investigator for resolution. Any changes to the study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF. 
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5.2 
DATA QUALITY ASSURANCE 
Ironwood performs quality control and assurance checks on all of its clinical studies. Section 5.4 
provides details regarding study monitoring procedures. 
The study may be subject to audit by Ironwood, its representatives, or regulatory authorities. In 
the event of an audit, the Investigator must agree to allow Ironwood, representatives of 
Ironwood, or the FDA or other regulatory agencies access to all study records. 
5.3 
ELECTRONIC CASE REPORT FORMS AND DATA MANAGEMENT 
All data relating to the study will be recorded in the patient’s source documentation and eCRF to 
be provided by Ironwood or designee via the electronic data capture (EDC) system. Source 
documentation supporting the eCRF data should indicate the patient’s participation in the study 
and should document the dates and details of study procedures, AEs, all observations, and patient 
status. The Investigator is responsible for verifying that all data entries on the eCRFs are accurate 
and correct and ensuring that all data are entered in a timely manner, as soon as possible after the 
information is collected. An explanation should be provided for any missing data. The 
Investigator must provide through the EDC system his or her formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for each 
patient. 
Ironwood will retain the final eCRF data and corresponding audit trails. A copy of the final 
archival eCRF in the form of a compact disc or other electronic media will be placed in the 
Investigator’s study file. 
A record of screen failures and pretreatment failures will be maintained for patients who do not 
qualify for randomization, including the reason for the failure. 
5.4 
STUDY MONITORING 
Ironwood performs quality control and assurance checks on all of its clinical studies. Before any 
patients are enrolled in the study, a representative of Ironwood or its authorized designee will 
meet with the Investigator and his/her staff to review relevant and important study-related 
information including, but not limited to, the protocol, the Investigator’s Brochure, the eCRFs 
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and instructions for their completion using the EDC system, the procedure for obtaining 
informed consent, and the procedure for reporting AEs and SAEs. 
An Ironwood representative, the Clinical Site Monitor, will monitor the progress and conduct of 
the study by periodically conducting monitoring visits and by frequent communications 
(telephone, e-mail, letter, and fax) with the study centers. The site monitor will ensure that the 
study is conducted according to the protocol and regulatory requirements. During monitoring 
visits, the information recorded on the eCRFs will be verified against source documents. Upon 
request of the monitor, auditor, IRB, or regulatory authority, the Investigator should make all 
requested study-related records available for direct access. 
All aspects of the study will be carefully monitored by Ironwood or its designee for compliance 
with applicable government regulations with respect to GCP and current standard operating 
procedures. 
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6. 
STUDY SPONSORSHIP 
6.1 
INVESTIGATOR AND STUDY TERMINATION 
Ironwood may terminate Investigator participation at any institution for any reason. If 
participation is ended at the site by either Ironwood or the Investigator, the Investigator must 
• Return all study medications and any study materials to Ironwood; 
• In cases where the Investigator opts to self-terminate, provide a written statement describing 
why the study was terminated prematurely. 
 
Ironwood may terminate the study in its entirety or at a specific center at any time for any 
reason, including but not limited to the following: 
• Failure to enroll patients 
• Protocol violations 
• Inaccurate or incomplete data 
• Unsafe or unethical practice 
• Questionable safety of the study medication 
• Suspected lack of efficacy of the study medication 
• Administrative decision 
 
6.2 
REPORTING AND PUBLICATION 
All data generated in this study will be the property of Ironwood. An integrated clinical and 
statistical report will be prepared at the completion of the study. 
Publication of the results by the Investigator will be subject to mutual agreement between the 
Investigator and Ironwood. 
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7. 
INVESTIGATOR OBLIGATIONS 
7.1 
DOCUMENTATION 
The Investigator must provide the Sponsor with the following documents BEFORE the 
enrollment of any subjects, in accordance with ICH E6 (Note: Ironwood must be notified if there 
are any changes to these documents): 
1. Completed and signed Form FDA 1572 (Statement of Investigator) including all sub-
investigators involved in the study 
2. Financial disclosure form(s) for the Investigator and all sub-investigators listed on Form 
FDA 1572 
3. Current, signed curricula vitae of the Investigator and all sub-investigators 
4. Current medical license of the Investigator and all sub-investigators (as applicable) 
5. IRB approval letter for the protocol and ICF 
6. IRB-approved ICF to be used 
7. IRB approval of recruitment advertising (if applicable) 
8. A list of IRB members and their qualifications, and a description of the committee’s working 
procedures 
9. Protocol Approval Page signed by the Investigator 
10. Fully executed Clinical Trial Agreement 
11. Written document containing the name, location, certification number, and date of 
certification of the local laboratory to be used for laboratory assays and those of other 
facilities conducting tests 
12. List of normal laboratory values and units of measurements for all laboratory tests required 
by the protocol. This list is required for each local laboratory to be used during the study. 
 
During the study, the Investigator must maintain the following essential/administrative 
documents related to the study: 
1. Signed Protocol Signature Page 
2. Financial disclosure form(s) for the Investigator and all sub-investigators (as applicable) if 
updated 
3. Curricula vitae of any new Investigator(s) and/or sub-investigators involved in the study 
4. Current medical license of the Investigator and all sub-investigators (as applicable) if updated 
5. Signed Form FDA 1572 
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6. IRB Approval Notification for the following: 
a. Protocol 
b. Informed consent document 
c. Recruitment advertising (if applicable) 
d. Amendment(s) (if applicable) 
e. Annual review of the protocol and the informed consent document 
f. SAEs 
g. Study closure 
7. SAE Reports 
8. Drug Inventory Forms (drug receipts, drug dispensing, and inventory forms) 
9. Name and address of local or central laboratory, list of normal laboratory values and units of 
measurement, as well as laboratory certification or hospital accreditation 
10. Updates of medical/laboratory/technical procedures/tests: 
a. Normal value(s)/ranges(s) 
b. Certification 
c. Accreditation 
d. Established quality control and/or external quality assessment 
e. Other validation (where required) 
11. Record of retained body fluids/tissue samples (if any) 
12. Correspondence with Sponsor 
13. Written assurance of continuing approval (at least annually) as well as a copy of the annual 
progress report submitted to the IRB must also be provided to the Sponsor. Any changes in 
this study or unanticipated problems involving risks to the patients must be reported 
promptly to the IRB. An Investigator must not make any changes in a study without IRB and 
Sponsor approval, except when necessary to eliminate apparent immediate hazards to the 
subjects. All protocol amendments must be submitted to the IRB and approved. 
14. Responsibility Log 
15. Other logs (e.g., screening, enrollment) 
16. Signed ICFs 
17. Patient source documentation 
18. eCRFs 
19. Audit certificate(s), if applicable 
 
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7.2 
PERFORMANCE 
The Investigator must demonstrate reasonable efforts to obtain qualified patients for the study. 
The Sponsor may terminate the study with any Investigator for any reason, including, but not 
limited to, Investigator nonperformance or Investigator noncompliance. 
7.3 
USE OF INVESTIGATIONAL MATERIALS 
The Investigator will acknowledge that the drug supplies are investigational and as such must be 
used strictly in accordance with the protocol and only under the supervision of the Investigator or 
sub-investigators. Study medication must be stored in a safe and secure temperature-monitored 
location. The Investigator must maintain adequate records documenting the receipt and 
disposition of all study supplies. The study center must record the date the study medication was 
received and maintain a dispensing record in which to record each patient’s use. Study 
medication will be dispensed to patients at the Randomization Visit on Day 1, at the Week 2 
Visit on Day 15 (± 3 days) and at the Week 4 Visit on Day 29 (± 3 days). A complete 
reconciliation of study medication will be performed at the site close out visit with a final 
accountability report provided to Ironwood as part of the site close out report. Written 
instructions for return of all unused and reconciled study medication to an appropriate waste 
handler will be provided prior to the end of the study. No study medication may be destroyed by 
study centers without prior written permission of Ironwood. 
7.4 
RETENTION AND REVIEW OF RECORDS 
Records and documents pertaining to the conduct of this study, including eCRFs, source 
documents, ICFs, laboratory test results, and medication inventory records, must be retained by 
the Investigator in accordance with locally applicable regulatory requirements; and, in any event, 
for a minimum period of 5 years.  
No study records shall be destroyed without notifying Sponsor and giving Sponsor the 
opportunity to take such study records or authorizing in writing the destruction of records after 
the required retention period. 
If the Investigator retires, relocates, or otherwise withdraws from the responsibility of keeping 
the study records, custody must be transferred to another person (Ironwood, IRB, or other 
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Investigator) who will accept the responsibility. Ironwood must be notified of and agree to the 
change. 
7.5 
PATIENT CONFIDENTIALITY 
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. All patient records will be identified only by initials and patient 
identification (PID) number. Patient 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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8. 
REFERENCE LIST 
1. Safaie-Shirazi S, DenBesten L, Zike WL. Effect of bile salts on the ionic permeability of the 
esophageal mucosa and their role in the production of esophagitis. Gastroenterol 
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2. Kivilaakso E, Fromm D, Silen W. Effect of bile salts and related compounds on esophageal 
mucosa. Scand J Gastroenterol Suppl 1981;67:119-21. 
3. Nishijima K, Miwa K, Miyashita T, et al. Impact of the biliary diversion procedure on 
carcinogenesis in Barrett’s esophagus surgically induced by duodenogastroesophageal reflux 
in rats. Ann Surg 2004;240:57-67. 
4. Nehra D, Howell P, William CP, et al. Toxic bile acids in gastro-oesophageal reflux disease: 
influence of gastric acidity. Gut 1999;44:598-602. 
5. Bachir GS, Leigh-Collis J, Wilson P, Pollak EW. Diagnosis of incipient reflux esophagitis: a 
new test. South Med J 1981;74:1072-4. 
6. Vaezi MF, Richter JE. Contribution of acid and duodenogastro-oesophageal reflux to 
oesophageal mucosal injury and symptoms in partial gastrectomy patients. Gut 1997;41:297-
302. 
7. Kono K, Takahashi A, Sugai H, et al. Trypsin activity and bile acid concentrations in the 
esophagus after distal gastrectomy. Dig Dis Sci 2006;51:1159-64. 
8. Gerson LB, Kahrilas PJ, Fass R. Insights into gastroesophageal reflux disease-associated 
dyspeptic symptoms. Clin Gastroenterol Hepatol 2011;9:824-33. 
9. Friedenberg FK, Hanlon A, Vanar V, et al. Trends in gastroesophageal reflux disease as 
measured by the National Ambulatory Medical Care Survey. Dig Dis Sci 2010;55:1911-7. 
10. Dickman R, Boaz M, Aizic S, Beniashvili Z, Fass R, Niv Y. Comparison of clinical 
characteristics of patients with gastroesophageal reflux disease who failed proton pump 
inhibitor therapy versus those who fully responded. J Neurogastroenterol Motil 2011;17:387-
94. 
11. Tack J, Koek G, Demedts I, Sifrim D, Janssens J. Gastroesophageal reflux disease poorly 
responsive to single-dose proton pump inhibitors in patients without Barrett’s esophagus: 
acid reflux, bile reflux, or both? Am J Gastroenterol 2004;99:981-8. 
12. Bechi P, Pucciani F, Baldini F, et al. Long-term ambulatory enterogastric reflux monitoring. 
Validation of a new fiberoptic technique. Dig Dis Sci 1993;38(7):1297-306. 
13. Thomas C, Pellicciari R, Pruzanski M, Auswerx J, Schoonjans K. Targeting bile-acid 
signalling for metabolic diseases. Nat Rev Drug Discov 2008;7(8):678-93. 
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14. Staels B. A review of bile acid sequestrants: potential mechanism(s) for glucose-lowering 
effects in type 2 diabetes mellitus. Postgrad Med 2009;121(3):25-30. 
15. De Fabiani E, Mitro N, Gilardi F, Caruso D, Galli G, Crestani M. Coordinated control of 
cholesterol catabolism to bile acids and of gluconeogenesis via a novel mechanism of 
transcription regulation linked to the fasted-to-fed cycle. J Biol Chem 2003;278(40):39124-
132. 
16. Cariou B, Duran-Sandoval D, Kuipers F, Staels B. Farnesoid X receptor: a new player in 
glucose metabolism? Endocrinology 2005;146(3):981-3. 
17. Dimenäs E, Glise H, Hallerbäck B, Hernqvist H, Svedlund J, Wiklund I. Quality of life in 
patients with upper gastrointestinal symptoms. An improved evaluation of treatment 
regimens? Scand J Gastroenterol.1993;28(8):681–687. 
18. Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive 
Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a 
psychometric evaluation in patients with chronic major depression. Biol Psychiatry 
2003;54(5):573-83. 
19. Ware J Jr, 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. 
20. The EuroQol Group. EuroQol--a new facility for the measurement of health-related quality 
of life. Health Policy 1990;16(3):199-208. 
21. 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. 
22. Hollander M, Wolfe DA. Chapter 10: Tests Designed to Detect Broad Alternatives. In: 
Nonparametric Statistical Methods. New York, NY: John Wiley & Sons; 1973. p. 219. 
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10. 
INVESTIGATOR’S STATEMENT 
Study Title: 
A Phase 2b, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Dose-range-finding Trial of IW-3718 Administered Orally for 8 Weeks to 
Patients with Symptomatic Gastroesophageal Reflux Disease Not 
Completely Responsive to Proton Pump Inhibitors 
Study Number: 
ICP-3718-202 
Final Date: 
27 July 2016 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol. 
 
Signed:  
 
 
Date:   
 
 
Investigator Name: ___________________________ 
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11. 
APPENDICES 
 
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APPENDIX 1 
Please answer the following questions to help us understand the symptoms you experienced 
since waking today because of your reflux disease.  For each question, please choose the answer 
most appropriate for you.  
Over the past 24 hours, how would you rate the severity of your [insert symptom]? 
0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe 
1. Heartburn 
2. Burning feeling behind the breastbone or in the center of the upper stomach 
3. Pain behind the breastbone or in the center of the upper stomach 
4. Difficulty swallowing 
5. Hoarseness 
6. Coughing 
 
Over the past 24 hours, how often did you experience [insert symptom] 
0=Never, 1= Rarely, 2=Sometimes, 3=Often, 4=Very often 
1. Regurgitation (liquid or food moving upwards towards your throat or mouth) 
2. An acid or bitter taste in the mouth  
3. Burping  
4. Cough 
mRESQ-eD 
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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 91 of 173 
APPENDIX 2 
DAILY DYSPEPSIA SYMPTOMS 
Completed before going to bed each night. Note: all items are assessed on a 0-to-10 numerical 
rating scale [NRS] with anchors of 0=not having the symptom and 10= having the worst possible 
symptom 
1. Over the past 24 hours, rate your worst nausea (feeling like you might throw up). 
NRS anchors: 0= No nausea, 10= Worst possible nausea 
2. Over the past 24 hours, rate your worst stomach fullness after you finished eating. 
NRS anchors: 0= No stomach fullness, 10= Worst possible stomach fullness 
3. Over the past 24 hours, how would you rate the difficulty you had finishing your meals 
because you felt full too quickly 
NRS anchors: 0= No difficulty, 10= Worst possible difficulty  
4. Over the past 24 hours, how would you rate your worst abdominal pain? 
NRS anchors: 0= No pain, 10= Worst possible pain 
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IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 92 of 173 
APPENDIX 3 
DAILY ASSESSMENT OF SLEEP 
Completed each morning upon waking. 
Awakenings 
Last night, did you wake up during the night after falling asleep?  
[Yes, No]  
[If yes], how many times did you wake up last night after falling asleep?  
[Enter number of times] 
Sleep Time 
How long did you sleep last night?   Do not count any time you lay in bed, but did not sleep.  
[Enter hours, enter minutes]  
Overall Sleep Quality 
Please rate the overall quality of your sleep last night. 
1=Very poor 
2=Poor 
3=Fair 
4=Good 
5=Very good 
Document Date: 05-Aug-2016 09:10


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 93 of 173 
APPENDIX 4 
PROHIBITED MEDICATIONS 
All medicine listed in the sections below are excluded during the Screening, Pretreatment, 
Randomization, and Treatment Periods. A 1-day washout means the that the particular medicine 
is not allowed during the calendar day before the EGD and Bravo pH monitoring; a 5-day 
washout means that the particular medicine is not allowed during the 5 calendar days before the 
EGD and Bravo pH monitoring; a 14-day washout means that the particular medicine is not 
allowed during the 14 calendar days before the Pretreatment Visit. 
Patients should be on a stable dose of all concomitant medications at the time of the Screening 
Visit and should intend to maintain their usual medication regimen throughout the study. 
Changes in concomitant medication regimens or use of a new concomitant medication other than 
as described below is not allowed during the study unless required to treat an AE or is prescribed 
by a physician to treat another emergent medical issue. 
1-DAY WASHOUT 
 Antacids 
 Sucralfate 
5-DAY WASHOUT 
 H2 Receptor Antagonists (prescribed or over-the-counter [OTC]) (e.g. cimetidine, 
ranitidine, famotidine, and nizatidine). 
 
14-DAY WASHOUT 
• Bile acid sequestrants (e.g., Welchol (colesevelam), cholestyramine, and colestipol) 
• Drugs with a known drug-drug interaction or a potential for a drug-drug interaction with 
colesevelam (cyclosporine, levothyroxine [and other thyroid replacement therapies], 
olmesartan medoxomil, phenytoin, warfarin) 
• Drugs with a narrow therapeutic index (e.g. warfarin, digoxin, theophylline) 
• Prokinetic agents (e.g. metoclopramide, tegaserod, erythromycin); anti-cholinergic and anti-
muscarinic agents (e.g. dicyclomine, flavoxate, scopolamine, hyoscyamine, propantheline, 
oxybutynin, tolterodine, solifenacin, darifenacin, and trospium) 
[Note: inhaled ipratropium and tiotropium are permitted] 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 94 of 173 
• Antipsychotic agents (e.g., risperidone, haloperidol, droperidol, chlorpromazine, 
perphenazine, all phenothiazines, quetiapine, olanzapine, clozapine) 
• GABAergics (e.g., baclofen, valproic acid, gabapentin, pregabalin, benzodiazepine) 
• Calcium channel blockers (e.g., verapamil, nifedipine, diltiazem, amlodipine, felodipine, 
nicardipine, nimodipine, nisoldipine) 
• Beta blockers (e.g., metoprolol, timolol, atenolol, betaxolol) 
• All narcotics either alone or in combination (e.g., tramadol, codeine, morphine, 
propoxyphene, loperamide, diphenoxylate) 
[Note: narcotics used as anesthesia for an EGD require a 7 calendar day wash-out prior to the 
patient entering into the Pretreatment Period.] 
• Tricyclic antidepressants (e.g. amitriptyline, imipramine, and nortriptyline) 
[Note: Patients may take another single antidepressant (such as a selective serotonin reuptake 
inhibitor {SSRI}, or serotonin-norepinephrine reuptake inhibitor {SNRI} medication) as long 
as the dose has been stable for at least 30 days prior to the Screening Visit and the patient 
plans to continue a stable dose of the medications throughout the study. Use of more than 1 
antidepressant medication is exclusionary.] 
• Other gastric-retentive drugs (e.g., Glumetza, Gralise) 
 
Notes Regarding Concomitant Medications: 
Patients must have been on once-daily (QD) PPI therapy for at least 8 weeks before the 
Screening Visit. 
Daily use of estrogens and/or low-dose aspirin (up to 162 mg/day) is permitted if, after an 
appropriate evaluation (e.g., history and physical exam), the Investigator believes these 
medications are not contributing to the patient’s symptoms. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) are permitted for occasional use. Chronic use is 
not permitted. 
Oral contraceptives containing ethinyl estradiol and norethindrone have a known drug-drug 
interaction with colesevelam. All female patients of childbearing potential using oral 
contraceptives with the ingredients listed above as birth control must agree to use another 
additional form of contraception from the date they sign the ICF until 24 hours after their final 
dose of study drug (e.g. condom). 
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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 95 of 173 
APPENDIX 5 
LOS ANGELES CLASSIFICATION OF ESOPHAGITIS 
Classification 
Definition 
Not Present 
No breaks (erosions) in the esophageal mucosa. (However, edema, erythema, 
or friability may be present.) 
Grade A 
One or more mucosal breaks not more than 5 mm in maximum length. 
Grade B 
One or more mucosal breaks more than 5 mm in maximum length, but not 
continuous between the tops of 2 mucosal folds. 
Grade C 
Mucosal breaks that are continuous between the tops of 2 or more mucosal 
folds, but involve less than 75% of the esophageal circumference. 
Grade D 
Mucosal breaks that involve at least 75% of the esophageal circumference. 
 
Document Date: 05-Aug-2016 09:10


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 96 of 173 
APPENDIX 6 
WEEKLY AND END OF TREATMENT ASSESSMENTS 
Degree of Relief Assessments  
Administered weekly starting during Pretreatment Period: 
How would you rate your heartburn (a burning sensation in your chest, behind the breastbone) 
over the past 7 days? 
How would you rate your regurgitation (the feeling of stomach contents, either liquid or food, 
moving upwards to your throat or mouth) over the past 7 days? 
Administered weekly during Treatment Period: 
Compared to before you started this study, how would you rate your overall GERD symptoms 
over the past 7 days? 
Response Scale for all Degree of Relief Assessments: 
1=Significantly relieved 
2=Moderately relieved 
3=Somewhat relieved 
4=Unchanged 
5=Somewhat worse 
6=Moderately worse 
7=Significantly worse 
 
Global Treatment Satisfaction Assessment  
Administered weekly during Treatment Period: 
How would you rate your satisfaction with the study treatment? 
1=Very dissatisfied 
2=Dissatisfied 
3=Neither satisfied nor dissatisfied 
4=Satisfied 
5=Very satisfied 
 
 
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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 97 of 173 
Bothersomeness Assessments  
Administered weekly starting during Pretreatment Period: 
How much were you bothered by heartburn (a burning sensation in your chest, behind the 
breastbone) over the past week? 
How much were you bothered by regurgitation (the feeling of stomach contents, either liquid or 
food, moving upwards to your throat or mouth) over the past week? 
1=Not at all 
2=A little bit 
3=A moderate amount 
4=A great deal 
5=An extreme amount 
 
Swallow Item Question 
Administered End of Treatment Visit only: 
How difficult were the tablets to swallow? 
1=Not at all difficult  
2=A little difficult 
3=Moderately difficult 
4=Extremely difficult 
 
 
 
Document Date: 05-Aug-2016 09:10


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 98 of 173 
APPENDIX 7 
IN-CLINIC ASSESSMENTS 
  
EQ-5D-3L 
 
USA (English) © 1998 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
Health Questionnaire 
 
English version for the USA 
 
By placing a checkmark in one box in each group below, please indicate which 
statements best describe your own health state today. 
Mobility 
 
I have no problems in walking about 
 
I have some problems in walking about 
 
I am confined to bed 
 
 
 
Self-Care 
 
I have no problems with self-care 
 
I have some problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
 
 
Usual Activities (e.g. work, study, housework, family or leisure 
activities) 
 
I have no problems with performing my usual activities 
 
I have some problems with performing my usual activities 
 
I am unable to perform my usual activities 
 
 
 
Pain / Discomfort 
 
I have no pain or discomfort 
 
I have moderate pain or discomfort 
 
I have extreme pain or discomfort 
 
 
 
Anxiety / Depression 
 
I am not anxious or depressed 
 
I am moderately anxious or depressed 
 
I am extremely anxious or depressed 
 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 99 of 173 
 
 
 
 
 
 
 
 
 
 
 
2 
 
USA (English) © 1998 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
9 0 
8 0 
7 0 
6 0 
5 0 
4 0 
3 0 
2 0 
1 0 
100
0 
 
 
 
To help people say how good or bad a health state is, 
we have drawn a scale (rather like a thermometer) on 
which the best state you can imagine is marked 100 and 
the worst state you can imagine is marked 0. 
 
We would like you to indicate on this scale how good or 
bad your own health is today, in your opinion. Please do 
this by drawing a line from the box below to whichever 
point on the scale indicates how good or bad your health 
state is today. 
 
 
 
 
Best imaginable 
health state
Worst imaginable 
health state 
Your own health 
state today 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 100 of 173 
GSRS-Self 
AstraZeneca, 1995. All rights reserved.  
 
(AMOS 97:04) 
GSRS - US-English.    
 
These questions should not be used, copied or distributed in any form without permission from AstraZeneca R&D, HEOR, 
SE-431 83 Mölndal, Sweden, PROinformation@astrazeneca.com 
 
 
THE GASTROINTESTINAL SYMPTOM RATING SCALE 
(GSRS) 
 
 
 
Please read this first: 
 
 
This survey contains questions about how you have been feeling and what  
 
it has been like DURING THE PAST WEEK. Mark the choice that best  
 
applies to you and your situation with an “X” in the box. 
 
 
1. 
Have you been bothered by PAIN OR DISCOMFORT IN YOUR UPPER  
ABDOMEN OR THE PIT OF YOUR STOMACH during the past week? 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
2. 
Have you been bothered by HEARTBURN during the past week? (By heartburn 
we mean an unpleasant stinging or burning sensation in the chest.) 
 
 
 
No discomfort at all 
  
Minor discomfort 
  
Mild discomfort 
  
Moderate discomfort 
  
Moderately severe discomfort 
  
Severe discomfort 
  
Very severe discomfort 
 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 101 of 173 
AstraZeneca, 1995. All rights reserved.  
 
(AMOS 97:04) 
GSRS - US-English.    
 
These questions should not be used, copied or distributed in any form without permission from AstraZeneca R&D, HEOR, 
SE-431 83 Mölndal, Sweden, PROinformation@astrazeneca.com 
 
 
3. 
Have you been bothered by ACID REFLUX during the past week? (By acid reflux 
we mean the sensation of regurgitating small quantities of acid or flow of sour or 
bitter fluid from the stomach up to the throat.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
4. 
Have you been bothered by HUNGER PAINS in the stomach during the past 
week? (This hollow feeling in the stomach is associated with the need to eat 
between meals.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
5. 
Have you been bothered by NAUSEA during the past week? (By nausea we 
mean a feeling of wanting to throw up or vomit.) 
 
 
 
No discomfort at all 
  
Minor discomfort 
  
Mild discomfort 
  
Moderate discomfort 
  
Moderately severe discomfort 
  
Severe discomfort 
  
Very severe discomfort 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 102 of 173 
AstraZeneca, 1995. All rights reserved.  
 
(AMOS 97:04) 
GSRS - US-English.    
 
These questions should not be used, copied or distributed in any form without permission from AstraZeneca R&D, HEOR, 
SE-431 83 Mölndal, Sweden, PROinformation@astrazeneca.com 
 
 
6. 
Have you been bothered by RUMBLING in your stomach during the past week? 
(Rumbling refers to vibrations or noise in the stomach.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
7. 
Has your stomach felt BLOATED during the past week? (Feeling bloated refers to 
swelling often associated with a sensation of gas or air in the stomach.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
8. 
Have you been bothered by BURPING during the past week? (Burping refers to 
bringing up air or gas from the stomach via the mouth, often associated with 
easing a bloated feeling.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 103 of 173 
AstraZeneca, 1995. All rights reserved.  
 
(AMOS 97:04) 
GSRS - US-English.    
 
These questions should not be used, copied or distributed in any form without permission from AstraZeneca R&D, HEOR, 
SE-431 83 Mölndal, Sweden, PROinformation@astrazeneca.com 
 
 
9. 
Have you been bothered by PASSING GAS OR FLATUS during the past week? 
(Passing gas or flatus refers to the need to release air or gas from the bowel,  
often associated with easing a bloated feeling.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
10. 
Have you been bothered by CONSTIPATION during the past week? (Constipation 
refers to a reduced ability to empty the bowels.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
11. 
Have you been bothered by DIARRHEA during the past week? (Diarrhea refers to 
a too frequent emptying of the bowels.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 104 of 173 
AstraZeneca, 1995. All rights reserved.  
 
(AMOS 97:04) 
GSRS - US-English.    
 
These questions should not be used, copied or distributed in any form without permission from AstraZeneca R&D, HEOR, 
SE-431 83 Mölndal, Sweden, PROinformation@astrazeneca.com 
 
 
12. 
Have you been bothered by LOOSE STOOLS during the past week? (If your 
stools (motions) have been alternately hard and loose, this question only refers to 
the extent you have been bothered by the stools being loose.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
13. 
Have you been bothered by HARD STOOLS during the past week? (If your stools 
(motions) have been alternately hard and loose, this question only refers to the 
extent you have been bothered by the stools being hard.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
14. 
Have you been bothered by an URGENT NEED TO HAVE A BOWEL 
MOVEMENT during the past week? (This urgent need to go to the toilet is often 
associated with a feeling that you are not in full control.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 105 of 173 
AstraZeneca, 1995. All rights reserved.  
 
(AMOS 97:04) 
GSRS - US-English.    
 
These questions should not be used, copied or distributed in any form without permission from AstraZeneca R&D, HEOR, 
SE-431 83 Mölndal, Sweden, PROinformation@astrazeneca.com 
 
 
15. When going to the toilet during the past week, have you had the SENSATION OF 
 
NOT COMPLETELY EMPTYING THE BOWELS? (This feeling of incomplete 
 
emptying means that you still feel a need to pass more stool despite having 
 
exerted yourself to do so.) 
 
 
 
No discomfort at all 
 
 
Minor discomfort 
 
 
Mild discomfort 
 
 
Moderate discomfort 
 
 
Moderately severe discomfort 
 
 
Severe discomfort 
 
 
Very severe discomfort 
 
 
 
PLEASE CHECK THAT ALL QUESTIONS HAVE BEEN ANSWERED! 
 
THANK YOU FOR YOUR CO-OPERATION. 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 106 of 173 
 
QIDS-SR 
 
CHECK THE ONE RESPONSE TO EACH ITEM THAT BEST DESCRIBES YOU FOR THE PAST SEVEN DAYS.
Pg. 1 of 2
During the past seven days...
During the past seven days...
8.  Decreased Weight (Within the Last Two Weeks):
   I have not had a change in my weight.
   I feel as if I have had a slight weight loss.
   I have lost 2 pounds or more.
   I have lost 5 pounds or more.
0
1
2
3
   I take more than 60 minutes to fall asleep, more than
   half the time.
   I take at least 30 minutes to fall asleep, more than
   half the time.
   I take at least 30 minutes to fall asleep, less than
   half the time.
   I never take longer than 30 minutes to fall asleep.
1.  Falling Asleep:
0
1
2
3
5.  Feeling Sad:
   I do not feel sad.
   I feel sad less than half the time.
   I feel sad more than half the time.
   I feel sad nearly all of the time.
0
1
2
3
0
1
2
3    I awaken more than once a night and stay awake
   for 20 minutes or more, more than half the time.
   I wake up at least once a night, but I go back to
   sleep easily.
   I have a restless, light sleep with a few brief
   awakenings each night.
   I do not wake up at night.
2.  Sleep During the Night
0
1
2
3    I awaken at least one hour before I need to, and
   can't go back to sleep.
   I almost always awaken at least one hour or so
   before I need to, but I go back to sleep eventually.
   More than half the time, I awaken more than 30
   minutes before I need to get up.
   Most of the time, I awaken no more than 30 minutes
   before I need to get up.
3.  Waking Up Too Early:
0
1
2
3    I sleep longer than 12 hours in a 24-hour period
   including naps.
   I sleep no longer than 12 hours in a 24-hour period
   including naps.
   I sleep no longer than 10 hours in a 24-hour period
   including naps.
   I sleep no longer than 7-8 hours/night, without
   napping during the day.
4.  Sleeping Too Much:
0
1
2
3
   I eat much less than usual and only with personal effort.
   I eat somewhat less often or lesser amounts of food than
   usual.
   There is no change in my usual appetite.
   I rarely eat within a 24-hour period, and only with
   extreme personal effort or when others persuade me to
   eat.
6.  Decreased Appetite:
0
1
2
3    I feel driven to overeat both at mealtime and between
   meals.
   I regularly eat more often and/or greater amounts of
   food than usual.
   I feel a need to eat more frequently than usual.
   There is no change from my usual
   appetite.
7.  Increased Appetite:
9.  Increased Weight (Within the Last Two Weeks):
   I have not had a change in my weight.
   I feel as if I have had a slight weight gain.
   I have gained 2 pounds or more.
   I have gained 5 pounds or more.
0
1
2
3
Please complete either 6 or 7   (not both)
Please complete either 8 or 9   (not both)
- OR -
- OR -
The Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report) (QIDS-SR16)
Name or ID: _____________________________     Date: _____________________________ 
Document Date: 05-Aug-2016 09:10


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Confidential 
Page 107 of 173 
 
 
 
 
Pg. 2 of 2
   I have impulses to move about and am quite restless.
During the past seven days...
During the past seven days...
0
1
2
3    I cannot concentrate well enough to read or cannot
   make even minor decisions.
   Most of the time, I struggle to focus my attention or
   to make decisions.
   I occasionally feel indecisive or find that my attention
   wanders.
   There is no change in my usual capacity to
   concentrate or make decisions.
10.  Concentration / Decision Making:
0
1
2
3    I think almost constantly about major and minor
   defects in myself.
   I largely believe that I cause problems for others.
   I am more self-blaming than usual.
   I see myself as equally worthwhile and deserving as
   other people.
11.  View of Myself:
0
1
2
3    I think of suicide or death several times a day in
   some detail, or I have made specific plans for
   suicide or have actually tried to take my life.
   I think of suicide or death several times a week for
   several minutes.
   I feel that life is empty or wonder if it's worth living.
   I do not think of suicide or death.
12.  Thoughts of Death or Suicide:
0
1
2
3    I have virtually no interest in formerly pursued
   activities.
   I find I have interest in only one or two of my
   formerly pursued activities.
   I notice that I am less interested in people or
   activities.
   There is no change from usual in how interested I
   am in other people or activities.
13.  General Interest
0
1
2
3    I really cannot carry out most of my usual daily activities
   because I just don't have the energy.
   I have to make a big effort to start or finish my usual daily
   activities (for example, shopping, homework, cooking, or
   going to work).
   I get tired more easily than usual.
   There is no change in my usual level of energy.
14.  Energy Level:
0
1
2
3    I am often unable to respond to questions without
   extreme effort.
   It takes me several seconds to respond to most
   questions and I'm sure my thinking is slowed.
   I find that my thinking is slowed down or my voice
   sounds dull or flat.
   I think, speak, and move at my usual rate of speed.
15.  Feeling Slowed Down:
0
1
2
3    At times, I am unable to stay seated and need to pace
   around.
   I'm often fidgety, wringing my hands, or need to shift
   how I am sitting.
   I do not feel restless.
16.  Feeling Restless:
 The Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report) (QIDS-SR16)
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SF-12v2 
SF-12v2® Health Survey Single-Item Acute Recall for Handheld Device 
Item Name 
Question Text 
Answer Text 
1 
Answer Text 
2 
Answer Text 
3 
Answer Text 
4 
Answer Text 
5 
Answer Text 
6 
 
Your Health and Well-Being 
 
 
 
 
 
 
 
This survey asks for your views about 
your health.  This information will help 
keep track of how you feel and how well 
you are able to do your usual activities. 
Thank you for completing this survey! 
 
For each of the following questions, 
please select the one box that best 
describes your answer. 
 
 
 
 
 
 
SF36v2_GH1 
In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
The following questions are about 
activities you might do during a typical 
day.  Does your health now limit you in 
these activities?  If so, how much? 
 
 
 
 
 
 
SF36v2_PF02 
Does your health now limit you in 
moderate activities, such as moving a 
table, pushing a vacuum cleaner, 
bowling, or playing golf?  If so, how 
much? 
Yes, limited a 
lot 
Yes, limited a 
little 
No, not 
limited at all 
  
  
 
SF36v2_PF04 
Does your health now limit you in 
climbing several flights of stairs?  If so, 
how much? 
Yes, limited a 
lot 
Yes, limited a 
little 
No, not 
limited at all 
  
  
 
 
During the past week, how much of the 
time have you had any of the following 
problems with your work or other regular 
daily activities as a result of your 
physical health? 
 
 
 
 
 
 
SF36v2_RP2 
During the past week, how much of the 
time have you accomplished less than 
you would like as a result of your 
physical health? 
All of the time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
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SF-12v2® Health Survey Single-Item Acute Recall for Handheld Device 
Item Name 
Question Text 
Answer Text 
1 
Answer Text 
2 
Answer Text 
3 
Answer Text 
4 
Answer Text 
5 
Answer Text 
6 
SF36v2_RP3 
During the past week, how much of the 
time were you limited in the kind of work 
or other activities as a result of your 
physical health? 
All of the time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
 
During the past week, how much of the 
time have you had any of the following 
problems with your work or other regular 
daily activities as a result of any 
emotional problems (such as feeling 
depressed or anxious)? 
 
 
 
 
 
 
 
SF36v2_RE2 
During the past week, how much of the 
time have you accomplished less than 
you would like as a result of any 
emotional problems (such as feeling 
depressed or anxious)? 
 
All of the time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
SF36v2_RE3 
During the past week, how much of the 
time have you done work or other 
activities less carefully than usual as a 
result of any emotional problems (such 
as feeling depressed or anxious)? 
 
All of the time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
SF36v2_BP2 
During the past week, how much did 
pain interfere with your normal work 
(including both work outside the home 
and housework)? 
 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
These questions are about how you feel 
and how things have been with you 
during the past week.  For each 
question, please give the one answer 
that comes closest to the way you have 
been feeling. 
 
 
 
 
 
 
 
SF36v2_MH3 
How much of the time during the past 
week have you felt calm and peaceful?   
All of the time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
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SF-12v2® Health Survey Single-Item Acute Recall for Handheld Device 
Item Name 
Question Text 
Answer Text 
1 
Answer Text 
2 
Answer Text 
3 
Answer Text 
4 
Answer Text 
5 
Answer Text 
6 
SF36v2_VT2 
How much of the time during the past 
week did you have a lot of energy?   
All of the time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
SF36v2_MH4 
How much of the time during the past 
week have you felt downhearted and 
depressed?   
All of the time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
SF36v2_SF2 
During the past week, how much of the 
time has your physical health or 
emotional problems interfered with your 
social activities (like visiting with friends, 
relatives, etc.)? 
All of the time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
 
SF-12v2® Health Survey  1994, 2002, 
2010, 2012 Medical Outcomes Trust and 
QualityMetric Incorporated. 
All rights reserved. 
SF-12® is a registered trademark of  
Medical Outcomes Trust. 
(SF-12v2® Health Survey Acute, United 
States (English)) 
 
 
 
 
 
 
SF-12v2® Health Survey  1994, 2002, 2010, 2012 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-12® is a registered trademark of Medical Outcomes Trust. 
(SF-12v2® Health Survey Acute, United States (English)) 
 
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Swallow Item Question 
Administered End of Treatment Visit only: 
How difficult were the tablets to swallow? 
1=Not at all difficult  
2=A little difficult 
3=Moderately difficult 
4=Extremely difficult 
 
 
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APPENDIX 8 
EXAMPLE “WHITE DIET” 
Acceptable foods: 
 Water 
 Milk 
 Chicken 
 Fish 
 Potatoes 
 
 
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APPENDIX 9 
BRAVO PH RECORDER INSTRUCTIONS AND 
PATIENT DIARY 
 
 
 
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Bravo® pH  
Patient Diary 
 
 
 
DOC-2124-01 
Patient Instructions 
The purpose of this pH study is to monitor the 
frequency and duration of gastric reflux during a 
normal day. To get the most accurate results, you 
must eat, drink, work, and exercise as you normally 
would. 
                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
DO NOT take any antacid or anti-reflux drugs during 
your study unless instructed to do so by your 
physician. If in doubt, contact your physician. 
 
Recording Events  
Events include meals, sleep and “other” types of 
activities with duration. Record an event in the Patient 
Diary sheet by marking the type of the event and 
writing down the event starting and stopping times, 
using the time displayed on the Bravo pH recorder. 
You can record a meal or a sleep event automatically 
also by pressing the appropriate event button on the 
Bravo pH Recorder. 
 
Meals 
includes snacks 
 
Sleep 
includes lying down 
 
Other 
includes sports and 
other activities 
 
To record “other” type events use the Patient Diary 
(next page).  
Recording Symptoms  
Symptoms include heartburn, regurgitation, and chest 
pain.  
Record a symptom in the Patient Diary by marking 
the type of the symptom and writing down the 
symptom appearance time using the time displayed 
on the Bravo pH Recorder. You can record a 
symptom automatically also by pressing the 
appropriate symptom button on the Bravo pH 
Recorder. 
Symptom 
Button 
Symptom 
Icon 
 
 
 
The green indicator 
light turns on for 3 
seconds and a beep is 
heard (if the audio 
alert feature is turned 
on).  This tells you that 
the symptom was 
recorded. 
 
 
 
 
 
Recorder Placement when lying down 
You may remove the Bravo pH recorder when lying 
down or you may leave it on you. If you choose to 
remove it, place it on a stable surface within arm’s 
length of your chest with the display facing up and 
the symptom buttons facing towards you. 
 
Recorder Out of Range 
If the Bravo pH recorder is too distant from the Bravo 
pH capsule and reception is weak, it beeps for 30 
seconds and the icon 
 (for 48-hour procedure) or 
 (for 96-hour procedure) disappears from the 
screen to indicate loss of communication. Move the 
recorder closer to you until the beep stops and 
the  
 or 
 icon reappears on the screen. 
If you have any questions or encounter technical 
issues during your study, call 
__________________________  
at _______________________________________. 
At the completion of your pH study, return the Bravo 
pH recorder and your Patient Diary to the 
Endoscopy/GI Lab at: 
 
 
 
 
 
 
 
 
 
Manufactured by: 
 
Given Imaging 
3950 Shackleford Road 
Duluth, GA 30096, United States 
www.givenimaging.com 
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DOC-2124-01 
 
Bravo® pH Patient 
Diary 
Start Time ____:____      End Time ____:____ 
Patient    ______________________________ 
Recorder ______________________________ 
Capsule ID ____________________________ 
   
 
 
 
Always refer to the time displayed on the recorder to write down the Time of Event above. 
 
Recording event on the Bravo pH recorder 
 
Press any of the three Symptom Buttons (chest pain, regurgitation, heartburn) once 
for each individual event. 
 
 
Press the Meal Button once at the start of the meal and once at the end of the meal. In 
between the two presses, the button LED will blink until the button is pressed to mark 
the end the event. 
 
Press the Supine Button once when lying down for bed and once at the end of the lying 
period. In between the two presses, the button LED will blink until the button is 
pressed to mark the end the event. 
 
Notes: 
All button functions are active only when backlight is ON. If OFF, pressing any of the enabled recorder buttons 
will first turn backlight ON and no function will be activated. Pressing the desired button when the backlight is 
ON will activate the desired function. 
 
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APPENDIX 10 
COGNITIVE DEBRIEFING INTERVIEWS TO 
EVALUATE THE CONTENT VALIDITY OF THE 
MODIFIED REFLUX SYMPTOM QUESTIONNAIRE 
(mRESQ-eD) STUDY MANUAL 
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Cognitive Debriefing Interviews to 
Evaluate the Content Validity of the 
Modified Reflux Symptom Questionnaire 
(mRESQ-eD) 
Study Manual 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 6.0 
July 27, 2016 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................3 
LIST OF ATTACHMENTS ............................................................................................................4 
ABBREVIATIONS .........................................................................................................................5 
1. 
INTRODUCTION ...................................................................................................................6 
2. 
OBJECTIVES ..........................................................................................................................7 
3. 
METHODOLOGY ..................................................................................................................8 
3.1 
STUDY DESIGN...........................................................................................................8 
3.2 
INTERVIEW MATERIALS .........................................................................................9 
3.3 
INTERVIEW SAMPLE.................................................................................................9 
3.3.1 
Number of patients and sites ................................................................................9 
3.3.2 
Interview eligibility criteria .................................................................................9 
3.4 
INTERVIEW RECRUITMENT ..................................................................................11 
3.4.1 
Site onboarding and training ..............................................................................11 
3.4.2 
Process ...............................................................................................................12 
3.5 
COGNITIVE DEBRIEFING INTERVIEWS ..............................................................13 
3.5.1 
Conduct ..............................................................................................................13 
3.5.2 
Procedures ..........................................................................................................13 
3.5.3 
Adverse event reporting .....................................................................................14 
3.5.4 
Qualitative data analysis ....................................................................................14 
4. 
DATA PROTECTION AND STORAGE .............................................................................16 
5. 
REFERENCES ......................................................................................................................17 
  
 
 
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LIST OF TABLES 
Table 1. 
Cognitive interview schedule by cohort ..............................................................8 
 
 
 
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LIST OF ATTACHMENTS 
Attachment A 
Patient-Completed Screening Questions 
Attachment B 
Site-Completed Screening Form: Cohort 2 
Attachment C 
Site-Completed Screening Form: Cohort 3 
Attachment D 
Cognitive Debriefing Interview Guide: Evaluating the Modified Reflux     
Symptoms Questionnaire Electronic Diary (mRESQ-eD) 
 
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ABBREVIATIONS 
AE 
Adverse Event 
EGD 
Esophagogastroduodenoscopy 
FDA 
US Food and Drug Administration 
GERD 
Gastroesophageal Reflux Disease 
GI 
Gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IRB 
Independent Review Board 
mRESQ-eD 
Modified Reflux Symptoms Questionnaire Electronic Diary 
PPI 
Proton Pump Inhibitors 
PRO 
Patient-Reported Outcome 
RESQ 
Reflux Symptom Questionnaire 
rGERD 
Refractory Gastroesophageal Reflux Disease 
SAE 
Serious Adverse Event 
 
 
 
 
  
 
 
 
 
 
 
 
 
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1. 
INTRODUCTION 
The measurement properties of a modified version of the Reflux Symptom Questionnaire 
(RESQ) are being examined in the ICP-3718-202 protocol. The ICP-3718-202 trial is evaluating 
the safety, efficacy, and dose-response relationship of IW-3718 administered orally to patients 
who continue to experience GERD symptoms while receiving once-daily, optimized, standard-
dose PPIs. In keeping with the FDA’s guidance for instrument modification, Ironwood would 
like to document the content validity of the modified RESQ electronic diary (mRESQ-eD) 
through cognitive debriefing interviews. Endpoint Outcomes personnel will conduct cognitive 
debriefing interviews with participants recruited for the ICP-3718-202 protocol. This study 
manual outlines the procedures specific to the cognitive debriefing interviews. 
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2. 
OBJECTIVES 
The primary objective of the cognitive debriefing interviews is to evaluate the content validity of 
the mRESQ-eD and qualitatively examine how rGERD patients think about and define a 
meaningful change in symptom improvement. To achieve the primary objective, cognitive 
debriefing interviews of the mRESQ-eD with 30 ICP-3718-202 study participants will be 
conducted. 
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3. 
METHODOLOGY 
3.1 
STUDY DESIGN 
A subset of ICP-3718-202 clinical trial participants will be invited to participate in cognitive 
debriefing interviews. A total of 30 eligible patients will be scheduled for interviews. The 
interview sample will be divided into three cohorts: 
• Cohort 1: Patients in Cohort 1 will meet all ICP-3718-202 study eligibility criteria and will 
complete the mRESQ-eD daily for the duration of the Pretreatment Period and at least four 
weeks of the Treatment Period (n=20). Patients in Cohort 1 must have completed the 
mRESQ-eD rather than the RESQ in order to be eligible to participate in the cognitive 
interviews.  
• Cohort 2: Patients in Cohort 2 will meet select ICP-3718-202 study eligibility criteria (see 
section 3.3.2 below), including the ICP-3718-202 study eligibility criterion for erosive 
esophagitis (evaluated by EGD) and/or evidence of pathological acid reflux (evaluated with 
the Bravo® device), and be mRESQ-eD naïve (n=5). Screen failures are not eligible for 
Cohort 2. 
• Cohort 3: Patients in Cohort 3 will meet select ICP-3718-202 study eligibility criteria (see 
section 3.3.2 below), excluding the ICP-3718-202 study eligibility criterion for erosive 
esophagitis (evaluated by EGD) and/or evidence of pathological acid reflux (evaluated with 
the Bravo® device), and be mRESQ-eD naïve (n=5). Cohort 3 will be comprised of screen 
failures for ICP-3718-202.  
Cohorts will be scheduled for interviews during the clinical trial visits outlined in Table 1 below. 
All patients will be consented prior to the interview occurring. 
Table 1. 
Cognitive interview schedule by cohort 
Cohort 
Schedule Interview to Occur During: 
Cohort 1 
Week 4 or Week 8 Visit 
Cohort 2 
Pretreatment Visit 
Cohort 3 
Any time after screen fail.  Interviews will be scheduled to coincide 
with other Cohort 1 or 2 interviews as scheduled for the same day. 
 
Regardless of cohort or interview timing, all interview participants will be cognitively debriefed 
on the mRESQ-eD and asked to provide input on what constitutes a meaningful change in 
symptom improvement on the mRESQ-eD.  
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3.2 
INTERVIEW MATERIALS 
In addition to this Study Manual, the following materials have been developed for consenting, 
screening and conducting the cognitive debriefing interviews:  
• Patient-Completed Screening Questions (Attachment A); 
• Site-Completed Screening Form: Cohort 2 (Attachment B);  
• Site-Completed Screening Form: Cohort 3 (Attachment C); and 
• Cognitive Debriefing Interview Guide (Attachment D).  
3.3 
INTERVIEW SAMPLE 
3.3.1 
Number of patients and sites 
A total of 30 clinical trial participants will be enrolled from a subset of sites participating in the 
ICP-3718-202 study. The interview sample will be divided into the three cohorts outlined in 
section 3.1. 
3.3.2 
Interview eligibility criteria 
The interview eligibility criteria for Cohort 1 is the same as the ICP-3718-202 study eligibility 
criteria. Patients in Cohort 1 must have completed the mRESQ-eD rather than the RESQ in order 
to be eligible for the cognitive interviews. Patients are eligible for Cohort 2 if they meet all of the 
interview inclusion and exclusion criteria outlined below. Patients are eligible for Cohort 3 if 
they meet inclusion criteria 1 through 7 and all of the exclusion criteria outlined below.  
Inclusion criteria 
1. Patient has signed the optional ICF (specific to the interview) before the interview is 
conducted. 
2. Patient is able to speak, read, write, and comprehend US English. 
3. In the judgement of the investigator, the patient has adequate communication skills to reflect 
on his/her experience with GERD during the qualitative interview. 
4. Patient is willing and able to participate in a 60-minute interview. 
 
 
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5. According to the Patient-Completed Screening Questions 1a and/or 2, the patient reports 
heartburn and/or regurgitation on ≥ 4 days during the past 7 days.1 
6. According to the Patient-Completed Screening Question 1b, the patient reports heartburn 
severity of ≥ “mild” on average over the past 7 days. 
7. According to the Patient-Completed Screening Question 1c, the patient reports heartburn 
severity of ≥ “moderate” at its worst over the past 7 days. 
8. (Cohort 2 only) Patient has an EGD with approximately 48 to 96 hours of pH monitoring 
(with a Bravo® device) during the Screening Period (while the patient continues taking their 
PPI) that demonstrates 1 or more of the following: 
a. Erosive esophagitis (Grade A or greater based on the Los Angeles classification of 
esophagitis) on EGD; and/or 
b. Evidence of pathological acid reflux (pH is < 4 for ≥ 4.2% of the recording time) during 
at least 1 of the 24-hour time intervals of pH testing with the Bravo® device. 
Exclusion criteria 
1. Patient is unable to understand the nature, scope, and possible consequences of the interview, 
and/or presents evidence of an uncooperative attitude. 
2. Patient does not meet any of the following ICP-3718-202 inclusion criteria: 
a. Patient is an ambulatory, community-dwelling male or nonpregnant female and is at least 
18 years old at the Screening Visit. Lactating females must agree not to breastfeed (for 
the interview study, pregnant and breastfeeding females are not disqualified). 
b. Patient has a diagnosis of GERD and reports experiencing GERD symptoms (heartburn 
or regurgitation) on ≥ 4 days per week during the 8 weeks before the Screening Visit 
while taking standard daily PPI therapy. 
3. Patient meets any of the following ICP-3718-202 exclusion criteria: 
a. Patient has a history of complete lack of GERD symptom response to PPIs in the past. 
b. Patient reports epigastric pain or burning as his/her predominant symptom at the 
Screening Visit. 
c. Patient has a history of gastroparesis, bowel obstruction, or is at risk for a bowel 
obstruction (e.g., patient has an organic gastrointestinal [GI] motility disorders or a 
history of major GI surgery).  
 
_____________________________ 
 
1 This criterion is met when patients respond in the following manner on the Patient-Completed Screening 
Questions: Question 1a response ≥ 4 days; Question 2 response ≥ 4 days; or the sum of the responses to 
Question 1a and Question 2 is ≥ 4 days. 
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d. Patient has any alarm symptoms including but not limited to GI bleeding, anemia, 
vomiting, or unexpected weight loss any time during the Screening or Pretreatment 
Periods. 
e. Patient has undergone surgery that meets any of the following criteria: 
• 
Surgery of the GI tract (including gastric banding) other than an appendectomy, 
cholecystectomy, minor oral or rectal surgery (e.g., tonsillectomy, 
hemorrhoidectomy, rectocele repair) at any time before the Screening Visit; 
• 
An appendectomy during the 3 months before the Screening Visit or a 
cholecystectomy during the 6 months before the Screening Visit or minor oral or 
rectal surgery during the 30 days before the Screening Visit; 
• 
Non-GI surgery of the abdomen, pelvis, or retroperitoneal structures during the 
6 months before the Screening Visit; 
• 
Thoracic surgery during the 6 months before the Screening Visit; and/or 
• 
Other major non-GI surgery during the 30 days before the Screening Visit. 
f. Patient has previously undergone thoracic or abdominal radiotherapy. 
g. Patient has Gilbert’s disease, Crohn’s disease, diabetes mellitus, Zollinger-Ellison 
syndrome, pancreatitis, cholecystitis, or systemic sclerosis. 
h. 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. 
i. (Cohort 2 only) EGD, conducted during the Screening Period, reveals that the patient has 
long-segment Barrett’s esophagus (greater than 3 centimeters) or definite dysplastic 
changes in the esophagus, peptic ulcer disease, active GI bleeding, presence of 
esophageal strictures, presence of esophageal or fundic varices, erosive gastritis, or 
eosinophilic, herpetic or Candida esophagitis.  
If a patient screened for Cohort 2 does not meet the exclusion criterion 3i above due to the EGD 
or pH monitoring results, the patient may still be eligible to participate in Cohort 3. 
3.4 
INTERVIEW RECRUITMENT 
3.4.1 
Site onboarding and training 
Sites will be trained prior to screening and enrolling interview participants. During the training, 
sites will be informed about the process to determine eligibility and schedule interviews. 
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3.4.2 
Process 
The majority of the recruitment and interview scheduling responsibilities will be completed by 
the participating sites. Sites will contact Endpoint Outcomes to schedule interviews in 
accordance with Table 1. Endpoint Outcomes will work with the sites to determine a mutually 
acceptable time to interview the participants. The specific recruitment process for each cohort is 
outlined below. 
Cohort 1 patients will be invited to participate in the cognitive debriefing interview and will sign 
a separate optional consent. No screening is required to determine interview eligibility. Prior to 
each interview, site staff will email Endpoint Outcomes to confirm receipt of written informed 
consent. The 60-minute interview will be conducted in-person by an Endpoint Outcomes 
interviewer during the Week 4 or Week 8 Visit. Every effort will be made to accommodate in-
person interviews; however, allowances may be made for telephone interviews if scheduling 
prohibits in-person interviews.  
Cohorts 2 and 3 patients will be invited to participate in the cognitive debriefing interview and 
will sign a separate optional consent. In order to determine interview eligibility, potential 
participants will need to complete the Patient-Completed Screening Questions and site staff will 
need to complete the Site-Completed Screening Form: Cohort 2 or Site-Completed Screening 
Form: Cohort 3. Site staff will transmit copies of these redacted documents to Endpoint 
Outcomes, and will email Endpoint Outcomes to confirm receipt of written informed consent 
prior to the interview. The 60-minute interview will be conducted in-person by an Endpoint 
Outcomes interviewer during the Pretreatment Visit for Cohort 2 participants and any time after 
the Screening Visit for Cohort 3. Interviews for Cohort 3 participants should be scheduled to 
coincide with other Cohort 1 or 2 interviews at the site. Every effort will be made to 
accommodate in-person interviews; however, allowances may be made for telephone interviews 
if scheduling prohibits in-person interviews.  
 
 
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3.5 
COGNITIVE DEBRIEFING INTERVIEWS  
The Cognitive Debriefing Interview Guide (Attachment D) was prepared to facilitate the 
evaluation of the face and content validity of the mRESQ-eD. The Cognitive Debriefing 
Interview Guide includes questions targeting specific information related to patient perceptions 
of how well the mRESQ-eD captures the overall experience of symptoms related to rGERD. The 
Cognitive Debriefing Interview Guide will also facilitate a discussion regarding what constitutes 
a meaningful change in symptom improvement on the mRESQ-eD from the patient’s 
perspective.  
3.5.1 
Conduct 
The cognitive debriefing interviews will be conducted in-person by trained and experienced 
Endpoint Outcomes interviewers. Interviewers have completed National Institutes of Health 
Human Participant Protection Training, as well as internal data protection and interview training.   
The interviews will be conducted in-person at the site; however, allowances may be made for 
telephone interviews. If telephone interviews are used, patients will still be required to be in the 
clinic during the interview. Interviews will be conducted while the participant has the electronic 
diary in hand to most closely simulate the conditions during the ICP-3718-202 study. The diary 
used during the interview will be set to training mode. Data entered by the participant during the 
interview will be used only for purposes of this cognitive interview sub-study, and will not be 
part of the analysis for the main ICP-3718-202 protocol.  For in-person interviews, Endpoint 
Outcomes will provide an electronic diary for the participant to use during the interview. In the 
case of telephone interviews, the site will provide an electronic diary in training mode for use 
during the interview. 
3.5.2 
Procedures 
During each cognitive debriefing interview, patients will be asked to complete the mRESQ-eD 
using a “think-aloud” method whereby the patients are encouraged to verbalize their thoughts 
while completing the questions. Under this methodology, the interviewer simply reminds 
participants to verbalize their thought process (e.g., “what were you considering when you 
selected that answer?”).i  However, the think-aloud process does not always yield the data 
needed to answer all of the research questions (e.g., if the patient does not spontaneously think-
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aloud about a point of interest to the interviewers). For this reason, more specific verbal probing 
(e.g., “what does this question mean to you?”) is incorporated into the interviews as well to 
ensure the objectives of the research are accomplished. 
Each interview will be audio-recorded, with the patient’s consent, and last approximately 60-
minutes. Patients will be compensated by the site for their participation in an interview. 
3.5.3 
Adverse event reporting  
Definitions for adverse events (AEs) and serious adverse events (SAEs) and the procedures for 
reporting AEs are outlined in section 3.5.1 of the ICP-3718-202 protocol. While soliciting 
AEs/SAEs is not part of the cognitive debriefing interview, patients may spontaneously report 
potential AEs/SAEs during the course of the interview. If a potential AE/SAE is reported, the 
interviewer will notify the site investigator and study coordinator via email following the 
interview. Each email will use the following format: “During the course of the interview [Patient 
ID number] reported experiencing [event(s) as described by patient] during the course of the 
study. Please follow-up with the patient as appropriate regarding the event(s) per the study 
protocol.”  
3.5.4 
Qualitative data analysis 
Audio-recordings of the interviews will be transcribed verbatim and de-identified by removing 
identifying information such as names and places. An initial coding scheme will be developed 
based on the interview guide and research objectives, and applied and operationalized using 
ATLAS.ti version 7.5.11 or higher (ATLAS.ti GmbH, Berlin). The coding scheme will clearly 
define types of item interpretation issues so that they can be consistently applied across coders.    
The cognitive debriefing coding process will be guided by established qualitative research 
methods, including grounded theory and constant comparative method.i,ii Each transcript will be 
considered a unit of analysis, and data from all transcripts will be aggregated following coding. 
Once the cognitive debriefing interview data are aggregated, researchers will review all of the 
codes in order to ensure that the coding scheme has been used consistently by all coders and to 
ensure all relevant themes (e.g., unanticipated issues with items) have been captured during the 
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coding process. Ultimately, frequencies of codes will be reported, with accompanying exemplary 
quotes. 
In addition to the qualitative analyses described above, mRESQ-eD scores and Degree of Relief 
Assessment scores at baseline and Week 4 and Week 8 for Cohort 1 will be analyzed to inform 
what constitutes a meaningful change. Further, responses to “How much would you need to 
improve on the answer scale for the change to be meaningful” for each item will be summarized 
as well. 
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4. 
DATA PROTECTION AND STORAGE 
The interview audio-recordings and de-identified transcripts will be labeled by Patient ID 
number only and will be stored on a secure server only accessible to Endpoint Outcomes. 
Following completion of the interviews, Endpoint Outcomes will provide each site with a 
complete and accurate copy of the original audio-recording(s) for the site’s patient(s). Sites are 
expected to maintain the audio-recording(s) with other study documents according to applicable 
clinical trial regulations. 
 
 
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5. 
REFERENCES 
i 
Beatty P, Willis G.  Research synthesis: the practice of cognitive debriefing interviews.  
Public Opinion Quarterly 2007;71(2):287-311. 
ii 
Glaser BG, Strauss AL. The discovery of grounded theory: Strategies for qualitative 
research. New York: Aldine de Gruyter, 1967:1-18. 
iii 
Charmaz K. Grounded theory. In: Smith JA, Harré R, Van Langenhove L. Rethinking 
methods in psychology. London: Sage Publications, 1995: 27-49. 
 
 
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ATTACHMENT A:  mRESQ-eD COGNITIVE DEBRIEFING 
 
 
 
 
 
 
 
INTERVIEWS: PATIENT-COMPLETED 
 
 
 
 
 
 
 
SCREENING QUESTIONS 
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Patient-Completed Screening Questions 
 
The information included in this form is for the patient to complete in order to confirm the 
eligibility of a patient in Cohorts 2 or 3 for interviews. Patients in Cohort 1 are automatically eligible 
and do not need to be screened. 
This form should be maintained with other ICP-3718-202 study documents. A copy should be 
transmitted to: 
Endpoint Outcomes 
Attn: Siobhan McDonold 
Fax: 617-507-5654 
E-mail: siobhan.mcdonold@endpointoutcomes.com    
Patient ID 
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Screening Questions 
1a.    Over the past 7 days, how many days did you have heartburn (including pain or burning feeling 
behind the breastbone or in the center of the upper stomach)?  
  0 days 
  4 days 
  1 day 
  5 days 
  2 days 
  6 days 
  3 days 
  7 days 
 
If you answered 1 or more days to Question 1a above, answer Questions 1b and 1c below.  
If you answered “0 days” to Question 1a above, skip to Question 2.  
1b.    Over the past 7 days, how would you rate the severity of your heartburn on average (including 
pain or burning feeling behind the breastbone or in the center of the upper stomach)?  
  Very Mild 
  Mild 
  Moderate 
  Moderately Severe 
  Severe 
 
1c.    Over the past 7 days, how would you rate the severity of your heartburn at its worst (including 
pain or burning feeling behind the breastbone or in the center of the upper stomach)?  
  Very Mild 
  Mild 
  Moderate 
  Moderately Severe 
  Severe 
 
 
2.    Over the past 7 days, how many days did you have regurgitation (liquid or food moving upwards 
towards your throat or mouth) and/or reflux (acid or bitter taste in the mouth)? 
  0 days 
  4 days 
  1 day 
  5 days 
  2 days 
  6 days 
  3 days 
  7 days 
 
 
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ATTACHMENT B:  mRESQ-eD COGNITIVE DEBRIEFING 
INTERVIEWS: SITE-COMPLETED SCREENING 
QUESTIONS – COHORT 2 
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Site-Completed Screening Form: Cohort 2 
 
The information included in this form is for the investigator or a designated representative (e.g., 
study coordinator) to complete in order to confirm the eligibility of a patient in Cohort 2. To 
confirm the eligibility of a patient in Cohort 3, please refer to the Site-Completed Screening Form: 
Cohort 3. Patients in Cohort 1 are automatically eligible and do not need to be screened. 
This form should be maintained with other ICP-3718-202 study documents. A copy should be 
transmitted to: 
Endpoint Outcomes 
Attn: Siobhan McDonold 
Fax: 617-507-5654 
E-mail: siobhan.mcdonold@endpointoutcomes.com    
 
 
Patient ID 
IW-3718 
 
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# 
INTERVIEW INCLUSION CRITERIA 
YES 
NO 
1. Has the patient voluntarily provided written informed consent?  
1 
0 
2. Is the patient able to speak, read, write, and comprehend US English? 
1 
0 
3.
In the judgment of the investigator, does the patient have adequate 
communication skills to reflect on his/her experience with Gastrointestinal 
Reflux Disease (GERD) during a qualitative interview?  
1 
0 
4. Is the patient willing and able to participate in a 60-minute interview? 
1 
0 
5.
According to the Patient-Completed Screening Questions 1a and/or 2, does 
the patient report heartburn and/or regurgitation on ≥ 4 days during the 
past 7 days?2 
1 
0 
6.
According to the Patient-Completed Screening Question 1b, does the 
patient report heartburn severity of ≥ mild on average over the past 7 
days? 
1 
0 
7.
According to the Patient-Completed Screening Question 1c, does the 
patient report heartburn severity of ≥ moderate at its worst over the past 7 
days? 
1 
0 
8.
Does the patient have an esophagogastroduodenoscopy (EGD) with 
approximately 48 to 96 hours of pH monitoring (with a Bravo® device) 
demonstrating 1 or more of the following: 
a. Erosive esophagitis (Grade A or greater based on the Los Angeles 
classification of esophagitis) on EGD; and/or 
b. Evidence of pathological acid reflux (pH is < 4 for ≥ 4.2% of the 
recording time) during at least 1 of the 24-hour time intervals of 
pH testing with the Bravo device? 
1 
0 
 
Please review the following carefully before proceeding to the next section:  
 If the answers to any inclusion criterion questions 1 through 7 above is “NO”, please stop. This 
patient is not eligible to participate in the interview. You do not need to complete any further 
sections of this form.  
o If the answer to inclusion criterion question 8 above is “NO”, patient may still be eligible 
to participate in Cohort 3. Please refer to the Site-Completed Screening Form: Cohort 3.  
 If the answer to every inclusion criterion questions 1 through 8 above is “YES”, please proceed to 
evaluating the exclusion criteria below. This patient may be eligible to participate in the interview 
in Cohort 2. 
                                                 
2 This criterion is met when patients respond in the following manner on the Patient-Completed Screening 
Questions: Question 1a response ≥ 4 days; Question 2 response ≥ 4 days; or the sum of the responses to Question 
1a and Question 2 is ≥ 4 days. 
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# 
INTERVIEW EXCLUSION CRITERIA 
YES 
NO 
1. 
Is the patient unable to understand the nature, scope, and possible 
consequences of the interview, and/or presents evidence of an 
uncooperative attitude? 
1 
0 
2. 
Did the patient screen fail on any of the following ICP-3718-202 inclusion 
criteria? Check all that apply: 
 Patient is an ambulatory, community-dwelling male or nonpregnant 
female and is at least 18 years old at the Screening Visit. Lactating females 
must agree not to breastfeed (for the interview study, pregnant and 
breastfeeding females are not disqualified). 
 Patient has a diagnosis of GERD and reports experiencing GERD symptoms 
(heartburn or regurgitation) on ≥ 4 days per week during the 8 weeks 
before the Screening Visit while taking standard daily PPI therapy. 
1 
0 
3. 
Did the patient screen fail on any of the following ICP-3718-202 exclusion 
criteria? Check all that apply: 
 Patient has a history of complete lack of GERD symptom response to PPIs 
in the past. 
 Patient reports epigastric pain or burning as his/her predominant 
symptom at the Screening Visit. 
 Patient has a history of gastroparesis, bowel obstruction, or is at risk for 
a bowel obstruction (e.g., patient has an organic gastrointestinal [GI] 
motility disorders or a history of major GI surgery).  
 Patient has any alarm symptoms including but not limited to GI bleeding, 
anemia, vomiting, or unexpected weight loss any time during the 
Screening or Pretreatment Periods. 
 Patient has undergone surgery that meets any of the following criteria:  
b. Surgery of the GI tract (including gastric banding) other than an 
appendectomy, cholecystectomy, minor oral or rectal surgery 
(e.g., tonsillectomy, hemorrhoidectomy, rectocele repair) at any 
time before the Screening Visit; 
c. 
An appendectomy during the 3 months before the Screening 
Visit or a cholecystectomy during the 6 months before the 
Screening Visit or minor oral or rectal surgery during the 30 days 
before the Screening Visit; 
d. Non-GI surgery of the abdomen, pelvis, or retroperitoneal 
structures during the 6 months before the Screening Visit; 
e. Thoracic surgery during the 6 months before the Screening Visit; 
and/or 
f. 
Other major non-GI surgery during the 30 days before the 
Screening Visit. 
 Patient has previously undergone thoracic or abdominal radiotherapy. 
 Patient has Gilbert’s disease, Crohn’s disease, diabetes mellitus, 
Zollinger-Ellison syndrome, pancreatitis, cholecystitis, or systemic 
sclerosis. 
1 
0 
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# 
INTERVIEW EXCLUSION CRITERIA 
YES 
NO 
 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. 
 EGD, conducted during the Screening Period, reveals that the patient has 
long-segment Barrett’s esophagus (greater than 3 centimeters) or 
definite dysplastic changes in the esophagus, peptic ulcer disease, active 
GI bleeding, presence of esophageal strictures, presence of esophageal 
or fundic varices, erosive gastritis, or eosinophilic, herpetic or Candida 
esophagitis.  
 
Please review the following carefully before proceeding to the next section:  
 If the answer to any exclusion criterion question above is “YES”, this patient is not eligible to 
participate in the interview as part of Cohort 2.  
o If the answer to exclusion criterion question 3 above is “YES” due to the EGD results, 
the patient may still be eligible to participate in Cohort 3. Please refer to the Site-
Completed Screening Form: Cohort 3.  
 If the answer to every exclusion criterion question above is “NO” and the answer to every inclusion 
criterion question 1 through 8 above is “YES”, this patient is eligible to participate the interview in 
Cohort 2.  
 
Investigator Signature Required: 
Investigator signature: ___________________________________________________________ 
Date: ____________________ 
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ATTACHMENT C:  mRESQ-eD COGNITIVE DEBRIEFING 
INTERVIEWS: SITE-COMPLETED SCREENING 
QUESTIONS – COHORT 3
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mRESQ-eD Cognitive Interviews 
 
 
Page 1 of 4 
 
 
 
 
 
 
 
Patient ID 
Site-Completed Screening Form: Cohort 3 
 
The information included in this form is for the investigator or a designated representative (e.g., 
study coordinator) to complete in order to confirm the eligibility of a patient in Cohort 3. To 
confirm the eligibility of a patient in Cohort 2, please refer to the Site-Completed Screening Form: 
Cohort 2. Patients in Cohort 1 are automatically eligible and do not need to be screened. 
This form should be maintained with other ICP-3718-202 study documents. A copy should be 
transmitted to: 
Endpoint Outcomes 
Attn: Siobhan McDonold 
Fax: 617-507-5654 
E-mail: siobhan.mcdonold@endpointoutcomes.com    
AAPX-C 
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mRESQ-eD Cognitive Interviews 
 
 
 
 
 
 
 
 
Page 2 of 4 
 
 
 
 
 
 
 
Patient ID 
# 
INTERVIEW INCLUSION CRITERIA 
YES 
NO 
1. 
Has the patient voluntarily provided written informed consent?  
1 
0 
2. 
Is the patient able to speak, read, write, and comprehend US English? 
1 
0 
3. 
In the judgment of the investigator, does the patient have adequate 
communication skills to reflect on his/her experience with Gastrointestinal 
Reflux Disease (GERD) during a qualitative interview?  
1 
0 
4. 
Is the patient willing and able to participate in a 60-minute interview? 
1 
0 
5. 
According to the Patient-Completed Screening Questions 1a and/or 2, 
does the patient report heartburn and/or regurgitation on ≥ 4 days during 
the past 7 days?* 
1 
0 
6. 
According to the Patient-Completed Screening Question 1b, does the 
patient report heartburn severity of ≥ mild on average over the past 7 
days? 
1 
0 
7. 
According to the Patient-Completed Screening Question 1c, does the 
patient report heartburn severity of ≥ moderate at its worst over the past 
7 days? 
1 
0 
 
Please review the following carefully before proceeding to the next section:  
 If the answers to any inclusion criterion question above is “NO”, please stop. This patient is not eligible 
to participate in the interview. You do not need to complete any further sections of this form.  
 If the answer to every inclusion criterion question above is “YES”, please proceed to evaluating the 
exclusion criteria below. This patient may be eligible to participate in the interview. 
                                                     
* This criterion is met when patients respond in the following manner on the Patient-Completed Screening Questions: 
Question 1a response ≥ 4 days; Question 2 response ≥ 4 days; or the sum of the responses to Question 1a and 
Question 2 is ≥ 4 days. 
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mRESQ-eD Cognitive Interviews 
 
 
 
 
 
 
 
 
Page 3 of 4 
 
 
 
 
 
 
 
Patient ID 
# 
INTERVIEW EXCLUSION CRITERIA 
YES 
NO 
1. 
Is the patient unable to understand the nature, scope, and possible 
consequences of the interview, and/or presents evidence of an 
uncooperative attitude? 
1 
0 
2. 
Did the patient screen fail on any of the following ICP-3718-202 inclusion 
criteria? Check all that apply: 
 Patient is an ambulatory, community-dwelling male or nonpregnant 
female and is at least 18 years old at the Screening Visit. Lactating females 
must agree not to breastfeed (for the interview study, pregnant and 
breastfeeding females are not disqualified). 
 Patient has a diagnosis of GERD and reports experiencing GERD symptoms 
(heartburn or regurgitation) on ≥ 4 days per week during the 8 weeks 
before the Screening Visit while taking standard daily PPI therapy. 
1 
0 
3. 
Did the patient screen fail on any of the following ICP-3718-202 exclusion 
criteria? Check all that apply: 
 Patient has a history of complete lack of GERD symptom response to PPIs 
in the past. 
 Patient reports epigastric pain or burning as his/her predominant 
symptom at the Screening Visit. 
 Patient has a history of gastroparesis, bowel obstruction, or is at risk for a 
bowel obstruction (e.g., patient has an organic gastrointestinal [GI] 
motility disorders or a history of major GI surgery).  
 Patient has any alarm symptoms including but not limited to GI bleeding, 
anemia, vomiting, or unexpected weight loss any time during the 
Screening or Pretreatment Periods. 
 Patient has undergone surgery that meets any of the following criteria:  
a. Surgery of the GI tract (including gastric banding) other than an 
appendectomy, cholecystectomy, minor oral or rectal surgery 
(e.g., tonsillectomy, hemorrhoidectomy, rectocele repair) at any 
time before the Screening Visit; 
b. An appendectomy during the 3 months before the Screening Visit 
or a cholecystectomy during the 6 months before the Screening 
Visit or minor oral or rectal surgery during the 30 days before the 
Screening Visit; 
c. 
Non-GI surgery of the abdomen, pelvis, or retroperitoneal 
structures during the 6 months before the Screening Visit; 
1 
0 
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mRESQ-eD Cognitive Interviews 
 
 
 
 
 
 
 
 
Page 4 of 4 
 
 
 
 
 
 
 
Patient ID 
# 
INTERVIEW EXCLUSION CRITERIA 
YES 
NO 
d. Thoracic surgery during the 6 months before the Screening Visit; 
and/or 
e. Other major non-GI surgery during the 30 days before the 
Screening Visit. 
 Patient has previously undergone thoracic or abdominal radiotherapy. 
 Patient has Gilbert’s disease, Crohn’s disease, diabetes mellitus, Zollinger-
Ellison syndrome, pancreatitis, cholecystitis, or systemic sclerosis. 
 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. 
 
Please review the following carefully before proceeding to the next section:  
 If the answer to any exclusion criterion question above is “YES”, this patient is not eligible to 
participate in the interview.  
 If the answer to every exclusion criterion question above is “NO” and the answer to every inclusion 
criterion question above is “YES”, this patient is eligible to participate the interview.  
 
Investigator Signature Required: 
Investigator signature: ___________________________________________________________ 
Date: ____________________ 
 
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ATTACHMENT D:  mRESQ-eD COGNITIVE DEBRIEFING INTERVIEW  
 
 
 
 
 
 
      GUIDE 
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    Page 1 of 25  
 
 
 
 
 
 
 
Patient ID 
 
 
 
Cognitive Debriefing Interview Guide: Evaluating the 
Modified Reflux Symptoms Questionnaire Electronic 
Diary (mRESQ-eD) 
 
 
 
 
 
 
 
 
 
 
Site ID:  
Patient ID:   
Date of interview:  
Time of interview:  
Type of interview:   
 In person   Telephone  
Cohort:   1       2       3 
Name of interviewer: 
 
 
 
 
 
 
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    Page 2 of 25  
 
 
 
 
 
 
 
Patient ID 
 
 
 
 
Part 1: 
Interviewer Instructions 
Prior to the interview 
 
Verify receipt of written informed consent 
 
Verify confirmation of eligibility 
 
During the interview 
 
This interview guide is semi-structured in nature and meant to serve as a basis for the discussion. 
Actively listen, probe as necessary and take note of nonverbal communication during in-person 
interviews (e.g., long pauses, facial expressions, gestures).  
 
After the interview 
 
Thank the patient for his/her time. 
 
Write down brief overall impressions of the interview immediately after it is completed, making sure to 
note any issues encountered during the interview (e.g., time issues, patient’s understanding issues, 
etc.) that may explain the quality or quantity of the data. Overall impressions can be extremely useful 
and informative for the subsequent interviews, and therefore, you should be prepared to discuss 
preliminary interview findings with the research team based on your written notes and recollection. 
 
 
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    Page 3 of 25  
 
 
 
 
 
 
 
 
Patient ID 
 
 
 
 
Part 2:  
Study Introduction 
[Duration: 5/60 minutes] 
Introduction 
 
Thank you for your interest and willingness to be a part of the interview. 
 
My name is [first name] and I work with Endpoint Outcomes, a company that works with 
pharmaceutical companies to develop and modify questionnaires used by doctors when they treat 
patients like you. I will be interviewing you today. 
What to expect 
 
During the interview I will ask you to complete a questionnaire and provide your feedback on it. Please 
understand that there are no right or wrong answers. We welcome you to speak freely; your opinions 
and perspectives are appreciated. If you need to take a break, or would like to stop the interview at any 
time, you are free to do so. You also do not have to answer any of the interview questions if you don’t 
want to. 
 
Our interview is scheduled to last about 60 minutes.                                                    
 
I, as well as other researchers involved in this study, have been trained to maintain participant 
confidentiality. Personally identifying information, such as your name, will remain with Endpoint 
Outcomes and will only be accessible to research staff.   
 
Our conversation today will be audio-recorded so that we have an accurate record of the discussion. 
Please speak clearly and loudly so that you can be heard on the audio-recording. 
 
Do I have your permission to audio-record this session? 
- 
If yes: Thank you. I will ask you again for the record once I have the audio-recorder turned on. 
- 
If no: Do not proceed with the interview. 
 
Do you have any questions at this point? 
 
Once the audio-recorder is turned on 
 
This is interviewer, [state your name], here with patient [state patient’s ID]. 
 
Do I have your permission to audio-record this interview? 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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Patient ID 
 
 
 
 
Part 3:  
Think-Aloud and Cognitive Debriefing for the mRESQ-eD 
[Duration: 55/60 minutes] 
Think-aloud 
 
[Cohort 1]: Now I will ask you to complete the modified Reflux Symptoms Questionnaire (mRESQ-eD) 
using the electronic device. I know you have been completing the questionnaire for the last several 
weeks or so and you are already familiar with the questionnaire. 
 
[Cohorts 2 and 3]: Now I will ask you to complete a questionnaire called the modified Reflux Symptoms 
Questionnaire on an electronic device (mRESQ-eD).  
 
Please read the instructions and items, basically everything written on the screen, out loud. And as 
you’re choosing answers, please tell me verbally which answer you chose and why you chose that 
particular answer. You’re basically “thinking out loud” and telling me your thought process as you’re 
completing the questionnaire.  
 
For example, if I asked you how much fruit you ate this week, rather than just saying “three” you might 
say, “On Monday I ate a banana with breakfast, on Tuesday I had an apple at lunch, and on Thursday I 
ate an orange after lunch. So, I ate three pieces of fruit this week.” 
 
 I understand that this is not the way people usually complete questionnaires, so I might have to remind 
you to “think out loud.” I may also interrupt occasionally and ask you questions as you are completing 
the questionnaire. 
[Ensure participant has the mRESQ-eD in front of him/her] 
 
Please start completing the questionnaire in the manner we discussed.  
 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
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Patient ID 
 
Cognitive interviewing: Instructions  
Screen 1 
 
 
What do you think these instructions are asking you to do? Can you put them into your own words? 
- 
What does “reflux disease” mean to you?  
- 
What time period are you being asked to consider when answering the questions? 
- 
Was it clear or unclear to you what to do from reading these instructions? If unclear, why was it 
unclear? 
 
Would you reword it in any way? Please explain. 
 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
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Patient ID 
 
Cognitive Interviewing: Items 1-10
Screen 2 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does heartburn mean to you?  
 
What does the severity of your heartburn mean to you? 
- 
What does over the past 24 hours mean to you? 
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What does [response selected] mean to you? 
- 
What were you considering when you answered the question? 
- 
How far back were you thinking when you answered the question? 
- 
[If the participant selected “0=Did Not Have” ask]: Have you ever had heartburn? 
- 
[If the participant selected “1=Very Mild,” “2=Mild,” “3=Moderate,” “4=Moderately Severe” or 
“5=Severe,” ask]:  Thinking about improvement in your heartburn, what would need to improve for 
it to be meaningful to you? 
 
How often you have heartburn? 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
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Patient ID 
 
How long the heartburn lasts?  
 
How bad the heartburn is? 
- 
 [If the participant selected “5=Severe” ask]: How much would you need to improve on the answer 
scale (did not have, very mild, mild, moderate, moderately severe) for the change to be meaningful 
to you? Please explain. 
- 
[If the participant selected “4=Moderately Severe” ask]: How much would you need to improve on 
the answer scale (did not have, very mild, mild, moderate) for the change to be meaningful to you? 
Please explain. 
- 
[If the participant selected “3=Moderate” ask]: How much would you need to improve on the 
answer scale (did not have, very mild, mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “2= Mild” ask]: How much would you need to improve on the answer 
scale (did not have, very mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Very Mild” ask]: How much would you need to improve on the 
answer scale for the change to be meaningful to you? Please explain. 
- 
[If the participant selected anything other than “0=Did Not Have” ask]: What is more important to 
you: that your heartburn is less severe or happens less often? 
 
What do the other responses [run through each unchecked response] mean for you?  
 
Do the response choices seem to match the question? Why or why not? 
 
Would you reword or change anything about this item, including the response options? Please explain. 
 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
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    Page 8 of 25  
 
 
 
 
 
 
 
Patient ID 
 
 
 
 
Screen 3 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does burning feeling behind the breastbone or in the center of the upper stomach mean to 
you?  
 
What does the severity of your burning feeling behind the breastbone or in the center of the 
upper stomach mean to you? 
Note to interviewer: If the patient interprets the item on screen 3 similar to the item on screen 
2, establish if they are in fact the exact same or if they are at all different. 
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What were you considering when you answered the question? 
- 
How far back were you thinking when you answered the question? 
- 
[If the participant selected “0=Did Not Have” ask]: Have you ever had a burning feeling behind the 
breastbone or in the center of the upper stomach? 
- 
[If the participant selected “1=Very Mild,” “2=Mild,” “3=Moderate,” “4=Moderately Severe” or 
“5=Severe,” ask]:  Thinking about improvement in your burning feeling behind the breastbone or in 
the center of the upper stomach, what would need to improve for it to be meaningful to you? 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
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Patient ID 
 
How often you have a burning feeling behind the breastbone 
or in the center of the upper stomach? 
 
How long the burning feeling behind the breastbone or in the center of the upper stomach 
lasts?  
 
How bad the burning feeling behind the breastbone or in the center of the upper stomach is? 
- 
 [If the participant selected “5=Severe” ask]: How much would you need to improve on the answer 
scale (did not have, very mild, mild, moderate, moderately severe) for the change to be meaningful 
to you? Please explain. 
- 
[If the participant selected “4=Moderately Severe” ask]: How much would you need to improve on 
the answer scale (did not have, very mild, mild, moderate) for the change to be meaningful to you? 
Please explain. 
- 
[If the participant selected “3=Moderate” ask]: How much would you need to improve on the 
answer scale (did not have, very mild, mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “2= Mild” ask]: How much would you need to improve on the answer 
scale (did not have, very mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Very Mild” ask]: How much would you need to improve on the 
answer scale for the change to be meaningful to you? Please explain. 
- 
 [If the participant selected anything other than “0=Did Not Have” ask]: What is more important to 
you: that your burning feeling behind the breastbone or in the center of the upper stomach is less 
severe or happens less often? 
 
Do the response choices seem to match the question? Why or why not? 
 
Would you reword or change anything about this item, including the response options? Please explain. 
 
 
 
 
 
 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
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Patient ID 
 
 
 
 
Screen 4 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does pain behind the breastbone or in the center of the upper stomach mean to you?  
 
What does the severity of your pain behind the breastbone or in the center of the upper 
stomach mean to you? 
Note to interviewer: If the patient interprets the item on screen 4 similar to the item on 
screens 2 or 3, establish if they are in fact the exact same or if they are at all different. 
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What were you considering when you answered the question? 
- 
How far back were you thinking when you answered the question? 
- 
[If the participant selected “0=Did Not Have” ask]: Have you ever had pain behind the breastbone 
or in the center of the upper stomach? 
- 
[If the participant selected “1=Very Mild,” “2=Mild,” “3=Moderate,” “4=Moderately Severe” or 
“5=Severe,” ask]:  Thinking about improvement in your pain behind the breastbone or in the center 
of the upper stomach, what would need to improve for it to be meaningful to you? 
 
How often you have pain behind the breastbone or in the center of the upper stomach? 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
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    Page 11 of 25  
 
 
 
 
 
 
 
Patient ID 
 
How long the pain behind the breastbone or in the center of 
the upper stomach lasts?  
 
How bad the pain behind the breastbone or in the center of the upper stomach is? 
- 
 [If the participant selected “5=Severe” ask]: How much would you need to improve on the answer 
scale (did not have, very mild, mild, moderate, moderately severe) for the change to be meaningful 
to you? Please explain. 
- 
[If the participant selected “4=Moderately Severe” ask]: How much would you need to improve on 
the answer scale (did not have, very mild, mild, moderate) for the change to be meaningful to you? 
Please explain. 
- 
[If the participant selected “3=Moderate” ask]: How much would you need to improve on the 
answer scale (did not have, very mild, mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “2= Mild” ask]: How much would you need to improve on the answer 
scale (did not have, very mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Very Mild” ask]: How much would you need to improve on the 
answer scale for the change to be meaningful to you? Please explain. 
- 
 [If the participant selected anything other than “0=Did Not Have” ask]: What is more important to 
you: that your pain behind the breastbone or in the center of the upper stomach is less severe or 
happens less often? 
 
Do the response choices seem to match the question? Why or why not? 
 
Would you reword or change anything about this item, including the response options? Please explain. 
 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
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Patient ID 
 
 
 
 
Screen 5 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does difficulty swallowing mean to you?  
 
What does the severity of your difficulty swallowing mean to you? 
Note to interviewer: We want to understand if difficulty swallowing means having difficulty 
with the physical act of swallowing or if it means experiencing a sensation (e.g., pain, 
discomfort) while swallowing. If this is unclear based on the interpretation provided by the 
patient, probe further: 
- 
What makes swallowing difficult? 
 
Is it actually trying to swallow that is difficult?  
- 
What does it feel like when swallowing is difficult? 
 
 [If the subject reports pain when swallowing, ask]: Is difficulty swallowing the 
same as or different than pain when swallowing? Were you thinking about how it 
feels when answering the question? 
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What were you considering when you answered the question? 
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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
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Patient ID 
- 
How far back were you thinking when you answered the 
question? 
- 
 [If the participant selected “0=Did Not Have” ask]: Have you ever had difficulty swallowing? 
- 
[If the participant selected “1=Very Mild,” “2=Mild,” “3=Moderate,” “4=Moderately Severe” or 
“5=Severe,” ask]:  Thinking about improvement in your difficulty swallowing, what would need to 
improve for it to be meaningful to you? 
 
How often you have difficulty swallowing? 
 
How long the difficulty swallowing lasts?  
 
How bad the difficulty swallowing is? 
- 
 [If the participant selected “5=Severe” ask]: How much would you need to improve on the answer 
scale (did not have, very mild, mild, moderate, moderately severe) for the change to be meaningful 
to you? Please explain. 
- 
[If the participant selected “4=Moderately Severe” ask]: How much would you need to improve on 
the answer scale (did not have, very mild, mild, moderate) for the change to be meaningful to you? 
Please explain. 
- 
[If the participant selected “3=Moderate” ask]: How much would you need to improve on the 
answer scale (did not have, very mild, mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “2= Mild” ask]: How much would you need to improve on the answer 
scale (did not have, very mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Very Mild” ask]: How much would you need to improve on the 
answer scale for the change to be meaningful to you? Please explain. 
- 
 [If the participant selected anything other than “0=Did Not Have” ask]: What is more important to 
you: that your difficulty swallowing is less severe or happens less often? 
 
Do the response choices seem to match the question? Why or why not?  
 
Would you reword or change anything about this item, including the response options? Please expl
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
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    Page 14 of 25  
 
 
 
 
 
 
 
Patient ID 
 
 
 
 
Screen 6 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does hoarseness mean to you?  
 
What does the severity of your hoarseness mean to you? 
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What were you considering when you answered the question? 
- 
How far back were you thinking when you answered the question? 
- 
[If the participant selected “0=Did Not Have” ask]: Have you ever had hoarseness? 
- 
[If the participant selected “1=Very Mild,” “2=Mild,” “3=Moderate,” “4=Moderately Severe” or 
“5=Severe,” ask]:  Thinking about improvement in your hoarseness, what would need to improve 
for it to be meaningful to you? 
 
How often you have hoarseness? 
 
How long the hoarseness lasts?  
 
How bad the hoarseness is? 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
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Patient ID 
- 
 [If the participant selected “5=Severe” ask]: How much would you 
need to improve on the answer scale (did not have, very mild, mild, moderate, moderately severe) 
for the change to be meaningful to you? Please explain. 
- 
 [If the participant selected “4=Moderately Severe” ask]: How much would you need to improve on 
the answer scale (did not have, very mild, mild, moderate) for the change to be meaningful to you? 
Please explain. 
- 
[If the participant selected “3=Moderate” ask]: How much would you need to improve on the 
answer scale (did not have, very mild, mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “2= Mild” ask]: How much would you need to improve on the answer 
scale (did not have, very mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Very Mild” ask]: How much would you need to improve on the 
answer scale for the change to be meaningful to you? Please explain. 
- 
 [If the participant selected anything other than “0=Did Not Have” ask]: What is more important to 
you: that your hoarseness is less severe or happens less often? 
 
Do the response choices seem to match the question? Why or why not? 
 
Would you reword or change anything about this item, including the response options? Please explain. 
 
 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
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Patient ID 
 
 
 
 
Screen 7 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does cough mean to you?  
 
What does the severity of your cough mean to you? 
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What were you considering when you answered the question? 
- 
How far back were you thinking when you answered the question? 
- 
[If the participant selected “1=Very Mild,” “2=Mild,” “3=Moderate,” “4=Moderately Severe” or 
“5=Severe,” ask]: Do you think your cough is because of your GERD or something else? 
- 
[If the participant selected “0=Did Not Have” ask]: Have you ever had coughing due to your GERD? 
- 
[If the participant selected “1=Very Mild,” “2=Mild,” “3=Moderate,” “4=Moderately Severe” or 
“5=Severe,” ask]:  Thinking about improvement in your cough, what would need to improve for it to 
be meaningful to you? 
 
How often you have coughing? 
 
How long the coughing lasts?  
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
Page 163 of 173 
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Patient ID 
 
How bad the coughing is? 
- 
[If the participant selected “5=Severe” ask]: How much would you need to improve on the answer 
scale (did not have, very mild, mild, moderate, moderately severe) for the change to be meaningful 
to you? Please explain. 
- 
[If the participant selected “4=Moderately Severe” ask]: How much would you need to improve on 
the answer scale (did not have, very mild, mild, moderate) for the change to be meaningful to you? 
Please explain. 
- 
[If the participant selected “3=Moderate” ask]: How much would you need to improve on the 
answer scale (did not have, very mild, mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “2= Mild” ask]: How much would you need to improve on the answer 
scale (did not have, very mild) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Very Mild” ask]: How much would you need to improve on the 
answer scale for the change to be meaningful to you? Please explain. 
- 
 [If the participant selected anything other than “0=Did Not Have” ask]: What is more important to 
you: that your coughing is less severe or happens less often? 
 
Do the response choices seem to match the question? Why or why not? 
 
Would you reword or change anything about this item, including the response options? Please explain. 
 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
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    Page 18 of 25  
 
 
 
 
 
 
 
Patient ID 
 
 
 
 
Screen 8 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does regurgitation (liquid or food moving upwards towards your throat or mouth) mean to 
you?  
 
What does how often did you experience regurgitation (liquid or food moving upwards towards 
your throat or mouth) mean to you? 
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What does [response selected] mean to you? 
- 
What were you considering when you answered the question? 
- 
How far back were you thinking when you answered the question? 
- 
[If the participant selected “0=Never” ask]: Have you ever had regurgitation? 
- 
[If the participant selected “1=Rarely,” “2=Sometimes,” “3=Often,” or “4=Very Often,” ask]:  
Thinking about improvement in your regurgitation, what would need to improve for it to be 
meaningful to you? 
 
How often you have regurgitation? 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
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Patient ID 
 
How long the regurgitation lasts?  
 
How bad the regurgitation is? 
- 
[If the participant selected “4=Very Often” ask]: How much would you need to improve on the 
answer scale (never, rarely, sometimes, often) for the change to be meaningful to you? Please 
explain. 
- 
[If the participant selected “3=Often” ask]: How much would you need to improve on the answer 
scale (never, rarely, sometimes) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “2=Sometimes” ask]: How much would you need to improve on the 
answer scale (never, rarely) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Rarely” ask]: How much would you need to improve on the answer 
scale for the change to be meaningful to you? Please explain. 
- 
[If the participant selected anything other than “0=Never” ask]: What is more important to you: 
that your regurgitation happens less often or is less severe? 
 
What do the other responses [run through each unchecked response] mean for you?  
 
Do the response choices seem to match the question? Why or why not? 
 
Would you reword or change anything about this item, including the response options? Please explain. 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
Page 166 of 173 
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    Page 20 of 25  
 
 
 
 
 
 
 
Patient ID 
 
 
 
 
Screen 9 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does acid or bitter taste in the mouth mean to you?  
 
What does how often did you experience an acid or bitter taste in the month mean to you? 
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What were you considering when you answered the question? 
- 
How far back were you thinking when you answered the question? 
- 
[If the participant selected “0=Never” ask]: Have you ever had an acid or bitter taste in the mouth? 
- 
[If the participant selected “1=Rarely,” “2=Sometimes,” “3=Often,” or “4=Very Often,” ask]:  
Thinking about improvement in the acid or bitter taste in your mouth, what would need to improve 
for it to be meaningful to you? 
 
How often you have the acid or bitter taste in your mouth? 
 
How long the acid or bitter taste in your mouth lasts?  
 
How bad the acid or bitter taste in your mouth is? 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
Page 167 of 173 
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    Page 21 of 25  
 
 
 
 
 
 
 
Patient ID 
- 
[If the participant selected “4=Very Often” ask]: How much would 
you need to improve on the answer scale (never, rarely, sometimes, often) for the change to be 
meaningful to you? Please explain. 
- 
[If the participant selected “3=Often” ask]: How much would you need to improve on the answer 
scale (never, rarely, sometimes) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “2=Sometimes” ask]: How much would you need to improve on the 
answer scale (never, rarely) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Rarely” ask]: How much would you need to improve on the answer 
scale for the change to be meaningful to you? Please explain. 
- 
[If the participant selected anything other than “0=Never” ask]: What is more important to you: 
that your acid or bitter taste in the mouth happens less often or is less severe? 
 
Do the response choices seem to match the question? Why or why not? 
 
Would you reword or change anything about this item, including the response options? Please explain. 
 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
Page 168 of 173 
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    Page 22 of 25  
 
 
 
 
 
 
 
Patient ID 
 
 
 
 
Screen 10 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does burping mean to you?  
 
What does how often did you experience burping mean to you? 
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What were you considering when you answered the question? 
- 
How far back were you thinking when you answered the question? 
- 
[If the participant selected “0=Never” ask]: Have you ever had burping? 
- 
[If the participant selected “1=Rarely,” “2=Sometimes,” “3=Often,” or “4=Very Often,” ask]:  
Thinking about improvement in your burping, what would need to improve for it to be meaningful 
to you? 
 
How often you have burping? 
 
How long the burping lasts?  
 
How bad the burping is? 
IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
 
Confidential 
Page 169 of 173 
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    Page 23 of 25  
 
 
 
 
 
 
 
Patient ID 
- 
 [If the participant selected “4=Very Often” ask]: How much would 
you need to improve on the answer scale (never, rarely, sometimes, often) for the change to be 
meaningful to you? Please explain. 
- 
[If the participant selected “3=Often” ask]: How much would you need to improve on the answer 
scale (never, rarely, sometimes) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “2=Sometimes” ask]: How much would you need to improve on the 
answer scale (never, rarely) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Rarely” ask]: How much would you need to improve on the answer 
scale for the change to be meaningful to you? Please explain. 
- 
[If the participant selected anything other than “0=Never” ask]: What is more important to you: 
that your burping happens less often or is less severe? 
 
Do the response choices seem to match the question? Why or why not? 
 
Would you reword or change anything about this item, including the response options? Please explain. 
 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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    Page 24 of 25  
 
 
 
 
 
 
 
Patient ID 
 
 
 
 
Screen 11 
 
 
What does this question mean to you? Can you put the question into your own words? 
- 
What does coughing mean to you?  
 
What does how often did you experience coughing mean to you? 
- 
How is this question different than the previous question on coughing? 
 
Which is more meaningful to you, the severity of your coughing or how often you cough? 
 
Do you think both are important to ask? Please explain.  
 
I see you selected [patient’s response]. What made you choose that answer? 
- 
What were you considering when you answered the question? 
- 
How far back were you thinking when you answered the question? 
- 
[If the participant selected “0=Never” ask]: Have you ever had coughing? 
- 
[If the participant selected “4=Very Often” ask]: How much would you need to improve on the 
answer scale (never, rarely, sometimes, often) for the change to be meaningful to you? Please 
explain.TEST- 
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Patient ID 
- 
[If the participant selected “3=Often” ask]: How much would you 
need to improve on the answer scale (never, rarely, sometimes) for the change to be meaningful to 
you? Please explain. 
- 
[If the participant selected “2=Sometimes” ask]: How much would you need to improve on the 
answer scale (never, rarely) for the change to be meaningful to you? Please explain. 
- 
[If the participant selected “1=Rarely” ask]: How much would you need to improve on the answer 
scale for the change to be meaningful to you? Please explain. 
 
Do the response choices seem to match the question? Why or why not? 
 
Would you reword or change anything about this item, including the response options? Please explain. 
General impressions of mRESQ-eD 
 
I’d like to ask you some questions about your overall opinion of the questionnaire. 
 
How easy or difficult was it for you to think about your symptoms over 24 hours when answering the 
questions? 
 
Is the time of day that you answer the questions important?  
- 
Would you answer the same or differently in the morning versus at night? 
 
Was it easy or difficult for you to transition from one set of response options used for the questions on 
screens 2-7 and another set of response options used for questions on screens 8-11? Please explain. 
 
Were there any words that may be difficult or hard for someone to understand when completing the 
questionnaire? If so, which ones and why? 
 
Is there anything important related to your experience with GERD that is missing in the questionnaire? 
If so, do you think we should add it? 
 
Are any of the questions redundant, in other words, asking you about the same thing? If so, which ones 
and why? 
 
What is your opinion on how the questionnaire looks on the device? 
Thank you! 
 
Thank you for your time. We appreciate you sharing your experiences and providing feedback. 
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Clinical Study Protocol: ICP-3718-202-P-03 
 
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Confidential 
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IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: ICP-3718-202-P-03 
 
27 July 2016 
Acceptable Dose Levels of the Various PPIs for Participation in the Trial1
PPI
Generic Name
Common
Brand Name(s)
Acceptable Dose Levels 
for 
Non-Erosive Esophagitis2
Acceptable Dose Level 
for 
Erosive Esophagitis 
dexlansoprazole
Dexilant®, Kapidex®
30-60 mg QD
60 mg QD
esomeprazole
Nexium®
20-40 mg QD
40 mg QD
lansoprazole
Prevacid®
15-30 mg QD
30 mg QD
omeprazole
Prilosec®
20 mg QD
20 mg QD
pantoprazole
Protonix®
No indication
40 mg QD
rabeprazole
AcipHex®
20 mg QD
20 mg QD
1.
The dose levels are acceptable provided that the PPI treatment has been optimized. 
(Optimized means treatment that, according to the Investigator’s judgment, could not be 
further improved by changing the brand or timing of PPI administration.)
2. For dexlansoprazole, esomeprazole, and lansoprazole, the approved dose level for non-
erosive esophagitis is the first one that is listed. However, either dose is acceptable for 
enrollment in the study. 
APPENDIX 11 
PPI DOSE LEVELS DURING STUDY PARTICIPATION 
Document Date: 05-Aug-2016 09:10

SAP_000.pdf: 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
INTRODUCTION ...................................................................................................................9 
2. 
STUDY OBJECTIVES ..........................................................................................................10 
3. 
STUDY DESIGN...................................................................................................................11 
4. 
STUDY ASSESSMENTS .....................................................................................................13 
4.1 
EFFICACY ASSESSMENTS .....................................................................................13 
4.1.1 
Symptom Severity and Relief Assessments .......................................................13 
4.1.1.1 
Daily Assessments ...................................................................................13 
4.1.1.2 
Weekly Assessments ................................................................................14 
4.1.2 
GSRS-Self ..........................................................................................................15 
4.1.3 
End-of-Treatment Question ...............................................................................15 
4.1.4 
QIDS-SR-16 .......................................................................................................16 
4.1.5 
mRESQ Cognitive Debriefing Interviews .........................................................16 
4.2 
HEALTH OUTCOMES ASSESSMENTS ..................................................................16 
4.2.1 
SF-12V2 Health Survey .....................................................................................16 
4.2.2 
EQ-5D-3L ..........................................................................................................16 
4.3 
SAFETY ASSESSMENTS ..........................................................................................17 
4.3.1 
Adverse Events ..................................................................................................17 
4.3.2 
Medical History .................................................................................................17 
4.3.3 
Physical Examination, Body Weight, and Height .............................................17 
4.3.4 
Electrocardiograms ............................................................................................18 
4.3.5 
Vital Signs ..........................................................................................................18 
4.3.6 
Clinical Laboratory Determinations ..................................................................18 
4.3.7 
Esophagogastroduodenoscopy ...........................................................................20 
4.3.8 
Bravo ..................................................................................................................20 
4.3.9 
Bilitec .................................................................................................................20 
4.4 
SCHEDULE OF EVENTS ..........................................................................................20 
5. 
STATISTICAL METHODS ..................................................................................................26 
5.1 
GENERAL CONSIDERATIONS ...............................................................................26 
5.1.1 
Data Display and Summary ...............................................................................26 
5.1.2 
Handling of Missing Values ..............................................................................26 
5.1.3 
Statistical Significance and Multiplicity ............................................................26 
5.1.4 
Interim Analysis and Data Monitoring ..............................................................26 
5.1.5 
Multicenter Studies ............................................................................................26 
5.2 
ANALYSIS POPULATIONS .....................................................................................27 
5.2.1 
Screened Population...........................................................................................27 
5.2.2 
Randomized Population .....................................................................................27 


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5.2.3 
Modified Intent-to-Treat Population ..................................................................27 
5.2.4 
Per-Protocol Population .....................................................................................27 
5.2.5 
Safety Population ...............................................................................................28 
5.3 
PROTOCOL DEVIATIONS .......................................................................................28 
5.4 
PATIENT DISPOSITION ...........................................................................................28 
5.5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................28 
5.6 
MEASUREMENT OF TREATMENT COMPLIANCE .............................................29 
5.7 
EXTENT OF EXPOSURE ..........................................................................................30 
5.8 
PRIOR AND CONCOMITANT MEDICATION .......................................................30 
5.9 
EDIARY COMPLIANCE ...........................................................................................30 
5.10 
EFFICACY ANALYSIS .............................................................................................31 
5.10.1 
Primary Efficacy Parameter ...............................................................................33 
5.10.2 
Secondary Efficacy Parameters .........................................................................34 
5.10.3 
Other Efficacy Parameters .................................................................................36 
5.10.4 
Exploratory Analyses .........................................................................................37 
5.10.5 
Subgroup Analyses ............................................................................................38 
5.10.6 
Rescue Medicine Use .........................................................................................39 
5.11 
HEALTH OUTCOMES ANALYSIS ..........................................................................40 
5.11.1 
SF-12V2 Health Survey .....................................................................................40 
5.11.2 
EQ-5D-3L ..........................................................................................................40 
5.12 
SAFETY ANALYSIS ..................................................................................................40 
5.12.1 
Adverse Events ..................................................................................................41 
5.12.2 
Clinical Laboratory Parameters .........................................................................42 
5.12.3 
Vital Sign Parameters ........................................................................................43 
5.12.4 
ECG Parameters .................................................................................................44 
5.12.5 
Other Safety Parameters ....................................................................................45 
5.13 
DETERMINATION OF SAMPLE SIZE ....................................................................45 
6. 
CHANGES FROM ANALYSES PLANNED IN THE PROTOCOL ...................................46 
7. 
DATA HANDLING CONVENTIONS .................................................................................47 
7.1 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS ...........................................................................................................47 
7.2 
MISSING DATE OF THE LAST DOSE OF STUDY DRUG ...................................47 
7.3 
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS ..........................47 
7.4 
MISSING RELATIONSHIP TO STUDY DRUG FOR ADVERSE EVENTS ..........47 
7.5 
MISSING DATE INFORMATION FOR ADVERSE EVENTS ................................48 
7.6 
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS ..........................................................................................................50 
7.6.1 
Incomplete Start Date ........................................................................................50 
7.6.2 
Incomplete Stop Date .........................................................................................51 


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7.7 
CHARACTER VALUES OF CLINICAL LABORATORY PARAMETERS ...........51 
7.8 
HEALTH OUTCOMES PARAMETERS ...................................................................52 
7.8.1 
Short Form 12 Health Survey Version 2............................................................52 
7.8.2 
EuroQol-5 dimension (EQ-5D-3L) ....................................................................55 
8. 
REFERENCES ......................................................................................................................57 
9. 
APPENDICES .......................................................................................................................58 
 


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LIST OF IN-TEXT TABLES 
Table 4.3-1. 
Clinical Laboratory Tests ...................................................................................19 
Table 4.4-1. 
Schedule of Events .............................................................................................21 
Table 5.1-1. 
Definition of Geographic Regions .....................................................................27 
Table 5.10-1. 
Analysis Time Windows for Efficacy Analysis – Daily Assessments ..............32 
Table 5.10-2. 
Analysis Time Windows for Efficacy Analysis – Weekly Assessments ...........33 
Table 5.12-1. 
Visit Time Windows for Safety Analysis ..........................................................41 
Table 5.12-2. 
Criteria for Potentially Clinically Significant Laboratory Results ....................42 
Table 5.12-3. 
Criteria for Potentially Clinically Significant Vital Signs .................................44 
Table 5.12-4. 
Criteria for Potentially Clinically Significant ECG Parameters ........................45 
Table 7.7-1. 
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters ..........................................................................................................52 
Table 7.8-1. 
Summary of Formulas for Scoring and Transforming Scales ...........................53 
Table 7.8-2. 
1998 General US Population Means and Standard Deviations Used to 
Derive Short Form-12 Health Survey, Version 2.0, z-Scores—Acute Form ....54 
Table 7.8-3. 
1990 Factor Score Coefficients Used to Derive Physical Component 
Summary and Mental Component Summary Scale Scores—Standard and 
Acute Forms .......................................................................................................54 
Table 7.8-4. 
EuroQol Quality-of-Life Questionnaire Utility Index .......................................56 
 


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LIST OF IN-TEXT FIGURES 
Figure 3.0-1. 
Overview of Study Design .................................................................................11 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Full Term 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BPM 
beats per minute 
CMH 
Cochran-Mantel-Haenszel 
DHSS 
daily heartburn severity score 
DRFS 
daily regurgitation frequency score 
ECG 
electrocardiogram 
eCRF 
electronic clinical report form 
eDiary 
electronic diary 
EGD 
esophagogastroduodenoscopy 
EOT 
end of treatment 
EQ 
EuroQol 
GERD 
gastroesophageal reflux disease 
GSRS 
the Gastrointestinal Symptoms Rating Scale 
ICF 
informed consent form 
IPD 
important protocol deviation 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
LS 
least-squares 
OC 
observed cases 
MedDRA 
the Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
MMRM 
mixed model for repeated measures 
mRESQ-eD 
the modified Reflux Symptom Questionnaire Electronic Diary 
PCS 
potentially clinically significant 


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Abbreviation 
Full Term 
PID 
patient identification 
PPI 
proton pump inhibitor 
PP 
per-protocol 
PT 
preferred term 
QD 
once daily 
QIDS 
the Quick Inventory of Depressive Symptomatology 
ROC 
receiver operating characteristic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
Le Système International d'Unités (International System of Units) 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
WHSS 
weekly heartburn severity score 
WRFS 
weekly regurgitation frequency score 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and/or specified in the amended 
protocol of Study ICP-3718-202 (dated 27 July 2016). Specifications for the tables, figures, and 
data listings are contained in a separate document.


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2. 
 STUDY OBJECTIVES 
The objectives of this study are to evaluate the safety, efficacy, and dose-response relationship of 
IW-3718 administered orally to patients who have gastroesophageal reflux disease (GERD) and 
continue to experience GERD symptoms while receiving once-daily (QD), optimized, standard-
dose proton pump inhibitors (PPIs).




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(symptom bothersomeness and degree of relief questions) at least once during the last 7 calendar 
days before the Randomization Visit in order to be eligible for randomization. 
Treatment Period: The Treatment Period begins with treatment assignment and lasts for 8 weeks. 
Patients will be stratified by whether they have, or do not have, erosive esophagitis on the 
screening esophagogastroduodenoscopy (EGD) and randomly assigned to 1 of 4 treatments 
(1:1:1:1) within each stratum: placebo, 500 mg IW-3718 BID, 1000 mg IW-3718 BID, or 1500 
mg IW-3718 BID. During this period, patients will continue to use the eDiary to provide their 
daily assessments (GERD symptoms, dyspepsia symptoms, assessment of sleep, and use of per-
protocol rescue medicine) and weekly assessments (symptom bothersomeness, degree of relief, 
and treatment satisfaction questions). 


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4. 
STUDY ASSESSMENTS 
4.1 
EFFICACY ASSESSMENTS 
The daily patient assessments used to determine the primary and secondary efficacy parameters 
are the daily assessment of heartburn symptoms (assessed on a 0-to-5 ordinal severity scale) 
obtained from the modified Reflux Symptom Questionnaire Electronic Diary (mRESQ-eD). 
Additional assessments will also be used to determine the other efficacy parameters, as described 
in the sections that follow. 
4.1.1 
Symptom Severity and Relief Assessments 
4.1.1.1 
Daily Assessments 
During the Pretreatment and Treatment Periods, patients will enter information into their eDiary 
at approximately the same time each day.  
• GERD symptoms (mRESQ-eD) completed once daily before going to bed each night.  
Note: The following items are assessed on a 0-5 severity scale: 0=Did not have, 
1=Very mild, 2=Mild, 3=Moderate, 4=Moderately severe, 5=Severe 
 
- 
Heartburn 
- 
Burning feeling behind breastbone or in the center of the upper stomach 
- 
Pain behind the breastbone or in the center of the upper stomach 
- 
Difficulty swallowing 
- 
Hoarseness 
- 
Cough 
 
Note: The following items are assessed on a 0-4 frequency scale: 0=Never, 1= Rarely, 
2=Sometimes, 3=Often, 4=Very often 
 
- 
Regurgitation (liquid or food) moving upwards toward your throat or mouth 
- 
An acid or bitter taste in the mouth 
- 
Burping 
- 
Coughing 
 
• Dyspepsia symptoms completed once daily before going to bed each night.  
Note: All items are assessed on a 0-to-10 numerical rating scale (NRS) with 0=not having the 
symptom and 10=having the worst possible level of the symptom 
 


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- 
Worst nausea (feeling like you might throw up) 
- 
Worst stomach fullness after you finished eating 
- 
Difficulty you had finishing your meals because you felt full too quickly 
- 
Worst abdominal pain 
 
• Assessment of sleep completed once daily upon getting up each morning (5:00 a.m. to 12:00 
p.m.) 
 
- 
Last night, did you wake up during the night after falling asleep? Y/N 
- 
[If yes], how many times did you wake up last night after falling asleep?  
- 
How long did you sleep last night? Do not count any time you lay in bed, but did not 
sleep.  
- 
Please rate the overall quality of your sleep last night. 1=very poor, 2=poor, 3=fair, 
4=good, 5=very good 
 
• Use of per-protocol rescue medicine (antacids) 
• PPI administration 
 
4.1.1.2 
Weekly Assessments 
The following information will be entered into the eDiary each week at about the same time as 
the evening daily assessment: 
• Degree of relief questions  
Note: all items are assessed on a 7-point balanced ordinal scale: 1=Significantly relieved, 
2=Moderately relieved, 3=Somewhat relieved, 4=Unchanged, 5=Somewhat worse, 
6=Moderately worse, 7=Significantly worse 
 
- 
How would you rate your heartburn (a burning sensation in your chest, behind the 
breastbone) over the past 7 days? 
- 
How would you rate your regurgitation (the feeling of stomach contents, either liquid or 
food, moving upwards to your throat or mouth) over the past 7 days? 
- 
Compared to before you started this study, how would you rate your overall GERD 
symptoms over the past 7 days? 
 
• Global Treatment Satisfaction Assessment  
Note: the following items will be assessed on a 5-point ordinal scale: 1=Very dissatisfied, 
2=Dissatisfied, 3=Neither satisfied nor dissatisfied, 4=Satisfied, 5=Very satisfied 
 
- 
How would you rate your satisfaction with the study treatment? 




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4.1.4 
QIDS-SR-16 
The Quick Inventory of Depressive Symptomatology (QIDS)-SR-16 is a self-completed 
questionnaire 
 
 
 
 
 
 
4.1.5 
mRESQ Cognitive Debriefing Interviews 
A sample of patients at selected sites will be asked to participate in an optional symptom diary 
interview, either via phone or face to face. During the one-time interview, patients will be asked 
to respond to open-ended questions intended to assess the content validity of the mRESQ-eD 
instrument. The analysis of these cognitive debriefing interview data will be described in a 
separate document. 
4.2 
HEALTH OUTCOMES ASSESSMENTS 
4.2.1 
SF-12V2 Health Survey 
The SF-12V2 (see Appendix II) is a widely used generic measure of health status 
 
 
 
 
 
 
 
 
4.2.2 
EQ-5D-3L 
The EuroQol (EQ)-5D-3L (see Appendix III) is a generic measure of health status widely used in 
Europe. 
 
 


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4.3 
SAFETY ASSESSMENTS 
4.3.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient. All AEs will be 
captured from the time the patient signs the informed consent until 7 days following the EOT 
Visit. 
For all AEs, the investigator will provide an assessment of causal relationship to study 
medication (related or unrelated) and an assessment of the severity (mild, moderate, or severe). 
All AEs will also be categorized as serious or non-serious. 
4.3.2 
Medical History 
A complete medical history will be performed as defined in the Schedule of Events 
(Table 4.4-1). 
4.3.3 
Physical Examination, Body Weight, and Height 
A complete physical examination will be performed as defined in the Schedule of Events 
(Table 4.4-1). A physical examination will include the following assessments: general 
appearance; head, ears, eyes, nose, and throat; cardiovascular system; neck; respiratory system; 
musculoskeletal system; abdomen/liver/spleen; nervous system; lymph nodes; skin; neurologic 
status; and mental status. Breast, genitourinary, and rectal examinations are optional. 
Each patient’s weight will be recorded at every study visit; height will only be recorded at the 
Screening Visit. 


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4.3.4 
Electrocardiograms 
A 12-lead electrocardiogram (ECG) will be performed as defined in the Schedule of Events 
(Table 4.4-1). 
4.3.5 
Vital Signs 
Vital sign measurements will be performed as defined in the Schedule of Events (Table 4.4-1). 
Vital sign measurements include oral temperature (°C), respiratory rate, systolic and diastolic 
blood pressure (BP), and pulse. Respiratory rate, pulse, and BP readings will be taken after the 
patient has been seated for at least 5 minutes. 
4.3.6 
Clinical Laboratory Determinations 
Blood and urine samples for clinical laboratory tests will be collected at the visits defined in the 
Schedule of Events (Table 4.4-1). The clinical laboratory evaluations will include the clinical 
chemistry, hematology, coagulation, and urinalysis parameters presented in Table 4.3-1. 
 
 


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Table 4.3-1. 
Clinical Laboratory Tests 
Clinical Chemistry 
Hematology (CBC) 
Complete Urinalysis 
A1C 
Hematocrit 
pH and specific gravity 
Albumin 
Hemoglobin 
Bilirubin 
Alkaline phosphatase 
Platelet count 
Glucose 
ALT 
MPV 
Ketones 
AST 
RBC count 
Leukocytes 
Bicarbonate 
WBC count 
Nitrites 
BUN 
WBC differential 
Occult blood 
Calcium 
(% and absolute) 
Protein 
Chloride 
Basophils 
Urobilinogen 
Total cholesterol 
Eosinophils 
 
HDL cholesterol 
Lymphocytes 
 
LDL cholesterol  
Monocytes 
 
Creatinine 
Neutrophils 
 
GGT 
RBC indices 
 
Glucose 
MCH 
 
Iron 
MCHC 
 
LDH 
MCV 
 
Magnesium 
RDW 
 
Phosphorus 
Coagulation 
 
Potassium 
aPTT 
 
Sodium 
PT 
 
Total bilirubin 
 
 
Total protein 
 
 
Triglycerides 
 
 
Uric acid 
 
 
Abbreviations: A1C = glycated hemoglobin; ALT = alanine aminotransferase; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; 
GGT = gamma glutamyl transferase; HDL = high-density lipoprotein; LDH = lactate dehydrogenase; LDL = low-
density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume; MPV = mean platelet volume; PT = prothrombin time; RBC = red blood cell; 
RDW = red cell distribution width; WBC = white blood cell 
 
A blood sample for serum pregnancy testing will be collected from all female patients of 
childbearing potential at the Screening and EOT Visits, and a urine sample will be collected at 
the Randomization Visit (prior to dosing) and the Week 4 Visit. These pregnancy test results 
must be negative for patient eligibility. Ironwood may perform non-genetic analyses on existing 
plasma or serum samples for research purposes (e.g., bile in serum). 


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A urine screen for selected drugs of abuse (cocaine, barbiturates, amphetamines, opiates, 
benzodiazepines, and cannabinoids) and a serum alcohol screen will be performed at the 
Screening Visit. 
4.3.7 
Esophagogastroduodenoscopy 
At all sites, an EGD will be performed on all patients at the screening visit.  An additional EGD 
will be performed at the Week 8/EOT Visit in all patients who had an EGD during the Screening 
Period that demonstrated Grade C or D esophagitis. 
4.3.8 
Bravo 
At all sites, all patients will undergo 48 to 96 hours of pH testing with the Bravo device. If for 
some reason 96 hours of testing is not possible, then approximately 48 hours of testing is 
acceptable. In addition, for the entire 48-96-hour Bravo pH monitoring period, patients will also 
complete a paper diary, recording at a minimum all instances of meals, snacks, drinks, and/or 
resting in the supine position. 
4.3.9 
Bilitec 
At certain participating sites, selected patients who are screened with EGD and Bravo testing 
will also receive insertion of a Bilitec device during the same procedure. Patient selection will be 
dependent on Investigator judgement and patient consent. All such patients will return to the site 
approximately 24 hours after the procedure for removal of the device. 
4.4 
SCHEDULE OF EVENTS 
The schedule of study procedures and assessments is presented by visit in the Schedule of Events 
in Table 4.4-1. 


IW-3718 
 
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Table 4.4-1. 
Schedule of Events 
 
Screening 
Period 
(Up to 4 
weeks)w 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-
up 
Visit Days → 
Screening 
Visit (Day -49 
to Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -1) 
Randomization 
Visit 
(Day 1) 
Week 2 
Visit 
(Day 15 
± 3) 
Week 4 
Visit 
(Day 29 
± 3) 
Week 8 / 
End-of-treatment 
Visit  
(Day 57 + 3) 
EOT 
+ 7 days 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Study Procedure ↓ 
 
 
 
 
 
 
 
Inclusion and Exclusion 
Criteria Verification 
X 
X 
X 
 
 
 
 
Signing of ICF 
X 
 
 
 
 
 
 
IWRS Registration (a) 
X 
X 
X 
X 
X 
X 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination (b) 
X 
 
 
 
 
X 
 
Body Weight and Height (c)  
X 
X 
X 
X 
X 
X 
 
H2RA/Antacid Washout (d) 
X 
 
 
 
 
 
 
Bilitec Monitoring (e) 
X 
 
 
 
 
 
 
EGD (f) 
X 
 
 
 
 
X 
 
48 to 96 Hours of pH Testing 
with Bravo Device (g) 
X 
 
 
 
 
 
 
Seated Vital Signs (h)  
X 
X 
X 
X 
X 
X 
 
12-Lead ECG (i) 
X 
 
X 
 
 
X 
 
Prior and Concomitant 
Medications (j) 
X 
X 
X 
X 
X 
X 
 


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Table 4.4-1. 
Schedule of Events 
 
Screening 
Period 
(Up to 4 
weeks)w 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-
up 
Visit Days → 
Screening 
Visit (Day -49 
to Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -1) 
Randomization 
Visit 
(Day 1) 
Week 2 
Visit 
(Day 15 
± 3) 
Week 4 
Visit 
(Day 29 
± 3) 
Week 8 / 
End-of-treatment 
Visit  
(Day 57 + 3) 
EOT 
+ 7 days 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Study Procedure ↓ 
 
 
 
 
 
 
 
Clinical Laboratory Tests (k) 
X 
 
X 
 
X 
X 
 
Serum Pregnancy Test (l) 
X 
 
 
 
 
X 
 
Urine Pregnancy Test (l) 
 
 
X 
 
X 
 
 
Drug and Alcohol Screen (m) 
X 
 
 
 
 
 
 
AE Evaluations (n) 
X 
X 
X 
X 
X 
X 
 
Rescue Medicine Dispensed (o) 
 
X 
X 
X 
X 
 
 
PDA Training and 
Dispensation 
 
X 
 
 
 
 
 
Saliva Collection (p) 
X 
X 
X 
 
X 
X 
 
eDiary (q) 
 
X 
X 
X 
X 
X 
 
Weekly Symptom and 
Treatment Assessments (r) 
 
X 
X 
X 
X 
X 
 
GSRS-Self 
 
 
X 
 
X 
X 
 
QIDS-SR-16 
 
 
X 
 
 
 
 
SF-12V2 
 
 
X 
 
X 
X 
 
EQ-5D-3L 
 
 
X 
 
X 
X 
 
Randomization 
 
 
X 
 
 
 
 


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Table 4.4-1. 
Schedule of Events 
 
Screening 
Period 
(Up to 4 
weeks)w 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-
up 
Visit Days → 
Screening 
Visit (Day -49 
to Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -1) 
Randomization 
Visit 
(Day 1) 
Week 2 
Visit 
(Day 15 
± 3) 
Week 4 
Visit 
(Day 29 
± 3) 
Week 8 / 
End-of-treatment 
Visit  
(Day 57 + 3) 
EOT 
+ 7 days 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Study Procedure ↓ 
 
 
 
 
 
 
 
Study Medication Dispensed (s) 
 
 
X 
X 
X 
 
 
Study Medication Return (t) 
 
 
 
X 
X 
X 
 
PDA Return 
 
 
 
 
 
X 
 
mRESQ-eD Debrief Interview 
(x) 
 
X (x) 
 
 
X (x) 
 
 
End of Treatment Question (u) 
 
 
 
 
 
X 
 
Safety Follow-up Call (v) 
 
 
 
 
 
 
X 
Abbreviations: AE = adverse event; BP = blood pressure; CBC = complete blood count; ECG = electrocardiogram; EGD = esophagogastroduodenoscopy; 
EOT = End-of-treatment; EQ = EuroQol; GSRS = Gastrointestinal Symptoms Rating Scale; H2RA = histamine-2 receptor antagonist; HEENT = head, eyes, ears, 
nose, and throat; ICF = informed consent form; IWRS = interactive web response system; PDA = personal digital assistant; PPI = proton pump inhibitor; 
QID = Quick Inventory of Depressive Symptomology; mRESQ-eD = modified Reflux Symptom Questionnaire Electronic Diary; SAE = serious adverse event; 
SF = short form 
a. 
Site personnel will interact with IWRS to register the patient visit and transition the patient to the next appropriate study period. 
b. A physical examination should include the following assessments: general appearance; HEENT; neck; cardiovascular; respiratory; abdomen/liver/spleen; 
musculoskeletal; lymph nodes; skin; neurologic; nervous system, and mental status. Breast, genitourinary, and rectal examinations are optional and may be 
performed at the discretion of the Investigator. 
c. 
Height will be measured only at the Screening Visit.  
d. During the Screening Period, patients will begin to washout H2RAs and antacids. H2RAs should be stopped 5 calendar days prior to the EGD and Bravo pH 
monitoring and antacids should be stopped 1 calendar day prior to the EGD and Bravo pH monitoring. Patients may resume antacid use upon completion of 
the Bravo testing, but must refrain from H2RA use for the remainder of the study.  During the Pretreatment Period, patients will refrain from using any anti-
reflux medications, antacids, and H2RAs, except for the antacids that are provided as rescue medicine). Patients will continue to use their current PPI during 
the Pretreatment Period. 


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e. 
At selected sites, selected patients who are screened for the study with EGD and Bravo testing will also be given the option of having a Bilitec monitor 
inserted during the same procedure. These patients will return 24 hours later for removal of the probe. The results of the Bilitec test will not affect 
qualification for enrollment.  The Bilitec device and Bravo recorder internal clocks must be synchronized, and both devices should be activated concurrently; 
however, if it is not possible to simultaneously activate both devices, the Bravo recorder should be activated first, with the Bilitec device activation 
immediately (within 5 minutes) after the Bravo pH recorder activation. 
f. 
All patients will be required to undergo an EGD during the Screening Period. There must be a minimum of 7 days between the EGD and the start of the 
Pretreatment Period to allow for pH testing and patient stabilization. An EGD will be performed at the Week 8 / EOT Visit in all patients who have Grade C 
or D esophagitis (based on the Los Angeles classification of esophagitis) on the EGD obtained during the Screening Period.  
g. Approximately 48 to 96 hours of pH testing with the Bravo device. If for some reason 96 hours of testing is not possible, then approximately 48 hours of 
testing is acceptable. During the entire period of Bravo pH monitoring (approximately 48-96 hours), patients will record ingestion of anything other than 
water by depressing the ‘meal’ button on the Bravo recorder upon the beginning and completion of the meal, snack, or drink.  Patients will also record any 
periods during which they are lying down by depressing the ‘supine’ button on the Bravo recorder at the beginning and upon completion of the supine 
period.  In addition, for the entire 48-96-hour Bravo pH monitoring period, patients will complete a paper diary, recording at a minimum all instances of 
meals, snacks, drinks, and/or resting in the supine position. 
h. Vital sign measurements include oral temperature (°C), respiratory rate, systolic and diastolic BP, and pulse. Respiratory rate, BP, and pulse measurements 
must be obtained after the patient has been seated for at least 5 minutes. 
i. 
12-Lead ECGs should be obtained after the patient has been supine for at least 5 minutes. 
j. 
Prior medications will be collected at the Screening Visit as follows: all medicines taken by the patient during the 30 days before the Screening Visit, most 
recent use of an H2RA, and most recent use of an antacid. 
k. Clinical laboratory tests include clinical chemistry, hematology (CBC), coagulation, and urinalysis.  If the triglyceride value exceeds the protocol-specified 
criteria and the patient was not under fasted conditions, the patient may return to complete a fasted lipid panel. 
l. 
For all female patients of childbearing potential, a negative serum pregnancy test must be documented at the Screening Visit, and a negative urine pregnancy 
test must be documented at the Randomization Visit (before dosing) in order for the patient to be randomized into the study. A urine pregnancy test will be 
obtained at the Week 4 Visit; a serum pregnancy test will be conducted at the EOT Visit. 
m. Patients must undergo a urine drug screen for selected drugs of abuse (cocaine, barbiturates, amphetamines, opiates, benzodiazepines, and cannabinoids) and 
a serum alcohol screen at the Screening Visit. 
n. All AEs will be captured from the time the patient signs the ICF through the EOT Visit. 
o. Rescue medicine will be supplied to patients at the Pretreatment Visit, and if needed, at subsequent visits. 
p. At each of the indicated visits, patients will provide approximately 1 mL of saliva for future use (bile acids will be quantified in the saliva, and the quantity 
of bile acid may be used to define potential responders to IW-3718). At the time of saliva collection, study site staff will collect the following information: 
time of day, time of patient’s last meal, and time of last study medication administration. During the Randomization Visit, study site staff will collect the 
saliva sample immediately following the light snack but prior to study drug administration. 
q. The eDiary will be dispensed at the Pretreatment Visit and patients must complete at least 5 days each week during the 14 days before the Treatment Period 
in order to be eligible for randomization. Patients should bring their eDiary to each visit. The eDiary will collect daily PPI administration, rescue medication 
use, mRESQ-eD (daily), Daily Assessment of Sleep (daily), Daily Dyspepsia Symptoms (daily).  
r. 
Symptom bothersomeness and symptom relief items (weekly); Treatment satisfaction (weekly). 
s. 
The first dose of study medication will be administered in the clinic with liquid and a snack at the Randomization Visit. At all other visits, patients will take 
their study medication prior to arriving at the clinic, but will be dispensed additional doses needed until the next study visit. 
t. 
Treatment compliance with study drug will be assessed based on return of unused tablets. 
u. All patients will be asked an EOT question regarding the difficulty of swallowing the IW-3718 or placebo tablets. 


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v. Study site will contact each patient via telephone 7 days after the EOT Visit to collect information pertaining to ongoing AEs/SAEs and information 
concerning any new AEs/SAEs since the EOT Visit. 
w. Ironwood may grant a one-week extension of the screening period window if needed for logistical delays (e.g., subject travel, scheduling issues, delays in 
test results, equipment malfunction, etc.).  Approval should be requested from Ironwood prior to each extension. 
x. Patients participating in the optional mRESQ-eD Cognitive Debriefing interviews will be assigned to one of three interview groups.  Interviews will take 
place at different timepoints depending on the patient’s group assignment.


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5. 
STATISTICAL METHODS 
5.1 
 GENERAL CONSIDERATIONS 
All statistical analyses will be performed using SAS Version 9.3 (or later) for Windows. 
5.1.1 
Data Display and Summary 
All summaries will be presented by treatment unless specified otherwise. Descriptive statistics 
including the number of patients, mean, standard deviation (SD), median, minimum, and 
maximum will be calculated for continuous variables. Frequencies and percentages for each 
category will be calculated for categorical variables. Percentages will be based on the total 
number of non-missing values. The number missing will be presented, but without a percentage. 
5.1.2 
Handling of Missing Values 
Unless stated otherwise, missing data will not be imputed. 
5.1.3 
Statistical Significance and Multiplicity 
All hypothesis tests will be two-sided with a 5% significance level, and 95% confidence intervals 
will be used, unless stated otherwise. No adjustments for multiplicity are planned; p-values will 
be reported as nominal. 
5.1.4 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
5.1.5 
Multicenter Studies 
This study is being conducted in approximately 70 centers. Due to the potential of small numbers 
of patients per center, data will be pooled by center into the following 5 geographic regions (as 
listed in Table 5.1-1): Northeast, Southeast, Midwest, Southwest, and West. All analyses using 
trial center will use this 5-category geographic region variable. 


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Table 5.1-1. 
Definition of Geographic Regions 
Northeast 
Southeast 
Midwest 
Southwest 
West 
CT 
AL 
IA 
AZ 
CA 
DE 
AR 
IL 
NM 
CO 
MA 
FL 
IN 
OK 
ID 
MD 
GA 
KS 
TX 
MT 
ME 
KY 
MI 
 
NV 
NH 
LA 
MN 
 
OR 
NJ 
MS 
MO 
 
UT 
NY 
NC 
ND 
 
WA 
PA 
SC 
NE 
 
WY 
RI 
TN 
OH 
 
 
VT 
VA 
SD 
 
 
 
WV 
WI 
 
 
5.2 
ANALYSIS POPULATIONS 
5.2.1 
Screened Population 
The Screened Population consists of all patients who signed informed consent and received a 
patient identification (PID) number. 
5.2.2 
Randomized Population 
The Randomized Population consists of all patients in the Screened Population who were 
randomized to a treatment group in the study. 
5.2.3 
Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) Population consists of all patients in the Randomized 
Population who received at least one dose of study treatment. 
5.2.4 
Per-Protocol Population 
The Per-Protocol (PP) Population consists of all patients in the mITT Population who have a 
minimum of 6 weeks of eDiary data for the heartburn severity and regurgitation frequency scores 
and > 80% compliance with study treatment for the available Treatment Period days. 


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5.2.5 
Safety Population 
The Safety Population consists of all patients in the Randomized Population who received at 
least one dose of study treatment. 
5.3 
PROTOCOL DEVIATIONS 
Protocol deviations and Significant Protocol Deviations (SPD) will be identified and documented 
for all randomized patients prior to unblinding. The number and percentage of subjects with 
SPDs will be presented by study treatment and SPD category. Listings of protocol deviations and 
SPDs will also be provided. 
5.4 
PATIENT DISPOSITION 
The number and percentage of patients included in the mITT, PP, and Safety Populations will be 
presented overall and by treatment group for the Randomized Population. The number of patients 
in the Screened Population will be presented overall. 
The number and percentage of screen failures (i.e., patients who entered the Screening Period but 
not the Pretreatment Period) and patients ineligible for randomization (i.e., patients who entered 
the Pretreatment Period but were not randomized), along with the associated reasons for failure 
or ineligibility, will be tabulated overall for the Screened Population. 
The number and percentage of patients who completed treatment, who completed the study, and 
who prematurely discontinued (overall and by reason for discontinuation) will be presented for 
each treatment group and overall for the Randomized Population. 
5.5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic parameters (age; age group; race; ethnicity; sex; weight; height; and body mass 
index [BMI], calculated as weight [kg]/(height [m])2) will be summarized by treatment group for 
the Randomized, mITT, and PP Populations. Baseline efficacy assessments (including GERD 
symptoms, dyspepsia symptoms, assessments of sleep, bothersomeness assessments, and the 
degree of relief assessments) will be summarized by treatment group for the mITT and PP 
Populations. 


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Abnormalities in patients’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 18.1. The number and percentage of 
patients with abnormalities in medical and surgical histories in each system organ class (SOC) 
and preferred term (PT) will be summarized by treatment group for the Safety Population. 
5.6 
MEASUREMENT OF TREATMENT COMPLIANCE 
The first dose of study medication will be taken in clinic at the Randomization Visit (Day 1). 
Patients should take their second dose that evening immediately upon completion of dinner. 
During the Treatment Period, patients will take study medication BID at home, in the morning 
(immediately upon completion of breakfast) and in the evening (immediately upon completion of 
dinner), even on study visit days. The last dose of study medication will be taken the morning of 
the EOT Visit. The double-dummy dosing requires all patients to take three tablets for each dose. 
Dosing compliance for the Treatment Period is defined as the number of tablets taken by a 
patient during the Treatment Period divided by the number of tablets that were expected to be 
taken during the Treatment Period multiplied by 100. The total number of tablets taken will be 
calculated as total number of tablets dispensed minus total number of tablets returned minus total 
number of tablets lost. The total number of tablets expected to be taken during the Treatment 
Period is the number of days between the date of first dose taken and the date of last dose taken, 
inclusive, multiplied by 6 (multiplied by 6 minus 3 if the last dose is a morning dose). Patients 
will be included in the period summary only for the periods they were on study (i.e., the periods 
that are prior to or contain the last dose date). 
Descriptive statistics for study drug compliance will be presented for the Safety Population by 
treatment group. 
Patients will record their PPI administration each day (once daily) in their eDiary. PPI 
compliance for a specified period is defined as the number of days for which a patient answered 
Yes to the PPI administration question in the eDiary divided by the total number of days for 
which the patient provided an answer (Yes or No) to the PPI administration question in that 
period multiplied by 100. PPI compliance will be summarized by treatment group for the Safety 
Population. 


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5.7 
EXTENT OF EXPOSURE 
Exposure to study drug for the Safety Population during the double-blind treatment period will 
be summarized by treatment group in terms of treatment duration, calculated as the number of 
days from the date of the first dose of double-blind study drug to the date of the last dose of 
double-blind study drug, inclusive. Treatment duration will also be categorized as <7 days; 
≥7 days and <14 days; ≥14 days and <28 days; ≥28 days and <42 days; ≥42 days and <56 days; 
≥56 days. 
Patient-years, defined as exposure to the study drug in years, will be summarized by treatment 
group for the Safety Population. 
5.8 
PRIOR AND CONCOMITANT MEDICATION 
Prior medication is defined as any medication taken before the date of the first dose of double-
blind study drug. Concomitant medication is defined as any medication taken on or after the date 
of the first dose of double-blind study drug during the Treatment Period. Medications started 
after the date of the last dose of double-blind study drug will not be considered concomitant 
medications. 
Both prior and concomitant medications will be coded by drug name and therapeutic class using 
World Health Organization Drug Dictionary Enhanced (WHO DDE) December 2015. The use of 
prior and concomitant medications will be summarized for the Safety Population by the number 
and percentage of patients in each treatment group receiving each medication within each 
therapeutic class. If a patient took a specific medication multiple times or took multiple 
medications in the same category (based on Anatomical-Therapeutic-Chemical classification), 
that patient would be counted only once for the coded drug name or therapeutic class. 
5.9 
EDIARY COMPLIANCE 
Patients are required to enter their diary assessments into the eDiary before going to bed each 
night and upon getting up each morning during the Pretreatment and Treatment Periods. A daily 
report is considered complete if all questions in both the morning diary and evening diary 
(excluding the weekly assessments) are answered, with the following exceptions. 


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• For the first day of the Pretreatment Period, only the evening diary is expected. 
• For the last day of the Pretreatment Period, only the morning diary is pertinent. 
• For the first day of the Treatment Period, only the evening diary is pertinent. 
• For the EOT Visit day, only the morning diary is expected. 
 
eDiary compliance will be calculated for baseline (the Pretreatment Period), the Treatment 
Period, and weekly. For each period, eDiary compliance will be calculated as the number of 
completed daily reports divided by the expected number of daily reports in the period multiplied 
by 100. eDiary compliance will be summarized by treatment group for the mITT Population. In 
addition, the number and percentage of patients with ≥80% vs. <80% eDiary compliance for 
each period, as well as the number and percentage of patients with ≥4 vs. <4 complete daily 
reports each week, will be presented by treatment group for the mITT Population. 
5.10 
EFFICACY ANALYSIS 
Unless otherwise specified, efficacy analyses will be based on both the mITT and the PP 
Populations. 
Baseline values for efficacy parameters will be derived from the eDiary and/or electronic clinical 
report form (eCRF) data collected for the last week of the Pretreatment Period (or Week -1), 
specifically the period from 7 days prior to the day of randomization up to the time of 
randomization. If data for Week -1 is not available, data for Week -2 (the second last week of the 
Pretreatment Period) will be used. 
For continuous efficacy parameters, the analysis value for an analysis period is defined as the 
average of the non-missing values during that period. 
For weekly responder parameters based on daily eDiary assessments, a patient who missed 4 or 
more daily assessments during an analysis week will not be considered a responder for that 
week. 
Table 5.10-1 provides the analysis time windows allowed for efficacy analyses based on daily 
assessments and Table 5.10-2 provides the analysis time windows allowed for efficacy analyses 
based on weekly assessments. 


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Table 5.10-1. 
Analysis Time Windows for Efficacy Analysis – Daily Assessments 
Period 
Analysis Week 
Beginsa 
Endsa 
Pretreatment 
(Baselineb) 
Week -2  
Day -14  
Day -8 
Week -1 
Day -7 
Day -1 (Day before 
randomization) c 
Treatment 
 
Week 1  
Day 1 (Day of 
Randomization) d 
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 
••• 
••• 
••• 
a. 
Relative to the date of randomization (Day 1). 
b. Baseline values for efficacy parameters will be derived from the daily eDiary collected in the Pretreatment 
Period Week -1 (Week -2 if data from Week -1 not available) 
c. 
Day 1 for efficacy parameters derived from the morning diary. 
d. Day 2 for efficacy parameters derived from the morning diary. 
 


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Table 5.10-2. 
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 (Day before 
randomization) 
Treatment 
 
Week 1  
Day 7 
Day 10 
Week 2  
Day 11 
Day 17 
Week 3  
Day 18 
Day 24 
Week 4  
Day 25 
Day 31 
Week 5  
Day 32 
Day 38 
Week 6  
Day 39 
Day 45 
Week 7 
Day 46 
Day 52 
Week 8 
Day 53 
Day 59 
Week 9 
Day 60 
Day 66 
••• 
••• 
••• 
a. 
Relative to the date of randomization (Day 1). 
b. Baseline values for efficacy parameters will be derived from the eDiary collected in the Pretreatment Period 
Week -1 (Week -2 if data from Week -1 not available) 
5.10.1 
Primary Efficacy Parameter 
The primary efficacy parameter is the percent change from baseline (i.e., the Pretreatment 
Period) to Week 8 in weekly heartburn severity score (WHSS). 
The WHSS for an analysis week is defined as the average of available daily heartburn severity 
scores (DHSS) during that week. DHSS is defined as the maximum of the 3 items measuring 
heartburn (Heartburn, Burning feeling behind chestbone or in the center of the upper stomach, 
and Pain behind chestbone or in the center of the upper stomach) from a particular day collected 
with the mRESQ-eD instrument. For a handful of patients who were assigned to an older version 
of the instrument, Burning feeling behind the chestbone and Burning feeling in the center of the 
upper stomach were assessed separately. For analysis purposes, the maximum of the two will be 
used to represent the item of Burning feeling behind chestbone or in the center of the upper 
stomach. Similarly, Pain behind chestbone and Pain in the center of the upper stomach were 
assessed separately for these patients. For analysis purposes, the maximum of the two will be 
used. 


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Percent change from baseline to Week 8 in WHSS (both last-observation-carried-forward 
[LOCF] and observed-case [OC]) will be summarized by treatment group. Each IW-3718 group 
will be compared with the placebo group using an analysis of covariance (ANCOVA) model 
with treatment group and esophagitis status (erosive esophagitis or no erosive esophagitis) as 
fixed-effect terms and baseline WHSS as a covariate. The least-squares (LS) mean for each 
treatment group, LSM difference between each IW-3718 group and the placebo group along with 
the corresponding confidence interval, and p-values for the pairwise comparisons vs. placebo 
will be presented. In addition, a linear contrast among the LS means for treatment groups will be 
conducted to test the overall ordinal dose response. 
The treatment by esophagitis status interaction will be explored (using an ANCOVA model with 
an additional term for the interaction and/or plotting treatment group means by esophagitis 
status) to evaluate whether quantitative or qualitative interaction is present. If warranted, 
treatment comparisons within each esophagitis status will be conducted. 
As a sensitivity analysis, percent change from baseline to Week 8 in WHSS will be evaluated 
employing a mixed model for repeated measures (MMRM) framework with week (categorical), 
treatment group, week-by-treatment group, and esophagitis status as fixed-effect terms and 
baseline WHSS as a covariate. A compound symmetry covariance structure will be used to 
model the covariance of within-patient results. Exploratory analyses with unstructured and 
autoregressive (1) covariance structures will also be considered. 
The cumulative distribution function (CDF) of percent change from baseline to Week 8 in 
WHSS will be plotted by treatment group. To aid in the interpretation of the graphical 
presentation, a two-sample Kolmogorov-Smirnov test will be conducted between each IW-3718 
group and the placebo group. 
5.10.2 
Secondary Efficacy Parameters 
The secondary efficacy parameters include the following: 
1. Percent change from baseline to Week 4 in WHSS 
2. Change from baseline to Week 8 in WHSS 
3. Change from baseline to Week 4 in WHSS 


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4. Proportion of patients who are overall heartburn responders 
An overall heartburn responder is a patient who is a weekly heartburn responder for at least 
4 of the 8 treatment weeks and for at least 1 of the final 2 treatment weeks (i.e., Week 7 and 
Week 8).  A weekly heartburn responder is a patient with a decrease of ≥ 30% from baseline 
in WHSS. 
5. Proportion of patients with a DHSS of no more than very mild (≤ 1) on any day during 
Week 8 
6. Proportion of patients with a DHSS of no more than very mild (≤ 1) on any day during 
Week 4 
7. The number of days where DHSS was no more than very mild (≤ 1) during Week 8 
8. The number of days where DHSS was no more than very mild (≤ 1) during Week 4 
9. Change from baseline in the weekly average of each mRESQ-eD item by week. 
10. Proportion of heartburn-free days during Week 8 
A heartburn free day is a day where DHSS=0. 
11. Proportion of heartburn-free days during Week 4 
The continuous parameters (#1, 2, 3, 7, 8, 9, 10, and 11) will be analyzed employing similar 
methods as described for the primary efficacy parameter. 
For the analysis of responder parameters (#4, 5, and 6), the counts and proportion of responders 
will be calculated for each treatment group. The proportions of responders between each IW-
3718 group and the placebo group will be compared using a Cochran-Mantel-Haenszel (CMH) 
test controlling for esophagitis status. The CMH test is the primary analysis for responder 
parameters. The difference in the proportion of responders between each IW-3718 group and the 
placebo group as well as the CMH estimates of odds ratio (IW-3718 over placebo) will be 
presented, along with the corresponding confidence intervals. 
Corresponding to secondary efficacy parameters 7, 8, 10, and 11, additional analyses will be 
provided for the following parameters: 7a. Proportion of Days where DHSS was no more than 
very mild (≤ 1) during the 8-week Treatment Period; 8a. Proportion of Days where DHSS was 
no more than very mild (≤ 1) during the first 4 weeks of the Treatment Period; 10a. Proportion of 
heartburn-free days during the 8-week Treatment Period; 11a. Proportion of heartburn-free days 
during the first 4 weeks of the Treatment Period. 


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5.10.3 
Other Efficacy Parameters 
Other efficacy parameters include the following: 
1. Percent change from baseline to Week 8 in weekly regurgitation frequency score (WRFS) in 
patients with a baseline WRFS of ≥ 2 (sometimes) 
The WRFS for an analysis week is defined as the average of available daily regurgitation 
frequency scores (DRFS) during that week. DRFS is defined as the maximum of the 2 items 
measuring regurgitation (Regurgitation [liquid or food moving upwards toward your throat 
or mouth] and An acid or bitter taste in the mouth) from a particular day collected with the 
mRESQ-eD instrument. 
2. Percent change from baseline to Week 4 in WRFS in patients with a baseline WRFS of 2 
(sometimes) 
3. Change from baseline to Week 8 in WRFS 
4. Change from baseline to Week 4 in WRFS 
5. Proportion of patients who are overall regurgitation responders (of patients with a baseline 
WRFS of ≥ 2 [sometimes]) 
An overall regurgitation responder is a patient who is a weekly regurgitation responder for 
at least 4 of the 8 treatment weeks and for at least 1 of the final 2 treatment weeks (i.e., Week 
7 and Week 8). A weekly regurgitation responder is a patient with a decrease of ≥ 30% from 
baseline in WRFS. 
6. Proportion of patients with a DRFS of no more than rarely (≤ 1) on any day during Week 8 
7. Proportion of patients with a DRFS of no more than rarely (≤ 1) on any day during Week 4 
8. Change from baseline to Week 8 in the number of days per week where DRFS was no more 
than rarely (≤ 1) 
9. Change from baseline to Week 4 in the number of days per week where DRFS was no more 
than rarely (≤ 1) 
10. Change from baseline to Week 8 in the weekly average of each of the daily symptom 
assessments 
11. Weekly means for daily sleep assessments (number of awakenings, hours of sleep, sleep 
quality) 
12. Weekly means for weekly symptom bothersomeness assessments, symptom relief 
assessments, and treatment satisfaction assessment 
For analysis of continuous parameters (#1, 2, 3, 4, 8, 9, 10, 11, and 12), summary statistics will 
be presented by treatment group. Each IW-3718 group will be compared with the placebo group 
using an ANCOVA model with treatment group and esophagitis status as fixed-effect terms and 


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the corresponding baseline efficacy parameter value as a covariate. Note that for parameters 
without a baseline value (e.g., Treatment Satisfaction), an ANOVA model (in lieu of ANCOVA) 
will be used with treatment group and esophagitis status as fixed-effect terms. 
For analysis of responder parameters (#5, 6, and 7), the counts and proportion of responders will 
be calculated for each treatment group. The proportions of responders between each IW-3718 
group and the placebo group will be compared using a CMH test controlling for esophagitis 
status. 
Corresponding to efficacy parameters 8 and 9, additional analyses will be provided for the 
following parameters: 8a. Change from baseline to the 8-week Treatment Period in proportion of 
days where DRFS was no more than rarely (≤ 1); 9a. Change from baseline to the first 4 weeks 
of Treatment Period in proportion of days where DRFS was no more than rarely (≤ 1). 
Change/percent change from baseline in WHSS, WRFS, and the weekly average of each of the 
individual daily symptom assessment items (GERD & dyspepsia) will be summarized/analyzed 
by week, and the LS mean changes/LS mean percent changes will be plotted across treatment 
weeks. 
The proportion of Degree of Relief responders (reported a score of 1-Significantly Relieved or 2-
Moderately Relieved on the Degree of Relief question for at least 4 of the 8 treatment weeks) 
will be summarized by treatment group for heartburn, regurgitation, and overall GERD 
symptoms. 
In addition, the GSRS-self will be summarized by treatment group by visit for each of the 
15 items and for each of the 5 domains: abdominal pain (3 items), reflux symptoms (2 items), 
indigestion (4 items), diarrhea (3 items), and constipation (3 items).  The EOT Visit difficulty of 
swallowing question will also be summarized by presenting the count and proportion of patients 
in each of the 4 categories (from Not at all Difficult to Extremely Difficult) by treatment group. 
5.10.4 
Exploratory Analyses 
The following analyses intend to explore the relationship between measures of bile acid, acid 
reflux, and clinical response. 


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a. Sensitivity and specificity of bile acid levels measured in saliva as a test for bile acid 
pathophysiology with Bilitec test findings as the reference standard 
b. Correlation between Bilitec test findings and Bravo pH monitoring results 
c. Bilitec test findings as a predictor of response to treatment 
d. Bile acid levels in saliva as a predictor of response to treatment 
e. Bravo pH monitoring results as a predictor of response to treatment  
Analyses (a) and (b) will be conducted based on the Screened Population; all other analyses will 
be conducted using the mITT Population. 
5.10.5 
Subgroup Analyses 
Subgroup Analyses of efficacy parameters will be based on the mITT Population. 
Esophagitis Status 
Subgroup analysis by esophagitis status (erosive esophagitis vs. no erosive esophagitis at 
screening) will be performed for the following efficacy parameters. 
- 
Percent change from baseline to Week 8 in WHSS 
- 
Overall Heartburn Responder 
- 
Percent change from baseline to Week 8 in WRFS 
- 
Overall Regurgitation Responder 
- 
Percent change from baseline to Week 8 in saliva bile acid level 
 
Baseline WHSS 
Subgroup analysis by baseline WHSS (≤3 vs. >3) will be performed for the following efficacy 
parameters. 
- 
Percent change from baseline to Week 8 in WHSS 
- 
Overall Heartburn Responder 
 
Baseline WRFS 
Subgroup analysis by baseline WRFS (≤3 vs. >3) will be performed for the following efficacy 
parameters. 
- 
Percent change from baseline to Week 8 in WRFS 
- 
Overall Regurgitation Responder 


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Baseline Bile Acid Level in Saliva 
Subgroup analysis by baseline bile acid level in saliva (positive vs. negative) will be performed 
for the following efficacy parameters. 
- 
Percent change from baseline to Week 8 in WHSS 
- 
Overall Heartburn Responder 
- 
Percent change from baseline to Week 8 in WRFS 
- 
Overall Regurgitation Responder 
 
Bilitec Monitoring Status 
Subgroup analysis by Bilitec monitoring status (performed vs. not performed at screening) will 
be performed for the following efficacy parameters. 
- 
Percent change from baseline to Week 8 in WHSS 
- 
Overall Heartburn Responder 
- 
Percent change from baseline to Week 8 in WRFS 
- 
Overall Regurgitation Responder 
 
Bilitec Bile Acid Status 
Subgroup analysis by Bilitec bile acid status (positive vs. negative at screening) will be 
performed for the following efficacy parameters. 
- 
Percent change from baseline to Week 8 in WHSS 
- 
Percent change from baseline to Week 8 in WRFS 
5.10.6 
Rescue Medicine Use 
Patients will report the frequency of their nighttime use of rescues medicine (liquid antacid) in 
the morning diary and their daytime use of rescue medicine in the evening diary. Nighttime use, 
daytime use, and overall daily use of rescue medicine will be summarized by treatment group for 
each treatment week and for the Treatment Period. 


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5.11 
HEALTH OUTCOMES ANALYSIS 
5.11.1 
SF-12V2 Health Survey 
Change from baseline to Week 4 and Week 8 in SF-12V2 (both LOCF and OC) will be 
summarized by treatment group for each of the 8 health concepts (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]) and for each of the two summary measures (the physical 
component and mental component). 
5.11.2 
EQ-5D-3L 
Change from baseline to Week 4 and Week 8 in EQ-5D-3L (both LOCF and OC) will be 
summarized by treatment group for each of the 5 questions assessing the following domains: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Change from 
baseline to Week 4 and Week 8 in heath state as assessed by a 0 to 100 visual analogue scale 
(both LOCF and OC) will also be summarized by treatment group. 
5.12 
SAFETY ANALYSIS 
Safety analyses will be performed using the Safety Population. Safety data summaries will be 
presented for each treatment group as well as for IW-3718 overall. 
For analysis of safety parameters, the last non-missing value before the first dose of double-blind 
study drug will be used as baseline.  
Table 5.12-1 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. 


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Table 5.12-1. 
Visit Time Windows for Safety Analysis 
Derived Visit 
Scheduled Test / Visit Daya 
Window 
Baseline 
Day 1 
Days ≤ 1 
Day 15 Visit 
Day 15 
Days [2, 22] 
Day 29 Visit 
Day 29 
Days [23, 43] 
Day 57 Visit 
Day 57 
Days ≥ 44 
End of Treatmentb 
Final or termination visit 
a. 
Relative to the date of randomization; Day 1 = the day of randomization. 
b. “End of Treatment” will be presented in analysis tables for safety parameters, including clinical laboratory 
and vital signs.  
 
Test/Visit Day will be calculated as follows: test/visit date – date of randomization. 
5.12.1 
Adverse Events 
Adverse events will be coded by system organ class and preferred term using the MedDRA 
dictionary, version 18.1. 
An AE will be considered a treatment-emergent adverse event (TEAE) if it started after the first 
dose of study drug or started prior to the first dose of study drug but increased in severity after 
the first dose of study drug. 
The incidence of TEAEs will be presented by system organ class and preferred term. The 
incidence of Severe TEAEs, TEAEs related to study drug, TEAEs leading to discontinuation of 
study drug, and treatment-emergent serious adverse events (SAEs) will also be presented, 
separately, by system organ class and preferred term. If a patient has more than 1 AE coded to 
the same preferred term, the patient will be counted only once for that preferred term using the 
highest severity and closest relationship to study drug. 
The incidence of common (≥ 3% of patients in any treatment group) TEAEs will be presented 
using preferred terms by decreasing frequency in the IW-3718 overall group. 
Data listings will be provided for deaths, SAEs, and AEs leading to discontinuation of study 
drug. 


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Additional analyses will be conducted on constipation as an AE of interest. Median time from 
study drug initiation to onset of the first occurrence of constipation will be estimated using the 
Kaplan-Meier method. Duration of treatment-emergent constipation will also be summarized. If 
a patient had multiple occurrences of treatment-emergent constipation, the occurrence with the 
longest duration will be used in the summary.  
5.12.2 
Clinical Laboratory Parameters 
Clinical laboratory test values (in SI unit) will be summarized for each assessment time point. 
Change from baseline values will be summarized for each assessment time point post baseline. 
Clinical laboratory test values will be considered potentially clinically significant (PCS) if they 
meet either the lower-limit or higher-limit PCS criterion listed in Table 5.12-2. The incidence of 
change in clinical laboratory values from non-PCS at baseline to PCS post baseline will be 
tabulated for patients with available non-PCS values at baseline and at least 1 assessment post 
baseline. A supportive listing of patients with PCS post-baseline values will be provided, 
including the PID number, trial center, baseline value, and all post-baseline (including non-PCS) 
values. A listing of all AEs for patients with post-baseline PCS laboratory values will also be 
provided. 
Table 5.12-2. 
Criteria for Potentially Clinically Significant Laboratory Results 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Albumin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Alanine aminotransferase 
U/L 
— 
≥ 3 × ULN 
Alkaline phosphatase 
U/L 
— 
≥ 3 × ULN 
Aspartate aminotransferase 
U/L 
— 
≥ 3 × ULN 
Bicarbonate 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Bilirubin, total 
μmol/L 
— 
> 1.5 × ULN 
Calcium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Chloride 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Cholesterol, total 
mmol/L 
— 
> 1.6 × ULN 
Creatinine 
μmol/L 
— 
> 1.3 × ULN 
Glucose 
mmol/L 
< 0.8 × LLN 
> 1.4 × ULN 


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Table 5.12-2. 
Criteria for Potentially Clinically Significant Laboratory Results 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
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. 
5.12.3 
Vital Sign Parameters 
Vital sign values will be summarized for each assessment time point. Change from baseline 
values will be summarized for each assessment time point post baseline. 


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Vital sign values will be considered PCS if they meet both the observed-value criterion and the 
change-from-baseline criterion listed in Table 5.12-3. The incidence of PCS vital signs will be 
tabulated for patients with a baseline value and at least 1 post-baseline assessment. A supportive 
listing of patients with PCS vital signs will be provided, including the PID number, trial center, 
baseline value, and all post-baseline (including non-PCS) values. In addition, a listing of all AEs 
that occurred in patients who had PCS vital sign values will be provided. 
Table 5.12-3. 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteriaa 
Observed Value 
Change from Baseline 
Sitting systolic blood 
pressure, mm Hg 
High 
≥ 180 
Increase of ≥ 20 
Low 
≤ 90 
Decrease of ≥ 20 
Sitting diastolic blood 
pressure, mm Hg 
High 
≥ 105 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Sitting pulse rate, bpm 
High 
≥ 120 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Weight, kg 
High 
— 
Increase of ≥ 7% 
Low 
— 
Decrease of ≥ 7% 
a. 
A post-baseline value is considered potentially clinically significant if it meets both the observed-value and the 
change-from-baseline criteria. 
bpm = beats per minute. 
5.12.4 
ECG Parameters 
ECG values will be summarized for baseline and the EOT Visit. Change from baseline values 
will be summarized for the EOT Visit. ECG values will be categorized as low, normal, or high 
based on reference ranges provided by the site. Shifts from baseline to end of study will be 
tabulated for the following categories: normal, abnormal not clinically significant, and abnormal 
clinically significant. ECG values will be PCS if they meet the higher limit PCS criteria listed in 
Table 5.12-4. The incidence of change in ECG values from non-PCS at baseline to PCS post 
baseline will be tabulated for patients with non-PCS values at baseline and at least 1 assessment 
post baseline. 


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Table 5.12-4. 
Criteria for Potentially Clinically Significant ECG Parameters 
ECG Parameter 
Unit 
Higher Limit 
QRS duration 
msec  
≥ 150 
PR interval 
msec 
≥ 250 
QTc interval  
msec 
> 500 
5.12.5 
Other Safety Parameters 
Any physical examination abnormality that the investigator considers to be potentially clinically 
significant will be reported as an AE. No separate analysis of Physical Examinations is planned. 
5.13 
DETERMINATION OF SAMPLE SIZE 
The sample size per arm was determined by estimating the overall power of a linear trend test in 
a one-way design that included placebo and all the active treatment arms (500 mg BID, 1000 mg 
BID, and1500 mg BID of IW-3718). The efficacy endpoint of interest in the previous Phase 2a 
study (ICP-3718-201) was change from baseline in daytime heartburn defined as the presence of 
heartburn since the patient awoke that morning (assessed in the evening) and assessed with an 
11-point [0 to 10] NRS, where 0=none and 10=very severe. In that study, IW-3718 demonstrated 
treatment differences near 0.70 points for change over the treatment period (e.g., -0.73 vs. -1.38 
for placebo and IW-3718, respectively), and standard deviations near 1.35 for the LSMs. 
Employing these historical values, a study with 58 patients per arm (the expected number of 
patients at Week 8 given an enrollment of 260 patients) will have statistical power of at least 
80% for the overall trend test (i.e., linear contrast) where the highest active treatment arm reflects 
110% of the previously observed treatment difference and the lowest 2 active treatment arms 
reflect 55% of the same (two-sided, α=0.05). At the proposed sample size, a subsequent pairwise 
comparison between placebo and an active treatment arm reflecting the previously observed 
treatment difference will have 80% statistical power (two-sided, α=0.05). 


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6. 
CHANGES FROM ANALYSES PLANNED IN THE 
PROTOCOL 
a. One additional analysis population (the Randomized Population) was defined in the SAP that 
was not previously defined in the Protocol. 
b. Patient disposition will be summarized for the Randomized Population as opposed to the 
mITT Population as specified in the Protocol. 


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7. 
DATA HANDLING CONVENTIONS 
7.1 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS 
If a patient has repeated assessments prior to the start of double-blind study drug, then the results 
from the final non-missing assessment made prior to the start of the double-blind study drug will 
be used as baseline. If end-of-study assessments are repeated or if unscheduled visits occur, the 
last non-missing post baseline assessment will be used as the end-of-study assessment for 
generating summary statistics. However, all post-baseline assessments will be used for PCS 
value determination as described above and all assessments will be presented in the data listings. 
7.2 
MISSING DATE OF THE LAST DOSE OF STUDY DRUG 
When the date of the last dose of double-blind study drug is missing for a patient in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all efforts 
are made it is still missing, the last eDiary entry date will be used as the last dose date.  
7.3 
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS 
If severity is missing for an AE that started prior to the first dose of double blind study drug, all 
efforts should be made to obtain the severity from the investigator. If it is still missing after all 
efforts, then a severity of “Mild” will be assigned. If the severity is missing for an AE that started 
after the first dose of double-blind study drug, then a severity of “Severe” will be assigned. The 
imputed values for the missing severity assessment will be used for the incidence summary, 
while the actual missing values will be presented in data listings. 
7.4 
MISSING RELATIONSHIP TO STUDY DRUG FOR ADVERSE 
EVENTS 
If the relationship to study drug is missing for an AE that started after the first dose of double-
blind study drug, all efforts should be made to obtain the relationship from the investigator. If it 
is still missing after all efforts, a causality of “Related” will be assigned in the corresponding 
analysis derived data set. The imputed values for the missing relationship to double-blind study 
drug will be used only for incidence summary, while the actual missing values will be presented 
in data listings. 


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7.5 
MISSING DATE INFORMATION FOR ADVERSE EVENTS 
The following imputation rules apply to cases in which the start date is incomplete (i.e., partial 
missing) for adverse events. 
a. If AEs occurred during the Screening or Pretreatment Period (i.e., the Screening or 
Pretreatment Period is checked on the AE eCRF) 
Missing day and month 
• If the year is the same as the year of the date of informed consent, then the day and month of 
the date of informed consent will be assigned to the missing fields. 
• If the year is prior to the year of the date of informed consent, then December 31 will be 
assigned to the missing fields. 
• If the year is after the year of the date of informed consent, then January 1 will be assigned to 
the missing fields. 
 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
 
Missing day only  
• If the month and year are the same as the month and year of the date of informed consent, 
then the date of informed consent will be assigned to the missing day. 
• If either the year is before the year of the date of informed consent or if both years are the 
same but the month is before the month of the date of informed consent, then the last day of 
the month will be assigned to the missing day. 
• If either the year is after the year of the date of informed consent or if both years are the same 
but the month is after the month of the date of informed consent, then the first day of the 
month will be assigned to the missing day. 
 
If the stop date is complete and it is before the date of randomization and the imputed start date 
as above is after the stop date, the start date will be imputed by the stop date. If the stop date is 
complete and it is on or after the date of randomization and the imputed start date as above is 
after the stop date, the start date will be imputed by the date immediately before the date of 
randomization. 


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


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• If the stop date is after the date of the first dose of double-blind study drug, the date of the 
first dose of double-blind study drug will be assigned to the missing start date. 
• If the stop date is before the date of the first dose of double-blind study drug, the stop date 
will be assigned to the missing start date. 
7.6 
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS 
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or stop 
date will be imputed. When the start date and the stop date are both incomplete for a patient, 
impute the start date first. 
7.6.1 
Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month 
• If the year of the incomplete start date is the same as the year of the date of the first dose of 
double-blind study drug, then the day and month of the date of the first dose will be assigned 
to the missing fields. 
• If the year of the incomplete start date is prior to the year of the date of the first dose of 
double-blind study drug, then December 31 will be assigned to the missing fields. 
 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of double-blind study drug, then the day of the date of the first dose will 
be assigned to the missing day. 
• If either the year is before the year of the date of the first dose of double-blind study drug or 
if both years are the same but the month is before the month of the date of the first dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day. 


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• If either the year is after the year of the date of the first dose of double-blind study drug or if 
both years are the same but the month is after the month of the date of the first dose of 
double-blind study drug, then the first day of the month will be assigned to the missing day. 
7.6.2 
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of double-blind study drug is missing, replace it with the last diary entry date. If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the imputed 
stop date will be equal to the start date. 
Missing day and month 
• If the year of the incomplete stop date is prior to the year of the date of the last dose of 
double-blind study drug, then December 31 will be assigned to the missing fields. 
 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
 
Missing day only 
• If either the year is before the year of the date of the last dose of double-blind study drug or if 
both years are the same but the month is before the month of the date of the last dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day. 
7.7 
CHARACTER VALUES OF CLINICAL LABORATORY PARAMETERS 
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table due to, for example, it being a character string rather than a numerical type, a coded value 
needs to be appropriately determined and used in the statistical analyses. However, the actual 
values as reported in the database will be presented in data listings. 
Table 7.7-1 shows examples of how some possible laboratory results should be coded for the 
analysis. 


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Table 7.7-1. 
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters 
Laboratory Test, 
SI Unit 
Possible Laboratory Results 
Coded Value for Analysis 
CHEMISTRY 
ALT, U/L 
< 5 
0 
AST, U/L 
< 5 
0 
Bilirubin, total, μmol/L 
< 2 
0 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités 
(International System of Units). 
7.8 
HEALTH OUTCOMES PARAMETERS 
7.8.1 
Short Form 12 Health Survey Version 2 
The SF-12 is a multipurpose, short-form health survey consisting of 12 questions designed for 
use in clinical practice and research, health policy evaluations, and general population surveys. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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7.8.2 
EuroQol-5 dimension (EQ-5D-3L) 
The 5-item responses of the EQ-5D-3L define a health state that can be converted into a single 
summary utility index that assigns weights (ie, value) to each level. Different weights are 
available. 
 
 
 




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8. 
REFERENCES 
1. Dimenäs E, Glise H, Hallerbäck B, Hernqvist H, Svedlund J, Wiklund I. Quality of life in 
patients with upper gastrointestinal symptoms. An improved evaluation of treatment 
regimens? Scand J Gastroenterol.1993;28(8):681–687. 
2. Ware John E.Jr., Kosinski M. A 12-Item Short-Form Health Survey: Construction of Scales 
and Preliminary Tests of Reliability and Validity. Med Care 1996;34:220-33. 
3. Shaw JW, Johnson JA, Coons SJ. U.S. valuation of the EQ-5D health states: development 
and testing of the D1 valuation model. Med Care 2005;43:203-20. 


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9. 
APPENDICES 
 
 


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APPENDIX I 
GSRS-SELF 
 
 




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