Conditions: Gastroesophageal Reflux Disease (GERD)
Keywords: Gastroesophageal Reflux Disease GERD Proton Pump Inhibitors IW-3718
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 495
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate the safety and efficacy of IW-3718 administered to patients with GERD who continue to have persistent symptoms, such as heartburn and regurgitation, while receiving once-daily (QD), standard-dose PPIs.

Detailed description:

Arms:
arm 1: Three 500 mg IW-3718 tablets administered twice daily (BID), immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day. arm 2: Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.

Interventions: intervention 1: IW-3718 intervention 2: placebo intervention 3: Standard-dose PPIs QD
Intervention descriptions: intervention 1: oral tablet intervention 2: oral tablet intervention 3: background therapy

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol: C3718-301
Amendment 2, 14 August 2020 
Study Title:
A Phase 3, Randomized, Double-blind, Placebo-controlled, 
Parallel-group, Multicenter Trial of Oral IW-3718 Administered 
to Patients with Gastroesophageal Reflux Disease while receiving 
Proton Pump Inhibitors 
Study Number:
C3718-301 
Study Phase: 
3 
Product Name:
IW-3718 
Indication: 
IW-3718 is indicated as an adjunct to proton pump inhibitors to 
treat persistent (also referred to as refractory) gastroesophageal 
reflux disease symptoms such as heartburn and regurgitation that 
are not resolved with proton pump inhibitor therapy alone. 
Sponsor:
Ironwood Pharmaceuticals, Inc.
100 Summer Street, Suite 2300 
Boston, MA 02110 USA
Sponsor Contact: 
  
Medical Monitor:
 
Date 
Original Protocol:
15 March 2018 
Amendment #1
23 June 2018 
Amendment #2
14 August 2020 
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.


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 2 of 105 
SYNOPSIS 
Study Number: C3718-301 
Study Title: A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter Trial of Oral IW-3718 Administered to Patients with Gastroesophageal Reflux 
Disease while receiving Proton Pump Inhibitors 
Study Centers: Approximately 100 centers in the United States and Canada 
Development Phase: 3 
Objectives: The objective of this study is to evaluate the safety and efficacy of IW-3718 
administered to patients with GERD who continue to have persistent symptoms, such as 
heartburn and regurgitation, while receiving once-daily (QD), standard-dose proton pump 
inhibitors (PPIs). 
Methodology: This is a multicenter, randomized, double-blind, placebo-controlled, parallel-
group, 8-week study, consisting of 4 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. Eligible patients will continue to take their PPI and 
will be randomized to placebo or to 1500 mg IW-3718 BID. 
 
Overview of Study Design 
 
 
* This visit represents the end of the study
EE = erosive esophagitis; EGD=esophagogastroduodenoscopy; EOT=end of treatment; SD PPI = standard dose proton pump inhibitor
Screening
Period
Pretreatment
Period
Treatment Period
Day 1 to Day 57
14 to 21 days
Up to 35 days
Screening
Visit
(Day -56 to
Pretreatment
Visit)
Pretreatment
Visit
(Day -21 to
Day -14)
Randomization
Visit
(Day 1)
Week 4 Visit
(Day 29 ± 3)
Week 8 / 
EOT
Visit*
(Day 57 +3)
SD PPI
Note:  There is no Day 0
EGD & Bravo 
(≥7d prior to 
Pretreatment
Visit)
1500 mg IW-3718 twice daily 
Placebo twice daily
Stratify by 
EE Status
EGD for EE pts 
Study Drug Treatment (+ SD PPI)
Follow
-up
7 days
Safety
Phone
Call
(EOT +7d)
SD PPI
Stratified by 
EE Status 
(present, not present) + 
baseline WHSS (<3, ≥3)
; WHSS = Weekly Heartburn Severity Score


IW-3718 
 
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Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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Screening Period: The Screening Period starts with the signature of the informed consent form 
(ICF) and may last for up to 35 days. During this period, patients’ eligibility for entry into the 
Pretreatment Period will be determined. Two procedures will be required during the Screening 
Period in all patients (all will be done while patients continue to take their PPI):  
• An esophagogastroduodenoscopy (EGD)  
• Up to 96 hours of pH testing with the Bravo™ device, a capsule-based pH monitor 
implanted above the lower esophageal sphincter (LES).  
The patient must have been adherent to their standard PPI dosage regimen (as per product 
label) for the 8 weeks prior to the Screening Visit and during the entire Screening Period. 
Histamine-2 receptor antagonists (H2RAs) should be stopped at least 5 days prior to the EGD 
and Bravo pH monitoring; antacids should be stopped at least 1 day prior to the EGD and 
Bravo pH monitoring. The EGD must be performed during the Screening Period and should be 
performed 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 use antacids if 
needed until 1 day prior to entering the Pretreatment Period. The end of the Screening Period 
coincides with the start of the Pretreatment Period. 
Pretreatment Period: The Pretreatment Period is defined as the 14 to 21 days immediately 
before the Randomization Visit. Patients who meet all eligibility criteria, including pH 
requirements as per the central pH read, will continue into the Pretreatment Period. 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 liquid antacid that is dispensed as 
rescue medicine (aluminum hydroxide / magnesium hydroxide). Patients will provide the 
following daily and weekly symptom assessments using a handheld electronic diary (eDiary):  
Daily Assessments 
• GERD symptoms, recorded in the evening before going to bed, using the modified 
Reflux Symptom Questionnaire Electronic Diary (mRESQ-eD; Appendix 1) 
• Use of per-protocol rescue medicine, recorded in the evening before going to bed 
• Sleep disturbance due to GERD symptoms, recorded upon getting up in the morning 
(Appendix 2) 
Weekly Assessments  
• Degree of relief of GERD symptoms (Appendix 3) 
• GERD symptom bothersomeness (Appendix 3) 
Patients will be required to complete the daily assessments for at least 5 days each week 
during the last 14 days before the Randomization Visit and the weekly assessments at least 
once during the last 7 days before the Randomization Visit to be eligible for randomization. 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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Patients will be instructed to take their PPI approximately 30-60 minutes before breakfast each 
day, even on study visit days. Patients who satisfy 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 their baseline weekly heartburn severity score  (WHSS, defined as 
the average heartburn severity score over the last 7 days prior to randomization of <3 vs. ≥3; 
see Criteria for Evaluation, below) and randomly assigned within each stratum to placebo or 
1500-mg IW-3718 BID (1:1). The treatment randomization schedule will be managed by a 
central vendor. Enrollment will be monitored to ensure that no single center contributes > 10% 
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 and assessment of sleep), weekly 
assessments (degree of relief of GERD symptoms, symptom bothersomeness, and treatment 
satisfaction questions). At the end of the treatment period study medication will be 
discontinued and patients will return for an End-of-Treatment (EOT) Visit. All patients who 
have erosive esophagitis (LA classification A-D) on EGD at Screening and completed ≥4 
weeks of treatment will have a repeat EGD at their EOT Visit. Patients will also complete all 
End-of-Treatment assessments. 
Study Population:  The study population will consist of adult patients with diagnosed GERD 
who continue to have persistent (also referred to as refractory) symptoms, such as heartburn 
and regurgitation, while receiving QD PPI therapy and have evidence of pathological acid 
reflux during the Screening Period as determined using the Bravo device. Patients will be 
stratified for treatment assignment at the time of randomization based on the presence of 
erosions (erosions, no erosions) and by baseline WHSS (<3 vs. ≥3). The study will aim to 
enroll up to 50% of patients with esophageal erosions. Patients must be receiving 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 labelling. Approximately 660 patients (330 patients per treatment arm) will be 
randomized to treatment.  
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 male or female (if female, nonpregnant) and is at least 18 years 
old at the Screening Visit.  
3. Patient has a diagnosis of GERD and reports experiencing GERD symptoms (heartburn or 
regurgitation) on average ≥ 4 days per week over the last 8 weeks before the Screening 
Visit. 
4. Patient has been receiving standard-labeled dose, QD, PPI therapy (treatment that, 
according to the Investigator’s judgment, could not be further improved by changing the 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 5 of 105 
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 (see Appendix 7). Patients who have their PPI modified during the Screening 
Period may be re-screened after 8 weeks of standard-labeled dose QD PPI therapy 
provided they have not previously entered the Pretreatment Period. 
5. Up to 96 hours of pH monitoring (with a Bravo device) during the Screening Period (while 
the patient continues taking their PPI) demonstrates 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 as confirmed by centralized review of pH monitoring. 
6. During the last 7 days before randomization patient reports an average heartburn severity 
(HS, maximum of Items #1 and #2 on mRESQ-eD) of ≥ 2 (mild) and has a daily HS ≥ 3 
(moderate) for at least 2 of those days. 
7. Female patients must be postmenopausal for ≥1 year, surgically sterile (ie, bilateral 
oophorectomy, hysterectomy, or tubal ligation); or must agree to completely abstain from 
heterosexual intercourse; or, if heterosexually active, must agree to use 1 of the following 
methods of birth control from the date she signs the ICF until 24 hours after her final dose 
of study drug: 
a. Progesterone implant or an intrauterine device (IUD) 
b. Combination of 2 highly effective birth control methods (eg, diaphragm with 
spermicide plus a condom, condom with spermicide plus a diaphragm or cervical cap, 
hormonal contraceptive [eg, oral and transdermal patch] plus a barrier method, partner 
with vasectomy [conducted ≥60 days before the Screening Visit or confirmed via 
sperm analysis] plus a hormone or barrier method). 
8. Females of childbearing potential must have a negative urine or serum pregnancy test at the 
Screening Visit and at the Randomization Visit prior to dosing. Positive urine test results 
will be confirmed by a serum pregnancy test. 
9. Patient agrees not to make any changes to their usual diet or exercise regimen during the 
study. 
10. Patient is able to successfully use the eDiary, and has adequately completed the eDiary 
questions on at least 5 days each week and the weekly questions at least once during the 14 
days before the start of the Treatment Period. 
11. Patient is compliant with QD PPI dosing during the 14 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 at least one of the languages to be used for patient-reported 
outcome (PRO) assessments. 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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13. 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. 
2. Patient reports epigastric pain or epigastric burning as his or her predominant symptom at 
the Screening Visit. 
3. Patient has a diagnosis of gastroparesis per gastric emptying study, or a history of bowel 
obstruction, or is at risk for a bowel obstruction (eg, patient has an organic gastrointestinal 
[GI] motility disorders or a history of major GI surgery).  
4. Patient has a history of serum triglyceride concentrations > 500 mg/dL on a fasting 
specimen, or has serum triglyceride concentrations > 500 mg/dL on a fasting specimen at 
Screening.  
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; eg, the patient has osteoporosis or osteomalacia) and will 
be put at risk by receiving colesevelam for 8 weeks. 
7. Patient has an active swallowing disorder that would compromise their ability to swallow 
the study medication.  
8. Patient has any alarm symptoms including, but not limited to, GI bleeding, anemia, 
vomiting, or unexpected weight loss at 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 (eg, 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. 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 7 of 105 
11. Patient has large (>5 cm) hiatal hernia. 
12. 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.  
13. Patient has Gilbert’s disease, Crohn’s disease, diabetes mellitus (defined as A1C >6.5%), 
Zollinger-Ellison syndrome, pancreatitis, cholecystitis, or systemic sclerosis. 
14. Patient has elevated (defined as > 1.5 times the upper limit of normal by the laboratory) 
levels of serum bilirubin at Screening.  
15. Patient has a history of clinically significant hypersensitivity or allergies to any of the 
excipients contained in the study medication (active or placebo).  
16. 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. 
17. Patient has active substance abuse or history of chronic substance abuse (including 
alcoholism but not including nicotine) within 12 months before the Screening Visit or is 
positive for any of the following at the Screening Visit unless legally prescribed for 
anything but gastrointestinal pain: amphetamines, benzodiazepines, opiates, barbiturates, 
cocaine, or phencyclidine.  
Note:  Marijuana use, whether prescribed or not, is prohibited from 30 days before 
screening through the duration of the study. Use of illicit drugs is not allowed during the 
study. 
18. 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.)  
19. 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. 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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Page 8 of 105 
20. 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.  
21. 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. 
22. Patient has previously entered the Treatment Period of a IW-3718 study. 
23. Patient has previously entered the Pretreatment Period of this study. (Note: patients who 
failed the Pretreatment Period due to abnormal laboratory findings or timing issues may 
be re-screened.) 
24. 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: 
• 1500 mg IW-3718 BID: Three 500 mg IW-3718 oral tablets administered BID, 
immediately after the morning and evening meals. Dose reductions are not permitted. 
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 126 days, including the Screening Period and Follow-up. 
Criteria for Evaluation: 
Primary and Key Secondary Efficacy Assessments 
The once-daily assessment of heartburn symptoms and regurgitation symptoms obtained from 
the mRESQeD will be used to determine the primary and key secondary efficacy parameters.  
The items used to measure heartburn severity will be the 2 items in the Heartburn Domain 
assessed on a 0-to-5 ordinal severity scale: 
• 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 used to measure 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 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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Other Efficacy Assessments 
The following GERD symptoms obtained from the mRESQeD will be assessed once-daily:  
• Difficulty swallowing, hoarseness, and cough severity, each assessed on a 0-to-5 
ordinal severity scale  
• Burping frequency, assessed on a 0-4 frequency scale 
In addition, Sleep Disturbance due to GERD symptoms - including difficulty falling asleep 
and the number of nighttime awakenings during the prior evening will be recorded each 
morning. 
Heartburn severity will be assessed once daily in the evening, before bed, on a 0-to-5 ordinal 
severity scale. 
The following patient-reported items will be assessed once weekly: 
• Degree of Relief of heartburn, regurgitation, and overall GERD symptoms, each rated 
on 7-point balanced ordinal scale (1=significantly relieved, 4=unchanged, 
7=significantly worse); Degree of Relief of heartburn, regurgitation, and overall GERD 
symptoms on 7-point patient global impression of change scale (compared to before 
you started the study; 1=significantly relieved, 4=unchanged, 7=significantly worse) 
• Bothersomeness of heartburn, regurgitation, and overall GERD symptoms, each rated 
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) 
• Global Treatment Satisfaction, rated on a 5-point ordinal scale (1=very dissatisfied, 
3=neither satisfied nor dissatisfied, 5=very satisfied) 
Other Assessments 
The following questionnaires will be administered during the study at the Randomization, 
Week 4, and EOT Visits: 
• EuroQol (EQ)-5D-3L 
• 
Work Productivity and Activity Index (WPAI)-GERD-Sleep  
Safety Assessments: 
Adverse event (AE) recording, clinical laboratory measures (clinical chemistry, hematology, 
coagulation, and urinalysis), vital sign measurements, ECGs, and physical examinations. 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
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Statistical Methods 
Analysis Populations: 
Screened Population consists of all patients who signed informed consent and received a 
patient identification (PID) number. 
Randomized Population consists of all patients who were assigned to a treatment group 
(placebo or IW-3718) via randomization. 
Safety Population consists of all randomized patients who received at least 1 dose of study 
drug.  
Modified Intent-to-Treat (mITT) Population consists of all randomized patients who 
received at least 1 dose of study drug and had at least 1 postbaseline primary efficacy 
assessment. 
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 2-sided and with a confidence level of 95%. Details of the data handling methods will 
be specified in the statistical analysis plan (SAP). Unless otherwise specified, the week prior 
to randomization will be considered the baseline for efficacy analyses.  For safety analyses, 
the baseline value is defined as the last non-missing value measured before administration of 
study treatment. All statistical analyses will be performed using SAS® Version 9.4 (or later) 
for Windows. 
Primary Efficacy Parameter 
Change from baseline at Week 8 in Weekly Heartburn Severity Score (WHSS). 
• 
The WHSS for a week is the average of the non-missing Daily Heartburn Severity 
Scores (DHSS) for that week. Rules for missingness of data will be prespecified in the 
SAP finalized before database lock. 
• 
The DHSS for a day is the greater score of the 2 mRESQ items assessing heartburn 
severity (“Burning feeling behind the breastbone or in the center of the upper stomach” 
and “Pain behind the breastbone or in the center of the upper stomach”) for that day. 
Where 1 of the 2 mRESQ heartburn severity items is missing for the day, the 
maximum will be the score of the remaining item; where both items are missing for the 
day, the DHSS will be missing. 
Key Secondary Efficacy Parameters 
1. Change from baseline at Week 8 in Weekly Regurgitation Frequency Score (WRFS) 
• 
The WRFS for a week is the average of the non-missing Daily Regurgitation 
Frequency Scores (DRFS) for that week. Rules for missingness of data will be 
prespecified in the SAP finalized before database lock. 
• 
DRFS for a day is the greater score of the 2 mRESQ items assessing regurgitation 
frequency (“Regurgitation [liquid or food moving upwards toward your throat or 
mouth]” and “An acid or bitter taste in the mouth”) for that day. 


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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2. Overall Heartburn Responder: a patient who is a weekly heartburn responder for at least 
4 weeks, including at least 1 of the last 2 weeks (Weeks 7 and 8), during the 8-week 
Treatment Period. 
• 
A weekly heartburn responder is a patient with a decrease from baseline of ≥ 45% in 
Weekly Heartburn Severity Score (WHSS). 
• 
Rules for missingness of data will be prespecified in the SAP finalized before database 
lock. 
3. Proportion of heartburn-free days during the 8-week Treatment Period. 
• 
Proportion of heartburn-free days is calculated as the number of heartburn-free 
(DHSS=0) days divided by the number of diary entry days. 
Efficacy Analysis Methods 
For analysis of the primary efficacy and first key secondary efficacy parameters, continuous 
parameters (eg, change from baseline), descriptive statistics (patient number [n], mean, 
standard deviation, median, and range) will be presented for each treatment group. The 
IW-3718 group will be compared with the placebo group by employing a linear mixed-effects 
model for repeated measures (MMRM) framework with week (categorical), treatment group, 
week-by-treatment group and week-by-baseline value interactions, baseline esophagitis status 
(present vs. not present), and baseline WHSS (<3 vs. ≥3) as fixed-effect terms and baseline 
value as a covariate, with patient as a random effect. An unstructured covariance structure will 
be used. Least-squares mean (LSM) for each treatment group, LSM difference between the 
IW-3718 group and the placebo group and a 95% confidence interval for the difference at 
Week 8, as well as the p-value for comparison versus placebo will be presented. 
For analysis of responder parameters (ie, responder vs. non-responder), the counts and 
proportions of responders will be calculated for each treatment group. The proportions of 
responders between the IW-3718 group and the placebo group will be compared using a 
Cochran-Mantel-Haenszel (CMH) test controlling for baseline esophagitis status (erosive 
esophagitis vs. no erosive esophagitis) and baseline WHSS (<3 vs. ≥3). The CMH test is the 
primary analysis for responder parameters. The difference in the proportion of responders 
between the IW-3718 group and the placebo group, as well as the CMH estimate of the odds 
ratio (IW-3718 over placebo) and a 95% confidence interval for the odds ratio, will also be 
presented. 
Time-dependent proportion parameters, defined as days the event of interest occurs, divided 
by the number of eDiary entry days within the 8-week Treatment Period (eg, proportion of 
heartburn-free-days), will be analyzed using a Poisson model which is appropriate for count 
data. The analysis includes the treatment, the baseline esophagitis status (present vs. not 
present), baseline WHSS (<3 vs. ≥3), covariate of baseline proportion of event-free days, with 
the eDiary entry days adjusted in the model. In the case of overdispersion, a negative binomial 
model instead of Poisson regression will be implemented. Model estimates in difference 
between the rates for IW-3718 and placebo groups will be calculated with corresponding 95% 
confidence interval and p-value associated with the comparisons to placebo. 
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, clinical 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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Page 12 of 105 
laboratory evaluations, vital signs, ECGs, and physical examination. For each safety 
parameter, the last non-missing assessment made before the first dose of study drug will be 
used as the baseline for all analyses of that safety parameter.  
Sample Size Determination and Controlling for Type-I Error 
The sample size calculations for the primary and key secondary efficacy parameters are based 
on results from patients with evidence of pathological acid reflux (positive baseline Bravo 
status) in Study ICP-3718-202, which had a similar study population as the current study.  
The primary efficacy parameter is Change from Baseline at Week 8 in WHSS, and key 
secondary efficacy parameters include: 
• Change from Baseline at Week 8 in WRFS 
• Overall Heartburn Responder 
• Proportion of Heartburn-free Days during the 8-week Treatment Period  
Using data from patients in Study ICP-3718-202, we derived the estimated results at end of the 
study as follows: 
Order of 
Hypothesis 
Testing 
Parameter 
Placebo  
(+ PPIs) 
1500 mg IW-3718 
(+ PPIs) 
1 
Change from Baseline at Week 8 in WHSS 
N = 43 
Mean = -1.58 
SD = 1.20 
N =51 
Mean = -2.01 
SD = 1.29 
2 
Change from Baseline at Week 8 in WRFS 
N = 43 
Mean = -0.81 
SD = 1.12 
N = 51 
Mean = -1.26 
SD = 0.91 
3 
Overall Heartburn Responder 
18/49 = 36.7% 
31/55 = 56.4% 
4 
Proportion of Heartburn-free Days during 
the 8-week Treatment Period 
N = 48 
Mean = 0.195 
SD = 0.2822 
N = 55 
Mean = 0.268 
SD = 0.2928 
The efficacy parameters will be tested sequentially according to the above order at a 2-sided 
significance level of 0.05 so that the overall type-I error rate is maintained at 0.05.  
Based on bootstrap simulations, a sample size of 330 patients per group will provide 
approximately 99% power to detect a treatment difference between 1500-mg IW-3718 (while 
receiving PPIs) and placebo (while receiving PPIs) for the primary efficacy parameter, 
assuming the randomized population in this study is consistent with the selected population 
from Study ICP-3718-202. Power that is based on simulations for all type-I error controlling 
key efficacy parameters are presented in the table below. The 2-sample t-test was used for 
continuous parameters and the Chi-square test was used for the responder parameter. 
 
 
 
 
 


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 13 of 105 
 
Order of 
Hypothesis 
Testing 
Parameters 
Power for Fixed Sequence Testing 
1 
Change from Baseline at Week 8 in WHSS 
99% 
2 
Change from Baseline at Week 8 in WRFS 
99% 
3 
Overall Heartburn Responder 
99% 
4 
Proportion of Heartburn-free Days during the 
8-week Treatment Period 
88% 
 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 14 of 105 
SCHEDULE OF EVALUATIONS 
 
Screening 
Period 
(Up to 5 
weeks) 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-
up 
Visit Days → 
Screening 
Visit (Day 
-56 to 
Day -15) 
Pretreatment 
Visit 
(Day -21 to 
Day -1) 
Randomization 
Visit 
(Day 1) 
Week 4 
Visit 
(Day 29 
± 3) 
Week 8 / 
End-of-
Treatment 
Visit  
(Day 57 + 3) 
Safety 
Phone 
Call 
(EOT 
+ 7d) 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
 
Study Procedure ↓ 
 
 
 
 
 
 
Inclusion and Exclusion 
Criteria Verification 
X 
X 
X 
 
 
 
Signing of ICF 
X 
 
 
 
 
 
IWRS Registration (a) 
X 
X 
X 
X 
X 
 
Demographics 
X 
 
 
 
 
 
Medical & Disease History 
X 
 
 
 
 
 
Physical Examination (b) 
X 
 
 
 
X 
 
Body Weight and Height (c)  
X 
X 
X 
X 
X 
 
H2RA/Antacid Washout (d) 
X 
 
 
 
 
 
EGD (e) 
X 
 
 
 
X 
 
Up to 96 Hours of pH Testing 
with Bravo Device (f) 
X 
 
 
 
 
 
Seated Vital Signs (g)  
X 
 
X 
X 
X 
 
12-Lead ECG (h) 
X 
 
X 
 
X 
 
Prior and Concomitant 
Medications & Procedures (i) 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Tests (j) 
X 
 
X 
X 
X 
 
Pregnancy Test (k) 
X 
 
X 
X 
X 
 
Drug and Alcohol Screen (l) 
X 
 
 
 
 
 
AE Evaluations (m) 
X 
X 
X 
X 
X 
X 
Rescue Medicine Dispensed (n) 
 
X 
X 
X 
 
 
eDiary Training and 
Dispensation 
 
X 
 
 
 
 
eDiary (o) 
 
X 
X 
X 
X 
 
Weekly Symptom and 
Treatment Assessments  
 
X 
X 
X 
X 
 
WPAI-Sleep-GERD 
 
 
X 
X 
X 
 
EQ-5D-3L 
 
 
X 
X 
X 
 
Randomization 
 
 
X 
 
 
 
Study Medication Dispensed 
(p) 
 
 
X 
X 
 
 
Study Medication Return (q) 
 
 
 
X 
X 
 
eDiary Return 
 
 
 
 
X 
 
Follow-up Phone Call (r) 
 
 
 
 
 
X 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 15 of 105 
Abbreviations: AE = adverse event; BP = blood pressure; CBC = complete blood count; ECG = electrocardiogram; 
EGD = esophagogastroduodenoscopy; EOT = End-of-treatment; EQ = EuroQol; H2RA = histamine-2 receptor antagonist; 
HEENT = head, eyes, ears, nose, and throat; ICF = informed consent form; IWRS = interactive web response system; 
PPI = proton pump inhibitor; mRESQeD = modified Reflux Symptom Questionnaire Electronic Diary; SAE = serious 
adverse event 
 
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; 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 washout H2RAs at least 5 days prior, and antacids 1 day prior, to the EGD 
and Bravo testing. 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 liquid antacid that is provided as rescue medication 
(aluminum hydroxide / magnesium hydroxide). 
e. 
All patients will be required to undergo an EGD during the Screening Period. There should be a minimum of 7 days 
between the EGD and the start of the Pretreatment Period to allow for pH testing and patient stabilization. A repeat 
EGD will be performed at the Week 8 / EOT Visit for all patients who have completed at least 4 weeks of treatment 
and had erosive esophagitis on the screening EGD (based on the Los Angeles [LA] classification of esophagitis, see 
Appendix 5) as determined by either the site personnel or the central reader.  
f. 
Up 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.  
g. 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. 
h. 12-Lead ECGs should be obtained after the patient has been supine for at least 5 minutes. 
i. 
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 PPIs, H2RAs, and antacids. Concomitant medications and 
procedures will be collected in the EDC system. 
j. 
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. 
k. For all female patients of childbearing potential, a negative urine or serum pregnancy test must be performed and 
documented at the Screening Visit, and at the Randomization Visit (before dosing) in order for the patient to be 
randomized into the study. A urine or serum pregnancy test will also be obtained at the Week 4 and EOT Visits. All 
positive urine pregnancy test results will be confirmed by a serum pregnancy test. 
l. 
Patients must undergo a urine drug screen for selected drugs of abuse (cocaine, barbiturates, amphetamines, opiates, 
benzodiazepines, cannabinoids, and phencyclidine) and a serum alcohol screen at the Screening Visit. 
m. For randomized patients, all AEs will be captured from the time the patient signs the ICF through the Follow-up 
Phone call. 
n. Rescue medicine (aluminum hydroxide / magnesium hydroxide) will be supplied to patients at the Pretreatment Visit, 
and if needed, at subsequent visits. 
o. The eDiary will be dispensed at the Pretreatment Visit. Patients must complete daily questions at least 5 days each 
week during the 14 days before the Treatment Period and must complete the weekly questions at least once during the 
7 days before the Treatment Period in order to be eligible for randomization. Patients should bring their eDiary to 
each visit. The eDiary will be used for daily assessments (PPI administration, mRESQ-eD, dyspepsia symptoms, 
sleep disturbance, and rescue medication use), and weekly assessments (degree of relief, symptom bothersomeness, 
symptom relief, treatment satisfaction, and questionnaires).  
p. 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 study medication prior to arriving at the clinic but will be dispensed 
additional doses needed until the next study visit. 
q. Treatment adherence with study drug will be assessed based on return of unused tablets. 
r. 
Study site will contact each patient via telephone 7 days after the EOT Visit to collect information pertaining to 
ongoing AEs/SAEs/concomitant medications/concomitant therapies, and information concerning any new AEs/SAEs 
/concomitant medications/concomitant therapies since the EOT Visit.  
 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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Page 16 of 105 
STUDY CONTACTS & IDENTIFICATION 
Protocol Inquiries and 
Contract Research 
Organization (CRO) 
Medical Monitor 
 
 
 
CRO  
 
 
 
 
Clinical Laboratory 
 
 
 
 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 17 of 105 
SPONSOR CONTACTS & IDENTIFICATION 
Sponsor 
Ironwood Pharmaceuticals, Inc. 
100 Summer Street, Suite 2300 
Boston, MA 02110  
 
 
 
Medical Monitor 
 
 
 
Ironwood Contact 
 
 
 
Drug Safety Physician 
(Serious Adverse Event 
[SAE] Reporting) 
 
 
  
Dedicated SAE Telephone, 
Facsimile, and Email 
 
 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 18 of 105 
TABLE OF CONTENTS 
SYNOPSIS.......................................................................................................................................2 
SCHEDULE OF EVALUATIONS ...............................................................................................14 
STUDY CONTACTS & IDENTIFICATION ...............................................................................16 
SPONSOR CONTACTS & IDENTIFICATION ..........................................................................17 
TABLE OF CONTENTS...............................................................................................................18 
LIST OF IN-TEXT TABLES ........................................................................................................21 
LIST OF IN-TEXT FIGURES.......................................................................................................22 
LIST OF APPENDICES ................................................................................................................23 
LIST OF ABBREVIATIONS ........................................................................................................24 
1. 
INTRODUCTION .................................................................................................................26 
1.1 
BILE ACIDS AND GERD ..........................................................................................26 
1.2 
IW-3718 .......................................................................................................................27 
1.3 
IW-3718 CLINICAL TRIALS IN GERD PATIENTS ...............................................28 
2. 
STUDY OBJECTIVES..........................................................................................................33 
3. 
INVESTIGATIONAL PLAN ................................................................................................34 
3.1 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION....................................34 
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS ..................................................................................................37 
3.3 
SELECTION OF STUDY POPULATION .................................................................37 
3.3.1 
Eligibility Criteria ..............................................................................................37 
3.3.1.1 
Inclusion Criteria......................................................................................37 
3.3.1.2 
Exclusion Criteria ....................................................................................39 
3.3.2 
Screening Failures..............................................................................................41 
3.3.3 
Removal of Patients from Therapy or Assessment ............................................41 
3.3.4 
Replacement Procedures ....................................................................................43 
3.4 
STUDY TREATMENTS .............................................................................................43 
3.4.1 
Investigational Product ......................................................................................43 
3.4.1.1 
IW-3718 ...................................................................................................43 
3.4.1.2 
Placebo .....................................................................................................43 
3.4.1.3 
Rescue Medicine ......................................................................................43 
3.4.1.4 
Treatment Adherence ...............................................................................44 
3.4.2 
Packaging and Labeling .....................................................................................44 
3.4.3 
Storage and Stability ..........................................................................................44 
3.4.4 
Method of Assigning Patients to Treatment Groups..........................................45 
3.4.5 
Selection of Dosage in the Study .......................................................................45 
3.4.6 
Selection and Timing of Dose for Each Patient .................................................46 
3.4.7 
Blinding..............................................................................................................46 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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Page 19 of 105 
3.4.8 
Prior and Concomitant Medications ..................................................................47 
3.4.8.1 
Rescue Medication ...................................................................................47 
3.4.8.2 
Prohibited Medicines ...............................................................................47 
3.4.9 
Diet and Exercise ...............................................................................................48 
3.5 
SAFETY AND EFFICACY ASSESSMENTS............................................................48 
3.5.1 
Adverse Events ..................................................................................................48 
3.5.1.1 
Definitions................................................................................................48 
3.5.1.2 
Procedures for Recording Adverse Events ..............................................49 
3.5.1.3 
Procedures for Collecting and Reporting Serious Adverse Events .........50 
3.5.1.4 
Recording Requirements..........................................................................53 
3.5.1.5 
Termination of Patients from the Study ...................................................55 
3.5.2 
Medical and Disease History .............................................................................56 
3.5.3 
Physical Examination, Body Weight, and Height .............................................56 
3.5.4 
Electrocardiograms ............................................................................................56 
3.5.5 
Vital Signs..........................................................................................................57 
3.5.6 
Clinical Laboratory Determinations...................................................................57 
3.5.7 
Efficacy Assessments.........................................................................................59 
3.5.7.1 
Daily Assessments ...................................................................................59 
3.5.7.2 
Weekly Assessments................................................................................60 
3.5.7.3 
Study Visit Assessments ..........................................................................61 
3.5.8 
Other Assessments .............................................................................................62 
3.5.8.1 
Esophagogastroduodenoscopy .................................................................62 
3.5.8.2 
Bravo™ ....................................................................................................62 
3.6 
SCHEDULE OF EVENTS ..........................................................................................62 
3.6.1 
Screening Period (Day -49 to Day -15) .............................................................63 
3.6.1.1 
Screening Visit (Visit 1) Procedures........................................................63 
3.6.1.2 
Pretreatment Visit (Visit 2) Procedures ...................................................64 
3.6.2 
Treatment Period (Day 1 to Day 57)..................................................................64 
3.6.2.1 
Randomization Visit (Visit 3) Procedures ...............................................64 
3.6.2.2 
Week 4 (Visit 4) Procedures ....................................................................65 
3.6.2.3 
Week 8/End-of-treatment (Visit 5) Procedures .......................................66 
3.6.3 
Follow-up Phone Call ........................................................................................66 
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 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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3.7.4.1 
Primary Efficacy Parameter .....................................................................70 
3.7.4.2 
Key Secondary Efficacy Parameters........................................................71 
3.7.4.3 
Analysis Methods for Primary and Key Secondary Efficacy 
Parameters ................................................................................................71 
3.7.4.4 
Controlling Type-I Error ..........................................................................72 
3.7.4.5 
Sensitivity Analysis of Primary Efficacy Parameter ...............................73 
3.7.4.6 
Handling of Missing Data ........................................................................73 
3.7.4.7 
Exploratory Efficacy Parameters and Analysis Methods ........................73 
3.7.5 
Safety Analyses..................................................................................................75 
3.7.5.1 
Adverse Events ........................................................................................76 
3.7.5.2 
ECGs, Vital Signs, and Clinical Laboratory Tests ..................................76 
3.7.6 
Interim Analysis .................................................................................................76 
3.7.7 
Determination of Sample Size ...........................................................................76 
3.8 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ...78 
4. 
ETHICAL CONSIDERATIONS ...........................................................................................79 
4.1 
INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE..............................79 
4.2 
PATIENT INFORMATION AND INFORMED CONSENT .....................................80 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ............................81 
5.1 
GENERATION OF STUDY RECORDS ....................................................................81 
5.2 
DATA QUALITY ASSURANCE ...............................................................................81 
5.3 
ELECTRONIC CASE REPORT FORMS AND DATA MANAGEMENT ...............82 
5.4 
STUDY MONITORING .............................................................................................82 
6. 
STUDY SPONSORSHIP.......................................................................................................84 
6.1 
INVESTIGATOR AND STUDY TERMINATION ...................................................84 
6.2 
REPORTING AND PUBLICATION ..........................................................................84 
7. 
INVESTIGATOR OBLIGATIONS ......................................................................................85 
7.1 
DOCUMENTATION...................................................................................................85 
7.2 
PERFORMANCE ........................................................................................................87 
7.3 
USE OF INVESTIGATIONAL MATERIALS ...........................................................87 
7.4 
RETENTION AND REVIEW OF RECORDS ...........................................................87 
7.5 
PATIENT CONFIDENTIALITY ................................................................................88 
8. 
REFERENCE LIST ...............................................................................................................89 
9. 
SPONSOR SIGNATURE ......................................................................................................90 
10. INVESTIGATOR SIGNATURE...........................................................................................91 
11. APPENDICES .......................................................................................................................92 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 21 of 105 
LIST OF IN-TEXT TABLES 
Table 1. 
Overall Heartburn and Regurgitation Responders  (Study ICP-3718-202; 
Modified Intent-to-Treat Population).................................................................31 
Table 2. 
Adverse Event Causality ....................................................................................54 
Table 3. 
Clinical Laboratory Tests...................................................................................58 
Table 4. 
Analysis Time Windows for Efficacy Analysis – Daily Assessments ..............69 
Table 5. 
Analysis Time Windows for Efficacy Analysis – Weekly Assessments...........70 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 22 of 105 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Overview of Study Design .................................................................................34 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 23 of 105 
LIST OF APPENDICES 
Appendix 1 
MODIFIED REFLUX SYMPTOM QUESTIONNAIRE ELECTRONIC 
DIARY (mRESQ-eD) ........................................................................................93 
Appendix 2 
OTHER DAILY ASSESSMENTS ....................................................................94 
Appendix 3 
WEEKLY ASSESSMENTS ..............................................................................95 
Appendix 4 
PROHIBITED MEDICATIONS .......................................................................97 
Appendix 5 
LOS ANGELES CLASSIFICATION OF ESOPHAGITIS ..............................99 
Appendix 6 
IN-CLINIC ASSESSMENTS ..........................................................................100 
Appendix 7 
PPI DOSE LEVELS DURING STUDY PARTICIPATION ..........................105 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 24 of 105 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BID 
twice daily 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
CRO 
contract research organization 
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 
EE 
erosive esophagitis 
EGD 
esophagogastroduodenoscopy 
EOT 
End-of-treatment 
EQ 
EuroQol 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
GI 
Gastrointestinal 
H2RA 
histamine-2 receptor antagonist 
HCl 
Hydrochloride 
HS 
heartburn severity 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 25 of 105 
IWRS 
interactive web response system 
LA 
Los Angeles 
LDL-C 
low-density lipoprotein cholesterol 
LSM 
least-square mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
MMRM 
mixed-effects model for repeated measures 
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 
PRO 
patient-reported outcome 
QD 
once daily 
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 
WPAI 
Work Productivity and Activity Impairment Questionnaire 
WRFS 
weekly regurgitation frequency score 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 26 of 105 
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.(1-4) 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) A recent survey using the NIH 
PROMIS® GERD scale found that half of the North American general population reported 
heartburn symptoms in the last week, and one-third reported regurgitation symptoms in the last 
week.(9) GERD is associated with rising healthcare utilization and cost.(10) 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.(11) 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.(12) 
There is significant evidence to support DGER as a putative mechanism for persistent GERD 
(also referred to as refractory 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.(12) 
There is considerable clinical and nonclinical evidence that bile acid can cause esophageal 
damage both in conjunction with stomach acid as well as independently.(2, 5) 
In this study we require all patients to have acid reflux as confirmed by the Bravo™ reflux 
testing system, whereby a capsule that measures pH is inserted into the patient’s esophagus at the 
time of the patient’s screening esophagogastroduodenoscopy (EGD). Using this criterion will 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 27 of 105 
avoid enrolling patients with functional (non-reflux-evident) forms of GERD, who would be less 
responsive to IW-3718 treatment. 
1.2 
IW-3718 
Ironwood is developing IW-3718 as an adjunct to PPI therapy for treatment of persistent GERD 
(also referred to as refractory GERD) in patients whose heartburn and regurgitation symptoms 
are not resolved with PPI therapy alone. IW-3718 is a sustained-release engineered form of 
colesevelam hydrochloride (henceforth referred to as colesevelam), a bile acid sequestrant.  
IW-3718 tablets are formulated as an extended-release, solid, oral-dosage form intended to 
extend the release of colesevelam into the stomach. As a result of the sustained release, 
colesevelam binds to the 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. Subsequently the bile acid-colesevelam complex will travel down the GI tract and be 
excreted without being absorbed. 
The extended-release formulation in IW-3718 tablets is based on Assertio’s Acuform® 
technology which utilizes swelling polymers to allow the tablet to be retained in the stomach for 
up to 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 released in the stomach and upper GI tract in a near zero-order manner. It’s theorized 
that the resulting sustained levels of colesevelam in the stomach will prevent bile acids from 
refluxing into the esophagus. The Acuform technology is well-characterized, and currently 
utilized in several Food and Drug Administration (FDA)-approved drugs such as Glumetza® 
(metformin HCl, extended release), Proquin® XR (ciprofloxacin HCl monohydrate, extended 
release), and Gralise™ once-daily (gabapentin) tablets. 
Colesevelam is an orally administered, non-absorbed, non-digestible polymer that binds bile 
acids in the GI tract. Colesevelam was initially approved in 2000 in the United States (US) as the 
active ingredient in Welchol™ and indicated 1) as an adjunct to diet and exercise for reduction 
of elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia 
(as monotherapy or in combination with statin therapy), 2) to reduce LDL-C levels in boys and 
postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia as 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
Confidential 
Page 28 of 105 
monotherapy or in combination with a statin after failing an adequate trial of diet therapy, and 3) 
to improve glycemic control in adults with type 2 diabetes mellitus. Colesevelam is currently 
available as an immediate-release formulation only for these indications. Colesevelam has also 
been approved for use in the EU as Cholestagel® (2004) and in Canada as Lodalis™ (2011). 
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. 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. 
Apart from the IW-3718 development program, 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). 
1.3 
IW-3718 CLINICAL TRIALS IN GERD PATIENTS 
IW-3718 has been evaluated in 2 clinical trials in patients with continuing GERD symptoms 
despite their PPI treatment.  
ICP-3718-201 was a 4-week, randomized, double-blind, placebo-controlled, proof-of-concept, 
Phase 2a 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. 
Esophagogastroduodenoscopy 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 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
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assessed over the four-week period to determine severity of heartburn-related symptoms. A 
BilitecTM device was used as an optional procedure for measuring bile reflux. 
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%). 
ICP-3718-202 was an 8-week, randomized, double-blind, placebo-controlled, dose-ranging, 
Phase 2b study in patients with continued GERD symptoms despite ongoing per-label QD PPI 
therapy. Patients were randomized in a 1:1:1:1 fashion to receive either IW-3718 500 mg,  
1000 mg, or 1500 mg, or placebo twice daily while continuing their per-label QD PPI therapy. 
EGD and approximately 48 to 96 hours of pH monitoring (using the Bravo device) were required 
at Screening. Patients who either had significant acid regurgitation (pH<4 for ≥4.2 % of a 24-
hour period) or esophageal erosion noted during the EGD were eligible for randomization. 
Randomization to double-blind treatment was stratified by whether patients had, or did not have, 
erosive esophagitis on the screening EGD. Bilitec monitoring of bilirubin levels was optional for 
all patients at selected sites. 
Patients who completed screening entered the 14- to 21-day Pretreatment Period to promote 
patient familiarity and compliance with study procedures and to establish baseline patient-
reported outcomes for the assessment of efficacy following treatment. Patients were instructed to 
take their PPI approximately 30-60 minutes before breakfast each day, even on study visit days. 
GERD symptoms were assessed daily using a modified version of the Reflux Symptom 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
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Questionnaire Electronic Diary (mRESQ-eD). Patients who satisfied all of the entry criteria 
during the Pretreatment Period entered the 8-week Treatment Period. The primary endpoint was 
percent change from baseline to Week 8 in 6-point heartburn severity score (0=none, 5=severe). 
Secondary endpoints included percent change from baseline in heartburn severity score and 5-
point regurgitation frequency score (0=never, 4=very often) by week, and overall heartburn 
responders and overall regurgitation responders. Responder criteria required at least a 30% 
decrease from baseline in weekly heartburn score (or regurgitation score) for at least 4 of 8 
treatment weeks, including ≥1 of the 2 final weeks. 
A total of 282 patient were randomized. The modified ITT Population included 280 patients (68-
71 patients per treatment arm), approximately half (52%) of whom had EGD confirmation of 
erosive esophagitis (EE) at baseline (52%). Demographics and baseline characteristics were 
generally similar across the treatment groups. For the primary endpoint, dose-dependent 
improvements were observed in Week-8 heartburn severity scores; percent changes from 
baseline were -46.0, -49.0, -55.1, and -58.0 for the placebo, IW-3718 500 mg, 1000 mg, and 
1500 mg treatment groups, respectively (dose-response test nominal p-value = 0.02). The 
treatment difference for the IW-3718 1500 mg group compared with placebo was -11.9 (nominal 
p-value = 0.04). Week-8 percent change from baseline in regurgitation frequency score was 
significantly better for the IW-3718 1500 mg group (-55.4) compared with placebo (-37.9) 
(difference -17.5; nominal p-value = 0.01). Numerical gains were seen at each week of treatment 
starting at Week 2 for heartburn severity for the IW-3718 1500 mg group versus placebo. Greater 
weekly improvements were seen at this dose in EE patients. Overall responder rates for 
heartburn and regurgitation were 52.9% and 46.3% for the IW-3718 1500 mg group compared 
with 37.1% and 34.3% for the placebo group, respectively; greater improvements compared with 
placebo were seen in EE patients (Table 1). Note that although a 30% reduction was defined in 
the protocol as being the criterion for a weekly improvement in WHSS and WRFS, pre- and 
post-hoc pooled anchor-based analyses suggested that a 45% reduction is better at defining a 
clinically significant response to treatment. 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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Table 1. 
Overall Heartburn and Regurgitation Responders  
(Study ICP-3718-202; Modified Intent-to-Treat Population) 
 
% Responders 
 
 
 
IW-3718 
 
Parameter 
 Placebo 
w/ PPI 
500 mg 
w/PPI 
1000 mg 
w/PPI 
1500 mg  
w/ PPI 
Treatment 
Difference1 
Heartburn   
 
 
 
 
 
≥ 30% Responder  
 
 
 
 
 
All patients (N=280)  
54.3 
52.1 
62.0 
66.2 
11.9 
EE patients (N=145)  
47.2 
50.0 
59.5 
69.4 
22.2 
≥ 45% Responder  
 
 
 
 
 
All patients (N=280)  
37.1 
43.7 
42.3 
52.9 
15.8 
EE patients (N=145)  
30.6 
41.7 
32.4 
50.0 
19.4 
 
 
 
 
 
 
Regurgitation2   
 
 
 
 
 
≥ 30% Responder  
 
 
 
 
 
All patients (N=277)  
42.9 
55.7 
64.3 
64.2 
21.3 
EE patients (N=142)  
36.1 
54.3 
58.3 
62.9 
26.7 
≥ 45% Responder  
 
 
 
 
 
All patients (N=277)  
34.3 
38.6 
37.1 
46.3 
12.0 
EE patients (N=142)  
27.8 
40,0 
27.8 
42.9 
15.1 
EE=erosive esophagitis; PPI=proton pump inhibitor 
1. IW-3718 1500 mg compared with placebo 
2. Patients with no regurgitation at baseline were excluded.  
 
IW-3718 was well tolerated in patients with persistent GERD at twice-daily doses of 500 mg, 
1000 mg, and 1500 mg. The most common TEAEs occurring in >5% of IW-3718 patients 
overall were constipation (8.1% of IW-3718 patients and 7.1% of placebo patients), nausea 
(6.2% of IW-3718 patients and 2.9% of placebo patients), and flatulence (5.7% of IW-3718 
patients and 4.3% of placebo patients). There were 6 total SAEs (2 patients each in the placebo 
and 1500 mg IW-3718 groups, and 1 patient each in the IW-3718 500 mg and IW-3718 1000 mg 
groups) - all SAEs were assessed by the Investigator as unrelated to study treatment. Ten patients 
discontinued the study due to TEAEs, 3 patients each in the placebo, IW-3718 1000 mg, and 
IW-3718 1500 mg groups, and 1 patient in the IW-3718 500 mg group. No clinically significant 
changes were attributable to treatment with any of the IW-3718 treatment groups for any 
hematology, clinical chemistry, coagulation, urinalysis, vital signs, or ECG parameters, other 
than reduced total cholesterol and LDL-C, which is consistent with the known pharmacologic 
effects of colesevelam. 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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Based on the results of the ICP-3718-202 study, a twice-daily dose of 1500 mg IW-3718 was 
selected for further investigation in 2 Phase 3 trials. 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to evaluate the safety and efficacy of IW-3718 administered to 
patients with GERD who continue to have persistent symptoms, such as heartburn and 
regurgitation, while receiving once-daily (QD), standard-dose PPIs. 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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3. 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION 
The study consists of three distinct periods as illustrated in the figure below. The study will 
enroll patients whose heartburn and regurgitation symptoms are not resolved with once-daily 
(QD) PPI therapy alone. Eligible patients will continue to take their PPI and will be randomized 
to placebo or to 1500 mg IW-3718 BID.  
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 meals each day. 
Screening Period:  The Screening Period starts with the signature of the informed consent form 
(ICF) and may last for up to 35 days. During this period, patient eligibility for entry into the 
* This visit represents the end of the study
EE = erosive esophagitis; EGD=esophagogastroduodenoscopy; EOT=end of treatment; SD PPI = standard dose proton pump inhibitor
Screening
Period
Pretreatment
Period
Treatment Period
Day 1 to Day 57
14 to 21 days
Up to 35 days
Screening
Visit
(Day -56 to
Pretreatment
Visit)
Pretreatment
Visit
(Day -21 to
Day -14)
Randomization
Visit
(Day 1)
Week 4 Visit
(Day 29 ± 3)
Week 8 / 
EOT
Visit*
(Day 57 +3)
SD PPI
Note:  There is no Day 0
EGD & Bravo 
(≥7d prior to 
Pretreatment
Visit)
1500 mg IW-3718 twice daily 
Placebo twice daily
Stratify by 
EE Status
EGD for EE pts 
Study Drug Treatment (+ SD PPI)
Follow
-up
7 days
Safety
Phone
Call
(EOT +7d)
SD PPI
Stratified by 
EE Status 
(present, not present) + 
baseline WHSS (<3, ≥3)
; WHSS = Weekly Heartburn Severity Score


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
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Pretreatment Period will be determined. Two procedures will be required during the Screening 
Period in all patients (all will be done while patients continue to take their PPI):  
• An esophagogastroduodenoscopy (EGD)  
• Up to 96 hours of pH testing with the Bravo device, a capsule-based pH monitor 
implanted above the lower esophageal sphincter (LES)  
The patient must have been adherent to their standard PPI dosage regimen (as per product label) 
for the 8 weeks prior to the Screening Visit and during the entire Screening Period. Histamine-2 
receptor antagonists (H2RAs) should be stopped at least 5 days prior to the EGD and Bravo pH 
monitoring; antacids should be stopped at least 1 day prior to the EGD and Bravo pH 
monitoring. The EGD must be performed during the Screening Period and should be performed 
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 use antacids if needed until 1 day 
prior to entering the Pretreatment Period. The end of the Screening Period coincides with the 
start of the Pretreatment Period. 
Pretreatment Period:  The Pretreatment Period is defined as the 14 to 21 days immediately 
before the Randomization Visit. Patients who meet all eligibility criteria, including pH 
requirements as per the central pH read, will continue into the Pretreatment Period. 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 liquid antacid that is dispensed as 
rescue medicine (aluminum hydroxide / magnesium hydroxide). Patients will provide the 
following daily and weekly symptom assessments using a handheld electronic diary (eDiary): 
Daily Assessments 
• GERD symptoms, recorded in the evening before going to bed, using the modified 
Reflux Symptom Questionnaire Electronic Diary (mRESQ-eD; Appendix 1) 
• Use of per-protocol rescue medicine, recorded in the evening before going to bed 
• Sleep disturbance due to GERD symptoms, recorded upon getting up in the morning 
(Appendix 2) 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
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Weekly Assessments  
• Degree of relief of GERD symptoms (Appendix 3) 
• GERD symptom bothersomeness (Appendix 3) 
Patients will be required to complete the daily assessments for at least 5 days each week during 
the last 14 days before the Randomization Visit and the weekly assessments at least once during 
the last 7 days before the Randomization Visit in order to be eligible for randomization. 
Patients will be instructed to take their PPI approximately 30-60 minutes before breakfast each 
day, even on study visit days. Patients who satisfy 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, EE on the screening 
EGD, and by their baseline weekly heartburn severity score (WHSS, defined as the average 
heartburn severity score over the last 7 days prior to randomization of <3 vs. ≥3; see 
Section 3.5.7.1) and randomly assigned within each stratum to placebo or 1500-mg IW-3718 
BID (1:1). Dose reductions are not permitted. The treatment randomization schedule will be 
managed by a central vendor. Enrollment will be monitored to ensure that no single center 
contributes > 10% 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, assessment of sleep 
disturbance), weekly assessments (degree of relief of GERD symptoms, symptom 
bothersomeness, and treatment satisfaction questions). At the end of the treatment period study 
medication will be discontinued and patients will return for an End-of-Treatment visit. A repeat 
EGD will be performed at the Week 8/EOT Visit for all patients who have completed at least 
4 weeks of treatment and had erosive esophagitis on the screening EGD (based on the Los 
Angeles [LA] classification of esophagitis, see Appendix 5) as determined by either the site 
personnel or the central reader. Patients will also complete all End-of-Treatment assessments. 
For details regarding the assessments during each study period, see the Schedule of Evaluations 
in the protocol synopsis. 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS 
A double-blind, placebo-controlled, parallel-group, multicenter 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), 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 test therapy 
and to familiarize patients with data collection methodology (ie, 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 
The study population will consist of adult patients with diagnosed GERD whose heartburn and 
regurgitation symptoms are not resolved with once-daily (QD) PPI therapy alone and have 
evidence of acid reflux during the Screening Period as determined using the Bravo device. 
Patients will be stratified for treatment assignment at the time of randomization based on the 
presence of esophageal erosions (erosions, no erosions) and by baseline WHSS (<3 vs. ≥3). The 
study will aim to enroll up to 50% of patients with esophageal erosions. Patients must be 
receiving 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 labelling. Approximately 660 patients (330 patients per treatment arm) 
will be randomized to treatment. 
3.3.1 
Eligibility Criteria 
3.3.1.1 
Inclusion Criteria 
Each patient must meet all the following criteria to be eligible for enrollment in this study: 
1. 
Patient has signed an ICF before any study-specific procedures are performed. 
2. 
Patient is an ambulatory male or female (if female, nonpregnant) and is at least 18 years old 
at the Screening Visit.  


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
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3. 
Patient has a diagnosis of GERD and reports experiencing GERD symptoms (heartburn or 
regurgitation) on average ≥ 4 days per week over the last 8 weeks before the Screening 
Visit. 
4. 
Patient has been receiving 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 (see 
Appendix 7). Patients who have their PPI modified during the Screening Period may be re-
screened after 8 weeks of standard-labeled dose, QD, PPI therapy provided they have not 
previously entered the Pretreatment Period. 
5. 
Up to 96 hours of pH monitoring (with a Bravo device) during the Screening Period (while 
the patient continues taking their PPI) demonstrates 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 as confirmed by centralized review of pH monitoring. 
6. 
During the last 7 days before randomization patient reports an average heartburn severity 
(HS, maximum of Items #1 and #2 on mRESQ-eD) of ≥ 2 (mild) and has a daily HS ≥ 3 
(moderate) for at least 2 of those days. 
7. 
Female patients must be postmenopausal for ≥1 year, surgically sterile (ie, bilateral 
oophorectomy, hysterectomy, or tubal sterilization [tie, clip, band, or burn]); or must agree 
to completely abstain from heterosexual intercourse; or, if heterosexually active, must agree 
to use 1 of the following methods of birth control from the date she signs the ICF until 24 
hours after their final dose of study drug: 
a. Progesterone implant or an intrauterine device (IUD) 
b. Combination of 2 highly effective birth control methods (eg, diaphragm with spermicide 
plus a condom, condom with spermicide plus a diaphragm or cervical cap, hormonal 
contraceptive [eg, oral and transdermal patch] plus a barrier method, partner with 
vasectomy [conducted ≥60 days before the Screening Visit or confirmed via sperm 
analysis] plus a hormone or barrier method). 
8. 
Females of childbearing potential must have a negative urine or serum pregnancy test at the 
Screening Visit and at the Randomization Visit prior to dosing. Positive urine test results 
will be confirmed by a serum pregnancy test. 
9. 
Patient agrees not to make any changes to their usual diet or exercise regimen during the 
study 
10. Patient is able to successfully use the eDiary, and has adequately completed the eDiary 
questions on at least 5 days each week and the weekly questions at least once during the 14 
days before the start of the Treatment Period. 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
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11. Patient is compliant with QD PPI dosing during the 14 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 at least one of the languages to be used for PRO assessments. 
13. 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. 
2. 
Patient reports epigastric pain or epigastric burning as his or her predominant symptom at 
the Screening Visit. 
3. 
Patient has a diagnosis of gastroparesis per gastric emptying study, or a history of bowel 
obstruction, or is at risk for a bowel obstruction (eg, patient has an organic gastrointestinal 
[GI] motility disorders or a history of major GI surgery).  
4. 
Patient has a history of serum triglyceride concentrations > 500 mg/dL on a fasting 
specimen, or has serum triglyceride 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; eg, the patient has osteoporosis or osteomalacia) and will 
be put at risk by receiving colesevelam for 8 weeks. 
7. 
Patient has an active swallowing disorder that would compromise their ability to swallow 
the study medication.  
8. 
Patient has any alarm symptoms including, but not limited to, GI bleeding, anemia, 
vomiting, or unexpected weight loss at 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, or minor oral or rectal surgery (eg, 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 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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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. Patient has large (>5 cm) hiatal hernia. 
12. 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.  
13. Patient has Gilbert’s disease, Crohn’s disease, diabetes mellitus (defined as A1C >6.5%), 
Zollinger-Ellison syndrome, pancreatitis, cholecystitis, or systemic sclerosis. 
14. Patient has elevated (defined as > 1.5 times the upper limit of normal by the laboratory) 
levels of serum bilirubin at Screening. 
15. Patient has a history of clinically significant hypersensitivity or allergies to any of the 
excipients contained in the study medication (active or placebo).  
16. 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. 
17. Patient has active substance abuse or history of chronic substance abuse (including 
alcoholism but not including nicotine) within 12 months before the Screening Visit or is 
positive for any of the following at the Screening Visit unless legally prescribed for 
anything but gastrointestinal pain:  amphetamines, benzodiazepines, opiates, barbiturates, 
cocaine, or phencyclidine. 
Note:  Marijuana use, whether prescribed or not, is prohibited from 30 days before 
screening through the duration of the study. Use of illicit drugs is not allowed during the 
study. 
18. 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, 


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Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
 
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could represent a safety concern if the patient participates in the study, or could confound 
the study-specified assessments of safety or efficacy.)  
19. 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. 
20. 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.  
21. 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. 
22. Patient has previously entered the Treatment Period of an IW-3718 study. 
23. Patient has previously entered the Pretreatment Period of this study. (Note: patients who 
failed the Pretreatment Period due to abnormal laboratory findings or timing issues may be 
re-screened.) 
24. 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 
Screening Failures 
For all patients who are ineligible to participate in the trial, the reason for their screening failure 
will be recorded in the eCRF. Reasons for screening failure are as follows: 
• Inclusion/Exclusion not met (specify) 
• Protocol violation  
• Withdrawal of consent  
• Adverse event  
• Lost to follow up  
• Other (specify) 
3.3.3 
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. 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
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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: 
• Adverse event(s) 
• Non-compliance with study drug 
• Protocol violation 
• Withdrawal of consent 
• Symptomatic deterioration  
• Lost to follow-up  
(Note: every effort must be made to contact the patient; a certified letter must be sent.) 
• Study termination by the Sponsor 
• Physician decision 
• Randomized in error 
• Other reasons  
 
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). Randomized 
patients who discontinue from the study for any reason should complete the assessments required 
at the EOT Visit at the time of their discontinuation. 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. 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
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3.3.4 
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 light blue-green, 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 hydroxytoluene, 
magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, FD&C Blue 
#1, and iron oxide yellow. Tablets should be taken whole and never broken, crushed, or chewed.  
Patients randomized to receive IW-3718 will self-administer the three 500 mg IW-3718 tablets 
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 light blue-green, oval shaped, 
film-coated, oral tablets containing microcrystalline cellulose, polyethylene oxide, colloidal 
silicon oxide, butylated hydroxytoluene, magnesium stearate, polyvinyl alcohol, polyethylene 
glycol, titanium dioxide, talc, FD&C Blue #1, and iron oxide yellow. Tablets should be taken 
whole and never broken, crushed, or chewed. 
Patients randomized to receive placebo will self-administer the three placebo tablets BID 
immediately after the morning and evening meals. 
3.4.1.3 
Rescue Medicine 
Antacid rescue medicine will be provided to patients as a bottled liquid (magnesium hydroxide 
200 mg/aluminum hydroxide 200 mg per 5 mL). 
During completion of the nighttime eDiary questions, patients will be asked about their rescue 
medicine use by responding to the following questions: 


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• “How many times did you use your rescue medicine (liquid antacid) during the past 24 
hours?” 
 
3.4.1.4 
Treatment Adherence 
Patients will be dispensed the appropriate number of Sponsor-packaged, labeled bottles 
containing 210 tablets needed until the next study visit (see Section 3.6). Patients will be asked to 
return all bottles (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 210-count 
bottles. Study medication will be uniquely numbered and labeled in a double-blind fashion that 
conforms to regulatory requirements. 
3.4.3 
Storage and Stability 
IW-3718 tablets and matching placebo will be shipped at controlled room temperature between 
15°C and 25°C (59°F and 77°F) and must be stored at room temperature between 20°C and 25°C 
(68°F and 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°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. 
Antacid rescue medicine (aluminum hydroxide / magnesium hydroxide liquid) will be supplied 
by the clinical sites and stored in accordance with the manufacturer’s instructions.  


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3.4.4 
Method of Assigning Patients to Treatment Groups 
Eligible patients will be stratified by whether they have or do not have erosive esophagitis on the 
screening EGD, and by their baseline WHSS (<3 vs. ≥3), and then randomized through central 
randomization in a 1:1 ratio to receive either 1500 mg IW-3718 BID or placebo BID, both 
administered in addition to the patient’s per-label QD PPI therapy. 
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, an oral dose of 1500 mg IW-3718 BID (total daily dose of 3000 mg/day) 
given as an adjunct to QD PPI for 56 days, will be studied to evaluate the safety and efficacy of 
IW-3718 in a placebo-controlled study. Dose reductions are not permitted. This dose was 
selected for Phase 3 evaluation based on the results of Phase 2b Study ICP-3718-202. In that 
dose-ranging study, which evaluated IW-3718 doses of 500 mg, 1000 mg, and 1500 mg BID 
compared with placebo, dose-dependent improvement compared with placebo was observed for 
the primary endpoint, percent change from baseline in heartburn severity at Week 8. The 1500 
mg dose showed an improvement in heartburn severity from baseline of -58.0 compared with a 
placebo improvement of -46.0 (nominal p-value = 0.04).  Percent change from baseline in 
regurgitation frequency score at Week 8 was also significantly improved for IW-3718 1500 mg 
(-55.4) versus placebo (-37.9) (nominal p=0.01). Additional improvement for IW-3718 1500 mg 
relative to the IW-3718 500 mg and 1000 mg doses when compared with placebo were noted for 
other endpoints, including the heartburn and regurgitation responder endpoints; greater 
improvement was also noted for the IW-3718 1500 mg dose group within the EE subpopulation. 
IW-3718 1500 mg was generally well-tolerated in Study ICP-3718-202. The incidence of TEAEs 
for the IW-3718 1500 mg group (44.1%) was comparable to the overall IW-3718 incidence 
(46.2%) and to placebo (41.4%). There was a dose-related trend in the incidence of patients who 
had nausea (2.9%, 4.2%, 5.6%, and 8.8% of patients in the placebo, 500-mg, 1000-mg, and 
1500-mg IW-3718 groups, respectively). Otherwise, no dose-related trends were noted for any 
TEAEs. 


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3.4.6 
Selection and Timing of Dose for Each Patient 
Patients will be randomized to receive 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. 
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 (ie, Day -21 through Day 57 [+ 3 days]). The PPI will be taken each day, 
approximately 30-60 minutes before breakfast. 
During completion of the daily eDiary 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 (ie, 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, 


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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. 
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 a PPI 
• Most recent use of an H2RA  
• Most recent use of an antacid  
 
Any medication/procedure taken/undergone by a patient during the study (beginning at the 
Screening Visit through the Follow-up Phone Call), including any new medications/procedures 
added or changes in medications/procedures previously reported, and the reason for its use will 
be documented in the source documents and collected in the EDC system. 
3.4.8.1 
Rescue Medication 
During the Pretreatment and Treatment Periods, patients may use dispensed, protocol-permitted 
liquid 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. 


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3.4.9 
Diet and Exercise 
Per the inclusion criteria, patients must agree not to make any changes to their usual diet or 
exercise regimen during the study. 
3.5 
SAFETY AND EFFICACY ASSESSMENTS 
Safety will be evaluated by adverse event (AE) reports (discussed herein), standard clinical 
laboratory assessments, vital signs, physical examinations, medical history, and ECGs. The 
timing of safety and efficacy assessments is presented in Section 3.6. 
3.5.1 
Adverse Events 
3.5.1.1 
Definitions 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug-related. 
An AE, therefore, can be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
Serious Adverse Event 
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
• Death 
• Life-threatening experience: An AE is considered "life-threatening" if, in the view of 
either the Investigator or Sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an AE that, had occurred in a more severe 
form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization: AEs requiring 
hospital admissions that are less than 24 hours in duration do not meet this criterion. A 


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scheduled hospitalization for a preexisting condition that has not worsened during 
participation in the study does not meet this criterion. Preplanned hospitalizations for an 
elective medical/surgical procedure or routine check-ups do not meet this criterion. 
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly or birth defect 
• Is considered an important medical event: Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
Treatment-emergent Adverse Event 
A treatment-emergent AE (TEAE) is an event that emerges, or a preexisting event that worsens, 
any time after administration of the first dose of study drug (Day 1). 
3.5.1.2 
Procedures for Recording Adverse Events 
The Investigator will record all AEs from the time informed consent is obtained until completion 
of the Follow-up Phone Call. At each study visit, the Investigator will inquire about the 
occurrence of AE/SAEs since the last visit. 
The occurrence of an AE or SAE may come to the attention of site personnel during study visits 
and interviews of a study subject presenting for medical care, or upon review by a study monitor. 
All AEs including SAEs will be captured on the appropriate eCRF. Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to study 
product and to PPI (assessed only by those with the training and authority to make a diagnosis), 
and time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All SAEs will be followed to adequate 
resolution or stabilization for up to a maximum of 30 days after last dose. 


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Any medical condition that is present when a subject is screened and does not deteriorate 
(worsen in severity and/or frequency) should be recorded as Medical History and not as an AE. 
However, if the study subject’s condition deteriorates at any time during the study, it will be 
recorded as an AE. AEs characterized as intermittent require documentation of onset and 
duration of each episode. 
Pretreatment AEs will be collected and captured in the subject’s source documentation from the 
time the subject signs the ICF until the subject receives study drug. Pretreatment AEs in 
randomized patients will additionally be entered 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 subject’s eCRF 
only if the Investigator considers them clinically significant and/or they necessitate intervention. 
3.5.1.3 
Procedures for Collecting and Reporting Serious Adverse Events 
The Investigator or designee is to report any SAE to Ironwood Pharmacovigilance within 24 
hours of becoming aware of the event that occurred during the reporting period. 
All SAEs will be submitted using the safety reporting tool within the EDC system. The SAE 
report file will be generated and be available for download once the SAE is submitted by the 
investigator or designee via the EDC system.  The investigator or designee will send by email the 
SAE report file as an attachment to Ironwood Pharmacovigilance.  The system will prompt the 
Investigator or designee to provide as much information as possible, including the following: 
• SAE term 
• Serious criteria 
• Severity 
• Causality assessment to study drug and to PPI 
• Action taken with study drug 
• Narrative explaining the context of the SAE outcome 
 


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If all SAE information is not available at the time of the initial report, follow-up SAE reports will 
be completed and submitted within the same reporting timelines as initial reports using the EDC 
system. If the EDC system is not available, the Investigator or designee will complete the hard-
copy SAE form, including all of the required information noted above. The completed form 
should then be provided to the Sponsor using the contact information below: 
Ironwood Pharmacovigilance Contact Information 
 
 
 
 
The Investigator or designee should receive confirmation from Ironwood that the SAE 
information (via EDC or hard-copy form) was received within 24 hours after its submission.  In 
the event this receipt confirmation is not received, the Investigator or designee will alert 
Ironwood Pharmacovigilance. 
The Investigator is required to follow SAEs until resolution or stabilization for up to a maximum 
of 30 days after last dose. Resolution is defined as: 
• Resolved with or without residual effects (sequelae) 
• A return to baseline for a preexisting condition 
• The Investigator does not expect any further improvement or worsening of the event 
• Fatal outcome: If an autopsy is performed on a deceased subject, the autopsy report and 
death certificate must be provided to Ironwood as soon as it is available. 
 
3.5.1.3.1 
Reporting of SAEs to the IRB 
The Investigator will receive prompt notification of SAEs, with the use of the study product, that 
are both unexpected and related, or any finding that suggests a significant risk for patients. The 
Investigator will promptly inform the IRB of the notification and insert the notification in the 
Investigator’s Regulatory Binder in accordance with local regulations. 
All applicable expedited safety reports will be forwarded, by Ironwood, to the Investigator. 


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The Investigator will inform Ironwood of any local regulatory or IRB requirements not covered 
by the procedures in this or the prior section. 
3.5.1.3.2 
Reporting of Pregnancy 
Any female patient who becomes pregnant while participating in the study will be withdrawn 
from the study. 
Information on any pregnancies in female patients, or the female partner of a male patient, will 
be collected from the Screening Visit until the completion of the Follow-up Phone Call. 
If the patient or the female partner of a male patient becomes pregnant after receiving study drug 
during the study, the Investigator will collect and record the pregnancy information on the 
Pregnancy Reporting Form and submit it via fax or e-mail to Ironwood Pharmacovigilance 
within 24 hours of learning of the pregnancy. (Note: If the female partner of a male patient 
becomes pregnant, the Investigator must attempt to obtain consent to collect pregnancy 
information [including status of the newborn, if applicable] before reporting information to 
Ironwood). If not all information on the Pregnancy Reporting Form is available at the time of the 
initial report, follow-up Pregnancy Reporting Forms will be completed and submitted via fax or 
e-mail to Ironwood Pharmacovigilance within 24 hours of becoming aware of new information. 
The Investigator is required to attempt follow-up on the pregnancy until the completion of the 
pregnancy. Information on the status of the mother and newborn will be forwarded to Ironwood 
within 24 hours of the Investigator becoming aware. Generally, follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be an SAE and reported as such. A 
spontaneous abortion is always considered to be an SAE and will be reported as such. 
Furthermore, any SAE occurring as a result of a post-study pregnancy and considered reasonably 
related to the investigational product by the Investigator, will be reported to Ironwood as 
described in Section 3.5.1.3. While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 


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3.5.1.4 
Recording Requirements 
Severity 
The Investigator or delegated physician will provide an assessment of the severity of each AE by 
recording a severity rating in the patient’s source documentation and on the AE page of the 
patient’s eCRF. Severity, which is a description of the intensity of manifestation of the AE, is 
distinct from seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality. Severity will be assessed according to the 
following scale: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant. 
Severe: 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
AEs should be recorded using the maximum intensity of the event (eg, if a patient reported 
nausea lasting 3 days, one start date and stop date should be recorded along with the maximum 
intensity experienced for that event over that 3-day timeframe). 
Relationship to Study Drug and to PPI 
The Investigator must assess the relationship of each AE (including SAEs) to the use of study 
drug or to ongoing PPI therapy using a 2-category scale (not related or related) based on clinical 
judgment and using all available information, and may include consideration of the following 
factors: 


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• Possible alternative causes of the AE, including the disease under treatment, preexisting 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors 
• The temporal association between study drug/PPI exposure and onset of the AE 
• Whether the manifestations of the AE are consistent with known actions or toxicity of 
the investigational product or PPI 
• Whether the AE resolved or improved with stopping use of the study drug; judgment 
should be used if multiple products are discontinued at the same time 
 
The causality assessment must be recorded in the patient’s source documentation and on the AE 
page of the patient’s CRF. The causal relationship between study drug and the AE will be 
assessed using the categories shown in Table 2. 
Table 2. 
Adverse Event Causality 
Category 
Definition 
Not related 
An AE is not associated with study medication or PPI if: 
- 
Lack of a temporal relationship to study drug administration makes a causal 
relationship improbable (eg, the event did not occur within a reasonable time frame 
following administration of the study medication); and/or 
- 
Other causative factor(s) (eg, a preexisting clinical condition, other concomitant 
treatments) more likely explain the occurrence of the event, and 
- 
The event did not improve with stopping of the investigational product, and/or 
- 
The event did not recur upon re-exposure with investigational product 
Related 
An AE is attributed to the study medication or PPI if: 
- 
A temporal relationship to study drug administration makes a causal relationship 
plausible (eg, the event occurred within a reasonable time frame following 
administration of study medication); and/or 
- 
Other causative factor(s) (eg, the patient’s clinical condition, other concomitant 
treatments) either do not explain the event or are less equally likely to have led to 
the occurrence of the event, or 
- 
The event improved with stopping of the investigational product, and/or 
- 
The event recurred upon re-exposure with investigational product 
 


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Laboratory Abnormalities 
The Investigator will review clinical laboratory values for significance and consideration as an 
AE. All the following laboratory abnormalities should be captured as AEs: 
• Any laboratory test result that meets criteria for an SAE 
• Any laboratory abnormality that results in study discontinuation 
• Any laboratory abnormality that requires the patient to receive specific corrective 
therapy 
• Any laboratory abnormality that the Investigator considers to be clinically significant 
 
Ongoing abnormal laboratory values/conditions that are being treated at baseline will be captured 
as an AE if the condition increases in severity and/or frequency during the study or if the 
condition requires more frequent treatment. If a patient is treated for an abnormal laboratory 
value just before the Screening Visit, then the medical history should reflect the severity of the 
condition before treatment. 
3.5.1.5 
Termination of Patients from the Study 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The Investigator will make reasonable efforts to 
keep each patient in the study. However, if the Investigator removes a patient from the study or if 
the patient declines further participation, the evaluations required at the Week 8/EOT Visit 
should be performed, if possible. All evaluations and observations, together with the description 
of the reason(s) for study withdrawal, must be recorded in the patient’s source documentation 
and subsequently on the appropriate page of the patient’s eCRF. The reasons for patient 
withdrawal from the study are provided in Section 3.3.3.  
An effort must be made to determine why a patient fails to return or is dropped from the study. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up should be recorded in source documents and reported where 
applicable on the eCRF. All reasons for discontinuation of treatment should be documented. 


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If a patient cannot be reached at the end of the trial for the Safety Phone Call, the site should 
make every effort to contact the patient, including sending a certified letter. In every case, the 
patient outcome, including lost to follow-up information, will be documented. 
3.5.2 
Medical and Disease History 
A complete medical and disease history will be obtained as defined in the Schedule of 
Evaluations within the protocol synopsis. 
3.5.3 
Physical Examination, Body Weight, and Height 
A physical examination will be obtained as defined in the Schedule of Evaluations. 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 
Skin 
Lymph nodes 
Mental status 
Neurologic 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. 
3.5.4 
Electrocardiograms 
A 12-lead ECG will be performed as defined in the Schedule of Evaluations within the protocol 
synopsis and documented on the eCRF. Electrocardiograms should be obtained after the patient 
has been supine for at least 5 minutes. 


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3.5.5 
Vital Signs 
Vital signs will be collected at the visits defined in the Schedule of Evaluations within the 
protocol synopsis. Respiratory rate, pulse, and BP readings will be taken after the patient has 
been seated for at least 5 minutes. 
3.5.6 
Clinical Laboratory Determinations 
Blood and urine samples for clinical laboratory tests will be collected at the visits defined in the 
Schedule of Evaluations within the protocol synopsis. The clinical laboratory evaluations will 
include the clinical chemistry, hematology, coagulation, and urinalysis parameters presented in 
Table 3. 
 


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Table 3. 
Clinical Laboratory Tests 
Clinical Chemistry 
Hematology (CBC) 
Complete Urinalysis 
Albumin 
Hematocrit 
pH and specific gravity 
Alkaline phosphatase 
Hemoglobin 
Bilirubin 
ALT 
Platelet count 
Glucose 
AST 
MPV 
Ketones 
Bicarbonate 
RBC count 
Leukocytes 
BUN 
WBC count 
Nitrites 
Calcium 
WBC differential 
Occult blood 
Chloride 
(% and absolute) 
Protein 
Total cholesterol 
Basophils 
Urobilinogen 
HDL cholesterol 
Eosinophils 
 
LDL cholesterol  
Lymphocytes 
 
Creatinine 
Monocytes 
 
GGT 
Neutrophils 
 
Glucose 
RBC indices 
 
HbA1C 
MCH 
 
Iron 
MCHC 
 
LDH 
MCV 
 
Magnesium 
RDW 
 
Phosphorus 
Coagulation 
 
Potassium 
aPTT 
 
Sodium 
PT 
 
Total bilirubin 
 
 
Total protein 
 
 
Triglycerides 
 
 
Uric acid 
 
 
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; GGT = gamma glutamyl transferase; 
HbA1C = glycated hemoglobin; 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 pregnancy test will be administered to all female patients of childbearing potential (ie, women 
who are not postmenopausal or who have not had a bilateral oophorectomy, hysterectomy, or 
tubal ligation) at the Screening, Randomization (prior to dosing), Week 4, and EOT Visits. These 
pregnancy test results must be negative for patient eligibility. All positive urine pregnancy tests 
results will be confirmed by a serum pregnancy test.  


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A urine screen for selected drugs of abuse (cocaine, barbiturates, amphetamines, opiates, 
benzodiazepines, cannabinoids, and phencyclidine) and a serum alcohol screen will be 
performed at the Screening Visit. 
3.5.7 
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. 
3.5.7.1 
Daily Assessments 
During the Pretreatment and Treatment Periods, patients will enter information into their eDiary 
at approximately the same time each day. 
• GERD symptom assessments (mRESQ-eD, Appendix 1) will be completed by the patient 
once daily, in the evening before bed.  
The following GERD symptoms 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 Burning feeling behind the 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 
The following GERD symptoms 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 


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• Assessment of sleep disturbance due to GERD symptoms (Daily Sleep Disturbance due to 
GERD, Appendix 2), completed once daily upon getting up each morning (5:00 a.m. to 12:00 
p.m.) 
o Last night, did you have trouble falling asleep because of GERD symptoms? 
[Yes/No] 
o Last night, how many times did you wake up during the night because of GERD 
symptoms? [0,1, 2, 3-5, 6 or more times] 
• 
Use of per-protocol rescue medicine (antacid) will be completed by the patient once daily, in 
the evening before bed. 
o “How many times did you use your rescue medicine (liquid antacid) during the 
past 24 hours?” 
• Heartburn severity is assessed once daily in the evening before bed on a 0-5 severity scale: 
0=Did not have, 1=Very mild, 2=Mild, 3=Moderate, 4=Moderately severe, 5=Severe 
 
3.5.7.2 
Weekly Assessments 
The following information will be entered into the eDiary once each week during an entry of the 
evening diary (see Appendix 3): 
• 
Degree of relief assessment  
The following 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 pain or 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? 
How would you rate your overall GERD symptoms over the past 7 days? 
Compared to before you started this study, how would you rate your heartburn (a pain or burning 
sensation in your chest, behind the breastbone) over the past 7 days? 
Compared to before you started this study, 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? 


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Compared to before you started this study, how would you rate your overall GERD symptoms 
over the past 7 days? 
• Bothersomeness Assessment.  
The following items are 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 
How much were you bothered by heartburn (a pain or burning sensation in your chest, behind the 
breastbone) over the past 7 days? 
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 7 days? 
How much were you bothered by your overall GERD symptoms over the past 7 days? 
• Treatment Satisfaction Assessment  
The following items are 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? 
 
3.5.7.3 
Study Visit Assessments 
The following assessments will be performed at the study visits indicated: 
• 
WPAI-Sleep Disturbance-GERD 
The Work Productivity and Activity Impairment Questionnaire: Sleep Disturbance-GERD 
(WPAI-Sleep-GERD) includes questions about time lost from work, reduced productivity 
while at work, and reduced productivity while doing regular daily activities resulting from 
sleep disturbance due to GERD symptoms. Patients will complete the WPAI-Sleep-GERD at 
the Randomization Visit, the Week 4 Visit, and at the EOT Visit and will record their 
responses in the eDiary. 
• 
EQ-5D-3L 
The EuroQol (EQ)-5D-3L is a generic measure of health widely used in Europe.(13) 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.(14) The 


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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 and will record their responses in the eDiary. 
3.5.8 
Other Assessments 
3.5.8.1 
Esophagogastroduodenoscopy 
All patients will be required to undergo an EGD during the Screening Period. There should be a 
minimum of 7 days between the EGD and the start of the Pretreatment Period to allow for pH 
testing and patient stabilization. EGDs will be interpreted by the local site personnel and by a 
central reader.  Details are provided in a separate study manual (Image Acquisition Guidelines 
for Ironwood Pharmaceuticals, Inc. Protocols C3718-301/C3718-302; WorldCare Clinical). 
An EGD will be performed at the Week 8 / EOT Visit in all patients who completed at least 
4 weeks of treatment and had erosive esophagitis on the EGD obtained during the Screening 
Period (based on the Los Angeles [LA] classification of esophagitis [Appendix 5], as determined 
by either the site personnel or the central reader). 
3.5.8.2 
Bravo™ 
At all sites, all patients will undergo up 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. All patients will return to the site with their Bravo pH monitor after approximately 96 
hours (or 48 hours where applicable) to return the recording device. To determine eligibility, a 
centralized review of pH monitoring will be conducted for each patient. Please refer to the Bravo 
Site Manual for specific instructions. 
3.6 
SCHEDULE OF EVENTS 
The schedule of study procedures and assessments is presented by visit in the Schedule of 
Evaluations within the Protocol Synopsis. Procedures and assessments by study visit are 
provided in the following sections. 


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3.6.1 
Screening Period (Day -49 to Day -15) 
3.6.1.1 
Screening Visit (Visit 1) Procedures 
• 
Review of inclusion and exclusion criteria 
• 
Signing of ICF 
• 
Register visit in IWRS 
• 
Demographics 
• 
Medical and disease history 
• 
Physical examination 
• 
Body weight and height 
• 
Begin H2RA and antacid washout (for 5 days before the EGD and Bravo pH monitoring 
[H2RA] and 1 calendar day before the EGD and Bravo pH monitoring [antacids]) 
• 
EGD (see Section 3.5.8.1) 
• 
Up 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) 
• 
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, antacid, and PPI) 
• 
Collection of blood and urine samples for clinical laboratory test, including: 
 
Clinical chemistry 
 
Hematology (complete blood count [CBC]) 
 
Coagulation 
 
Urinalysis 
• 
Pregnancy test for all female patients of childbearing potential (must be confirmed 
negative; positive urine test results will be confirmed via serum pregnancy test) 
• 
Drug and alcohol screening, including a urine drug screen for selected drugs of abuse 
(cocaine, barbiturates, amphetamines, opiates, benzodiazepines, cannabinoids, and 
phencyclidine) and a serum alcohol screen 
• 
AE evaluation (throughout the Screening Period) 


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3.6.1.2 
Pretreatment Visit (Visit 2) Procedures 
• 
Register visit in IWRS 
• 
Review of inclusion and exclusion criteria 
• 
Body weight 
• 
Prior and concomitant medications and procedures 
• 
AE evaluation (throughout the Pretreatment Period) 
• 
Liquid antacid rescue medicine dispensation 
• 
eDiary training and dispensation (for recording daily and weekly evaluations throughout 
the Pretreatment and Treatment Periods) 
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. 
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 and procedures 
• 
Collection of blood and urine samples for clinical laboratory tests, including: 
 
Clinical chemistry 
 
Hematology (CBC) 
 
Coagulation 
 
Urinalysis 
• 
Pregnancy test for all female patients of childbearing potential (must be confirmed 
negative; positive urine test results will be confirmed via serum pregnancy test) 
• 
AE evaluation (throughout the Treatment Period) 


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• 
Liquid antacid rescue medicine dispensation (if needed) 
• 
Review eDiary 
• 
WPAI-Sleep Disturbance-GERD 
• 
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).  
3.6.2.2 
Week 4 (Visit 4) Procedures 
• 
Register visit in IWRS 
• 
Body weight 
• 
Seated vital signs 
• 
Concomitant medications and procedures 
• 
Collection of blood and urine samples for clinical laboratory tests, including: 
 
Clinical chemistry 
 
Hematology (CBC) 
 
Coagulation 
 
Urinalysis 
• 
Pregnancy test for all female patients of childbearing potential (must be confirmed 
negative; positive urine test results will be confirmed via serum pregnancy test) 
• 
AE evaluation (throughout the Treatment Period) 
• 
Liquid antacid rescue medicine dispensation (if needed) 
• 
Review eDiary 
• 
WPAI-Sleep Disturbance-GERD 
• 
EQ-5D-3L 
• 
Study medication dispensed 
• 
Return of all unused study medication  


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3.6.2.3 
Week 8/End-of-treatment (Visit 5) Procedures 
• 
Register visit in IWRS 
• 
Physical examination 
• 
Body weight 
• 
EGD (A repeat EGD will be performed at the Week 8 / EOT Visit for all patients who have 
completed at least 4 weeks of treatment and had erosive esophagitis on the screening EGD 
[based on the LA classification of esophagitis, see Appendix 5] as determined by either the 
site personnel or the central reader; see Section 3.5.8.1)  
• 
Seated vital signs 
• 
12-lead ECG 
• 
Concomitant medications and procedures 
• 
Collection of blood and urine samples for clinical laboratory tests, including: 
 
Clinical chemistry 
 
Hematology (CBC) 
 
Coagulation 
 
Urinalysis 
• 
Pregnancy test for all female patients of childbearing potential (must be confirmed 
negative; positive urine test results will be confirmed via serum pregnancy test) 
• 
AE evaluation (throughout the Treatment Period) 
• 
Review eDiary 
• 
WPAI-Sleep Disturbance-GERD 
• 
EQ-5D-3L 
• 
Return of all unused study medication  
• 
Return eDiary 
3.6.3 
Follow-up Phone Call 
The study site will contact all patients via telephone 7 days following the EOT Visit to collect 
information regarding ongoing AEs/SAEs/concomitant medications and any new 
AEs/SAEs/concomitant medications and procedures since the EOT Visit (Section 3.6.2.3). This 
information will be recorded via EDC. 


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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 3.6.2.3) at the time of their discontinuation. 
3.7 
STATISTICAL METHODS 
Statistical analysis methods are summarized in the following sections. 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 
Screened Population consists of all patients who signed informed consent and received a patient 
identification (PID) number. 
Randomized Population consists of all patients who were assigned to a treatment group 
(placebo or IW-3718) via randomization. 
Safety Population consists of all randomized patients who received at least 1 dose of study drug.  
Modified Intent-to-Treat (mITT) Population consists of all randomized patients who received 
at least 1 dose of study drug and had at least 1 postbaseline primary efficacy assessment. 
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 count and 
proportion of patients in each category. Unless otherwise specified, all confidence intervals will 
be 2-sided and with a confidence level of 95%. Details of the data handling methods will be 
specified in the SAP. Unless otherwise specified, the week prior to randomization will be 
considered the baseline for efficacy analyses.  For safety analyses, the baseline value is defined 
as the last non-missing value measured before administration of study treatment. All statistical 
analyses will be performed using SAS® Version 9.4 (or later) for Windows. 


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3.7.3 
Patient Disposition, Demographics, and Baseline Characteristics 
The count and proportion of patients included in the Randomized, Safety, and mITT 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 (ie, patients who enter the Screening Period but not 
the Pretreatment Period) and pretreatment failures (ie, patients who enter the Pretreatment Period 
but are not randomized), along with the associated reasons for failure, will be tabulated overall 
for the Screened Population. 
The count and proportion of patients who complete the study and who prematurely discontinue 
will be presented for each treatment group and overall for the Randomized 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 Randomized Population. 
Demographic parameters (eg, age, sex, race, weight, height, and body mass index) and other 
baseline characteristics (including heartburn severity, regurgitation frequency, and the weekly 
assessments) will be summarized by treatment group. 
3.7.4 
Efficacy Analyses 
Table 4 and Table 5 provide the analysis time windows allowed for the efficacy analyses in the 
Pretreatment and Treatment Periods. 
 


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Table 4. 
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) 
Treatment 
Week 1  
Day 1 (Day of 
Randomization) 
Day 7 
Week 2  
Day 8 
Day 14 
Week 3  
Day 15  
Day 21 
Week 4  
Day 22 
Day 28  
Week 5  
Day 29 
Day 35 
Week 6  
Day 36 
Day 42 
Week 7 
Day 43 
Day 49 
Week 8 
Day 50 
Day 56 
Week 9 
Day 57 
Day 63 
••• 
••• 
••• 
a. 
Relative to the day of randomization (Day 1).  There is no Day 0. 
b. Baseline for efficacy parameters will be derived from the daily eDiary collected for Pretreatment Week -1 
(Week -2 if data for Week -1 not available); specifically for the proportion endpoints (defined as days with the 
event of interest divided by the number of diary entry days), the last 14 days (Week -2 to Week -1) prior to day 
of randomization will be used. 


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Table 5. 
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 day of randomization (Day 1).  There is no Day 0. 
b. Baseline for efficacy parameters will be derived from the eDiary collected for Pretreatment Week -1 (Week -2 
if data for Week -1 not available) 
 
3.7.4.1 
Primary Efficacy Parameter 
The primary efficacy parameter of the study is defined as the change from baseline at Week 8 in 
WHSS. 
• The WHSS for a week is the average of the non-missing Daily Heartburn Severity 
Scores (DHSS) for that week. Rules for missingness of data will be prespecified in 
the SAP finalized before database lock. 
• The DHSS for a day is the greater score of the 2 mRESQ items assessing heartburn 
severity (“Burning feeling behind the breastbone or in the center of the upper 
stomach” and “Pain behind the breastbone or in the center of the upper stomach”) for 
that day. Where 1 of the 2 mRESQ heartburn severity items is missing for the day, the 
maximum will be the score of the remaining item; where both items are missing for 
the day, the DHSS will be missing. 


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3.7.4.2 
Key Secondary Efficacy Parameters 
There are 3 key secondary efficacy parameters.  Hypothesis testing of these key secondary 
efficacy parameters (and the primary efficacy parameter) will be controlled for multiplicity. 
1. Change from baseline at Week 8 in Weekly Regurgitation Frequency Score (WRFS) 
• The WRFS for a week is the average of the non-missing Daily Regurgitation 
Frequency Scores (DRFS) for that week. Rules for missingness of data will be 
prespecified in the SAP finalized before database lock. 
• The DRFS for a day is the greater score of the 2 mRESQ items assessing 
regurgitation frequency (“Regurgitation [liquid or food moving upwards toward your 
throat or mouth]” and “An acid or bitter taste in the mouth”) for that day. 
2. 
Overall Heartburn Responder: a patient who is a weekly heartburn responder for at least 
4 weeks, including at least 1 of the last 2 weeks (Weeks 7 and 8), during the 8-week 
Treatment Period. 
• A weekly heartburn responder is a patient with a decrease from baseline of ≥ 45% in 
Weekly Heartburn Severity Score (WHSS).  
• Rules for missingness of data will be prespecified in the SAP finalized before 
database lock. 
3. Proportion of heartburn-free days during the 8-week Treatment Period 
• Proportion of heartburn-free days is calculated as the number of heartburn-free 
(DHSS=0) days divided by the number of diary entry days. 
3.7.4.3 
Analysis Methods for Primary and Key Secondary Efficacy Parameters 
For analysis of the primary efficacy and first key secondary efficacy parameters, continuous 
parameters (eg, change from baseline), descriptive statistics (patient number [n], mean, standard 
deviation, median, and range) will be presented for each treatment group. The IW-3718 group 
will be compared with the placebo group by employing a linear mixed-effects model for repeated 
measures (MMRM) framework with week (categorical), treatment group, week-by-treatment 
group and week-by-baseline value interactions, baseline esophagitis status (present vs. not 
present), and baseline WHSS (<3 vs. ≥3) as fixed-effect terms and baseline value as a covariate, 
with patient as a random effect. An unstructured covariance structure will be used. Least-squares 
mean (LSM) for each treatment group, LSM difference between the IW-3718 group and the 


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placebo group and a 95% confidence interval for the difference at Week 8, as well as the p-value 
for comparison versus placebo will be presented. 
For analysis of responder parameters (ie, responder vs. non-responder), the counts and 
proportions of responders will be calculated for each treatment group. The proportions of 
responders between the IW-3718 group and the placebo group will be compared using a 
Cochran-Mantel-Haenszel (CMH) test controlling for baseline esophagitis status (erosive 
esophagitis vs. no erosive esophagitis) and baseline WHSS (<3 vs. ≥3). The CMH test is the 
primary analysis for responder parameters. The difference in the proportion of responders 
between the IW-3718 group and the placebo group, as well as the CMH estimate of the odds 
ratio (IW-3718 over placebo) and a 95% confidence interval for the odds ratio, will also be 
presented. 
Time-dependent proportion parameters, defined as days the event of interest occurs, divided by 
the number of eDiary entry days within the 8-week Treatment Period (eg, proportion of 
heartburn-free-days), will be analyzed using a Poisson model which is appropriate for count data.  
The analysis includes the treatment, the baseline esophagitis status (present vs. not present), 
baseline WHSS (<3 vs. ≥3), covariate of baseline proportion of event-free days, with the eDiary 
entry days adjusted in the model. In the case of overdispersion, a negative binomial model 
instead of Poisson regression will be implemented. Model estimates in difference between the 
rates for IW-3718 and placebo groups will be calculated with corresponding 95% confidence 
interval and p-value associated with the comparisons to placebo . 
3.7.4.4 
Controlling Type-I Error 
To maintain an overall type-I error rate of 0.05, the primary and 3 key secondary efficacy 
parameters will be tested sequentially according to the following order, each at a 2-sided 
significance level of 0.05. 
Order 
Parameter 
1 
Change from Baseline at Week 8 in WHSS (primary) 
2 
Change from Baseline at Week 8 in WRFS 
3 
Overall Heartburn Responder 
4 
Proportion of Heartburn-free Days during the 8-week Treatment Period 


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Testing of subsequent parameters will not be performed unless all previous parameters have been 
tested statistically significant (p≤0.05).  
3.7.4.5 
Sensitivity Analysis of Primary Efficacy Parameter 
For the primary parameter, change from baseline in WHSS at Week 8, a sensitivity analysis will 
be conducted; details will be provided in the SAP.  
3.7.4.6 
Handling of Missing Data 
For the primary efficacy analysis, change from baseline at Week 8 in WHSS, no imputation will 
be performed on missing data. The WHSS will be computed as the average of daily scores for 
that week. Rules for the average calculation will be prespecified in the SAP finalized before 
database lock. 
A pattern-mixture model with control-based pattern imputation will be implemented as a 
multiple imputation method to explore the effects of missing data on the primary efficacy 
parameter. The details of this approach will be provided in the SAP.  
3.7.4.7 
Exploratory Efficacy Parameters and Analysis Methods 
Exploratory efficacy parameters will be explored outside of the formal testing procedures and 
not controlled for multiplicity.  
Change or percent change for continuous parameters will be analyzed using the MMRM 
approach as described for the primary efficacy parameter, change from baseline at Week 8 in 
WHSS. 
Categorical responder parameters will be analyzed using the CMH testing method as described 
for the key secondary efficacy analysis for Overall Heartburn Responder. 
Time-dependent proportion parameters, defined as days the event of interest occurs, divided by 
the number of diary entry days within the 8-week Treatment Period (eg, proportion of heartburn-
free-days), will be analyzed using a Poisson model which is appropriate for count data.  The 
analysis is similar to that described for the key secondary efficacy analysis for the proportion of 
heartburn-free days during the 8-week Treatment Period. 


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The exploratory efficacy endpoints and proposed analysis methods are listed below: 
Item 
No. 
Exploratory Efficacy Endpoints 
Analysis Methods 
1. 
Percent change from baseline at Week 8 in WHSS 
MMRM for change from 
baseline at Week 8. 
2. 
Overall Heartburn Responders with baseline WHSS ≥3 
CMH 
3. 
Change from baseline in proportion of days when heartburn did 
not occur (DHSS = 0) or was very mild (DHSS = 1) during the 
8-week Treatment Period  
Analysis of covariance 
(ANCOVA) 
4. 
Proportion of days when heartburn did not occur (DHSS=0) or 
was very mild (DHSS=1) during the 8-week Treatment Period  
Poisson regression for 
proportions 
5. 
Percent change from baseline at Week 8 in WRFS 
MMRM for change from 
baseline at Week 8. 
6. 
Change from baseline in proportion of days when regurgitation 
did not occur (DRFS = 0) or rarely occurred (DRFS = 1) during 
the 8-week Treatment Period  
ANCOVA 
7. 
Proportion of regurgitation free (DRFS = 0) days during the 
8-week Treatment Period   
Poisson regression for 
proportions 
8. 
Proportion of days when regurgitation did not occur (DRFS=0) 
or rarely occurred (DRFS=1) during the 8-week Treatment 
Period 
Poisson regression for 
proportions 
9. 
Overall Regurgitation Responder: a patient who is a Weekly 
Regurgitation Responder for at least 4 weeks, including at least 
1 of the last 2 weeks (Weeks 7 and 8), during the 8-week 
Treatment Period 
• 
A Weekly Regurgitation Responder is a patient with a 
decrease of ≥ 45% from baseline in WRFS  
• 
A patient who reports DRFS for less than 4 days during a 
week will not be considered a Weekly Regurgitation 
Responder for that week 
CMH 
10. 
Change from baseline at Week 8 in each mRESQ item  
MMRM for change from 
baseline at Week 8. 
11. 
Proportion of nights with difficulty falling asleep due to GERD 
during the 8-week Treatment Period 
Poisson regression for 
proportions 
12. 
Proportion of days with nighttime awakening (≥1 time) due to 
GERD during the 8-week Treatment Period  
Poisson regression for 
proportions 
13. 
Degree of relief of heartburn/regurgitation/overall GERD 
symptoms responder: 
• Degree of relief responder: patient who reported a score of    
1-Significantly Relieved or 2-Moderately Relieved on the 
Degree of Relief question for at least 4 weeks, including at 
least 1 of the last 2 weeks (Weeks 7 and 8), during the 8-week 
Treatment Period 
CMH 
14. 
Change from baseline at Week 8 in 
heartburn/regurgitation/overall GERD symptoms 
bothersomeness 
MMRM for change from 
baseline at Week 8. 
15. 
Proportion of days with rescue medication use during the 8-
week Treatment Period  
Poisson regression for 
proportions  


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Item 
No. 
Exploratory Efficacy Endpoints 
Analysis Methods 
16. 
Erosive esophagitis (EE) healed (not present) at Week 8 
CMH 
17. 
Proportion of patients with erosive esophagitis (EE) improved 
by at least 1 grade at Week 8   
CMH 
 
Descriptive supportive summary for following variables will be generated for mITT population. 
Item 
No. 
Description of Summary 
1. 
Percent change from baseline in WHSS by week  
2. 
Percent change from baseline in WRFS by week  
3. 
Change from baseline in WHSS by week 
4. 
Change from baseline in WRFS by week 
5. 
Change from baseline in each mRESQ item by week  
6. 
Proportion of heartburn-free (DHSS=0) days by week 
7. 
Proportion of regurgitation-free (DRFS=0) days by week 
8. 
Proportion of days when heartburn did not occur (DHSS=0) or was very mild (DHSS=1) by 
week  
9. 
Proportion of days when regurgitation did not occur (DRFS=0) or rarely occurred (DRFS=1) by 
week 
10. 
Proportion of nights with difficulty falling asleep due to GERD by week 
11. 
Proportion of days with nighttime awakening (≥1 time) due to GERD by week 
12. 
Proportion of days with rescue medication use by week  
13. 
Degree of relief of heartburn/regurgitation/overall GERD symptoms by week 
14. 
Heartburn/regurgitation/overall GERD symptoms bothersomeness by week 
15. 
Treatment satisfaction by week 
16. 
Shift in erosive esophagitis (EE) grade from baseline at Week 8 
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, clinical laboratory 
evaluations, vital signs, ECGs, and physical examination. For each safety parameter, the last 
non-missing assessment made before the first dose of study drug will be used as the baseline for 
all analyses of that safety parameter. 


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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 occurred after initial study 
medication administration and within 1 day of the last dose of study medication. The 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 severe TEAEs, 
study drug-related AEs, AEs leading to study drug discontinuation, and treatment-emergent 
SAEs will also be tabulated by SOC, preferred term, and treatment group. Listings will be 
provided for deaths (if any), SAEs, and AEs leading to study drug 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. 
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 time point 
post baseline will also 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 calculations for the primary and key secondary efficacy parameters are based on 
results from patients with evidence of pathological acid reflux (positive baseline Bravo status) in 
Study ICP-3718-202, which had a similar study population as the current study.  
The primary efficacy parameter is Change from Baseline at Week 8 in WHSS, and key 
secondary efficacy parameters include: 
• Change from Baseline at Week 8 in WRFS 
• Overall Heartburn Responder 
• Proportion of Heartburn-free Days during the 8-week Treatment Period  


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Using data from patients in Study ICP-3718-202, we derived the estimated results at end of the 
study as follows: 
Order of 
Hypothesis 
Testing 
Parameter 
Placebo  
(+ PPIs) 
1500 mg IW-3718 
(+ PPIs) 
1 
Change from Baseline at Week 8 in WHSS 
N = 43 
Mean = -1.58 
SD = 1.20 
N =51 
Mean = -2.01 
SD = 1.29 
2 
Change from Baseline at Week 8 in WRFS 
N = 43 
Mean = -0.81 
SD = 1.12 
N = 51 
Mean = -1.26 
SD = 0.91 
3 
Overall Heartburn Responder 
18/49 = 36.7% 
31/55 = 56.4% 
4 
Proportion of Heartburn-free Days during 
the 8-week Treatment Period 
N = 48 
Mean = 0.195 
SD = 0.2822 
N = 55 
Mean = 0.268 
SD = 0.2928 
The efficacy parameters will be tested sequentially according to the above order at a 2-sided 
significance level of 0.05 so that the overall type-I error rate is maintained at 0.05 Based on 
bootstrap simulations, a sample size of 330 patients per group will provide approximately 99% 
power to detect a treatment difference between 1500-mg IW-3718 (while receiving PPIs) and 
placebo (while receiving PPIs) for the primary efficacy parameter, assuming the randomized 
population in this study is consistent with the selected population from Study ICP-3718-202. 
Power that is based on simulations for all type-I error controlling key efficacy parameters are 
presented in the table below. The 2-sample t-test was used for continuous parameters and the 
Chi-square test was used for the responder parameter. 
Order of 
Hypothesis 
Testing 
Parameters 
Power for Fixed Sequence Testing 
1 
Change from Baseline at Week 8 in WHSS 
99% 
2 
Change from Baseline at Week 8 in WRFS 
99% 
3 
Overall Heartburn Responder 
99% 
4 
Proportion of Heartburn-free Days during the 
8-week Treatment Period 
88% 
 
 
 


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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/IEC) must be approved by the IRB/IEC 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/IEC review and approval. However, the IRB/IEC 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 (ie, 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, the European Directive 2001/20/EC relating to the 
implementation of good clinical practice (GCP) in the conduct of clinical trials on medicinal 
products for human use, and applicable regulatory requirements.    
4.1 
INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE 
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/IEC. 
All IRB/IEC approvals must be dated and signed by the IRB/IEC Chairman or his or her 
designee and must identify the IRB/IEC 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/IEC approvals should be forwarded to Ironwood. All 
correspondence with the IRB/IEC should be maintained in the Investigator File. 
No drug will be released to the site to dose a patient until written IRB/IEC 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/IEC. The Investigator must supply Ironwood with 
written documentation of the approval of the continued clinical research. 
The IRB/IEC 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/IEC that approved the 
study. Amendments to the protocol must be submitted in writing to the Investigator’s IRB/IEC 
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/ IEC for the purposes of obtaining and 
documenting consent. 
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 trial will include approximately 100 study centers in the US and Canada. 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/IEC 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/IEC, 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 and the study monitoring plan. 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. 
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. 


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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 
This trial is one of 2 similar studies of IW-3718 that plan to enroll a combined population of 
approximately 1300 patients. 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, or qualified designee, 
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 
and instructions for their completion using the EDC system, the procedure for obtaining 
informed consent, and the procedure for reporting AEs and SAEs. 
The clinical site monitor (Ironwood or qualified designee) 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 


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visits, the information recorded on the eCRFs will be verified against source documents. Upon 
request of the monitor, auditor, IRB/IEC, or regulatory authority, the Investigator should make 
all requested study-related records available for direct access. 
Ironwood or its designee will monitor the study in compliance with applicable government 
regulations with respect to GCP, the study monitoring plan, 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/IEC approval letter for the protocol and ICF 
6. IRB/IEC-approved ICF to be used 
7. IRB/IEC approval of recruitment advertising (if applicable) 
8. A list of IRB/IEC 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 


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5. Signed Form FDA 1572 
6. IRB/IEC 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/IEC 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/IEC. An Investigator must not make any changes in a study without 
IRB/IEC and Sponsor approval, except when necessary to eliminate apparent immediate 
hazards to the subjects. All protocol amendments must be submitted to the IRB/IEC and 
approved. 
14. Responsibility Log 
15. Other logs (eg, 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, 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/IEC, 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. Gastroenterology. 
1975;68:728-33. 
2. Kivilaakso E, Fromm D, Silen W. Effect of bile salts and related compounds on isolated 
esophageal mucosa. Surgery. 1980;87(3):280-5. 
3. Nishijima K, Miwa K, Miyashita T, Kinami S, Ninomiya I, Fushida S, et al. Impact of the 
biliary diversion procedure on carcinogenesis in Barrett's esophagus surgically induced by 
duodenoesophageal reflux in rats. Ann Surg. 2004;240(1):57-67. 
4. Nehra D, Howell P, Williams CP, Pye JK, Beynon J. Toxic bile acids in gastro-oesophageal 
reflux disease: influence of gastric acidity. Gut. 1999;44(5):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(9):1072-4. 
6. Vaezi MF, Richter JE. Contribution of acid and duodenogastro-oesophageal reflux to 
oesophageal mucosal injury and symptoms in partial gastrectomy patients [see comment]. 
Gut1468-3288. 1998;41:297-302. 
7. Kono K, Takahashi A, Sugai H, Iizuka H, Fujii H. Trypsin activity and bile acid 
concentrations in the esophagus after distal gastrectomy. Dig Dis Sci. 2006;51(6):1159-64. 
8. Gerson LB, Kahrilas PJ, Fass R. Insights Into Gastroesophageal Reflux Disease-Associated 
Dyspeptic Symptoms. Clin Gastroenterol Hepatol. 2011;9(10):824-33. 
9. Cohen E, Bolus R, Khanna D, Hays RD, Chang L, Melmed GY, et al. GERD symptoms in 
the general population: prevalence and severity versus care-seeking patients. Dig Dis Sci. 
2014;59(10):2488-96. 
10. Friedenberg FK, Hanlon A, Vanar V, Nehemia D, Mekapati J, Nelson DB, et al. Trends in 
gastroesophageal reflux disease as measured by the National Ambulatory Medical Care 
Survey. Dig Dis Sci. 2010;55(7):1911-7. 
11. 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. Journal of neurogastroenterology and 
motility. 2011;17(4):387-94. 
12. 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(6):981-877. 
13. EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. 
The EuroQol Group. Health Policy. 1990;16:199-208. 
14. 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. 


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9. 
SPONSOR SIGNATURE 
Study Title: 
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-
group, Multicenter Trial of Oral IW-3718 Administered to Patients with 
Gastroesophageal Reflux Disease while receiving Proton Pump Inhibitors 
Study Number: 
C3718-301 
Final Date: 
14 August 2020 
 
This clinical study protocol was subject to critical review and has been approved by the sponsor. 
If an electronic signature was obtained, it will appear on the final page of this document. 
 
Signed:  
 
 
Date:   
 
 
 
 
 
 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
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10. 
INVESTIGATOR SIGNATURE 
Study Title: 
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-
group, Multicenter Trial of Oral IW-3718 Administered to Patients with 
Gastroesophageal Reflux Disease while receiving Proton Pump Inhibitors 
Study Number: 
C3718-301 
Final Date: 
14 August 2020 
 
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 
MODIFIED REFLUX SYMPTOM QUESTIONNAIRE 
ELECTRONIC DIARY (MRESQ-ED) 
Instructions: Please answer the following questions to help us understand the symptoms you 
experienced over the past 24 hours because of your reflux disease. For each question, please 
choose the answer most appropriate for you. 
1. 
Over the past 24 hours, how would you rate the severity of your burning feeling behind 
the breastbone or in the center of the upper stomach? 
 
Did not have/ Very mild/ Mild/ Moderate/ Moderately severe/ Severe 
2. 
Over the past 24 hours, how would you rate the severity of your pain behind the 
breastbone or in the center of the upper stomach? 
 
Did not have/ Very mild/ Mild/ Moderate/ Moderately severe/ Severe 
3. 
Over the past 24 hours, how would you rate the severity of your difficulty swallowing? 
 
Did not have/ Very mild/ Mild/ Moderate/ Moderately severe/ Severe 
4. 
Over the past 24 hours, how would you rate the severity of your hoarseness? 
 
Did not have/ Very mild/ Mild/ Moderate/ Moderately severe/ Severe 
5. 
Over the past 24 hours, how would you rate the severity of your cough? 
 
Did not have/ Very mild/ Mild/ Moderate/ Moderately severe/ Severe 
6. 
Over the past 24 hours, how often did you experience regurgitation (liquid or food 
moving upwards towards your throat or mouth)? 
 
Never/ Rarely/ Sometimes/ Often/ Very often 
7. 
Over the past 24 hours, how often did you experience an acid or bitter taste in the 
mouth? 
 
Never/ Rarely/ Sometimes/ Often/ Very often 
8. 
Over the past 24 hours, how often did you experience burping? 
 
Never/ Rarely/ Sometimes/ Often/ Very often 


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APPENDIX 2 
OTHER DAILY ASSESSMENTS 
Heartburn 
  
The following question will be answered by the patient in the evening diary.  
 
Over the past 24 hours, how would you rate the severity of your heartburn? 
0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe 
 
Sleep Disturbance due to GERD 
 
The following questions will be answered by the patient upon getting up each morning (5:00 
a.m. to 12:00 p.m.) using the eDiary: 
 
Falling Asleep 
Last night, did you have trouble falling asleep because of GERD symptoms? 
[Yes, No] 
Awakenings 
Last night, how many times did you wake up during the night because of GERD symptoms? 
 
0 
1 time 
2 times 
3-5 times 
6 or more times 


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APPENDIX 3 
WEEKLY ASSESSMENTS 
Degree of Relief Assessments  
Administered weekly during Pretreatment and Treatment Periods: 
How would you rate your heartburn (a pain or 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? 
How would you rate your overall GERD symptoms over the past 7 days? 
Compared to before you started this study, how would you rate your heartburn (a pain or burning 
sensation in your chest, behind the breastbone) over the past 7 days? 
Compared to before you started this study, 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? 
 
 
 
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 
 


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Bothersomeness Assessments  
Administered weekly during Pretreatment and Treatment Periods: 
How much were you bothered by heartburn (a pain or burning sensation in your chest, behind the 
breastbone) over the past 7 days? 
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 7 days? 
How much were you bothered by your overall GERD symptoms over the past 7 days? 
1=Not at all 
2=A little bit 
3=A moderate amount 
4=A great deal 
5=An extreme amount 
 
 
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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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 days before the EGD and 
Bravo pH monitoring; a 14-day washout means that the particular medicine is not allowed during 
the 14 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]) (eg, cimetidine, ranitidine, 
famotidine, and nizatidine). 
 
14-DAY WASHOUT 
• Bile acid sequestrants (eg, Welchol [colesevelam], cholestyramine, and colestipol) 
• Drugs with a known drug-drug interaction or a potential for a drug-drug interaction with 
colesevelam (cyclosporine, olmesartan medoxomil, phenytoin, warfarin) 
• Drugs with a narrow therapeutic index (eg, warfarin, theophylline) 
• Prokinetic agents (eg, metoclopramide, tegaserod, erythromycin); anti-cholinergic and anti-
muscarinic agents (eg, dicyclomine, flavoxate, scopolamine, hyoscyamine, propantheline, 
oxybutynin, tolterodine, solifenacin, darifenacin, and trospium) 
[Note: inhaled ipratropium and tiotropium are permitted] 
• Antipsychotic agents (eg, risperidone, haloperidol, droperidol, chlorpromazine, 
perphenazine, all phenothiazines, quetiapine, olanzapine, clozapine) 
• GABAergics (eg, baclofen, valproic acid, gabapentin, pregabalin, benzodiazepine) 


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• Calcium channel blockers (eg, verapamil, nifedipine, diltiazem, amlodipine, felodipine, 
nicardipine, nimodipine, nisoldipine) 
• Beta blockers (eg, metoprolol, timolol, atenolol, betaxolol) 
• All narcotics either alone or in combination (eg, tramadol, codeine, morphine, propoxyphene, 
loperamide, diphenoxylate) 
[Note: narcotics used as anesthesia for an EGD require a 7-day wash-out prior to the patient 
entering into the Pretreatment Period.] 
• Tricyclic antidepressants (eg, amitriptyline, imipramine, and nortriptyline) 
[Note: Patients may take another single antidepressant (such as a selective serotonin reuptake 
inhibitor, 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 (eg, 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 and continue to take their PPI through the EOT visit. PPIs that are formulated in 
combination with other drugs are not permitted (eg, Zegerid® [omeprazole/sodium bicarbonate], 
Vimovo® [esomeprazole/naproxen]). 
Daily use of estrogens and/or low-dose aspirin (up to 162 mg/day) is permitted if, after an 
appropriate evaluation (eg, 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 were shown not to have a 
drug-drug interaction with IW-3718 (see the IW-3718 Investigator’s Brochure, Edition 5, dated 
10 March 2020). All female patients of childbearing potential may use oral contraceptives with 
the ingredients listed above as birth control and must agree to use an additional form of 
contraception, from the date they sign the ICF until 24 hours after their final dose of study drug 
(eg, condom). 


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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. 
 


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APPENDIX 6 
IN-CLINIC ASSESSMENTS 
EQ-5D-3L 


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Work Productivity and Activity Index (WPAI) - Sleep Disturbance - GERD 


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Clinical Study Protocol:  C3718-301 Amendment 2 
 
14 August 2020 
Confidential 
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APPENDIX 7 
PPI DOSE LEVELS DURING STUDY PARTICIPATION 
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 they represent standard, labeled-dose PPI treatment.  
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.  


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IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Summary of Changes for Protocol Amendment 1: C3718-301 
23 June 2018 
 
Confidential 
Page 2 of 8 
 
 
SPONSOR SIGNATURE 
 
If an electronic signature was obtained, it will appear on the final page of this document. 
 
Signature:  
 
 
Date: ______________ 
 
 
 
 
 
 
 
 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Summary of Changes for Protocol Amendment 1: C3718-301 
23 June 2018 
 
Confidential 
Page 3 of 8 
 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2 
1. 
SUMMARY OF THE PROTOCOL AMENDMENT .............................................................4 
2. 
PROTOCOL SECTION(S) CHANGED .................................................................................5 
 


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Summary of Changes for Protocol Amendment 1: C3718-301 
23 June 2018 
 
Confidential 
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1. 
SUMMARY OF THE PROTOCOL AMENDMENT 
A summary of the protocol sections that have been amended are listed below: 
• Updated proposed indication wording & sponsor contact on protocol cover page 
• Revision of the Study Schema 
• Specified rescue medication to be used and that sites will obtain and provide it to patients 
• Clarified that patients will be stratified by the presence or not of erosive esophagitis and 
their baseline heartburn severity 
• Noted where appropriate that an EGD must be completed at the End-of-Treatment (EOT) 
Visit for all patients who had evidence of erosive esophagitis 
• Clarified that patients with cholecystectomy are eligible if procedure was ≥6 months prior 
to Screening 
• Updated list of key secondary and additional endpoints 
• Made additional updates to the statistical methods, including updates to sample size 
calculations 
• Clarified that SAEs will be followed to adequate resolution or stabilization for up to a 
maximum of 30 days after last dose 
• Expanded reference to collection of concomitant medications to “concomitant 
medication/therapy” 
• Updated sections regarding the recording of screen failures and patients who prematurely 
discontinue from the trial 
• Updated AE recording to capture of the relationship of AEs to to ongoing PPI therapy 
• Other editorial and formatting changes to improve protocol readability and utility 
 


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Summary of Changes for Protocol Amendment 1: C3718-301 
 
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2. 
PROTOCOL SECTION(S) CHANGED 
The protocol sections that were amended are detailed in the table below.  The relevant section and page number is referenced as well 
as the description of the change.  
 
Item # 
Section 
Description of Change 
1 
Cover Page - Indication 
New Text: “IW-3718 is indicated as an adjunct to proton pump inhibitors to treat 
persistent gastroesophageal reflux disease symptoms such as heartburn and regurgitation 
that are not resolved with proton pump inhibitor therapy alone.” 
 
Old Text:  “Gastroesophageal reflux disease (GERD) with persistent symptoms such as 
heartburn and regurgitation while receiving proton pump inhibitor (PPI) therapy” 
2 
Sponsor Contact & 
Identification 
New Sponsor Contacts: 
 
 
 
 
 
 
 
   
 
3 
Sudy Synopsis - Study Schema The study schema was updated for clarity.  
4 
Sections: Synopsis, Schedule 
of Evaluations, and Sections 
3.1, 3.4.1, 3.6.1, 3.6.2 
Clarified information regarding rescue medication type (liquid aluminum hydroxide / 
magnesium hydroxide) and that the clinical sites will supply to enrolled study patients. 
The table below contains a list of major changes from original clinical protocol C3718-301 to amended protocol C3718-301. 


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Summary of Changes for Protocol Amendment 1: C3718-301 
 
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Item # 
Section 
Description of Change 
5 
Synopsis, and Sections 3.1, 
3.4.4, 3.7.4.4,  
Clarified that patients will be stratified by the presence or not of erosive esophagitis and 
their baseline heartburn severity. 
 
Revised text (Synopsis):  “Patients will be stratified by whether they have, or do not have, 
erosive esophagitis on the screening EGD, and by their baseline heartburn severity level 
(average heartburn severity score over the last 7 days prior to randomization of <3 vs. 
≥3; see Criteria for Evaluation) and randomly assigned within each stratum to placebo or 
1500 mg IW-3718 BID (1:1).” 
6 
Synopsis, Sections 3.1, 3.5.8.1, 
3.6.2.3 
Clarified that an EGD must be completed at the End-of-Treatment (EOT) Visit for all 
patients who had evidence of erosive esophagitis and who completed at least 4 weeks of 
study drug treatment. 
 
Revised text (Section 3.1):  “At the end of the treatment period study medication will be 
discontinued and patients will return for an End-of-Treatment (EOT) Visit. All patients 
who have erosive esophagitis (LA classification A-D) on EGD at Screening and 
completed ≥4 weeks of treatment will have a repeat EGD at their EOT Visit.” 
7 
Synopsis, Section 3.3.1.2  
Study Eligibility Criteria: 
 
Revised inclusion criteria wording to permit a single weekly eDiary entry during the 14 
days prior to the Treatment Period. 
Revised Inclusion Criteria #10: 
Patient is able to successfully use the eDiary, and has adequately completed the eDiary 
questions on at least 5 days each week and the weekly questions at least once during the 
14 days before the start of the Treatment Period. 


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Summary of Changes for Protocol Amendment 1: C3718-301 
 
23 June 2018 
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Item # 
Section 
Description of Change 
Corrected wording of exclusion criteria #9 that patients who had cholecystectomy within 
6 months before the Screening Visit were ineligible.  
Corrected wording in Section 3.3.1.1 to match criteria within the Study Synopsis. 
Revised Text Exclusion Criteria #9: 
1. 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 
8 
Synopsis and Section 3.7.4.2 
and 3.7.4.3  
Modified the Key and Additional Secondary Endpoints: 
 
Added Overall Heartburn Responder – patients with a baseline weekly heartburn severity 
score (WHSS) ≥ 3 and the first key secondary endpoint. 
Replaced Overall Regurgitation Responder with the Proportion of Heartburn-free Days 
during the 8-week Treatment Period and the 4th key secondary endpoint. 
 
Made changes to the list of planned additional secondary endpoints. 
9 
Section 3.7.4.4 
Revised wording:  “Cumulative distribution function (CDF) of percent change from 
baseline to Week 8 in WHSS and WRFS will be plotted by treatment group.” 
10 
Synopsis, and Sections 3.7.4.8, 
3.7.7 
Revised sample size calculations based on Phase 2b study results and the addition of the 
Overall Heartburn Responder as a key secondary endpoint. Added details regarding the 


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Summary of Changes for Protocol Amendment 1: C3718-301 
 
23 June 2018 
Confidential 
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Item # 
Section 
Description of Change 
handling of missing data. Updated list of planned additional efficacy parameters. 
11 
Sections 3.5.1.2 
Clarified that SAEs will be followed for a maximum of 30 days following the last dose 
of study drug. 
 
Revised text: “All SAEs will be followed to adequate resolution or stabilization for up to 
a maximum of 30 days after last dose.” 
12 
Sections 3.5.1.2, 3.6 
Expanded reference to collection of concomitant medications to “concomitant 
medication/therapy”  
13 
Section 3.3.2 and Section 
3.5.1.5 
Added Screen Failures (Section 3.3.2) detailing instructions for recording screen failure 
information on the eCRF. Modified Section 3.5.1.5 to eliminate redundance with new 
section. 
14 
Section 3.3.3 
Updated wording regarding the reasons for removal of patients from therapy or 
assessment. 
15 
Section 3.5.1 
Updated AE recording to include the capture of the relationship of AEs to study drug and 
to ongoing protocol pump inhibitor (PPI) therapy. 
16 
Section 3.5.7 
Updated wording and layout of Efficacy Assessment section for clarity. 
17  
Appendix 1 
Reformatted mRESQ-eD tool for clarity. 
18 
Entire Document 
Small editorial and formatting changes were made to improve protocol readability. 
 


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Summary of Changes for Protocol Amendment 2: C3718-301 
Final Version, 14 August 2020 
Ironwood Substance Identifier:
IW-3718 
Protocol Number: 
C3718-301 
Original Protocol Date:
27 March 2018 
Protocol Amendment 1 
 
 
Date
23 June 2018 
Regions 
United States 
Canada 
EU 
Sites
All Sites 
Protocol Amendment 2 
Date
14 August 2020 
Regions 
United States 
Canada 
 
Sites
All Sites 
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.


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: C3718-301 
 
14 August 2020 
 
Confidential 
Page 2 of 25 
 
 
SPONSOR SIGNATURE 
If an electronic signature was obtained, it will appear on the final page of this document. 
 
Signature:  
 
 
Date: ______________ 
 
 
 
 
 
 
 
 
 


IW-3718 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Study Protocol: C3718-301 
 
14 August 2020 
 
Confidential 
Page 3 of 25 
 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2 
1. 
SUMMARY OF THE PROTOCOL AMENDMENT .............................................................4 
2. 
PROTOCOL SECTIONS CHANGED ....................................................................................5 
 


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14 August 2020 
 
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1. 
SUMMARY OF THE PROTOCOL AMENDMENT 
The major protocol revisions are listed below: 
• In accordance with guidance from the US FDA, the primary and key secondary efficacy 
endpoints have been changed. The analytical methods, including sequential testing to 
control Type-I error, have been updated accordingly. 
• To support the anchor-based analyses corresponding to the ‘Change from baseline at 
Week 8’ endpoints, 3 weekly ‘Degree of Relief’ patient-reported items were added.  
These 3 new items ask the patient to compare their current degree of relief to that 
experienced before the start of the study. 
• The power calculations for the sample size were recalculated to reflect the new primary 
and key secondary efficacy parameters. 
• Endpoints listed as “Additional Secondary Efficacy Parameters” and the “Additional 
Efficacy Parameters” were consolidated into a new section “Exploratory Efficacy 
Parameters”. New exploratory endpoints were added. 
• Changes were made to one of the study’s eligibility criteria for consistency between the 
synopsis and body of the protocol. 
• Enrollment of patients without esophageal erosions was revised to state that the study 
will aim to enroll up to 50% of patients with esophageal erosions. 
• Updates were made to the prohibited medication and concomitant medication guidance. 
• The Sponsor’s study contact information was updated. 
 


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Summary of Changes for Amended Protocol: C3718-301 
 
14 August 2020 
 
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2. 
PROTOCOL SECTIONS CHANGED 
The table below contains a list of changes from Protocol C3718-301 Amendment 1 to Protocol C3718-301 Amendment 2. 
 
Item # 
Section 
Page # 
Description of Change 
1.  Sponsor Contact & 
Identification 
1, 17 
New address: 
 
Ironwood Pharmaceuticals, Inc. 
100 Summer Street, Suite 2300 
Boston, MA 02110, USA 
 
New Medical Monitor: 
 
 
 
 
 
New Drug Safety Physician (Serious Adverse Event [SAE] Reporting):  
 
 
 
 


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Summary of Changes for Amended Protocol: C3718-301 
 
14 August 2020 
 
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Item # 
Section 
Page # 
Description of Change 
2.  Study Synopsis, Study Centers 
 
2 
The European Union (EU) was removed from the list of countries with study centers. 
3.  Study Synopsis, Methodology 
2 
The figure showing the Overview of Study Design indicated that randomization will be 
stratified by baseline erosive esophagitis. This was updated to denote that 
randomization will be stratified by baseline erosive esophagitis status (present, not 
present) and by Weekly Heartburn Severity Score (WHSS; <3, ≥3). 
4.  Study Synopsis, Methodology, 
Screening Period 
3 
A correction was made to the duration of time that patients must be adherent to their 
PPI regimen (italic and strikethrough text represent a change from the previous 
version):  
The patient must have been adherent to their standard PPI dosage regimen (as per 
product label) for the 30 days 8 weeks prior to the Screening Visit and during the 
entire Screening Period. 
5.  Study Synopsis, Study 
Population 
4 
Enrollment of patients without esophageal erosions was revised to state that the study 
will aim to enroll up to 50% of patients with esophageal erosions. 
6.  Study Synopsis, Criteria for 
Evaluation, Other Efficacy 
Assessments 
9 
Three weekly ‘Degree of Relief’ patient-reported items were added. These 3 new items 
ask the patient to compare their current degree of relief to that experienced before the 
start of the study: 
Degree of Relief of heartburn, regurgitation, and overall GERD symptoms on 
7-point patient global impression of change scale (compared to before you started 
the study; 1=significantly relieved, 4=unchanged, 7=significantly worse) 
 
7.  Study Synopsis, Statistical 
Methods, Analysis Populations 
 
10 
The Analysis Populations were modified as follows (italic and strikethrough text 
represent a change from the previous version): 
The Screened Population consists of all patients who signed informed consent 
and received a patient identification (PID) number to participate in the study. 
The Randomized Population consists of all patients who are randomly were 
assigned to a treatment group (placebo or IW-3718) via randomization either 
placebo or 1500 mg IW-3718. 
The Safety Population consists of all randomized patients who received at least 1 
dose of study drug treatment. 


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Summary of Changes for Amended Protocol: C3718-301 
 
14 August 2020 
 
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Item # 
Section 
Page # 
Description of Change 
The modified Intent-To-Treat (mITT) Population consists of all randomized 
patients who received at least one 1 dose of study treatment drug and have had at 
least 1 postbaseline primary efficacy assessment. one daily heartburn severity 
assessment post baseline 
The Per-Protocol (PP) Population is defined as those patients in the mITT 
Population who have a minimum of 6 weeks of daily heartburn severity 
assessments and ≥80% compliance with study treatment and the PPIs for the period 
during which they are on study. 
 
8.  Study Synopsis, Statistical 
Methods, Primary Efficacy 
Parameter  
10 
The Primary Efficacy Parameter was changed from “Overall Heartburn Responder” to:  
Change from baseline at Week 8 in Weekly Heartburn Severity Score (WHSS). 
• 
The WHSS for a week is the average of the non-missing Daily Heartburn 
Severity Scores (DHSS) for that week. Rules for missingness of data will be 
prespecified in the SAP finalized before database lock. 
• 
The DHSS for a day is the greater score of the 2 mRESQ items assessing 
heartburn severity (“Burning feeling behind the breastbone or in the center of 
the upper stomach” and “Pain behind the breastbone or in the center of the 
upper stomach”) for that day. Where 1 of the 2 mRESQ heartburn severity 
items is missing for the day, the maximum will be the score of the remaining 
item; where both items are missing for the day, the DHSS will be missing. 
9.  Study Synopsis, Statistical 
Methods, Key Secondary 
Efficacy Parameters 
10-11 
The Key Secondary Efficacy Parameters were changed from:  
1. Overall Heartburn Responder – patients with a baseline WHSS ≥ 3 
2. Percent change from baseline to Week 8 in WHSS 
3. Percent change from baseline to Week 8 in Weekly Regurgitation Frequency 
Score (WRFS) 
4. Proportion of heartburn-free days during the 8-week Treatment Period. 
 
to:  
 
1.  
Change from baseline at Week 8 in Weekly Regurgitation Frequency Score 
(WRFS) 


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Item # 
Section 
Page # 
Description of Change 
• 
The WRFS for a week is the average of the non-missing Daily Regurgitation 
Frequency Scores (DRFS) for that week. Rules for missingness of data will be 
prespecified in the SAP finalized before database lock. 
• 
DRFS for a day is the greater score of the 2 mRESQ items assessing 
regurgitation frequency (“Regurgitation [liquid or food moving upwards 
toward your throat or mouth]” and “An acid or bitter taste in the mouth”) for 
that day. 
2.  Overall Heartburn Responder: a patient who is a weekly heartburn responder for 
at least 4 weeks, including at least 1 of the last 2 weeks (Weeks 7 and 8), during 
the 8-week Treatment Period. 
• 
A weekly heartburn responder is a patient with a decrease from baseline of 
≥ 45% in Weekly Heartburn Severity Score (WHSS). 
• 
Rules for missingness of data will be prespecified in the SAP finalized before 
database lock. 
3.  
Proportion of heartburn-free days during the 8-week Treatment Period. 
• 
Proportion of heartburn-free days is calculated as the number of heartburn-free 
(DHSS=0) days divided by the number of diary entry days. 
 
10.  Study Synopsis, Efficacy 
Analysis Methods 
11 
 
 
Previous text: 
For analysis of the primary efficacy parameter and other 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 the IW-
3718 group and the placebo group will be compared using a Cochran-Mantel-
Haenszel (CMH) test controlling for esophagitis status (erosive esophagitis vs. no 
erosive esophagitis), baseline heartburn severity level (<3 vs. ≥3), and geographic 
region. The CMH test is the primary analysis for responder parameters. The 
difference in the proportion of responders between the IW-3718 group and the 
placebo group, as well as the CMH estimate of the odds ratio (IW-3718 over 
placebo) and a 95% confidence interval for the odds ratio, will also be presented. 
For analysis of continuous parameters (e.g., percent change from baseline), 
descriptive statistics (patient number [n], mean, standard deviation, median, and 
range) will be presented for each treatment group. The IW-3718 group will be 
compared with the placebo group by employing a mixed model for repeated 


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measures (MMRM) framework with week (categorical), treatment group, week-by-
treatment group, esophagitis status, and geographic region as fixed-effect terms and 
baseline value as a covariate (if applicable). A compound symmetry covariance 
structure will be used. Least-squares mean (LSM) for each treatment group, LSM 
difference between the IW-3718 group and the placebo group and a 95% confidence 
interval for the difference, as well as the p-value for comparison versus placebo will 
be presented. 
Cumulative distribution function (CDF) of percent change from baseline to Week 8 
in WHSS and WRFS will be plotted by treatment group. To interpret the graphical 
representation of the CDF across treatment, a two-sample Kolmogorov-Smirnov test 
will be conducted.  
Revised text: 
For analysis of the primary efficacy and first key secondary efficacy parameters, 
continuous parameters (eg, change from baseline), descriptive statistics (patient 
number [n], mean, standard deviation, median, and range) will be presented for each 
treatment group. The IW-3718 group will be compared with the placebo group by 
employing a linear mixed-effects model for repeated measures (MMRM) 
framework with week (categorical), treatment group, week-by-treatment group and 
week-by-baseline value interactions, baseline esophagitis status (present vs. not 
present), and baseline WHSS (<3 vs. ≥3) as fixed-effect terms and baseline value as 
a covariate, with patient as a random effect. An unstructured covariance structure 
will be used. Least-squares mean (LSM) for each treatment group, LSM difference 
between the IW-3718 group and the placebo group and a 95% confidence interval 
for the difference at Week 8, as well as the p-value for comparison versus placebo 
will be presented. 
For analysis of responder parameters (ie, responder vs. non-responder), the counts 
and proportions of responders will be calculated for each treatment group. The 
proportions of responders between the IW-3718 group and the placebo group will 
be compared using a Cochran-Mantel-Haenszel (CMH) test controlling for baseline 
esophagitis status (erosive esophagitis vs. no erosive esophagitis) and baseline 
WHSS (<3 vs. ≥3). The CMH test is the primary analysis for responder parameters. 
The difference in the proportion of responders between the IW-3718 group and the 
placebo group, as well as the CMH estimate of the odds ratio (IW-3718 over 
placebo) and a 95% confidence interval for the odds ratio, will also be presented. 


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Time-dependent proportion parameters, defined as days the event of interest occurs, 
divided by the number of eDiary entry days within the 8-week Treatment Period 
(eg, proportion of heartburn-free-days), will be analyzed using a Poisson model 
which is appropriate for count data. The analysis includes the treatment, the baseline 
esophagitis status (present vs. not present), baseline WHSS (<3 vs. ≥3), covariate of 
baseline proportion of event-free days, with the eDiary entry days adjusted in the 
model. In the case of overdispersion, a negative binomial model instead of Poisson 
regression will be implemented. Model estimates in difference between the rates for 
IW-3718 and placebo groups will be calculated with corresponding 95% confidence 
interval and p-value associated with the comparisons to placebo. 
11.  Synopsis, Sample Size 
Determination and Controlling 
for Type-I Error 
12-13 
The sample size power calculations were revised to reflect the new primary and key 
secondary efficacy parameters using data from previously completed Phase 2b 
Study ICP-3718-202 which enrolled a similar study population. The revised text is as 
follows: 
The sample size calculations for the primary and key secondary efficacy parameters 
are based on results from patients with evidence of pathological acid reflux (positive 
baseline Bravo status) in Study ICP-3718-202, which had a similar study population 
as the current study.  
The primary efficacy parameter is Change from Baseline at Week 8 in WHSS, and 
key secondary efficacy parameters include: 
• 
Change from Baseline at Week 8 in WRFS 
• 
Overall Heartburn Responder 
• 
Proportion of Heartburn-free Days during the 8-week Treatment Period  
Using data from patients in Study ICP-3718-202, we derived the estimated results at 
end of the study as follows: 
 
 
 
 
 
 
 
 


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Order of 
Hypothesis 
Testing 
Parameter 
Placebo  
(+ PPIs) 
1500 mg IW-3718 
(+ PPIs) 
1 
Change from Baseline at Week 8 
in WHSS 
N = 43 
Mean = -1.58 
SD = 1.20 
N =51 
Mean = -2.01 
SD = 1.29 
2 
Change from Baseline at Week 8 
in WRFS 
N = 43 
Mean = -0.81 
SD = 1.12 
N = 51 
Mean = -1.26 
SD = 0.91 
3 
Overall Heartburn Responder 
18/49 = 36.7% 
31/55 = 56.4% 
4 
Proportion of Heartburn-free Days 
during the 8-week Treatment 
Period 
N = 48 
Mean = 0.195 
SD = 0.2822 
N = 55 
Mean = 0.268 
SD = 0.2928 
The efficacy parameters will be tested sequentially according to the above order at 
a 2-sided significance level of 0.05 so that the overall type-I error rate is 
maintained at 0.05.  
Based on bootstrap simulations, a sample size of 330 patients per group will 
provide approximately 99% power to detect a treatment difference between 
1500-mg IW-3718 (while receiving PPIs) and placebo (while receiving PPIs) for 
the primary efficacy parameter, assuming the randomized population in this study 
is consistent with the selected population from Study ICP-3718-202. Power that is 
based on simulations for all type-I error controlling key efficacy parameters are 
presented in the table below. The 2-sample t-test was used for continuous 
parameters and the Chi-square test was used for the responder parameter.  


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Order of 
Hypothesis 
Testing 
Parameters 
Power for 
Fixed 
Sequence 
Testing 
1 
Change from Baseline at Week 8 in WHSS 
99% 
2 
Change from Baseline at Week 8 in WRFS 
99% 
3 
Overall Heartburn Responder 
99% 
4 
Proportion of Heartburn-free Days during the 8-week 
Treatment Period 
88% 
 
 
12.  Schedule of Events, EGD 
(esophagogastroduodenoscopy), 
Footnote E 
14-15 
Text was revised as per an Administrative Letter dated 28 May 2019 to clarify which 
patients will have a repeat EGD (italic and strikethrough text represent a change from 
the previous version): 
A repeat EGD will be performed at the Week 8 / EOT Visit for all patients who 
have completed at least 4 weeks of treatment and had erosive esophagitis on the 
screening EGD (based on the Los Angeles [LA] classification of esophagitis, see 
Appendix 5) as determined by either the site personnel or the central reader. An 
EGD will be performed at the Week 8 / EOT Visit in all patients who have Grades 
A, B, C, or D esophagitis (based on the Los Angeles [LA] classification of 
esophagitis) on the EGD obtained during the Screening Period and have completed 
≥4 weeks of treatment. 
13.  Schedule of Events, Drug and 
Alcohol Screen Footnote L 
14-15 
Phencyclidine had been required in the previous version of the protocol and was added 
to the list of drugs of abuse included in the urine screen. 
14.  Section 1.2, IW-3718 
27 
Depomed, the manufacturer of Acuform®, was updated to its current name, Assertio. 


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15.  Section 3.1, Overall Study 
Design and Plan: Description 
(Figure and Treatment Period) 
34, 36 
Figure 1, Overview of Study Design, was updated to denote that randomization will be 
stratified by baseline EE status (present, not present) and Weekly Heartburn Severity 
Score (WHSS; <3, ≥3). 
Text was updated for clarity (italic and strikethrough text represent a change from the 
previous version): 
Patients will be stratified by whether they have, or do not have, EE on the 
screening EGD, and by their baseline weekly heartburn severity level score (WHSS, 
defined as the average heartburn severity score over the last 7 days prior to 
randomization of <3 vs. ≥3; see Section 3.5.7.1) and randomly assigned within 
each stratum to placebo or 1500 mg IW-3718 BID (1:1). 
16.  Section 3.1, Overview of Study 
Design and Plan: Description 
(Screening Period) 
35 
A correction was made to the duration of time that patients must be adherent to their 
PPI regimen (italic and strikethrough text represent a change from the previous 
version): 
The patient must have been adherent to their standard PPI dosage regimen (as per 
product label) for the 30 days 8 weeks prior to the Screening Visit and during the 
entire Screening Period. 
17.  Section 3.1, Overview of Study 
Design and Plan: Description 
(Treatment Period) 
36 
Text was revised as per an Administrative Letter dated 28 May 2019 to clarify which 
patients will have a repeat EGD (italic and strikethrough text represent a change from 
the previous version): 
A repeat EGD will be performed at the Week 8 / EOT Visit for all patients who 
have completed at least 4 weeks of treatment and had erosive esophagitis on the 
screening EGD (based on the Los Angeles [LA] classification of esophagitis, see 
Appendix 5) as determined by either the site personnel or the central reader. All 
patients who have erosive esophagitis (LA classification A-D) on EGD at 
Screening and completed ≥4 weeks of treatment will have a repeat EGD at their 
EOT Visit. 
18.  Section 3.3, Selection of Study 
Population 
37 
Text was updated to reflect the new sample size and the stratification by baseline EE 
status and WHSS (italic and strikethrough text represent a change from the previous 
version): 
Patients will be stratified for treatment assignment at the time of randomization 
based on the presence of esophageal erosions (erosions, no erosions) and by 
baseline WHSS (<3 vs. ≥3). Enrollment of patients without esophageal erosions will 
be capped at approximately The study will aim to enroll up to 50% of total 


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enrollment patients with esophageal erosions. Patients must be receiving 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 labelling. Approximately 660 patients (330 patients 
per treatment arm) will be randomized to treatment. 
19.  Section 3.3.1.2, Exclusion 
Criteria 
40 
Criterion # 14 was modified to reflect the criterion as listed in the Synopsis and 
guidance from an Administrative Letter dated 10 October 2018. Only elevated serum 
bilirubin at Screening (and not during the Pretreatment Period) is exclusionary. 
20.  Section 3.4.4; Method of 
Assigning Patients to a 
Treatment Group 
45 
Text was updated to reflect the stratification by baseline EE status and WHSS (italic 
and strikethrough text represent a change from the previous version): 
Eligible patients will be stratified by whether they have or do not have erosive 
esophagitis on the screening EGD, and by their baseline heartburn severity level 
WHSS (<3 vs. ≥3), and then randomized through central randomization in a 1:1 ratio 
to receive either 1500 mg IW-3718 BID or placebo BID, both administered in 
addition to the patient’s per-label QD PPI therapy. 
21.  Section 3.5.1.3, Procedures for 
Collecting and Reporting 
Serious Adverse Events 
50 
References to XML file formats were deleted. 
22.  Section 3.5.6, Clinical 
Laboratory Determinations 
59 
Phencyclidine had been required in the previous version of the protocol and was added 
to the list of drugs of abuse included in the urine screen. 
23.  Section 3.5.7.2, Weekly 
Assessments 
60-61 
Three weekly ‘Degree of Relief’ patient-reported items were added. These 3 new items 
ask the patient to compare their current degree of relief to that experienced before the 
start of the study: 
• 
Compared to before you started this study, how would you rate your heartburn 
(a pain or burning sensation in your chest, behind the breastbone) over the past 
7 days? 
• 
Compared to before you started this study, 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? 


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24.  Section 3.5.8.1, 
Esophagogastroduodenoscopy 
62 
The following operational details were added for the EGD interpretation (italic and 
strikethrough text represent a change from the previous version): 
All patients will be required to undergo an EGD during the Screening Period. 
There should be a minimum of 7 days between the EGD and the start of the 
Pretreatment Period to allow for pH testing and patient stabilization. EGDs will be 
interpreted by the local site personnel and by a central reader. Details are 
provided in a separate study manual (Image Acquisition Guidelines for Ironwood 
Pharmaceuticals, Inc. Protocols C3718-301/C3718-302; WorldCare Clinical). 
 
An EGD will be performed at the Week 8 / EOT Visit in all patients who 
completed at least 4 weeks of treatment and had erosive esophagitis on the EGD 
obtained during the Screening Period patients (based on the Los Angeles [LA] 
classification of esophagitis, [see Appendix 5]) on the EGD obtained during the 
Screening Period as determined by either the site personnel or the central reader) 
who completed at least 4 weeks of treatment.  
25.  Section 3.5.8.2, Bravo™ 
62 
To reflect the use of a central reader, the following text was added: 
To determine eligibility, a centralized review of pH monitoring will be conducted 
for each patient. 
26.  Section 3.6.1.1, Screening Visit 
(Visit 1) Procedures 
63 
Phencyclidine was added to the list of drugs of abuse included in the urine drug screen. 
27.  Section 3.6.2.3, Week 8/End-
of-treatment (Visit 5) 
Procedures 
66 
For EGD, the following clarification was added (italic and strikethrough text represent 
a change from the previous version): 
EGD (A repeat EGD will be performed at the Week 8/EOT Visit for all patients 
who have completed at least 4 weeks of treatment and had erosive esophagitis on 
the screening EGD [based on the LA classification of esophagitis, see Appendix 5] 
as determined by either the site personnel or the central reader patients with 
erosions [LA Classification Grades A-D] at Screening; see Section 3.5.8.1.) 
28.  Section 3.7.1, Analysis 
Populations 
67 
The Analysis Populations were modified as follows (italic and strikethrough text 
represent a change from the previous version): 
The Screened Population consists of all patients who signed informed consent 
and received a patient identification (PID) number to participate in the study. 


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The Randomized Population consists of all patients who are randomly were 
assigned to a treatment group (placebo or IW-3718) via randomization either 
placebo or 1500 mg IW-3718. 
The Safety Population consists of all randomized patients who received at least 1 
dose of study drug treatment. 
The modified Intent-To-Treat (mITT) Population consists of all randomized 
patients who received at least one 1 dose of study treatment drug and have had at 
least 1 postbaseline primary efficacy assessment. one daily heartburn severity 
assessment post baseline 
The Per-Protocol (PP) Population is defined as those patients in the mITT 
Population who have a minimum of 6 weeks of daily heartburn severity 
assessments and ≥80% compliance with study treatment and the PPIs for the period 
during which they are on study. 
 
29.  Section 3.7.3, Patient 
Disposition, Demographics, and 
Baseline Characteristics 
68 
Text was changed to reflect the deletion of the Per Protocol (PP) population (italic and 
strikethrough text represent a change from the previous version): 
The count and proportion of patients included in the Randomized, mITT, PP, and 
Safety, and mITT Populations will be presented overall and by treatment group. The 
number of patients in the Screened Population will be presented overall. 
30.  Section 3.7.4; Efficacy 
Analyses, Table 4 
69 
In Table 4, footnote “b” was revised as follows (italic and strikethrough text represent 
a change from the previous version):  
b. 
Unless otherwise specified, bBaseline for efficacy parameters will be derived 
from the daily eDiary collected for Pretreatment Week -1 (Week -2 if data for Week 
-1 not available); specifically for the proportion endpoints (defined as days with the 
event of interest divided by the number of diary entry days), the last 14 days    
(Week -2 to Week -1) prior to day of randomization will be used. 
 
31.   Section 3.7.4.1; Primary 
Efficacy Parameter 
70 
The Primary Efficacy Parameter was changed from “Overall Heartburn Responder” to:  
Change from baseline at Week 8 in Weekly Heartburn Severity Score (WHSS). 
• 
The WHSS for a week is the average of the non-missing Daily Heartburn 
Severity Scores (DHSS) for that week. Rules for missingness of data will be 
prespecified in the SAP finalized before database lock. 


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• 
The DHSS for a day is the greater score of the 2 mRESQ items assessing 
heartburn severity (“Burning feeling behind the breastbone or in the center of 
the upper stomach” and “Pain behind the breastbone or in the center of the 
upper stomach”) for that day. Where 1 of the 2 mRESQ heartburn severity 
items is missing for the day, the maximum will be the score of the remaining 
item; where both items are missing for the day, the DHSS will be missing. 
32.  Section 3.7.4.2; Key Secondary 
Efficacy Parameters 
71 
The Key Secondary Efficacy Parameters were changed from:  
1. 
Overall Heartburn Responder – patients with a baseline WHSS ≥ 3 
2. 
Percent change from baseline to Week 8 in WHSS 
3. 
Percent change from baseline to Week 8 in Weekly Regurgitation Frequency 
Score (WRFS) 
4. 
Proportion of heartburn-free days during the 8-week Treatment Period. 
 
to:  
 
1. 
Change from baseline at Week 8 in Weekly Regurgitation Frequency Score 
(WRFS) 
• 
The WRFS for a week is the average of the non-missing Daily 
Regurgitation Frequency Scores (DRFS) for that week. Rules for 
missingness of data will be prespecified in the SAP finalized before 
database lock. 
• 
DRFS for a day is the greater score of the 2 mRESQ items assessing 
regurgitation frequency (“Regurgitation [liquid or food moving upwards 
toward your throat or mouth]” and “An acid or bitter taste in the mouth”) 
for that day. 
2. 
Overall Heartburn Responder: a patient who is a weekly heartburn responder 
for at least 4 weeks, including at least 1 of the last 2 weeks (Weeks 7 and 8), 
during the 8-week Treatment Period. 
• 
A weekly heartburn responder is a patient with a decrease from baseline 
of ≥ 45% in Weekly Heartburn Severity Score (WHSS). 
• 
Rules for missingness of data will be prespecified in the SAP finalized 
before database lock. 
3. 
Proportion of heartburn-free days during the 8-week Treatment Period. 


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• 
Proportion of heartburn-free days is calculated as the number of 
heartburn-free (DHSS=0) days divided by the number of diary entry days. 
 
33.  Section 3.7.4.3, Analysis 
Methods for the Primary and 
Key Secondary Efficacy 
Parameters 
71-72 
The section was renamed (italic text represents an addition):“Analysis Methods for the 
Primary and Key Secondary Efficacy Parameters”.  
Previous text: 
For analysis of the primary efficacy parameter and other 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 the 
IW-3718 group and the placebo group will be compared using a Cochran-Mantel-
Haenszel (CMH) test controlling for esophagitis status (erosive esophagitis vs. no 
erosive esophagitis), baseline heartburn severity level (<3 vs. ≥3), and geographic 
region. The CMH test is the primary analysis for responder parameters. The 
difference in the proportion of responders between the IW-3718 group and the 
placebo group, as well as the CMH estimate of the odds ratio (IW-3718 over 
placebo) and a 95% confidence interval for the odds ratio, will also be presented. 
For analysis of continuous parameters (e.g., percent change from baseline), 
descriptive statistics (patient number [n], mean, standard deviation, median, and 
range) will be presented for each treatment group. The IW-3718 group will be 
compared with the placebo group by employing a mixed model for repeated 
measures (MMRM) framework with week (categorical), treatment group, week-by-
treatment group, esophagitis status, and geographic region as fixed-effect terms 
and baseline value as a covariate (if applicable). A compound symmetry 
covariance structure will be used. Least-squares mean (LSM) for each treatment 
group, LSM difference between the IW-3718 group and the placebo group and a 
95% confidence interval for the difference, as well as the p-value for comparison 
versus placebo will be presented. 
Cumulative distribution function (CDF) of percent change from baseline to Week 8 
in WHSS and WRFS will be plotted by treatment group. To aid in the 
interpretation of the graphical representation of the CDF across treatment, a two-
sample Kolmogorov-Smirnov test will be conducted.  
Revised text: 


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Summary of Changes for Amended Protocol: C3718-301 
 
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For analysis of the primary efficacy and first key secondary efficacy parameters, 
continuous parameters (eg, change from baseline), descriptive statistics (patient 
number [n], mean, standard deviation, median, and range) will be presented for 
each treatment group. The IW-3718 group will be compared with the placebo 
group by employing a linear mixed-effects model for repeated measures (MMRM) 
framework with week (categorical), treatment group, week-by-treatment group and 
week-by-baseline value interactions, baseline esophagitis status (present vs. not 
present), and baseline WHSS (<3 vs. ≥3) as fixed-effect terms and baseline value 
as a covariate, with patient as a random effect. An unstructured covariance 
structure will be used. Least-squares mean (LSM) for each treatment group, LSM 
difference between the IW-3718 group and the placebo group and a 95% 
confidence interval for the difference at Week 8, as well as the p-value for 
comparison versus placebo will be presented. 
For analysis of responder parameters (ie, responder vs. non-responder), the counts 
and proportions of responders will be calculated for each treatment group. The 
proportions of responders between the IW-3718 group and the placebo group will 
be compared using a Cochran-Mantel-Haenszel (CMH) test controlling for baseline 
esophagitis status (erosive esophagitis vs. no erosive esophagitis) and baseline 
WHSS (<3 vs. ≥3). The CMH test is the primary analysis for responder parameters. 
The difference in the proportion of responders between the IW-3718 group and the 
placebo group, as well as the CMH estimate of the odds ratio (IW-3718 over 
placebo) and a 95% confidence interval for the odds ratio, will also be presented. 
Time-dependent proportion parameters, defined as days the event of interest 
occurs, divided by the number of eDiary entry days within the 8-week Treatment 
Period (eg, proportion of heartburn-free-days), will be analyzed using a Poisson 
model which is appropriate for count data. The analysis includes the treatment, the 
baseline esophagitis status (present vs. not present), baseline WHSS (<3 vs. ≥3), 
covariate of baseline proportion of event-free days, with the eDiary entry days 
adjusted in the model. In the case of overdispersion, a negative binomial model 
instead of Poisson regression will be implemented. Model estimates in difference 
between the rates for IW-3718 and placebo groups will be calculated with 
corresponding 95% confidence interval and p-value associated with the 
comparisons to placebo. 


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34.  Section 3.7.4.4, Controlling 
Type-I Error 
72-73 
The section was revised to reflect the new primary and 3 key secondary efficacy 
parameters. The primary and key secondary efficacy parameters will be tested 
sequentially according to the following order, each at a 2-sided significance level 
of 0.05: 
 
 
Order 
Parameter 
1 
Change from Baseline at Week 8 in WHSS (primary) 
2 
Change from Baseline at Week 8 in WRFS 
3 
Overall Heartburn Responder 
4 
Proportion of Heartburn-free Days during the 8-week Treatment Period 
Testing of subsequent parameters will not be performed unless all previous parameters 
have been tested statistically significant (p≤0.05) 
35.  Section 3.7.4.5, Sensitivity 
Analysis of Primary Efficacy 
Parameter 
73 
Text was revised as follows (italic and strikethrough text represent a change from the 
previous version):  
 
For the primary and first secondary endpoint, parameter, change from baseline in 
WHSS at Week 8, a sensitivity analysis will be conducted; details will be provided 
in the SAP where both a reduction of at least 45% in WHSS and no decrease in 
proportion of heartburn-free days are required for a patient to be considered a 
weekly heartburn responder. 
36.  Section 3.7.4.6, Handling of 
Missing Data 
73 
Text was revised as follows (italic and strikethrough text represent a change from the 
previous version):  
 
In the primary analysis of the primary efficacy parameter Overall Heartburn 
Responder and first key secondary efficacy parameter Overall Regurgitation 
Responder – patients with a baseline WHSS ≥ 3, a patient who reported daily 
symptom severity scores for less than 4 days during a week will not be considered a 
weekly responder for that week. This approach essentially classifies the weekly 
symptom severity score as missing for any treatment week (intermittent or post-
dropout) for which less than 4 daily scores are available. Furthermore, this approach 
imputes a weekly responder status of “non-responder” for that week. 


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In the primary analysis of the key secondary efficacy parameters Percent Change 
from Baseline to Week 8 in WHSS and WRFS, no imputation will be performed on 
missing data. The weekly symptom severity score will be computed as the average 
of all available daily scores for that week, regardless of the number of daily score 
available for that week. If there is not a single daily score available for a week, then 
the weekly score for that week is missing and is included in the MMRM analysis as 
missing. 
For the primary efficacy analysis, change from baseline at Week 8 in WHSS, no 
imputation will be performed on missing data. The WHSS will be computed as the 
average of daily scores for that week. Rules for the average calculation will be 
prespecified in the SAP finalized before database lock. 
A pattern-mixture model with control-based pattern imputation will be implemented 
as a multiple imputation method to explore the effects of missing data on the 
primary and key secondary efficacy parameters. The details of this approach will be 
provided in the SAP. 
37.  Section 3.7.4.7, Exploratory 
Efficacy Parameters and 
Analysis Methods 
73-75 
The previous Section 3.7.4.3, “Additional Secondary Efficacy Parameters” and the 
previous Section 3.7.4.8, “Additional Efficacy Parameters” were consolidated into a 
new section: Section 3.7.4.7, “Exploratory Efficacy Parameters and Analysis 
Methods”. Parameters that were previous “Key Secondary Efficacy Parameters”, 
previous “Additional Secondary Efficacy Parameters”, and “Additional Efficacy 
Parameters”, were all preserved in this new consolidated section listing endpoints and 
descriptive supportive summaries. 
In addition, 3 new endpoints were added: 
 
Change from baseline of proportion in days when heartburn did not occur 
(DHSS = 0) or was very mild (DHSS = 1) during the 8-week Treatment Period 
 
Change from baseline in proportion of days when regurgitation did not occur 
(DRFS = 0) or rarely occurred (DRFS = 1) during the 8-week Treatment 
Period 
• 
Proportion of patients with erosive esophagitis (EE) improved by at least 
1 grade at Week 8 
Globally, endpoints and descriptive data summaries phrased as “change from baseline 
to Week 8” were rephrased as “change from baseline at Week 8”. 


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Summary of Changes for Amended Protocol: C3718-301 
 
14 August 2020 
 
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Item # 
Section 
Page # 
Description of Change 
38.  Section 3.7.7, Determination of 
Sample Size 
76-77 
The sample size power calculations were revised to reflect the new primary and key 
secondary efficacy parameters using data from previously completed Phase 2b 
Study ICP-3718-202 which enrolled a similar study population. The revised text is as 
follows: 
The sample size calculations for the primary and key secondary efficacy parameters 
are based on results from patients with evidence of pathological acid reflux (positive 
baseline Bravo status) in Study ICP-3718-202, which had a similar study population 
as the current study.  
The primary efficacy parameter is Change from Baseline at Week 8 in WHSS, and 
key secondary efficacy parameters include: 
• 
Change from Baseline at Week 8 in WRFS 
• 
Overall Heartburn Responder 
• 
Proportion of Heartburn-free Days during the 8-week Treatment Period  
Using data from patients in Study ICP-3718-202, we derived the estimated results at 
end of the study as follows: 
 
Order of 
Hypothesis 
Testing 
Parameter 
Placebo  
(+ PPIs) 
1500 mg IW-3718 
(+ PPIs) 
1 
Change from Baseline at Week 8 
in WHSS 
N = 43 
Mean = -1.58 
SD = 1.20 
N =51 
Mean = -2.01 
SD = 1.29 
2 
Change from Baseline at Week 8 
in WRFS 
N = 43 
Mean = -0.81 
SD = 1.12 
N = 51 
Mean = -1.26 
SD = 0.91 
3 
Overall Heartburn Responder 
18/49 = 36.7% 
31/55 = 56.4% 
4 
Proportion of Heartburn-free Days 
during the 8-week Treatment 
Period 
N = 48 
Mean = 0.195 
SD = 0.2822 
N = 55 
Mean = 0.268 
SD = 0.2928 
 


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Summary of Changes for Amended Protocol: C3718-301 
 
14 August 2020 
 
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Item # 
Section 
Page # 
Description of Change 
The efficacy parameters will be tested sequentially according to the above order at 
a 2-sided significance level of 0.05 so that the overall type-I error rate is 
maintained at 0.05.  
Based on bootstrap simulations, a sample size of 330 patients per group will 
provide approximately 99% power to detect a treatment difference between 
1500-mg IW-3718 (while receiving PPIs) and placebo (while receiving PPIs) for 
the primary efficacy parameter, assuming the randomized population in this study 
is consistent with the selected population from Study ICP-3718-202. Power that is 
based on simulations for all type-I error controlling key efficacy parameters are 
presented in the table below. The 2-sample t-test was used for continuous 
parameters and the Chi-square test was used for the responder parameter.  
 
Order of 
Hypothesis 
Testing 
Parameters 
Power for 
Fixed 
Sequence 
Testing 
1 
Change from Baseline at Week 8 in WHSS 
99% 
2 
Change from Baseline at Week 8 in WRFS 
99% 
3 
Overall Heartburn Responder 
99% 
4 
Proportion of Heartburn-free Days during the 8-week 
Treatment Period 
88% 
 
 
39.  Section 5, Investigators and 
Study Administrative Structure 
81 
The European Union (EU) was removed from the list of countries with study centers. 
40.  Appendix 3, Weekly 
Assessments 
96 
For consistency with Protocol Section 3.5.7.2, the following question was added: 
“How much were you bothered by your overall GERD symptoms over the past 
7 days?” 
 


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Summary of Changes for Amended Protocol: C3718-301 
 
14 August 2020 
 
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Item # 
Section 
Page # 
Description of Change 
41.  Appendix 3, Weekly 
Assessments 
95 
Three weekly ‘Degree of Relief’ patient-reported items were added. These 3 new items 
ask the patient to compare their current degree of relief to that experienced before the 
start of the study: 
• 
Compared to before you started this study, how would you rate your heartburn 
(a pain or burning sensation in your chest, behind the breastbone) over the past 
7 days? 
• 
Compared to before you started this study, 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? 
42.  Appendix 4, Prohibited 
Medications, 14-Day Washout 
97 
In accordance with results from a completed drug-drug interaction study, C3718-103 as 
described in the Investigator’s Brochure (Edition 5, dated 10 March 2020), 
levothyroxine and digoxin were removed from the list of prohibited medications 
(strikethrough text represents a deletion from the previous version): 
• 
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) 
43.  Appendix 4, Prohibited 
Medications, Notes Regarding 
Concomitant Medications 
98 
PPIs formulated in combination with other drugs were prohibited. 
In accordance with results from a completed drug-drug interaction study, C3718-103, 
and as described in the Investigator’s Brochure (Edition 5, dated 10 March 2020), no 
drug-drug interaction was observed when IW-3718 was dosed in combination with oral 
contraceptives containing ethinyl estradiol and norethindrone. As such, this type of 
medication is now permitted as a single contraceptive modality.  
Changes were as follows (italic and strikethrough text represent changes from the 
previous version): 
Patients must have been on once-daily (QD) PPI therapy for at least 8 weeks before 
the Screening Visit and continue to take their PPI through the EOT visit. PPIs that 
are formulated in combination with other drugs are not permitted (eg, Zegerid® 
[omeprazole/sodium bicarbonate], Vimovo® [esomeprazole/naproxen]). 
 


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Item # 
Section 
Page # 
Description of Change 
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. 
 
Oral contraceptives containing ethinyl estradiol and norethindrone have a known 
were shown not to have a drug-drug interaction with colesevelam IW-3718 (see the 
IW-3718 Investigator’s Brochure, Edition 5, dated 10 March 2020). All female 
patients of childbearing potential may use using oral contraceptives with the 
ingredients listed above as birth control and must agree to use without using 
another an additional form of contraception, from the date they sign the ICF until 
24 hours after their final dose of study drug (eg, condom). 
44.  Entire Document 
All 
Small editorial and formatting changes were made to improve protocol readability. 
 


The data and information related to my line function, which has been included 
with this file, are truthful and accurate.
Signature Page for VV-CLIN-004512 
v1.0
Approval
Approval

SAP_001.pdf: 
Ironwood Pharmaceuticals, Inc. 
 
IW-3718 
Statistical Analysis Plan: C3718-301 
 
14 January 2021 
 
1 
 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
 
VERSION: 1.0 
DATE OF PLAN: 14 January 2021 
 
STUDY DRUG: 
IW-3718 
PROTOCOL NUMBER: 
C3718-301 
STUDY TITLE: 
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Trial of 
Oral IW-3718 Administered to Patients with Gastroesophageal Reflux Disease while receiving 
Proton Pump Inhibitors 
 
SPONSOR: 
Ironwood Pharmaceuticals, Inc. 
100 Summer Street, Suite 2300 
Boston, MA 02110 
 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY OBJECTIVES ..............................................................................................10 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
General Description ....................................................................................................11 
3.2. 
Discussion of Study Design, Including Choice of Control Group .............................11 
3.3. 
Treatment Administered .............................................................................................12 
3.4. 
Assigning Patient to Treatment Group .......................................................................12 
3.5. 
Blinding ......................................................................................................................13 
4. 
DETERMINATION OF SAMPLE SIZE ...................................................................14 
5. 
PHARMACOKINETICS, EFFICACY, AND SAFETY ASSESSMENTS ...............16 
5.1. 
Pharmacokinetic Assessments ....................................................................................16 
5.2. 
Efficacy Assessments .................................................................................................16 
5.2.1. 
Primary Efficacy Assessment .....................................................................................20 
5.2.2. 
Secondary Efficacy Assessments ...............................................................................20 
5.2.3. 
Other Efficacy Assessments .......................................................................................20 
5.3. 
Health Outcomes Assessments ...................................................................................21 
5.4. 
Other Assessments ......................................................................................................21 
5.5. 
Safety Assessments .....................................................................................................22 
5.5.1. 
Adverse Events ...........................................................................................................22 
5.5.1.1. 
Adverse Events Causality Assessment .......................................................................23 
5.5.1.2. 
Classification of Adverse Event Severity ...................................................................23 
5.5.1.3. 
Serious Adverse Events ..............................................................................................24 
5.5.2. 
Medical and Disease History ......................................................................................24 
5.5.3. 
Physical Examination, Body Weight, and Height ......................................................24 
5.5.4. 
Vital Signs ..................................................................................................................25 
5.5.5. 
Electrocardiograms .....................................................................................................25 
5.5.6. 
Clinical Laboratory Data ............................................................................................25 
6. 
STATISTICAL METHODS .......................................................................................26 
6.1. 
General Methods .........................................................................................................26 


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6.2. 
Adjusting for Baseline Characteristics and Covariates ..............................................26 
6.3. 
Handling of Dropouts/Missing Data Imputation Method ...........................................26 
6.4. 
Interim Analysis and Data Monitoring .......................................................................26 
6.5. 
Multicenter Studies .....................................................................................................27 
6.6. 
Multiple Comparisons/Multiplicity ............................................................................27 
6.7. 
Examination of Subgroups .........................................................................................27 
7. 
ANALYSIS METHODS ............................................................................................28 
7.1. 
Analysis Populations ..................................................................................................28 
7.2. 
Patient Disposition ......................................................................................................28 
7.3. 
Demographics and Other Baseline Characteristics .....................................................29 
7.4. 
Compliance .................................................................................................................29 
7.4.1. 
Treatment Compliance ................................................................................................29 
7.4.2. 
eDiary Compliance .....................................................................................................29 
7.5. 
Extent of Exposure .....................................................................................................30 
7.6. 
Protocol Deviations ....................................................................................................31 
7.7. 
Prior and Concomitant Medication .............................................................................31 
7.8. 
Rescue Medicine Use .................................................................................................31 
7.9. 
Efficacy Analysis ........................................................................................................32 
7.9.1. 
Primary Efficacy Parameter ........................................................................................32 
7.9.1.1. 
Estimands ....................................................................................................................32 
7.9.1.2. 
Analysis of the Primary Efficacy Parameter ..............................................................33 
7.9.1.3. 
Sensitivity Analysis Based on Multiple Imputation – Missing Not at Random 
(MNAR) ......................................................................................................................34 
7.9.2. 
Key Secondary Efficacy Parameters ..........................................................................35 
7.9.2.1. 
Analysis of the Secondary Efficacy Parameters .........................................................36 
7.9.3. 
Exploratory Efficacy Parameters ................................................................................37 
7.10. 
Safety Analysis ...........................................................................................................39 
7.10.1. 
Adverse Events ...........................................................................................................40 
7.10.2. 
Clinical Laboratory Parameters ..................................................................................40 
7.10.3. 
Vital Signs ..................................................................................................................42 
7.10.4. 
ECG Parameters ..........................................................................................................43 
7.10.5. 
Medical and Disease History ......................................................................................44 
7.10.6. 
Physical Examination .................................................................................................44 


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7.11. 
Health Outcome Analysis ...........................................................................................44 
7.11.1. 
WPAI-Sleep Disturbance-GERD ...............................................................................44 
7.11.2. 
EQ-5D-3L ...................................................................................................................44 
8. 
REFERENCES ...........................................................................................................45 
APPENDIX 1. MISSING DATA SIMULATION TO SUPPORT THE KEY 
EFFICACY PARAMETERS SCORING ALGORITHM ..........................................46 
APPENDIX 2. VISIT WINDOW SLOTTING CONVENTIONS .............................................52 
APPENDIX 3. POOLING OF TRIAL CENTERS .....................................................................54 
APPENDIX 4. SCHEDULE OF EVALUATIONS ....................................................................55 
APPENDIX 5. MODIFIED REFLUX SYMPTOM QUESTIONNAIRE 
ELECTRONIC DIARY ..............................................................................................58 
APPENDIX 6. OTHER DAILY ASSESSMENTS.....................................................................59 
APPENDIX 7. WEEKLY ASSESSMENTS ..............................................................................60 
APPENDIX 8. LOS ANGELES CLASSIFICATION OF ESOPHAGITIS ...............................62 
 
 
 


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LIST OF TABLES 
Table 1:  
Study ICP-3718-202 - Summary of Efficacy Parameters at Week 8 
(BRAVO+) .................................................................................................................14 
Table 2:  
Hypothesis Testing Order and Power for Fixed Sequence Testing ............................15 
Table 3: 
Efficacy Assessment Instruments and Parameters .....................................................17 
Table 4: 
Testing Order of Efficacy Parameters for the Fixed Sequence Testing .....................27 
Table 5: 
Subgroup Variables ....................................................................................................27 
Table 6: 
Analysis and Assumptions of the Secondary Efficacy Parameters ............................36 
Table 7: 
Exploratory Efficacy Parameters and Analysis Methods ...........................................37 
Table 8: 
Criteria for Potentially Clinically Significant Laboratory Results .............................41 
Table 9: 
Criteria for Potentially Clinically Significant Vital Signs ..........................................43 
Table 10: Criteria for Potentially Clinically Significant ECG Parameters .................................43 
Table 11: Simulation Results for WHSS During the 8-week Treatment Period ........................48 
Table 12: Simulation Results for WRFS During the 8-week Treatment Period .........................49 
Table 13: Simulation Results for PHFD During the 8-week Treatment Period .........................51 
Table 14: Visit Time Windows for Safety Analysis ...................................................................52 
Table 15: Analysis Time Windows for Efficacy Analysis – Daily Assessments .......................52 
Table 16: Analysis Time Windows for Efficacy Analysis – Weekly Assessments ...................53 
Table 17: Definition of Geographic Regions ..............................................................................54 
Table 18: Schedule of Evaluations .............................................................................................55 
 
 
 


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LIST OF FIGURES 
Figure 1: 
Overview of Study Design ..........................................................................................12 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BID 
twice daily 
BP 
blood pressure 
BPM 
beats per minute 
CDF 
cumulative distribution function 
CI 
confidence interval 
CMH 
Cochran Mantel-Haenszel 
CRO 
contract research organization 
DHSS 
Daily Heartburn Severity Score 
DPP 
Data Presentation Plan 
DRFS 
Daily Regurgitation Frequency Score 
eCRF 
electronic case report form 
eDiary 
electronic diary 
ECG 
electrocardiogram 
EE 
erosive esophagitis 
EGD 
esophagogastroduodenoscopy 
EOT 
end of treatment 
EQ 
EuroQol 
GERD 
gastroesophageal reflux disease 
HEENT 
head, ears, eyes, nose, throat 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IPD 
important protocol deviations 
IWRS 
interactive web response system 
LLN 
lower limit of normal 
IRT 
interactive response technology 
LS 
least squares 
MAR 
missing at random 


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MCMC 
Monte-Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MI 
multiple imputation 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
mRESQ-eD 
modified Reflux Symptom Questionnaire - electronic Diary 
non-EE 
without erosive esophagitis 
OHR 
Overall Heartburn responder 
PCS 
potentially clinically significant 
PHFD 
proportion of heartburn-free days 
PT 
preferred term 
PID 
patient identification number 
PPI 
proton pump inhibitors 
QD 
once daily 
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 
US 
United States 
WHSS 
Weekly Heartburn Severity Score 
WPAIQ 
Work Productivity and Activity Impairment Questionnaire 
WRFS 
Weekly Regurgitation Frequency Score 
 


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1. 
INTRODUCTION 
Study C3718-301 is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study of oral IW-3718 administered to patients with gastroesophageal reflux disease 
(GERD) while receiving proton pump inhibitors (PPIs).  
This statistical analysis plan (SAP) describes the statistical analysis methods for all data 
collected according to the following documents: 
• Study Protocol C3718-301 (Amendment 2, dated 14 August 2020). 
• Electronic Case Report Form (eCRF) Version 1.0 (dated 27 May 2020). 
• Electronic Dairy (eDiary) (dated 10 July 2018) 
Specifications for tables, figures, and listings are contained in a separate standard document, the 
Data Presentation Plan (DPP). 


Ironwood Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan: C3718-301 
 
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2. 
STUDY OBJECTIVES 
The objective of this study is to evaluate the safety and efficacy of IW-3718 administered to 
patients with gastroesophageal reflux disease (GERD) who continue to have persistent 
symptoms, such as heartburn and regurgitation, while receiving once-daily (QD), standard-dose 
proton pump inhibitors (PPIs). 


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3. 
STUDY DESIGN 
3.1. 
General Description 
Study C3718-301 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
8-week study, consisting of 4 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 in equal proportions (1:1) to 1500-mg IW-3718 or matching placebo twice daily 
(BID). 
The total duration of patient participation is expected to last up to 18 weeks, including up to 
35 days of Screening, 14 to 21 days of the Pretreatment Period, 8 weeks of the double-blind 
Treatment Period, and 7 days of Follow-up. During the Screening Period, patients undergo an 
esophagogastroduodenoscopy (EGD) and up to 96 hours of pH testing with the Bravo™ device 
while taking their standard-dose PPI. During the Pretreatment Period, patients will continue to 
take their PPI and will provide the daily and weekly symptom assessments using a handheld 
electronic diary (eDiary). Patients meeting all the entry criteria for this trial at the end of the 
Pretreatment Period will enter the double-blind Treatment Period. During the Treatment Period, 
patients 1) will continue to take their usual label-dose PPI approximately 30-60 minutes before 
breakfast each day, 2) will take the double-blind study drug (IW-3718 or matching placebo) 
immediately after the morning and evening meals each day, and 3) will use the eDiary to provide 
their daily and weekly symptom assessments. Patients who had erosive esophagitis (EE) at 
Screening and completed ≥4 weeks of treatment will have a repeat EGD at the End of Treatment 
(EOT) Visit. The study site will contact all patients via telephone 7 days following the EOT Visit 
to collect information regarding adverse events (AEs) and concomitant medications/procedures. 
3.2. 
Discussion of Study Design, Including Choice of Control Group 
A randomized, double-blind, placebo-controlled, parallel-group, multicenter 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 avoid baseline characteristics selection bias for different treatment groups 
on the part of the participants and investigators. Blinded treatment is used to reduce potential 
bias during data collection and evaluation of clinical results. The placebo arm is used to control 
the subject’s expectation that a treatment would have an effect, to optimize sensitivity, to 
maintain the scientific rigor of the study, and to validate the study internally. 
This study has a 14- to 21-day Pretreatment Period to establish a baseline without test therapy 
and to familiarize patients with data collection methodology (ie, eDiary), and an 8-week 
Treatment Period to compare the test treatment with a placebo control. Finally, there is a 7-day 
follow-up phone call. 
 
 


Ironwood Pharmaceuticals, Inc. 
IW-3718 
Statistical Analysis Plan: C3718-301 
14 January 2021 
12
Figure 1: 
Overview of Study Design  
3.3. 
Treatment Administered  
During the Pretreatment and Treatment Periods, all patients will take their current prescribed, 
label-dose PPI. The PPI will be taken each day, approximately 30-60 minutes before breakfast. 
During the Treatment Period, patients will be instructed to take study drug (IW-3718 or 
matching placebo) in the morning (immediately upon completion of breakfast) and in the 
evening (immediately upon completion of dinner) each day, except for the first dose, which will 
be taken with liquid and a snack in clinic at the Randomization Visit on Day 1. 
Lastly, during the Pretreatment and Treatment Periods, patients may also take site-dispensed, 
protocol-permitted antacid as rescue medicine when their heartburn becomes intolerable. 
3.4. 
Assigning Patient to Treatment Group 
Patients who meet all the inclusion criteria and none of the exclusion criteria will be randomized 
into the study at the Randomization Visit on Day 1. Approximately 550 patients will be stratified 
by 1) whether they have or do not have EE on the screening EGD and 2) their baseline heartburn 
severity level (<3 vs. ≥3); and randomized through central randomization in a 1:1 ratio to either 
1500-mg IW-3718 BID (while taking their usual label-dose PPI) or placebo BID (while taking 
their usual label-dose PPI). 
* This visit represents the end of the study
EE = erosive esophagitis; EGD=esophagogastroduodenoscopy; EOT=end of treatment; SD PPI = standard dose proton pump inhibitor;
WHSS = Weekly Heartburn Severity Score
Screening
Period
Pretreatment
Period
Treatment Period
Day 1 to Day 57
14 to 21 days
Up to 35 days
Screening
Visit
(Day -56 to
Pretreatment
Visit)
Pretreatment
Visit
(Day -21 to 
Day -14
Randomization
Visit
(Day 1)
Week 4 Visit
(Day 29 ± 3)
Week 8 /
EOT
Visit*
(Day 57 +3)
SD PPI
Note:  There is no Day 0
EGD & Bravo 
(≥7d prior to
Pretreatment
Visit)
1500 mg IW-3718 twice daily 
Placebo twice daily
Stratify by 
EE Status
EGD for EE pts
Study Drug Treatment (+ SD PPI)
Follow
-up
7 days
Safety
Phone
Call
(EOT +7d)
SD PPI
Stratified by 
EE Status 
(present, not present) + 
baseline WHSS (<3, ≥3)


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The computer-generated randomization schedule was prepared by an independent statistician not 
otherwise associated with the study. Randomization numbers will be assigned by interactive web 
response system (IWRS). 
3.5. 
Blinding 
This is a double-blind study. Ironwood Pharmaceuticals, Inc. (Ironwood, the Sponsor) study 
personnel, the site investigators, all other site study personnel, and the patient will remain 
blinded to individual patient treatment assignments throughout the study. Procedures for 
unblinding in the case of an emergency are included in Clinical Study Protocol C3718-301, 
Section 3.4.7.  
  


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4. 
DETERMINATION OF SAMPLE SIZE 
The sample size of 660 patients (330 patients per treatment group) was chosen to ensure 
adequate power for using the fixed sequence testing method for the primary and key secondary 
efficacy parameters.  
The power calculations for the primary and key secondary efficacy parameters are based on 
results from patients with evidence of pathological acid reflux (positive baseline Bravo status) in 
Study ICP-3718-202 that had a similar study population as the current study.  
The primary efficacy parameter of the study is the Change from Baseline at Week 8 in Weekly 
Heartburn Severity Score (WHSS), and key secondary efficacy parameters include: 
• Change from Baseline at Week 8 in Weekly Regurgitation Frequency Score (WRFS) 
• Overall Heartburn Responder (OHR) 
• Proportion of Heartburn-free Days during the 8-week Treatment Period (PHFD) 
For definition of the efficacy parameters above, refer to Section 7.9.1.2 and Section 7.9.2.  
Using data from patients in Study ICP-3718-202 with similar inclusion/exclusion criteria as the 
current study, ie, subjects with a positive baseline BRAVO status, we derived the estimated 
results at end of the study as follows: 
Table 1:  
Study ICP-3718-202 - Summary of Efficacy Parameters at Week 8 
(BRAVO+) 
Order of 
Hypothesis 
Testing 
Parameters 
Placebo  
BID  
(+ PPIs) 
1500 mg IW-3718 
BID  
(+ PPIs) 
1 
Change from Baseline at Week 8 in 
WHSS 
N = 43 
Mean = -1.58 
SD = 1.20 
N =51 
Mean = -2.01 
SD = 1.29 
2 
Change from Baseline at Week 8 in 
WRFS 
N = 43 
Mean = -0.81 
SD = 1.12 
N = 51 
Mean = -1.26 
SD = 0.91 
3 
Overall Heartburn Responder 
18/49 = 36.7% 
31/55 = 56.4% 
4 
Proportion of Heartburn-free Days 
during the 8-week Treatment Period 
N = 48 
Mean = 0.195 
SD = 0.2822 
N = 55 
Mean = 0.268 
SD = 0.2928 
Based on a resampling with replacement-based bootstrap simulations, controlling for 
multiplicity, assuming there are approximately 45% patients with erosive esophagitis (EE), a 
sample size of 330 patients per group will provide approximately 99% power to detect a 
treatment difference between 1500-mg IW-3718 (while receiving PPIs) and placebo (while 
receiving PPIs) for the primary efficacy parameter, assuming the randomized population in this 
study is consistent with the selected population from Study ICP-3718-202. Power for other key 
efficacy parameters is listed in Table 2 below. The 2-sample t-test was used for continuous 
parameters and the Chi-square test was used for the responder parameter.  


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Table 2:  
Hypothesis Testing Order and Power for Fixed Sequence Testing 
Order of 
Hypothesis 
Testing 
Parameters 
Power for 
Fixed 
Sequence 
Testing 
1 
Change from Baseline at Week 8 in WHSS 
99% 
2 
Change from Baseline at Week 8 in WRFS 
99% 
3 
Overall Heartburn Responder 
99% 
4 
Proportion of Heartburn-free Days during the 8-week Treatment Period 
88% 
These efficacy parameters will be tested sequentially according to the above order at a 2-sided 
significance level of 5%, so that the overall type I error rate is maintained at 5%. 


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5. 
PHARMACOKINETICS, EFFICACY, AND SAFETY 
ASSESSMENTS 
5.1. 
Pharmacokinetic Assessments  
There are no pharmacokinetic assessments planned for this study. 
5.2. 
Efficacy Assessments  
The efficacy assessment instruments that will be used to derive the efficacy parameters are listed 
along with the instrument names, questionnaires, measurement scales, references, and associated 
efficacy parameter(s) in Table 3.  
 
 
 
 
 


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Table 3: 
Efficacy Assessment Instruments and Parameters 
Instruments  
Parameters 
Questionnaires 
Measurement Scales 
Reference 
mRESQ-eDa 
• Weekly Heartburn 
Severity Score (WHSS) 
• Overall Heartburn 
Responder (OHR) 
Item 1 - Burning feeling behind the 
breastbone or in the center of the 
upper stomach.  
Item 2 - Pain behind the breastbone or 
in the center of the upper stomach 
0 = Did not have, 1 = Very mild, 
2 = Mild, 3=Moderate, 4 = Moderately 
severe, 5 = Severe. 
Appendix 5  
 
Weekly Regurgitation 
Frequency Score (WRFS) 
Item 6 - Regurgitation (liquid or food 
moving upwards toward your throat 
or mouth)  
Item 7 - An acid or bitter taste in the 
mouth 
0 = Never, 1 = Rarely, 2 = Sometimes, 
3 = Often, 4 = Very often 
Appendix 5  
 
Proportion of Heartburn-
free Days during the 8-
week Treatment Period 
(PHFD) 
Item 1 - Burning feeling behind the 
breastbone or in the center of the 
upper stomach 
0 = Did not have 
Appendix 5  
 
GERD Symptoms 
Item 3 - Difficulty swallowing 
Item 4 - Hoarseness 
Item 5 - Cough 
0 = Did not have, 1 = Very mild, 
2 = Mild, 3 = Moderate, 4 = Moderately 
severe, 5 = Severe 
Appendix 5  
 
GERD symptom - Burping 
Item 8 - Burping 
0 = Never, 1 = Rarely, 2 = Sometimes, 
3 = Often, 4 = Very often 
Appendix 5  
Other Daily 
Assessments 
Sleep Disturbance Due to 
GERD - Falling Asleep 
Last night, did you have trouble 
falling asleep because of GERD 
symptoms? 
Yes, No 
Appendix 6  
 
Sleep Disturbance Due to 
GERD - Awakenings 
Last night, how many times did you 
wake up during the night because of 
GERD symptoms? 
0, 1 time, 2 times, 3-5 times, 6 or more 
times 
Appendix 6  
 
Use of rescue medicine 
(antacid) 
How many times did you use your 
rescue medicine (liquid antacid) 
during the past 24 hours? 
 
Appendix 6  


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Instruments  
Parameters 
Questionnaires 
Measurement Scales 
Reference 
 
Heartburn score  
Over the past 24 hours, how would 
you rate the severity of your 
heartburn 
0 = Did Not Have, 1 = Very Mild, 
2 = Mild, 3 = Moderate, 4 = Moderately 
Severe, 5 = Severe 
Appendix 6  
Weekly 
Assessments 
Degree of Relief 
• How would you rate your 
heartburn (a pain or 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? 
• How would you rate your overall 
GERD symptoms over the past 7 
days? 
1 = Significantly relieved, 
2 = Moderately relieved, 3 = Somewhat 
relieved, 4 = Unchanged, 5 = Somewhat 
worse, 6 = Moderately worse, 
7 = Significantly worse 
Appendix 7  
 
Bothersomeness  
• How much were you bothered by 
heartburn (a pain or burning 
sensation in your chest, behind the 
breastbone) over the past 7 days? 
• 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 7 
days? 
• How much were you bothered by 
your overall GERD symptoms 
over the past 7 days? 
1 = Not at all, 2 = A little bit, 3 = A 
moderate amount, 4 = A great deal, 
5 = An extreme amount 
Appendix 7  


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Instruments  
Parameters 
Questionnaires 
Measurement Scales 
Reference 
 
Treatment Satisfaction 
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 
Appendix 7  
Los Angeles 
classification 
of esophagitis 
• Erosive esophagitis 
healed 
• Erosive esophagitis 
improved by at least one 
grade 
 
1. Not present = No breaks (erosions) in 
the esophageal mucosa. (However, 
edema, erythema, or friability may be 
present.) 
2. Grade A = One (or more) mucosal 
break no longer than 5 mm that does 
not extend between the tops of two 
mucosal folds. 
3. Grade B = One (or more) mucosal 
break more than 5 mm long that does 
not extend between the tops of two 
mucosal folds. 
4. Grade C = One (or more) mucosal 
break that is continuous between the 
tops of two or more mucosal folds, but 
which involve less than 75% of the 
circumference. 
5. Grade D = One (or more) mucosal 
break which involves at least 75% of 
the esophageal circumference. 
Appendix 8 
a. 
mRESQ-eD = modified Reflux Symptom Questionnaire – electronic Diary. 
 
 
 


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5.2.1. 
Primary Efficacy Assessment 
The daily patient assessments of heartburn, using Items 1 and 2 of the mRESQ-eD (Table 3) and 
recorded once daily in the evening before bed via eDiary, will be used to derive the primary 
efficacy parameter WHSS (see Section 7.9.1.2). 
Baseline WHSS is derived based on the patient’s daily eDiary responses to the mRESQ-eD 
questionnaire, using the web-based system provided by CRF Health. There are 2 possible 
derivations for the baseline WHSS: 
1. CRF Health-derived WHSS 
2. Sponsor-derived WHSS 
The Sponsor-derived WHSS baseline (Item 2 in the list above) will be used for all analyses. 
5.2.2. 
Secondary Efficacy Assessments 
The daily patient assessments of regurgitation, using Items 6 and 7 of the mRESQ-eD (Table 3) 
and recorded once daily in the evening before bed via eDiary, will be used to determine 
secondary efficacy parameter WRFS. Items 1 and 2 of the mRESQ-eD (Table 3) will be used to 
determine key secondary efficacy parameter OHR, and Item 1 of the mRESQ-eD (Table 3) will 
be used to derive the key secondary efficacy parameter PHFD. 
5.2.3. 
Other Efficacy Assessments 
The efficacy assessments of Items 3, 4, 5 and 8 of the mRESQ-eD (Table 3), together with the 
assessments below, are used in determining the additional efficacy parameters. 
Other Daily Assessments 
1. Additional GERD symptom assessments are completed by patients once daily in the 
evening before bed via eDiary (Table 3): 
• Difficulty swallowing (Item 3 of the mRESQ-eD) 
• Hoarseness (Item 4 of the mRESQ-eD) 
• Cough (Item 5 of the mRESQ-eD) 
• Burping (Item 8 of the mRESQ-eD) 
2. Assessment of sleep disturbance due to GERD symptoms (Daily Sleep Disturbance due 
to GERD [Table 3]) are completed by patients once daily upon getting up each morning 
via eDiary: 
• Last night, did you have trouble falling asleep because of GERD symptoms?  
• Last night, how many times did you wake up during the night because of GERD 
symptoms? 
3. Use of per-protocol rescue medicine (Table 3) is completed by patients once daily in the 
evening before bed via eDiary:  
• How many times did you use your rescue medicine (liquid antacid) during the past 24 
hours? 


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4. Heartburn score is rated by patients once daily in the evening before bed via eDiary 
(Table 3) 
Weekly Assessments 
The following information is completed by patients once each week during the evening before 
bed via eDiary (Table 3): 
1. Degree of Relief Assessment  
2. Bothersomeness Assessment 
3. Treatment Satisfaction Assessment 
EGD Assessments 
The following information is collected by the review the EGDs, obtained at the times specified in 
the protocol, according to the Los Angeles Classification of Esophagitis (Table 3): 
1. Erosive Esophagitis Healing Assessment 
5.3. 
Health Outcomes Assessments 
WPAI-Sleep Disturbance-GERD 
The Work Productivity and Activity Impairment Questionnaire: Sleep Disturbance-GERD 
(WPAI-Sleep-GERD) include questions about time lost from work, reduced productivity while at 
work, and reduced productivity while doing regular daily activities resulting from sleep 
disturbance due to GERD symptoms. Patients will complete the WPAI-Sleep-GERD at the 
Randomization Visit, the Week 4 Visit, and at the EOT Visit and will record their responses in 
the eDiary. 
EQ-5D-3L 
The EuroQol (EQ)-5D-3L is a generic measure of health widely used in Europe (2). 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. 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 and will record their responses in the eDiary. 
5.4. 
Other Assessments 
Esophagogastroduodenoscopy 
All patients will be required to undergo an EGD during the Screening Period. There should 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 for all 
patients who have completed at least 4 weeks of treatment and had erosive esophagitis on the 
screening EGD (based on the Los Angeles Classification of Esophagitis, Appendix 8) as 
determined by either the site personnel or the central reader.  


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Baseline EE status is determined using images created during a screening EGD by the local 
reads. These images are read and interpreted both by local physicians and centrally. There were 
3 different approaches to determine the baseline EE status: 
1. The site coordinator used the web-based reporting system provided by Suvoda to enter 
the EE information into the Interactive Response Technology (IRT) system. This 
information was used for randomization. 
2. The site coordinator entered the local reads into the eCRF. 
3. Central review: In some cases, the images received by the central reviewers were of poor 
quality and the central-reviewing physicians were unable to read the images. Thus, as a 
practical matter, the values were set to missing. The central reads are not used to overturn 
the local reads, and the central reads are not used anywhere in the study. 
The local reads (Item 2 in the list above) of EE status will be used for statistical inference, while 
the central reads (Item 3 in the list above) will be used for the esophageal erosion healing 
analysis only.  
5.5. 
Safety Assessments 
Safety will be evaluated by AEs and serious adverse events (SAEs), standard clinical laboratory 
assessments, vital signs, physical examinations, medical and disease history, and 
electrocardiograms (ECGs). Planned timepoints for all safety assessments are provided in the 
Schedule of Evaluations (Appendix 4). 
5.5.1. 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. 
An AE, therefore, can be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. A procedure is not an AE, 
but the reason for a procedure may be an AE. 
A treatment-emergent adverse event (TEAE) is an event that emerges, or a preexisting event that 
worsens (with a new start date), any time after administration of the first dose of study drug 
during the treatment emergent period, which is defined as the date and time of the first treatment 
to the date and time on or ≤ 1 day of the last treatment. In fact, there is an Investigator assigned 
flag on the eCRF to indicate an TEAE. The Investigator will provide an assessment of the AE 
relationship to study drug and AE severity for each AE.   
The AE assessment (interview) will be collected from the time the patient signed the informed 
consent until completion of the Follow-up Phone Call. At each trial visit, the investigator will 
inquire about the occurrence of AEs/SAEs since the last visit.  In addition, certain laboratory 
abnormalities and changes in vital signs, physical examination findings, and 12-lead ECG 
parameters are considered AEs per protocol if the Investigator considers them clinically 
significant and/or they necessitate intervention. These abnormal findings will be captured on the 
AE page of the electronic case report form (eCRF).  


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5.5.1.1. 
Adverse Events Causality Assessment 
For all AEs, the investigator must provide an assessment of causal relationship to the study drug. 
The investigator must assess the relationship of each AE (including SAEs) to the use of a study 
drug using a 2-category scale (not related or related) based on clinical judgment and using all 
available information, and may include consideration of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, 
preexisting conditions, concomitant use of other drugs, and presence of 
environmental or genetic factors 
• The temporal association between drug exposure and onset of the AE 
• Whether the manifestations of the AE are consistent with known actions or toxicity of 
the study drug 
• Whether the AE resolved or improved with stopping use of the study drug. 
•  Judgment should be used if multiple products are discontinued at the same time. 
The causality assessment must be recorded in the patient’s source documentation and on the AE 
page of the patient’s eCRF. The causal relationship between study drug and the AE will be 
assessed using the categories shown in the following table: 
Category 
Definition 
Not related 
 
An AE is not associated with study medication if: 
- Lack of a temporal relationship to study drug administration makes a causal 
relationship improbable (eg, the event did not occur within a reasonable time frame 
following administration of the study medication); and/or 
- Other causative factor(s) (eg, a preexisting clinical condition, other concomitant 
treatments) more likely explain the occurrence of the event, and 
- The event did not improve with stopping of the investigational product, and/or 
- The event did not recur upon re-exposure with investigational product 
Related 
An AE is attributed to the study medication if: 
- A temporal relationship to study drug administration makes a causal relationship 
plausible (eg, the event occurred within a reasonable timeframe following 
administration of study medication); and/or 
- Other causative factor(s) (eg, the patient’s clinical condition, other concomitant 
treatments) either do not explain the event or are less equally likely to have led to the 
occurrence of the event, or 
- The event improved with stopping of the investigational product, and/or 
- The event recurred upon re-exposure with investigational product 
5.5.1.2. 
Classification of Adverse Event Severity 
The investigator or delegated physician will provide an assessment of the severity of each AE by 
recording a severity rating in the patient’s source documentation and on the AE page of the 
patient’s eCRF. Severity, which is a description of the intensity of manifestation of the AE, is 
distinct from seriousness, which implies a patient outcome or AE-required treatment measure 


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associated with a threat to life or functionality. Severity will be assessed according to the 
following scale by the investigators: 
Mild 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of 
daily living, causing discomfort, but poses no significant or permanent 
risk of harm to the research participant. 
Severe 
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
AEs should be recorded using the maximum intensity of the event (eg, if a patient reported 
nausea lasting 3 days, 1 start date and 1 stop date should be recorded along with the maximum 
intensity experienced for that event over that 3-day timeframe). 
5.5.1.3. 
Serious Adverse Events 
All adverse events will be categorized as Serious or Non-Serious. An AE is considered “serious” 
if, in the view of either the Investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions 
• A congenital anomaly or birth defect 
Is considered an important medical event: It may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
5.5.2. 
Medical and Disease History 
A complete medical and disease history will be performed as defined in the Schedule of 
Evaluations (Appendix 4).  
5.5.3. 
Physical Examination, Body Weight, and Height 
A complete physical examination will be performed as defined in the Schedule of Evaluations 
(Appendix 4). A physical examination will include the following assessments: general 
appearance; head, ears, eyes, nose, and throat (HEENT); cardiovascular system; neck; 
respiratory system; musculoskeletal system; abdomen/liver/spleen; skin; lymph nodes; mental 
status; and neurologic status. Breast, genitourinary, and rectal examinations are optional at the 
discretion of the investigator. 


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Each patient’s weight will be recorded at every study visit; height will only be recorded at the 
Screening Visit. 
5.5.4. 
Vital Signs 
Vital sign measurements will be performed as defined in the Schedule of Evaluations (Appendix 
4). Respiratory rate, pulse, and blood pressure readings will be taken after the patient has been 
seated for at least 5 minutes. 
5.5.5. 
Electrocardiograms 
A 12-lead ECG will be performed as defined in the Schedule of Evaluations (Appendix 4). ECGs 
should be obtained after the patient has been supine for at least 5 minutes. 
5.5.6. 
Clinical Laboratory Data 
Blood and urine samples for clinical laboratory tests will be collected at the visits defined in the 
Schedule of Evaluations (Appendix 4). The clinical laboratory tests for hematology, chemistry, 
urinalysis, coagulation, pregnancy test and drug screening will be performed. For details refer to 
Clinical Study Protocol C3718-301, Section 3.5.6. 


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6. 
STATISTICAL METHODS 
6.1. 
General Methods 
In general, descriptive statistics will be presented by treatment group and by visit, as applicable. 
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. All hypothesis tests 
will be 2-sided with a 5% significance level, and 95% confidence intervals (CIs) will be used. 
Baseline EE status (EE vs. non-EE) that is based on local reader’s assessments using images 
created during a screening EGD, and baseline WHSS (<3 vs. ≥3) per eDiary assessments by 
mRESQ-ed questionnaire are used for analysis, whenever it is appropriate. 
All statistical analyses will be performed using SAS Version 9.4 (or later). 
6.2. 
Adjusting for Baseline Characteristics and Covariates 
Analyses of efficacy parameters will be adjusted by randomization stratification variables 
baseline EE status (EE vs. non-EE) and baseline WHSS (<3 vs. ≥3). 
As a general approach, the baseline value will be included in the linear mixed effects-model for 
repeated measures (MMRM) and Poisson model analysis as a covariate when the postbaseline or 
change from baseline values are analyzed, and the randomization stratification variables baseline 
EE status and baseline WHSS (<3 vs. ≥3) will be adjusted in the analysis model as well. 
Heterogeneity of slopes will be explored, when appropriate. 
6.3. 
Handling of Dropouts/Missing Data Imputation Method 
The WHSS (Section 7.9.1.2) is the average of non-missing Daily Heartburn Severity Scores 
(DHSS) for the week (Appendix 1). If a patient who reported DHSS for fewer than 1 day during 
a week within the Treatment Period for a given week, then WHSS is missing for that week. 
The WRFS (Section 7.9.2) for a week is the average of the non-missing Daily Regurgitation 
Frequency Scores (DRFS) for that week (Appendix 1). If a patient who reported DRFS for fewer 
than 1 day during a week within the Treatment Period for a week, then WRFS is missing for the 
week. 
For responder parameters, OHR (Section 7.9.2), a patient who reported daily symptom severity 
scores for fewer than 4 days during a week within the Treatment Period will be considered a 
non-responder for that week. A patient will be deemed a weekly non-responder for all weeks 
following the patient’s discontinuation from the study.  
Unless stated otherwise, missing data will not be imputed for any of the efficacy parameters. 
6.4. 
Interim Analysis and Data Monitoring 
No interim analyses are planned to compare treatment groups with respect to efficacy or safety 
prior to formal completion of the trial. 


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6.5. 
Multicenter Studies 
This study is being conducted in approximately 100 centers. For reporting purpose, study centers 
will be pooled into the following 6 geographic regions (as listed in Appendix 3): US Northeast, 
US Southeast, US Midwest, US Southwest, US West and Canada. 
6.6. 
Multiple Comparisons/Multiplicity 
The overall family-wise Type I error rate for the primary and key secondary efficacy analyses 
will be controlled at the α = 5% level by employing a fixed sequence testing method. If the 
primary hypothesis for the comparison between the placebo group and the IW-3718 group is 
statistically significant (α < 5%) in the mITT Population (defined in Section 7.1), then the 
primary objective of the trial will have been achieved and the next hypothesis can be tested; 
otherwise, testing will stop. The testing of each subsequent hypothesis is conditioned upon all the 
previous hypotheses being rejected at the 5% level of significance. If a hypothesis is not rejected 
at the 5% level of significance, then all remaining hypotheses are deemed not statistically 
significant.  
Table 4: 
Testing Order of Efficacy Parameters for the Fixed Sequence Testing  
Testing Order 
Parameters 
1 
Change from Baseline in WHSS at Visit 5 (Week 8) 
2 
Change from Baseline in WRFS at Visit 5 (Week 8) 
3 
Overall Heartburn Responders  
4 
Proportion of Heartburn-free Days During the 8-week Treatment Period 
6.7. 
Examination of Subgroups 
Subgroup analyses will be performed on the primary efficacy parameter, using the subgroups 
defined in Table 5. 
Table 5: 
Subgroup Variables 
Subgroup Variables 
Subgroups 
Age (years) 
18 to <40; 40 to <65; ≥ 65 
Sex 
Female; Male 
Race 
Caucasian; Black/African American; Other  
Ethnic Origin 
Hispanic; Non-Hispanic 
Body Mass Index (BMI) 
<30 kg/m2; ≥30 kg/m2 
Baseline EE Status 
EE; non-EE 
Baseline WHSS  
<3; ≥ 3 


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7. 
ANALYSIS METHODS 
7.1. 
Analysis Populations 
• Screened Population consists of all patients who signed informed consent and 
received a patient identification (PID) number. 
• Randomized Population consists of all patients who were assigned to a treatment 
group (placebo or IW-3718) via randomization. 
• Final Efficacy Analysis Randomized Population consists of all patients who were 
randomized prior to or on August 4, 2020.  
• Safety Population consists of all randomized patients who received at least 1 dose of 
study drug.  Safety analysis will be based on the Safety Population, in which patients 
are evaluated according to the treatment they received. 
• Modified Intent-to-Treat (mITT) Population consists of all patients who were 
randomized prior to or on August 4, 2020, and who received at least 1 dose of study 
drug and had at least 1 postbaseline primary efficacy assessment. This population will 
be used for the final efficacy analysis. 
• Sensitivity Analysis (SA) Population consists of all randomized patients who 
received at least 1 dose of study drug and had at least 1 postbaseline primary efficacy 
assessment. This population will be used for the efficacy sensitivity analysis at 
completion of the study. 
7.2. 
Patient Disposition 
The number and percentage of screen failure patients (ie, patients who entered the Screening 
Period but not the Pretreatment Period), the number and percentage of pretreatment failures (ie, 
patients who entered the Pretreatment Period but were not randomized), along with the 
associated reasons for failure, will be tabulated overall for the Screened Population. Patients who 
initially failed screening and were re-screened will only be counted once, that is, the PID used 
for the rescreened patients will be listed for patient disposition, while the PID assigned for the 
original screening will not be analyzed or listed.  
The number and percentage of randomized patients who were included in the Safety Population, 
who were included in the mITT Population, who completed the Treatment Period, and who 
prematurely discontinued treatment will be presented overall and by treatment group. A patient is 
considered to have completed the Treatment Period if the patient completed the 8 weeks of 
treatment and the EOT Visit that was recorded on the end-of-treatment eCRF page. The reason 
for premature discontinuation as recorded on the eCRF will also be summarized by treatment 
group and overall. 
The number and percentage of patients who prematurely discontinued treatment will be 
presented for each treatment group by time of discontinuation, defined as the week (Week 1 
through Week 8) in which the treatment discontinuation occurred. 
The number of patients screened, the number and percentage of patients randomized will be 
presented by study center within each geographic region (See Appendix 3 for the definitions of 


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the geographic regions). A separate disposition table will be generated to include the SA 
Population and other relevant information.  
7.3. 
Demographics and Other Baseline Characteristics 
Demographic parameters (age, age group, race, ethnicity, sex), baseline characteristics (weight, 
height, and BMI that calculated as weight in kg/[height in m]2), will be summarized descriptively 
for the Safety, mITT and SA Populations by treatment group and overall. 
Baseline efficacy parameters and randomization stratification variables (including EE status, 
WHSS and its category [3 vs. ≥3], WRFS, proportion of heartburn-free days, the weekly score of 
each mRESQ item, sleep disturbance, symptom bothersomeness, and degree of symptom relief) 
will be summarized descriptively for the mITT and SA Populations by treatment group. 
There are several different data derivations for baseline WHSS (Section 5.2.1) and EE status 
(Section 5.4), the baseline values for each of them will be reported separately for the mITT and 
SA Populations. 
7.4. 
Compliance  
7.4.1. 
Treatment Compliance 
Compliance with study drug dosing (IW-3718 or matching placebo) is defined as the total 
number of tablets taken by a patient during the study divided by the number of tablets that were 
expected to be taken, multiplied by 100. The total number of tablets taken will be calculated 
based on the following formula: 
total number of tablets dispensed – (number of tablets returned + number of tablets lost)  
The number of tablets lost is recorded on eCRF. The total number of tablets expected to be taken 
during the study equals the number of days in the study times 6 (minus 3 if the date ends on the 
day of EOT Visit). 
The study drug compliance data will be reported using descriptive statistics for the Safety 
Population by treatment group. The compliance data will be categorized for increment of 20%, 
and it will be presented using patient counts and percentages for the Safety Population by 
treatment group. Additionally, compliance to PPI for the Pretreatment Period and for the 
Treatment Period will be summarized respectively similarly as the study drug.  
7.4.2. 
eDiary Compliance 
Patients are required to enter their diary assessments into the eDiary before bed each night, 
except assessment of sleep disturbance that is assessed 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: 
• 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 will be used. 
• For the first day of the Treatment Period, only the evening diary will be used. 
• For the EOT Visit day, only the morning diary is expected. 


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eDiary compliance will be calculated for baseline (the Pretreatment Period), the Treatment 
Period, and weekly within the Treatment Period. 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.  
The eDiary compliance data will be reported using descriptive statistics for the mITT Population 
by treatment group. The compliance data will be classified by increment of 20%, and it will be 
presented using patient counts and percentages for the mITT Population by treatment group. 
Additionally, categorized (≥4 vs. <4) weekly eDiary data will be presented using patient counts 
and percentages by treatment group for the mITT Population.  
7.5. 
Extent of Exposure  
Exposure to study drug will be calculated as the number of days from the date of first dose taken 
to the date of last dose taken in the Treatment Period:  
Treatment Duration = Date of last dose of study drug - Date of first dose of study drug + 1 
Exposure to study drug for the Safety Population during the Treatment Period will be 
summarized descriptively by treatment group. Treatment duration will also be categorized as (in 
days):  
• 1  
• >1 to ≤7  
• >7 to ≤14 
• >14 to ≤21 
• >21 to ≤28 
• >28 to ≤35 
• >35 to ≤42 
• >42 to ≤49 
• >49 to ≤56 and 
• >56 
The number and percent of patients in each category will be presented by treatment group for the 
Safety Population.  
Patient-years, defined as total exposure days to the study drug across all patients and divided by 
365.25, will be summarized for the WI-3718 group for the Safety Population. 
Additionally, exposure to PPI for the Pretreatment Period and for the Treatment Period will be 
summarized, respectively, similarly to the study drug. 
 
 


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7.6. 
Protocol Deviations  
Protocol deviations and Important Protocol Deviations (IPD) will be identified and documented 
for all randomized patients prior to unblinding through programmatic checks of the study data 
and select individual data reviews. IPDs will be determined based on a blinded review of all 
protocol deviations and protocol deviation categories prior to database lock and unblinding; this 
review will be performed by members of the Ironwood Clinical Trial team, including but not 
limited to the Study Program Manager, Clinical Medical Monitor. and Study Biostatistician.  
The number and percentage of patients with IPDs will be presented by treatment group and IPD 
category for the Randomized Population. Protocol deviations and IPDs will be provided by 
patient in data listings for the Randomized Population. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion page of the 
eCRF. 
7.7. 
Prior and Concomitant Medication  
Patient’s daily eDiary recording of PPI administration will not be reported as a prior or 
concomitant medication. Instead, it will be summarized separately. Details are specified in 
Section 7.4.1 and Section 7.5. 
Prior medication is defined as any medication started before the date of the first dose of study 
drug.  
Concomitant medication is defined as any medication with a start date prior to, or on the date of 
the first dose of study drug and continuing after the first dose of study drug, or with a start date 
between the dates of the first and last doses of study drug, inclusive. Any medication with a start 
date after the date of the last study drug will not be considered a concomitant medication.  
Both prior and concomitant medications will be coded by drug name and therapeutic class using 
WHO Drug dictionary B2 format, March 2018 version or above. The use of prior and 
concomitant medications will be summarized for the Safety Population as the number and 
percentage of patients in each treatment group receiving each medication within each therapeutic 
class. If a patient took a specific medication multiple times or took multiple medications in the 
same category (based on Anatomical-Therapeutic-Chemical classification), that patient would be 
counted only once for the coded drug name or therapeutic class. The use of per-protocol rescue 
medicines is collected separately in the eDiary (Section 7.8). 
7.8. 
Rescue Medicine Use  
During the Pretreatment and Treatment Periods, patients may use dispensed, protocol-permitted 
rescue medicine when their heartburn becomes intolerable. Patients will report the frequency of 
their use of rescue medicine (liquid antacid) in the evening eDiary before bed for the day. 
Overall daily use of rescue medicine will be summarized for each treatment week by treatment 
group for the Safety Population. 


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7.9. 
Efficacy Analysis  
The final efficacy analysis will be based on the mITT, while the SA Population will be used for 
the sensitivity efficacy analysis, and the analyses will be conducted according to the treatment 
assigned. Baseline values for efficacy parameters are defined as: 
• For change from baseline continuous parameter and derived dichotomized response 
variables, the baseline will be derived from the eDiary and/or 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.   
• A time dependent proportion efficacy parameter that is defined as days the event of 
interest occurs, divided by the number of diary entry days during the relevant period. 
Its baseline period is the last 14 days (Week -2 to Week -1) prior to day of 
randomization. 
For the change from baseline and response variables, if data for Week -1 are not available, data 
for Week -2 (the second last week of the Pretreatment Period) will be used.  
For responder parameters derived from daily eDiary assessments, a patient who missed 4 or 
more daily assessments an analysis week will be consider a missing for that week and will be 
defined as a non-responder for that week. For continuous efficacy parameters, the analysis value 
for an analysis period is defined as the average of the non-missing values during that period 
(Appendix 1). If a patient who reported assessments for fewer than 1 day during a week within 
the Treatment Period, the average is missing for that week. For efficacy parameters no further 
imputation will be performed (see Section 7.9.1.3 for sensitivity analyses employing multiple 
imputation [MI] methods). Any efficacy assessments measured after the last dose date will not 
be included for analysis.  
All primary and secondary efficacy parameters are listed in Table 4 will be tested in the given 
order to protect the overall family wide alpha level at 5%. The mITT Population will be used for 
the final analysis for all efficacy parameters. The SA Population will be used for the efficacy 
sensitivity analysis that include selected efficacy parameters at completion of the study. 
7.9.1. 
Primary Efficacy Parameter 
7.9.1.1. 
Estimands 
The primary efficacy estimands that are prepared to support regulatory decisions, are described 
below. 
The While on Treatment Strategy for the primary efficacy parameter will be used. It is defined 
by the following: 
• Treatment: intervention IW-3718 (1500 mg), while receiving PPIs.  
• Population: patients in the mITT with GERD who continue to have persistent 
symptoms, such as heartburn and regurgitation, while receiving once-daily (QD), 
standard-dose PPIs. 


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• Variable: Weekly Heartburn Severity Score (WHSS) derived for each treatment visit. 
The WHSS for a week is the average of the non-missing Daily Heartburn Severity 
Scores (DHSS) for that week.  
• Intercurrent event: the following intercurrent events will be considered: 
a. Discontinuation of treatment due to lack of efficacy 
b. Lost to follow-up 
c. Discontinuation of treatment due to AE 
d. Discontinuation in the study by physician’s decision 
e. Withdrawing consent 
f. Withdraw due to protocol violations 
• Population-level summary: mean difference in change from baseline between 
treatment groups.  
Henceforth, for simplicity, background therapy PPIs will be omitted when referring to study drug 
treatment (IW-3718 and placebo). 
7.9.1.2. 
Analysis of the Primary Efficacy Parameter 
The primary efficacy parameter of the study is defined as the change from baseline in WHSS at 
Visit 5 (Week 8):  
• The WHSS for a week is the average of the non-missing Daily Heartburn Severity 
Scores (DHSS) for that week (Appendix 1).  
• The DHSS for a day is the greater score of the 2 mRESQ-eD items assessing 
heartburn severity (“Burning feeling behind the breastbone or in the center of the 
upper stomach” and “Pain behind the breastbone or in the center of the upper 
stomach”) for that day. Where one of the 2 mRESQ-eD heartburn severity items is 
missing for the day, the maximum will be the score of the remaining item; where if 
both of the items are missing for the day, the DHSS will be missing. 
The primary efficacy parameter will be analyzed using a linear mixed-effects model for repeated 
measures (MMRM). The model will include WHSS change from Baseline at postbaseline 
scheduled visits up to Week 8 as dependent variable; treatment, randomization stratification 
variables Baseline EE status (present versus not present) and Baseline WHSS severity level 
(<3 versus ≥3), Week (as a categorical variable), Week-by-treatment and Week-by-Baseline 
WHSS interactions as fixed effects; Baseline WHSS as a continuous covariate; and subject as a 
random effect. The Kenward-Roger approximation will be used to estimate denominator degree 
of freedom and adjust standard errors. An unstructured covariance matrix will be used for the 
MMRM analysis. In the case that the convergence is an issue, the compound symmetry 
covariance structure will be used. Least square (LS) mean for each treatment group, LS mean 
difference between the IW-3718 group and the placebo group and a 95% CI for the difference, as 
well as the P value for comparison versus placebo will be presented. For this analysis, the 
primary contrast of interest is at Visit 5 (Week 8) for IW-3718 compared with placebo. 


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A corresponding line graph of LS mean with 95% CI by treatment group and Week will be 
presented. Cumulative distribution function (CDF) of change from baseline at Week 8 in WHSS 
to be plotted by treatment group. To aid in the interpretation of the graphical representation of 
the CDF across treatment group, a 2-sample Kolmogorov-Smirnov test will be conducted.  If the 
P-value of the Kolmogorov-Smirnov test is small, conclude that the two treatment groups were 
sampled from populations with different distributions. The populations may differ in median, 
variability, or the shape of the distribution. 
CDF plots of change from Baseline at each week in WHSS by treatment group and patient-
reported weekly Degree of Relief Assessments (comparing the symptoms over the past 7 days, 
Appendix 7) classified anchor will be provided. For a sense of variability in the distribution of 
the classified heartburn relief anchor category, percentile (10th, 25th, 75th and 90th) of change 
from Baseline to each week in WHSS by treatment group and the anchor will be tabulated. 
7.9.1.3. 
Sensitivity Analysis Based on Multiple Imputation – Missing Not at Random 
(MNAR) 
The analysis specified in this section will be executed only when a superiority result that favors 
the active treatment group for the primary efficacy parameter is obtained. 
To characterize the extent of missing data associated with the primary efficacy parameter, the 
number and percentage of patients with missing evening diaries will be presented by treatment 
group for the mITT Population for each week of the Treatment Period.  
The primary efficacy analysis (MMRM) relies on the assumption that the missing data 
mechanism follows the missing at random (MAR) scenario. In this case, it is assumed that the 
reason for data being missing may depend on observed data, but not on the unobserved missing 
data. The likelihood based MMRM analysis is an appropriate method for the statistical analysis 
under MAR assumption. 
The following sensitivity analysis model, which are within the pattern-mixture model 
framework, will be used to examine the robustness of the primary efficacy analysis results for the 
missing not at random (MNAR) mechanisms. Under MNAR, it is assumed that the reason for 
data being missing is related to the unobserved missing data.  
The imputations are based on the distribution of placebo group responses over time. The 
underlying assumption is that the missing data for a patient on the active treatment follow the 
distribution of the placebo responses, i.e., the mean values and intra-subject correlations based 
on the placebo responses will be applied. Moreover, the intercurrent events will generate MNAR 
(informative) missing, which will have impact on determining of drug effect. A designated 
penalty will be prespecified for this type of missing mechanism, in order to adjust the treatment 
effect estimation to determine a possible “true” treatment effect. 
The model is implemented in 4 steps:  
Step 1: Imputations  
For change from baseline data, a total of 200 sets of posterior mean and co-variance estimates 
are extracted from the available non-missing placebo data. One hundred of the posterior sets will 
be applied to the pooled active treatment group, while the other 100 will be applied to the 
placebo group. One set of imputations for all missing values will be generated based on each 
variation of posterior estimates. All 100 datasets for imputations within a treatment group will be 


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ordered from 1 to 100 and combined between pooled active treatment group and placebo, for a 
total of 100 completely imputed datasets.  
Step 2: Adjustments 
For patients who have any intercurrent events, a penalty will be designated to the imputed values 
at the last scheduled visit (Visit 5, Week 8). The penalty is applied to the 2 treatment arms by 
adding a fraction of the estimated SD for the primary efficacy parameter (the square root of the 
estimated element for the last scheduled visit of the co-variance matrix R from the primary 
MMRM model): (0×SD), (0.25×SD), (0.50×SD). 
Step 3: Analysis of Complete Datasets  
The primary efficacy parameter will be analyzed for each of the 100 complete datasets with 
imputed and the designated penalty applied data at the last scheduled visit (Visit 5, Week 8), 
using an analysis of covariance with treatment group as factors and the baseline value as a 
covariate. 
Step 4: Inference  
Rubin’s Rules will be applied to pool the desired statistical quantities that include LS mean 
difference estimates, associated 95% CI and p-value, and associated SEs. 
Efficacy conclusion of the study is based on the analysis described in Section 7.9.1.2. In the 
current section, a different missing mechanism is assumed for the data, it is a supportive outcome 
for the primary efficacy effect analysis. 
7.9.2. 
Key Secondary Efficacy Parameters 
There are 3 key secondary efficacy parameters which will be included in the hypothesis testing 
procedure. 
1. 
Change from Baseline at Week 8 in WRFS 
• The WRFS is an average of the non-missing Daily Regurgitation Frequency Scores 
(DRFS) for that week (Appendix 1).  
• The DRFS for a day is the greater score of the 2 mRESQ-eD items assessing 
regurgitation frequency (“Regurgitation [liquid or food moving upwards toward your 
throat or mouth]” and “An acid or bitter taste in the mouth”) for that day.  Where 1 of 
the 2 mRESQ-eD regurgitation frequency items is missing for the day, the maximum 
will be the score of the remaining item; where both of the items are missing for the 
day, the DRFS will be missing. 
2. 
Overall Heartburn Responder (OHR) 
• An OHR is a patient who is a Weekly Heartburn Responder for at least 4 weeks, 
including at least 1 of the last 2 weeks (Weeks 7 and 8), during the 8-week Treatment 
Period. 
• A patient who reports a DHSS for less than 4 days during a week will be considered a 
non-responder for that week. 
• A Weekly Heartburn Responder is a patient with a decrease of ≥45% from baseline in 
WHSS.  


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3. 
Proportion of heartburn-free days during the 8-week Treatment Period 
• Proportion of heartburn-free days is calculated as the number of heartburn-free 
(DHSS = 0) days divided by the number of diary entry days (Appendix 1).  
7.9.2.1. 
Analysis of the Secondary Efficacy Parameters  
If the primary efficacy comparison generates a superiority result for IW-3718, the secondary 
efficacy parameters will be tested and so on. The testing order and analysis methods are listed 
below: 
Table 6: 
Analysis and Assumptions of the Secondary Efficacy Parameters 
Order of 
Hypothesis 
Testing 
Parameters 
Analysis Method and Outputs 
Assumptions 
1 
Change from 
Baseline at Week 
8 in WRFS 
Efficacy parameter WRFS will be analyzed using the 
MMRM approach like the primary efficacy 
parameter, WHSS change from baseline.  
MAR 
2 
Overall 
Heartburn 
Responder  
The proportions of responders between the IW-3718 
group and the placebo group will be compared using 
a Cochran-Mantel-Haenszel (CMH) test controlling 
for baseline EE status (present vs. not present), 
baseline WHSS (<3 vs. ≥3). The CMH test is the 
primary analysis for responder parameters. The 
estimated odds ratio (IW-3718 over placebo) 
associated 95% CI and P value based on CMH test 
will be tabulated. Additionally, difference in 
responder rate with a 95% Newcombe CI (3) will 
also be provided. 
Missing will 
not be 
imputed. 
3 
Proportion of 
Heartburn-free 
Days During the 
8-week 
Treatment Period 
The data will be analyzed using the Poisson 
regression, which is appropriate for count data. The 
analysis includes the fixed categorical effect of 
treatment, the baseline esophagitis status (present vs. 
not present) and baseline WHSS (<3 vs. ≥3), the 
covariate of baseline proportion of heartburn-free 
days, and with the diary entry duration (in days) as a 
weight variablea adjusted in the model.  
Model estimates in difference of incidence rate 
between the IW-3718 treatment group and placebo 
will be represented with corresponding 95% CI and 
P-value associated with the comparisons to placebo. 
In the case of overdispersion, a negative binomial 
model instead of Poisson regression will be 
implemented. 
Data 
following a 
Poisson 
distribution. 
Missing data 
will not be 
imputed. 
a. 
The weight variable weights the overdispersion parameter, which has the default value of 1. The weight variable 
does not have to be an integer, if it is less than or equal to 0 or if it is missing, the corresponding observation is 
not used for modeling analysis. 


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Like the primary efficacy parameter, a corresponding line graph of LS mean with 95% CI by 
treatment group and Week for WRFS will be presented. CDF of change from baseline at Week 8 
in WRFS to be plotted by treatment group. To aid in the interpretation of the graphical 
representation of the CDF across treatment group, a 2-sample Kolmogorov-Smirnov test will be 
conducted.  
CDF plots of change from Baseline at each week in WRFS by treatment group and patient-
reported weekly Degree of Relief Assessments (comparing the symptoms over the past 7 days, 
Appendix 7) classified anchor will be provided. For a sense of variability in the distribution of 
the classified heartburn relief anchor category, percentile (10th, 25th, 75th and 90th) of change 
from Baseline to each week in WRFS by treatment group and the anchor will be tabulated. 
7.9.3. 
Exploratory Efficacy Parameters 
Exploratory efficacy parameters will be explored outside of the formal testing procedures and 
not controlled for multiplicity. The mITT Population will be used for the analyses. If appropriate, 
for selected efficacy parameters, the SA Population will be used for sensitivity analysis. The 
baseline definitions for different type of parameters can be found in Section 7.9.  
• Change or percent change continuous parameters will be analyzed using the MMRM 
approach like the primary efficacy parameter, WHSS change from baseline. 
• Categorical responder parameters will be analyzed utilizing the CMH testing method 
that is proposed for the secondary efficacy analysis for OHR. 
• Time dependent proportion parameters, defined as days the event of interesting 
occurs divided by the number of eDiary entry days during the relevant period, will be 
analyzed applying Poisson molding, which is appropriate for count data. The analysis 
is similarly as the analysis for the proportion of the heartburn-free days during the 8-
week Treatment Period.  
The exploratory efficacy parameters and proposed analysis methods are listed below: 
Table 7: 
Exploratory Efficacy Parameters and Analysis Methods 
Item 
No. 
Efficacy Endpoints 
Analysis Methods 
1. 
Percent change from baseline at Week 8 in WHSS 
MMRM for change 
from baseline to Week 
8. 
2. 
Overall Heartburn Responders with baseline WHSS ≥3 
CMH 
3. 
Change from baseline of proportion of days when heartburn did not 
occur (DHSS = 0) or was very mild (DHSS = 1) during the 8-week 
Treatment Period 
Analysis of covariance 
(ANCOVA) 
4. 
Proportion of days when heartburn did not occur (DHSS=0) or was 
very mild (DHSS=1) during the 8-week Treatment Period  
Poisson regression for 
proportions 
5. 
Percent change from baseline at Week 8 in WRFS 
MMRM for change 
from baseline to Week 
8. 


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Item 
No. 
Efficacy Endpoints 
Analysis Methods 
6. 
Change from baseline proportion of days when regurgitation did not 
occur (DRFS = 0) or rarely occurred (DRFS = 1) during the 8-week 
Treatment Period 
ANCOVA 
7. 
Proportion of regurgitation free (DRFS = 0) days during the 8-week 
Treatment Period  
Poisson regression for 
proportions 
8. 
Proportion of days when regurgitation did not occur (DRFS=0) or 
rarely occurred (DRFS=1) during the 8-week Treatment Period 
Poisson regression for 
proportions 
9. 
Overall Regurgitation Responder: a patient who is a Weekly 
Regurgitation Responder for at least 4 weeks, including at least 1 of 
the last 2 weeks (Weeks 7 and 8), during the 8-week Treatment 
Period 
• A Weekly Regurgitation Responder is a patient with a decrease of 
≥45% from baseline in WRFS  
• A patient who reports DRFS for less than 4 days during a week 
will not be considered a Weekly Regurgitation Responder for that 
week 
CMH 
10. 
Change from baseline to Week 8 in each mRESQ item  
MMRM for change 
from baseline to Week 
8. 
11. 
Proportion of nights with difficulty falling asleep due to GERD 
during the 8-week Treatment Period 
Poisson regression for 
proportions 
12. 
Proportion of days with nighttime awakening (≥1 time) due to GERD 
during the 8-week Treatment Period 
Poisson regression for 
proportions 
13. 
Degree of relief of heartburn/regurgitation/overall GERD symptoms 
responder: 
• Degree of relief responder: patient who reported a score of 1-
Significantly Relieved or 2-Moderately Relieved on the Degree of 
Relief question for at least 4 weeks, including at least 1 of the last 
2 weeks (Weeks 7 and 8), during the 8-week Treatment Period 
CMH 
14. 
Change from baseline at Week 8 in heartburn/regurgitation/overall 
GERD symptoms bothersomeness 
MMRM for change 
from baseline to Week 
8. 
15. 
Proportion of days with rescue medication use during the 8-week 
Treatment Period  
Poisson regression for 
proportions  
16. 
Erosive esophagitis (EE) healed (not present) at Week 8 
CMH (the central 
reads and the local 
reads will be analyzed, 
respectively) 


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Item 
No. 
Efficacy Endpoints 
Analysis Methods 
17. 
Proportion of patients with erosive esophagitis (EE) improved by at 
least 1 grade at Week 8 
CMH (the central 
reads and the local 
reads will be analyzed, 
respectively) 
Descriptive supportive summary for following variables will be generated for SA population. 
Item 
No. 
Description of Summary 
1. 
Percent change from baseline in WHSS by week  
2. 
Percent change from baseline in WRFS by week  
3. 
Change from baseline in WHSS by week 
4. 
Change from baseline in WRFS by week 
5. 
Change from baseline in each mRESQ item by week 
6. 
Proportion of heartburn-free (DHSS=0) days by week 
7. 
Proportion of regurgitation-free (DRFS=0) days by week 
8. 
Proportion of days when heartburn did not occur (DHSS=0) or was very mild (DHSS=1) by 
week  
9. 
Proportion of days when regurgitation did not occur (DRFS=0) or rarely occurred 
(DRFS=1) by week 
10. 
Proportion of nights with difficulty falling asleep due to GERD by week 
11. 
Proportion of days with nighttime awakening (≥1 time) due to GERD by week 
12. 
Proportion of days with rescue medication use by week  
13. 
Degree of relief of heartburn/regurgitation/overall GERD symptoms by week 
14. 
Heartburn/regurgitation/overall GERD symptoms bothersomeness by week 
15. 
Treatment satisfaction by week 
16. 
Shift in erosive esophagitis (EE) grade from baseline to Week 8 
7.10. 
Safety Analysis  
All safety parameters will be summarized using descriptive statistics. Safety analyses will be 
performed on the Safety Population. The safety parameters will include AEs, clinical laboratory 
evaluations, vital signs, ECGs, and physical examination. For each safety parameter, the last 
non-missing assessment made before the first dose of study drug will be used as the baseline for 
all analyses of that safety parameter. 
The treatment group designation for safety summaries is based on the treatment the patient 
actually received. The “treatment actually received” for a patient who received treatment other 


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than the assigned treatment (even if only a single dose) during the treatment period will be 
defined as the treatment of which the patient actually took, regardless of the treatment assigned. 
7.10.1. 
Adverse Events 
AEs will be coded by system organ class and preferred term using the MedDRA dictionary, 
version 23.0 which contains the COVID-19 specific terms. An AE will be considered a 
treatment-emergent AE (TEAE) if the AE started after initial study drug administration and 
within 1 day of the last dose of study drug. In addition, an AE that started before initial study 
drug but worsened after the first dosing of the study drug is also considered a TEAE.  
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated:  
• by system organ class (SOC) and preferred term (PT) 
• by SOC, PT, and severity 
• by SOC, PT, and relationship to study drug.  
If a patient has more than one TEAE coded to the same PT, the patient will be counted only once 
for that PT by identifying those TEAEs with the highest severity and the closest relationship to 
study drug.   
The incidence of the following TEAEs will be summarized by PT: 
• Most frequent (≥2% of patients in any treatment group) TEAEs 
• Treatment Emergent SAEs  
• TEAEs leading to premature discontinuation of study drug.  
All AE summary tables will be SOC sorted alphabetically and have PT within each SOC sorted 
by decreasing frequency for IW-3718 group. 
A TEAE summary table with all the non-SAEs by SOC and PT will be generated to support the 
clinicaltrials.gov reporting purpose.  
AE listings will be presented for all patients with AEs, screened patients with SAEs, patients 
with AEs leading to discontinuation, all SAEs (no matter it is treatment-emerge or not) and 
patients who died (if any), respectively. 
7.10.2. 
Clinical Laboratory Parameters  
Descriptive statistics for clinical laboratory values (in SI units) and changes from the baseline 
values at each assessment time point will be presented by treatment group for each clinical 
laboratory parameter. All laboratory data will be listed. The clinical laboratory parameters are 
listed in Section 5.5.6.  
For each clinical laboratory parameter, the number and percentage of patients with potentially 
clinically significant (PCS) postbaseline clinical laboratory values will be tabulated by treatment 
group for data collecting no more than 1 day after the last dose. The criteria for PCS laboratory 
values are described in Table 8. The percentages will be calculated relative to the number of 
patients with available non-PCS baseline values and at least 1 post-baseline assessment. The 


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potential numerator will be the total number of patients with available non-PCS baseline values 
and at least 1 post-baseline PCS value in the corresponding postbaseline period.  
A supportive listing for patients with PCS postbaseline values will be provided, including the 
PID number, study center, baseline and postbaseline values for each visit, and a flag indicating 
the PCS laboratory values. 
Table 8: 
Criteria for Potentially Clinically Significant Laboratory Results 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Albumin 
g/L 
<0.9 × LLN 
>1.1 × ULN 
Alanine aminotransferase 
U/L 
— 
≥3 × ULN 
Alkaline phosphatase 
U/L 
— 
≥3 × ULN 
Aspartate aminotransferase 
U/L 
— 
≥3 × ULN 
Bicarbonate 
mmol/L 
<0.9 × LLN 
>1.1 × ULN 
Bilirubin, total 
μmol/L 
— 
>1.5 × ULN 
Calcium 
mmol/L 
<0.9 × LLN 
>1.1 × ULN 
Chloride 
mmol/L 
<0.9 × LLN 
>1.1 × ULN 
Cholesterol, total 
mmol/L 
— 
>1.6 × ULN 
Creatinine 
μmol/L 
— 
>1.3 × ULN 
Glucose 
mmol/L 
<0.8 × LLN 
>1.4 × ULN 
Magnesium 
mmol/L 
<0.9 × LLN 
>1.1 × ULN 
Phosphate 
mmol/L 
<0.9 × LLN 
>1.1 × ULN 
Potassium 
mmol/L 
<0.9 × LLN 
>1.1 × ULN 
Protein, total  
g/L 
<0.9 × LLN 
>1.1 × ULN 
Sodium 
mmol/L 
<0.9 × LLN 
>1.1 × ULN 
Urea nitrogen 
mmol/L 
— 
>1.2 × ULN 
Uric acid  
μmol/L 
<0.9 × LLN 
>1.1 × ULN 
HEMATOLOGY 
Basophils, absolute cell count 
109/L 
— 
>3 × ULN 
Eosinophils, absolute cell count 
109/L 
— 
>3 × ULN 
Hematocrit 
Ratio 
<0.9 × LLN 
>1.1 × ULN 


Ironwood Pharmaceuticals, Inc. 
 
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14 January 2021 
 
42 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
Hemoglobin 
g/L 
<0.9 × LLN 
>1.1 × ULN 
Lymphocytes, absolute cell count 
109/L 
<0.8 × LLN 
>1.5 × ULN 
Mean corpuscular hemoglobin 
Pg 
— 
>3 × ULN 
Mean corpuscular hemoglobin concentration 
g/L 
— 
>3 × ULN 
Mean corpuscular volume 
fL 
<0.9 × LLN 
>1.1 × ULN 
Monocytes, absolute cell count 
109/L 
— 
>3 × ULN 
Neutrophils, absolute cell count 
109/L 
<0.8 × LLN 
>1.5 × ULN 
Platelet count 
109/L 
<0.5 × LLN 
>1.5 × ULN 
Red blood cell count 
1012/L 
<0.9 × LLN 
>1.1 × ULN 
White blood cell count 
109/L 
<0.7 × LLN 
>1.5 × ULN 
LLN = lower limit of normal value provided by the laboratory; SI = Le Système International d’Unités (International 
System of Units); ULN = upper limit of normal value provided by the laboratory. 
7.10.3. 
Vital Signs  
Descriptive statistics for body weight and vital signs (ie, oral temperature, respiratory rate, 
systolic and diastolic blood pressure, and pulse rate) and changes from baseline values at each 
visit will be presented by treatment group, and all the data will be listed. 
The number and percentage of patients with PCS postbaseline vital signs will be tabulated by 
treatment group for data collecting no more than 1 day after the last dose. A vital sign value will 
be considered PCS if it meets both the observed value criterion and the change from baseline 
value criterion. The criteria for PCS vital sign values is detailed in Table 9. The percentages will 
be calculated relative to the number of patients with baseline values and at least 1 assessment in 
the corresponding postbaseline period. The numerator will be the total number of patients with 
available baseline values and at least 1 PCS value in the corresponding postbaseline period.  
A supportive listing for patients with PCS postbaseline values will be provided, including the 
PID number, study center, baseline and postbaseline values for each visit, and a flag indicating 
the PCS vital sign values. 


Ironwood Pharmaceuticals, Inc. 
 
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14 January 2021 
 
43 
Table 9: 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteriaa 
Observed Value 
Change from Baseline 
Seated systolic blood 
pressure, mmHg 
High 
≥180 
Increase of ≥20 
Low 
≤90 
Decrease of ≥20 
Seated diastolic blood 
pressure, mmHg 
High 
≥105 
Increase of ≥15 
Low 
≤50 
Decrease of ≥15 
Seated 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 postbaseline value is considered potentially clinically significant if it meets both the criteria for observed 
value and the criteria for change from baseline. 
bpm = beats per minute 
7.10.4. 
ECG Parameters 
Descriptive statistics for ECG variables (eg, QRS duration, QT interval, PR interval, and QTcF 
interval.) and their changes from baseline at each assessment time point will be presented by 
treatment group. ECG interpretation will be summarized by visit. A shift table from baseline to 
each visit for qualitative ECG results will be presented. 
In addition, the number and percentage of patients with PCS postbaseline ECG will be tabulated 
by treatment group for data collecting no more than 1 day after the last dose. An ECG value will 
be considered PCS if it meets the observed value criterion. The criteria for PCS ECG values is 
detailed in Table 10. The percentages will be calculated relative to the number of patients with 
available non-PCS baseline values and at least 1 postbaseline assessment. The potential 
numerator will be the total number of patients with available non-PCS baseline values and at 
least 1 postbaseline PCS value in the corresponding post-baseline period. 
A supportive listing for patients with PCS postbaseline values will be provided, including the 
PID number, study center, baseline and postbaseline values for each visit, and a flag indicating 
the PCS ECG values.  
Table 10: 
Criteria for Potentially Clinically Significant ECG Parameters 
ECG Parameter 
Unit 
Higher Limit 
QRS duration 
msec  
≥150 
PR interval 
msec 
≥250 
QTcF interval  
msec 
>500 


Ironwood Pharmaceuticals, Inc. 
 
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14 January 2021 
 
44 
7.10.5. 
Medical and Disease History 
Abnormalities in patients’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 21.0. The number and percentage of 
patients with abnormalities in medical and surgical histories in each system organ class (SOC) 
and preferred term will be presented by treatment group and overall, for the Safety Population. 
7.10.6. 
Physical Examination 
No separate analysis for physical examinations is planned; a listing will be provided for physical 
examination findings. 
7.11. 
Health Outcome Analysis  
Health outcome analyses will be performed on the SA Population. 
7.11.1. 
WPAI-Sleep Disturbance-GERD 
Change from baseline in hours missed from work due to sleep disturbance from GERD as a 
percentage of total hours (the summation of hours missed due to sleep disturbance from GERD, 
hours missed due to any other reason, and hours worked) will be summarized by treatment group 
at Weeks 4 and 8 and analyzed using a similar MMRM approach described in Section 7.9.1.2.  
Change from baseline in the effect of sleep disturbance due to GERD on work productivity and 
sleep disturbance due to GERD on regular daily activities other than work at a job will be 
summarized, respectively, by treatment group at Weeks 4 and 8 and analyzed using a similar 
MMRM approach described in Section 7.9.1.2. 
7.11.2. 
EQ-5D-3L 
Each of the 5 questions assessing mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression will be summarized by treatment group and by frequency distribution 
(profile) of the EQ-5D descriptive system (“No problems”, “Some problems”, “Extreme 
problems”) at baseline, Week 4 and Week 8. Comparison between treatment groups at Week 8 
will be performed utilizing the CMH test, controlling for strata: baseline EE status (present vs. 
not present), baseline heartburn severity level (<3 vs. ≥3) and the associate p-value will be 
reported. In addition, shift in response to each question from baseline to each visit postbaseline 
will be summarized using a shift table. 
Change from baseline at week 4 and Week 8 in health state as assessed by a 0 to 100 visual 
analogue scale will be summarized by treatment group and analyzed using a similar MMRM 
approach described in Section 7.9.1.2. 


Ironwood Pharmaceuticals, Inc. 
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Statistical Analysis Plan: C3718-301 
14 January 2021 
45 
8.
REFERENCES
1. Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency
Guidance for Industry, U.S. Department of Health and Human Services Food and Drug
Administration (June, 2020)
2. EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life.
The EuroQol Group. Health Policy. 1990; 16:199-208.
3. Newcombe, R. Interval estimation for the difference between independent proportions:
Comparison of eleven methods. Stat. Med. l 998; 17: 873-890.
4. Cohen, J. Statistical power analysis for the behavioral sciences, Hillsdale, NJ, Lawrence
Earlbaum Associates. 1988
5. 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.
6. Ratitch, B., O'Kelly, M. and Tosiello, R. (2013), Missing data in clinical trials: from clinical
assumptions to statistical analysis using pattern mixture models. Pharmaceut. Statist.,
12: 337–347. doi: 10.1002/pst.1549
7. Rubin DB (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons Ltd.,
New York.


Ironwood Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan: C3718-301 
 
14 January 2021 
 
46 
Appendix 1. 
Missing Data Simulation to Support the Key Efficacy 
Parameters Scoring Algorithm  
A missing data simulation study was conducted to assess the impact of the missing data on the 
scoring algorithm of the key efficacy parameters. The following assumptions were made for the 
simulation: 
• Patients with evidence of pathological acid reflux (positive Bravo status) at baseline 
in Study ICP-3718-202 represent a study population that is similar to the current 
study population. 
• The efficacy parameters WHSS, WRFS and PHFD in the current study follow the 
same underlying data distribution as in Study ICP-3718-202. 
In Study ICP-3718-202, 45 patients with a positive Bravo status at baseline had non-missing 
daily assessments in the placebo and IW-3718 1500 mg BID groups combined.  The daily 
assessments were used to derive the efficacy parameters WHSS, WRFS and PHFD. These 
45 patients were used for the simulation study.  
In Study ICP-3718-202, approximately 10% of patients prematurely discontinued from the study. 
In the initial simulation, it was assumed that 10% of patients had a given number of missing 
daily data at each week (ie, the missing data rate). In a second simulation, it was assumed that 
20% of patients had a given number of missing daily data at each week.  
Daily Scores  
Derivation of PHFD is based on Item #1 of mRESQ-eD (Appendix 5). The simulations were run 
on the value of Item #1. 
The daily score that is used to derive the WHSS is the greater score of Item #1 and Item #2 of the 
mRESQ-eD, which both assess heartburn severity for a given day.  
Similar to the WHSS, the daily score that is used to derive the WRFS is the greater score of Item 
#6 and Item #7 of the mRESQ-ed, which both assess regurgitation frequency for a given day. 
It was assumed that a scenario whereby a patient misses 1 of the 2 mRESQ-eD items does not 
occur. The reason is that when a patient answers a mRESQ-eD question, the next question 
automatically appears on the device, and it cues the patient to answer that question. Given the 
nature of the device, there are most likely only 2 scenarios for the mRESQ-eD data collection: 1) 
a patient answers all mRESQ-eD items; 2) none of the items are answered. The experience of 
Study ICP-3718-202 supports this. There was no instance where the eDiary had partial data for a 
given day. Similarly, this has been the experience in the 2 ongoing Phase 3 studies.  
Based on the above discussions, the simulations conducted for WHSS and WRFS began with the 
daily scores, rather than the item scores. The WHSS and WRFS are calculated as the weekly 
average of the non-missing daily scores. 
Weekly Heartburn Severity Score and Weekly Regurgitation Frequency Score 
For the weekly scoring algorithm, a minimum number of non-missing daily scores over the 
7-day period should be required to calculate the weekly scores. In the simulation study, we 
randomly replaced non-missing daily scores with missing daily scores for an increasing number 


Ironwood Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan: C3718-301 
 
14 January 2021 
 
47 
of days, beginning with 1 day and proceeding up to 6 days. We also ran the simulations with 
2 different percentages of patients with missing data at each week, 10% and 20%. 
A patient cluster is defined as all patient daily scores with a weekly repeated measures structure. 
Given the sample size of the current study, approximately 550 patients, and a patient cluster 
bootstrapping resampling based on Study ICP-3718-202 subset that includes 45 patients, we 
performed the following steps for the simulation: 
1. A bootstrapping resampling process with replacement to select 550 patient clusters with 
2000 replications was applied. 
2. In each replicated dataset, a given percentage (eg, 10% or 20%) of patient clusters was 
randomly selected.  
3. In each replicated dataset, in each patient cluster that was selected for in Step 2, at each 
week, a given number of daily scores (ie, 4, 5, or 6 days) was randomly selected and set 
to missing. (Each patient has a planned 8 weeks of data assessments and at each week 
there are 7 planned daily scores.)  
4. Average change from baseline by week was calculated for both non-missing and missing 
data, respectively. 
Across all replicated datasets, for both the data without any missing daily scores and the data 
replaced by daily missing scores, their resultant weekly average score, median, and standard 
deviation were calculated. Comparing the summary scores between these 2 data conditions 
helped us determine the minimum number of non-missing daily scores that should be included in 
the efficacy parameter scoring algorithms. 
The summary statistics for the efficacy parameter WHSS are presented in Table 11. The 
descriptive summary statistics were calculated for both the non-missing daily score data and the 
missing daily score data, by the number of days with missing data (ie, 4, 5, or 6 days). The data 
were compared using ratios.  
The comparisons show that the means, medians, and standard deviations are almost the same for 
the non-missing and missing data, across the different combinations of overall missing rate and 
number of daily scores missing. Specifically, for the extreme case of 20% of patient clusters with 
6 daily scores missing in each week, the weekly average change from baseline compared to the 
non-missing data shows that the means, medians, and standard deviations are almost the same. 
Given this finding, the results suggest that, for the current study, even if a patient has only 1 
valid daily score within a week, it still can be used to represent the average for the week, to 
generate a robust analysis result. The summary is based on a total of 2000 replicated datasets, 
and for each of the replicated datasets the number of patients is 550. 
 
 


Ironwood Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan: C3718-301 
 
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48 
Table 11: 
Simulation Results for WHSS During the 8-week Treatment Period 
Week 
Non-Missing 
With Missing 
Ratio  
(With Missing/Non-missing) 
10% Missing in Each Replicated Data 
 
Mean 
Median 
SD 
Missinga 
Mean 
Median 
SD 
Mean 
median 
SD 
1 
-0.69 
-0.7 
1.04 
4 
-0.69 
-0.7 
1.05 
1 
1 
1.01 
2 
-1.14 
-1.1 
1.13 
 
-1.14 
-1.1 
1.14 
1 
1 
1.01 
3 
-1.36 
-1.3 
1.18 
 
-1.36 
-1.3 
1.19 
1 
1 
1.01 
4 
-1.62 
-1.7 
1.24 
 
-1.62 
-1.7 
1.25 
1 
1 
1.01 
5 
-1.75 
-1.7 
1.30 
 
-1.75 
-1.7 
1.31 
1 
1 
1.01 
6 
-1.84 
-1.9 
1.22 
 
-1.84 
-1.9 
1.23 
1 
1 
1.01 
7 
-1.84 
-2.0 
1.29 
 
-1.84 
-2.0 
1.30 
1 
1 
1.01 
8 
-1.91 
-1.9 
1.34 
 
-1.91 
-1.9 
1.35 
1 
1 
1.01 
 
 
 
 
 
 
 
 
 
 
 
1 
-0.69 
-0.7 
1.04 
5 
-0.69 
-0.7 
1.07 
1 
1 
1.03 
2 
-1.14 
-1.1 
1.13 
 
-1.14 
-1.1 
1.15 
1 
1 
1.02 
3 
-1.36 
-1.3 
1.18 
 
-1.36 
-1.3 
1.20 
1 
1 
1.02 
4 
-1.62 
-1.7 
1.24 
 
-1.62 
-1.7 
1.26 
1 
1 
1.02 
5 
-1.75 
-1.7 
1.30 
 
-1.75 
-1.7 
1.32 
1 
1 
1.01 
6 
-1.84 
-1.9 
1.22 
 
-1.84 
-1.9 
1.24 
1 
1 
1.02 
7 
-1.84 
-2.0 
1.29 
 
-1.84 
-2.0 
1.31 
1 
1 
1.01 
8 
-1.91 
-1.9 
1.34 
 
-1.91 
-1.9 
1.36 
1 
1 
1.01 
 
 
 
 
 
 
 
 
 
 
 
1 
-0.69 
-0.7 
1.04 
6 
-0.69 
-0.7 
1.10 
1 
1 
1.06 
2 
-1.14 
-1.1 
1.13 
 
-1.14 
-1.1 
1.18 
1 
1 
1.05 
3 
-1.36 
-1.3 
1.18 
 
-1.36 
-1.3 
1.23 
1 
1 
1.04 
4 
-1.62 
-1.7 
1.24 
 
-1.62 
-1.7 
1.28 
1 
1 
1.04 
5 
-1.75 
-1.7 
1.30 
 
-1.75 
-1.7 
1.34 
1 
1 
1.03 
6 
-1.84 
-1.9 
1.22 
 
-1.84 
-1.9 
1.26 
1 
1 
1.04 
7 
-1.84 
-2.0 
1.29 
 
-1.84 
-2.0 
1.33 
1 
1 
1.03 
8 
-1.91 
-1.9 
1.34 
 
-1.91 
-2.0 
1.38 
1 
1 
1.03 
 
 
20% Missing in Each Replicated Data 
 
1 
-0.69 
-0.7 
1.04 
4 
-0.69 
-0.7 
1.07 
1 
1 
1.03 
2 
-1.14 
-1.1 
1.13 
 
-1.14 
-1.1 
1.16 
1 
1 
1.02 
3 
-1.36 
-1.3 
1.18 
 
-1.36 
-1.3 
1.20 
1 
1 
1.02 
4 
-1.62 
-1.7 
1.24 
 
-1.62 
-1.6 
1.26 
1 
1 
1.02 
5 
-1.75 
-1.7 
1.30 
 
-1.75 
-1.7 
1.32 
1 
1 
1.01 
6 
-1.84 
-1.9 
1.22 
 
-1.84 
-1.9 
1.24 
1 
1 
1.02 
7 
-1.84 
-2.0 
1.29 
 
-1.84 
-2.0 
1.31 
1 
1 
1.01 
8 
-1.91 
-1.9 
1.34 
 
-1.91 
-1.9 
1.36 
1 
1 
1.01 
 
 
 
 
 
 
 
 
 
 
 
1 
-0.69 
-0.7 
1.04 
5 
-0.69 
-0.6 
1.09 
1 
0.9 
1.05 
2 
-1.14 
-1.1 
1.13 
 
-1.14 
-1.1 
1.18 
1 
0.9 
1.04 


Ironwood Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan: C3718-301 
 
14 January 2021 
 
49 
Week 
Non-Missing 
With Missing 
Ratio  
(With Missing/Non-missing) 
10% Missing in Each Replicated Data 
 
Mean 
Median 
SD 
Missinga 
Mean 
Median 
SD 
Mean 
median 
SD 
3 
-1.36 
-1.3 
1.18 
 
-1.36 
-1.3 
1.22 
1 
1 
1.04 
4 
-1.62 
-1.7 
1.24 
 
-1.62 
-1.6 
1.28 
1 
1 
1.03 
5 
-1.75 
-1.7 
1.30 
 
-1.75 
-1.7 
1.34 
1 
1 
1.03 
6 
-1.84 
-1.9 
1.22 
 
-1.84 
-1.9 
1.25 
1 
1 
1.03 
7 
-1.84 
-2.0 
1.29 
 
-1.84 
-2.0 
1.33 
1 
1 
1.03 
8 
-1.91 
-1.9 
1.34 
 
-1.91 
-2.0 
1.38 
1 
1 
1.02 
 
 
 
 
 
 
 
 
 
 
 
1 
-0.69 
-0.7 
1.04 
6 
-0.69 
-0.7 
1.16 
1 
1 
1.12 
2 
-1.14 
-1.1 
1.13 
 
-1.14 
-1.1 
1.23 
1 
0.9 
1.09 
3 
-1.36 
-1.3 
1.18 
 
-1.36 
-1.3 
1.28 
1 
1 
1.08 
4 
-1.62 
-1.7 
1.24 
 
-1.62 
-1.7 
1.33 
1 
1 
1.07 
5 
-1.75 
-1.7 
1.30 
 
-1.75 
-1.7 
1.38 
1 
1 
1.06 
6 
-1.84 
-1.9 
1.22 
 
-1.84 
-2.0 
1.30 
1 
1 
1.07 
7 
-1.84 
-2.0 
1.29 
 
-1.84 
-2.0 
1.37 
1 
1 
1.06 
8 
-1.91 
-1.9 
1.34 
 
-1.91 
-2.0 
1.42 
1 
1 
1.06 
a. 
Number of daily scores missing.  
Table 12 shows summary results for the WRFS. These results show a similar pattern to that 
observed for WHSS and a similar conclusion can be drawn. That is, for the current study setting, 
the WRFS data are robust, and 1 daily score can be used to represent a weekly average value for 
data analysis. The summary is based on a total of 2000 replicated datasets, and for each of the 
replicated datasets the number of patients is 550. 
Table 12: 
Simulation Results for WRFS During the 8-week Treatment Period 
Week 
Non-Missing 
With Missing 
Ratio  
(With Missing/Non-missing) 
10% Missing in Each Replicated Data 
 
Mean 
Median 
SD 
Missinga 
Mean 
Median 
SD 
Mean 
median 
SD 
1 
-0.43 
-0.3 
0.76 
4 
-0.43 
-0.3 
0.77 
1 
1 
1.02 
2 
-0.78 
-0.7 
0.93 
 
-0.78 
-0.7 
0.94 
1 
1 
1.01 
3 
-0.78 
-0.7 
1.02 
 
-0.78 
-0.7 
1.03 
1 
1 
1.01 
4 
-0.96 
-0.8 
1.06 
 
-0.96 
-0.8 
1.06 
1 
1 
1.01 
5 
-0.98 
-0.8 
1.06 
 
-0.97 
-0.8 
1.07 
1 
1 
1.01 
6 
-0.95 
-0.9 
1.00 
 
-0.95 
-0.9 
1.01 
1 
1 
1.01 
7 
-0.96 
-0.9 
1.04 
 
-0.96 
-0.9 
1.05 
1 
1 
1.01 
8 
-1.07 
-1.1 
1.11 
 
-1.07 
-1.1 
1.12 
1 
1 
1.01 
 
 
 
 
 
 
 
 
 
 
 
1 
-0.43 
-0.3 
0.76 
5 
-0.43 
-0.3 
0.78 
1 
1 
1.03 
2 
-0.78 
-0.7 
0.93 
 
-0.78 
-0.7 
0.95 
1 
1 
1.02 
3 
-0.78 
-0.7 
1.02 
 
-0.78 
-0.7 
1.04 
1 
1 
1.02 
4 
-0.96 
-0.8 
1.06 
 
-0.96 
-0.8 
1.07 
1 
1 
1.01 
5 
-0.98 
-0.8 
1.06 
 
-0.97 
-0.8 
1.07 
1 
1 
1.01 


Ironwood Pharmaceuticals, Inc. 
 
IW-3718 
Statistical Analysis Plan: C3718-301 
 
14 January 2021 
 
50 
Week 
Non-Missing 
With Missing 
Ratio  
(With Missing/Non-missing) 
10% Missing in Each Replicated Data 
 
Mean 
Median 
SD 
Missinga 
Mean 
Median 
SD 
Mean 
median 
SD 
6 
-0.95 
-0.9 
1.00 
 
-0.95 
-0.9 
1.02 
1 
1 
1.01 
7 
-0.96 
-0.9 
1.04 
 
-0.96 
-0.9 
1.06 
1 
1 
1.01 
8 
-1.07 
-1.1 
1.11 
 
-1.07 
-1.1 
1.13 
1 
1 
1.01 
 
 
 
 
 
 
 
 
 
 
 
1 
-0.43 
-0.3 
0.76 
6 
-0.43 
-0.3 
0.81 
1 
1 
1.07 
2 
-0.78 
-0.7 
0.93 
 
-0.78 
-0.7 
0.97 
1 
1 
1.04 
3 
-0.78 
-0.7 
1.02 
 
-0.78 
-0.7 
1.06 
1 
1 
1.04 
4 
-0.96 
-0.8 
1.06 
 
-0.96 
-0.8 
1.09 
1 
1 
1.03 
5 
-0.98 
-0.8 
1.06 
 
-0.98 
-0.8 
1.09 
1 
1.1 
1.03 
6 
-0.95 
-0.9 
1.00 
 
-0.95 
-0.9 
1.04 
1 
1 
1.03 
7 
-0.96 
-0.9 
1.04 
 
-0.96 
-0.9 
1.07 
1 
1 
1.03 
8 
-1.07 
-1.1 
1.11 
 
-1.07 
-1.1 
1.14 
1 
1 
1.03 
 
 
20% Missing in Each Replicated Data 
 
1 
-0.43 
-0.3 
0.76 
4 
-0.43 
-0.3 
0.78 
1 
1.1 
1.03 
2 
-0.78 
-0.7 
0.93 
 
-0.78 
-0.7 
0.95 
1 
1 
1.02 
3 
-0.78 
-0.7 
1.02 
 
-0.78 
-0.7 
1.04 
1 
1 
1.02 
4 
-0.96 
-0.8 
1.06 
 
-0.96 
-0.8 
1.07 
1 
1 
1.01 
5 
-0.98 
-0.8 
1.06 
 
-0.98 
-0.8 
1.07 
1 
1 
1.01 
6 
-0.95 
-0.9 
1.00 
 
-0.95 
-0.9 
1.02 
1 
1 
1.02 
7 
-0.96 
-0.9 
1.04 
 
-0.96 
-0.9 
1.06 
1 
1 
1.01 
8 
-1.07 
-1.1 
1.11 
 
-1.07 
-1.1 
1.13 
1 
1 
1.01 
 
 
 
 
 
 
 
 
 
 
 
1 
-0.43 
-0.3 
0.76 
5 
-0.43 
-0.3 
0.81 
1 
1.1 
1.06 
2 
-0.78 
-0.7 
0.93 
 
-0.78 
-0.7 
0.97 
1 
1 
1.03 
3 
-0.78 
-0.7 
1.02 
 
-0.78 
-0.7 
1.05 
1 
1 
1.03 
4 
-0.96 
-0.8 
1.06 
 
-0.96 
-0.8 
1.08 
1 
1 
1.03 
5 
-0.98 
-0.8 
1.06 
 
-0.97 
-0.8 
1.09 
1 
1.1 
1.03 
6 
-0.95 
-0.9 
1.00 
 
-0.95 
-0.9 
1.03 
1 
1 
1.03 
7 
-0.96 
-0.9 
1.04 
 
-0.96 
-0.9 
1.07 
1 
1 
1.03 
8 
-1.07 
-1.1 
1.11 
 
-1.07 
-1.1 
1.14 
1 
1 
1.02 
 
 
 
 
 
 
 
 
 
 
 
1 
-0.43 
-0.3 
0.76 
6 
-0.43 
-0.3 
0.87 
1 
0.9 
1.14 
2 
-0.78 
-0.7 
0.93 
 
-0.78 
-0.7 
1.01 
1 
1 
1.08 
3 
-0.78 
-0.7 
1.02 
 
-0.78 
-0.7 
1.10 
1 
1 
1.07 
4 
-0.96 
-0.8 
1.06 
 
-0.96 
-0.9 
1.12 
1 
1.1 
1.06 
5 
-0.98 
-0.8 
1.06 
 
-0.97 
-0.9 
1.13 
1 
1.1 
1.06 
6 
-0.95 
-0.9 
1.00 
 
-0.95 
-0.9 
1.07 
1 
1.1 
1.07 
7 
-0.96 
-0.9 
1.04 
 
-0.96 
-1.0 
1.11 
1 
1 
1.06 
8 
-1.07 
-1.1 
1.11 
 
-1.07 
-1.1 
1.18 
1 
0.9 
1.06 
a. 
Number of daily scores missing. 


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Proportion of Heartburn-free Days During the 8-week Treatment Period  
A similar bootstrapping resampling process for patient clusters that was used for the parameters 
WHSS and WRFS can be applied to PHFD. The descriptive summary statistics were calculated 
for both the non-missing daily score data and the missing daily score data, by the number of days 
with missing data (ie, 4, 5, or 6 days). The results are presented in Table 13.  
The comparisons show that the means, medians, and standard deviations are almost the same for 
the non-missing and missing data, across different combinations of overall missing rate and 
number of daily scores missing. This suggests that the algorithm for calculating the PHFD (the 
number of heartburn-free days divided by the number of diary entry days) is robust. The 
summary is based on a total of 2000 replicated datasets, and for each of the replicated datasets 
the number of patients is 550. 
Table 13: 
Simulation Results for PHFD During the 8-week Treatment Period 
Non-Missing 
With Missing 
Ratio  
(With Missing/Non-missing) 
10% Missing in Each Replicated Data 
Mean 
Median 
SD 
Missinga 
Mean 
Median 
SD 
Mean 
median 
SD 
0.307 
0.2 
0.315 
4 
0.307 
0.2 
0.315 
1 
1 
1 
0.307 
0.2 
0.315 
5 
0.308 
0.2 
0.315 
1 
1 
1 
0.307 
0.2 
0.315 
6 
0.307 
0.2 
0.316 
1 
1 
1 
 
20% Missing in Each Replicated Data 
 
0.307 
0.2 
0.315 
4 
0.307 
0.2 
0.315 
1 
1 
1 
0.307 
0.2 
0.315 
5 
0.308 
0.2 
0.316 
1 
1 
1 
0.307 
0.2 
0.315 
6 
0.308 
0.2 
0.317 
1 
1 
1.01 
a. 
Number of daily scores missing. 


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Appendix 2. 
Visit Window Slotting Conventions 
Visit Time Windows for Safety Analysis 
Table 14 below presents the visits assigned for the safety analysis corresponding to the range of 
trial days (window) during which an actual visit may have occurred. 
Table 14: 
Visit Time Windows for Safety Analysis 
Derived Visit 
Scheduled Test / Visit Daya 
Window 
Baseline 
Day 1 
Days ≤1 
Week 4 (Day 29) Visit 
Day 29 
Days [2, 43] 
Week 8 (Day 57) Visit 
Day 57 
Days ≥44 
End of Treatmentb 
End of Treatment Visit 
a. 
Relative to the day of randomization (Day 1) 
b. “End of Treatment” will be presented in analysis tables for safety parameters, including ECG, clinical 
laboratory, and vital signs. 
Test/Visit Day will be calculated as follows: test/visit date – date of randomization + 1. 
If there are multiple values available for the same Visit, the data with the latest date for that visit 
will be utilized for summary. 
Visit Time Windows for Efficacy Analysis 
Table 15 presents the analysis weeks assigned for the efficacy analysis of the patient diary data 
related to daily GERD symptom assessment. These analysis weeks will be used in the 
calculations for all week-based parameters (eg, WHSS, WRFS, etc.). 
Table 15: 
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 day of randomization (Day 1). There is no Day 0.  
b. Baseline for efficacy parameters will be derived from the eDiary collected for Pretreatment Week -1 (Week -2 if 
data for Week -1 not available), specifically for the time dependent proportion parameters (defined as days with 
the event of interesting divided by the number of diary entry days during the relevant period) the last 14 days 
(Week -2 to Week -1) prior to day of randomization will be used. 


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c. Day -1 for efficacy parameters derived from the morning diary. 
d. Day 1 for efficacy parameters derived from the morning diary. 
Table 16 presents the analysis weeks assigned for the efficacy analysis of the patient diary data 
related to Weekly Questions (eg, degree of relief questions, symptom bothersomeness questions, 
and treatment satisfaction questions). 
Table 16: 
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 day of randomization (Day 1). There is no Day 0.  
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), unless otherwise specified. 
c.  All values that were assessed prior to or on the day of the last dose will be used for the efficacy analysis. 
However, all values, regardless of whether they were collected prior to or after the last dose, will be used 
for the sensitivity analysis.  
In general, weekly questions will be assigned only to the analysis week for which the question 
covers at least 4 days of that week. 
If patients answer the weekly questions multiple times for a week, for each question, the average 
of the respective answers will be assigned as the weekly value. 
 
 
e. All values that were assessed prior to or on the day of the last dose will be used for the efficacy analysis. 
However, all values, regardless of whether they were collected prior to or after the last dose, will be used 
for the sensitivity analysis.  


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Appendix 3. 
Pooling of Trial Centers 
Because of the potential of many study centers to have a small number of patients, the centers 
will be pooled by the following 6 geographic regions (as listed in Table 17): US Northeast, US 
Southeast, US Midwest, US Southwest, US West and Canada.  
Table 17: 
Definition of Geographic Regions 
US Northeast 
US 
Southeast 
US 
Midwest 
US 
Southwest 
US West 
Canada 
CT 
AL 
IA 
AZ 
CA 
CANADA 
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 
- 
- 
- 


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Appendix 4. 
Schedule of Evaluations  
Table 18: 
Schedule of Evaluations 
 
Screening Period 
(Up to 5 weeks) 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-up 
Visit Days → 
Screening Visit 
(Day -56 to Day -
15) 
Pretreatment Visit 
(Day -21 to Day -
1) 
Randomization 
Visit 
(Day 1) 
Week 4 
Visit 
(Day 29 ± 3) 
Week 8 / End-
of-Treatment 
Visit  
(Day 57 + 3) 
Safety Phone 
Call 
(EOT 
+ 7d) 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
 
Study Procedure ↓ 
 
 
 
 
 
 
Inclusion and Exclusion Criteria Verification 
X 
X 
X 
 
 
 
Signing of ICF 
X 
 
 
 
 
 
IWRS Registration (a) 
X 
X 
X 
X 
X 
 
Demographics 
X 
 
 
 
 
 
Medical & Disease History 
X 
 
 
 
 
 
Physical Examination (b) 
X 
 
 
 
X 
 
Body Weight and Height (c)  
X 
X 
X 
X 
X 
 
H2RA/Antacid Washout (d) 
X 
 
 
 
 
 
EGD (e) 
X 
 
 
 
X 
 
Up to 96 Hours of pH Testing with Bravo Device (f) 
X 
 
 
 
 
 
Seated Vital Signs (g)  
X 
 
X 
X 
X 
 
12-Lead ECG (h) 
X 
 
X 
 
X 
 
Prior and Concomitant Medications & Procedures (i) 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Tests (j) 
X 
 
X 
X 
X 
 
Pregnancy Test (k) 
X 
 
X 
X 
X 
 
Drug and Alcohol Screen (l) 
X 
 
 
 
 
 
AE Evaluations (m) 
X 
X 
X 
X 
X 
X 
Rescue Medicine Dispensed (n) 
 
X 
X 
X 
 
 
eDiary Training and Dispensation 
 
X 
 
 
 
 
eDiary (o) 
 
X 
X 
X 
X 
 


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Screening Period 
(Up to 5 weeks) 
Pretreatment 
Period  
(2 weeks) 
Treatment Period 
(8 weeks) 
Follow-up 
Visit Days → 
Screening Visit 
(Day -56 to Day -
15) 
Pretreatment Visit 
(Day -21 to Day -
1) 
Randomization 
Visit 
(Day 1) 
Week 4 
Visit 
(Day 29 ± 3) 
Week 8 / End-
of-Treatment 
Visit  
(Day 57 + 3) 
Safety Phone 
Call 
(EOT 
+ 7d) 
Visit Numbers → 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
 
Study Procedure ↓ 
 
 
 
 
 
 
Weekly Symptom and Treatment Assessments  
 
X 
X 
X 
X 
 
WPAI-Sleep-GERD 
 
 
X 
X 
X 
 
EQ-5D-3L 
 
 
X 
X 
X 
 
Randomization 
 
 
X 
 
 
 
Study Medication Dispensed (p) 
 
 
X 
X 
 
 
Study Medication Return (q) 
 
 
 
X 
X 
 
eDiary Return 
 
 
 
 
X 
 
Follow-up Phone Call (r) 
 
 
 
 
 
X 
Abbreviations: AE = adverse event; BP = blood pressure; CBC = complete blood count; ECG = electrocardiogram; EGD = esophagogastroduodenoscopy; 
EOT = End-of-treatment; EQ = EuroQol; H2RA = histamine-2 receptor antagonist; HEENT = head, eyes, ears, nose, and throat; ICF = informed consent form; 
IWRS = interactive web response system; PPI = proton pump inhibitor; mRESQ-eD = modified Reflux Symptom Questionnaire Electronic Diary; SAE = serious 
adverse event 
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; 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 washout H2RAs at least 5 days prior, and antacids 1 day prior, to the EGD and Bravo testing. 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 liquid antacid that is provided as rescue medication 
(aluminum hydroxide / magnesium hydroxide). 
e. 
All patients will be required to undergo an EGD during the Screening Period. There should be a minimum of 7 days between the EGD and the start of the 
Pretreatment Period to allow for pH testing and patient stabilization. A repeat EGD will be performed at the Week 8 / EOT Visit for all patients who have 
completed at least 4 weeks of treatment and had erosive esophagitis on the screening EGD (based on the Los Angeles [LA] classification of esophagitis, see 
Appendix 8) as determined by either the site personnel or the central reader.  
f. 
Up 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.  


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g. 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. 
h. 12-Lead ECGs should be obtained after the patient has been supine for at least 5 minutes. 
i. 
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 PPIs, H2RAs, and antacids. Concomitant medications and procedures will be collected in the EDC system. 
j. 
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. 
k. For all female patients of childbearing potential, a negative urine or serum pregnancy test must be performed and documented at the Screening Visit, and at 
the Randomization Visit (before dosing) in order for the patient to be randomized into the study. A urine or serum pregnancy test will also be obtained at the 
Week 4 and EOT Visits. All positive urine pregnancy test results will be confirmed by a serum pregnancy test. 
l. 
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. 
m. For randomized patients, all AEs will be captured from the time the patient signs the ICF through the Follow-up Phone call. 
n. Rescue medicine (aluminum hydroxide / magnesium hydroxide) will be supplied to patients at the Pretreatment Visit, and if needed, at subsequent visits. 
o. The eDiary will be dispensed at the Pretreatment Visit. Patients must complete daily questions at least 5 days each week during the 14 days before the 
Treatment Period and must complete the weekly questions at least once during the 7 days before the Treatment Period in order to be eligible for 
randomization. Patients should bring their eDiary to each visit. The eDiary will be used for daily assessments (PPI administration, mRESQ-eD, dyspepsia 
symptoms, sleep disturbance, and rescue medication use), and weekly assessments (degree of relief, symptom bothersomeness, symptom relief, treatment 
satisfaction, and questionnaires).  
p. 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 
study medication prior to arriving at the clinic but will be dispensed additional doses needed until the next study visit. 
q. Treatment adherence with study drug will be assessed based on return of unused tablets. 
r. 
Study site will contact each patient via telephone 7 days after the EOT Visit to collect information pertaining to ongoing AEs/SAEs/concomitant 
medications/concomitant therapies, and information concerning any new AEs/SAEs /concomitant medications/concomitant therapies since the EOT Visit.  
 


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Appendix 5. 
Modified Reflux Symptom Questionnaire Electronic Diary  
Instructions: Please answer the following questions to help us understand the symptoms you 
experienced over the past 24 hours because of your reflux disease. For each question, please 
choose the answer most appropriate for you. 
1. 
Over the past 24 hours, how would you rate the severity of your burning feeling behind 
the breastbone or in the center of the upper stomach? 
0=Did not have/ 1=Very mild/ 2=Mild/ 3=Moderate/ 4=Moderately severe/ 5=Severe 
2. 
Over the past 24 hours, how would you rate the severity of your pain behind the 
breastbone or in the center of the upper stomach? 
0=Did not have/ 1=Very mild/ 2=Mild/ 3=Moderate/ 4=Moderately severe/ 5=Severe 
3. 
Over the past 24 hours, how would you rate the severity of your difficulty swallowing? 
0=Did not have/ 1=Very mild/ 2=Mild/ 3=Moderate/ 4=Moderately severe/ 5=Severe 
4. 
Over the past 24 hours, how would you rate the severity of your hoarseness? 
0=Did not have/ 1=Very mild/ 2=Mild/ 3=Moderate/ 4=Moderately severe/ 5=Severe 
5. 
Over the past 24 hours, how would you rate the severity of your cough? 
0=Did not have/ 1=Very mild/ 2=Mild/ 3=Moderate/ 4=Moderately severe/ 5=Severe 
6. 
Over the past 24 hours, how often did you experience regurgitation (liquid or food 
moving upwards towards your throat or mouth)? 
0=Never/ 1=Rarely/ 2=Sometimes/ 3=Often/ 4=Very often 
7. 
Over the past 24 hours, how often did you experience an acid or bitter taste in the 
mouth? 
0=Never/ 1-Rarely/ 2=Sometimes/ 3=Often/ 4=Very often 
8. 
Over the past 24 hours, how often did you experience burping? 
0=Never/ 1=Rarely/ 2=Sometimes/ 3=Often/ 4=Very often 


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Appendix 6. 
Other Daily Assessments  
Heartburn 
The following question will be answered by the patient in the evening diary.  
Over the past 24 hours, how would you rate the severity of your heartburn? 
0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe 
Sleep Disturbance Due to GERD 
The following questions will be answered by the patient upon getting up each morning (5:00 
a.m. to 12:00 p.m.) using the eDiary: 
Falling Asleep 
Last night, did you have trouble falling asleep because of GERD symptoms? 
[Yes, No] 
Awakenings 
Last night, how many times did you wake up during the night because of GERD symptoms? 
0 
1 time 
2 times 
3-5 times 
6 or more times 
Use of per-protocol rescue medicine (antacid) 
How many times did you use your rescue medicine (liquid antacid) during the past 24 hours? 
0 
1 time 
2 times 
3-5 times 
6 or more times 


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Appendix 7. 
Weekly Assessments  
Degree of Relief Assessments  
Administered weekly during Pretreatment and Treatment Periods: 
How would you rate your heartburn (a pain or 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? 
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 
Bothersomeness Assessments  
Administered weekly during Pretreatment and Treatment Periods: 
How much were you bothered by heartburn (a pain or burning sensation in your chest, behind the 
breastbone) over the past 7 days? 
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 7 days? 
How much were you bothered by your overall GERD symptoms over the past 7 days? 
1=Not at all 
2=A little bit 
3=A moderate amount 
4=A great deal 
5=An extreme amount 
Treatment Satisfaction Assessment  
Administered weekly during Treatment Period: 
How would you rate your satisfaction with the study treatment? 
1=Very dissatisfied 
2=Dissatisfied 


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3=Neither satisfied nor dissatisfied 
4=Satisfied 
5=Very satisfied 


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Appendix 8. 
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 break no longer than 5 mm that does not extend 
between the tops of two mucosal folds. 
Grade B 
One (or more) mucosal break more than 5 mm long that does not extend 
between the tops of two mucosal folds. 
Grade C 
One (or more) mucosal break that is continuous between the tops of two or 
more mucosal folds but which involve less than 75% of the circumference. 
Grade D 
One (or more) mucosal break which involves at least 75% of the esophageal 
circumference.