A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study Evaluating the Safety and Efficacy of Different Doses of IW-1973 Over 12 Weeks in Patients With Heart Failure With Preserved Ejection Fraction
Phase: PHASE2
Conditions: Heart Failure With Preserved Ejection Fraction
Sponsor: Akebia Therapeutics



IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
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TABLE OF CONTENTS 
KEY STUDY ROLES .....................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................4 
SPONSOR SIGNATURE ..............................................................................................................11 
INVESTIGATOR’S SIGNATURE ...............................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................13 
SYNOPSIS .....................................................................................................................................16 
ELIGIBILITY CRITERIA.............................................................................................................19 
INCLUSION CRITERIA.........................................................................................................19 
EXCLUSION CRITERIA .......................................................................................................21 
SCHEDULE OF EVENTS ............................................................................................................24 
1. 
INTRODUCTION .................................................................................................................27 
1.1 
HEART FAILURE WITH PRESERVED EJECTION FRACTION ..........................27 
1.2 
PATHOPHYSIOLOGY OF HFPEF............................................................................27 
1.3 
RATIONALE FOR USE OF AN SGC STIMULATOR IN HFPEF ...........................28 
1.3.1 
IW-1973 .............................................................................................................29 
1.3.1.1 
Nonclinical Data in Support of Clinical HFpEF Investigations ..............29 
2. 
STUDY OBJECTIVES ..........................................................................................................30 
3. 
INVESTIGATIONAL PLAN ................................................................................................31 
3.1 
OVERALL STUDY DESIGN AND PLAN ................................................................31 
3.2 
DISCUSSION OF STUDY DESIGN AND CONTROL GROUP ..............................33 
3.3 
STUDY DURATION ..................................................................................................34 
3.4 
STUDY POPULATION ..............................................................................................34 
3.4.1 
Removal of Patients from Therapy or Assessment ............................................34 
3.4.2 
Early Termination Procedures ...........................................................................35 
3.5 
STUDY TREATMENT(S) ..........................................................................................36 
3.5.1 
Description of Treatment(s) ...............................................................................36 
3.5.1.1 
Investigational Product ............................................................................36 
3.5.1.2 
Placebo .....................................................................................................36 
3.5.1.3 
Packaging and Labeling ...........................................................................36 
3.5.1.4 
Dosage......................................................................................................36 
3.5.1.5 
Storage and Accountability ......................................................................37 
3.5.2 
Method of Assigning Patients to Treatment Groups..........................................38 
3.5.3 
Selection of Dosage in the Study .......................................................................38 
3.5.4 
Selection and Timing of Dose for Each Patient and Dose Reduction ...............39 
3.5.4.1 
Study Drug Administration ......................................................................39 
3.5.4.2 
Dose Reduction ........................................................................................39 
3.5.5 
Treatment Compliance .......................................................................................40 

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Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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3.8.13.1 
Causality Assessment...............................................................................52 
3.8.13.2 
Severity Assessment ................................................................................53 
3.8.13.3 
Serious Adverse Events ...........................................................................53 
3.8.13.4 
Recording Adverse Events .......................................................................54 
3.8.13.5 
Reporting Serious Adverse Events ..........................................................55 
3.8.14 
Cardiac Events ...................................................................................................56 
3.8.15 
Pharmacokinetic Assessments ...........................................................................56 
3.8.16 
Genotyping (Optional, per Patient Consent) ......................................................56 
4. 
STUDY ENDPOINTS ...........................................................................................................57 
4.1 
PRIMARY ENDPOINTS ............................................................................................57 
4.1.1 
Primary Safety ...................................................................................................57 
4.1.2 
Primary Efficacy ................................................................................................57 
4.2 
SECONDARY ENDPOINTS ......................................................................................57 
4.2.1 
Secondary Efficacy ............................................................................................57 
4.3 
EXPLORATORY ENDPOINTS .................................................................................57 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 
STATISTICAL METHODS ..................................................................................................60 
5.1 
GENERAL CONSIDERATIONS ...............................................................................60 
5.1.1 
Continuous Endpoints ........................................................................................60 
5.1.2 
Responder Endpoints .........................................................................................60 
5.2 
DETERMINATION OF SAMPLE SIZE ....................................................................61 
5.3 
ANALYSIS POPULATIONS .....................................................................................62 
5.4 
PATIENT DISPOSITION ...........................................................................................62 
5.5 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ..................................62 
5.6 
DRUG EXPOSURE AND COMPLIANCE ................................................................62 
5.7 
PRIOR AND CONCOMITANT MEDICATIONS AND PROCEDURES ................63 
5.8 
MAJOR PROTOCOL DEVIATIONS .........................................................................63 
5.9 
EFFICACY ANALYSES ............................................................................................63 
5.9.1 
Controlling for Multiplicity ...............................................................................63 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
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LIST OF IN-TEXT TABLES 
Table 1. 
Key Study Participants .........................................................................................2 
Table 2. 
External Data Evaluation Bodies and Study Committees ...................................3 
Table 3. 
Dose Regimen by Treatment Period Week ........................................................36 
Table 4. 
Dose Regimen by Treatment Period Week ........................................................37 
Table 5. 
Categories of SAEs Triggering Individual Stopping Criteria and DMC 
Review ...............................................................................................................43 
Table 6. 
New York Heart Association (NYHA) Functional Classification .....................47 
Table 7. 
Clinical Laboratory Tests ...................................................................................48 
 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
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LIST OF IN-TEXT FIGURES 
Figure 1. 
Study Schematic ................................................................................................31 
 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
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LIST OF APPENDICES 
Appendix 1 
Prohibited Medicines and Supplements .............................................................82 
Appendix 2 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ......................................83 
Appendix 3 
Sheehan Disability Scale (SDS) ........................................................................87 
Appendix 4 
EuroQOL 5-dimension Questionnaire (EQ-5D-5L) ..........................................89 
Appendix 5 
Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR-
16) ......................................................................................................................92 
Appendix 6 
6-Minute Walk Test Method ..............................................................................94 
 
 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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INVESTIGATOR’S SIGNATURE 
Study Title: 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 
2 Study Evaluating the Safety and Efficacy of Different Doses of IW-
1973 over 12 Weeks in Patients with Heart Failure with Preserved 
Ejection Fraction (CAPACITY HFpEF) 
Study Number: 
C1973-204 
Final Date: 
27 June 2018 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
 
 
Signed: 
 
 
Date:  
 
 
 
Print Name: 
 
 
 
 
 
 
 
 
 
 
 
 
 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
6MWT 
6-minute walk test 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ANCOVA 
analysis of covariance  
ARB 
angiotensin receptor blocker 
AUC 
area under the curve 
BID 
twice daily (2×/day) 
BMI 
body mass index (kg/m2) 
BP 
blood pressure 
CBC 
complete blood count 
CDF 
cumulative distribution function 
cGMP 
cyclic guanosine 3’,5’-monophosphate 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
CMH 
Cochran-Mantel-Haenszel 
CPET 
cardiopulmonary exercise test  
CYP3A 
cytochrome P450 3A 
DMC 
Data Monitoring Committee 
DSS 
Dahl salt-sensitive 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
E/e’ ratio  
mitral peak velocity [E]/mitral annulus early diastolic recoil velocity [e’] 
EF 
ejection fraction 
eGFR 
estimated glomerular filtration rate (mg/mL/1.73 m2) 
EIU 
exposure in utero 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
h 
hour(s) 
HFpEF 
heart failure with preserved ejection fraction  

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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Abbreviation 
Term 
HFrEF 
heart failure with reduced ejection fraction 
HOMA-IR 
homeostatic model assessment to quantify insulin resistance 
HPF 
high power field 
ICF  
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IUD 
intrauterine device 
IV 
intravenous 
IWRS 
interactive web response system 
 
 
kg 
kilogram 
kg/m2 
kilograms/meters squared (body mass index) 
LA 
left atrial 
LSM 
least-squares mean 
LV 
left ventricular 
LVEDP 
left ventricular end-diastolic pressure 
LVEDV 
left ventricular end-diastolic volume  
LVESV 
left ventricular end-systolic volume  
m 
minute  
mITT 
modified intent to treat 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MI 
myocardial infarction 
mL 
milliliter 
mmHg 
millimeters of mercury 
MPV 
mean platelet volume 
MRA 
mineralocorticoid receptor antagonists  

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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Abbreviation 
Term 
NO 
nitric oxide 
NT-proBNP 
N-terminal pro B-type natriuretic peptide  
NYHA 
New York Heart Association  
pd 
postdose 
PDE 
phosphodiesterase 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QD 
once daily (1×/day) 
 
 
QOL 
quality of life 
RBC 
red blood cell 
RDW 
red blood cell distribution width 
RER 
respiratory exchange ratio  
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
 
 
sGC 
soluble guanylate cyclase 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
UACR 
urine albumin creatinine ratio 
UGT 
uridine diphosphate–glucuronosyl transferase 
ULN 
upper limit of normal 
US 
United States 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
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SYNOPSIS 
Sponsor 
Ironwood Pharmaceuticals, Inc. 
Name of Finished Product 
IW-1973 Tablet (praliciguat) 
Name of Active Ingredient 
IW-1973 
Study Title 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study Evaluating the 
Safety and Efficacy of Different Doses of IW-1973 over 12 Weeks in Patients with Heart Failure 
with Preserved Ejection Fraction (CAPACITY HFpEF) 
Study Number 
C1973-204 
Study Phase: 2 
Study Objectives 
Primary  
• To assess the safety of oral IW-1973 when administered for approximately 12 weeks to 
patients with heart failure with preserved ejection fraction (HFpEF) 
• To evaluate effect of oral IW-1973 on peak exercise capacity when administered for 
approximately 12 weeks to patients with HFpEF, both in all patients and in patients without 
permanent or persistent atrial fibrillation  
Secondary  
• To evaluate the effect of oral IW-1973 on exercise and functional capacity when 
administered for approximately 12 weeks to patients with HFpEF  
Study Design 
This Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
will evaluate the safety and efficacy of IW-1973 compared with placebo when administered 
daily for approximately 12 weeks (2 weeks of twice-daily [BID] dosing followed by 10 weeks of 
once-daily [QD] dosing) in the indicated patient population. 
At the Day 1 Visit, eligible patients will be stratified by atrial fibrillation status and by baseline 
peak VO2 RURIDJH- and sex-adjusted normal values and with respiratory 
H[FKDQJHUDWLR>5(5@DVGHWHUPLQHGE\FDUGLRSXOPRQDU\H[HUFLVHWHVW>&3(7@. Patients 
will be randomized in a 1:1 ratio to daily 40 mg IW-1973 or placebo (see Study Treatment 
below). All patients will receive their first morning BID dose in the clinic on Day 1 and their 
first QD dose at the Week 2 Visit (Day 15 [±3]); for these 2 visits, patients must stay in the 
clinic for approximately 4 hours postdose and will be released at the Investigator’s discretion 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
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after undergoing safety, efficacy, and pharmacokinetic (PK) assessments per the Schedule of 
Events. At the Week 4, Week 8, and End of Treatment visits, patients will again return to the 
clinic for study drug administration; for safety, efficacy, and PK assessments; and to receive 
additional study drug and other supplies, as applicable. Patients will return to the clinic 28 days 
(Day 113 ±7) after their last study drug dose for the final Follow-up Visit. 
Study Treatment 
Patients will receive study drug for up to 89 days.  
For patients randomized via Protocol Amendment 2 (or earlier): On Day 1, patients will be 
randomized in a 1:1:1:1 ratio to the following 4 regimens: 
Dose 
Weeks 1 and 2, BID Dosing  
Weeks 3 through 12, QD Dosing 
10 mg 
one 5-mg IW-1973 Tablet, orally twice daily 
two 5-mg IW-1973 Tablets, orally once daily 
20 mg 
one 10-mg IW-1973 Tablet, orally twice daily 
two 10-mg IW-1973 Tablets, orally once daily 
40 mg 
one 20-mg IW-1973 Tablet, orally twice daily 
two 20-mg IW-1973 Tablets, orally once daily 
Placebo 
one matching placebo tablet, orally twice daily 
two matching placebo tablets, orally once daily 
BID=twice daily; QD=once daily 
 
For patients randomized starting with Amendment 3 to the protocol: Patients will be randomized 
on Day 1 in a 1:1 ratio to the following 2 regimens: 
Dose 
Weeks 1 and 2, BID Dosing  
Weeks 3 through 12, QD Dosing 
40 mg 
one 20-mg IW-1973 Tablet, orally twice daily 
two 20-mg IW-1973 Tablets, orally once daily 
Placebo 
one matching placebo tablet, orally twice daily 
two matching placebo tablets, orally once daily 
BID=twice daily; QD=once daily 
 
Study Population and Planned Number of Patients 
The study will enroll approximately 184 adult patients with established heart failure and limited 
exercise capacity with ejection fraction of at least 40% and who have at least 2 of 4 risk factors 
for HFpEF (diabetes/prediabetes, hypertension, obesity, advanced age >\HDUV@7KHQXPEHU
of patients admitted with permanent or persistent atrial fibrillation will be limited to 
approximately 36 in the study. 
See Eligibility Criteria for full inclusion and exclusion criteria. 
Study Assessments 
Safety: Medical history, prior and concomitant medications and surgeries/procedures, and 
adverse events will be collected. Physical examination, vital sign measurements including 
orthostatic blood pressure, clinical laboratory tests, pregnancy tests, and electrocardiograms will 
be performed. 
Efficacy: CPET, 6-minute walk tests (6MWT), and echocardiography will be performed. New 
York Heart Association (NYHA) functional classification will be determined. Cardiac events 
will be analyzed. Blood and urine will be collected for biomarker determinations.  
Patient-reported outcomes: Patients will self-administer the following questionnaires: Kansas 
City Cardiomyopathy Questionnaire (KCCQ), Sheehan Disability Scale (SDS), EuroQol-5D-5L 
(EQ-5D-5L), and Quick Inventory of Depressive Symptomatology (QIDS)-SR-16. 
Pharmacokinetics: Blood will be collected to determine plasma concentrations of IW-1973. 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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Dose Reduction, Individual Stopping Criteria, and Data Monitoring Committee (DMC) 
Per Investigator discretion, a dose reduction for an individual patient is allowed after 
consultation with the Medical Monitor. If approved, the patient will reduce his or her daily dose 
by half, ie, from 2 to 1 tablet daily. It is recommended that the patient to be evaluated in the 
clinic in association with any dose modification. Each patient’s dose may only be reduced once 
and will not be increased after reduction. 
Also on an individual basis, a patient will be discontinued from study drug dosing if any of the 
following are reported: a study drug-related serious adverse event (SAE) of spontaneous 
bleeding; a life-threatening symptomatic hypotension-related SAE; or 2 study drug-related 
symptomatic hypotension-related SAEs.  
An independent DMC will review trial safety data both periodically and on an ad hoc basis. 
After each periodic or ad hoc review of safety data, the DMC will recommend trial continuation, 
continuation with modification, or termination. Details will be provided in a DMC charter, 
which will be developed in collaboration with the DMC members and will be finalized before 
the first patient is randomized. 
Statistical Methods 
There will be no statistical adjustment for multiple testing. All reported p-values will be 
considered nominal. Ninety-two patients per arm will provide approximately 90% power to 
detect a clinically meaningful difference between the 40-mg IW-1973 treatment arm and the 
placebo treatment arm in change from baseline at Week 12 peak VO2 in all patients and/or in 
patients without permanent or persistent atrial fibrillation. 
Final Date:  27 June 2018 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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ELIGIBILITY CRITERIA 
INCLUSION CRITERIA 
Patients must meet all of the following criteria to be eligible for enrollment in this study: 
1. Patient has signed an informed consent form (ICF) before any study-specific procedures are 
performed. 
2. 3DWLHQWLVDQDPEXODWRU\PDOHRUIHPDOH45 years old at the Screening Visit. 
3. Patient has heart failure with ejection fraction (EF) of 0% as assessed within 12 months of 
the Screening Visit, without previously documented EF of <40%. (If echocardiography 
results are not documented in the patient’s medical history, the Investigator may perform an 
echocardiography at the Screening Visit.) Eligibility will be based on Investigator analysis. 
4. Patient has a peak VO2 measuring <80% of age- and sex-adjusted normal (see table) and a 
UHVSLUDWRU\H[FKDQJHUDWLR5(5at the Baseline Visit cardiopulmonary exercise test 
(CPET) as determined by the CPET Core Lab.  
 
Age- and Sex-adjusted Normal Peak VO2 
Age (years) 
Sex 
Normal Peak VO2  
(mL O2/kg/min) 
80% of Normal Peak VO2 
(mL O2/kg/min) 
50-59 
M 
36 
28.8 
50-59 
F 
29 
23.2 
60-69 
M 
33 
26.4 
60-69 
F 
27 
21.6 
>70 
M 
29 
23.2 
>70 
F 
27 
21.6 
Source: Fletcher et al, 1995 (1) 
F=female; M=male 
 
5. Patient may have permanent or persistent atrial fibrillation; total number of patients with 
permanent or persistent atrial fibrillation will be limited to approximately 36. (Note: Patients 
with intermittent [paroxysmal] atrial fibrillation must be in normal sinus rhythm at the time 
of the baseline CPET; these patients will not count toward the limit of 36 patients with 
permanent or persistent atrial fibrillation.) 
6. Patient has evidence in medical history supporting clinical heart failure syndrome consisting 
of at least 1 of the following: 
a. Hospitalization or emergency department visit for heart failure within the past year, with 
at least 2 of the following documented:   
o Volume overload on presentation as evidenced by at least 2 of the following 
5 signs: jugular venous distension, pitting edema 1+, ascites, pulmonary 
congestion on chest x-ray, or pulmonary rales  

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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o B-type natriuretic peptide (BNP) >VLQXVUK\WKP@200 pg/mL [atrial 
fibrillation]) or N-terminal pro BNP (NT-proBNP) (>300 [sinus rhythm] or 
600 pg/mL [atrial fibrillation])  
o Treatment with intravenous (IV) diuretics with clinical response 
b. %13>VLQXVUK\WKP@pg/mL [atrial fibrillation]) or NT-proBNP (>300 [sinus 
rhythm], >600 pg/mL [atrial fibrillation]) within the past 6 months. (If needed for 
eligibility, a sample for NT-proBNP level may be collected at the Screening Visit.) 
c. Echocardiographic evidence within the past 12 months of at least 2 of the following: left 
ventricular (LV) hypertrophy, left atrial (LA) enlargement, or diastolic dysfunction 
PHGLDO(H
UDWLR15)  
d. Hemodynamic evidence of elevated filling pressures, as indicated by pulmonary capillary 
wedge pressure 15 mmHg at rest or >25 mmHg with exercise within the past 12 months, 
or left ventricular end-diastolic pressure 15 mmHg 
7. Patient has New York Heart Association (NYHA) Class II-IV symptomatology as assessed at 
the time of the Screening Visit. The classifications are described in Section 3.8.7 (Table 6). 
8. Patient is on stable dose(s) of any current cardiovascular medication (eg, angiotensin-
converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], beta-blockers, 
mineralocorticoid receptor antagonists [MRAs]) for at least 1 month before the Baseline and 
Randomization Visits with the regimen expected to remain unchanged for the duration of the 
trial. Diuretic doses do not need to be stable. 
9. Patient meets at least 2 of the following criteria at the Screening Visit:  
a. Diagnosis of type 2 diabetes mellitus or prediabetes (currently treated or hemoglobin A1c 
 
b. History of hypertension (on at least 1 antihypertensive medication or has current seated 
blood pressure [BP] >140/90 mmHg) 
c. Body mass index (BMI) >30 kg/m2 
d. $JH\HDUV 
10. Female patient must be postmenopausal QRPHQVHVIRUFRQVHFXWLYHPRQWKV or 
surgically sterile (ie, bilateral oophorectomy, hysterectomy, or tubal sterilization [tie, clip, 
band, or burn]). Female patients of reproductive potential 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 60 days after the 
final dose of study drug: 
a. Progesterone implant and/or an intrauterine device (IUD), or 
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 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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contraceptive [eg, oral and transdermal patch] combined with a barrier method, partner 
wLWKYDVHFWRP\>FRQGXFWHGGD\VEHIRUHWKH6FUHHQLQJ9LVLWRUFRQILUPHGYLDVSHUP
analysis] plus a hormone or barrier method).   
11. Male patients who are not VXUJLFDOO\VWHULOHE\YDVHFWRP\FRQGXFWHG days before the 
Screening Visit or confirmed via sperm analysis) must agree to completely abstain from 
heterosexual intercourse or, if heterosexually active, must agree to use a highly effective 
birth control method (eg, condom with spermicide; partner IUD; partner diaphragm or 
cervical cap; partner hormonal contraceptive [including progesterone implant]; or 
postmenopausal partner [QRPHQVHVIRUFRQVHFXWLYHPRQWKV]) starting from the 
Screening Visit through 60 days after the final dose of study drug. 
12. Patient must agree not to make any major lifestyle (eg, diet, exercise) changes from the 
Screening Visit through the Follow-up Visit. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will not be eligible to participate in the study:  
1. Patient has had acute coronary syndrome or percutaneous coronary intervention within 
30 days before Randomization. 
2. Patient has had cardiac transplantation or has cardiac transplantation planned during the 
study. 
3. Patient has had coronary artery bypass graft, cardiac mechanical support implantation, or 
other cardiac surgery in the 3 months before the Screening Visit or planned during the study. 
4. Patient has severe chronic obstructive pulmonary disease (COPD) as defined by chronic 
oxygen dependence. Nighttime oxygen is not exclusionary. 
5. Patient had had heart failure hospitalization with discharge within 30 days before the 
Baseline Visit. 
6. Patient has hypertrophic cardiomyopathy (obstructive or nonobstructive), restrictive 
cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac sarcoidosis, or known 
amyloid cardiomyopathy. 
7. Patient has uncontrolled arrhythmias other than permanent or persistent atrial fibrillation. 
8. Patient has history of uncorrected congenital cardiac disease affecting LV function. 
9. Patient has evidence of severe chronotropic incompetence, as indicated by a heart rate 
response <55% of predicted maximum heart rate (220 – age) per Baseline Visit CPET. 
10. Patient has any history of platelet dysfunction, hemophilia, von Willebrand disease, 
coagulation disorder causing a bleeding diathesis, other bleeding diathesis, or significant, 
nontraumatic bleeding episodes, such as from a gastrointestinal source. 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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11. Patient has uncorrected thyroid disease. 
12. Patient has severe aortic stenosis or severe mitral regurgitation. 
13. Patient has seated systolic BP <110 mmHg at the Screening Visit and on Day 1 before 
Randomization. For these determinations of eligibility, BP will be the average of 
3 measurements obtained at approximately 2-minute intervals after the patient has been 
VLWWLQJTXLHWO\IRU minutes. 
14. Patient has estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 at the Screening 
Visit and/or is receiving dialysis. 
15. Patient has direct bilirubin >2 times upper limit of normal (×ULN, as defined by laboratory) 
or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×ULN at the 
Screening Visit.  
16. Patient has received IV inotropic therapy within 30 days before the Screening Visit. 
17. Patient is unable to take oral medications. 
18. Patient has active or treated malignancies within 12 months of the Screening Visit, except for 
basal cell carcinoma. 
19. Patient has previously received IW-1973, has received any other investigational drug during 
the 30 days or 5 half-lives of that investigational drug (whichever is longer) before the 
Screening Visit, is planning to receive another investigational drug at any time during the 
study, has an active investigational medical device currently implanted, and/or is planning to 
have an investigational medical device implanted at any time during the study. 
20. Patient has comorbid condition with an expected survival less than 6 months. 
21. Patient has any medical condition that, in the Investigator’s opinion, could lead to difficulty 
complying with protocol procedures (eg, 6-minute walk test, CPET) or could prohibit 
completion of the study. Specifically, patients should not be primarily limited in their 
physical activity by joint, leg, hip or back pain, or gait unsteadiness. 
22. Patient has evidence of active hepatitis or human immunodeficiency virus antibody at the 
Screening Visit. 
23. Patient has clinically significant (per Investigator judgment) history of viral or bacterial 
infection within 4 weeks of the Baseline Visit. 
24. Patient has had surgery with general anesthesia in the 6 weeks before the Screening Visit or 
has scheduled or planned surgery with general anesthesia during the study. 
25. Patient has a history of active alcoholism or drug addiction during the 12 months before the 
Screening Visit and/or has a positive drug screen at the Screening Visit for amphetamines, 
barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, propoxyphene without a 
prescription for a medically defined condition. 

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26. Patient is taking specific inhibitors of phosphodiesterase 5 (PDE5), nonspecific inhibitors of 
PDE5 (including dipyridamole and theophylline), any supplements for the treatment of 
erectile dysfunction, riociguat, and/or nitrates or nitric oxide (NO) donors in any form. These 
medications and supplements are prohibited from 7 days before Randomization through the 
duration of the study. 
Patient is taking strong cytochrome P450 3A (CYP3A) inhibitors, examples of which include 
azole antifungals, macrolide antibiotics, protease inhibitors, and diltiazem. These 
medications and excessive grapefruit intake are prohibited 14 days before Randomization 
through the duration of the trial. 
See Appendix 1 for a more detailed list of prohibited medicines and supplements. 
27. Patient has a history of clinically significant hypersensitivity or allergy to any of the 
ingredients contained in the active or placebo drug products. 
28. Female patient is pregnant (positive urine pregnancy test) or is breastfeeding. Breastfeeding 
is not allowed from Screening Visit through 60 days after the final dose of study drug.  
29. Female patient who may wish to become pregnant and/or plans to undergo egg donation or 
egg harvesting for current or future in vitro fertilization during the study and/or within at 
least 60 days after the final dose of study drug. 
30. Male patient unwilling to refrain from sperm donation during the study and for at least 
60 days after the final dose of study drug. 
31. Patient will not be able to adhere to the trial assessment schedule or, in the clinical judgment 
of the Investigator, is otherwise not suitable for the trial. 
 
NOTES:  
• Patients may be rescreened should they discontinue in the Screening Period due to visit 
window deviations or other administrative reasons.  
• Laboratory values or BPs that are outside the range specified in the protocol may be repeated 
to confirm eligibility during the Screening Period at the Investigator’s discretion after 
consultation with the Medical Monitor. 
• The Screening and Baseline Visits can be combined if the visit occurs within 14 days of 
5DQGRPL]DWLRQDQGWKHSDWLHQWKDVIDVWHGIRU hours.  
• With prior approval by the Medical Monitor, local laboratory results may be used to 
determine study eligibility. In this instance, SDWLHQWVPXVWKDYHIDVWHGIRU hours prior to 
collection of the laboratory samples and duplicate samples must be drawn—1 set will be used 
for determination of study eligibility by the local laboratory and the second set will be sent to 
the Central laboratory for inclusion in the study database. The Randomization Visit can then 
occur on the next day. 

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SCHEDULE OF EVENTS 
 
Visit Days ĺ 
Study Procedure Ļ 
Screening Period 
Treatment Period 
FU Period 
Screening 
Visit* (Day -
45 to -3) 
Baseline*Visit 
(Day -14 
to -3) 
Randomization 
Visit (Day 1) 
Week 2 Visit 
(Day 15 ±3) 
Week 4 Visit 
(Day 29 ±3) 
Week 8 
Visit  
(Day 57 ±3) 
Week 12/ EOT 
Visit (Day 85 -
7/+4) 
FU Visit  
(Day 113 ±7) 
ICF signed 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
X 
 
 
 
 
 
Prior & concomitant 
medications and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (a) 
complete 
pre CPET 
predose  
predose  
predose  
predose  
predose  
complete 
Vital signs (BP, pulse, 
RR, & oral temperature) 
(b) 
X 
pre CPET 
SUHK 
pd: 1,3,4h 
(±20m) 
SUHK 
pd: 1,3,4h 
(±20m) 
SUHK 
SUHK 
SUHK 
X 
Weight, height 
W, H 
W 
W 
W 
W 
W 
W 
W 
NYHA classification 
X 
 
X 
 
 
 
X 
X 
Hepatitis, HIV screen 
X 
 
 
 
 
 
 
 
Urine drug screen  
X 
 
 
 
 
 
 
 
Urine pregnancy (c) 
X 
pre CPET 
predose 
predose 
predose 
predose 
predose 
X 
Urinalysis sample (d) 
X 
 
predose 
predose 
predose 
predose 
predose 
X 
Serum chemistry, CBC, 
coagulation (d) 
X 
pre CPET 
 predose 
predose 
predose 
predose  
predose 
X 
Hemoglobin A1c 
X 
pre CPET 
 
 
 
predose 
predose 
X 
12-lead ECG (e) 
X 
pre CPET 
predose 
predose 
predose 
predose 
predose 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
CPET (f) 
 
X 
 
 
 
postdose 
>1h (or 
±3 days) (f) 
postdose >1h 
 
6MWT (g) 
 
post CPET 
>1h  
 
 
 
post CPET 
>1h (g) 
post CPET >1h 
 
NT-proBNP sample (d,h) 
X (if needed) 
pre CPET 
 
 
 
 
predose 
 
Echocardiography (i) 
X (if needed) 
X (for baseline) 
 
 
 
X 
 

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Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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Visit Days ĺ 
Study Procedure Ļ 
Screening Period 
Treatment Period 
FU Period 
Screening 
Visit* (Day -
45 to -3) 
Baseline*Visit 
(Day -14 
to -3) 
Randomization 
Visit (Day 1) 
Week 2 Visit 
(Day 15 ±3) 
Week 4 Visit 
(Day 29 ±3) 
Week 8 
Visit  
(Day 57 ±3) 
Week 12/ EOT 
Visit (Day 85 -
7/+4) 
FU Visit  
(Day 113 ±7) 
Fasting plasma glucose & 
insulin (d) 
 
pre CPET  
predose 
 
 
predose 
predose 
X 
UACR sample supplies 
dispensed 
 
X 
 
 
 
X 
 
 
First-void urine samples 
(j) 
 
 
preVisit 
 
 
 
preVisit 
 
Pharmacokinetic blood 
samples 
 
 
predose 
pd:1,2,4h 
(±20m) 
predose 
pd:1,2,4h 
(±20m) 
predose 
predose 
predose 
pd:1,2,4h 
(±20m) 
X 
Orthostatic (sitting to 
standing) pulse, BP (k) 
 
 
SUHK 
pd: 2,4h (±20m) 
SUHK 
pd: 2,4h 
(±20m) 
 
 
SUHK 
 
Randomization 
 
 
X 
 
 
 
 
 
Study drug dispensed 
 
 
X 
X 
X 
X 
 
 
In-clinic study drug (l) 
 
 
X 
X 
X 
X 
X 
 
Study drug return 
 
 
 
X 
X 
X 
X 
 
Study completion 
 
 
 
 
 
 
 
X 
 
 

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Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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1. 
INTRODUCTION 
1.1 
HEART FAILURE WITH PRESERVED EJECTION FRACTION 
Heart failure with preserved ejection fraction (HFpEF) is a significant source of morbidity and 
mortality in the United States (US) and globally.(2, 3) It currently comprises approximately 50% 
of new heart failure diagnoses in the US, and the prevalence is estimated to be at least 1% of the 
population, or more than 3 million Americans.(2, 4) Patients with HFpEF account for 
approximately half of hospitalizations for heart failure and are frequently re-admitted following 
discharge.(5) Mortality rates over 5 years for patients diagnosed with HFpEF have been reported 
to range from 55% to 74%.(6) Patients with HFpEF have the signs and symptoms of heart 
failure, which may include dyspnea, orthopnea, lower extremity edema, pulmonary congestion, 
and cardiomegaly; tend to have low activity levels and a suboptimal quality of life (QOL); and 
frequently experience depression.(7) Although there are approved treatments for heart failure 
with reduced ejection fraction (HFrEF) that reduce death and hospitalization for heart failure, 
currently there are no approved chronic medications specifically for HFpEF. Given the lack of 
approved therapies, there is significant unmet medical need for the large population of HFpEF 
patients. 
1.2 
PATHOPHYSIOLOGY OF HFpEF 
Diastolic dysfunction has long been recognized as a key element of impaired cardiac function in 
HFpEF. Hypertension likely plays a role in diastolic dysfunction, but more recently other factors 
have been proposed to contribute to HFpEF. Microvascular inflammation has been hypothesized 
to play an important role in HFpEF pathophysiology.(8) HFpEF patients often have comorbid 
obesity and diabetes mellitus, which may contribute to a systemic inflammatory state. 
Microvascular inflammation is associated with reduced nitric oxide (NO) bioavailability that in 
turn results in reduced production of cyclic guanosine 3’,5’-monophosphate (cGMP) by soluble 
guanylate cyclase (sGC).(9) Decreased cGMP levels result in impaired activation of protein 
kinase G with multiple resultant effects, including impaired phosphorylation of titin, leading to 
increased myocardial compliance and increased synthesis of collagen.(10) This cascade of 
effects, stemming from reduced NO bioavailability, may be important in the reduced ventricular 
compliance and myocardial remodeling that is sometimes seen in HFpEF.  

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Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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Other mechanisms of derangement in NO-sGC-cGMP signaling may also contribute to the 
pathophysiology. For example, endothelial dysfunction can result in vascular stiffness and an 
inability to properly regulate vascular flow to skeletal muscle, which may lead to impaired 
oxygen extraction and diminished exercise capacity.(11) Furthermore, many patients with 
HFpEF also exhibit pulmonary artery hypertension.  
1.3 
RATIONALE FOR USE OF AN sGC STIMULATOR IN HFpEF 
Based on the key role of NO deficiency leading to impaired NO-sGC-cGMP signaling in the 
pathophysiology of the disease, the potential value of sGC stimulators in the treatment of HFpEF 
is plausible.(12, 13) Administration of a single dose of the sGC stimulator riociguat to patients 
with pulmonary hypertension secondary to HFpEF did not have an acute effect on pulmonary 
artery pressures (the primary variable) or pulmonary arterial wedge pressure, but did result in 
improvements in stroke volume and a reduction in systemic vascular resistance.(14) Chronic 
administration of an sGC stimulator may reduce pulmonary arterial pressures, an effect that 
would be beneficial in patients with HFpEF. 
In a Phase 2b trial in HFpEF patients, the investigational sGC stimulator vericiguat improved 
QOL parameters, an effect that was most prominently demonstrated by an improvement in 
physical limitation subscale scores; a beneficial effect on the biomarker N-terminal pro B-type 
natriuretic peptide (NT-proBNP) or in left atrial (LA) dimension by echocardiography was not 
demonstrated.(15)  
Studies of other drugs with effects on intracellular cGMP, such as sildenafil, have been studied 
for the treatment of HFpEF, and the results have been mixed.(16) In contrast, 2 small studies of 
inorganic nitrates administered as beetroot juice improved the submaximal aerobic endurance in 
HFpEF patients after acute administration in 1 study, and after 1 week of treatment in the 
other.(17, 18) The use of the organic nitrate isosorbide mononitrate in patients with HFpEF has 
demonstrated no benefit.(19) Organic nitrates release NO nonspecifically, potentially resulting in 
systemic sGC activation and untargeted smooth muscle relaxation. Furthermore, released NO 
can react with superoxide to form highly reactive and damaging peroxynitrite ion. In contrast, 
sGC stimulators increase local cGMP signaling in tissues and do not generate peroxynitrite. 

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Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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1.3.1 
IW-1973 
For a detailed description of the properties of IW-1973 and the results of the nonclinical and 
clinical studies conducted thus far, please refer to the most recent Investigator’s Brochure.   
1.3.1.1 
Nonclinical Data in Support of Clinical HFpEF Investigations 
Pharmacologic activation of sGC with NO donors has shown cardiac benefit in animal models 
and in the clinic.(20) The effects of IW-1973 on cardiac morphology, function, and biomarkers 
have been explored in models of HFrEF and HFpEF. In the Dahl salt-sensitive (DSS) rat model, 
6 weeks of treatment with IW-1973 resulted in lower levels of the cardiac stress marker 
NT-proBNP, lower cardiac weight, higher ejection fraction (EF), and increased left ventricular 
(LV) end systolic internal dimension compared to the vehicle-treated control group. IW-1973 
treatment also led to a dose-dependent reduction in systemic blood pressure (BP), improvements 
in renal function and histology, and a reduction in expression of fibrotic markers in the DSS 
model. Exposures achieved with repeated administration of 40 mg/day IW-1973 to healthy 
subjects in clinical study ICP-1973-102 were comparable to the exposures associated with 
cardiac effects in the DSS rat model. In a rat post-myocardial infarction (MI) model of HFrEF, 
treatment with IW-1973 (10 mg/kg/day) for 8 weeks resulted in significant decrease in levels of 
NT-proBNP and improvements in echocardiographic measures LV end systolic area, LV 
end-systolic volume (LVESV), and LV fractional area change compared to the control group. 
Together, these data support investigation of IW-1973 as a potential therapy for HFpEF.  

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Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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2. 
STUDY OBJECTIVES 
Primary  
• To assess the safety of oral IW-1973 when administered for approximately 12 weeks to 
patients with HFpEF 
• To evaluate the effect of oral IW-1973 on peak exercise capacity when administered for 
approximately 12 weeks to patients with HFpEF, both in all patients and in patients without 
permanent or persistent atrial fibrillation  
 
Secondary  
• To evaluate the effect of oral IW-1973 on exercise and functional capacity when 
administered for approximately 12 weeks to patients with HFpEF  
 
Exploratory  

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Clinical Trial Protocol: C1973-204 Amendment 3 
 
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3. 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN AND PLAN 
This Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
will evaluate the safety and efficacy of IW-1973 compared with placebo. The study will enroll 
approximately 184 adults with established heart failure and limited exercise capacity with EF of 
at least 40% and who have at least 2 of 4 risk factors for HFpEF (diabetes/prediabetes, 
hypertension, obesity, advanced age) (see Eligibility Criteria). Patients will be stratified by atrial 
fibrillation status and by baseline peak VO2 RUof age- and sex-adjusted normal 
values with respiratory exchange ratio [RER] DVGHWHUPLQHGE\FDUGLRSXOPRQDU\H[HUFLVH
test [CPET]) and randomized in a 1:1 ratio to daily IW-1973 or placebo, as described in 
Section 3.5.2. The number of patients admitted with permanent or persistent atrial fibrillation 
will be limited to under 20% of target enrollment (36 patients).  
The study will consist of 3 distinct periods, a Screening Period, a Treatment Period, and a 
Follow-up Period (Figure 1). 
Figure 1. 
Study Schematic 
 
 
Follow-up
Visit
(Day 113 ±7)
Screening *
Visit 
(Day -45 to -3)
Randomization
Visit
(Day 1)
End of Treatment
Visit
(Day 85 -7/+4)
Screening 
Period 
Treatment
Period
Follow-up 
Period
Up to 45 days
85 (-7/+4) days
28 (±7) days
Week 2 
Visit
(Day 15 ±3)
Week 4
Visit
(Day 29 ±3)
Week 8
Visit
(Day 57 ±3)
40 mg IW-1973 daily
BID
QD
1 and 2
3 to 12
Dosing
Week
Placebo
Baseline*
Visit
(Day -14 to -3)
*Screening and Baseline 
Visits may be combined 
if visit occurs within 14 
days of Randomization 
and patient has fasted 
K

IW-1973 Tablet (praliciguat) 
 
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Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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Screening Period:  The Screening Period will begin with the signature of the ICF at the 
Screening Visit and may last up to 45 days. At the Screening Visit, patients will undergo 
screening procedures to determine their initial eligibility. At the Baseline Visit, patients will 
return to the clinic for additional screening procedures to determine their eligibility, including 
CPET, vital sign measurements, and blood and urine sample collections, and to receive supplies 
to take home. The end of the Screening Period will coincide with the beginning of the Treatment 
Period. The Screening Visit may be combined with the Baseline Visit if the patient is fasted for 
blood and urine collections. CPET and 6-minute walk test (6MWT) must occur within the 
14-day period before Randomization. 
Treatment Period: The Treatment Period will begin on Day 1 at Randomization and will end 
after the End of Treatment Visit on Day 85 (-7/+4 days). At the Day 1 Visit, eligible patients will 
be stratified as described in Section 3.1 and randomized as described in Section 3.5.2 to receive 
daily IW-1973 or placebo for approximately 12 weeks. Dosing on Days 1 to 14 (±3) will be BID 
(twice daily); dosing on Day 15 (±3) onward will be QD (once daily).  
At the Randomization (Day 1) Visit, patients will receive their morning BID dose of study drug 
in the clinic. At the Week 2 Visit (Day 15 [±3]), patients will return to the clinic and receive their 
QD dose of study drug in the clinic. Patients will undergo safety, efficacy, and PK assessments, 
including blood and urine collections at prespecified times (see Schedule of Events) and will 
receive study drug supply. At both visits, patients must stay in the clinic a minimum of 
approximately 4 hours postdose and thereafter may be allowed to leave the clinic at the 
Investigator’s discretion. 
At the Week 4 Visit, Week 8 Visit, and End of Treatment Visit, patients will return to the clinic 
for study drug administration; safety, efficacy, and PK assessments; and study drug and other 
supplies, as applicable. 
Follow-up Period: The Follow-up Period will begin immediately after the End of Treatment 
Visit on Day 85 (-7/+4 days) and will last for 28 (±7) days. On Day 113 (±7 days), patients will 
return to the clinic for the final Follow-up Visit (see Schedule of Events). 

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Clinical Trial Protocol: C1973-204 Amendment 3 
 
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3.2 
DISCUSSION OF STUDY DESIGN AND CONTROL GROUP 
A double-blind, placebo-controlled, randomized study design was chosen to provide comparable 
treatment groups and minimal chance of selection or investigator bias in accordance with the 
concepts in 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). Placebo was chosen as the control to determine the rate 
of spontaneously occurring treatment-emergent adverse events (TEAEs) and to reduce the 
potential for bias in the reporting of AEs.  
This study has a 12-week Treatment Period to compare the effects of IW-1973 to a placebo 
control. The treatment duration of 12 weeks is sufficient in length to observe changes in 
functional assessments, CPET and 6MWT, as well as hemodynamic measures. Noninvasive 
CPET provides detailed physiologic information during exercise including data on respiratory 
gas exchange, ventilation, BP, heart rate, and oxygen saturation. CPET also provides an 
objective measure of volition and is highly reproducible, which enables assessment of treatment 
effect in a relatively small number of patients.(21) The 6MWT (Appendix 6) provides a simple 
assessment of functional capacity that is easy to perform, requires no equipment or advanced 
training, and is based on an activity of daily living. Because subjects select their own exercise 
intensity, the 6MWT reflects everyday functional capacity and provides a global evaluation of 
the organ/physiologic systems involved in exercise.(22) Assessments will also include patient-
reported questionnaires that assess health status, generic and disease-specific QOL, symptoms of 
depression, and functional disability. These assessments allow a better understanding of the trial 
population at baseline as well as an evaluation of the potential impact of IW-1973 treatment on 
patients’ own assessments of their health and QOL. 
Patients will be stratified by baseline peak VO2 (CPET) to minimize the potential impact of 
baseline disease severity imbalance between treatment groups. In addition, patients will be 
stratified by atrial fibrillation status to minimize imbalance between treatment groups.   
Enrichment is utilized in this study design by limiting enrolling patients with permanent or 
persistent atrial fibrillation at screening to under 20% of target enrollment. This design ensures 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
Page 34 of 95 
that a standalone study population of patients without permanent or persistent atrial fibrillation is 
adequately powered to evaluate efficacy.  
Individual stopping criteria and Data Monitoring Committee (DMC) safety reviews (Section 3.7) 
ensure that individual and/or all dosing will stop should an unacceptable safety signal be 
detected. Patients will have a Follow-up Visit at the clinic 28 (±7) days after their final dose of 
study drug to determine if any AEs have developed and if any AEs that were ongoing at the time 
of discharge have resolved. In addition, at the Follow-up Visit as well at each study visit, female 
patients of reproductive potential will have a pregnancy test. 
3.3 
STUDY DURATION 
Patients will receive daily study drug for up to 89 days. Total patient participation will be 109 to 
165 days, including the Screening, Treatment, and Follow-up Periods. 
3.4 
STUDY POPULATION 
The study will enroll approximately 184 adult patients who have established heart failure with an 
EF of at least 40% and limited exercise capacity (peak VO2 <80% of age- and sex-adjusted 
normal values). In addition, patients must have at least 2 of the following 4 risk factors for 
HFpEF: diabetes/prediabetes, hypertension, obesity, and/or advanced age \HDUV.  
The number of patients admitted with permanent or persistent atrial fibrillation will be limited to 
approximately 36, total, in the study. 
For details, see Eligibility Criteria. 
3.4.1 
Removal of Patients from Therapy or Assessment 
A premature discontinuation will occur when a patient who has been randomized ceases 
participation in the study. 
A patient will be considered to have completed the study after completing the Follow-up Visit on 
Day 113 (±7). 

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Clinical Trial Protocol: C1973-204 Amendment 3 
 
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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) 
• Protocol violation, including lack of compliance 
• Lost to follow-up (every effort should be made to contact the patient; a certified letter should 
be sent) 
• Withdrawal of consent (attempts should be made to determine the reason for the patient 
withdrawing consent if possible)  
• Study termination by the Sponsor 
• Other reasons (eg, administrative reasons or pregnancy) 
 
The Sponsor will be notified of any premature patient discontinuation. The date the patient is 
withdrawn from the study and the reason for discontinuation will be recorded on the study 
termination form of the electronic case report form (eCRF). Patients who discontinue from the 
study will be followed until resolution of all AEs or until the unresolved AEs are judged by the 
Investigator to have stabilized. 
If a patient does not return for a scheduled visit, the study center should contact the patient. An 
effort will be made to contact the patient, including sending a certified letter. In every case, the 
patient outcome, including lost to follow-up information, will be documented. 
3.4.2 
Early Termination Procedures 
Patients who discontinue study drug for any reason should complete the assessments required at 
the End of Treatment Visit at the time of their discontinuation and should complete the 
Follow-up Visit 28 ±7 days after their final dose of study drug. If the End of Treatment Visit 
occurs more than 7 days after the patient’s final dose of study drug, the PK blood draw can be 
reduced to 1 sample. 

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Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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3.5 
STUDY TREATMENT(S) 
3.5.1 
Description of Treatment(s) 
3.5.1.1 
Investigational Product 
IW-1973 Tablets are 20-mg oral tablets that are white, round, and match in appearance. 
3.5.1.2 
Placebo 
Placebo tablets match IW-1973 Tablets in appearance. 
3.5.1.3 
Packaging and Labeling 
IW-1973 and placebo tablets will be provided by PCI Pharma Services (Rockford, IL) on behalf 
of Ironwood in 100-cc high-density polyethylene (HDPE) induction-sealed bottles, 35 tablets per 
bottle, containing two 1-gram mole desiccant sieves and 4 to 6 inches of purified polyester coil.   
3.5.1.4 
Dosage 
For patients randomized through Amendment 2 (or earlier), Table 3 summarizes the dosage and 
dosing regimen for each treatment arm by Treatment Period week. 
Table 3. 
Dose Regimen by Treatment Period Week 
Dose 
Weeks 1 and 2, BID Dosing  
Weeks 3 through 12, QD Dosing 
10 mg 
one 5-mg IW-1973 Tablet, orally twice daily 
two 5-mg IW-1973 Tablets, orally once daily 
20 mg 
one 10-mg IW-1973 Tablet, orally twice daily 
two 10-mg IW-1973 Tablets, orally once daily 
40 mg 
one 20-mg IW-1973 Tablet, orally twice daily 
two 20-mg IW-1973 Tablets, orally once daily 
Placebo 
one matching placebo tablet, orally twice daily 
two matching placebo tablets, orally once daily 
BID=twice daily; QD=once daily 
 
Beginning with Amendment 3 to the protocol, new patients will be randomized to either 40 mg 
IW-1973 or placebo, as summarized in Table 4. 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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Table 4. 
Dose Regimen by Treatment Period Week 
Dose 
Weeks 1 and 2, BID Dosing  
Weeks 3 through 12, QD Dosing 
40 mg 
one 20-mg IW-1973 Tablet, orally twice daily 
two 20-mg IW-1973 Tablets, orally once daily 
Placebo 
one matching placebo tablet, orally twice daily 
two matching placebo tablets, orally once daily 
BID=twice daily; QD=once daily 
 
3.5.1.5 
Storage and Accountability 
IW-1973 Tablet and placebo to match must be stored under refrigerated conditions, 2° to 8°C 
(36° to 46°F) at the study sites. Any deviation from these storage conditions must be reported to 
Ironwood and use of the study drug suspended until re-authorization has been provided by 
Ironwood. If a temperature excursion above 8°C (46°F) up to a maximum temperature of 30°C 
(86°F) occurs for no longer than 24 hours, the clinical site is authorized by Ironwood 
Pharmaceuticals to continue using study drug after documentation of the excursion has been 
completed. If a temperature excursion below 2°C (<36°F) or above 30°C (>86°F) occurs for any 
period of time, or from 8 to 30°C for a period longer than 24 hours, the use of the study drug is 
suspended until authorization for its continued use has been provided by Ironwood. 
Once distributed to patients, patients will be instructed to keep bottles at room temperature.  
The Investigator must ensure that the receipt and use of all study drug supplied is recorded. All 
study drug supplies must be retained in a locked room that may only be accessed by the 
pharmacist, Investigator, or other duly designated persons. Study drug 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. 
Subjects will be instructed to return all unused study drug to the study center. All returned and 
unused study drug must be retained at the site. At Week 2, unused study drug will be returned to 
the clinic, accountability will be performed, and any unused study drug will be dispensed back to 
the study subject. At the end of the study, a complete reconciliation of the study drug supplies 
will be performed (ie, tablets will be counted). A copy of the final Drug Accountability Log will 
be provided to Ironwood. All unused and reconciled drug supplies will be returned to PCI 
Pharma Services or destroyed according to standard institutional policy or per written instruction 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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from Ironwood should an alternate disposition be requested. No study drug is to be destroyed 
without prior written permission of Ironwood. A copy of the Certificate of Destruction or 
equivalent shall be provided to Ironwood once available. 
3.5.2 
Method of Assigning Patients to Treatment Groups 
A centralized interactive web response system (IWRS) will be used to randomly assign patients 
to study treatment. The computer-generated randomization schedule will be prepared by an 
independent statistician not otherwise associated with the conduct of the study. 
Approximately 184 patients who meet all of the Inclusion Criteria and none of the Exclusion 
Criteria will be stratified by permanent/persistent atrial fibrillation status (yes or no) and by 
baseline peak VO2 (<60% or RIDJH- and sex-adjusted normal values and with 5(5 
as determined by CPET). An upper limit of approximately 36 patients with permanent or 
persistent atrial fibrillation will be set in the IWRS.   
Patients enrolled under Amendment 2 to the protocol (or earlier) were randomized 1:1:1:1 to 
daily 10 mg IW-1973, 20 mg IW-1973, 40 mg IW-1973, or placebo at the Randomization Visit 
on Day 1. Beginning with Amendment 3 to the protocol, new patients will be randomized in a 
1:1 ratio to daily doses of either 40 mg IW-1973 or placebo. 
3.5.3 
Selection of Dosage in the Study 
This Phase 2 study will evaluate oral IW-1973 (40 mg), administered daily for 12 weeks. The 
dose level selection was originally based on data from the following study: 
• Phase 1b study ICP-1973-102: “A 2-stage Phase 1 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of IW-1973 Tablet Formulation in Healthy 
Volunteers in an Open-label, Single-dose, Crossover Stage Followed by a Randomized, 
Double-blind, Placebo-controlled, Multiple-ascending-dose with Optional Up-titration Stage” 
 
In the Phase 1b multiple-ascending-dose (MAD) study (ICP-1973-102), along with preliminary 
data from C1973-201 and C1973-202 that were received subsequent to finalization of the 
original protocol, 40 mg IW-1973 was considered adequately tolerated and was therefore chosen 
for evaluation in this patient population.  

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Administration of split doses during the first 2 weeks of dosing is expected to reduce the initial 
time to maximum observed plasma concentration and to minimize variations in IW-1973 plasma 
concentrations during the approach to steady state, which may improve tolerability.  
3.5.4 
Selection and Timing of Dose for Each Patient and Dose Reduction 
3.5.4.1 
Study Drug Administration 
During Weeks 1 and 2, patients will be instructed to take study drug BID (2×/day), as 1 tablet in 
the morning and 1 tablet approximately 12 hours later in the evening, and preferably at 
approximately the same times each day. Starting with the Week 2 Visit (Day 15 ±3), patients will 
be instructed to take study drug QD (1×/day), as 2 tablets in the morning, preferably at 
approximately the same time each day. Patients should take study drug with water, may take 
study drug with or without food and, for QD dosing, may swallow the 2 tablets together, if 
desired.  
On study visit days, patients will receive their study drug dose in the clinic. (On Randomization 
Day, patients will receive only their morning dose in the clinic.) Study visits should be scheduled 
in the morning to accommodate study drug dosing schedules and fasting requirements (Section 
3.6.2).  
Permitted concomitant medications should be taken as usual, may be taken at the same time as 
study drug, and do not need to be taken in the clinic on study visit days. 
3.5.4.2 
Dose Reduction 
Per Investigator discretion, dose reduction is allowed after consultation with the Medical 
Monitor. If dose reduction is approved, the patient will be allowed to reduce his or her daily dose 
by half, ie, from 2 tablets daily to 1 tablet daily (in the morning). It is recommended for the 
patient to be evaluated in the clinic in association with any dose modification. Each patient’s 
dose may only be reduced once and will not be increased after reduction.  

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3.5.5 
Treatment Compliance 
The appropriate amount of study drug will be dispensed to patients in prelabeled bottles. Patients 
will be asked to return all bottles (including unused tablets) at the subsequent study visit for 
assessment of compliance with the dosing regimen.  
Treatment compliance will be based on count of pills. 
3.5.6 
Blinding 
This study is double blind and placebo controlled. The Investigators, patients, and Sponsor will 
be blinded to treatment assignments. The investigational product and placebo will be supplied as 
oral tablets that match in appearance.  
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 safety of 
the patient. Except in a medical emergency, the Investigator and study center staff will remain 
blinded during the conduct of the study and until, at a minimum, 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 IWRS in the event of a 
medical emergency. In advance of breaking the blind, the Investigator should make all 
reasonable efforts to notify and discuss the circumstances requiring unblinding with the Medical 
Monitor or designee. If the treatment blind is broken, the reason and the date must be recorded 
and signed by the Investigator and information regarding the unblinding should be submitted as 
soon as possible to the Sponsor. If the Investigator is unblinded to the treatment assignment of a 
patient, the patient will be immediately withdrawn from study drug dosing, and early termination 
procedures (Section 3.4.2) should be followed. 
To allow ongoing safety monitoring during the conduct of the study, members of an external 
DMC will review summaries of unblinded safety data. Please refer to Section 5.13 for details. 
3.5.7 
Prior and Concomitant Therapy and Procedures 
At the Screening Visit, the following information will be recorded for each patient: 
• All medications (including name, dosage, and schedule) the patient is taking (ongoing) 

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• All prior medications (including name, dosage, and schedule) taken during the 30 days 
before the Screening Visit 
• Prior procedures and surgeries 
 
Beginning at the Screening Visit, any medication (including name, dosage, and schedule) or 
change in medication taken by a patient during the study will be documented in the source 
documents and the eCRF along with the time of use and the reason for use. Also beginning at the 
Screening Visit, any medical procedure or surgery that the patient undergoes will be documented 
in the source documents and the eCRF along with the start and stop date and reason. 
Permitted concomitant medications should be taken as prescribed, may be taken at the same time 
as study drug, and do not need to be taken in the clinic on study visit days. 
Prohibited medications and supplements are listed in Sections 3.6.1 and Appendix 1. 
3.6 
RESTRICTIONS 
3.6.1 
Prohibited Medicines and Supplements 
The following medicines and supplements are prohibited from 7 days before the Randomization 
Visit (Day 1) through the duration of the trial: 
• Specific inhibitors of phosphodiesterase 5 (PDE5) (including sildenafil and tadalafil) 
• Nonspecific inhibitors of PDE5 (including dipyridamole and theophylline) 
• Any supplements for the treatment of erectile dysfunction 
• Riociguat, or any sGC stimulator 
• Nitrates or NO donors in any form  
 
The following medicines and supplements are prohibited from 14 days before the Randomization 
Visit (Day 1) through the duration of the trial: 
• Strong inhibitors of CYP3A; examples include azole antifungals, macrolide antibiotics, 
protease inhibitors, diltiazem, and concentrated grapefruit supplements 
 
See Appendix 1 for a more detailed list of prohibited medicines and supplements. 

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Should there be an urgent need for nitrate administration, it should occur in a monitored 
in-patient setting. 
3.6.2 
Fluid and Food  
Patients should fast overnight (at least 8 hours) before all study visits, except the Screening Visit, 
and will continue fasting until the pre-CPET and predose blood and urine samples have been 
collected. See Section 3.8.8 for additional details. 
Patient must agree not to make any major changes to their diet from the Screening Period 
through the Follow-up Visit. 
3.6.3 
Patient Activity  
Patient must agree not to make any major changes to their exercise routine from the Screening 
Period through the Follow-up Visit. 
3.6.3.1 
Sexual Activity and Birth Control 
Female patients who are not postmenopausal QRPHQVHVIRUFRQVHFXWLYHPRQWKVor 
surgically sterile (ie, bilateral oophorectomy, hysterectomy, or tubal sterilization [tie, clip, band, 
or burn]), 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 60 days after her final dose of study drug: 
• Progesterone implant and/or an intrauterine device (IUD) 
• 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] combined with a barrier method, partner with 
YDVHFWRP\>FRQGXFWHGGD\VEHIRUHWKH6FUHHQLQJ9LVLWRUFRQILUPHGYLDVSHUPDQDO\VLV@
plus a hormone or barrier method)  
 
Female patients must wait at least 60 days after the final dose of study drug to try to become 
pregnant and/or to undergo egg donation or egg harvesting for current or future in vitro 
fertilization. 

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Male patients who are not surgically stHULOHE\YDVHFWRP\FRQGXFWHG days before the 
Screening Visit or confirmed via sperm analysis), must agree to completely abstain from 
heterosexual intercourse, or, if heterosexually active, must agree to use a highly effective birth 
control method (eg, condom with spermicide, partner IUD, partner diaphragm or cervical cap, 
partner hormonal contraceptive [including progesterone implant], or postmenopausal partner [no 
PHQVHVIRUFRQVHFXWLYHPRQWKV]) from the Screening Visit through 60 days after the final 
dose of study drug. 
Male patients must refrain from sperm donation during the study through at least 60 days after 
the final dose of study drug. 
3.6.3.2 
Breastfeeding 
Breastfeeding is not allowed from Screening Visit through 60 days after the final dose of study 
drug. 
3.7 
INDIVIDUAL STOPPING CRITERIA AND DATA MONITORING 
COMMITTEE REVIEWS 
If any events included in Table 5 are reported during the study and are judged to be both study 
drug related and a serious adverse event (SAE; per causality and SAE definitions in the protocol 
[Section 3.8.13.3]), individual stopping criteria or DMC review will be triggered per the criteria 
in Sections 3.7.1 and 3.7.2. The inclusion of these events is based on the clinical experience with 
IW-1973, the prescribing information for the sGC stimulator riociguat (23), and the patient 
population for this study.  
Table 5. 
Categories of SAEs Triggering Individual Stopping Criteria and DMC 
Review 
Treatment-emergent Study Drug-related SAE Category 
Number of patients to 
trigger DMC review 
Symptomatic hypotension-related events  
(eg, syncope) 
5 
Spontaneous bleeding events  
(eg, hemoptysis, vaginal hemorrhage, ovarian hemorrhage, subdural 
hemorrhage, hematemesis, hematochezia) 
2 
DMC=Data Monitoring Committee; SAE=serious adverse event 
 

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3.7.1 
Individual Stopping Criteria 
On an individual basis, a patient will be discontinued from study drug dosing if any of the 
following is reported for that patient: 
• 1 study drug-related spontaneous bleeding SAE 
• 1 study drug-related symptomatic hypotension-related SAE that is life threatening per 
protocol definition (Section 3.8.13.3) 
• 2 study drug-related symptomatic hypotension-related SAEs  
 
At the Investigator’s or Sponsor’s discretion, any AE(s) of concern can likewise be the basis for 
patient discontinuation from the trial. 
3.7.2 
Data Monitoring Committee Reviews 
An independent DMC will review trial safety data both periodically and on an ad hoc basis per 
the SAE criteria in Table 5 (eg, spontaneous bleeding SAEs reported in 2 patients). After each 
periodic or ad hoc review of safety data, the DMC will recommend trial continuation, 
continuation with modification, or termination. Refer to Section 5.13 for details regarding the 
DMC, the scheduled and ad hoc reviews, the data that will be provided for review, and Sponsor 
decision making.  
3.8 
STUDY PROCEDURES AND ASSESSMENTS 
The procedures and assessments described below will be performed according to the Schedule of 
Events. 
3.8.1 
Informed Consent 
Before a potential study participant undergoes any study-specific evaluations or procedures, he 
or she must provide written, informed consent. Please see Section 6.2 for more information.  
3.8.2 
Medical History 
A complete medical history, including disease-specific history and history of smoking, will be 
recorded at the Screening Visit. 

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3.8.3 
 

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3.8.4 
Physical Examination 
Physical examinations, either complete, symptom-directed, and/or of the cardiovascular system 
will be performed. A complete physical examination of each patient should include assessment 
of the following, at minimum: 
General appearance 
Head, eyes, ears, nose, and throat 
Cardiovascular system 
Neck 
Respiratory system 
Musculoskeletal system 
Abdomen/liver/spleen 
Nervous system 
Lymph nodes 
Skin 
Neurologic status 
Mental status 
 
Breast, genitourinary, and rectal examinations are optional and may be performed at the 
discretion of the Investigator. For Treatment Period visits, physical exam may be symptom-
directed or limited to cardiovascular system at the Investigator’s discretion. Any new, clinically 
significant abnormal findings from physical examinations will be reported as an AE. 
Each patient’s weight will be recorded at each study visit; height will only be recorded at the 
Screening Visit. 
3.8.5 
Vital Signs  
Vital signs will include seated BP, pulse, respiratory rate, and oral temperature (°C). All vital 
signs should be measured after the patient has been sitting quietly for at least 5 minutes. For the 
Screening and Randomization Visits, BPs for eligibility will be the average of 3 measurements 
obtained at approximately 2-minute intervals.  
3.8.6 
Orthostatic Blood Pressure and Pulse 
Sitting-to-standing BP and pulse measurements will be used for calculation of orthostatic BP and 
pulse. Patients should sit quietly for at least 5 minutes before sitting measurements are taken, 
then assume a standing position for 2 minutes (±1 m) before standing measurements are taken.  
3.8.7 
NYHA Functional Classification 
At each timepoint, including for purposes of study eligibility, each patient’s NYHA classification 
should reflect a contemporaneous assessment of functional status. Note that patients 

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experiencing any functional limitation whatsoever should be classified as NYHA Class II or 
higher. 
Table 6. 
New York Heart Association (NYHA) Functional Classification 
Class 
Description 
I 
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases 
of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-56 
 
3.8.8 
Blood and Urine Sample Collection 
3.8.8.1 
Clinical Laboratory Tests 
Blood and urine samples will be collected for clinical laboratory tests. Except for the Screening 
Visit, patients must fast for at least 8 hours before these sample collections. Laboratory values 
used for determination of eligibility must be fasted. Blood samples should be collected after 
electrocardiograms (ECGs) or at least 10 minutes before ECGs, when applicable. 
The clinical laboratory evaluations will include the serum chemistry, hematology (complete 
blood count [CBC]), coagulation, urinalysis, and additional tests presented in Table 7. 

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Table 7. 
Clinical Laboratory Tests 
Serum Chemistry 
Hematology (CBC) 
Urinalysis 
Albumin 
Hematocrit 
Color and appearance 
Alkaline Phosphatase 
Hemoglobin 
pH and Specific Gravity 
ALT 
Platelet count 
Bilirubin 
AST 
    MPV 
Glucose 
Bicarbonate 
RBC count 
Ketones 
Bilirubin (total and direct) 
RBC indices 
Leukocytes 
BUN 
    MCH 
Nitrites 
Calcium 
    MCHC 
Occult blood 
Chloride 
    MCV 
Protein 
Cholesterol 
RDW 
Urobilinogen 
Creatinine 
WBC count 
Microscopic:  
GGT 
WBC differential 
   Including bacteria, RBCs, WBCs 
Glucose 
  (% and absolute): 
   per HPF if dipstick is abnormal 
HDL-c 
    Basophils 
 
LDH 
    Eosinophils 
Additional blood tests 
LDL-c (calculated) 
    Lymphocytes 
Hemoglobin A1c 
Magnesium 
    Monocytes 
Fasting plasma glucose 
Phosphorus 
    Neutrophils 
Fasting plasma insulin 
Potassium 
 
 
Sodium 
Coagulation 
Additional urine tests 
Total Protein 
aPTT 
Urine albumin & creatinine for UACR* 
Triglycerides 
Prothrombin time 
 
Uric acid 
INR 
 
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; CBC=complete blood count; GGT=gamma glutamyl transferase; HPF=high power 
field; INR=International Normalized Ratio; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; MPV=mean platelet 
volume; RBC=red blood cell; RDW=red blood cell distribution width; UACR=urine albumin-creatinine ratio; 
WBC=white blood cell.  
* Samples should be first-void urine samples collected on the morning before or the morning of the applicable 
study visit. Patients will be supplied with specimen collection supplies at the preceding study visit. 
 
3.8.8.2 
Pregnancy Tests 
For female patients of reproductive potential, a negative pregnancy test (by urine dipstick) must 
be documented at all study visits with results available before dosing, when applicable. In the 
event of a positive pregnancy test, the test will be repeated. If pregnancy is confirmed, see 
Section 3.8.13.5. 
Pregnancy tests are not required for female patients who are postmenopausal (no menses for 
 consecutive months) or surgically sterile (ie, bilateral oophorectomy, hysterectomy, or tubal 
sterilization [tie, clip, band, or burn]). 

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3.8.8.3 
Hepatitis, HIV, and Drug Screens 
Screens for a hepatitis panel and human immunodeficiency virus (HIV) antibody will be 
performed at the Screening Visit. 
A urine drug screen for the following drugs will be performed at the Screening Visit: 
Amphetamines 
Cocaine 
Phencyclidine (PCP) 
Barbiturates 
Opiates 
Propoxyphene 
Benzodiazepines 
 
 
 
3.8.8.4 
Urine Creatinine Ratio  
The urine albumin creatinine ratio (UACR) will be calculated as urine albumin (mg/dL) / urine 
creatinine (g/dL).  
Urine albumin and urine creatinine levels will be determined as part of the clinical laboratory 
tests (Table 7). Patients will be given urine collection supplies and will collect a first-void urine 
sample on the morning before or the morning of the specified study visit.  
3.8.8.5 
Estimated Glomerular Filtration Rate 
Estimated glomerular filtration rate (eGFR) will be based on the serum creatinine level 
determined as part of the clinical laboratory tests (Table 7) and will be calculated according to 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation.(29)  
The CKD-EPI equation, expressed as a single equation, is  
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ZKHUH6FULVVHUXPFUHDWLQLQHțLVIRUIHPDOHVDQGIRUPDOHVĮLV-0.329 for females and -0.411 for males, 
min indicates the minimum RI6FUț RUDQGPD[LQGLFDWHVWKHPD[LPXPRI6FUțRU 
 
3.8.8.6 
Homeostatic Model Assessment to Estimate Insulin Resistance (HOMA-IR) 
Values from fasting plasma glucose and insulin levels (Table 7) will be used in the Homeostatic 
Model Assessment to estimate insulin resistance (HOMA-IR).(30, 31)  

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The HOMA-IR equation is  
HOMA-IR=(FPI × FPG)/22.5, 
where FPI is fasting plasma insulin concentration (mU/L) and FPG is fasting plasma glucose 
(mmol/L). 
3.8.8.7 
  
 
 
 
3.8.9 
Electrocardiograms 
Twelve-lead ECGs should be obtained after the patient has been supine for at least 5 minutes. 
ECGs should be performed before blood collections or at least 10 minutes after blood 
collections, when applicable. 
3.8.10 
Echocardiography 
Echocardiography may be performed at the Screening Visit to confirm eligibility. If performed at 
the Screening Visit, it can be used for baseline and does not need to be repeated. If 
echocardiography is not performed at the Screening Visit, the baseline echocardiography may be 
performed at either the Baseline or the Randomization Visit (predose). Echocardiography will 
also be performed at the End of Treatment Visit. When applicable, echocardiography should be 
performed before or at least 1 hour after exercise (CPET, 6MWT) is completed. 
Echocardiography measurements for eligibility may be determined by the Investigator. 
Echocardiography measurements for efficacy analyses will be determined by an independent, 
central Echocardiography Core Lab that is blinded to treatment assignment.  

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At a minimum, the following echocardiographic variables will be determined: 
• Mitral E/e’ ratio (mitral peak velocity [E]/mitral annulus early diastolic recoil velocity [e’]) 
• LA volume 
• LVEF 
• LV chamber dimensions (LVESV and left ventricular end-diastolic volume [LVEDV]) 
• LV wall thickness (septal and posterior)  
 
3.8.11 
CPET 
CPET will be performed using a study-specific protocol; details will be provided in a CPET 
study manual. Each study site will be CPET qualified for the study. Patients must use the same 
form of exercise (treadmill or bicycle) for all 3 CPETs, and the method of exercise should be 
recorded in the patient's eCRF. In general, patients will exercise to peak capacity beginning with 
unloaded exercise and continuing with a symptom-limited incremental ramp to peak VO2 with 
5(5)RUWKHEDVHOLQH&3(75(5PXVWEH)RU:HHNDQG(QGRI7UHDWPHQW&3(7V
SDWLHQWVVKRXOGH[HUFLVHWRPD[LPXPHIIRUWLGHDOO\WR5(5 
CPET should be performed at the same time of day (±2 h) and should be timed to occur 1 hour 
postdose, when applicable. The CPET will precede the 6MWT when applicable, which will be 
started 1 hour after the CPET is completed. 
CPET measurements for eligibility and for efficacy analyses will be determined by an 
independent central CPET Core Lab. 
At a minimum, the following measures will be determined: 
x Peak VO2 (mL O2/kg/min) 
x RER 
x Ventilatory efficiency (VE/VCO2 slope) 
x Peak Power Output at Ventilatory Anaerobic Threshold (watts) 
 
Other parameters of interest may be analyzed. 

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3.8.12 
6-minute Walk Test 
The distance, in meters, travelled in 6 minutes will be measured using a study-specific 6MWT 
protocol (Appendix 6). 
The 6MWTs should be performed at approximately the same time of day (within a 4-hour 
window) and must be started at least 1 hour after CPET is completed, when applicable. 
3.8.13 
Adverse Events   
All patients will be monitored for AEs throughout the study. All AEs will be recorded in 
accordance with the procedures outlined in this section. 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  
An AE, therefore, can be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
An AE includes, but is not limited to, the following: 
• Any unfavorable changes in general condition 
• Any clinically significant worsening of a preexisting condition 
• Any intercurrent diseases and accidents 
 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
3.8.13.1 
Causality Assessment 
For all AEs, the Investigator must provide an assessment of causal relationship to study drug. 
The causality assessment must be recorded in the patient’s source documentation and on the AE 
page of the subject’s eCRF. Causal relationship must be assessed according to the following: 
Related:   
An event where there is a reasonable possibility of a causal relationship between 
the event and the study drug 
Unrelated:   Any other event 

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3.8.13.2 
Severity Assessment 
The Investigator will provide an assessment of the severity of each AE by recording a severity 
rating in the patient’s source documentation and on the AE page of the patient’s eCRF. Severity, 
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. 
 
3.8.13.3 
Serious Adverse Events 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• Death 
• Life-threatening:  the patient was at immediate risk of death from the reaction as it occurred 
(ie, it does not include a reaction that hypothetically might have caused death if it had 
occurred in a more severe form) 
• Hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity:  a substantial disruption of a person’s ability to 
conduct normal daily functions 
• Congenital anomaly/birth defect 
• Important medical events: events that may not result in death, be life threatening, or require 
hospitalization. Such an event may be considered serious when, based on appropriate medical 
judgment, it may jeopardize the subject and may require medical or surgical intervention to 
prevent 1 of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency department or at home, 

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blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
Emergency room visits that do not result in admission to the hospital should be evaluated for 1 of 
the other serious outcomes (eg, life-threatening, other serious [medically important] event). 
3.8.13.4 
Recording Adverse Events 
Adverse events will be collected and recorded from the time the patient signs the ICF at the 
Screening Visit through the Follow-up Visit. All AEs, regardless of the assumption of a causal 
relationship with study procedures or study medication, must be recorded in the patient’s source 
documentation and subsequently on the appropriate AE page of the patient’s eCRF. This record 
includes AEs the patient reports spontaneously, those observed by the Investigator, and those 
elicited by the Investigator in response to open-ended questions during the study, such as “Have 
you had any health problems since your last visit?” 
For every AE, the Investigator must: 
• Provide an assessment of the severity, causal relationship to the study medication, and 
seriousness of the event 
• Document all actions taken with regard to the study medication (ie, no action taken, 
treatment temporarily interrupted, or treatment discontinued)  
• Detail any other treatment measures taken for the AE, including concomitant medications 
and/or procedures 
 
Pretreatment AEs will be collected from the time the patient signs the ICF until the patient 
receives study drug. 
Laboratory abnormalities and changes in vital signs, physical examination findings, and 12-lead 
ECG parameters should be considered AEs and reported on the AE page of the patient’s eCRF if 
the Investigator considers them clinically significant and/or they necessitate intervention. 
Any medical condition that is present when a patient is screened and does not worsen in severity 
and/or frequency should be reported as Medical History and not as an AE. However, if the 
condition does deteriorate in severity and/or frequency at any time during the study, it should be 
reported as an AE. 

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3.8.13.5 
Reporting Serious Adverse Events 
All AEs that meet any of the serious criteria must be reported to Medpace Clinical Safety within 
24 hours from the time that site personnel first learn of the event. All SAEs must be recorded in 
the subject’s source documentation and, subsequently, entered into the electronic data capture 
(EDC) system on the appropriate AE reporting page of the subject’s eCRF, whether or not an 
event is considered causally related to study medication. Once the AE eCRF has been completed 
or updated, Medpace Safety will be notified electronically and retrieve the form.  
If an event meets serious criteria and it is not possible to access the EDC system, the site should 
send an e-mail to Medpace Safety at 
 or call the 
Medpace SAE Reporting Line (phone number listed below), and fax the completed paper Back 
Up SAE form to Medpace Safety (fax number listed below) within 24 hours of awareness.  
When the EDC system becomes available, the SAE information must be entered within 24 hours 
of the system becoming available. 
Contact Information for Medpace Clinical Safety: 
Safety Inbox E-mail: 
 
SAE Reporting Line: 
 
Safety Fax: 
 
When follow-up is obtained or requested by Medpace Clinical Safety, the additional information 
should be recorded on AE eCRF (as applicable) or sent to Medpace Clinical Safety within 
24 hours of receipt by the site. Copies of discharge summaries, consultant reports, autopsy 
reports, and any other relevant documents may be requested. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE. These measures and the patient’s response to these measures should 
be recorded. All SAEs, regardless of relationship to study medication, will be followed by the 
Investigator until satisfactory resolution, until the Investigator deems the SAE to be chronic or 
stable, or until the patient is lost to follow-up. Clinical, laboratory, and diagnostic measures 
should be employed by the Investigator as needed to adequately determine the etiology of the 
event. 

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The Investigator will be responsible for reporting all SAEs to the IRB/IEC, as applicable. 
Ironwood will be responsible for reporting to the regulatory authorities. 
Special Situation: Exposure to Study Drug During Pregnancy  
A patient who reports pregnancy before study drug randomization must be withdrawn from the 
study. The pregnancy will be recorded as a reason for screen failure. Since there will have been 
no exposure to study drug, there will be no need to notify Medpace Clinical Safety of the 
pregnancy. 
A patient who reports pregnancy after randomization must discontinue study drug at once. The 
site must notify Medpace Clinical Safety within 24 hours from the time that site personnel first 
learn of the pregnancy (via email or SAE Reporting line). Medpace Clinical Safety will send the 
site an Exposure in Utero (EIU) Form for completion within 24 hours. The site should make 
reasonable efforts to follow the pregnancy to term and notify Medpace Clinical Safety of the 
pregnancy outcome (within 24 hours of being informed) or if outcome is associated with an SAE 
(eg, if the mother is hospitalized, spontaneous abortion, congenital anomaly), the site should 
follow SAE reporting procedures, as discussed above. 
3.8.14 
Cardiac Events  
Hospitalizations of cardiovascular etiology and all deaths will be classified by the central, 
independent, blinded cardiac events adjudicator(s).  
3.8.15 
Pharmacokinetic Assessments 
Blood samples will be collected for PK assessments. 
3.8.16 
 
 
 
 
  

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4. 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
4.1.1 
Primary Safety 
• Incidence of TEAEs and study drug-related TEAEs 
4.1.2 
Primary Efficacy 
• Change from baseline in peak VO2 (CPET) at Week 12 
 
4.2 
SECONDARY ENDPOINTS 
4.2.1 
Secondary Efficacy 
• Change from baseline in 6MWT distance at Week 12 
• Change in ventilatory efficiency as defined by VE/VCO2 slope (CPET) at Week 12 
• CPET Responders (Responders are subjects who improve by at least 1.5 mL O2/kg/min in 
peak VO2 from baseline to Week 12. Subjects who are hospitalized or who die due to heart 
failure during the study Treatment Period are considered nonresponders.) 
4.3 
EXPLORATORY ENDPOINTS 

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5. 
STATISTICAL METHODS 
5.1 
GENERAL CONSIDERATIONS 
Descriptive statistics (n, mean or geometric mean, standard deviation, minimum, median, 
maximum, 25th and 75th percentiles) will be calculated to summarize continuous variables. Count 
and percentage of patients in each category will be calculated to summarize categorical variables.  
Additionally, inferential statistical analysis will be performed on primary and secondary efficacy 
endpoints described in Sections 5.1.1 and 5.1.2.  
5.1.1 
Continuous Endpoints 
For continuous endpoints (eg, absolute change from baseline and percent change from baseline), 
an analysis of covariance (ANCOVA) model will be fitted with treatment group and 
stratification factors as categorical variable terms and the corresponding baseline efficacy value 
as a covariate. Least squares means (LSMs) and 95% confidence intervals for each treatment 
group as well as LSM difference between the 40-mg IW-1973 group and the placebo group will 
be presented, along with the corresponding confidence intervals and p-values. The cumulative 
distribution function (CDF) of change from baseline will be plotted by treatment group. To aid in 
the interpretation of the graphical representation of the CDF across treatments, a two-sample 
Kolmogorov-Smirnov test will be conducted.  
5.1.2 
Responder Endpoints 
For responder endpoints, the proportions of responders between the 40-mg IW-1973 group and 
the placebo group will be compared using a Cochran-Mantel-Haenszel (CMH) test controlling 
for stratification factors. The difference in the proportion of responders between the 40-mg 
IW-1973 group and the placebo group as well as the CMH estimates of odds ratio and p-values 
will be presented, along with the corresponding confidence intervals.  
Additional details regarding the statistical methods will be provided in the Statistical Analysis 
Plan (SAP), to be finalized before unblinding of the study. 

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5.2 
DETERMINATION OF SAMPLE SIZE 
The study is not designed to formally test a single statistical hypothesis; however, approximately 
184 subjects will provide approximately 90% power to detect a mean difference of 
1.3 (mL O2/kg/min) between the 40-mg IW-1973 treatment arm and the placebo treatment arm in 
change from baseline at Week 12 peak VO2. This estimate is based on the Evaluable Population 
(defined in Section 5.3), including patients with permanent or persistent atrial fibrillation at 
Screening, and using the follow assumptions: 
• 5% Type I error for a 2-sided test  
• Mean Peak VO2 change from baseline at Week 12 for Placebo arm is 0.0 (mL O2/kg/min) 
• Mean Peak VO2 change from baseline at Week 12 for 40 mg IW-1973 is 1.3 (mL O2/kg/min) 
• Equal standard deviation for all treatment arms at 2.5 (mL O2/kg/min) for change from 
baseline at Week 12 
• 10% attrition prior to Week 12 CPET 
• 10% of the total number of patients were randomized to either the 10- or 20-mg IW-1973 
dose groups under Amendment 2 of the protocol (or earlier)  
• Reduced treatment effect for IW-1973 in subjects with permanent or persistent atrial 
fibrillation at Screening 
 
Additionally, under similar assumptions, this sample size will also provide 90% power to detect 
a mean difference of 1.5 (mL O2/kg/min) on the same endpoint on the well-defined subgroup of 
a minimum of approximately 148 patients without permanent or persistent atrial fibrillation at 
Screening.   

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5.3 
ANALYSIS POPULATIONS 
ITT Population 
All randomized subjects 
Safety Population 
All randomized patients who take at least 1 dose of study medication 
mITT Population 
All randomized patients who take at least 1 dose of study drug and 
have at least 1 evaluable baseline measurement.  
Evaluable Population All patients in the mITT who complete 8 weeks of dosing (±3 days) 
and have at least 1 evaluable postbaseline assessment. Other criteria 
may be established and reviewed before database lock and unblinding. 
PK Population 
All patients who have received at least 1 dose of IW-1973 
ITT=intent to treat; mITT=modified intent to treat 
 
5.4 
PATIENT DISPOSITION 
The total number of screened patients and the number of patients who are screen failures will be 
tabulated. The number of patients who were randomized and the number and percentage of 
patients included in each population will be presented by treatment group. The number and 
percentage of patients who completed the study or discontinued early, as well as the reasons for 
discontinuation, will be presented by treatment group. 
5.5 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic parameters (eg, age, sex, race, ethnicity, weight, height, BMI and other baseline 
characteristics will be summarized by treatment group for the Safety, Evaluable, and modified 
intent-to-treat (mITT) Populations, using descriptive statistics as defined in Section 5.1.  
5.6 
DRUG EXPOSURE AND COMPLIANCE 
Exposure to study drug, calculated as the number of days from the first dose taken to the date of 
the last dose taken, inclusive, will be summarized by treatment group for the Safety Population. 
The total number of doses taken between each scheduled visit and overall for the entire study 
will be calculated for each subject. Compliance will be based on the number of doses expected to 
be taken. Percent compliance for study medication will be summarized by treatment group and 
overall for each scheduled visit and overall for the ITT Population. Compliance rates will also be 
FDWHJRUL]HGDVPLVVLQJDQGDQG!, and summarized by treatment 
group.  

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5.7 
PRIOR AND CONCOMITANT MEDICATIONS AND PROCEDURES 
Prior medicines and procedures are defined as any medicine taken or procedure performed on the 
patient before the date of first dose of study drug. 
Concomitant medicines and procedures are defined as any medicines taken or procedures 
performed on the patient on or after the date of first dose of study drug. Any medicines taken or 
procedures performed after the date of last dose of study drug will not be considered concomitant 
for purposes of analysis. Both prior and concomitant medicine use will be summarized by the 
number and percentage of patients in each treatment group receiving each medicine within each 
therapeutic class for the Intent-to-treat (ITT) Population. Multiple medicines within the same 
category (based on Anatomical-Therapeutic-Chemical classification) will only be counted once 
for that patient. 
5.8 
MAJOR PROTOCOL DEVIATIONS 
Major protocol deviations will be identified and documented based on a review of protocol 
deviations before database lock and treatment unblinding. The categories of major protocol 
deviations to be reviewed include, but are not limited to, patients who: 
• Did not meet key inclusion/exclusion criteria 
• Received disallowed concomitant medication(s) that could meaningfully impact 
interpretation of study results 
• Had overall treatment compliance rate <80% or >120% 
 
The number and percentage of subjects with major protocol deviations will be summarized by 
type of deviation and by treatment group for the ITT Population. All major protocol deviations 
will be presented in a data listing. 
5.9 
EFFICACY ANALYSES 
5.9.1 
Controlling for Multiplicity 
Due to the exploratory nature of this study, there is no adjustment on the p-values for multiple 
testing. All reported p-values are considered nominal. A p-YDOXHLQGLFDWHVWKDWWKH
treatment samples are less likely to have been drawn from the same distribution by chance alone. 

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5.9.2 
Analyses on the Primary Efficacy Endpoint 
An ANCOVA analysis as described in Section 5.1.1 will be performed on the primary efficacy 
endpoint as defined in Section 4.1.2 with treatment group and stratification factors as categorical 
variable terms and the corresponding baseline CPET value as a covariate on each of the 
following 2 populations: 
• Evaluable Population   
• A subgroup of the Evaluable Population, excluding patients who had permanent or persistent 
atrial fibrillation at baseline 
Sensitivity analyses similar to the above analysis will be performed on each of the above 
2 analyses using the mITT Population. In these analyses, patients without a Week 12 CPET 
measurement will carry Week 8 or earlier postbaseline measurement forward. Patients with no 
postbaseline CPET measurement will be assigned 0 as improvement, or no change from baseline. 
Details of the sensitivity analysis will be included in the SAP.  
5.9.3 
Analyses on the Secondary Efficacy Endpoints 
All secondary and exploratory analyses will be performed on the Evaluable Population and a 
subgroup of the Evaluable Population excluding patients with permanent or persistent atrial 
fibrillation at baseline.  
ANCOVA models described in Section 5.1.1 will be used to compare the 40-mg IW-1973 group 
with the placebo group on the following secondary endpoints. 
• Change from baseline in 6MWT distance at Week 12   
• Change in ventilatory efficiency as defined by VE/VCO2 slope (CPET) at Week 12   
 
Proportions of responders based on CPET will be compared using a responder analysis as 
described in Section 5.1.2. 
Details of other analysis, such as exploratory analysis 
 
   

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5.10 
SAFETY ANALYSES 
All safety parameters will be analyzed with descriptive statistics as described in Section 5.1 on 
the Safety Population. The safety parameters will include AEs, TEAEs, clinical laboratory 
evaluations, vital signs, ECG, and physical examination. For each applicable safety parameter, 
the last nonmissing assessment made before randomization will be used as the baseline for all 
analyses of that safety parameter. 
5.10.1 
Adverse Events 
Adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA) available at the start of the study and will be summarized by MedDRA 
system organ class (SOC), preferred term (PT), and treatment group. Listings will be provided 
for pretreatment AEs, TEAEs, severe AEs, study drug-related AEs, SAEs, and AEs leading to 
study discontinuation. 
TEAEs are those AEs that started or worsened in severity after the administration of study drug. 
TEAEs will be summarized for each treatment group by SOC and PT; PT and severity, by SOC; 
PT and relationship to study drug; and by SOC, PT. If a patient has more than 1 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.  
In addition, the incidence of AEs leading to premature discontinuation of study drug will be 
summarized by treatment group. Listings of pretreatment AEs, TEAEs, severe TEAEs, study 
drug-related AEs, SAEs, AEs leading to study discontinuation, and AEs leading to death (if any) 
will be provided. 
5.10.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values (in standard units) and changes from the 
baseline values at each assessment time point will be presented by treatment group for each 
clinical laboratory parameter. 

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5.10.3 
Vital Signs 
Descriptive statistics for vital signs (ie, pulse rate, systolic and diastolic BP, respiratory rate, 
temperature, and body weight) and changes from baseline values at each visit will be presented 
by treatment group. 
5.10.4 
ECGs 
Descriptive statistics for ECG parameters and changes from the baseline values at each 
assessment time point will be presented by treatment group. 
The number and percentage of patients with ECG abnormalities that are considered TEAEs by 
the Investigator will be tabulated by treatment group. A listing of all AEs for patients with 
ECG-related TEAEs will also be provided. 
5.11 
PK 
 
PK analyses will be based on the PK Population. Descriptive statistics will be calculated for 
plasma concentrations of IW-1973 at each assessed timepoint by study visit. 
 
 
 
 
5.12 
 

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5.13 
DATA MONITORING COMMITTEE 
An independent DMC will be given the responsibility to review trial safety and provide guidance 
consistent with the objectives of the study and appropriate ethical requirements.  
The DMC will comprise recognized experts in cardiovascular disease and 1 biostatistician who 
have experience in clinical trials and are not otherwise involved in the conduct of this trial. Their 
only role in this study will be as a member of the DMC, thus ensuring their independent review 
of safety data.  
Periodic safety review meetings will be scheduled after approximately 50 patients and after 
100 patients have completed 2 weeks of the Treatment Period (but at least twice every 
12 months, unless a different frequency is deemed appropriate by the DMC Chair). For these 
periodic reviews, the DMC will be provided with unblinded summaries of TEAE data by 
treatment groups. An independent statistician will be responsible for summarizing and 
submitting these safety data to members of the DMC. All data presentations for the DMC will be 
performed using the Safety Population. All data that are available at the time of each analysis 
will be presented. If a safety/tolerability signal or concerning AE imbalance is identified at a 
review, the committee may request additional safety data (eg, vital signs, concomitant 

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medications) At each meeting, the DMC will review cumulative TEAE data and recommend trial 
continuation, modification, or termination. 
The DMC will also be required to perform ad hoc review(s) per SAE criteria in Table 5. In this 
circumstance, the committee will be provided with narrative descriptions and all relevant clinical 
supporting documentation related to the SAEs under review. Upon request, the subjects’ 
unblinded treatment and dose level information will be provided to the committee.  
In addition to the periodic and ad hoc reviews, during the trial, committee members will be 
provided with blinded reports on all SAEs.  
The DMC or the Sponsor may request ad hoc meetings at any time and at their discretion. 
There are no predefined stopping rules for the trial (for individual stopping rules, see 
Section 3.7.1). However, the Sponsor, upon the recommendation of the DMC, may stop the 
study at any time for significant safety concerns. If the DMC recommends stopping or modifying 
the trial, a senior review team from the Sponsor will have the opportunity to review the 
blinded/unblinded data and discuss study findings with the DMC. The Sponsor may also seek 
input from relevant regulatory authorities. The Sponsor will make the final decision on the 
recommendation and will relay its decision to the DMC and relevant regulatory authorities. 
Additional details will be provided in the DMC charter, which will be developed in collaboration 
with the DMC members and will be finalized before the first patient is randomized. 
5.14 
INTERIM ANALYSES 
Planned interim safety analyses will be performed for the sole purpose of providing preliminary 
safety analyses to the DMC (Section 5.12.4).  
An additional optional interim analysis to review unblinded efficacy data to assist with the 
planning of future studies may be performed after at least one half of the anticipated subjects 
(N92) have completed the last visit. If performed, details regarding the interim analysis will be 
included in the SAP, along with updates to the data management plan as necessary. An 
independent statistician (who will not be involved in study data collection or interpretation) 
performing the interim analysis and Ironwood staff members, as identified in the SAP, may be 

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unblinded. Review of the interim analysis for planning purposes will operate independently of 
the study data monitoring and endpoint adjudication committees.  
5.15 
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. Before 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 will be 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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6. 
ETHICAL CONSIDERATIONS 
6.1 
INSTITUTIONAL REVIEW BOARD/INSTITUTIONAL ETHICS 
COMMITTEE 
Before 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 applicable Institutional Review Board 
(IRB) or Institutional Ethics Committee (IEC). 
All IRB/IEC approvals must be dated and signed by the IRB/IEC Chairperson 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 will 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 approval 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 ICH Good Clinical Practice (GCP) 
guidelines and any relevant and applicable local and national 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 before patients being enrolled into the amended protocol. 
6.2 
PATIENT INFORMATION AND INFORMED CONSENT 
Informed consent procedures will comply with the Code of Federal Regulations (CFR) 21, 
Parts 50 and 312. 

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The written ICF must be approved by the IRB/IEC for the purposes of obtaining and 
documenting consent. 
Before entry into the study, each patient will be provided with a written explanation of the study. 
It is the responsibility of the Investigator or appropriately trained health professional to give each 
patient full and adequate information regarding the objectives and procedures of the study and 
the possible risks involved. Patients will then be given the opportunity to ask questions and the 
Investigator will be available to answer questions as needed. Patients will be informed of their 
right to withdraw from the study at any time without prejudice. After this explanation and before 
entering the study, the patient will voluntarily sign the study-specific ICF. The patient will 
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 and the patient will be 
reconsented. The revised ICF must be submitted to the IRB/IEC for review and approval before 
its use. 

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7. 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE 
This study will be performed at multiple study sites. The Investigator at each study site will be 
responsible for ensuring that the study is conducted according to the signed Clinical Trial 
Agreement, the protocol, IRB/IEC requirements, and ICH 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 eCRF. 
7.1 
GENERATION OF STUDY RECORDS 
Before activating each site, Ironwood or its designated representative will verify the 
qualifications of each Investigator, inspect study site facilities as necessary, 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 site visits to review 
protocol compliance, compare eCRFs and individual patient’s medical records, assess drug 
accountability (in a blinded manner), and ensure that the study is being conducted according to 
pertinent regulatory requirements. All eCRFs will be verified with source documentation. The 
review of medical records will be performed in a manner that ensures patient confidentiality is 
maintained. 
The Clinical Site Monitor will discuss instances of missing or uninterpretable data with the 
Investigator for resolution. Any changes to the study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF. 

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7.2 
DATA QUALITY ASSURANCE 
Ironwood performs quality control and assurance checks on all of its clinical studies. Section 7.4 
provides details regarding study monitoring procedures. 
The study may be subject to audit by Ironwood, its representatives, or regulatory authorities. In 
the event of an audit, the Investigator must agree to allow Ironwood, representatives of 
Ironwood, or the Food and Drug Administration (FDA) or other regulatory agencies access to all 
study records. 
7.3 
ELECTRONIC CASE REPORT FORMS AND DATA MANAGEMENT 
Study data will be recorded in the patient’s source documentation and entered in eCRF in 
Ironwood or designee's EDC system. Source documentation supporting the eCRF data should 
indicate the patient’s participation in the study and should document the dates and details of 
study procedures, AEs, all observations, and patient status. The Investigator is responsible for 
verifying that all data entries on the eCRFs are accurate and correct and ensuring that all data are 
entered in a timely manner, as soon as possible after the information is collected. An explanation 
should be provided for any missing data. The Investigator must provide through the EDC system 
his or her formal approval of all the information in the eCRFs and changes to the eCRFs to 
endorse the final submitted data for each patient. 
Ironwood will retain the final eCRF data and corresponding audit trails. A copy of the final 
archival eCRF in the form of a compact disc or other electronic media will be placed in the 
Investigator’s study file. 
A record of screen failures and pretreatment failures will be maintained for patients who do not 
qualify for enrollment, including the reason for the failure. 
7.4 
STUDY MONITORING 
An Ironwood representative, the Clinical Site Monitor, will monitor the progress and conduct of 
the study by periodically conducting monitoring visits and by frequent communications 
(telephone, e-mail, letter, and fax) with the study sites. The site monitor will ensure that the study 
is conducted according to the protocol and regulatory requirements. During monitoring visits, the 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
Page 75 of 95 
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. 
All aspects of the study will be carefully monitored by Ironwood or its designee for compliance 
with applicable government regulations with respect to GCP and current standard operating 
procedures. 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
Page 76 of 95 
8. 
STUDY SPONSORSHIP 
8.1 
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; alternatively, study 
medication may be destroyed on site with prior approval by 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 
 
8.2 
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 agreement between the 
Investigator and Ironwood. 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
Page 77 of 95 
9. 
INVESTIGATOR OBLIGATIONS 
9.1 
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. 
9.2 
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 site must record the date the study medication was 
received and maintain a dispensing record in which to record each patient’s use. A complete 
reconciliation of study medication will be performed at the site close-out visit with a final 
accountability log provided to Ironwood as part of the site close-out report. Written approval for 
return of all unused and reconciled study medication or destruction by an appropriate waste 
handler will be provided before the end of the study. No study medication may be destroyed by 
study site without prior written permission of Ironwood. 
9.3 
RETENTION AND REVIEW OF RECORDS 
The investigator will retain records and documents pertaining to the conduct of this study, 
including eCRFs, source documents, ICFs, laboratory test results, and medication inventory 
records, for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified.   
The Sponsor may request retention of records for a longer period of time; therefore, 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. 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
Page 78 of 95 
If the Investigator retires, relocates, or otherwise withdraws from the responsibility of keeping 
the study records, custody must be transferred to another person (Ironwood, IRB, or other 
Investigator) who will accept this responsibility. Ironwood must be notified of and agree to the 
change in advance. 
9.4 
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 by patient identification 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 patient ID number and the full name, address, and 
telephone number of each patient is listed. 

IW-1973 Tablet (praliciguat) 
 
Ironwood Pharmaceuticals, Inc. 
Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
Page 79 of 95 
10. 
REFERENCE LIST 
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failure with preserved ejection fraction. Curr Heart Fail Rep. 2014;11(4):354-65. 
3. Oktay AA, Rich JD, Shah SJ. The emerging epidemic of heart failure with preserved ejection 
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Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
Confidential 
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PRESERVED EF (SOCRATES-PRESERVED) study. Eur Heart J. 2017;38(15):1119-27. 
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Clinical Trial Protocol: C1973-204 Amendment 3 
 
27 June 2018 
 
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27 June 2018 

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