A 12-Week, Randomized, Double-Blind, Placebo-Controlled Study With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Tenapanor for the Treatment of Constipation-Predominant Irritable Bowel Syndrome (IBS-C)
Phase: PHASE3
Conditions: Constipation Predominant Irritable Bowel Syndrome
Sponsor: Ardelyx

16.1 
Study Information 
16.1.1 
Protocol and protocol amendments 
The following documents are included: 
• Final protocol, dated 18 Aug 2015 
Ardelyx, Inc. 
RDX5791 
IND# 108,732 
TEN-01-301 
CONFIDENTIAL
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Ardelyx, Inc. 
 
Clinical Study Protocol  
 
Protocol No. TEN-01-301 
 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 1 of  73 
Supersedes Date: NA 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol No. TEN-01-301 
 
A 12-Week, Randomized, Double-Blind, Placebo-Controlled Study with a 4-Week 
Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Tenapanor for the 
Treatment of Constipation-Predominant Irritable Bowel Syndrome (IBS-C) 
 
18 August 2015 
Edition No. 1 
 
 
 
SPONSOR: 
 
Ardelyx, Inc. 
34175 Ardenwood Blvd. 
Fremont, CA  USA  94555 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document and the information contained herein or attached hereto ("Confidential Material") are confidential 
and proprietary to Ardelyx, Inc.. This Confidential Material should be viewed only by those individuals or 
companies that have been given prior authorization to do so by Ardelyx, Inc. ("Authorized Users"). This 
Confidential Material should not be made available in any form to any person or company, other than the 
Authorized Users and their respective employees or associates on a need-to-know basis, without the prior written 
consent from Ardelyx, Inc. 
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Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 2 of  73 
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PROTOCOL SUMMARY 
Study Title 
A 12-Week, Randomized, Double-Blind, Placebo-Controlled Study 
with a 4-Week Randomized Withdrawal Period to Evaluate the 
Efficacy and Safety of Tenapanor for the Treatment of Constipation-
Predominant Irritable Bowel Syndrome (IBS-C) 
Sponsor 
Ardelyx, Inc. 
Study Phase 
3 
Treatment 
Groups  
2 treatment groups; ~600 subjects total; ~300/group with a ratio of 
1:1 Tenapanor:placebo  
No. of Sites 
100-120 
Dose Form and 
Frequency 
Tablet(s), placebo matched 
Twice daily (BID)  
Doses 
Placebo, and tenapanor 50 mg BID (total daily doses; placebo, and 
100 mg) 
Methodology 
This is a 12-week, multi-center, randomized, double-blind, placebo 
controlled study with a 4-week randomized withdrawal (RW) period 
to evaluate tenapanor 50 mg BID in subjects with IBS-C (Rome III 
criteria). A 2:1 screen to randomization ratio is expected.  
Duration 
For each subject, the entire study will last for a total of 18 weeks; 
including 16 weeks of treatment, preceded by a 2 week screening 
period. 
2-Week 
Screening Period 
At the beginning of the 2-week screening period (Day -14), the 
following will be performed:  
Subjects will provide written consent and be fully assessed for 
eligibility into the study.  The assessments will include: 
inclusion/exclusion criteria, medical histories (including details about 
co-morbid disorders), physical exam, vital signs, ECG, and clinical 
laboratory tests.  During the 2-week screening period, subjects will 
self-report, on a daily basis, information about the status of their IBS-
C symptoms via an electronic diary.  
At the end of the screening period, prior to the subject returning for 
Visit 2 (randomization), a member of the site staff will confirm a 
subject’s eligibility with regard to the information they have reported 
in their electronic diary during screening.  If the information captured 
in the diary deems them eligible, and they continue to meet the 
inclusion criteria, which includes meeting the Rome III criteria for 
IBS with constipation, the subject will be randomized into a 
treatment group.  
 
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Edition Date: 18 August 2015 
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12-Week Treatment 
Period 
During the 12-week double-blind treatment period, subjects will 
record daily assessments including: frequency and timing of 
bowel movements; sensation of complete bowel emptying; 
consistency of bowel movements (BSFS); degree of straining, 
worst abdominal pain, abdominal discomfort, abdominal bloating, 
abdominal fullness and abdominal cramping; and use and timing 
of rescue medication.  Subjects will also record weekly 
assessments including: adequate relief of IBS symptoms, degree 
of relief of IBS symptoms, IBS severity, and constipation severity.  
The IBS-QOL questionnaire will be administered during 
screening, at the end of treatment and at the end of the RW period; 
and Treatment Satisfaction will be evaluated monthly.  The 
subject will return for study visits every two or four weeks (see 
schedule of events).  Subjects will undergo safety assessments at 
these visits, which may include a physical exam, ECG, vital signs, 
and clinical labs.  Adverse events and concomitant medications 
will be recorded.  Medication compliance will be monitored and 
the subjects will be given additional study drug as appropriate.   
4-Week RW Period 
At the end of the treatment period, subjects who complete the 
study in the tenapanor group will be randomized to either 
tenapanor 50 mg BID or placebo BID (1:1) and subjects who 
complete the study in the placebo group will be assigned to 
receive tenapanor 50 mg BID. 
During the 4-week RW period, subjects will continue to record 
daily and weekly assessments, update concomitant medication as 
necessary and update adverse events information as appropriate. 
At the end of the 4-week RW period subjects will return to the 
clinic for safety assessments, which may include a physical exam, 
ECG, vital signs, and clinical labs.   
General 
Inclusion/Exclusion 
Criteria 
Inclusion Criteria: 
 18 to 75 years old 
 Females must be of non-childbearing potential; either 
postmenopausal for at least 12 months as confirmed by 
follicle-stimulating hormone test (if < 60 years old), or 
surgically sterile (e.g., tubal ligation, hysterectomy, 
bilateral oophorectomy with appropriate documentation). 
If of child-bearing potential, must have negative 
pregnancy test at Visits 1 and 2, and confirm the use of 
one of the appropriate means of contraception as listed in 
Section 5.2. 
 Males must agree to use an appropriate method of barrier 
contraception (e.g., latex condom with a spermicidal 
agent) or have documented surgical sterilization 
 Subject is ambulatory 
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 Subject meets definition of IBS-C using Rome III Criteria 
for the Diagnosis of IBS  
 Subject meets screening eligibility criteria (see below) 
 A colonoscopy based on AGA guidelines; every 10 years 
at ≥ 50 years old, or the occurrence of any warning signs 
(i.e., unexplained weight loss, non-hemorrhoid blood in 
stools)  
 Ability to communicate well with the Investigator and to 
comply with the requirements of the entire study, 
including an understanding of how to use the touch-tone 
telephone electronic diary. 
 Written informed consent and a willingness to participate 
in the study as it is described. 
 Daily access to a touch tone telephone.  
 
Exclusion Criteria: 
 Functional diarrhea as defined by Rome III criteria 
 IBS with diarrhea (IBS-D), mixed IBS (IBS-M), or 
unsubtyped IBS as defined by Rome III criteria  
 Diagnosis or treatment of any clinically symptomatic 
biochemical or structural abnormality of the GI tract 
within 6 months prior to screening, or active disease 
within 6 months prior to screening; including but not 
limited to cancer, inflammatory bowel disease, 
diverticulitis, duodenal ulcer, erosive esophagitis, gastric 
ulcer, pancreatitis (within 12 months of screening), 
cholelithiasis, amyloidosis, ileus, non-controlled GERD, 
gastrointestinal obstruction, ischemic colitis or carcinoid 
syndrome. 
 Subject has a potential CNS cause of constipation (e.g., 
Parkinson’s disease, spinal cord injury, or multiple 
sclerosis) 
 Use of medications that are known to affect stool 
consistency (Prohibited Medications), including fiber 
supplements, anti-diarrheals, cathartics, antacids, opiates, 
prokinetic drugs, laxatives, enemas, antibiotics during the 
screening period; unless specified as rescue medication, 
and used accordingly 
o Patients on a stable, continuous regimen of fiber, 
bulk laxatives, stool softeners, or probiotics for the 
30 days prior to the screening visit are allowed, 
provided they agree to maintain a stable regimen 
throughout the trial  
 Subject has a history or current evidence of laxative abuse 
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(in the clinical judgment of the physician)  
 Hepatic dysfunction (ALT [SGPT] or AST [SGOT] >2.5 
times the upper limit of normal) or renal impairment 
(serum creatinine > 2mg/dL) 
 Any evidence of or treatment of malignancy (other than 
localized basal cell, squamous cell skin cancer or cancer in 
situ that has been resected) within the previous year 
 Any surgery on the stomach, small intestine or colon, 
excluding appendectomy or cholecystectomy (unless 
within 60 days of screening visit) 
 Pregnant or lactating women 
 A major psychiatric disorder (DSM-III-R or DSM-IV) 
including major depression or other psychoses that has 
required hospitalization in the last 3 years. History of 
attempted suicide or uncontrolled bipolar disorder 
 Alcohol or substance abuse in the last year 
 Participation in other clinical trials within 1 month prior to 
Day –14 (beginning of screening period) 
 Clinical evidence of significant cardiovascular, respiratory, 
renal, hepatic, gastrointestinal, hematologic, neurologic, 
psychiatric or any disease that may interfere with the 
subject successfully completing the trial 
 Subject has been randomized into any Phase 1 or 2 study 
in which Tenapanor was a treatment 
 Subject is involved in the conduct and/or administration of 
this trial as an investigator, subinvestigator, trial 
coordinator, or other staff member, or the subject is a first 
degree family member, significant other, or relative 
residing with one of the above persons involved in the trial 
 If, in the opinion of the Investigator the subject is unable 
or unwilling to fulfill the requirements of the protocol or 
has a condition, which would render the results 
uninterpretable 
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 Screening 
Eligibility Criteria 
to qualify for the 
Treatment Period 
Subject eligibility, according to the IBS symptom information 
captured in the diary during the 2-week screening period will 
be determined electronically by the eDiary/IVRS and provided 
to the clinical site staff upon request.   
 Subjects must have ≥78 % compliance (≥11 of 14 days) 
with completing the daily assessments via the touch-tone 
telephone diary 
 Subjects must have a weekly stool frequency of <3 CSBMs 
(complete spontaneous bowel movements) and ≤5 SBMs 
(spontaneous bowel movements)  
 For the daily worst abdominal pain assessment, subjects 
must have an average weekly abdominal pain score of ≥3 on 
an 11 point numerical rating scale (NRS)    
 Rescue medication as defined in Section 5.5 (laxative, 
enema, and/or suppository) usage for ≤2 of the 14 days; 
none within 48 hours prior to randomization 
 No use of a prohibited medication, except rescue medication 
as defined in Section 5.5 
 No watery stools (Type 7 on the Bristol Stool Form Scale; 
for any SBM, or loose (mushy) stools (Type 6 on the BSFS) 
for >1 SBM 
Efficacy Variables: 
Primary:  
 6/12 week overall responder rate (weekly responder for 
6/12 weeks for both CSBM and abdominal pain, described 
below) vs placebo 
Key Secondary:  
 6/12 week overall CSBM responder rate (weekly 
responder for 6/12 weeks; ≥ 1 CSBM from baseline) vs 
placebo  
 6/12 week overall abdominal pain responder rate (weekly 
responder for 6/12 weeks; decrease of ≥30% of worst 
abdominal pain from baseline) vs placebo 
 9/12 week overall responder rate (weekly responder for 
9/12 weeks for both CSBM and abdominal pain, described 
below) vs placebo 
 9/12 week overall CSBM responder rate (weekly 
responder for 9/12 weeks; ≥ 1 CSBM from baseline and ≥ 
3 CSBM) vs placebo  
 9/12 week overall abdominal pain responder rate (weekly 
responder for 9/12 weeks; decrease of ≥30% of worst 
abdominal pain from baseline) vs placebo 
 Durable overall responder rate (weekly responder for 9/12 
weeks and 3 of the last 4 weeks for both CSBM and 
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abdominal pain) vs placebo 
 Durable overall CSBM responder rate (weekly responder 
for 9/12 weeks and 3 of the last 4 weeks; ≥ 1 CSBM from 
baseline and ≥ 3 CSBM) vs placebo 
 Durable overall abdominal pain responder rate (weekly 
responder for 9/12 weeks and 3 of the last 4 weeks; 
decrease of ≥30% of worst abdominal pain from baseline) 
vs placebo 
 
Other Secondary Variables 
 
Daily/weekly assessments of other bowel habits including:  
frequency of CSBMs, frequency of spontaneous bowl 
movements (SBMs), stool consistency, degree of straining, 
worst abdominal pain, abdominal discomfort, abdominal 
bloating, abdominal fullness, and abdominal cramping, 
IBS severity, constipation severity, IBS-QOL, adequate 
relief of IBS symptoms, degree of relief of IBS symptoms, 
and treatment satisfaction.  
Statistical 
Considerations 
Summary tabulations will be presented that will display 
descriptive statistics for each treatment group. For subject 
disposition, demographic and baseline characteristics, medical 
history, gastrointestinal disease history, and prior medications, an 
overall column (i.e., all subjects combined) will be included. For 
continuous variables, descriptive statistics will include the number 
of subjects, mean, standard deviation, minimum, median, and 
maximum values. For categorical variables, descriptive statistics 
will include the number and percent of subjects in each category.  
 
All subjects who meet the study entry inclusion/exclusion criteria, 
receive at least one dose of study drug, and have at least one valid 
week of efficacy assessment data (minimum of 4 days) will be 
included in the ITT analysis set. Subjects will be analyzed 
according to the treatment group into which they were 
randomized. The ITT analysis set will be the primary analysis set 
for efficacy analysis. 
 
Responder rate efficacy variables will be analyzed using a 
Cochran-Mantel-Haenszel (CMH) test with pooled investigator 
site as a stratification (adjustment) variable. Summary statistics 
will include the pairwise risk difference with placebo along with 
the asymptotic 95% confidence interval (CI). The adjusted relative 
risk (adjusted for pooled investigator site) will be based on the 
ratio of responder rates for placebo versus tenapanor. The 95% CI 
versus placebo will also be presented for the adjusted relative risk.  
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Continuous efficacy variables will be analyzed using an analysis 
of covariance (ANCOVA) or analysis of variance (ANOVA) 
model.  The ANCOVA model will have terms for pooled 
investigator site, treatment group, and baseline as the covariate. 
The ANOVA model will have terms for pooled investigator site 
and treatment group. The hypotheses will be based on the LS 
means difference from placebo. 
 
Safety analyses will include summaries for adverse events, 
clinical laboratory tests, vital signs, 12-lead ECGs, and physical 
exams. Compliance and concomitant medications will also be 
summarized. 
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TABLE OF CONTENTS 
PROTOCOL SUMMARY ................................................................................................... 2 
TABLE OF CONTENTS..................................................................................................... 9 
1. 
LIST OF ABBREVIATIONS ..................................................................................... 11 
2. 
INTRODUCTION AND STUDY RATIONALE ...................................................... 14 
2.1. 
Scientific Background ................................................................................ 14 
2.2. 
Description of Investigational Drug ........................................................... 14 
2.3. 
Previous Human Experience ...................................................................... 15 
2.4. 
Dose Rationale ............................................................................................ 19 
3. 
STUDY OBJECTIVES............................................................................................... 19 
3.1. 
Primary Objective ....................................................................................... 19 
3.2. 
Secondary Objectives ................................................................................. 19 
3.3. 
Exploratory Objective ................................................................................ 19 
4. 
INVESTIGATIONAL PLAN ..................................................................................... 19 
5. 
STUDY POPULATION ............................................................................................. 20 
5.1. 
General Considerations .............................................................................. 20 
5.2. 
Inclusion Criteria ........................................................................................ 21 
5.3. 
Exclusion Criteria ....................................................................................... 22 
5.4. 
Entry Criteria at End of 2-Week Screening Period .................................... 23 
5.5. 
Rescue Medication ..................................................................................... 23 
5.6. 
Prohibited Concurrent Medications ............................................................ 24 
5.7. 
Removal of Subjects from Therapy or Assessment ................................... 24 
6. 
TREATMENTS .......................................................................................................... 25 
6.1. 
Identity of Investigational Product ............................................................. 25 
6.2. 
Packaging, Storage, and Labeling .............................................................. 25 
6.3. 
Treatments to be Administered .................................................................. 25 
6.4. 
Randomization and Blinding ...................................................................... 26 
7. 
SCHEDULE OF ASSESSMENTS ............................................................................. 27 
8. 
STUDY EVALUATIONS .......................................................................................... 29 
8.1. 
Pre-Screening and Screening Period Procedures ....................................... 29 
8.2. 
Treatment Period Procedures ..................................................................... 30 
8.3. 
Randomized withdrawal (RW) period procedures ..................................... 32 
8.4. 
Safety and Efficacy Assessments ............................................................... 33 
8.5. 
Total Blood Volume Required for Study ................................................... 37 
8.6. 
Data Quality Assurance .............................................................................. 37 
9. 
ADVERSE EVENTS .................................................................................................. 38 
9.1. 
Adverse Event ............................................................................................ 38 
9.2. 
Severity ....................................................................................................... 38 
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9.3. 
Unexpected Adverse Drug Experience ...................................................... 39 
9.4. 
Causality ..................................................................................................... 39 
9.5. 
Serious Adverse Event ............................................................................... 40 
9.6. 
Procedures for Recording and Reporting AEs and SAEs .......................... 40 
9.7. 
Monitoring of Adverse Events and Period of Observation ........................ 41 
9.8. 
Pregnancy ................................................................................................... 42 
10. 
STATISTICAL CONSIDERATIONS ..................................................................... 42 
10.1. Determination of Sample Size .................................................................... 43 
10.2. Randomization and Stratification ............................................................... 43 
10.3. Analysis Sets .............................................................................................. 43 
10.4. Procedures for Handling Missing Data ...................................................... 43 
10.5. Methods of Pooling Data ............................................................................ 44 
10.6. Visit Windows ............................................................................................ 45 
10.7. Statistical Analyses ..................................................................................... 46 
11. 
ADMINISTRATIVE REQUIREMENTS ................................................................ 54 
11.1. Good Clinical Practice ................................................................................ 54 
11.2. Ethical Considerations ................................................................................ 54 
11.3. Subject Informed Consent and Information ............................................... 54 
11.4. Subject Confidentiality ............................................................................... 55 
11.5. Protocol Compliance .................................................................................. 55 
11.6. Study Monitoring and On-site Audits ........................................................ 56 
11.7. Case Report Form Completion ................................................................... 56 
11.8. Drug Accountability/Retention .................................................................. 56 
11.9. Study Completion or Premature Closure .................................................... 57 
11.10. Record Retention ........................................................................................ 57 
12. 
USE OF INFORMATION AND PUBLICATION .................................................. 59 
13. 
SIGNATURES.......................................................................................................... 60 
13.1. Investigator Signature ................................................................................. 60 
13.2. Sponsor Signature ....................................................................................... 61 
14. 
APPENDIX A: Rome III Criteria for the Diagnosis of IBS ..................................... 62 
15. 
APPENDIX B: Bristol Stool Form Scale (BSFS) .................................................... 63 
16. 
APPENDIX C: Clinical Laboratory Tests ................................................................ 64 
17. 
APPENDIX D:  Irritable Bowel Syndrome – Quality of Life 
Questionnaire (IBS-QOL)...................................................................................... 65 
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1. 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransaminase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransaminase 
BM 
Bowel movement 
BMI 
Body mass index 
BQL 
Below quantitation limit 
BSFS 
Bristol stool form scale 
BUN 
Blood urea nitrogen 
CIC 
Chronic idiopathic constipation 
CKD 
Chronic kidney disease 
CMH 
Cochran-mantel-haenszel 
CO2 
Carbon dioxide 
CRA 
Clinical research associate 
CRC 
Child resistant closure 
CRF 
Case report form;  
CRO 
Contract research organization 
CSBM 
Complete spontaneous bowel movement 
CTCAE 
Common terminology criteria for adverse events 
DSM 
Diagnostic and statistical manual of mental disorders 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ESRD 
End-stage renal disease 
FDA 
Food and drug administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
GERD 
Gastroesophageal reflux disease 
GI 
Gastrointestinal 
H+ 
Hydrogen 
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HDPE 
High density polyethylene 
HEK 
Human embryonic kidney cells 
hERG 
Human ether-a-go-go related gene 
HPMC 
Hydroxypropylmethylcellulose 
IB 
Investigator’s brochure 
IBS 
Irritable bowel syndrome 
IBS-C 
Constipation predominant irritable bowel syndrome 
IBS-D 
Diarrhea predominant irritable bowel syndrome 
IBS-M 
Mixed irritable bowel syndrome (constipation and 
diarrhea) 
IBS-QOL 
Irritable bowel syndrome quality of life questionnaire 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IEC 
Independent ethics committee 
IKr 
Current amplitude 
IRB 
Institutional review board 
ITT 
Intent to treat 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LOCF 
Last observation carried forward 
LS 
Least squares 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
Na+ 
Water/sodium 
NHE3 
Sodium-hydrogen antiporter 3 
NOAEL 
NRS 
No observed adverse effect level 
Numeric rating scale 
NSAID 
Non-steroidal anti-inflammatory drug 
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OBD 
Opioid bowel dysfunction 
OC 
Observed case 
P 
Probability; p-value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PRO 
Patient reported outcome 
QA 
Quality assurance 
QD 
Once daily 
RBC 
Red blood cell 
RW 
Randomized withdrawal 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBM 
Spontaneous bowel movement 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SOP 
Standard operating procedure 
TEAE 
Treatment emergent adverse event 
TLF 
Tables, listings, and figures 
WBC 
White blood cell count 
WHO 
World health organization 
WHODRL 
World health organization drug reference library 
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2. 
INTRODUCTION AND STUDY RATIONALE 
A major function of the gastrointestinal (GI) tract is to maintain intestinal 
water/sodium (Na+) homeostasis through a delicate balance of secretory and 
absorption mechanisms. The Na+/hydrogen (H+) antiporter NHE3 plays a dominant 
role in the Na+ re-uptake process. Tenapanor (also known as RDX5791 and 
AZD1722) is a GI-acting NHE3 inhibitor. Tenapanor is a minimally systemic, small 
molecule under investigation for the treatment of constipation-related diseases such as 
chronic idiopathic constipation (CIC), constipation predominant irritable bowel 
syndrome (IBS-C), and opioid bowel dysfunction (OBD). The proposed mechanism 
of action of tenapanor is to reduce Na+ re-uptake. This decrease in Na+ uptake 
increases the net fluid volume in the GI tract. Restoration of normal luminal fluid 
content facilitates intestinal transit and stimulates motility. 
This phase 3, multi-center, randomized, double blind, placebo-controlled, multi-
center study will evaluate the safety and efficacy of tenapanor in subjects with 
constipation predominant IBS (IBS-C) as defined by the Rome III criteria and who 
have active disease as determined during a two-week screening period.  Subjects who 
qualify and are randomized into the study will receive tenapanor 50 mg BID or 
matching placebo BID for 12 consecutive weeks.  At the end of this treatment period, 
there will be a four-week randomized withdrawal (RW) period.  For the RW period, 
subjects who received tenapanor during the 12-week treatment period will be 
randomized to receive either tenapanor 50 mg BID or placebo BID and those subjects 
who received placebo during the 12-week treatment period will receive tenapanor 50 
mg BID; this will all be performed under double-blind conditions. 
2.1. Scientific Background 
2.1.1 Overview of IBS 
Irritable bowel syndrome (IBS) is the most common disorder seen by 
gastroenterologists and is characterized by abdominal pain with associated alterations 
in bowel function. These changes in bowel patterns may manifest as diarrhea, 
constipation or an alternation between the two. As there are no pathognomonic, 
laboratory, endoscopic or radiographic abnormalities found in association with IBS it 
is considered a functional gastrointestinal (GI) disorder. The chronic nature of the 
multiple symptoms of IBS, combined with the lack of effective treatments, leads to 
significant health care resources being used by IBS subjects and impairment of 
subjects’ well-being and functional ability.  For research and regulatory purposes, the 
diagnosis of IBS has been described by the Rome III criteria as summarized in 
Section 14 (Appendix A). 
2.2. Description of Investigational Drug 
Tenapanor is chemically described as: (S)-N,N’-(10,17-dioxo-3,6,21,24-tetraoxa-
9,11,16,18-tetraazahexacosane-1,26-diyl)bis(3-((S)-6,8-dichloro-2-methyl-1,2,3,4-
tetrahydroisoquinolin-4-yl) benzenesulfonamide) dihydrochloride. Its empirical 
formula is C50H68Cl6N8O10S2.  
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Tenapanor (as the dihydrochloride salt) drug product will be supplied as white to off-
white oval biconvex film-coated tablets with the following excipients:
 
Tenapanor will be supplied at a dosage strength of 50 mg. 
Tablets are packaged in an opaque white HDPE (high-density polyethylene) bottle 
(66/bottle) with a white polypropylene CRC closure and induction seal plus desiccants. 
Tablets of tenapanor should be stored in the original packaging between 2°C and 30°C.  
Temperature excursions are allowed from -30°C to 50°C excursions for a maximum of 1 
week. 
 
2.3. Previous Human Experience 
2.3.1 Safety 
Tenapanor has been studied in 14 clinical trials in healthy volunteers, IBS-C, chronic 
kidney disease (CKD), and end-stage renal disease (ESRD) patients; greater than 
1000 subjects have received tenapanor.  In the single- and multiple-ascending dose 
phase 1 clinical trial where tenapanor was administered once a day, there were very 
few treatment emergent adverse events. In the SAD phase, 3 RDX5791-treated 
subjects (two 50 mg [33%], one 150 mg [17%]) and 2 placebo-treated subjects (20%) 
reported AEs. In the MAD phase, 11 tenapanor-treated subjects (two 3 mg [25%], two 
10 mg [25%], four 30 mg [50%], and three 100 mg [36%]) and 1 placebo-treated 
subject (13%) reported AEs. The majority of AEs in both phases were mild in 
severity and not considered to be related to study drug administration. 
In the Phase 1 dosing regimen clinical trial the most common TEAEs were 
gastrointestinal disorders, including abdominal pain (9.5% and 14.3% of subjects in 
the total tenapanor and placebo groups, respectively), abnormal gastrointestinal 
sounds (6% and 0%, respectively), and abdominal discomfort (4.8% and 0%, 
respectively). 
In a 4-week Phase 2a study in IBS-C subjects, where tenapanor was administered at 
10, 30, and 100 mg QD, the most common TEAEs among tenapanor-treated subjects 
were diarrhea, urinary tract infection, and headache (5 [4%] subjects each) and 
abdominal distention, flatulence, and nausea (3 [2%] subjects). No apparent dose 
relationship was seen with regard to the incidence of these commonly reported 
adverse events; there were no drug-related SAEs. 
In a 12-week Phase 2b study in IBS-C subjects, where tenapanor was administered at 
5, 20, and 50 mg BID, treatment with tenapanor was generally well tolerated. The 
majority of TEAEs were considered mild to moderate in severity. The most 
frequently reported TEAEs were diarrhea, headache, nausea, and urinary tract 
infection. Diarrhea was experienced by 0 (0.0%) subjects in the placebo group, 7 
(8.0%) subjects in the tenapanor 5 mg BID group, 11 (12.4%) subjects in the 
tenapanor 20 mg BID group, and 10 (11.2%) subjects in the tenapanor 50 mg BID 
group. The most frequently reported drug-related TEAEs were diarrhea, headache, 
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and abdominal pain. No deaths occurred during the study. Four subjects had an SAE: 
1 subject in the placebo group (osteomyelitis), 2 subjects in the tenapanor 5 mg BID 
group (laryngeal neoplasm and urinary tract infection), and 1 subject in the tenapanor 
20 mg BID group (small intestinal obstruction). None of the SAEs were considered to 
be related to study drug. 
The most common adverse events that led to discontinuation of study drug were 
diarrhea (3 [3.4%] subjects each in the tenapanor 5 mg, 20 mg, and 50 mg BID 
groups) and abdominal distension (3 [3.4%] subjects in the tenapanor 5 mg BID 
group). No other specific TEAE (preferred term) led to discontinuation for more than 
2 subjects in any treatment group. 
There were no clinically meaningful changes from baseline in laboratory tests, vital 
signs, ECGs, or physical examination findings. No apparent dose relationship was 
seen with regard to the incidence of these commonly reported adverse events; there 
were no drug-related SAEs. 
 
2.3.2 Efficacy 
2.3.2.1 Phase 2a study of Tenapanor (10, 30, 100 mg QD) in IBS-C subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.3.2.2 Phase 2b study of Tenapanor (5, 20, 50 mg BID) in IBS-C subjects 
 
 
 
 
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2.4. Dose Rationale 
Results from the Phase 2b study in IBS-C demonstrated that tenapanor 50 mg BID 
had statistically significant effects in the primary endpoint of CSBM responder rate 
with consistent effects in both overall and abdominal pain responder rates. Results 
from this study also demonstrated that 20 mg BID (the next lowest dose) did not have 
statistically significant effects in key endpoints.  Based on results from this double-
blind, placebo-controlled study, 50 mg BID was selected as the dose for this pivotal 
phase 3 clinical trial. 
3. 
STUDY OBJECTIVES 
3.1. Primary Objective 
The primary objective of this study is: 
 To assess the efficacy of tenapanor 50 mg for the treatment of IBS-C when 
administered twice daily (BID) for 12 consecutive weeks.  
3.2. Secondary Objectives 
The secondary objectives of this study are: 
 To assess the safety and tolerability of tenapanor 50 mg when administered twice 
daily (BID) for 12 consecutive weeks.  
 To assess the efficacy of tenapanor 50 mg BID after a 4-week placebo controlled 
randomized withdrawal period 
3.3. Exploratory Objective 
The exploratory objective of this study is: 
 To collect and store DNA for future exploratory research into plasma biomarkers 
and genes/genetic variation related to the gastrointestinal disease area or that may 
influence response (i.e., distribution, safety, tolerability and efficacy) to tenapanor 
4. 
INVESTIGATIONAL PLAN 
This is a Phase 3, multi-center, randomized, double-blind, placebo controlled study of 
tenapanor in subjects with IBS-C.  Patients who are 18 to 75 years old, meeting the 
definition of IBS-C as defined by the Rome III Criteria for the Diagnosis of IBS (see 
Appendix A) will undergo a battery of screening procedures to determine eligibility 
for the trial.  A 2:1 screen to randomization ratio is expected.   
The study will consist of a 2-week screening period, a 12-week treatment period, and 
a 4-week randomized withdrawal period. 
Approximately 2 weeks prior to study randomization, prospective subjects may be 
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assessed with respect to their meeting the eligibility requirements of the study.   
At the beginning of the 2-week screening period (Day -14), subjects will be 
questioned with respect to their eligibility for the study.  Those that meet the basic 
requirements will be asked to provide written informed consent.  The basic screening 
assessments will include: evaluation of the inclusion/exclusion criteria, medical 
history (including details about co-morbid disorders), physical exam, vital signs, 
ECG, and clinical laboratory tests, including urinalysis. Subjects must discontinue the 
use of all prohibited medications at Visit 1 (Screening/Day -14) for the duration of the 
study, as referenced in Section 5.6.  During the screening period, subjects will self-
report daily information about the status of their IBS symptoms via a touch-tone 
telephone diary. Each day, entries into the telephone diary (IVRS diary) must occur 
between 6PM and 11:59PM (local time). This will include information about their 
stool frequency, stool consistency, straining, abdominal pain, abdominal discomfort, 
abdominal bloating, abdominal fullness, abdominal cramping, and rescue medication 
usage. IBS severity, and constipation severity will be collected weekly through the 
IVRS diary. Subject compliance with the electronic diary will be monitored actively 
by the site staff and by the electronic diary system.   
At the end of the screening period, prior to the subject returning for Visit 2 
(Randomization), a member of the site staff will confirm a subject’s eligibility with 
regard to the information they have reported in their electronic diary during screening.  
If the information captured in the diary deems them eligible, and they continue to 
meet the inclusion criteria at Visit 2, a member of the site staff will randomize the 
subject into a treatment group using an interactive web-response system (IWRS).  
Subjects will be randomized into a treatment group according to a computer-
generated central randomization schema. All subjects who receive at least one dose of 
study drug, with at least one valid week of efficacy assessment data will be included 
in the intention-to-treat (ITT) analysis set. All subjects who receive at least one dose 
of study drug will be included in all analyses of safety data.   
During the 12-week double-blind treatment period and the 4-week double-blind 
randomized withdrawal period, subjects will continue to record daily and weekly 
assessments via a touch-tone telephone diary system as instructed. Subjects will be 
seen weeks 2, 4, 8, and 12 (Days 15, 29, 57, and 85) during the treatment period and 
week 2 (Day 99) of the RW period for study assessment visits.  Subject compliance 
with daily diary entries will be monitored on an ongoing basis as described above.  
Subject compliance with study drug will also be monitored closely by clinical site 
staff throughout the study 
Subjects will return to the site at the end of the 4-week randomized withdrawal period 
(week 16, Day 113) to obtain safety and other end-of-study information. 
5. 
STUDY POPULATION 
5.1. General Considerations 
Approximately six-hundred (600) subjects who meet all of the inclusion criteria, none 
of the exclusion criteria and demonstrate active IBS-C during a 2-week screening 
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period will be randomized into the study at approximately 100 to 120 US clinical 
centers.   
5.2. Inclusion Criteria 
Subjects meeting all of the following inclusion criteria will be eligible for enrollment: 
1. 18 to 75 years old 
2. Females must be of non-childbearing potential; either postmenopausal for at least 
12 months as confirmed by follicle-stimulating hormone test (if < 60 years old), 
or surgically sterile (e.g., tubal ligation, hysterectomy, bilateral oophorectomy 
with appropriate documentation). If of child-bearing potential, must have 
negative pregnancy test at Visits 1 and 2, and confirm the use of one of the 
following appropriate means of contraception: 
 oral birth control pills administered for at least one monthly cycle prior to 
study drug administration,  
 contraceptive patch worn for at least one monthly cycle prior to study drug 
administration,  
 progesterone implants,  
 IUDs,  
 abstinence from intercourse for two weeks prior to the study drug 
administration, throughout the 12-week treatment phase, and the 4-week 
randomized withdrawal phase, or 
 double barrier method,  
 sterilization of one or both partner(s).   
3. Males must agree to use an appropriate method of barrier contraception (e.g., 
latex condom with a spermicidal agent) or have documented surgical sterilization 
4. Subject is ambulatory 
5. Subject meets definition of IBS-C using Rome III Criteria (see Appendix A) for 
the Diagnosis of IBS  
6. Colonoscopy requirements 
 Subjects, age 50 years or older, must have had a colonoscopy within 10 years 
of enrollment (American Gastroenterological Association guidelines).   
 Patients of any age with unexplained warning symptoms (e.g., lower 
gastrointestinal bleeding, iron-deficiency anemia, clinically significant 
weight loss, systemic signs of infection or colitis) must have had a 
colonoscopy, with non-significant findings, after the onset or worsening of 
the warning symptoms.   
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7. Ability to communicate well with the Investigator and to comply with the 
requirements of the entire study, including an understanding of how to use the 
touch-tone telephone electronic diary 
8. Written informed consent and a willingness to participate in the study as it is 
described 
9. Daily access to a touch tone telephone 
5.3. Exclusion Criteria 
Subjects meeting one or more of the following exclusion criteria are not to be enrolled 
in the study: 
1. Functional diarrhea as defined by Rome III criteria (see Appendix A) 
2. IBS with diarrhea (IBS-D), mixed IBS (IBS-M), or unsubtyped IBS as defined by 
Rome III criteria (see Appendix A) 
3. Diagnosis or treatment of any clinically symptomatic biochemical or structural 
abnormality of the GI tract within 6 months prior to screening, or active disease 
within 6 months prior to screening.  Including but not limited to cancer, 
inflammatory bowel disease, diverticulitis, duodenal ulcer, erosive esophagitis, 
gastric ulcer, pancreatitis (within 12 months of screening), cholelithiasis, 
amyloidosis, ileus, non-controlled GERD, gastrointestinal obstruction or carcinoid 
syndrome 
4. Use of medications that are known to affect stool consistency as described in 
Section 5.6 (Prohibited Medications). Note: Patients on a stable, continuous 
regimen of fiber, bulk laxatives, stool softeners, or probiotics during the 30 days 
before the screening visit are allowed to continue, provided they maintain a stable 
dosage throughout the trial. 
5. Clinical evidence of significant cardiovascular, respiratory, renal, hepatic, 
gastrointestinal, hematologic, neurologic, psychiatric or any disease that may 
interfere with the subject successfully completing the trial   
6. The subject has a history or current evidence of laxative abuse (in the clinical 
judgment of the physician)   
7. Hepatic dysfunction (ALT [SGPT] or AST [SGOT] >2.5 times the upper limit of 
normal) or renal impairment (serum creatinine > 2mg/dL)   
8. Any evidence of or treatment of malignancy (other than localized basal cell, 
squamous cell skin cancer or cancer in situ that has been resected) within the 
previous year 
9. Any surgery on the stomach, small intestine or colon, excluding appendectomy 
and cholecystectomy 
10. If, in the opinion of the Investigator the subject is unable or unwilling to fulfill the 
requirements of the protocol or has a condition, which would render the results 
uninterpretable 
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11. A major psychiatric disorder (DSM-III-R or DSM-IV) including major depression 
or other psychoses that has required hospitalization in the last 3 years. History of 
attempted suicide or uncontrolled bipolar disorder. 
12. Alcohol or substance abuse in the last year 
13. Subject has been randomized into any Phase 1 or 2 study in which tenapanor was 
a treatment 
14. Subject is involved in the conduct and/or administration of this trial as an 
investigator, sub-investigator, trial coordinator, or other staff member, or the 
subject was a first degree family member, significant other, or relative residing 
with one of the above persons involved in the trial 
15. Participation in other clinical trials within 1 month prior to Day –14 (beginning of 
screening period) 
5.4. Entry Criteria at End of 2-Week Screening Period 
In order to be eligible for randomization, subjects must satisfy inclusion/exclusion 
criteria as described in Sections 5.2 and 5.3 and meet the subject reported outcome 
criteria collected during the 2-week screening period as described below.   
Subject eligibility, according to the IBS symptom information captured in the diary 
during the 2-week screening period, will be determined electronically by the 
interactive voice-response system and provided to the clinical site staff upon request.   
 Subjects must have ≥78 % compliance (≥11 of 14 days) with completing the daily 
assessments via the touch-tone telephone diary   
 Subjects must have a weekly stool frequency of <3 CSBMs (complete 
spontaneous bowel movements) and ≤5 SBMs (spontaneous bowel movements)  
 Subjects must have a mean stool consistency score of ≤3 using the 7-point Bristol 
Stool Form Scale (BSFS)  (see Appendix B) 
 For the daily assessment of abdominal pain, subjects must have an average 
weekly abdominal pain score of ≥3 on a 0-10 point scale.     
 Rescue medication usage for ≤ 2 of the 14 days; none within 48 hours prior to 
randomization 
 No use of a prohibited medication, except rescue medication as defined in Section 
5.5 
 No watery stools (Type 7 on the Bristol Stool Form Scale; (see Appendix B) for 
any SBM, or loose (mushy) stools (Type 6 on the BSFS) for >1 SBM 
5.5. Rescue Medication 
The following rescue medications are allowed for severe constipation (ie, at least 72 
hours after the subject’s previous BM or when symptoms become intolerable): 
 Bisacodyl 5 mg tablet or 10 mg suppository 
Rescue medication is allowed during the screening period, provided that there are no 
more than 2 uses and that none is used during the 2 days before randomization. 
Subjects are instructed to contact the investigator prior to taking a rescue medication 
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for severe constipation, and all rescue medication usage and time of usage must be 
recorded during the subject’s daily call to the IVRS.  A bowel movement will not be 
considered a spontaneous bowel movement (SBM) if it is reported less than 24 hours 
from the use of a rescue medication. 
5.6. Prohibited Concurrent Medications 
Administration of any concomitant therapy during the 7 days prior to the screening 
period, during the screening, treatment or RW periods should be recorded on the 
appropriate CRF page.  The following medications are specifically prohibited from 
use during the study (including screening and RW periods), unless specified as a 
rescue medication and used according to the procedure outlined in Section 5.5. 
 Antidiarrheals 
 Antacids which contain aluminum and/or magnesium (if used more than 3 days per 
week) 
 Enemas (except as defined in Section 5.5) 
 Antinausea agents (e.g., benzquinamide, trimethobenzamide) 
 Antispasmodic agents (e.g., Donnatal®, Librax®) 
 Laxatives or stool softeners (except a stable dose as defined in Section 5.3, #4) 
 Prokinetic agents (e.g., cisapride, metoclopramide) 
 Macrolide antibiotics (e.g., erythromycin, azithromycin) 
 Cholestyramine or WelChol® 
 5-HT3 antagonists (e.g., alosetron, ondanestron) 
 5-HT4 agonists (e.g., tegaserod) 
 Bismuth preparations 
 Anticholinergics (e.g., dicyclomine) 
 Narcotics and narcotic containing analgesics, including tramadol 
 Iron supplements (with the exception of multivitamins containing Iron and those 
individuals on a stable dose for > 30-days prior to screening period of Iron 
supplements) 
 NSAIDS  (if used more than 3 days per week); Aspirin ≤ 325 mg per day is allowed 
 All other analgesics (if used more than 3 days per week) 
 Anti-Parkinson agents (e.g. levodopa, deprenyl) 
 Antipsychotics, allowed if on a stable dose for > 30-days prior to screening period 
 Anticonvulsants used for seizure disorders 
 Antidepressants, allowed, if on a stable dose for > 30-day prior to screening period 
 Stimulants and amphetamine-like drugs 
 Misoprostol, alone or in combination 
 Lubiprostone (Amitiza®) or Linaclotide (Linzess®) 
5.7. Removal of Subjects from Therapy or Assessment 
Subjects will be discontinued from the study if any of the following conditions apply: 
1. A subject experiences a study drug related serious adverse event.   
2. A subject experiences severe diarrhea defined by a Bristol Stool Form Score 
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(Appendix B) of ≥ 6 and stool frequency ≥ 7/day (Common Terminology 
Criteria for Adverse Events [CTCAE] v4.0, Grade 3) for 2 consecutive days. 
Subjects will be informed that they have the right to withdraw from the study at any 
time for any reason, without prejudice to their medical care.  The Investigator may 
remove a subject if he/she feels this action is in the best interest of the subject.   
When a subject withdraws from the study, all of the necessary safety and tolerability 
assessments as described for Visit 8 should be obtained.  Subjects experiencing 
adverse reactions should be followed until the reaction has resolved or is clearly 
determined to be due to a subject’s stable or chronic condition.  Appropriate 
supportive and/or definitive therapy will be administered as required. 
Subjects will not be replaced.   
The reason(s) for a subject’s withdrawal from the study and their final assessments 
are to be recorded on the appropriate electronic case report form (eCRF) page.   
6. 
TREATMENTS 
6.1. Identity of Investigational Product  
Tenapanor (as the dihydrochloride salt) drug product will be supplied as white to off-
white oval biconvex film-coated tablets.. Matched placebo tablets will also be 
provided.   
6.2. Packaging, Storage, and Labeling 
The study drug will be supplied in white square HDPE bottles with child resistant 
polypropylene CRC closures with an induction seal plus desiccants.  Each bottle will 
contain sixty-six (66) tablets. 
Tenapanor and placebo tablets should be stored in the original packaging between 
2°C and 30°C. Temperature excursions are allowed from -30°C to 50°C excursions 
for a maximum of 1 week. 
Each bottle will be labeled with a single panel, double blind label.   
6.3. Treatments to be Administered 
Study drug will be dispensed only to eligible subjects under the supervision of the 
Investigator or identified sub-Investigator(s).  Eligible subjects will be randomized 
1:1 into one of two treatment groups: tenapanor 50 mg BID or placebo BID.  Subjects 
will take one tenapanor tablet or one matching placebo tablet twice daily, 
immediately prior to breakfast or the first meal of the day and immediately prior to 
dinner.   
Subjects will receive a 4-week supply of drug at Visit 2 (Day 1), Visit 4 (Day 29 ± 3), 
Visit 5 (Day 57 ± 3 days) and Visit 6 (Day 85 ± 3 days).  At Visits 4, 5, 6, and 8 (Day 
113 ± 3 days) the subject will be asked to return their unused drug and bottles.  All 
unused study drug and bottles should be returned to the study site.  Study drug 
compliance will be monitored closely by the clinical site staff and will be verified by 
the study monitor during on-site monitoring visits. 
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6.4. Randomization and Blinding 
Both randomization and blinding techniques will be used in this study to minimize 
bias.  Randomization will occur twice; at Visit 2 for the 12-week treatment phase and 
at Visit 6 for the 4-week randomized withdrawal period.  A computer generated 
randomization schema will be centrally available via an interactive web response 
system (IWRS) to all clinical centers that meet the requirements for participation in 
the study.  The IWR system can be accessed by a computer by individuals that have 
been issued a user ID and password.   
In order to double-blind the study, the study drug is labeled in a manner to ensure that 
neither investigators nor subjects can distinguish between treatment groups.   
In the case of a medical emergency where, in the Investigator’s judgment, the 
subject’s safety may be compromised without immediate knowledge of the exact 
treatment received, the Investigator can contact the IWRS help desk.   
All reasonable effort should be made to reach the Medical Monitor prior to 
unblinding.  If the treatment is unblinded, the Investigator should immediately 
contact: 
 
 
 
 
 
 
 
 
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7. 
SCHEDULE OF ASSESSMENTS 
The study flow chart, including all procedures to be performed during the study is presented below.  Prior to engaging in any study 
procedure, each subject must sign and date an informed consent form. 
 
 
Evaluation 
Screen 
Treatment Period 
RW Period 
Site Visit 
1 
2 
3 
4 
5 
6 
7 
8/ETh 
Study Day(s) 
-14 
1±3 
15±3 
29±3 
57±3 
85±3 
99±3 
113±3 
Informed Consenta 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History (including GI history) 
X 
Xb 
 
 
 
 
 
 
Prior/Concurrent Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
X 
 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
Height   
X 
 
 
 
 
 
 
 
Safety Laboratories 
X 
 
 
X 
 
X 
 
X 
Pharmacogenomics blood sampleg 
 
 
 
Xg 
 
Xg 
 
Xg 
Biomarker sample 
X 
 
 
 
 
X 
 
X 
FSH testd 
X 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
Urine Pregnancy testd 
X 
X 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
X 
 
X 
 
X 
12-lead electronic ECG 
X 
 
 
 
 
X 
 
X 
IVRS Training/Compliance Check & Reminder 
X 
X 
X 
X 
X 
X 
X 
 
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Evaluation 
Screen 
Treatment Period 
RW Period 
Site Visit 
1 
2 
3 
4 
5 
6 
7 
8/ETh 
Study Day(s) 
-14 
1±3 
15±3 
29±3 
57±3 
85±3 
99±3 
113±3 
IBS-QOL PRO 
 
X 
 
 
 
X 
 
X 
Treatment Satisfaction PRO 
 
 
 
X 
X 
X 
 
X 
Randomization  
 
X 
 
 
 
 
 
 
Randomization #2f 
 
 
 
 
 
X 
 
 
Daily PROse 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispensed/returned 
 
D 
 
D/R 
D/R 
D/R 
 
R 
Adverse Event Assessments 
 
 
X 
X 
X 
X 
X 
X 
aThe Informed Consent Form (ICF) must be signed before any study procedures are performed; The ICF may be signed before the 
Screening Visit. 
bMedical history for Visit 2; record only changes to Medical history from Visit 1. 
cVital signs include systolic and diastolic blood pressure (seated), heart rate, respiratory rate, temperature and body weight. 
dFSH is performed in post-menopausal women (at screening only);  pregnancy tests are performed on all females <60 years of age 
unless there is a documented method of sterilization, or FSH test confirms post-menopausal status. A positive urine pregnancy test 
will be verified with a serum pregnancy test.  
eDaily Patient Reported Outcomes will be collected via a phone diary and will include the following: frequency and time of each 
Bowel Movement (BM), sensation of complete bowel emptying, stool consistency (BSFS) of each BM, straining, abdominal pain, 
abdominal discomfort, abdominal bloating, abdominal fullness, abdominal cramping, use of and time of rescue medication, IBS 
severity (weekly), constipation severity (weekly), adequate relief of IBS symptoms (weekly, after randomization), degree of relief of 
IBS symptoms (weekly, after randomization). 
fAll subjects receiving Placebo will be switched to tenapanor 50 mg BID; Subjects receiving tenapanor 50 mg BID will be 
randomized 1:1 to receive either tenapanor 50 mg BID or Placebo 50 mg BID. 
gThe pharmacogenomics sample is optional and requires subject to specify acceptability on the informed consent. If a subject opts in, 
the blood sample can be taken at any one visit after randomization with a scheduled blood draw (Visit 4, 6, or 8). 
hProcedures described for Visit 8/ET (Early Termination) should be performed on all subjects who withdraw early from the study, if 
possible.
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8. 
STUDY EVALUATIONS 
The assessments to be performed during the study are outlined by study period, visit 
and study day below.  The day of randomization begins the clock for all subsequent 
visit days and dates.   
8.1. Pre-Screening and Screening Period Procedures 
Pre-screening may be performed using a telephone questionnaire/script to ascertain 
preliminary subject eligibility.  Potential subjects will be questioned with regard to 
their relevant medical history, GI history, current symptoms, and ability and interest 
in participating in a clinical trial.   
Each subject must sign and date an informed consent form prior to engaging in any 
study specific procedures. 
8.1.1 Evaluations and procedures at Visit 1 (Day –14) 
The procedures outlined for Visit 1 must be completed prior to enrolling the subject 
into the study.  The following procedures will be conducted at Visit 1: 
 Informed Consent (must be signed prior to discontinuing any prohibited 
medications or prior to the conduct of any study-related procedure) 
 Inclusion/Exclusion Criteria 
 Demographics 
 Medical History, including IBS-C history 
 Prior and Concomitant Medications 
 Physical Exam 
 Vital Signs 
 Height 
 Safety Laboratories 
 Biomarker sample 
 FSH Test, as appropriate 
 Serology 
 Urine Pregnancy Test 
 Urinalysis 
 ECG 
 Subjects will be instructed on the use of the telephone diary and begin 
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calling into the diary the evening of Visit 1 (Day -14) 
 Subjects will be instructed to discontinue the use of all prohibited 
medications as outlined in Section 5.6.   
8.1.2 Daily Patient Reported Outcomes (PRO) (Day –14 through Day 113)  
Subjects must assess their IBS symptoms daily via the touch-tone telephone diary 
system between 6PM and 11:59PM (local time): 
 Frequency and time of each Bowel Movement (BM) 
The following characteristics of each BM 
 Sensation of complete bowel emptying 
 Stool consistency (BSFS) of each BM 
 Severity of straining for each BM 
 Abdominal pain 
 Abdominal discomfort 
 Abdominal bloating 
 Abdominal fullness 
 Abdominal cramping 
 Use of and time of rescue medication 
 IBS severity (weekly) 
 Constipation severity (weekly) 
 Adequate Relief of IBS Symptoms (weekly, after randomization) 
 Degree of Relief of IBS Symptoms (weekly, after randomization) 
8.2. Treatment Period Procedures 
Each subject must meet the eligibility requirements as outlined in Sections 5.2, 5.3 
and 5.4 of this protocol prior to being randomized into the treatment phase of the 
study.   
8.2.1 Evaluations and procedures at Visit 2 (Day 1 ± 3) 
Prior to the subjects' return to the clinic for Visit 2, a member of the site staff will 
confirm the subjects’ eligibility in the IWR system.  At Visit 2, prior to 
randomization, the following tests/procedures will be performed and questionnaires 
completed.  After randomization, study drug will be dispensed. 
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 Inclusion/Exclusion Criteria (confirm eligibility) 
 Medical History (changes since last visit) 
 Concomitant Medications (changes since last visit) 
 Vital signs 
 Urine pregnancy test 
 IBS-QOL PRO 
 Randomization 
 Drug Dispensed 
8.2.2 Evaluations and procedures at Visit 3 (Day 15 ± 3)  
 Vital Signs 
 Adverse Events 
 Concomitant Medications (changes since last visit) 
8.2.3 Evaluations and procedures at Visit 4 (Day 29 ± 3) 
 Vital Signs 
 Safety Laboratories 
 Pharmacogenomics blood sample (if consented) 
 Urine Pregnancy Test 
 Urinalysis 
 Adverse Events 
 Concomitant Medications (changes since last visit) 
 Treatment Satisfaction PRO 
 Drug Returned 
 Drug Dispensed 
8.2.4 Evaluations and procedures at Visit 5 (Day 57 ± 5) 
 Vital Signs 
 Adverse Events 
 Concomitant Medications (changes since last visit) 
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 Treatment Satisfaction PRO 
 Drug Returned 
 Drug Dispensed 
8.2.5 Evaluations and procedures at Visit 6 (Day 85 ± 5) 
See Sections 8.3 and 8.3.1 for  Randomized Withdrawal procedures to occur at the 
end of the procedures described below for Visit 6. 
 Vital Signs 
 Physical Exam 
 Safety Laboratories 
 Pharmacogenomics blood sample (if consented and not performed yet) 
 Biomarker sample 
 Urine Pregnancy Test 
 Urinalysis 
 ECG 
 Adverse Events 
 Concomitant Medications (changes since last visit) 
 IBS-QOL PRO 
 Treatment Satisfaction PRO 
 Drug Returned 
8.3. Randomized withdrawal (RW) period procedures 
Each subject completing the 12-week treatment period will enter into a 4-week 
randomized withdrawal (RW) period.  Subjects who were receiving placebo will be 
given tenapanor 50 mg BID.  Subjects who were receiving tenapanor 50 mg BID will 
be randomized via IWRS in a double blind manner to receive either tenapanor 50 mg 
BID or placebo BID for four weeks.  Subjects are expected to continue to record daily 
and weekly diary information during this time 
8.3.1 Evaluations and procedures at Visit 6 (Day 85 ± 5) – RW Period 
 Randomization #2 via IWRS 
 Drug Dispensed 
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8.3.2 Evaluations and procedures at Visit 7 (Day 99 ± 5) – RW Period 
 Vital Signs 
 Adverse Events 
 Concomitant Medications (changes since last visit) 
8.3.3 Evaluations and procedures at Visit 8 (Day 113 ± 5) – RW Period 
 Vital Signs 
 Physical Exam 
 Safety Laboratories 
 Pharmacogenomics blood sample (if consented and not performed yet) 
 Biomarker sample 
 Urine Pregnancy Test 
 Urinalysis 
 ECG 
 Adverse Events 
 Concomitant Medications (changes since last visit) 
 IBS-QOL PRO 
 Treatment Satisfaction PRO 
 Drug Returned 
8.4. Safety and Efficacy Assessments 
8.4.1 Safety Assessments 
Safety assessments will be based on adverse events, clinical laboratory tests,  vital 
signs, ECG, and physical examinations,.   
Incidence of adverse events and clinically significant abnormal laboratory values will 
be determined at the completion of the study.  This study will help characterize the 
safety and tolerability profile of tenapanor 50 mg BID in IBS-C subjects.   
Safety assessments are described below.   
8.4.1.1 Adverse events 
Monitoring of treatment emergent adverse events will be conducted throughout the 
study beginning on Day 1 (Randomization).  Adverse events, including serious 
adverse events will be recorded in the eCRFs through the end of the 4-week 
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randomized withdrawal (RW) period.  All adverse events should be followed by the 
investigator until they are resolved or are clearly determined to be due to a subject’s 
stable or chronic condition or concurrent illness(es).  Definitions, documentation, and 
reporting of adverse events are described in detail in Section 9.   
8.4.1.2 Medical history and physical examination 
An abbreviated medical history will be obtained over the telephone at the time of the 
prescreening questionnaire (if performed) for the purpose of determining eligibility.  
A full medical history will be taken at Screening during Visit 1.  A complete physical 
examination will be conducted during Visits 1, 6 and 8.   
8.4.1.3 Electrocardiogram 
A 12-lead electrocardiogram will be obtained during Visits 1, 6 and 8. 
8.4.1.4 Vital signs 
Vital signs, including heart rate, respiratory rate, sitting systolic and diastolic blood 
pressure (SSBP, SDBP), temperature, and body weight will be obtained at all Visits.   
8.4.1.5 Clinical laboratory tests 
A central laboratory will perform clinical laboratory tests.  Blood samples will be 
drawn from subjects for serum chemistries and hematology at Visits 1, 4, 6 and 8.  
Urine will be taken for urinalysis at Visits 1, 2 (pregnancy test only), 4, 6, and 8.  A 
FSH test will be performed, as appropriate at Visit 1.  See Appendix C for specific 
laboratory tests.   
Clinical laboratory test values that are considered abnormal will be noted as clinically 
significant or non-clinically significant by the site investigator.  Clinical laboratory 
test values that are out of the normal limits are considered to be abnormal.   
Handling and shipment of clinical laboratory samples will be outlined in the Lab 
Manual.   
8.4.2 Efficacy Assessments 
Subjects will report efficacy assessments via an interactive voice response system 
(IVRS) utilizing a touch-tone telephone.  Efficacy assessments will be collected daily 
and weekly, unless otherwise specified, from the beginning of the screening period 
through the end of the randomized withdrawal period.  The daily questions will 
include information about bowel movement frequency, completeness of bowel 
emptying, stool consistency, straining, abdominal pain, abdominal discomfort, 
abdominal bloating, abdominal fullness, abdominal cramping, and use of rescue 
medications.  IBS severity and constipation severity will be collected weekly during 
the screening, treatment, and randomized withdrawal periods. Adequate relief of IBS 
symptoms and degree of relief of IBS symptoms will be collected weekly during the 
treatment and randomized withdrawal periods.  Treatment satisfaction (Visits 4, 5, 6, 
and 8) and IBS-QOL (Visits 2, 6, and 8) will also be evaluated during the subjects' 
site visit. 
A script detailing the IVRS diary questions and scales will be supplied to the clinical 
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site and to the subjects in the form of written subject information material.  The 
following questions will be asked to all subjects on a daily or weekly basis during the 
screening, treatment and randomized withdrawal periods.  
8.4.2.1 Abdominal Pain 
“How would you rate your worst abdominal pain over the past 24 hours? Please use 
the scale where 0 represents no abdominal pain and 10 represents very severe 
abdominal pain. Please enter a value between 0 and 10 followed by pound or hash 
sign.” 
8.4.2.2 Abdominal Discomfort 
“How would you rate your abdominal discomfort over the past 24 hours? Please use 
the scale where 0 represents no abdominal discomfort and 10 represents very severe 
abdominal discomfort.  Please enter value between 0 and 10 followed by pound or 
hash sign.” 
8.4.2.3 Abdominal Bloating 
“How would you rate your abdominal bloating over the past 24 hours? Please use the 
scale where 0 represents no abdominal bloating and 10 represents very severe 
abdominal bloating. Please enter a value between 0 and 10 followed by pound or hash 
sign.” 
8.4.2.4 Abdominal Cramping 
“How would you rate your abdominal cramping over the past 24 hours? Please use 
the scale where 0 represents no abdominal cramping and 10 represents very severe 
abdominal cramping. Please enter a value between 0 and 10 followed by pound or 
hash sign.” 
8.4.2.5  Abdominal Fullness 
“How would you rate your abdominal fullness over the past 24 hours? Please use the 
scale where 0 represents no abdominal fullness and 10 represents very severe 
abdominal fullness. Please enter a value between 0 and 10 followed by pound or hash 
sign.” 
8.4.2.6 Bowel Movement Frequency 
“How many bowel movements have you had in the past 24 hours?” 
8.4.2.6.1 Timing 
 “Please enter the time of bowel movement <number> using the 12 hour AM/PM 
format.” 
“For AM press 1, for PM press 2.” 
8.4.2.6.2 Sensation of Complete Bowel Emptying (For each bowel movement) 
“Did you feel like you completely emptied your bowels? For yes press 1 for no press 
2.” 
8.4.2.6.3 Stool Consistency using BSFS (Appendix B) (For each bowel movement) 
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“Refer to the Bristol Stool Form Scale given to you.  Please enter the number that 
best describes the consistency of bowel movement <number> following the scale:  
Press 1 for separate hard lumps, like nuts (hard to pass) 
Press 2 for sausage shaped but lumpy 
Press 3 for like a sausage but with cracks on its surface 
Press 4 for like a sausage or a snake, smooth and soft 
Press 5 for soft blobs with clear cut edges (passed easily) 
Press 6 for fluffy pieces with ragged edges, a mushy stool 
Press 7 for watery, no solid pieces (entirely liquid)”   
8.4.2.6.4 Straining (For each bowel movement) 
“How much did you strain during the bowel movement? Please use the following 
scale.  Press 1 for not at all. Press 2 for a little bit. Press 3 for a moderate amount. 
Press 4 for a great deal. Press 5 for an extreme amount.” 
8.4.2.7 Rescue medication 
If diary was completed the previous day “Have you taken any rescue medication 
over the past 24 hours? For yes press 1, for no press 2.”  
If diary was NOT completed the previous day “Have you taken any rescue 
medication over the past 48 hours? For yes press 1, for no press 2.”  
If yes. “Please enter the date you took the rescue medication, using the 8 digit format; 
2 digits for the month, 2 digits for the day and 4 digits for the year.” 
“Please enter the time you took rescue medication, using a 12 hour AM/PM format.” 
“For AM press 1, for PM press 2” 
The following questions will be asked once at the end of each week; when these 
questions are asked they will be the first questions asked to the subjects 
8.4.2.8 IBS Severity (weekly) 
“How would you rate the severity of your IBS over the past week?  Please use the 
following scale. Press 1 for None.  Press 2 for Mild. Press 3 for Moderate.  Press 4 for 
Severe. Press 5 for Very Severe.” 
8.4.2.9  Constipation Severity (weekly) 
“How would you rate the severity of your constipation over the past week?  Please 
use the following scale. Press 1 for None. Press 2 for Mild. Press 3 for Moderate. 
Press 4 for Severe. Press 5 for Very Severe.” 
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8.4.2.10 
Adequate Relief of IBS Symptoms (weekly) 
“Have you had adequate relief of your IBS symptoms over the past week?  Press 1 for 
Yes.  Press 2 for No.” 
8.4.2.11 
Degree of Relief of IBS Symptoms (weekly) 
“How would you rate the degree of relief of your IBS symptoms over the past week? 
Please use the following scale. Press 1 for Completely relieved. Press 2 for 
Considerably relieved. Press 3 for Somewhat relieved. Press 4 for Unchanged. Press 5 
for Somewhat worse. Press 6 for Considerably worse. Press 7 for As bad as I can 
imagine.” 
8.4.2.12 
Treatment Satisfaction (completed at site, not IVRS) 
At visits 4, 5, 6, and 8, subjects will be questioned about their overall satisfaction 
with the study drug’s ability to relieve IBS; with the following possible answers: 1= 
not at all satisfied, 2= a little satisfied, 3= moderately satisfied, 4 =quite satisfied, 5= 
very satisfied 
8.4.2.13 
Irritable Bowel Syndrome - Quality of Life (IBS-QOL) (completed at 
site, not IVRS) 
On Day 1 (Visit 2), after randomization, and at Visits 6 and 8 (Day 85, at the end of 
the treatment period; and Day 113, at the end of the randomized withdrawal period), 
subjects will be questioned about their quality of life.  The IBS-QOL (see Appendix 
D) measures 10 domains found to be relevant to patients with irritable bowel 
syndrome: emotional health, mental health, health belief, sleep, energy, physical 
functioning, diet, social role, physical role, and sexual relations.  The IBS-QOL 
consists of 34 questions. 
8.5. Total Blood Volume Required for Study 
Table 8-1 
Approximate Blood Volume per Subject 
Test 
Number of Samples 
Volume (mL) 
Total (mL) 
Serology (serum) 
1 
5 
5 
Hematology (blood) 
4 
3 
12 
Chemistry (serum) 
4 
7 
28 
Biomarker (seum) 
3 
7 
21 
Pharmacogenomics sample (blood) 
1 
7 
7 
Total 
13 
-- 
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8.6. Data Quality Assurance 
This clinical trial will be monitored according to current Ardelyx Standard Operating 
Procedures (SOP) or its CRO designee’s SOP.  Steps to be taken to assure the 
accuracy and reliability of data include the selection of qualified Investigators and 
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appropriate study sites, review of protocol procedures and the administration of 
informed consent with the Investigator and associated site personnel prior to study 
start, and periodic monitoring visits by Ardelyx personnel or its CRO designee.  
During the trial, the Investigator shall permit Ardelyx or its CRO designee to verify 
the progress of the trial on site as frequently as necessary.  Qualified personnel will 
review case report form data for accuracy and completeness against source 
documents during on-site monitoring.  Data discrepancies will be resolved with the 
Investigator or designees, as appropriate.  The Investigator shall make the eCRFs and 
source documents available, provide missing or corrected data and sign the eCRFs.  
After Ardelyx personnel, or its CRO designee, receive the CRFs, data management 
personnel will review the forms for completeness, logical consistency and safety. The 
eCRF must be amended after any inconsistencies found at this review have been 
resolved.  No personal information will be recorded on the eCRFs in accordance with 
HIPAA regulations.   
An independent Quality Assurance (QA) department, Ardelyx designees and/or 
regulatory authorities may review this trial.  This implies that auditors/inspectors will 
have the right to inspect the trial center(s) at any time during and/or after completion 
of the trial and will have access to source documents, including the subject's file.  By 
participating in this trial, Investigators agree to this requirement.  Measures will be 
undertaken to protect subject data handed over by the Investigator to Ardelyx and to 
inspectors against disclosure to unauthorized third parties and subject confidentiality 
will be maintained at all times. 
9. 
ADVERSE EVENTS 
9.1. Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject administered 
a pharmaceutical product, whether or not the occurrence has causal relationship with 
this treatment.  An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered 
related to the investigational product.  This includes any newly occurring event or 
previous condition that has increased in severity or frequency since the administration 
of the investigational product.   
Worsening of IBS symptoms is not considered an adverse event unless the frequency 
and/or severity of the symptom(s) is outside of what the subject considers normal for 
their IBS.   
9.2. Severity 
The term “severe” is used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction).  Even though the event itself may 
be of relatively minor medical significance (such as a severe headache), this is not the 
same as “serious,” which is based on subject/event outcome or action criteria as 
described above and are usually associated with events that pose a threat to a 
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subject’s life or functioning.  A severe adverse event is not necessarily serious.  For 
example, persistent nausea of several hours duration may be considered severe nausea 
but not meet the definition of a SAE.  On the other hand, a stroke resulting in only a 
minor degree of persistent disability may be considered mild, but would be defined as 
a SAE based on the above noted criteria.  Seriousness (not severity) serves as a guide 
for defining regulatory reporting obligations. 
For both serious and non-serious adverse events, the Investigator must determine the 
severity of the event using the following definitions: 
Mild 
The event does not interfere in a significant manner with the subject’s 
normal functioning level.  It may be an annoyance but does not cause any 
limitation in usual activity.   
Moderate The event produces some impairment of functioning but is not hazardous 
to health.  It is uncomfortable or an embarrassment and may cause some 
limitation in usual activity.   
Severe 
The event produces significant impairment or incapacitation and is a 
definite hazard to the subject’s health.   
9.3. Unexpected Adverse Drug Experience 
An unexpected adverse experience is any adverse drug experience, the specificity or 
severity of which is not consistent with the current Investigator’s Brochure, or if an 
Investigator’s Brochure is not required or available, which is not consistent with the 
risk information described in the general investigational plan or elsewhere in the 
current application, as amended.  “Unexpected,” as used in this definition refers to an 
adverse drug experience that has not previously been observed (e.g., included in the 
Investigator’s Brochure) rather than from the perspective of such an experience not 
being anticipated from the pharmacological properties of the pharmaceutical product.   
9.4. Causality 
Association of adverse events to the study drug will be made using the following 
definitions:   
Not related: The event is most likely produced by other factors such as the subject’s 
clinical condition, intercurrent illness, or concomitant drugs, and does not follow a 
known response pattern to the study drug, or the temporal relationship of the event to 
study drug administration makes a causal relationship unlikely 
Possibly-related: The event follows a reasonable temporal sequence from the time of 
drug administration, and/or follows a known response pattern to the study drug, but 
could have been produced by other factors such as the subject’s clinical condition, 
intercurrent illness, or concomitant drugs  
Probably-related: The event follows a reasonable temporal sequence from the time 
of drug administration, and/or follows a known response pattern to the study drug, 
and cannot be reasonably explained by other factors such as the subject’s clinical 
condition, intercurrent illness, or concomitant drugs.  
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9.5. Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence, that at any 
dose, regardless of causality: 
 results in death. 
 is life-threatening.  Life threatening means that the subject was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form might have 
caused death.   
 requires in-patient hospitalization or prolongation of existing 
hospitalization.  Hospitalization admissions and/or surgical operations 
scheduled to occur during the study period, but planned prior to study 
entry are not considered AEs if the illness or disease existed before the 
subject was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
 results in persistent or significant disability/incapacity.  Disability is 
defined as a substantial disruption of a persons’ ability to conduct normal 
life functions.   
 is a congenital anomaly/birth defect.   
 An important medical event that may not result in death, be life-
threatening, or require hospitalization but may be considered a SAE when, 
based upon appropriate medical judgment, it may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of SAE.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not 
result in in-patient hospitalization, or the development of drug dependency 
or drug abuse. 
9.6. Procedures for Recording and Reporting AEs and SAEs 
Adverse events, both serious and non-serious, will be reported between Day 1 
(Randomization) and the final visit (up to Day 113, Visit 8).  Medical events that 
occur between the signing of the informed consent and the first dose of study drug 
will be documented as part of the subject’s medical history and recorded on the 
appropriate eCRF page.   
All adverse events spontaneously reported by the subject and/or in response to an 
open question from study personnel or revealed by observation, physical examination 
or other diagnostic procedures will be recorded on the appropriate page of the eCRF.  
Any clinically relevant deterioration in laboratory tests or other clinical finding is 
considered an adverse event and must be recorded on the appropriate pages of the 
eCRF.  When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event or diagnosis. 
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All serious adverse events occurring during the course of the study must be 
reported by email, or fax immediately to:   
 
 
 
 
In no event shall a SAE be reported more than twenty-four (24) hours after the 
Investigator becomes aware of such event.  The report of an SAE by the 
Investigator must provide the following minimal information: protocol number, 
subject number, subject’s initials and date of birth, nature of the adverse event and 
attributes such as the severity of the event and causality.  Events will be considered 
suspected adverse drug reactions if classified by the Investigator as possibly-related 
or probably-related. 
A report of a SAE by telephone must always be confirmed by a written, more detailed 
report within 24 hrs of the Investigator becoming aware of the event.  The SAE 
Reporting Forms are provided to each clinical study site in the Study Manual.  The 
Investigator should provide the following documentation at the time of notification, if 
available: 
SAE Reporting Form 
Concomitant and support medication pages; 
Relevant diagnostic reports; 
Relevant laboratory reports; 
Admission notes; if applicable 
Hospital discharge summary; if applicable 
 
  
It is the responsibility of the Investigator to promptly notify the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) of all SAEs, as well as any 
unanticipated problems that involve significant risk to subjects.  A copy of the 
IRB/IEC notification should be placed in the sites’ regulatory binder.   
9.7. Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, will be recorded on the eCRFs up to 
and including the final visit (Day 113, Visit 8).  All adverse events should be 
monitored until they are resolved or are clearly determined to be due to a subject’s 
stable or chronic condition or concurrent illness(es).   
Follow-up data concerning the SAE (e.g., diagnostic test reports, physician's 
summaries, etc.) must also be submitted to the Sponsor as they become available, 
preferably by facsimile.  All serious adverse events, as well as any unanticipated 
problems that involve significant risk to subjects, must be promptly reported by the 
Investigator to his/her Institutional Review Board (IRB).  Should the FDA or other 
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pertinent regulatory authorities require that Ardelyx submit additional data on the 
event, the Investigator will be asked to provide those data to Ardelyx in a timely 
fashion.   
The Investigator will review each serious adverse event report and further evaluate 
the relationship of the adverse event to the study drug and to the subject’s underlying 
disease.  Based on the Investigator assessment of the adverse event, a decision will be 
made concerning the need for further action.  The primary consideration governing 
further action is whether new findings affect the safety of other subjects participating 
in the clinical study.  If the discovery of a serious and unexpected adverse event 
related to the study drug raises concern over the safety of its continued administration 
to subjects, the Sponsor will take immediate steps to notify the FDA and other 
pertinent regulatory authorities and all Investigators participating in clinical studies of 
the study drug.   
Any serious adverse event that occurs at any time after completion of the study, 
which the Investigator considers to be related to study drug, must be reported to 
Ardelyx within forty-eight (48) hours of the Investigator becoming aware of the 
event. 
9.8. Pregnancy 
Pregnancy by definition is not considered to be a serious adverse event unless the 
pregnancy or the outcome meets the criteria in Section 9.5..  However, pregnancy in 
subjects that have received the study drug must be followed to assess congenital 
anomalies.   
10. 
STATISTICAL CONSIDERATIONS 
This is a Phase 3, multi-center, randomized, double-blind, placebo controlled study of 
tenapanor in subjects with IBS-C.  Treatment to be administered consists of two 
treatment groups: placebo and tenapanor 50 mg twice daily (BID, total daily dose of 
100 mg) for 12 consecutive weeks. At the end of the treatment period there will be a 
4-week randomized withdrawal (RW) period in which all subjects in the placebo arm 
will be given tenapanor 50 mg BID and subjects in the tenapanor arm will be 
randomized 1:1 to receive either placebo or tenapanor 50 mg BID; this will be 
performed in a double-blind manner.  At least 600 subjects will be enrolled at 
approximately 100-120 US clinical centers.  Each center is expected to enroll 
approximately six (6) subjects, however, enrollment is competitive and centers will 
be allowed to enroll subjects beyond the expected site projection.   
A formal statistical analysis plan (SAP) will be developed, finalized, and signed-off 
on prior to the database lock and unblinding of treatment assignment.  It is anticipated 
that the SAP will be submitted prior to the first subject being enrolled in the study. 
This plan will confirm the analysis sets used in the analysis, outline all data handling 
conventions, and specify all statistical methods to be used for all safety and efficacy 
analyses. The SAP will pre-specify exploratory and sensitivity analyses as additions 
to analyses included in the protocol.  In particular, the primary analysis and key 
secondary analyses will remain the same. If after the data has been unblinded and 
additional analyses are implemented or planned analyses are changed, such deviations 
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will be documented in the clinical study report. Any implications for the 
interpretation of the trial results will be addressed.  A set of table, listing, and figure 
shells will also be part of this plan for internal use .  Any changes to the statistical 
considerations described in Section 10 of this protocol will be addressed in the SAP 
and will not be part of a protocol amendment. 
10.1. Determination of Sample Size 
A sample size of 300 in each treatment group would achieve 95% power to detect a 
difference of 0.15 (15%) between the placebo and tenapanor 50 mg BID 6/12 week 
overall responder rate when the tenapanor 50 mg BID responder rate is at least 45% 
under the alternative hypothesis and the responder rate in the placebo group is no 
closer than 15% from tenapanor 50 mg BID.  The test statistic used was the two-sided 
Fisher's exact test with significance level of 0.050 (5%).  This sample size also has 
80% power to detect an 11.6% difference in responder rates between the treatment 
groups when the responder rates are in the same range as above.  
10.2. Randomization and Stratification 
A computer generated randomization schema will be made available centrally to all 
clinical centers that meet the requirements for participation in the study via an 
interactive web response system (IWRS).  The IWRS can be accessed with a 
computer by individuals with a study-issued user ID and password implemented to 
limit access and document a user log.  The packaging and labeling of the study drug 
kits will be based on a separate drug packaging randomization schedule.  Upon 
satisfaction of the eligibility criteria, study site personnel will call into the IWRS and 
obtain permission to randomize the subject.  The IWRS will determine which drug 
package for the site to administer to the subject based on a randomization schedule 
where each treatment is allocated once using a block size of 4 within each study site. 
Hence, randomization will be stratified by study site with each study site ending up 
with whole and/or partial block sizes randomized.   
10.3. Analysis Sets 
Safety Analysis Set: 
All subjects who receive at least one dose of study drug will be included in all 
analyses of safety data.  Such subjects will be analyzed according to the treatment 
actually received. 
Intent to Treat (ITT) Analysis Set: 
All subjects who meet the study entry inclusion/exclusion criteria, receive at least one 
dose of study drug, and have at least one valid week of efficacy assessment data 
(minimum of 4 days) will be included in the ITT analysis set.  Subjects will be 
analyzed according to the treatment group into which they were randomized.  The 
ITT analysis set will be the primary analysis set for efficacy analysis. 
10.4. Procedures for Handling Missing Data 
      The primary analysis will be based on the observed data where weekly SBMs and 
CSBMs will be standardized to 7-day frequencies. This amounts to missing days 
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during the week being imputed with the mean for the non-missing days.  A valid 
week will require at least 4 non-missing diary days. Hence, for the primary analysis, 
weeks with less than 4 diary days are treated as a non-responder for that week.  To 
further assess the impact of missing weeks on the efficacy analyses, a sensitivity 
analysis will be carried out by treating weeks with less than 4 diary days as a 
responder for that week. 
 
    The valid week rule will also apply for stool consistency and straining score although it 
is assumed that if the diary was filled out for frequency of stools, it would also be 
filled out with respect to these items. However, the average weekly stool consistency 
and the average weekly straining score will be calculated on the observed number of 
responses without any standardization. For the purposes of calculating an average, 
days with no stools reported (i.e., a 0 was recorded for the answer to IVRS question 
6) will be scored as 0 for average weekly stool consistency and average weekly 
straining score. 
 
      An endpoint week will be defined as the last valid week during the 12-week treatment 
period where each weekly efficacy variable was obtained.  This amounts to creating 
an endpoint last observation carried forward such that each subject’s endpoint value 
represents the last experience while receiving study drug.  
 
      Otherwise, all other observed data will be used in the analyses. 
10.5. Methods of Pooling Data 
      For the purpose of adjusting for investigator effects in statistical models, investigator 
sites will be pooled into groups based on geographic region and number of subjects 
enrolled with an aim for comparable sample sizes among pooled investigator sites. 
The goal of the pooling strategy will be to avoid less than a minimum number of 
subjects per pooled investigator site.  The size of a pooled investigator site would 
generally not be larger than the total number of subjects enrolled at the highest 
enrolling individual investigator site. The pooled investigator sites will be used in all 
applicable analyses where adjustment for investigator effect is desired.  
 
Based on an average of 6 subjects per site to be enrolled, the primary pooled 
investigator site strategy will target 10 pools of approximately 60 subjects each 
(approximately 30 per treatment group per pooled investigator site). As a sensitivity 
analysis, a second pooling will have a target of 20 pools of approximately 30 subjects 
each (approximately 15 per treatment group per pooled investigator site). The actual 
designation of membership in a pooled investigator site cannot be made until the final 
enrollment quantities and final number of sites used is completed. The final pooling 
strategy will be defined before treatment unblinding, and will be provided as an 
addendum to the SAP. The goals stated above will be adhered to as closely as 
possible.  
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10.6. Visit Windows 
      Daily IVRS diary data are planned for daily collection starting on the day of the 
Screening visit and continuing until the planned Week 16 (Visit 8 Day 113) RW visit. 
 
      Weekly IVRS diary data are planned for each week of the 2-week screening period 
(when applicable), each week of the 12-week treatment period, and each week of the 
4-week RW period.  
 
      For all IVRS efficacy data, the date collected will be used to calculate a relative study 
day (Rel Day). The relative study day will be calculated as the number of days from 
the day of first dose. The date of the first dose date is Day 1. The preceding day is 
Day -1, the day before that is Day -2, etc. There is no Day 0. 
 
      Actual study periods will be defined as follows for the purposes of the efficacy 
evaluations: 
 
 Screening/Baseline Period (Rel Days -14 through Day -1): For the average weekly 
CSBMs, average weekly SBMs, average weekly stool consistency, average weekly 
straining score, and average weekly abdominal symptom score (pain, discomfort, 
bloating, cramping, and fullness), the most recent 7 days will be used to calculate 
Week -1 values (i.e., days -1 through -7) and remaining days will be used for Week -2 
calculations (i.e., day -8 through -14 or more if applicable). The baseline for these 
variables will then be based on the average of the week -2 and week -1 values. While 
the screening period may vary somewhat from 14 days, it will generally be required 
that subjects provide two weekly ratings of the weekly IVRS diary questions during 
this period. 
 
 Treatment Period: 
• 
Week 1 (Rel Day 1-7) 
• 
Week 2 (Rel Day 8-14), 
• 
Week 3 (Rel Day 15-21), 
• 
Week 4 (Rel Day 22-28), 
• 
Week 5 (Rel Day 29-35), 
• 
Week 6 (Rel Day 36-42), 
• 
Week 7 (Rel Day 43-49), 
• 
Week 8 (Rel Day 50-56), 
• 
Week 9 (Rel Day 57-63), 
• 
Week 10 (Rel Day 64-70), 
• 
Week 11 (Rel Day 70-77), and 
• 
Week 12 (Rel Day 78-84). 
      The week during which the day of the last dose occurs will be considered the last 
valid week during the 12-week treatment period, assuming it contains at least 4 valid 
daily IVRS diary days.  Otherwise, the last valid week will be the preceding week. 
The last valid week during the 12-week treatment period will be used as the endpoint 
week for weekly efficacy summaries. 
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      Only data captured from the first dose until the last dose will be used to derive the 
weeks during the 12-week treatment period, 
 
• RW Period: 
• 
Week 1 (Rel Day 1-7 after Randomization #2), 
• 
Week 2 (Rel Day 8-14 after Randomization #2), 
• 
Week 3 (Rel Day 15-21 after Randomization #2), and 
• 
Week 4 (Rel Day 22-28 after Randomization #2). 
      All data listings will contain a relative study day, regardless of whether the data was 
collected via IVRS diary or eCRF. 
 
10.7. Statistical Analyses 
      Summary tabulations will be presented that will display descriptive statistics for each 
treatment group. The number of observations, mean, standard deviation, minimum, 
median, and maximum values will be displayed for continuous variables, and the 
number and percent of subjects per category will be displayed for categorical data.  
For subject disposition, demographic and baseline characteristics, medical history, 
gastrointestinal disease history, and prior medications, an overall column (i.e., all 
subjects combined) will be included. 
 
Statistical analyses will be performed at the two-sided significance level of 0.050 
according to the testing procedure described below.  The testing procedure will 
preserve the experiment wise Type I error rate at 5%. All secondary p-values will be 
considered descriptive.   
10.7.1 Subject Disposition 
      Subject disposition information will be summarized by treatment group and overall. 
The number and percent of subjects who are randomized, who took a dose of study 
drug, who complete the study, and who withdraw early from the study will be 
presented.  The primary reason for early withdrawal will also be tabulated.  The 
number of subjects randomized will be used as the denominator for the percentage 
calculation. Subject disposition, inclusion / exclusion criteria, and protocol deviations 
will be listed. 
      The number and percent of subjects in each analysis set will also be tabulated. 
10.7.2 Demographic and Background Characteristics 
      The treatment groups will be descriptively assessed for comparability of demographic 
and baseline characteristics. Variables included in this assessment will be the 
demographic characteristics of age at informed consent (years), gender, race, 
ethnicity, body weight (kg), and BMI (kg/m2). Screening values (week -1, week -2) 
and baseline values (average of week -1 and week -2) for average weekly CSBMs, 
average weekly SBMs, average weekly stool consistency, average weekly straining 
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score, and average weekly abdominal symptoms of pain, discomfort, bloating, 
fullness, and cramping will also be summarized for each treatment group and overall. 
 
      Weekly ratings of IBS severity and constipation severity will also be summarized for 
each of the 2 weeks of the screening period. Both categorical and continuous 
descriptive statistics will be used for the weekly ratings. 
   
      Medical history and gastrointestinal (GI) history will be summarized for the number 
and percentage of subjects for each body system by treatment group and overall. 
Medical history includes verbatim terms recorded for the subjects. GI history includes 
duration (years) since IBS symptoms began before randomization, duration (months) 
since last colonoscopy before randomization, and whether colonoscopy findings are 
not significant. A summary table will be presented for each analysis set. Medical and 
GI history will also be listed. 
10.7.3 Prior/Concomitant Medication 
All prior and concomitant medications administered during the study will be coded 
using the latest available version of the World Health Organization (WHO) Drug 
Reference List. The number and percentage of subjects taking prior and concomitant 
medications will be summarized by Anatomical Therapeutic Chemical (ATC) class 
and preferred name by treatment group and overall.  A listing of all medications will 
be provided. 
10.7.4 Study Drug Exposure and Compliance 
      Days of exposure to study drug will be summarized with descriptive statistics by 
treatment group for each of the analysis sets. Summary statistics will also be 
presented for percent compliance to study drug by treatment group for each of the 
analysis sets. The percent compliance to study drug will be calculated as the total 
number of tablets dispensed minus the total number of tablets returned divided by 
two, times the number of days during the treatment period, then multiplied by 100. 
10.7.5 Efficacy Variables 
Efficacy variables in this trial will be captured via the IVRS on a daily basis (CSBM 
frequency, SBM frequency, consistency, straining, and abdominal symptoms of pain, 
discomfort, bloating, fullness, and cramping) or weekly basis (IBS severity, and 
constipation severity) during the screening (baseline) period, the 12 week treatment 
period, and the RW period.  Adequate relief of IBS symptoms and degree of relief of 
IBS symptoms will be collected weekly during the treatment period and RW period. 
The IBS-QOL will be collected by the eCRF prior to and at the end of the treatment 
period as well as the end of the RW period. Treatment satisfaction will be recorded at 
the end of each month during the treatment period and the end of the RW period.  Use 
of rescue medication is also collected daily throughout the screening, treatment, and 
RW periods.  Rescue medication usage is incorporated into the derivation of the 
efficacy variables but is not itself considered an efficacy variable. 
The primary efficacy variable will be the overall responder rate. An overall responder 
will be defined as a weekly responder for 6/12 weeks where both CSBM and 
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abdominal pain response criteria were met for the week. The CSBM and abdominal 
pain response criteria are defined below. The weekly overall responder rates will be 
summarized for each week of the treatment period and the RW period. 
The CSBM response criteria is defined as an increase of one or more change in 
average weekly CSBMs from baseline.  The definition of a CSBM is as follows: A 
CSBM is a SBM for which the subject responds “yes” to the following question; “Did 
you feel like you completely emptied your bowels?”  Any SBM which is preceded 
within 24 hours by the use of rescue medication will not be counted as a SBM and 
therefore also not counted as a CSBM as defined above.  Should a subject not have 
data reported for a given week (either due to a gap in reporting or due to 
discontinuation), the subject will be considered to be a non-responder for the week.  
A key secondary efficacy variable will be the overall CSBM responder rate. An 
overall CSBM responder will be defined as a weekly CSBM responder for 6/12 
weeks where the CSBM response criteria were met for the week. 
The average weekly CSBMs will be calculated as the sum of the number of CSBMs 
reported during each day of the defined weekly period divided by the number of days 
CSBMs were reported times 7. A valid week will require at least 4 days of SBM 
reporting. The average weekly CSBMs and change from baseline (where baseline is 
the average of the 2-weeks during the screening period) for each week of the 
treatment period and 4-week RW period will be summarized.  Baseline for the 4-
week RW period will be the last week of the treatment period. 
The abdominal pain response criteria is defined as a decrease of 30% or more of 
percent change from baseline in average weekly worst abdominal pain. Abdominal 
pain will be scored daily using the scale 0 = No pain to 10 = very severe pain. The 
average weekly abdominal pain score will be calculated as the average score for all 
days during a valid week. Should a subject not have data reported for a given week 
(either due to a gap in reporting or due to discontinuation), the subject will be 
considered to be a non-responder for the week. The average weekly abdominal pain 
score and percent change from baseline (where baseline is the average of the 2-weeks 
during the screening period) for each week of the treatment period and 4-week RW 
period will be summarized.  Baseline for the 4-week RW period will be the last week 
of the treatment period. 
A key secondary efficacy variable will be the overall abdominal pain responder rate. 
An overall abdominal pain responder will be defined as a weekly abdominal pain 
responder for 6/12 weeks where the abdominal pain response criteria were met for the 
week. 
Additional key secondary efficacy variables consist of the overall responder rate, 
overall CSBM responder rate, and overall abdominal pain responder rate calculated 
using a 9/12 week response criteria. Hence, for 9 out of the 12 weeks during the 
treatment period, the subject met the responder criteria for the 6/12 week responder 
rates.  In addition, for the 9/12 week CSBM responder criteria, it is also required that 
the average weekly CSBMs for the week are ≥3.  A third set of key secondary 
efficacy variables consist of the durable overall responder rate, durable overall CSBM 
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responder rate, and durable overall abdominal pain responder rate. The durable 
responder rates use the same 9/12 week response criteria and in addition, require the 
last 3/4 weeks of the treatment period to meet the response criteria.  
For each of the three sets of efficacy variables described above (i.e., 6/12, 9/12, and 
durable responders), several sensitivity analyses will be done. Instead of assuming 
non-response for missing weeks or weeks with less than 4 days of valid diary data, a 
sensitivity analysis will be carried out imputing response for these weeks. Similarly, 
instead of assuming a 30% reduction for percent change from baseline in abdominal 
pain, these analyses will be repeated using a 40% reduction and a 50% reduction as 
response criteria. Note that for these last 2 analyses, the CSBM responder analyses 
will not be repeated, only the overall and abdominal pain responder rates.     
Secondary efficacy variables will include the following: 
The proportion of subjects with ≥ 3 CSBMs per week will be summarized for the 
baseline, treatment, and RW periods. 
Average weekly SBMs will be calculated as described above for average weekly 
CSBMs.  Change from baseline for each week of the 12-week treatment period and 4-
week RW period will be summarized using the observed data.  Baseline for the 4-
week RW period will be the last week of the treatment period. 
Subjects will record the consistency of each of their bowel movements on a daily 
basis through the IVRS utilizing the BSFS scale (Appendix B). The average weekly 
stool consistency will be calculated as the average score for all valid SBMs during the 
week.  For purposes of calculating an average, days with no stools will be scored a 0.  
Change from baseline for each week of the 12-week treatment period and 4-week RW 
period will be summarized using the observed data. Baseline for the 4-week RW 
period will be the last week of the treatment period. 
Straining will be scored for each SBM using the scale 1 = not at all, 2 = a little bit, 3 
= a moderate amount, 4 = a great deal, 5 = an extreme amount.  The average weekly 
straining score will be calculated as the average score for all valid SBMs during the 
week. Change from baseline for each week of the 12-week treatment period and 4-
week RW period will be summarized using the observed data.  Baseline for the 4-
week RW period will be the last week of the treatment period. 
Abdominal discomfort, abdominal bloating, abdominal fullness, and abdominal 
cramping will be scored daily using the 0-10 point scale with 0 representing no 
presence of the symptom and 10 representing very severe presence of the symptom.  
The average weekly scores will be calculated as the average score for all days during 
a valid week. Percent change from baseline for each week of the 12-week treatment 
period and 4-week RW period will be summarized. In addition, responders at each 
week (i.e., 30% improvement from baseline)   and for 6/12 weeks on treatment will 
be defined in a similar manner as for abdominal pain responder rates. If no data is 
present to constitute a valid week, it will be assumed the subject did not respond.  
Otherwise, observed data will be used to summarize the average weekly abdominal 
symptom.  Baseline for the 4-week RW period will be the last week of the treatment 
period. 
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IBS severity and constipation severity will be scored on a weekly basis using the 
scale 1 = None, 2 = Mild, 3 = Moderate, 4 = Severe, 5 = Very Severe.  IBS severity 
scores and constipation severity scores for each week of the study will be summarized 
as categorical and continuous data. Observed data will be used for the summaries.  
Baseline for the 4-week RW period will be the last week of the treatment period. 
Adequate relief of IBS symptoms (1 = yes, and 2 = no) will be asked on a weekly 
basis.  The percentage of subjects with adequate relief for each week of the study will 
be summarized using observed data. 
Degree of relief of IBS symptoms will be scored on a weekly basis using 
1=completely relieved, 2=considerably relieved, 3=somewhat relieved, 4=unchanged, 
5=somewhat worse, 6=considerably worse, 7=as worse as I can imagine. Degree of 
relief scores for each week of the study will be summarized as categorical and 
continuous data using observed data. 
The IBS-QOL is a validated quality of life tool used for IBS subjects (see Appendix 
D). Subjects will be asked to complete this assessment a Visit 2 (prior to treatment), 
Visit 6 (at the end of the 12-week treatment period), and Visit 7 (at the end of the 4-
week RW period. The predetermined analysis provided with the tool will be used as 
described in the user manual. Details will be provided in the SAP.  Actual values and 
change from baseline values for each of the domain scores will be summarized.  
Baseline for the 4-week RW period will be the last week of the treatment period. 
Treatment satisfaction will be recorded by the subject at the end of each month during 
the treatment period (Visits 4, 5, and 6), and at the end of the RW period (Visit 8). 
Using the scale: 1= not at all satisfied, 2= a little satisfied, 3= moderately satisfied, 4 
=quite satisfied, 5= very satisfied.  The treatment satisfaction score will be 
summarized as a categorical and continuous variable. 
The following summarizes the efficacy variables planned for this study: 
Table 10-1                        Summary of Efficacy Variables and Designation 
Variable 
Designation 
Variable name  
Primary 
6/12 week overall responder rate 
Key Secondary 
6/12 week overall CSBM responder rate  
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Key Secondary 
6/12 week overall abdominal pain responder rate 
Key Secondary 
9/12 week overall responder rate 
Key Secondary 
9/12 week overall CSBM responder rate  
Key Secondary 
9/12 week overall abdominal pain responder rate 
Key Secondary 
Durable overall responder rate 
Key Secondary 
Durable overall CSBM responder rate  
Key Secondary 
Durable overall abdominal pain responder rate 
Sensitivity  
6/12 week overall responder rate with imputed responders 
Sensitivity  
6/12 week overall CSBM responder rate with imputed responders 
Sensitivity  
6/12 week overall abdominal pain responder rate with imputed responders 
Sensitivity  
9/12 week overall responder rate with imputed responders 
Sensitivity  
9/12 week overall CSBM responder rate with imputed responders 
Sensitivity  
9/12 week overall abdominal pain responder rate with imputed responders 
Sensitivity  
Durable overall responder rate with imputed responders 
Sensitivity  
Durable overall CSBM responder rate with imputed responders 
Sensitivity  
Durable overall abdominal pain responder rate with imputed responders 
Sensitivity 
6/12 week overall responder rate with 40% change in abdominal pain 
Sensitivity 
6/12 week overall 40% change in abdominal pain responder rate 
Sensitivity 
9/12 week overall responder rate with 40% change in abdominal pain 
Sensitivity 
9/12 week overall 40% change in abdominal pain responder rate 
Sensitivity 
Durable overall responder rate with 40% change in abdominal pain 
Sensitivity 
Durable overall 40% change in abdominal pain responder rate 
Sensitivity 
6/12 week overall responder rate with 50% change in abdominal pain 
Sensitivity 
6/12 week overall 50% change in abdominal pain responder rate 
Sensitivity 
9/12 week overall responder rate with 50% change in abdominal pain 
Sensitivity 
9/12 week overall 50% change in abdominal pain responder rate 
Sensitivity 
Durable overall responder rate with 50% change in abdominal pain 
Sensitivity 
Durable overall 50% change in abdominal pain responder rate 
Secondary 
Weekly overall responder rate 
Secondary 
Weekly CSBM responder rate  
Secondary 
Weekly abdominal pain responder rate 
Secondary 
Weekly proportion of subjects with ≥3 CSBMs per week 
Secondary 
Average weekly CSBMs 
Secondary 
Average weekly SBMs 
Secondary 
Average weekly stool consistency 
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Secondary 
Average weekly straining score 
Secondary 
Overall abdominal symptom responder rate 
Secondary 
Weekly abdominal discomfort responder rate  
Secondary 
Weekly abdominal bloating responder rate  
Secondary 
Weekly abdominal cramping responder rate  
Secondary 
Weekly abdominal fullness responder rate  
Secondary 
Average weekly abdominal pain score 
Secondary 
Average weekly abdominal discomfort score  
Secondary 
Average weekly abdominal bloating score 
Secondary 
Average weekly abdominal cramping score  
Secondary 
Average weekly abdominal fullness score   
Secondary 
Weekly IBS severity score 
Secondary 
Weekly constipation severity score 
Secondary 
Weekly adequate relief of IBS symptoms 
Secondary 
Weekly degree of relief of IBS symptoms score  
Secondary 
IBS-QOL (9 subscales) 
Secondary 
Treatment satisfaction 
 
10.7.6 Efficacy Analyses 
All efficacy variables involving responder rates or proportions will be analyzed using a 
Cochran-Mantel-Haenszel (CMH) test with pooled investigator site as a stratification 
(adjustment) variable. Summary statistics will include the pairwise risk difference with 
placebo along with the asymptotic 95% confidence interval (CI). The adjusted relative 
risk (adjusted for pooled investigator site) will be based on the ratio of responder rates for 
placebo versus tenapanor 50 mg BID. The 95% CI versus placebo will also be presented 
for the adjusted relative risk. 
All continuous efficacy variables derived from the daily IVRS questions (i.e., average 
weekly CSBMs, SBMs, stool consistency, straining score, abdominal symptoms of pain, 
discomfort, bloating, fullness, and cramping), as well as the weekly IBS severity, 
constipation severity, and IBS QOL will be analyzed using an analysis of covariance 
(ANCOVA) model with terms for pooled investigator site, treatment, and baseline as the 
covariable.  Degree of relief of IBS symptoms and treatment satisfaction will be analyzed 
using an analysis of variance (ANOVA) model with terms for pooled investigator site  
and treatment.   
When the ANCOVA model is implemented, the least square means (LSmeans) will be 
presented for the actual values and change/percent change from baseline values for each 
treatment group with the 95% CI. Statistical testing will only be carried out using the 
change/percent change from baseline since the p-values are the same between the two 
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analyses.  The LSmean difference versus placebo will also be presented with the 95% CI. 
When the ANOVA model is implemented, all of the above statistics will be presented for 
the actual values. 
A sequential testing procedure will be utilized to control the experiment wise Type I error 
rate for the primary efficacy variable. Because of the desire to also pre-specify key 
secondary efficacy variables, the sequential testing procedure will not inflate the overall 
5% level. The primary efficacy variable will be tested at the 5% level of significance.  If 
this test is significant, the first key secondary efficacy variable listed in Table 10-1 will 
be tested at the 5% level. If this test is significant, then the next variable is tested at the 
5% level. This procedure continues until one of the tests in the list results in a p-value 
>5%.  Variables up to this point in the list will be declared statistically significant.  
Interpretation of p-values for the secondary efficacy variables will be descriptive.   
In addition to the summaries of the efficacy variables described, figures will be provided 
depicting the actual means or the change/percent change from baseline for each treatment 
group at each assessment time. A secondary analysis will also include graphs depicting 
the cumulative distribution of the percentage reduction of abdominal pain.   
10.7.7 Safety Analyses 
Safety assessments will be based on the incidence, severity, and type of adverse events, 
and clinically significant changes in the subject’s clinical laboratory tests, vital signs, 
ECGs and physical examinations. 
Adverse events will be coded using the MedDRA adverse event coding system for 
purposes of summarization.  All adverse events reported will be listed in the data listings.  
Treatment emergent adverse events (TEAEs) will be tabulated, where treatment emergent 
is defined as any adverse event which occurs after administration of the first dose of 
study drug and up through the final visit (up to planned Day 113), any event that is 
considered drug-related regardless of the start date of the event, or any event that is 
present at baseline but worsens in severity or is subsequently considered drug-related by 
the investigator.  TEAEs will also be tabulated by whether events are considered related 
to treatment (possibly or probably drug-related, or unknown in relationship) and by 
severity.  Serious adverse events and TEAEs resulting in study discontinuation will be 
tabulated.   
Actual values and change from baseline values for clinical laboratory tests will be 
summarized for each visit collected during the study.The frequency of clinically 
significant abnormal laboratory test values will be tabulated by treatment group. Shift 
tables will be derived for changes in laboratory tests from screening to Visit 4, 6, and 8. 
Vital signs will be summarized descriptively for actual values and change from baseline 
values by treatment group and visit. Vital signs are collected at all study visits during the 
screening period, 12-week treatment period, and 4-week RW period. Baseline for the 
vital signs will be the average of results obtained during the screening period. 
 
Electrocardiogram results will be summarized descriptively for actual values and change 
from screening values by treatment group and visit (Screening (Visit 1/Day -14), Week 
12 (Visit 6/Day 85), and Week 16 (Visit 8/Day 113)). The overall interpretation will be 
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summarized with number of subjects and percentages for the normal and abnormal ECG 
result categories. 
 
All vital signs and electrocardiogram results will be listed. Abnormal or clinically 
significant results will be flagged. 
Physical examinations are collected at Screening (Visit 1/Day -14), Week 12 (Visit 6/Day 
85), and Week 16 (Visit 8/Day 113).  The number and percentage of subjects in each 
category will be presented for each visit by treatment group. 
All physical examination results will be listed. Abnormal physical exam results will be 
flagged. 
. 
11. 
ADMINISTRATIVE REQUIREMENTS 
11.1. Good Clinical Practice 
The study will be conducted in accordance with the current GCP/ICH Guidelines and 
relevant regulatory requirement(s).  Compliance with this standard provides public 
assurance that the rights, safety and well-being of trial subjects are protected, consistent 
with the principles that have their origin in the Declaration of Helsinki and that the 
clinical trial data are credible.  The Investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure.  Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected.  A Trial Master File will be established at 
the beginning of the study, maintained for the duration of the trial and retained according 
to appropriate regulations. 
11.2. Ethical Considerations 
The study will be conducted in accordance with ethical principles that have their 
origin in the Declaration of Helsinki.  The IRB/IEC will review all appropriate study 
documentation in order to safeguard the rights, safety and well-being of the subjects.  
The study will only be conducted at sites where IRB/IEC approval has been obtained.  
The protocol, Investigator Brochure, informed consent, advertisements (if applicable), 
written information given to the subjects (including subject information material), 
safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the Investigator. 
11.3. Subject Informed Consent and Information 
Prior to entry in the trial, the Investigator must explain to potential subjects or their 
legally acceptable representative, the trial and the implications of participation.  
Subjects will be told that their participation is voluntary and they may withdraw 
consent to participate at any time.  Subjects will be told that competent authorities 
and authorized Ardelyx personnel, its business partners or its CRO designee may 
access their records without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) and/or regulations.  By signing the Informed 
Consent Form (ICF) the subject or legally acceptable representative is authorizing 
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such access through an authorization meeting the requirements of the Health 
Insurance Portability and Accountability Act of 1996.  Each subject (or their legally 
authorized representative) that wants to participate in the study must sign and date the 
ICF (and other locally required documents) after the nature of the study has been fully 
explained prior to performing any study-related activities.  The subject (or their 
legally acceptable representative) will be given sufficient time to read the ICF and to 
ask additional questions.  After having obtained the consent, a copy of the informed 
consent document must be given to the subject.  In case the subject is unable to read, 
an impartial witness must attest the informed consent.  Subjects who are unable to 
comprehend the information provided can only be enrolled after consent by a legally 
acceptable representative.  
The consent form that is used must be approved by both the reviewing IRB and by 
Ardelyx or its CRO designee.   
All reports and communications relating to the study will identify subjects by initials 
and assigned number only.  A “Subject Screening Log” that reports on all subjects 
that were seen to determine eligibility for inclusion in the trial will also be completed 
by the Investigator.  
11.4. Subject Confidentiality 
The collection and processing of data from subjects enrolled in this trial will be 
limited to those data that are necessary to investigate the safety, quality and utility of 
the investigational product(s) used in this trial.  These data will be processed with 
adequate precautions to ensure confidentiality. 
In order to maintain subject/subject privacy, all CRFs, study drug accountability 
records, study reports and communications will identify the subject by initials and the 
assigned subject number.  The Investigator will grant monitor(s) and auditor(s) from 
Ardelyx, its designee(s) and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the CRFs and to audit the data 
collection process.  The subject’s confidentiality will be maintained and will not be 
made publicly available except to the extent permitted by the applicable laws and 
regulations. 
11.5. Protocol Compliance 
The Investigator will conduct the trial in compliance with the protocol provided by 
Ardelyx, and given approval by the IRB/IEC and the appropriate regulatory 
authority(ies).  Modifications to the protocol should not be made without agreement 
of both the Investigator and Ardelyx.  Changes to the protocol will require written 
IRB/IEC approval prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects.  The IRB/IEC may provide, if 
applicable regulatory authority(ies) permit, expedited review and approval for minor 
change(s) in ongoing trials that have the approval of the IRB/IEC.  Ardelyx will 
submit all protocol modifications to the regulatory authority(ies) in accordance with 
the governing regulations.   
When immediate deviation from the protocol is required to eliminate an immediate 
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hazard(s) to subjects, the Investigator will contact Ardelyx, if circumstances permit, 
to discuss the planned course of action  
11.6. Study Monitoring and On-site Audits 
Monitoring and auditing procedures developed by Ardelyx or its CRO designee will 
be followed, in order to comply with GCP guidelines.  Routine monitoring visits will 
be made to assure compliance with the study protocol, to review and compare the 
subject’s eCRF with source documents, to ensure adequate records of clinical 
supplies are maintained and to assess the continued suitability of the investigational 
site.  The Investigator agrees to allow the site monitors, and other authorized 
personnel or designees, access to the subject’s medical records, regulatory binder, 
study binder, and source documents as needed to assure the conduct of the study was 
within compliance.   
Upon completion of the study the site monitor will make a final assessment of the 
conduct of the study and inventory all clinical supplies to be returned to Ardelyx.  All 
unused study drug is to be returned to Ardelyx or designee.   
Regulatory authorities, the IEC/IRB, and/or Ardelyx’s clinical quality assurance 
group, its CRO designee or business partners may request access to all source 
documents, CRFs, and other study documentation for on-site audit or inspection.  
Direct access to these documents must be guaranteed by the Investigator, who must 
provide support at all times for these activities. 
11.7. Case Report Form Completion 
An Electronic Data Capture (EDC) system will be used for this study.  Electronic 
case report forms (eCRFs) will be accessed for each subject.   
eCRFs will be completed for each randomized study subject.  It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data 
reported in the subject’s eCRF.  Source documentation supporting the eCRF data 
should indicate the subject’s participation in the trial and should document the dates 
and details of study procedures, adverse events and subject status.   
The Investigator, or designated representative, should complete the eCRF pages as 
soon as possible after information is collected, preferably on the same day that a 
study subject is seen for an examination, treatment, or any other study procedure.  
Any outstanding entries must be completed immediately after the final examination.  
An explanation should be given for all missing data.   
Prior to submission within the EDC system, eCRFs must be reviewed for 
completeness and accuracy, and electronically signed and dated by the Investigator 
where indicated. 
11.8. Drug Accountability/Retention  
Accountability for the study drug at the trial site is the responsibility of the 
Investigator.  The Investigator will ensure that the study drug is used only in 
accordance with this protocol.  Where allowed, the Investigator may choose to assign 
some of the drug accountability responsibilities to a pharmacist or other appropriate 
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individual.  Drug accountability records indicating the study drug’s delivery date to 
the site, inventory at the site, use by each subject, and return to Ardelyx (or disposal 
of the drug, if approved by Ardelyx) will be maintained by the clinical site.  These 
records will adequately document that the subjects were provided the doses as 
specified in the protocol and should reconcile all study drug received from Ardelyx.  
Accountability records will include dates, quantities, batch/serial numbers, expiration 
dates (if applicable), and subject numbers.  Ardelyx or its CRO designee will review 
drug accountability at the site on an ongoing basis during on-site monitoring visits. 
The Investigator acknowledges that the study drug supplies are investigational and as 
such must be handled strictly in accordance with the protocol and container label.  
Supplies should be dispensed under the supervision of the Investigator or designee.  
Study drug will be stored in a limited access area and under the appropriate 
conditions as specified on delivery.   
Unused or partially used bottles of study drug will be stored until the study monitor at 
the end of the study performs a final inventory.  At the completion of this trial, all 
unused, partially unused, or empty multiple-dose bottles must be returned to Ardelyx, 
or designee.   
11.9. Study Completion or Premature Closure 
The Investigator will complete the study and the eCRF in satisfactory compliance 
with the protocol within approximately 1 week of study completion.   
Ardelyx reserves the right to close the investigational site or terminate the trial at any 
time.  Reasons for the closure of an investigational site or termination of a trial by 
Ardelyx may include: 
 Determination of unexpected, significant, or unacceptable risk to subjects 
 Failure to enter subjects at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient complete and/or evaluable data 
 Plans to modify, suspend or discontinue the development of the study drug 
Should the study be closed prematurely, all study materials (completed, partially 
completed, study drug, etc.) must be returned to Ardelyx. 
11.10. 
Record Retention 
All case report forms and all source documents (e.g., informed consent forms, 
laboratory reports, progress notes, medical histories, physical and diagnostic findings, 
diagnoses and dates of therapy prior to and during this study, drug 
dispensing/disposition records) that support case report forms of each subject must be 
retained in the files of the responsible Investigator for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region; or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period, however, if 
required by the applicable regulatory requirements.  The Investigator should take 
measures to prevent accidental or premature destruction of these records.  Under no 
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circumstances shall the Investigator re-locate or dispose of any trial documents before 
having obtained Ardelyx written approval.  If the Investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person 
willing to accept the responsibility.  Ardelyx must be notified in writing if a custodial 
change occurs.  If it becomes necessary for Ardelyx or a regulatory authority to 
review any documentation relating to this trial, the Investigator must permit access to 
such records.  Any difficulty in storing original records must be discussed with the 
study monitor prior to the initiation of the trial.  
  
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12. 
USE OF INFORMATION AND PUBLICATION 
All information regarding tenapanor supplied by Ardelyx to the Investigator or 
generated by the Investigator in accordance with the conduct of the study is 
privileged and confidential information of Ardelyx.  The Investigator agrees to use 
this information to accomplish the study and will not use it for other purposes without 
written consent from Ardelyx.  It is understood that there is an obligation to provide 
Ardelyx with complete data obtained during the study.  The information obtained 
from the clinical trial will be used by Ardelyx in connection with the development of 
tenapanor and may be disclosed by Ardelyx to regulatory authority(ies), other 
Investigators, potential corporate partners, or consultants as required.   
The Investigator’s right and obligations with respect to publishing or otherwise 
presenting information regarding the study are detailed in the Publication provisions 
of the Clinical Study Agreement among the Investigator, the clinical site and Ardelyx.  
The Investigator shall comply with such provisions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13. 
SIGNATURES 
13.1. Investigator Signature 
I have read Clinical Protocol TEN-01-301, Edition 1, dated 18 August 2015, A 12-
Week, Randomized, Double-Blind, Placebo-Controlled Study with a 4-Week 
Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Tenapanor for the 
Treatment of Constipation-Predominant Irritable Bowel Syndrome (IBS-C) and agree 
that it contains all necessary details for carrying out this study.  I will conduct the study 
as outlined herein. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study.  I will discuss this material with 
them to ensure they are fully informed regarding the drug and the conduct of the study.   
I will use only the informed consent form approved by Ardelyx or its CRO designee and 
the Institutional Review Board (IRB) and will fulfill all responsibilities for submitting 
pertinent information to the IRB responsible for this study.   
I further agree that Ardelyx, its designee(s) or its CRO designee shall have access to any 
source documents from which case report form information may have been generated. 
 
 
 
Principal Investigator printed name 
 
 
 
 
 
 
Principal Investigator signature 
 
Date 
 
 
 
 
 
 
 
Investigational site or name of institution and location 
(printed) 
 
 
 
 
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13.2. Sponsor Signature 
clinical study protocol has been reviewed and approved by Ardelyx, Inc. 
Edition No.: I 
Edition Date: 18 August 2015 
CONFIDENTIAL 
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14. 
APPENDIX A: Rome III Criteria for the Diagnosis of IBS 
 
Diagnostic Criteria* 
Recurrent abdominal pain or discomfort** at least 3 days per month in the last 3 months 
associated with 2 or more of the following: 
 
1. Improvement with defecation 
2. Onset associated with a change in frequency of stool 
3. Onset associated with a change in form (appearance) of stool 
 
*Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to 
diagnosis. 
**Discomfort means an uncomfortable sensation not described as pain. In pathophysiology 
research and clinical trials, a pain/discomfort frequency of at least 2 days a week during 
screening evaluation for subject eligibility. 
Supportive symptoms that are not part of the diagnostic criteria include abnormal stool 
frequency ([a] ≤ 3 bowel movements per week or [b] ≥3 bowel movements per day), 
abnormal stool form ([c] lumpy/hard stool or [d] loose/watery stool), [e] defecation straining, 
[f] urgency, or also a feeling of incomplete bowel movement, passing mucus, and bloating. 
 
Subtyping IBS by Predominant Stool Pattern is as follows: 
 
IBS with constipation (IBS-C): hard or lumpy stoolsa ≥25% and 
loose (mushy) or watery stoolsb <25% of bowel movements 
 
IBS with diarrhea (IBS-D): loose (mushy) or watery stoolsb ≥25% 
 and hard or lumpy stoola <25% of bowel movements. 
 
Mixed IBS (IBS-M): hard or lumpy stoolsa ≥25% and loose 
(mushy) or watery stoolsb ≥25% of bowel movements. 
 
Unsubtyped IBS—insufficient abnormality of stool consistency to 
meet criteria for IBS-C, D, or Mc. 
The validity and stability of such subtypes over time is unknown and should be the subject of 
future research. 
aBristol Stool Form Scale 1–2 (separate hard lumps like nuts [difficult to pass] or sausage 
shaped but lumpy). 
bBristol Stool Form Scale 6–7 (fluffy pieces with ragged edges, a mushy stool or watery, no 
solid pieces, entirely liquid). 
cIn the absence of use of antidiarrheals or laxatives 
 
Longstreth, GF, Thompson, WG, Chey, WD, Houghton, LA, Mearin, F, and Spiller, 
RC. Functional Bowel Disorders.  Gastroenterol. 2006;130:1480–1491.   
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15. 
APPENDIX B: Bristol Stool Form Scale (BSFS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. 
Scand. J. Gastroenterol. 1997;32(9):920–924.   
 
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16. 
APPENDIX C: Clinical Laboratory Tests 
 
Serum Chemistry 
 
Hematology 
Albumin  
WBC count 
Alkaline Phosphatase  
RBC 
 
ALT  
RBC Indices 
 
AST  
MCV 
 
Bicarb/CO2  
MCH 
 
Total Bilirubin  
MCHC 
 
Direct Bilirubin 
Hemoglobin 
 
Indirect Bilirubin 
Hematocrit 
 
Calcium  
Differential: 
 
Chloride 
Bands 
 
Total Cholesterol 
Monophils 
 
Creatinine  
Neutrophils 
 
Glucose 
Eosinophils 
 
Inorganic Phosphorous  
Lymphocytes 
 
LDH 
Basophils 
 
Potassium 
Platelet Count 
 
Total Protein 
 
 
Sodium 
 
 
Triglycerides 
 
 
BUN/Urea 
 
 
Uric Acid 
 
 
 
 
 
 
Urinalysis 
 
Serology 
Urine -hCG 
Appearance 
HIV  
Hepatitis B 
 
Specific Gravity 
Hepatitis C 
 
pH 
 
 
Protein 
 
FSH 
 
Glucose 
 
 
Ketones 
 
 
Blood 
 
 
Nitrite 
 
 
Microscopic 
 
 
 
 
 
 
 
 
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17.
APPENDIX D:  Irritable Bowel Syndrome – Quality of Life Questionnaire
(IBS-QOL)
The IBS-QOL was developed by Donald L. Patrick, Ph.D. at The University of 
Washington, Douglas A. Drossman, MD at The University of North Carolina, 
Novartis Pharmaceuticals Corporation, and Novartis Pharma AG. Authors hold 
joint copyright over the IBS-QOL and all its translations. 
Pages 66 through 73 
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IBS-QOL Original US English 2002 
IBS-QOL - United States/English  
IBS-QOL_AU1.0_eng-USori 
 PLEASE WRITE IN  
 TODAY'S DATE: ______   _____   _____ 
MONTH 
DAY 
YEAR 
PLEASE READ THIS CAREFULLY 
ON THE FOLLOWING PAGES YOU WILL FIND STATEMENTS CONCERNING BOWEL PROBLEMS
(IRRITABLE BOWEL SYNDROME) AND HOW THEY AFFECT YOU. 
FOR EACH STATEMENT, PLEASE CHOOSE THE RESPONSE THAT APPLIES BEST TO YOU AND
CIRCLE THE NUMBER OF YOUR RESPONSE. 
IF YOU ARE UNSURE ABOUT HOW TO RESPOND TO A STATEMENT, PLEASE GIVE THE BEST
RESPONSE YOU CAN. THERE ARE NO RIGHT OR WRONG RESPONSES.  
YOUR RESPONSES WILL BE KEPT STRICTLY CONFIDENTIAL. 
IF YOU HAVE ANY QUESTIONS, PLEASE CONTACT: 
**SITE ADDRESS AND PHONE NUMBER TO BE PLACED HERE** 
The IBS-QOL was developed by Donald L. Patrick, Ph.D. at The University of Washington, Douglas A. Drossman, MD at The 
University of North Carolina, Novartis Pharmaceuticals Corporation, and Novartis Pharma AG. Authors hold joint copyright 
over the IBS-QOL and all its translations. 
PARTICIPANT ID: 
Ardelyx, Inc
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Edition Date: 18 August 2015
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IBS-QOL - United States/English  
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Please Turn to Next Page 
1 
About how you feel 
Please think about your life over the past month (last 30 days), and look at the statements 
below.  Each statement has five different responses.  For each statement, please circle the 
response that best describes your feelings. 
Q1. 
I feel helpless because of my bowel problems. (Please circle one number) 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
Q2. 
I am embarrassed by the smell caused by my bowel problems. (Please circle one 
number) 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
Q3. 
I am bothered by how much time I spend on the toilet. (Please circle one number) 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
Q4. 
I feel vulnerable to other illnesses because of my bowel problems. (Please circle one 
number) 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
Q5. 
I feel fat/bloated because of my bowel problems. (Please circle one number) 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
Ardelyx, Inc
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IBS-QOL - United States/English  
IBS-QOL_AU1.0_eng-USori 
 
Please Turn to Next Page 
2 
Q6. 
I feel like I'm losing control of my life because of my bowel problems. (Please circle one 
number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q7. 
I feel my life is less enjoyable because of my bowel problems. (Please circle one 
number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q8. 
I feel uncomfortable when I talk about my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
 
 
Q9. 
I feel depressed about my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
 
 
Q10. 
I feel isolated from others because of my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
Ardelyx, Inc
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IBS-QOL - United States/English  
IBS-QOL_AU1.0_eng-USori 
 
Please Turn to Next Page 
3 
Q11. 
I have to watch the amount of food I eat because of my bowel problems. (Please circle 
one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q12. 
Because of my bowel problems, sexual activity is difficult for me. (Please circle one 
number)  
 
(If not applicable, please circle “NOT AT ALL”) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
 
 
Q13. 
I feel angry that I have bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
 
 
Q14. 
I feel like I irritate others because of my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q15. 
I worry that my bowel problems will get worse. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
Ardelyx, Inc
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IBS-QOL - United States/English  
IBS-QOL_AU1.0_eng-USori 
 
Please Turn to Next Page 
4 
Q16. 
I feel irritable because of my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
 
 
Q17. 
I worry that people think I exaggerate my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q18. 
I feel I get less done because of my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q19. 
I have to avoid stressful situations because of my bowel problems. (Please circle one 
number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q20. 
My bowel problems reduce my sexual desire. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
Ardelyx, Inc
Clinical Study Protocol
Protocol No. TEN-01-301
Edition No.: 1
Edition Date: 18 August 2015
CONFIDENTIAL 
Page 70 of 73
Supersedes Edition: NA
Supersedes Date: NA
71 of 74

 
 
IBS-QOL - United States/English  
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5 
Q21. 
My bowel problems limit what I can wear. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q22. 
I have to avoid strenuous activity because of my bowel problems. (Please circle one 
number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q23. 
I have to watch the kind of food I eat because of my bowel problems. (Please circle one 
number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q24. 
Because of my bowel problems, I have difficulty being around people I do not know 
well. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q25. 
I feel sluggish because of my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
Ardelyx, Inc
Clinical Study Protocol
Protocol No. TEN-01-301
Edition No.: 1
Edition Date: 18 August 2015
CONFIDENTIAL 
Page 71 of 73
Supersedes Edition: NA
Supersedes Date: NA
72 of 74

 
 
IBS-QOL - United States/English  
IBS-QOL_AU1.0_eng-USori 
 
Please Turn to Next Page 
6 
Q26. 
I feel unclean because of my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
 
 
Q27. 
Long trips are difficult for me because of my bowel problems. (Please circle one 
number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
 
 
Q28. 
I feel frustrated that I cannot eat when I want because of my bowel problems. (Please 
circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
 
 
Q29. 
It is important to be near a toilet because of my bowel problems. (Please circle one 
number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
 
 
Q30. 
My life revolves around my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
Ardelyx, Inc
Clinical Study Protocol
Protocol No. TEN-01-301
Edition No.: 1
Edition Date: 18 August 2015
CONFIDENTIAL 
Page 72 of 73
Supersedes Edition: NA
Supersedes Date: NA
73 of 74

 
 
IBS-QOL - United States/English  
IBS-QOL_AU1.0_eng-USori 
7 
Q31. 
I worry about losing control of my bowels. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q32. 
I fear that I won't be able to have a bowel movement. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q33. 
My bowel problems are affecting my closest relationships. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
A GREAT DEAL 
 
 
Q34. 
I feel that no one understands my bowel problems. (Please circle one number) 
 
1 
NOT AT ALL 
2 
SLIGHTLY 
3 
MODERATELY 
4 
QUITE A BIT 
5 
EXTREMELY 
Ardelyx, Inc
Clinical Study Protocol
Protocol No. TEN-01-301
Edition No.: 1
Edition Date: 18 August 2015
CONFIDENTIAL 
Page 73 of 73
Supersedes Edition: NA
Supersedes Date: NA
74 of 74