Clinical trial NCT02621892
Conditions: Constipation Predominant Irritable Bowel Syndrome
Sponsor: Ardelyx
Start date: 2015-10-01; Completion date: 2017-04-01
Enrollment: 606 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase 3, 12-week, randomized, double-blind, placebo-controlled, multi-center study will evaluate the safety and efficacy of tenapanor in subjects with constipation-predominant irritable bowel syndrome (IBS-C) as defined by the ROME III criteria and who have active disease as determined after a two-week screening period. Subjects who qualify and are randomized into the study will either receive 50mg BID of tenapanor or placebo BID for 12 week treatment period and then undergo a 4 week placebo controlled randomized withdrawal.

Detailed description:
During the 12-week treatment period, subjects will record daily assessments including: frequency and timing of bowel movements; sensation and complete bowel emptying; consistency of bowel movements; degree of straining, worst abdominal pain, abdominal discomfort, abdominal bloating, abdominal fullness and abdominal cramping. Subjects will also record weekly assessments including: adequate relief of IBS severity, and constipation severity.

At the end of the 12-week treatment period, there will be a 4-week randomized withdrawal period in which subjects who complete the study in Tenapanor group will be randomized to either Tenapanor 50mg BID or placebo BID (1:1) and subjects who complete the study in the placebo group will be assigned to receive Tenapanor 50mg BID.

Arms: arm 1: Tenapanor arm 2: Placebo
Interventions: intervention 1: Tenapanor intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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
1 of 74


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. 
2 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 2 of  73 
Supersedes Date: NA 
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.  
 
3 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 3 of  73 
Supersedes Date: NA 
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 
4 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 4 of  73 
Supersedes Date: NA 
 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 
5 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 5 of  73 
Supersedes Date: NA 
(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 
6 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 6 of  73 
Supersedes Date: NA 
 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 
7 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 7 of  73 
Supersedes Date: NA 
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.  
8 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 8 of  73 
Supersedes Date: NA 
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. 
9 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 9 of  73 
Supersedes Date: NA 
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 
10 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 10 of  73 
Supersedes Date: NA 
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 
11 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 11 of  73 
Supersedes Date: NA 
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 
12 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 12 of  73 
Supersedes Date: NA 
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 
13 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 13 of  73 
Supersedes Date: NA 
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 
14 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 14 of  73 
Supersedes Date: NA 
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.  
15 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 15 of  73 
Supersedes Date: NA 
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, 
16 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 16 of  73 
Supersedes Date: NA 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 17 of  73 
Supersedes Date: NA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.2.2 Phase 2b study of Tenapanor (5, 20, 50 mg BID) in IBS-C subjects 
 
 
 
 
18 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 18 of  73 
Supersedes Date: NA 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 19 of  73 
Supersedes Date: NA 
 
 
 
 
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 
20 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 20 of  73 
Supersedes Date: NA 
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 
21 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 21 of  73 
Supersedes Date: NA 
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.   
22 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 22 of  73 
Supersedes Date: NA 
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 
23 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 23 of  73 
Supersedes Date: NA 
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 
24 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 24 of  73 
Supersedes Date: NA 
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 
25 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 25 of  73 
Supersedes Date: NA 
(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. 
26 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 26 of  73 
Supersedes Date: NA 
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: 
 
 
 
 
 
 
 
 
27 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol  
 
Protocol No. TEN-01-301 
 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 27 of  73 
Supersedes Date: NA 
 
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 
 
28 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 28 of  73 
Supersedes Date: NA 
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.
29 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol  
 
Protocol No. TEN-01-301 
 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 29 of  73 
Supersedes Date: NA 
 
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 
30 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 30 of  73 
Supersedes Date: NA 
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. 
31 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 31 of  73 
Supersedes Date: NA 
 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) 
32 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 32 of  73 
Supersedes Date: NA 
 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 
33 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 33 of  73 
Supersedes Date: NA 
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 
34 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 34 of  73 
Supersedes Date: NA 
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 
35 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 35 of  73 
Supersedes Date: NA 
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) 
36 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 36 of  73 
Supersedes Date: NA 
“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.” 
37 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 37 of  73 
Supersedes Date: NA 
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 
-- 
73 
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 
38 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 38 of  73 
Supersedes Date: NA 
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 
39 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 39 of  73 
Supersedes Date: NA 
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.  
40 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 40 of  73 
Supersedes Date: NA 
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. 
41 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 41 of  73 
Supersedes Date: NA 
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 
42 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 42 of  73 
Supersedes Date: NA 
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 
43 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 43 of  73 
Supersedes Date: NA 
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 
44 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 44 of  73 
Supersedes Date: NA 
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.  
45 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 45 of  73 
Supersedes Date: NA 
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. 
46 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 46 of  73 
Supersedes Date: NA 
      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 
47 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 47 of  73 
Supersedes Date: NA 
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 
48 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 48 of  73 
Supersedes Date: NA 
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 
49 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 49 of  73 
Supersedes Date: NA 
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. 
50 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 50 of  73 
Supersedes Date: NA 
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  
51 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 51 of  73 
Supersedes Date: NA 
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 
52 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 52 of  73 
Supersedes Date: NA 
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 
53 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 53 of  73 
Supersedes Date: NA 
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 
54 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 54 of  73 
Supersedes Date: NA 
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 
55 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 55 of  73 
Supersedes Date: NA 
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 
56 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 56 of  73 
Supersedes Date: NA 
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 
57 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 57 of  73 
Supersedes Date: NA 
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 
58 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 58 of  73 
Supersedes Date: NA 
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.  
  
59 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 59 of  73 
Supersedes Date: NA 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
60 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 60 of  73 
Supersedes Date: NA 
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) 
 
 
 
 
61 of 74


Ardelyx, Inc. 
Clinical Study Protocol 
Protocol No. TEN-01-301 
13.2. Sponsor Signature 
clinical study protocol has been reviewed and approved by Ardelyx, Inc. 
Edition No.: I 
Edition Date: 18 August 2015 
CONFIDENTIAL 
Page 61 of 73 
Supersedes Edition: NA 
Supersedes Date: NA 
62 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 62 of  73 
Supersedes Date: NA 
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.   
63 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 63 of  73 
Supersedes Date: NA 
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.   
 
64 of 74


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 64 of  73 
Supersedes Date: NA 
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 
 
 
 
 
 
 
 
 
65 of 74


Ardelyx, Inc. 
Clinical Study Protocol  
Protocol No. TEN-01-301 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 18 August 2015 
 Page 65 of  73 
Supersedes Date: NA 
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 
66 of 74


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
Clinical Study Protocol
Protocol No. TEN-01-301
Edition No.: 1
Edition Date: 18 August 2015
CONFIDENTIAL
Page 66 of 73
Supersedes Edition: NA
Supersedes Date: NA
67 of 74


IBS-QOL - United States/English  
IBS-QOL_AU1.0_eng-USori 
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
Clinical Study Protocol
Protocol No. TEN-01-301
Edition No.: 1
Edition Date: 18 August 2015
CONFIDENTIAL 
Page 67 of 73
Supersedes Edition: NA
Supersedes Date: NA
68 of 74


 
 
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
Clinical Study Protocol
Protocol No. TEN-01-301
Edition No.: 1
Edition Date: 18 August 2015
CONFIDENTIAL 
Page 68 of 73
Supersedes Edition: NA
Supersedes Date: NA
69 of 74


 
 
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
Clinical Study Protocol
Protocol No. TEN-01-301
Edition No.: 1
Edition Date: 18 August 2015
CONFIDENTIAL 
Page 69 of 73
Supersedes Edition: NA
Supersedes Date: NA
70 of 74


 
 
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  
IBS-QOL_AU1.0_eng-USori 
 
Please Turn to Next Page 
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

SAP_001.pdf: 
16.1.9 
Documentation of statistical methods 
The following documents are included: 
• Final Statistical Analysis Plan, dated 16 Dec 2015 
Ardelyx, Inc. 
RDX5791 
IND# 108,732 
TEN-01-301 
CONFIDENTIAL
1 of 79


Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
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) 
 
 
 
 
Investigational Product: 
Tenapanor 
Protocol Number: 
TEN-01-301 
Development Phase: 
Phase 3 
Sponsor: 
Ardelyx, Inc. 
34175 Ardenwood Blvd.  
Fremont, CA  94555 
 
 
 
 
 
SAP Version V1.1 
SAP Date: 16 December 2015 
 
Original Protocol: 18 August 2015 
 
 
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. 
 
 
2 of 79


Ardelyx, Inc. 
Clinical Study Protocol TEN-0 l-30 I 
CONFIDENTIAL 
Version VI. I 
SIGNATURE PAGE 
Statistical Analysis Plan 
16 December 20 15 
STUDY TITLE: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Study with a 
4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety ofTenapanor 
for the Treatment of Constipation-Predominant Irritable Bowel Syndrome (IBS-C) 
We, the undersigned, have reviewed and approved this statistical analysis plan. 
Signature 
Page 2 of25 
Date 
3 of 79


Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
Page 3 of 25 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 4 
1. INTRODUCTION .......................................................................................................... 5 
2. STUDY CHARACTERISTICS ...................................................................................... 5 
2.1 Study Objectives ........................................................................................................... 5 
2.1.1 Primary Objective ............................................................................................... 5 
2.1.2 Secondary Objectives .......................................................................................... 5 
2.1.3 Exploratory Objective ......................................................................................... 5 
2.2 Study Design and Duration ........................................................................................... 5 
2.2.1 Treatments Administered .................................................................................... 7 
2.2.2 Randomization and Stratification ........................................................................ 7 
2.2.3 Duration of Study ................................................................................................ 7 
2.3 Efficacy and Safety Variables ..................................................................................... 11 
2.3.1 Efficacy Variables ............................................................................................. 11 
2.3.2 Safety Variables ................................................................................................ 16 
3. STATISTICAL METHODOLOGY ............................................................................. 16 
3.1 Determination of Sample Size .................................................................................... 16 
3.2 Analysis Sets ............................................................................................................... 17 
3.3 Procedures for Handling Missing Data ....................................................................... 17 
3.4 Methods of Pooling Data ............................................................................................ 18 
3.5 Visit Windows ............................................................................................................ 18 
3.6 Statistical Analyses ..................................................................................................... 19 
3.6.1 Subject Disposition ........................................................................................... 20 
3.6.2 Demographic and Background Characteristics ................................................. 20 
3.6.3 Prior/Concomitant Medication .......................................................................... 20 
3.6.4 Study Drug Exposure and Compliance ............................................................. 21 
3.7 Statistical Analyses ..................................................................................................... 21 
3.7.1 Efficacy Analyses .............................................................................................. 21 
3.8 Safety Analyses ........................................................................................................... 23 
3.8.1 Adverse Events .................................................................................................. 23 
3.8.2 Clinical Laboratory Tests .................................................................................. 24 
3.8.3 Vital Signs and 12-lead Electrocardiogram ...................................................... 25 
3.8.4 Physical Examination ........................................................................................ 25 
4. PROGRAMMING SPECIFICATIONS ....................................................................... 25 
 
 
4 of 79


Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
Page 4 of 25 
 
LIST OF ABBREVIATIONS  
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
BID 
twice per day 
BMI 
Body mass index 
BSFS  
Bristol stool form scale 
CSBM  
Complete spontaneous bowel movement 
eCRF 
Electronic case report form 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
IBS  
Irritable bowel syndrome 
IBS-C 
Constipation-predominant irritable bowel syndrome 
ITT  
Intent to treat 
IWRS 
IVRS 
Interactive web response system 
Interactive voice response system 
n, N 
Number of subjects with observations or number of subjects in an 
analysis set 
OC 
Observed cases  
QoL 
Quality of life 
QRS 
Principal deflection in ECG 
QT 
ECG interval 
QTc 
QT interval which has been corrected by taking into account heart 
rate 
SAP 
Statistical Analysis Plan 
SAE 
SBM 
Serious adverse event 
Spontaneous bowel movement  
TEAE 
Treatment-emergent adverse event 
5 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 5 of 25 
 
1. 
INTRODUCTION 
This document provides a description of the statistical methods and procedures to be 
implemented for the analyses of data from the Ardelyx, Inc. study with protocol number 
TEN-01-301. No deviations from this Statistical Analysis Plan (SAP) are anticipated. 
However, if any deviations occur, they will be documented in the final clinical study report. 
No deviation from the primary analyses will be considered. 
2. 
STUDY CHARACTERISTICS 
2.1 
Study Objectives 
This SAP will address the primary and secondary objectives for this study. The exploratory 
objective will be addressed at a later time through a separate analysis plan and/or report. 
2.1.1 
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.  
2.1.2 
Secondary Objectives 
The secondary objectives of this study are: 
 
 To assess the safety of tenapanor 50 mg when administered twice daily (BID) for 12 
consecutive weeks.  
 To assess the tolerability of tenapanor when administered twice daily (BID) for 12 
consecutive weeks 
 To assess the efficacy of tenapanor 50 mg twice daily (BID) after a 4-week placebo 
controlled randomized withdrawal period 
2.1.3 
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.  
2.2 
Study Design and Duration 
This is a phase 3, randomized, double blind, placebo-controlled, multi-center study and will 
evaluate the efficacy and safety of tenapanor in subjects with constipation predominant IBS 
6 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 6 of 25 
 
(IBS-C). Subjects who are 18 to 75 years old, meeting the definition of IBS-C as defined by 
the Rome III Criteria for the Diagnosis of irritable bowel syndrome (IBS) (see protocol 
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 (RW) period.  
Up to 4 weeks prior to study randomization, prospective subjects may be assessed with 
respect to their meeting the eligibility requirements of the study.  
At the beginning of the 2-week screening period (Visit 1/Day -14/Week -2), subjects will be 
questioned with respect to their eligibility for the study. Those who 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, 12-lead 
electrocardiogram (ECG), and clinical laboratory tests, including urinalysis. Subjects must 
discontinue the use of all prohibited medications at Visit 1 for the duration of the study. 
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 interactive 
voice-response system (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, constipation severity, adequate relief 
of IBS symptoms, and degree of relief of IBS symptoms will be collected weekly through the 
IVRS diary. Subject compliance with the electronic diary will be monitored actively by the 
site staff and the electronic diary system. 
At the end of the screening period, prior to the subject returning for randomization (Visit 
2/Day 1), 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 schedule an appointment for Visit 2 where the subject 
will complete additional baseline procedures, including the IBS-Quality of life questionnaire.  
Upon final eligibility, the subjects will be randomized into a treatment group according to a 
computer-generated central randomization schema using 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.  
Subjects will be randomized to receive either tenapanor 50 mg BID or placebo BID. 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.   
During the 12-week double-blind treatment period and the 4-week RW period, subjects will 
continue to record daily and weekly assessments via the IVRS as instructed. Subjects will be 
seen for study assessment visits at weeks 2, 4, 8, and 12 during the treatment period. Subject 
7 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 7 of 25 
 
compliance with study drug will be monitored. Subject compliance with daily diary entries 
will be monitored on an ongoing basis as described above. 
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. 
Subjects will return to the site for Visit 7 (Day 99/Week 14) and at the end of the 4-week RW 
period (Visit 8/Day 113/Week 16) to obtain safety and other follow-up information. 
2.2.1 
Treatments 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 ± 5 days) and Visit 6 (Day 84 ± 5 days).  At each visit 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. 
2.2.2 
Randomization and Stratification 
Both randomization and blinding techniques will be used in this study to minimize bias.  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. 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. 
2.2.3 
Duration of Study 
For each subject, the entire study will last for a total of 18 weeks, including a 2-week 
screening period, 12 weeks of treatment (tenapanor 50 mg BID or placebo BID), followed by 
8 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 8 of 25 
 
a 4-week randomized withdrawal (RW) period. The study flow chart, including all 
procedures to be performed during the study is presented below.   
 
 
 
 
 
9 of 79


Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
 
SCHEDULE OF ASSESSMENTS FOR THE STUDY 
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 
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 
 
 
 
X 
 
 
 
 
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 
 
IBS-QOL PRO 
 
X 
 
 
 
X 
 
X 
10 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 10 of 25 
 
Evaluation 
Screen 
Treatment Period 
RW Period 
Site Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Study Day(s) 
-14 
1±3 
15±3 
29±3 
57±3 
85±3 
99±3 
113±3 
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 
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 visit after randomization
11 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 11 of 25 
 
2.3 
Efficacy and Safety Variables 
2.3.1 
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 in 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 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. An endpoint week will be defined as the last valid week 
during the 12-week treatment period with an overall responder criteria assessment. 
The CSBM response criteria are 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 weekly CSBM responder rates will be 
summarized for each week of the treatment period and the RW period. An endpoint week 
will be defined as the last valid week during the 12-week treatment period with a CSBM 
response criteria assessment. 
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 multiplied by 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. An endpoint week will be defined as the last valid week during 
12 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 12 of 25 
 
the 12-week treatment period with an average weekly CSBM. Baseline for the 4-week RW 
period will be the last valid week of the treatment period. 
The abdominal pain response criterion is defined as a decrease of 30% or more of percent 
change in average weekly worst abdominal pain from baseline. 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. 
A valid week will require at least 4 days of abdominal pain reporting. 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. An endpoint week will be defined as the 
last valid week during the 12-week treatment period with an average weekly abdominal pain 
score. 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.  
For each of the sets of efficacy variables described above (i.e., 6/12 and 9/12 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 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 repeated, only the overall and abdominal pain responder rates.     
Secondary efficacy variables will include the following: 
 The durable overall responder rate, durable overall CSBM responder rate, and durable 
overall abdominal pain responder rate will be secondary efficacy variables. 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. 
The proportion of subjects with ≥ 3 CSBMs per week will be summarized for the baseline, 
treatment, and RW periods. An endpoint week will be defined as the last valid week during 
the 12-week treatment period with an average weekly CSBM. 
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 
13 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 13 of 25 
 
will be summarized using the observed data. An endpoint week will be defined as the last 
valid week during the 12-week treatment period with an average weekly SBM. 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 will be calculated as described for the CSBMs 
and SBMs. An endpoint week will be defined as the last valid week during the 12-week 
treatment period with an average weekly stool consistency. 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 will be calculated as described for the CSBMs 
and SBMs. An endpoint week will be defined as the last valid week during the 12-week 
treatment period with an average weekly straining score. 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 and 9/12 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 will be calculated as described for the 
CSBMs and SBMs. An endpoint week will be defined as the last valid week during the 12-
week treatment period with an average weekly abdominal symptom score. Each symptom 
will be assessed separately so it is possible for different symptoms to have different endpoint 
weeks. Baseline for the 4-week RW period will be the last week of the treatment period. 
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 these severity 
ratings will be the average of the two ratings during the screening period. An endpoint week 
will be defined as the last valid week during the 12-week treatment period with an IBS 
severity or constipation severity rating. Baseline for the 4-week RW period will be the last 
week of the treatment period. 
14 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 14 of 25 
 
Adequate relief of IBS symptoms (1 = yes, and 2 = no) will be asked on a weekly basis 
during the treatment and RW periods. The percentage of subjects with adequate relief for 
each week of the study will be summarized using observed data. An endpoint week will be 
defined as the last valid week during the 12-week treatment period with an adequate relief of 
IBS symptoms response. 
Degree of relief of IBS symptoms will be scored on a weekly basis during the treatment and 
RW periods 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. An endpoint week will be defined as the last valid week 
during the 12-week treatment period with a degree of relief of IBS symptoms response. 
The IBS-QoL is a validated quality of life tool used for IBS patients (see Appendix D of the 
protocol). 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 IBS-QoL includes 34 individual questions which measure 8 subscales 
found to be relevant to patients with IBS: dysphoria, interference with activity, body image, 
health worry, food avoidance, social reaction, sexual, relationships and overall. Each of the 
subscale scores is calculated using the criteria described in the IBS-QoL user manual 
attached as Appendix 1 to this SAP.  
All items in the IBS-QoL are negatively framed with the greatest response scale equaling the 
worst quality of life. When scored, all items are reversed so that the as IBS-QoL scores 
increase, quality of life increases. i.e., 1changes to 5, 2 changes to 4, 3 stays as 3, 4 changes 
to 2, and 5 changes to 1. Then the reversed individual responses to the 34 items are summed 
and averaged for a total score and then transformed to a 0-100 scale for ease of interpretation 
with higher scores indicating better IBS specific quality of life using the following formula: 
.
100
range
 
score
 
raw
 
possible
score)
 
possible
lowest 
 - 
items
 
 the
of
 
sum
 
(the
 
Score
 
Subscale


 
Actual values and change from baseline values for each of the subscale scores will be 
calculated and 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: 
15 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 15 of 25 
 
Table 2-1                        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  
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 
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 
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 
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 
Secondary 
Durable overall responder rate 
Secondary 
Durable overall CSBM responder rate  
Secondary 
Durable overall 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 
16 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 16 of 25 
 
Secondary 
Average weekly straining score 
Secondary 
6/12 and 9/12 Overall abdominal discomfort responder rate 
Secondary 
6/12 and 9/12 Overall abdominal bloating responder rate 
Secondary 
6/12 and 9/12 Overall abdominal cramping responder rate 
Secondary 
6/12 and 9/12 Overall abdominal fullness 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 
2.3.2 
Safety Variables 
Safety variables will include adverse event (AE) reporting throughout the trial, clinical 
laboratory tests (serum chemistry, hematology, and urinalysis), vital signs (including body 
weight and body mass index [BMI]), 12-lead ECG, and physical examinations.  
3. 
STATISTICAL METHODOLOGY 
3.1 
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.  
17 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 17 of 25 
 
3.2 
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, are randomized and 
receive at least one dose of study drug 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. 
Per-Protocol (PP) Analysis Set 
All subjects included in the ITT analysis set who complete the study as planned with no 
major protocol deviations will be included in the PP analysis set. Membership in this analysis 
set will be determined at a data review meeting prior to unblinding the randomization. This 
analysis set will be used as a sensitivity analysis relative to the ITT analysis set.  
3.3 
Procedures for Handling Missing Data 
The primary analysis will be based on the observed data where average weekly SBMs and 
CSBMs will be standardized to 7-day frequencies. This amounts to missing days 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) 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. In the few cases where no efficacy data is collected 
during the 12-week treatment period, the endpoint week will be considered a non-response or 
missing if no frequency or stool consistency data are obtained. 
Otherwise, all other observed data will be used in the analyses. 
18 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 18 of 25 
 
3.4 
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. Initial US geographic 
regions will consist of north east, east, south east, mid west, mid south, and west,  These 
regions could be further sub-divided based on enrollment but no sites will be classified 
outside of their logical geographical region.  
In terms of achieving comparable sample sizes, 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.  
3.5 
Visit Windows 
Daily IVRS diary data are planned for daily collection starting on the day of the Screening 
visit and continuing until the planned 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 
19 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 19 of 25 
 
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. 
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. 
3.6 
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%. 
20 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 20 of 25 
 
3.6.1 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. 
3.6.2 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 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. 
3.6.3 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. Prior 
medications include medications that were started and stopped prior to the first dose of study 
drug. Concomitant medications include medications that started any time and were taken at 
any time after the first dose of study drug until the end of the follow-up period. Medications 
missing both start and stop dates or having a start date prior to the start of study drug and 
missing stop date will be counted as concomitant. 
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. If a subject took a particular coded medication more than once, 
the subject will be counted once for that coded medication total. If a subject had more than 
one coded medication in a therapeutic class, the subject will be counted only once in that 
21 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 21 of 25 
 
therapeutic class total. Summary tables will be presented for each of the analysis sets. Prior 
medications will be summarized separately from concomitant medications. 
A listing of all medications including the reported term, preferred name, ATC class, start and 
stop dates, and other relevant data will be provided. 
3.6.4 
Study Drug Exposure and Compliance 
Days of exposure to randomized study drug will be summarized with descriptive statistics by 
treatment group for each of the analysis sets. In addition, a contingency table will be 
provided to display the number and percentage of subjects in each treatment group with 
exposure in the following categories: ≤2 weeks, >2 to ≤4 weeks, >4 to ≤8 weeks, >8 to ≤12 
weeks, and >12 weeks.  
Days of possible exposure is defined as: 
 
date of last dose of study drug – date of first dose of study drug + 1. 
When the last known dose date is missing, the last known clinic visit date during the 
treatment period will be used, and the plus 1 will be removed from the calculation. 
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. 
Summary statistics will be presented for percent compliance to study drug by treatment 
group. The count and percentage of subjects with overall compliance <80%, 80%-100%, 
100%-120% and >120% will also be tabulated by treatment group. 
3.7 
Statistical Analyses 
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.  
3.7.1 
Efficacy Analyses  
The primary objective of this study will be to demonstrate the superiority of tenapanor over 
placebo in the proportion of subjects who are weekly overall responders at 6 or more of the 
first 12 weeks of treatment. 
The ITT analysis set will be used for the analysis of the primary, key secondary, secondary, 
and all sensitivity analyses.  The PP analysis set will be used for the analysis of the primary, 
key secondary, and secondary variables as a separate sensitivity analysis. All efficacy 
22 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 22 of 25 
 
analyses will be carried out based on observed cases (OC) with imputation as described 
previously in Section 3.3. 
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. These analyses include subject based variables and variables 
summarized weekly. 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 
tenapanor 50 mg BID versus placebo. The 95% CI versus placebo will also be presented for 
the adjusted relative risk.  
All change from baseline or percent change from baseline 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 covariate.  These analyses include variables 
summarized weekly or on a visit basis.   
Actual values for 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 
analyses.  Treatment effects will be evaluated based on a 2-sided significance level of 0.050 
for the difference in LSmeans between treatment groups. The 95% CI for difference in  
LSmeans will also be presented.  When the ANOVA model is implemented, all of the above 
statistics will be presented for the actual values.  
The Mantel-Fleiss criterion for the CMH test will not be computed. Because the sample size 
of the two treatment groups is relatively large, the CMH test will be valid. Other secondary 
analyses using the ANCOVA model or ANOVA model will also not have assumptions 
testing (e.g., normality, parallelism, or homogeneity of variances) carried out.   
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 2-1 will be tested at the 
5% level. If this test is significant, then the next key secondary efficacy variable is tested at 
the 5% level. This procedure continues until one of the key secondary efficacy variables in 
the list (5 variables total) results in a p-value >5%.  Key secondary efficacy variables up to 
this point in the list will be declared statistically significant. 
23 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 23 of 25 
 
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. Figures depicting the means for each treatment group over 
time will be presented for average weekly CSBMs, SBMs, stool consistency, straining score, 
abdominal pain, discomfort, bloating, cramping, and fullness scores. Figures depicting the 
means for each treatment group over time will be presented for weekly IBS severity score, 
constipation severity score, adequate relief of IBS symptoms, and degree of relief of IBS 
symptoms. 
A secondary analysis will also include graphs depicting the cumulative distribution of the 
percentage reduction from baseline in abdominal pain.   
3.8 
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. 
3.8.1 
Adverse Events 
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. A treatment-emergent AE (TEAE) is 
any AE that starts on or after the first dose of study drug through the end of the RW period or 
any event that is considered drug related regardless of the start date, or any event which 
occurs prior to the first dose of study drug and worsens in severity after the first dose of study 
drug.  An AE is considered drug related if it is possibly related or probably related to study 
drug.  
TEAEs will also be tabulated by whether events are considered related to treatment and by 
severe severity.  Serious adverse events and TEAEs resulting in study discontinuation will be 
tabulated.   
Summarization of AEs will include subject incidence of the following: 
 All TEAEs 
 Drug-related TEAEs 
 Severe TEAEs 
 Severe and drug-related TEAEs 
 Serious Adverse Events (SAEs) 
 Drug-related SAEs 
 Death due to AEs 
 TEAEs leading to study drug discontinuation 
 Drug-related TEAEs leading to study drug discontinuation 
24 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 24 of 25 
 
An overall summary table will contain the number and percentage of subjects ever having 
one of the above listed subsets of AEs. All TEAEs will be summarized for each treatment 
group by MedDRA system organ class (SOC), by SOC and preferred term (PT), and by PT 
with the number and percentage of subjects. If a subject has more than 1 occurrence of the 
same TEAE, he/she will be counted only once within that preferred term and system organ 
class in the summary tables. The most severe occurrence of a repeat TEAE, as well as the 
most extreme relationship of the TEAE to the study drug will be used for the analyses.  
TEAEs related to study drug, severe TEAEs, serious adverse events (SAEs), and TEAEs 
leading to study drug discontinuation will be summarized in the same manner. That is, 
summaries will be provided for the numbers and percentages of subjects by SOC, SOC and 
PT, and PT. 
All AEs will be included in by-subject listings. Specific by-subject listings of SAEs and 
TEAEs leading to study drug discontinuation will be provided. The number of days between 
first dose and when the event occurred will be presented in listings as well (i.e., relative study 
day), as will duration of the AE. 
3.8.2 
Clinical Laboratory Tests 
The list of clinical laboratory tests collected for this study are presented in Appendix C of the 
protocol. Serum chemistry, hematology, and urinalysis results will be summarized with 
descriptive statistics at Screening (Visit 1/Day -14), Week 4 (Visit 4/Day 29), Week 12 (Visit 
6/Day 85), and Week 16 (Visit 8/Day 113) by treatment group. For continuous tests, actual 
values and change from screening will be summarized. For categorical tests, the number and 
percentage of subjects in each category will be presented for each visit. Serum chemistry 
tests included in these summaries will be albumin, alkaline phosphatase, ALT, AST, 
bicarb/CO2, total bilirubin, direct bilirubin, indirect bilirubin, calcium, chloride, total 
cholesterol, creatinine, glucose, inorganic phosphorous, LDH, potassium, total protein, 
sodium, triglycerides, BUN/urea, and uric acid. Hematology tests included in these 
summaries will be WBC, RBC, MCV, MCH, MCHC, hemoglobin, hematocrit, and platelet 
count. Differentials consisting of bands, monophils, neutrophils, eosinophils, lymphocytes, 
and basophils will be included in the listings only. Urinalysis tests included in these 
summaries will be appearance, specific gravity, and pH. Protein, glucose, ketones, blood, 
nitrite, and microscopic results will be presented in listings only.  
The frequency of clinically significant abnormal laboratory test values will be tabulated by 
treatment group. 
Shift tables classifying normal range results (low out of normal range, normal, or high out of 
normal range) between Screening and Week 4 (Visit 4/Day 29), Week 12 (Visit 6/Day 85), 
and Week 16 (Visit 8/Day 113) values will be tabulated by treatment group. Missing results 
for each pairwise summary will be tabulated.  
Data listings of clinical laboratory tests will include flags for abnormal results. 
25 of 79


 
Ardelyx, Inc. 
Clinical Study Protocol TEN-01-301   
CONFIDENTIAL 
Version V1.1 
Statistical Analysis Plan 
16 December 2015 
 
 
 
Page 25 of 25 
 
3.8.3 
Vital Signs and 12-lead Electrocardiogram 
Vital signs (body weight, BMI, heart rate, respiratory rate, mean sitting systolic blood 
pressure, mean sitting diastolic blood pressure, and temperature) 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 (heart rate, PR interval, QRS duration, QT, QTcB and QTcF 
intervals) 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 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. 
3.8.4 
Physical Examination 
Physical examinations (general appearance, HEENT, respiratory, cardiovascular, abdomen, 
skin, lymph nodes, musculoskeletal, extremities, and neurological) 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. 
4. 
PROGRAMMING SPECIFICATIONS 
The programming specifications, including the mock-up validity listings, list of analysis 
tables, figures, and data listings, will be prepared in a stand-alone document. The 
programming specification document will be finalized prior to database lock. 
 
26 of 79


 
 
A QUALITY OF LIFE MEASURE 
FOR PERSONS WITH 
IRRITABLE BOWEL SYNDROME 
(IBS-QOL) 
 
Donald L. Patrick, Ph.D., MSPH 
Douglas A. Drossman, MD 
Ihunnaya O. Frederick 
 
June 1997 
 
 
User’s Manual and Scoring Diskette 
 
 
 
U.S. Version 
 
 
University of Washington 
Seattle, Washington 
United States of America 
Emblem...Soul Catcher:  a Northwest Coast Indian symbol of physical and mental well-being. Artist: Marvin Oliver 
 
27 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
i
TABLE OF CONTENTS 
PURPOSE OF THIS MANUAL ...............................................................................................III 
ACKNOWLEDGMENTS ........................................................................................................ IV 
USER AGREEMENT............................................................................................................. V 
SUMMARY .........................................................................................................................1 
BACKGROUND AND SIGNIFICANCE ......................................................................................3 
Quality of Life in Persons with Irritable Bowel Syndrome ..............................3 
CONCEPTUAL MODEL AND APPROACH TO THE IBS-QOL ......................................................4 
Conceptual Model of Quality of Life..................................................................4 
Cultural Adaptation of the Instrument ..............................................................4 
The IBS-QOL Instrument....................................................................................5 
PSYCHOMETRIC PROPERTIES OF THE IBS-QOL....................................................................6 
Overview..............................................................................................................6 
Early Development: Item Generation and Reduction ......................................6 
Validation Study Sites, Recruitment, and Participation ..................................7 
Screening for IBS and Classification of IBS Symptom Pattern Types...........7 
Procedures and Measures .................................................................................7 
Psychometric Evaluation ...................................................................................9 
RESULTS.........................................................................................................................12 
Sample Characteristics ....................................................................................12 
Item reduction and Domain Structure of the IBS-QOL ..................................12 
Scores on HRQoL Assessment Instruments..................................................13 
RELIABILITY ....................................................................................................................15 
CONSTRUCT VALIDITY......................................................................................................16 
KNOWN-GROUPS DISCRIMINANT VALIDITY .........................................................................17 
28 of 79


 
 
IBSMAN.doc, 11/3/2005, 9:32:51 AM 
ii 
Reproducibility of Symptom-Pattern Classification.......................................19 
DISCUSSION.....................................................................................................................20 
Obtaining Comparative Data ............................................................................22 
ADMINISTRATION GUIDELINES ...........................................................................................23 
Interviewer Administration...............................................................................23 
SCORING THE IBS-QOL.....................................................................................................25 
Scoring Exercise and Test Dataset for the IBS-QOL......................................25 
LIST OF TABLES ..............................................................................................................27 
REFERENCES...................................................................................................................28 
APPENDIX A: SCREENING QUESTIONNAIRE ........................................................................31 
APPENDIX B: IBS-QOL QUESTIONNAIRE...........................................................................33 
APPENDIX C: IBS SYMPTOM FREQUENCY QUESTIONNAIRE .................................................41 
 
IBS SYMPTOM BOTHERSOMENESS QUESTIONNAIRE.................................................42 
APPENDIX D: DEMOGRAPHIC QUESTIONS...........................................................................43 
APPENDIX E: IBS-QOL INSTRUMENTS SPSS SCORING DISKETTE ......................................45 
 
29 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
iii
PURPOSE OF THIS MANUAL 
The purpose of this manual is to facilitate instrument administration, scoring, and 
interpretation of the United States version of the Irritable Bowel Syndrome Quality-of-Life 
Instrument.  This manual is specific to the U.S. version of the IBS-QOL instrument. 
 
 
 
 
 
 
Suggested citation: 
Patrick DL, Drossman DA, Frederick IO.  A Quality-of-Life Measure for Persons with 
Irritable Bowel Syndrome (IBS-QOL):  User’s Manual and Scoring Diskette for United States 
Version.  Seattle, Washington:  University of Washington, 1997. 
 
 
 
 
 
Address all inquiries concerning this manual to: 
Donald L. Patrick 
University of Washington 
146 N. Canal Street, Suite 310 
Seattle, Washington 98103 
United States of America 
Telephone number: 
(206) 616-7393 
Facsimile number: 
(206) 616-3135 
E-mail: 
 
donald@u.washington.edu 
30 of 79


 
 
IBSMAN.doc, 11/3/2005, 9:32:51 AM 
iv 
ACKNOWLEDGMENTS 
Preparation of this manual was supported by a grant to the University of Washington 
(Grant no. HTF 919 AMII) from the Novartis Company.  We thank Joseph DiCesare and Jeffrey 
Schein for their support of the data collection, analysis, and production of this manual. 
The IBS-QOL Investigator Team , in addition to the authors of this manual, Katherine L. 
Puder, formerly from the  Pharmacoeconomics Department, Sandoz Pharmaceuticals 
Corporation, East Hanover, New Jersey, and now Director, Outcomes Research, In-Line 
Products of SmithKline Beecham Pharmaceuticals and Division of Health Policy and 
Management, Columbia University School of Public Health, New York, New York and Joseph 
DiCesare, Pharmacoeconomics Department, Sandoz Pharmaceuticals Corporation, East Hanover, 
New Jersey.  All have reviewed this manual for completeness and correctness of the information. 
We thank Martin D. Gelfand, MD for his chart review and clinical opinion, Dawn 
Provenzale, MD and Dr. Gelfand for their help in recruiting participants, Mona Martin for 
project administration and review of the manuscript, Charlotte Glogau and Paul Froese for 
recruitment and general research assistance, Donald Bushnell and Zhiming Li, MD, Ph.D. for 
help in computing and data analysis. 
Finally, we wish to thank Amy Bonomi, MPH,  David R. Seber, Catherine McFarland, 
Shannon Manuszewski, and Darian Shaw (University of Washington Northwest Prevention 
Effectiveness Center) for their assistance in the production of this manual. 
The views expressed in this manual are the authors’ own and do not necessarily represent 
the opinions of the other investigators participating in the project nor the views or policy of the 
Novartis Corporation. 
31 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
v
 
USER AGREEMENT 
The University of Washington, the University of North Carolina, and Novartis 
Pharmaceuticals jointly hold the copyright to the IBS-QOL and one of these copyright holders 
must be notified in writing prior to using the instrument.  Permission to use the instrument in any 
pharmaceutical-related project must be requested and granted in writing from Novartis 
Pharmaceuticals. 
 
Donald L. Patrick, Ph.D., MSPH 
Department of Health Services, H689 
Box 357660, University of Washington 
Seattle, Washington 98195-7660 
Tel: 
(206) 616-7393 
Fax: 
(206) 616-3135 
 
Douglas A. Drossman, MD 
University of North Carolina at Chapel Hill 
Burnett Womack Building 
CB 7080, Room 420 
Chapel Hill, North Carolina 27599-7080 
Tel: 
(919) 966-0141 
Fax: 
(919) 966-8929 
 
Jeff Schein, Dr.PH, MPH 
Novartis 
59 Route 10, Bldg. 701/4 
East Hanover, New Jersey 07936 
Tel: 
(201) 503-7112 
Fax: 
(201) 503-6707 
 
© Univ. Washington, Univ. North Carolina, Novartis 1997, all rights reserved
32 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
1
SUMMARY 
How irritable bowel syndrome and its treatment affect quality of life is important to 
patients and their significant others, clinicians, researchers, and administrators of health care 
systems.  The overall objective of this project is to develop a quality-of-life measure specific to 
irritable bowel syndrome (IBS-QOL) that is grounded in the experience of persons with the 
syndrome and that meets criteria for use in epidemiologic investigations and clinical trials.  To 
date, the psychometric properties of the instrument have been tested at a point in time only, 
permitting evaluation of the IBS-QOL to discriminate among known groups and to test the 
measurement model, internal consistency, reproducibility, construct validity, interpretability and 
burden.  Later studies will permit investigation of the responsiveness of the measure and 
calculation of effect sizes for clinical trial use 
Instruments were sought using a conceptual model of the components of health-related 
quality of life that includes symptoms, functional status, perceived quality of life, and disability.  
No measure of perceived quality of life specific to IBS was found and thus instrument 
development proceeded for the IBS-QOL.  Finally, because the measure is intended for 
international use, cultural adaptation of the IBS-QOL was sought prior to the test of the cross-
sectional psychometric properties of the instrument in the United States. 
Qualitative interviews were conducted with persons who were diagnosed with irritable 
bowel syndrome using the Rome criteria.  Clinicians in the U.S. and Europe were also 
interviewed to elicit an item pool consisting of 117 items describing the subjective effects of IBS 
and its treatment.  This item pool was reduced through cognitive debriefing with an additional 
sample of persons with IBS and investigator review of each potential item.  Cultural adaptation 
for European versions was achieved through interviews with patients in European countries, 
forward and back translation, and harmonization.  These steps produced a 41-item version for 
testing in the U.S. 
Psychometric properties were evaluated with 156 persons with IBS, involving two 
administrations with 89 persons and comparison with generic health status and psychologic 
instruments.  Persons with IBS were recruited from advertisements in local newspapers and 
consulters in outpatient clinics in Seattle, Washington and Chapel Hill\Durham, North Carolina. 
The final IBS-QOL consists of 34 items that produce an overall score and eight subscale 
scores including Dysphoria, interference with activity, body image, health worry, food 
avoidance, social reaction, sexual, and relationships. 
The IBS-QOL demonstrated high internal consistency (Cronbach’s alpha= 0.95) and high 
reproducibility (ICC=0.86) with average time of 7 days (SD 1).  For discriminant validity: 
number of symptoms (p<.05), self-reported severity of symptoms (p<.001), and a validated 
severity measure for IBS, FBDSI (p<.001) significantly predicted IBS-QOL scores. Convergent 
validity analyses confirmed predictions that scores are more closely related to overall well-being 
(PGWB) than function (SF-36).  The IBS-QOL correlated strongly with total well-being (.45), 
health worry and concern (.45), and behavioral and emotional control (.41), and less strongly 
33 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
2 
with physical functioning (.36) and vitality (.30).  A lower correlation of -.22 was observed 
between the IBS-QOL and FBDSI. 
The original U.S. version of the IBS -QOL has high content validity, meets established 
psychometric criteria for reliability and cross-sectional validity, and is translated into five 
languages.  Testing of its responsiveness is warranted in future studies. 
34 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
3
BACKGROUND AND SIGNIFICANCE 
Quality of Life in Persons with Irritable Bowel Syndrome 
Irritable Bowel Syndrome (IBS) is a gastrointestinal disorder that manifests itself as 
chronic or recurrent symptoms of  abdominal pain associated with disturbed bowel function, i.e., 
diarrhea and/or constipation and/or symptoms of bloatedness and distension.  Symptoms 
consistent with the diagnosis of IBS vary from 9-22% in the population and tend to vary in 
frequency depending on the criteria used 1.  Like many functional disorders, IBS may be 
influenced by a variety of cultural, social environmental and behavioral factors.  Diet, hormonal 
influences (e.g., menses), psychologic stress and activity level may exacerbate IBS symptoms 2. 
Irritable bowel syndrome is a common disorder that can be associated with significant 
disability and health care costs 3.  Despite its prevalence in the population, understanding of the 
disorder and management of persons with the disorder has been difficult, in part because of a 
lack of precise definition and conflicting views of the pathophysiology of the condition. IBS is 
now believed to result from dysregulation of intestinal motor, sensory, and CNS function.  
Symptoms arise from both disturbances in intestinal motility and enhanced visceral sensitivity.  
Psychosocial processes play a role in the disorder, although are not part of the irritable bowel per 
se, since they influence illness recognition, use of services and treatments, and response to 
treatments, pharmacologic and non-pharmacologic. 
To improve the recognition and diagnosis, international working teams of experts, using 
a consensus approach, have developed a classification system known as the “Rome” criteria for 
24 functional gastrointestinal disorders 4.  The irritable bowel syndrome was defined as a 
“combination of chronic or recurrent gastrointestinal symptoms not explained by structural or 
biochemical abnormalities” which is “attributed to the intestines and associated with symptoms 
of pain and disturbed defecation and/or symptoms of bloatedness and distension”.  Thus, IBS can 
present with a constellation of symptoms that can be characterized by the layperson as 
abdominal pain, diarrhea, constipation, or a mixture of both. 
As scientific attention focuses increasingly on the understanding of and care for persons 
with IBS, concomitant interest arises in exploring how the disorder and its treatment influence 
health-related quality of life (HRQoL) of patients. Given the lack of clearly-identified structural 
and biochemical bases for IBS, quality of life concerns are extremely important to the 
understanding of how biology intermingles with the cultural, social, interpersonal, and 
psychological aspects. 
Reviews of the concepts contained in existing generic and gastrointestinal-specific 
measures of HRQoL and reports from focus groups with patients with IBS indicated, however, 
that no measure was currently available that addressed their specific concerns.  Furthermore, no 
measures were organized according to a formal conceptual structure for assessing quality of life 
for persons with IBS.  Because of these concerns, we developed and validated the Irritable 
Bowel Syndrome Quality of Life (IBS-QOL) instrument 5. 
35 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
4 
CONCEPTUAL MODEL AND APPROACH TO THE IBS-QOL 
Conceptual Model of Quality of Life 
The IBS-QOL instrument was constructed using a conceptual model of health-related 
quality of life proposed by Patrick and Erickson 6 that distinguishes symptoms, functional status, 
perceived quality of life and social disability as components.  In this multidimensional approach, 
assessment of disease and treatment outcomes may include measures of all these concepts and 
their relationships.  Where possible, existing measures are preferable to the time and other 
resources necessary to create and validate instruments.  Although a number of clinical 
assessment tools exist for IBS and numerous generic functional status measures are available, no 
measure specific to IBS was available that included self-reported measures of symptom 
frequency and bothersomeness as well as perceived quality of life.  While construction of 
symptom frequency and bothersomeness measures involve clinical consensus of items to 
include, the definition and assessment of perceived quality of life is grounded in the persons with 
the disorder and instrument development must involve these persons as closely as possible. 
Perceived quality of life is defined according to a needs-based model 7 that identifies 
quality of life as the degree to which most or all human needs are met.  This approach is similar 
to that developed by the World Health Organization in the cross-cultural development of a 
generic quality-of-life measure 8.  The WHOQOL group defined quality of life as individuals’ 
perceptions of their position in life in the context of the culture and value systems in which they 
live, and in relation to their goals, expectations, standards, and concerns 9.  The IBS-QOL was 
conceived to be such a quality-of-life measure specific to persons with the symptom 
constellations of irritable bowel syndrome and including all the human concerns related to these 
symptoms. 
Cultural Adaptation of the Instrument 
Because we wanted the IBS-QOL to be available for eventual use in international clinical 
trials, we also utilized standardized steps in the development and validation of cross-cultural 
quality-of-life measures formulated at the University of Washington 10, 11, 12.  Thus, we 
embarked on a cultural adaptation of the instrument concurrent with its development and 
validation in the United States.  The IBS-QOL has been adapted for use in the following 
language versions: UK English; Dutch; French; German; and Italian. 
Prior to the final generation of items for the first draft of the IBS-QOL, the list of 
potential items were reviewed by QOL-translation specialists for obvious difficulties that would 
be encountered in the translation process.  The final formulation of selected items was influenced 
by this early stage, as first step towards cross-cultural adaptation. 
The next step involved, primary and secondary consultants in each country.  In most 
cases, the primary consultants were quality-of-life experts and the secondary consultants were 
linguistic experts, thus combining diverse, yet relevant expertise.  Both consultants produced 
forward translations of the IBS-QOL, the Rome criteria for IBS, and demographic information.  
The primary and secondary consultants then worked together to reconcile their forward 
36 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
5
translations.  The primary consultant presented the reconciled version to a group of eight 
individuals with irritable bowel syndrome selected according to the Rome Criteria.  The purpose 
of this pretest was to ensure that people with IBS in that culture (1) found each question relevant 
in that culture; (2) identified items or questions that had not been elicited in the U.S., and (3) 
could understand each item.  The adaptation culminated in a harmonization meeting in which all 
problems in conceptual and linguistic equivalence of items generated in the U.S. were discussed, 
suggestions for additional items from each culture were presented and discussed, and a final 
forward translation was prepared for all components of the IBS-QOL, symptom measures, 
demographic information, and data collection forms.  A single back translation was prepared  by 
an independent translator and all discrepancies were reconciled with the primary consultant. 
Final modifications were made in the U.S. version of the IBS-QOL before proceeding with the 
U.S. validation study. 
Persons interested in the different language versions of the IBS-QOL should contact the 
following person for information on their availability: 
Tom Hogan 
Corporate Health Economics 
Novartis Corporation 
202/   Lichstrasse 
CH-4002 Basel, Switzerland 
Phone: 011-41-61-324-4703 
Fax: 
011-41-61-324-4296 
 
The IBS-QOL Instrument 
The IBS-QOL consists of  34 items (see Appendix B) relating to symptoms of IBS.  The 
IBS-QOL uses a 5-point Likert response scale to assess how much each item describes the 
respondent’s feelings to a particular symptom: not at all, slightly, moderately, quite a bit, and 
extremely or a great deal. All 34 items are scored through simple, summative scaling to derive an 
overall total score and eight subscales including Dysphoria, Interference with activity, Body 
Image, Health worry, Food avoidance, Social Reaction, Sexual, and Relationships.  To facilitate 
interpretation of scores, the summed total score is transformed to a 0-100 scale ranging from 0 
(poor quality of life) to 100 (maximum quality of life).  The IBS-QOL can be administered with 
the IBS Symptom Frequency and Bothersomeness Questionnaires contained in Appendix C. 
  
37 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
6 
PSYCHOMETRIC PROPERTIES OF THE IBS-QOL 
Overview 
Five consecutive steps were followed to develop and to conduct psychometric testing on 
the IBS-QOL: (1) establishment of a framework for assessment that identified components of a 
self-reported health and outcomes battery to contain measures of the symptoms of IBS, generic 
functional status and well-being, perceived quality of life specific to IBS, and work disability; 
(2) elicitation of QOL items specific to IBS in the United States; (3) evaluation of the cross-
cultural conceptual and linguistic equivalence of symptoms and QOL items; (4) development 
and refinement of the draft IBS-QOL questionnaire; and (5) evaluation of the psychometric 
properties of the IBS-QOL in a formal validation study using other instruments for validation 
and comparison. 
Early Development: Item Generation and Reduction 
Items for the IBS-QOL measure were developed from literature review, interviews with 
clinicians in the United States and Europe, and in-depth interviews of 40 individuals at the 
Universities of Washington and North Carolina with three symptom constellations of IBS: 
constipation predominant, diarrhea predominant, and mixed constipation/diarrhea.  These 
patients were identified and classified according to symptom constellation using the Rome 
Criteria (Appendix A). 
Interviews began by asking patients how IBS affected their quality of life and continued 
with prompts and open-ended responses.  Interviews were taped and transcribed to aid 
identification of statements considered important by respondents.  This elicitation process 
produced 117 potential items describing in the language of the participants how IBS affected 
perceived quality of life, interfered with the attainment of personal goals, or kept persons with 
the condition from meeting their perceived needs.  No items were copied from existing 
questionnaires.  All items were reviewed by investigators for their potential ability to be 
translated into European languages, their relevance to the needs-based model and all persons 
with the condition, their potential ability to discriminate among different levels of IBS severity, 
their importance as rated by patients, and their potential ability to detect change over time. 
For the initial item reduction phase, an additional 30 individuals participated in cognitive 
debriefing interviews to refine the measure.  Items that did not apply to all persons with IBS, 
were not subjective perceptions related to identified needs, were less important to persons with 
the condition, and were not potentially able to be culturally adapted in European languages were 
eliminated.  In cognitive debriefing, persons with the condition were asked to “think aloud” in 
responding to items, to address the meaning of their responses, to evaluate the format of the 
questions and response scales, and to address the relative importance of each item to overall 
quality of life. 
Investigator review of all items, the cognitive debriefing with thirty persons with IBS, 
and the cultural adaptation process reduced the original 117 items to a 41-item pilot quality-of-
life measure for the U.S. validation study. 
38 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
7
Validation Study Sites, Recruitment, and Participation 
Following a written protocol of standardized procedures, a multi-center, cross-sectional 
validation study was conducted by a multi-disciplinary team at the University of Washington in 
Seattle (UW) and the University of North Carolina at Chapel Hill (UNC).  The study was 
approved by the Institutional Review Boards (IRBs) at both universities. 
We set out to recruit 145 participants to participate in the study through GI practitioners 
and newspaper advertisement.  We established a sampling quota by type of IBS symptom pattern 
as follows: 60 with constipation-predominant symptoms, 35 with diarrhea predominant 
symptoms, and 50 with mixed symptomatology.  Enrollment criteria included persons who a) 
met the Rome Criteria diagnosis for IBS; b) had abdominal symptoms for at least 2 days each 
week; c) were age 18 to 65 years. We excluded persons unable to clearly understand the study 
procedures or questions posed to him or her; unable to complete the requirements of the study; 
and those with another medical condition that could explain bowel symptoms.  This assessment 
was made by chart review or discussion with the referring physician by one of the authors at the 
University of North Carolina at Chapel Hill and by a gastroenterologist in Seattle, Washington. 
Screening for IBS and Classification of IBS Symptom Pattern Types.  
We used the symptom-based diagnostic Rome criteria for screening and subclassifying 
IBS patients into any of three symptom pattern types.  Symptom pattern type was assessed by 
telephone at screening for entry into the study and by self-administration in the first 
questionnaire.  The actual questions and algorithm for classification is contained in Appendix A. 
Procedures and Measures 
Most participants received the first survey by mail, although five participants self-
administered the baseline questionnaire under supervision in the clinic at the University of North 
Carolina.  Of the 156 participants, 89 were randomized to retest 14 days later  and received the 
follow-up questionnaire in a sealed envelope with instructions on the outside for the day it was to 
be completed and with a postage paid return envelope.  Follow-up telephone calls were made 
two days after the package was mailed and on the day the retest was to be completed. 
The following measures, included in the baseline assessment, are described in the order 
of their appearance in the self-administered survey package: 
IBS-QOL.  Forty-one IBS-specific quality-of-life items (see Appendix B) were asked as 
descriptive statements using a recall period of the past month (30 days).  A 5-point Likert 
response scale was used to assess how much the statement described the feelings of the 
respondent: not at all, slightly, moderately, quite a bit, and extremely or a great deal. All items 
were sum-scored to calculate total scores.  To facilitate analysis and interpretation of scores, the 
summed scores were transformed to a 0-100 scale ranging from 0 (poor quality of life) to 100 
(maximum quality of life).  Transformation involved subtracting the lowest possible raw score 
from the actual raw score, dividing by possible raw score range, and multiplying by 100. 
39 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
8 
Symptom Frequency and Bothersomeness.  A 13-item self-administered IBS symptom 
questionnaire based on symptoms from the Rome Criteria and others known to be associated 
with IBS was constructed for use in this study Appendix C.  These items were generated by 
clinicians and researchers familiar with IBS and its treatment in both the United States and 
Europe.  This followed similar methodology used in other HRQoL validation studies using 
symptom frequency and bothersomeness as a measure of perceived impairment 6, 13.  Symptom 
frequency was assessed on a 7-point response scale (0=Never, 1=Almost never, 2=Seldom, 
3=Sometimes, 4=Often, 5=Almost always, 6=always).  Respondents were asked how often they 
had any of the symptoms in the past month (30 days).  Symptom bothersomeness was assessed 
on a 7-point response scale (0=Not bothersome to 6= Extremely bothersome).  Possible scores 
on both measures range from 0-91.  IBS symptom frequency and bothersomeness indexes were 
calculated by dividing total symptom scores by 13. 
Functional Bowel Disorder Severity Index (FBDSI).  This measure assesses illness 
severity in functional bowel disorders and has been used by clinicians to rate and to stratify 
patients by severity of illness 14.  The three components of this index are pain intensity, (0-100 
visual analogue scale), diagnosis of chronic functional abdominal pain, and number of doctor 
visits in the previous six months. We developed a self-administered version of this clinician 
rating scale and used this as an assessment of severity in addition to the symptom frequency and 
bothersomeness measures.  Consistent with the severity groupings previously reported 13 subjects 
having the FBDSI scores in the lowest quartile were considered to have mild severity (mild), 
those in the middle half, moderate severity (moderate), and those with the highest quartile 
scores, the greatest severity (severe). 
Medical Outcome Study Short Form (SF-36).  Generic functional status and well-being 
was assessed using the SF-36 questionnaire, a measure widely used in clinical practice and 
research, health care policy evaluations, and general population surveys 15.  This questionnaire 
produces a profile of eight domain scores, including physical functioning, physical role 
limitations, emotional role limitations, social functioning, bodily pain, general mental health, 
vitality, and general health perceptions.  Two summary measures can be constructed to assess the 
physical and mental components.  Each domain is scored from 0 (poor health) to 100 (optimal 
health). 
Psychological General Well-Being Scale (PGWB).  This 22-item measure of general 
psychological well-being was developed by 16 and can be scored as a total score or as six 
subscales of health worry and concern, positive well being, depressed mood, behavioral and 
emotional control, energy level, and tension and anxiety.  Scores range from 0-100; higher 
scores indicate higher well-being. 
The Symptom Check List (SCL90-R).  This is a 90-item self-report questionnaire that 
identifies nine psychological symptom complexes and yields a global score as well as the nine 
subdomain scores of somatization, obsessive compulsiveness, interpersonal sensitivity, 
depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Mean scores 
range from 0-4, with higher scores indicating greater psychological distress 17. 
40 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
9
Work-Loss Days.  Questions were included to investigate if a participant was not 
working because of his or her bowel problems and the number of work-loss days in the past year 
he or she attributed to bowel problems. 
Additional questions on the self-administered baseline survey included the following: 
Rome criteria, a self-rating of the severity of  bowel problems on a 3-point response scale of 
mild, moderate, and severe; and questions on gender, age, education, marital status, race, and 
income of study participants.  The survey completed at retest included the IBS-QOL, a global 
rating of change in quality of life over the last two weeks on a 15-point rating scale ranging from 
“a very great deal worse” to “a very great deal better”.  The retest questionnaire was printed on a 
different color of paper from the first to avoid any confusion and mistakes in mailing or data 
handling. Patients were paid $15 for each completed set of questionnaires returned. 
Background characteristics of participants were described by frequency, mean, standard 
deviation, minimum and maximum values, percentages, and missing data.  Other characteristics 
(i.e. gender, race, education level and working status) were described by the frequency and 
percentage of the response choices.  Some of these characteristics were controlled for in further 
analyses where appropriate.  The data from each site were first analyzed separately.  Data for 
both sites were then pooled in analyses after it was found that the samples were statistically 
similar. 
Psychometric Evaluation 
The psychometric testing of the IBS-QOL was conducted using standardized procedures 
18 and the instrument review criteria developed by the Scientific Advisory Committee of the 
Medical Outcomes Trust 19.  Because this was a cross-sectional validation study, no data are 
presented on change over time; this characteristic is being evaluated in the context of a clinical 
trial and longitudinal epidemiologic investigation. 
Item reduction.  Poorly performing items in an instrument adversely affect the scale's 
ability to discriminate between different groups of people (e.g., patients of different disease 
severity), as well as diminish its chances of detecting important changes that result from 
treatment.  To identify problematic items, the following criteria were used: 1) ceiling effect of an 
item in which >50% of participants circled Not at All, and thus could not improve on the item; 2) 
an item that had >5% missing data, 3) an item measuring a different construct demonstrated by 
an item-to-total correlation <0.40, and 4) pairs of items that showed redundancy of measurement 
by an inter-item correlation >0.70.  Items were removed if it was felt that this did not hurt the 
measure's content validity.  Since this is an inherently subjective judgment, we used cognitive 
debriefing reports, item importance ranking and investigator opinion before eliminating any 
item. 
Factor Analysis and Domain Structure of the IBS-QOL.  Confirmatory factor analysis 
was used to identify a possible subscale structure for representing relationships among sets of 
many interrelated variables 20.  In this study, principal component factor analysis with orthogonal 
rotation (using the varimax method) was performed on the 34-item IBS-QOL to explore its 
domain structure.  We expected the items to be grouped into distinct factors representing the 
different concepts being measured based on the correlation matrix of the items. 
41 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
10 
Internal Consistency Reliability.  Cronbach's alpha was used to assess internal 
consistency reliability, (i.e. the association among items within domains and the overall 
measure).  A high internal consistency suggests that the scale or subscales are measuring a single 
construct.  A minimum correlation of  0.70 are necessary for group comparisons, but it is 
preferred to have alpha values above 0.90 for individual comparisons.  Cronbach's alphas were 
computed for the IBS-QOL instrument using baseline data. 
Reproducibility, or the extent to which the IBS-QOL yielded stable scores among 
respondents whose bowel problems did not change,  was assessed by comparing the overall IBS-
QOL score at baseline and one week later.  Sixty percent of the patients within each group were 
randomly selected to be retested for reproducibility. 
We used responses to the global rating of change question at retest (-1 or “about the 
same/hardly worse at all”, 0 or “about the same”, and +1 or “about the same/ hardly better at 
all”) to identify respondents with stable bowel symptoms. We used the intraclass correlation 
coefficient (ICC) to evaluate reproducibility because it accounts for a lack of independence 
among measurements.  We also evaluated reproducibility on respondents who indicated that their 
bowel symptoms had worsened or improved on the global rating of change (-2 to -7 or +2 to +7).  
We expected that as the level of change increased, the ICC on the IBS-QOL would go down. 
Construct validity. Convergent and discriminant validity, types of construct validity, 
involve comparing logically related measures to see if they are correlated more strongly 
(convergent) or more weakly (discriminant) according to a priori expectations based on the 
content and theoretical relationships among constructs and their measures.  If expectations are 
met, then construct validity is supported for the particular population evaluated.  The PGWB, 
SF-36, and SCL90-R were used to assess convergent validity of the IBS-QOL.  Strengths of 
association were tested by calculating Pearson's product moment correlation coefficients on 
measures collected at baseline.  Based on previous correlations among psychologic measures in 
other HRQoL validation studies, a stronger correlation was considered to be 0.40 or above and a 
weaker correlation 0.39 or below. 
By consensus of the developers, we predicted that the IBS-QOL overall score would 
show stronger correlations with social functioning, bodily pain, role physical and vitality 
subscales and a weaker correlation with the general health and mental health subscales of the SF-
36.   Overall, we expected higher correlations between the overall scores of the IBS-QOL and 
the PGWB and SCL-90R measures than the correlations with the SF-36 subscales.  Furthermore, 
we hypothesized a stronger association between the positive well-being, depressed mood, 
tension and anxiety, health and worry concern and energy domains of the PGWB and the overall 
IBS-QOL score, with the remaining correlations indicating weaker associations.  The overall IBS 
score was anticipated to show lower correlations with all subscales of the SCL-90R. 
Known groups validity, another form of discriminant validity, was used to test the ability 
of the IBS-QOL to discriminate between groups varying on known characteristics independent 
of  or distal to the QOL measure.  We examined the distributions of the IBS symptom frequency 
and bothersomeness indices and used tertiles of the distribution to create three categories (mild, 
moderate and high) of symptom frequency and bothersomeness.  We anticipated that IBS-QOL 
scores would worsen as symptom frequency and bothersomeness increased.  Other  severity 
42 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
11
measures were also analyzed for known groups validity, including scores on the FBDSI,  self-
rating of severity, and number of IBS episodes in the past week.  We expected inverse 
associations between the IBS-QOL and FBDSI and  number of days in the past week with IBS 
symptoms. Similar to the symptom indices, we anticipated that IBS-QOL scores would be lower 
as the perceived rating of severity worsened from mild, moderate to severe.  Associations 
between the IBS-QOL and work loss and number of medical appointments were also explored, 
although no explicit hypotheses were made.  Discriminant validity was assessed using simple 
factorial analysis of variance (ANOVA).  QOL was included as the dependent variable and the 
main effect separated into tertiles or quartiles if it was a continuous variable to enhance 
interpretability.  Site, age, gender, and marital status were controlled for in these analyses. 
Statistical analyses were performed using a commercial software package 20. 
43 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
12 
RESULTS 
Sample Characteristics 
Two hundred forty people either responded to advertisements or were approached at 
Gastroenterology clinics and practices and asked to participate.  Of these 240, 169 (70%) were 
enrolled after fulfilling criteria for IBS and symptom pattern type.  Seventy one people who 
responded to the advertisements were not enrolled for the following reasons: 31 of them did not 
meet the Rome Criteria for IBS; 13 people qualified for the study but their appropriate IBS-type 
cells were full; 15 people did not meet the age criteria; 8 people could not be reached by 
telephone for various reasons; and 4 people decided not to participate.  Of the 169 persons 
recruited, 156 (92%) returned the self-administered questionnaire: 57 in Washington and 99 in 
North Carolina. 
Women comprised 89% of the sample, 53% were married; and the average age was 39 
(SD11.8).  Eighty-six percent of  the sample was white, and 78% had a university education.  
Median income was between $25,000 to $34,999.  Recruitment source was varied with 36% 
coming from advertisements, 61% from medical centers, and 5% from community medical 
practice.  At baseline, 22% reported symptoms consistent with constipation-predominant IBS, 
19% with diarrhea-predominant, and 60% with mixed.  Significant differences were observed 
between participants in North Carolina and Washington for recruitment source (significantly 
more from advertisements in Washington), age (Washington participants were significantly 
older), and marital status (significantly more persons had been divorced in Washington).  These 
differences were adjusted for during analysis.  No significant difference was seen by IBS type. 
Item reduction and Domain Structure of the IBS-QOL 
Seven items were eliminated from the 41-item questionnaire to arrive at the 34-item 
validated questionnaire.  One item was eliminated because of its ceiling effect (item 41); 5 items 
were eliminated because of their redundancy (high inter-item correlation) with other items and 1 
item was eliminated because of its low item-scale correlation.  Other items were considered for 
elimination based on their psychometric performance but were kept in the scale because of their 
relative importance to patients with IBS. 
An exploratory principal component factor analysis of this instrument identified a 
possible substructure of 8 factors, namely Dysphoria, Interference with activity, Body Image, 
Health worry, Food avoidance, Social Reaction, Sexual, and Relationships (See Appendix B).  
These were consistent with content of items with a few exceptions, and eigert-subscale structure 
of the measure was retained 5. 
44 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
13
Scores on HRQoL Assessment Instruments 
Table 1 shows the scores on the symptoms (Symptom Frequency and Bothersomeness 
Indices), generic functional status/well-being (SF-36), and IBS-specific quality-of-life (IBS-
QOL) measures by age groups and gender (all ages combined).  Although females reported more 
IBS symptoms and greater bothersomeness, no statistical differences were detected with the 
small number of male participants.  No pattern by age or gender was detected for functional 
status and well-being.  There were no significant differences in the IBS-QOL overall score by 
race, age, gender, education, marital status or income.  The subscale results show that quality of 
life scores were higher in the younger age group than in the older group but these differences 
were not statistically significant.  There was no difference in quality of life scores between male 
and female participants within subscale scores. 
45 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
14 
Table 1.  HRQoL Scores by age and gender 
 
18-44 Yrs 
45-65 Yrs 
All Ages 
Gender*** 
 
(n=110) 
(n=45) 
(n=155) 
Male (n=17) 
Female (n=138) 
HRQoL Measures 
Mean (SD) 
Mean (SD) 
Mean (SD) 
Mean (SD) 
Mean SD) 
IBS - Specific Quality 
of Life (IBS-QOL) ** 
    Overall 
    Dysphoria 
    Interference with 
 
Activity 
     Body Image 
     Health Worry 
     Food Avoidance 
     Social Reaction 
     Sexual 
     Relationships 
 
 
64.3 (18.0) 
64.0 (23.8) 
 
65.5 (21.5) 
63.6 (24.1) 
59.2 (24.6) 
43.6 (26.9) 
69.1 (22.1) 
76.3 (23.7) 
74.2 (21.2) 
 
 
60.6 (19.4) 
61.0 (24.4) 
 
57.3 (23.4) 
59.6 (24.6) 
59.3 (24.9) 
43.2 (26.4) 
70.3 (25.0) 
66.7 (34.9) 
67.6 (22.4) 
 
 
63.2 (18.5) 
63.1 (23.9) 
 
63.1 (22.3) 
62.5 (24.3) 
59.2 (24.6) 
43.4 (26.7) 
69.4 (22.9) 
73.5 (27.6) 
72.3 (21.7) 
 
 
64.2 (17.4) 
60.7 (24.2) 
 
56.1 (22.9) 
76.8 (21.5) 
66.2 (20.5) 
44.1 (24.1) 
71.7 (17.7) 
83.1 (22.5) 
71.1 (20.0) 
 
 
63.1 (18.6) 
63.4 (23.9) 
 
64.0 (22.2) 
60.7 (24.1) 
58.3 (25.0) 
43.4 (27.0) 
69.2 (23.5) 
72.3 (28.0) 
72.5 (21.9) 
Symptoms: 
     Symptom Frequency
 
Index* 
     Symptom
 
Bothersomeness
 
 
Index* 
 
 
42.6 (9.0) 
 
 
42.5 (11.7) 
 
 
41.1 (11.2) 
 
 
39.4 (12.9) 
 
 
42.2 (9.7) 
 
 
41.6 (12.1) 
 
 
36.7 (7.3) 
 
 
34.4 (10.7) 
 
 
42.9 (9.7) 
 
 
42.5 (12.0) 
Generic functional 
status/well-being: 
 
SF-36** 
    Physical Functioning 
    Role Physical 
    Role Emotional 
    Social Functioning 
    Bodily Pain 
    Mental Health 
    Vitality 
    General Health 
    Physical Component 
 
Summary 
    Mental Component 
 
Summary 
 
 
 
85.2 (19.2) 
53.6 (39.8) 
49.4 (41.8) 
63.0 (21.8) 
50.4 (18.2) 
57.6 (19.1) 
37.9 (20.0) 
58.3 (22.6) 
 
57.9 (17.7) 
 
53.1 (18.2) 
 
 
 
73.3 (25.7) 
43.3 (41.8) 
50.4 (43.6) 
59.4 (23.1) 
46.1 (21.4) 
55.9 (18.8) 
36.9 (19.2) 
52.4 (27.0) 
 
51.9 (22.0) 
 
50.5 (19.9) 
 
 
 
81.7 (21.9) 
50.7 (40.5) 
49.7 (42.2) 
61.9 (22.1) 
49.2 (19.2) 
57.1 (18.9) 
37.6 (19.7) 
56.6 (24.0) 
 
56.2 (19.2) 
 
52.4 (18.7) 
 
 
 
79.1 (22.0) 
52.9 (44.1) 
45.1 (45.6) 
61.0 (22.1) 
55.2 (19.0) 
54.4 (22.2) 
39.4 (21.4) 
52.3 (22.9) 
 
56.7 (20.7) 
 
50.4 (21.3) 
 
 
 
82.1 (21.9) 
50.4 (40.2) 
50.2 (41.9) 
62.1 (22.2) 
48.4 (19.2) 
57.5 (18.6) 
37.4 (19.6) 
57.1 (24.2) 
 
56.1 (19.1) 
 
52.6 (18.4) 
*Higher values indicate worse HRQoL   **Higher values indicate better HRQoL   
***Includes all ages 
(Numbers for individual measures vary slightly because of missing data) 
46 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
15
RELIABILITY 
The overall IBS-QOL showed a high internal consistency reliability as indicated by a 
Cronbach’s Alpha value of 0.95, indicating that the 34 items performed well together as a 
composite measure.  Each of the identified subscales had a high alpha value (0.74-0.93) with the 
exception of Relationships (0.63).  The internal reliability of the IBS-QOL (0.95) was 
comparable to the physical functioning of the SF-36 subscale (0.91) but higher than all the other 
subscales of the SF-36.  The Symptom frequency measure had an alpha of 0.71 and the symptom 
bothersomeness measure had an alpha value of 0.74. 
Reproducibility, as assessed with the intraclass correlation coefficient (ICC), was  0.86 
for those participants who reported no change in their bowel problems.  As expected, the ICC 
was lower for persons reporting change in their bowel problems.  Within the subscales, ICC 
ranged from 0.76 (Food Avoidance) to 0.89 (Body Image) with the exception of Relationships 
(0.69).  Similarly, ICC was lower for persons reporting change in the bowel problems within 
subscales.  The average retest period was 7 days (SD 1). 
Table 2.  IBS-QOL Internal Consistency and Reproducibility Results 
IBS-QOL 
Cronbach’s Alpha Coefficient 
(Time 1) 
Intraclass Correlation 
Coefficient (ICC) 
Overall Scale 
0.95 
0.86 
Subscales: 
 
 
 
Dysphoria 
0.92 
0.89 
 
Interference with  
 
 
Activity 
0.84 
0.88 
 
Body Image 
0.75 
0.85 
 
Health Worry 
0.70 
0.86 
 
Food Avoidance 
0.76 
0.76 
 
Social Reaction 
0.74 
0.84 
 
Sexual 
0.83 
0.77 
 
Relationships 
0.65 
0.69 
 
47 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
16 
CONSTRUCT VALIDITY 
The convergent and discriminant validity results comparing the IBS-QOL overall score 
and the SF-36 subscales confirmed our predicted hypothesis of stronger or weaker correlations 
with the exceptions of role-physical, mental health, and vitality (Table 3).  The strongest 
associations were with bodily pain (0.47) and social functioning (0.44).  Construct validity 
predictions for the relationship between overall IBS-QOL and the PGWB were confirmed only 
for the total score and health worry and concerns, which we thought, would correlate more 
strongly.  Again, energy and vitality correlations were lower than anticipated.  No exceptionally 
strong correlations were observed (Table 3).  IBS-QOL convergent and discriminant validity 
comparisons with the SCL-90R scores confirmed all but three of our predictions.  Correlations 
were particularly stronger than predicted for the global score, somatization, and obsessive-
compulsiveness subscales of the SCL-90R. 
Table 3.  Predicted vs. actual correlations between overall IBS-QOL and SF-36, PGWB, and SCL90-R. 
 
 
Predicted 
IBS-QOL Actual 
Confirmed (y/n) 
SF-36 
    Physical Functioning 
    Social Functioning 
    Role Physical 
    Role Emotional 
    Mental Health 
    Vitality 
    Bodily Pain 
    General Health 
Weaker 
Stronger 
Stronger 
Weaker 
Weaker 
Stronger 
Stronger 
Weaker 
.36 
.44 
.40 
.31 
.41 
.30 
.47 
.37 
Yes 
Yes 
Yes 
Yes 
No 
No 
Yes 
Yes 
PGWB 
    Total Score 
    Positive Well Being 
    Health Worry Concern 
    Depressed Mood 
    Behavioral and  
        Emotional Control 
    Energy and Vitality 
    Tension and Anxiety 
Stronger 
Stronger 
Stronger 
Stronger 
 
Weaker 
Stronger 
Stronger 
.45 
.37 
.45 
.33 
 
.41 
.31 
.37 
Yes 
No 
Yes 
No 
 
No 
No 
No 
SCL90-R 
    Global Score 
    Somatization 
    Obsessive Compulsiveness 
    Interpersonal Sensitivity 
    Depression 
    Anxiety 
    Hostility 
    Phobic Anxiety 
    Paranoid Ideation 
    Pyschoticism 
Weaker 
Weaker 
Weaker 
Weaker 
Weaker 
Weaker 
Weaker 
Weaker 
Weaker 
Weaker 
-.45 
-.44 
-.46 
-.35 
-.37 
-.39 
-.27 
-.36 
-.31 
-.34 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
• Weaker Correlation: <.40 
• Stronger Correlation: = >.40 
48 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
17
KNOWN-GROUPS DISCRIMINANT VALIDITY 
Table 4 compares the mean scores on the SF-36 and IBS-QOL for mild, moderate, and 
high IBS Symptom Frequency and Bothersomeness Index scores.  Participants with lower 
frequency and bothersomeness of IBS symptoms reported higher functional status and well-
being and higher quality of life.  A similar pattern was seen with the subscales scores of the IBS-
QOL. 
Table 4.  Comparison of high and low symptom frequency and bothersomeness reports and health-
related quality of life (HRQoL) measures. 
 
Symptom Frequency Index 
Symptom Bothersomeness 
Index 
 
HRQoL Measure* 
Mild 
(n = 56) 
Moderate 
(n = 49) 
High 
(n = 48) 
Mild 
(n = 51) 
Moderate 
(n = 49) 
High 
(n = 53) 
IBS-Specific Quality of Life(IBS-QOL): 
 
Overall 
 
Dysphoria 
 
Interference with Activity 
 
Body Image 
 
Health Worry 
 
Food Avoidance 
 
Social reaction 
 
Sexual 
 
Relationships 
69.7 
69.3 
67.5 
72.0 
68.5 
48.1 
77.6 
80.4 
77.4 
64.6 
63.9 
64.3 
64.3 
62.4 
42.7 
68.2 
77.6 
76.5 
55.0a 
55.9d 
58.0e 
50.3a 
46.2a 
39.6f 
61.5b 
62.5c 
62.9b 
72.2 
71.9 
70.7 
73.9 
70.0 
51.8 
78.3 
84.1 
80.1 
64.8 
63.0 
64.4 
64.3 
64.1 
42.5 
72.2 
77.3 
75.0 
53.8a 
55.5b 
55.7b 
50.5a 
45.3b 
37.0d 
58.6a 
60.9a 
63.1b 
General functional status/well-being:  SF - 36 
 Physical Functioning 
 Role Physical 
 Role Emotional 
 Social Functioning 
 Bodily Pain 
 Mental Health 
  Vitality 
  General Health 
 Physical Component  
 
Summary (PCS) 
 Mental Component   
 
Summary (MCS) 
85.5 
54.9 
56.6 
69.2 
57.0 
63.1 
42.7 
63.3 
 
62.2 
 
58.7 
87.8 
56.6 
46.3 
64.5 
51.5 
58.4 
40.4 
61.1 
 
60.3 
 
54.1 
71.8a 
41.2f 
43.8f 
50.8a 
39.0a 
49.1b 
29.4c 
43.7a 
 
45.4a 
 
42.9a 
86.7 
59.8 
58.2 
70.6 
59.3 
65.0 
44.7 
61.8 
 
63.9 
 
60.1 
85.4 
57.7 
47.6 
65.6 
50.9 
56.4 
37.0 
59.5 
 
59.3 
 
52.8 
74.2b 
36.8d 
42.1f 
50.2a 
39.0a 
50.3a 
31.8c 
48.5d 
 
46.3a 
 
44.2a 
Values are means, and statistical tests are analysis of variance 
*Higher values indicate better HRQoL 
ap< = 0.0001, bp< = 0.001, cp< = 0.005, dp< = 0.01, ep< = 0.05, f not significant 
As expected, the IBS-QOL total score was significantly different among severity groups 
(Table 5): among mild, moderate, and severe patients with regard to the FBDSI  severity 
measure (p<.0001) and mild, moderate and severe self-ratings by participants (p<.001).  The 
IBS-QOL did not discriminate, however, between the three symptom pattern types.  Persons with 
49 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
18 
diarrhea-predominant symptoms reported the lowest overall quality of life.  IBS-QOL scores 
were also not significantly different for number of episodes per week.  A significant association 
was found between IBS-QOL and the number of visits to the doctor for IBS problems in the past 
6 months (p<.05) and the number of missed work days in the past year.  The trend was for IBS-
QOL to be lower as number of visits increased and more work-loss days were reported. 
Table 5. Discriminant Validity of IBS-QOL 
Characteristic                                                    (n=155) 
IBS-QOL 
Mean  (SD) 
FBDSI
a  
 
       Mild 
73.04 (16.44) 
       Moderate 
64.25 (14.70) 
       Severe 
50.86 (20.69) 
Subjective Severity
b  
 
        Mild 
79.53 (11.72) 
        Moderate 
65.70 (16.01) 
        Severe 
49.77 (17.66) 
Type of IBS at Time 1
d  
 
        Constipation-predominant 
61.20 (19.22) 
         Mixed 
65.17 (18.04) 
         Diarrhea-predominant 
58.68 (18.26) 
Number of IBS Episodes per Week
d  
 
         0 to 2 
65.18 (19.55) 
         3 to 5 
65.55 (16.62) 
          6+ 
58.09 (19.76) 
Medical visits in past 6 months
c  
 
          0 visits 
65.60 (16.17) 
          1 visit 
68.73 (15.79) 
          2 visits 
55.52 (23.23) 
          3 visits 
59.76 (20.17) 
          4 visits 
61.56 (20.64) 
          5 or more visits 
53.03 (20.80) 
Missed work days in past year
c  
 
          0 day 
68.86 (17.66) 
          1-2 days 
68.63 (14.44) 
          3-5 days 
67.55 (16.54) 
          6 or more days 
54.62 (13.92) 
a: p<.0001, b: p<.001, c: p<.05, d: not significant  
50 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
19
Reproducibility of Symptom-Pattern Classification 
A total of 148 patients (95%) were stable with regard to Rome Criteria for IBS, 
independent of symptom type between screening and time 1.  Similarly, 82 patients (92%) of the 
89 retest patients fulfilled Rome Criteria for IBS, unrelated to symptom type.  Symptom types 
within Rome IBS overall category moved around.  Of the 156 patients enrolled into the study, 
108 (69%) remained stable from screening to baseline while 48 (31%) changed IBS types 
between screening and baseline.  Twenty nine patients of those who changed (60%) switched 
from constipation-predominant to mixed IBS, 14 patients (29%) changed from diarrhea-
predominant to mixed IBS, 4 patients (8%) switched from mixed to diarrhea IBS, and 1 patient 
(2%) changed from mixed to constipation-predominant IBS.  Among the 89 patients randomized 
to retest, 50 (56%) patients remained stable from screening to retest, 27 patients (30%) who 
switched pattern at baseline did not change at retest, 9 patients (10%) who were stable at 
baseline switched IBS pattern at retest, while 3 patients (3%) switched type at baseline and 
switched back to their initial pattern at retest. 
 
51 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
20 
DISCUSSION 
Within Gastroenterology, recent interest in the measurement of health related quality of 
life (HRQoL), and particularly with regard to the development of disease-specific questionnaires 
has occurred primarily for inflammatory bowel disease 21,22.  However, there is a compelling 
need to accurately evaluate quality of life in the functional gastrointestinal (GI) disorders.  In 
addition to being the most common of the GI disorders, recent studies now show that persons 
with functional GI disorders have major impairments in health status, and this has economic and 
health policy implications. 
For example, a randomized national study of 5,430 householders showed that those with 
irritable bowel syndrome (9.2% of the sample) had significantly more work absenteeism (13.4 
vs. 4.9 days; p<0.0001) and physician visits (5.52 vs. 1.86 visits/1 year; p<0.0001), than those 
without bowel symptoms, and the results were similar for those with other functional GI 
disorder.23.  In addition, a recent cost analysis showed that community subjects with IBS spent 
$742 (median)/year for health care when compared to $429 for control subjects without bowel 
symptoms 24. 
The health impact is even greater in clinical populations 25 using the SF-36, a generic 
measure of HRQoL, found that while persons with IBS had poorer physical and mental health 
than asymptomatic individuals, those with IBS who consulted physicians had poorer general 
health, vitality, physical role and social functioning than the non-consulters with IBS.  In another 
recent study evaluating the health status of patients seen at a major medical 23 those with 
functional GI disorders reported significantly more pain, had poorer daily function (Sickness 
Impact Profile-SIP), greater psychological distress (SCL-90), made more physician visits and 
even had more surgeries than patients having structural diagnoses (e.g., inflammatory bowel 
disease, acid peptic disease, liver disease etc.).  These studies support previous observations for 
IBS, that Psychosocial difficulties are greater in clinical populations 26, 27 and it highlights the 
value of having reliable and valid psychosocial assessment measures for studying clinical 
populations. 
Clearly, there is a need to evaluate HRQoL for patients with functional GI disorders.  
However, biologic or physiologic standards to assess the severity of these conditions do not 
exist, and generic measures of HRQoL, such as the SF-36 or SIP may be insensitive and poorly 
responsive for use in treatment trials.  For these reasons, we sought to develop, assess the 
psychometric properties and validate an IBS-specific quality of life measure that could be used 
in clinical trials and health status assessment. 
This study demonstrates that the IBS-QOL is a highly reliable and valid self-administered 
questionnaire to assess the perceived quality-of-life for persons with IBS.  The internal 
consistency of the overall IBS-QOL (0.95) exceeded the recommended cut-off of 0.70 for group 
comparisons and sufficient for individual comparison.  The reproducibility over the two-week 
study period was excellent.  Most of the expectations about how the IBS-QOL would perform in 
relation to other measures and with known groups were confirmed with a high degree of 
confidence.  Specifically, the IBS-QOL scores were strongly correlated with other health status 
measures including the SF-36, a generic measure of functional status, the SCL-90, a measure of 
52 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
21
psychological distress, a disease severity measure (FBDSI), and subjective ratings of severity, 
symptom frequency and bothersomeness, and the number of physician visits and days missed 
from work.  The strong associations found attest to the construct validity of the IBS-QOL 
measure.  Furthermore, the final items had face validity and cross-cultural relevance to the 
multinational panel of gastroenterologists involved in the study. The associations with a disease 
severity measure and a measure of symptom frequency and bothersomeness indicate that the 
IBS-QOL can augment this type of measure in clinical trials and epidemiologic investigations. 
The IBS-QOL, specific to this condition, showed a low pattern of scores suggesting some 
impairment of quality of life.  Within the subscales, lower scores were seen especially in 
interference with activity, food avoidance and health worry concern subscales of the IBS-QOL. 
This is consistent with clinical observations of patients having IBS.  A study of 148 persons with 
IBS belonging to the IBS Network also found that IBS "affected all aspects of their lives: work, 
leisure, travel, and relationships" 28.  Another study 29 found that "high proportions of 
participants were affected in their social, sexual and working lives by IBS symptoms".  Our 
results confirm the findings that IBS has a broad and significant impact on persons’ quality of 
life. 
A few other measures of health-related quality of life (HRQoL) have been developed for 
a variety of GI disorders 30 but do not capture the specific issues that relate to IBS.  The IBS-
QOL, constructed specifically for persons with IBS using a formal conceptual structure and 
multi-dimensional assessment, captures the concerns of patients with a high level of specificity 
and attribution to the bowel symptoms of IBS.  It may also prove to be a more responsive 
measure of HRQoL for persons with IBS, that is one capable of detecting minimally important 
changes that can be attributed to treatment 18.  This measure is also currently available in four 
European countries. 
Our study did not confirm that there are significant differences in HRQoL among the 
three symptom patterns of constipation-predominant, diarrhea-predominant, and mixed.  In 
addition, the symptom pattern classification was not highly reproducible in that it changed 
considerably between screening and baseline.  Thus, the concept of symptom pattern in IBS may 
not be viable, because symptoms shift and this alternating pattern is not stable enough for 
measuring a predominance of pattern or differences in the impact of different symptoms on 
HRQoL.  We did demonstrate, however, that frequency and bothersomeness of IBS symptoms 
impacts on HRQoL.  Assessment of symptoms and their impact continue to be important areas of 
investigation. 
This study was cross-sectional, and thus cannot investigate responsiveness or identify 
what is a minimally important difference in the IBS-QOL.  The measure is currently being used 
in a large clinical investigation of IBS and in preliminary clinical trials for drug development.  
Data from these studies will permit us to investigate this important property of the measure.  The 
validity of the subscale structure will also be better investigated in a study with larger sample 
size more representative of persons in the population with IBS. 
Since no physiologic measure is available for assessing IBS, the rigorous development of 
subjective, person reports of symptoms and HRQoL are important to the investigation and 
treatment of this disorder.  It is increasingly important to apply these patient report measures in 
53 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
22 
clinical and community investigations of functional bowel disorders.  The IBS-QOL will assist 
in these applications. 
Obtaining Comparative Data 
The cross-sectional design of this validation study restricts the generalization of its 
results.  However, this study provides cross-sectional comparison data only on a sample of 
persons residing in Washington and North Carolina.  Tables can be produced by age, gender, 
level of education, and other characteristics shown in the Demographic Questionnaire contained 
in Appendix D.  upon request to the University of Washington and at the cost of production of 
these tables.  Interpretation of effect sizes awaits longitudinal investigation of the IBS-QOL.  
The validity of the IBS-QOL was determined for IBS patients without regard to IBS type.  We 
recommend similar usage since the shift in IBS type between pre and post survey was evident.  
Finally, We have proven the internal consistency of the subscale structure of IBS-QOL.  The 
validity of the subscales will be tested in the longitudinal investigation of the IBS-QOL. 
54 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
23
ADMINISTRATION GUIDELINES 
The IBS-QOL- is contained in Appendix B. 
The IBS-QOL was designed for self-administration, but can be interview-administered if 
necessary.  The 34-item version takes approximately 10 minutes to complete.  No specific 
training is required to complete this instrument since the instructions are self-explanatory.  We 
encountered no problems in respondent completion of the IBS-QOL. 
Interview administration requires additional time to complete the IBS-QOL, and is 
recommended only for persons who cannot self-administer.  Because some of the questions are 
of a personal nature, self-administration is the preferred mode. 
Additional factors that should be considered when administering the IBS-QOL include 31. 
 
Participants should be instructed to complete the IBS-QOL in a quiet place away from 
the influence of others 
 
Educational level should  be considered before self-completion.  This can be done by 
asking persons what grade level they have completed or by administering a short reading 
comprehension test.  Persons with low literacy or diverse language skills should always 
be provided interview assistance. 
Interviewers should be trained to not introduce bias.  For example, interviewers should 
encourage respondents to provide one answer (response choice) for each question, and not to 
persuade participants to answer questions according to how the interviewer feels they should 
respond. 
Interviewer Administration 
Interviewers should be trained to minimize bias.  For example, interviewers should 
encourage respondents to provide one answer or response for each questions, to keep a focus on 
the questions being asked, and to take the time they need to come to an answer.  Interviewers can 
easily introduce bias if they give cues that would persuade participants to answer questions 
according to how the interviewer feels they should respond.  These cues can range from obvious 
things like language formation to more subtle things like when a smile is given and when it is 
not. 
As with any interviewer administered survey, the following guidelines should be taken 
into account: 
• 
wear proper attire 
• 
wear visible identification (picture, name, affiliation) 
• 
give explanation of the project 
• 
brief the respondent again on confidentiality 
• 
give approximate time to administer 
55 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
24 
• 
do not express your own opinions 
• 
maintain eye contact unless reading a long list 
• 
gain the respondent’s trust 
• 
make questionnaire accessible to respondent’s viewing 
• 
avoid bias in vocal inflection, posture, and facial expression 
• 
do not explain questions but respond to inquiries in words of question 
• 
do not put words in respondent’s mouth 
• 
keep respondent on track 
• 
use probes only when participant needs assistance 
• 
record all comments –yours and the respondent 
• 
record observations 
• 
thank respondents for their time 
When sitting down to begin, the interviewer should inform the respondent that there are 
no right or wrong answers, emphasizing that what is important is how they think and feel.  The 
respondent should be made to feel comfortable enough to ask the interviewer to slow down, 
repeat a question, speed up, or stop so that he/she can have time to think.  If appropriate, the 
respondent should have a copy of the questionnaire to follow along, regardless of their ability to 
read. 
For long lists, the lead in questions should be repeated sporadically so the respondent 
does not lose track of the response choices.  When about half way through the interview, the 
respondent should be cued to the time by encouragement that it is half done. 
56 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
25
SCORING THE IBS-QOL 
The IBS-QOL produces a quality-of-life profile for people with irritable bowel 
syndrome.  It is possible to derive eight subscale scores as well as a single global score.  Each 
item is taken to contribute equally to each subscale with each subscales containing the following 
items: 
Table 6. Subscales 
Subscales 
IBS-QOL Items 
Dysphoria (DY) 
IBS01,IBS06,IBS07,IBS09,IBS10,IBS13,IBS16,IBS30 
Interference with Activity (IN) 
IBS03,IBS18,IBS19,IBS22,IBS27,IBS29,IBS31 
Body Image (BI) 
IBS05,IBS21,IBS25,IBS26 
Health Worry (HW) 
IBS04,IBS15,IBS32 
Food Avoidance (FA) 
IBS11,IBS23,IBS28 
Social Reaction (SR) 
IBS02,IBS14,IBS17,IBS34 
Sexual (SX) 
IBS12,IBS20 
Relationships (RL) 
IBS08,IBS24,IBS33 
Overall (OV) 
All Items 
Subscales are scored through simple summative scaling.  All items are negatively framed 
with the greatest response scale equaling the worst quality of life.  When scored, all items are 
reversed so that the as IBS-QOL scores increase, quality of life increases.  All final  raw scores 
are transformed to a 0 to 100 scale using the following formula: 
Scale Score
the sum of the items -  lowest possible score
possible raw score range
  100
=
∗
 
This transformation converts the lowest and highest possible scores to zero and 100, 
respectively.  Scores between these values represent the percentage of the total possible score 
achieved.  The IBS-QOL instrument and scoring programs have used this transformation to 
provide comparative data for interpretation. 
Scoring Exercise and Test Dataset for the IBS-QOL 
Because of the complexity of scoring the IBS-QOL, a computer diskette with the 
necessary code for scoring algorithms and a test dataset are included with the manual for use in 
computing IBS-QOL subscale summary scores and for checking the accuracy of computations. 
The following files are included on the diskette: 
• ibsqol.dat 
ASCII (fixed format) text file consisting of data from 100 
administrations of the IBS-QOL. 
• ibsqoldl.sps 
SPSS code to read the data from “ibsqol.dat” into SPSS. 
• ibsqol.sps 
SPSS code containing scoring algorithms for obtaining subscale 
summary scores.  A hard copy of this code can be seen in 
Appendix E. 
57 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
26 
The purpose of this scoring exercise is to help IBS-QOL users to evaluate results from 
each step in the process of calculating subscale scores of the instrument.  A test dataset and SPSS 
code for scoring the IBS-QOL has been provided on a computer diskette in this packet.  The test 
dataset, which is called “IBSQOL.DAT” on the diskette, contains data from 100 administrations 
of the IBS-QOL.  The enclosed diskette also provides the user with the SPSS syntax that should 
be used to: 
• import raw data into SPSS format [IBSQOLDL.SPS] 
• derive the IBS-QOL subscale and overall scores [IBSQOL.SPS] 
The SPSS code (called “IBSQOL.SPS”) on the diskette begins by labeling all items, then 
recodes all items and checks for out-of-range values.  The eight subscales and the overall score 
are computed, transformed, and labeled.  The syntax can be seen in Appendix E). 
The following table presents statistics for the transformed scores for the IBS-QOL.  After 
scoring the test dataset, the means, standard deviations, and minimum and maximum observed 
values should agree with the values seen here. 
Table 7.  Descriptive Statistics 
100
.00
93.75
33.8125
22.7238
100
.00
96.43
34.7143
20.6950
100
.00
87.50
33.5000
22.5350
100
.00
91.67
38.9167
23.8676
100
.00
100.00
42.2500
21.8804
100
.00
75.00
28.3750
19.8721
98
.00
87.50
21.3010
22.7895
100
.00
83.33
36.0000
20.3739
98
4.41
81.62
33.7785
16.4751
98
DYSPHORIA SCORE (8
ITEM-TRANSFORMED)
INTERFERENCE WITH
ACTIVITY SCORE (7
ITEM-TRANSFORMED)
BODY IMAGE SCORE (4
ITEM-TRANSFORMED)
HEALTH WORRY SCORE
(3 ITEM-TRANSFORMED)
FOOD AVOIDANCE SCORE
(3 ITEM-TRANSFORMED)
SOCIAL REACTION
SCORE (4
ITEM-TRANSFORMED)
SEXUAL SCORE (2
ITEM-TRANSFORMED)
RELATIONSHIPS SCORE (3
ITEM-TRANSFORMED)
OVERALL SCORE (34
ITEM-TRANSFORMED)
Valid N (listwise)
N
Minimum
Maximum
Mean
Std.
Deviation
 
58 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
27
LIST OF TABLES 
Table 1. 
HRQoL Scores by age and gender  
 
 
 
 
Page 14 
Table 2. 
IBS-QOL Internal Consistency and Reproducibility Results   
Page 15 
Table 3. 
Predicted vs. Actual correlation’s between overall IBS-QOL and  
 
 
SF-36, PGWB, and SCL90-R  
 
 
 
 
Page 16 
Table 4. 
Comparison of high and low symptom frequency and bothersomeness 
 
 
reports and health-related quality of life (HRQoL) measures  
Page 17 
Table 5. 
Discriminant Validity of IBS-QOL   
 
 
 
Page 18 
Table 6. 
Subscales  
 
 
 
 
 
 
 
Page 25 
Table 7. 
Descriptive Statistics   
 
 
 
 
 
Page 26 
59 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
28 
REFERENCES 
 
1. 
Drossman, D.A., Camilleri, M, Whitehead, W.E. (1997). Irritable Bowel Syndrome: A 
technical review for practice guideline development. Gastroenterology, 112, pp. 2120-
2137. 
2. 
Drossman, D.A. (1994). Irritable bowel syndrome. Gastroenterologist, 2, pp. 315-326. 
3. 
Drossman, D.A., Li, Z., Leserman, J., Toomey, T.C., & Hu, Y. (1996). Health status by 
gastrointestinal diagnosis and abuse history. Gastroenterology, 110, pp. 999-1007 
4. 
Drossman, DA. (1994). The functional gastrointestinal disorders and their diagnosis: a 
coming of age.  In D. A. Drossman, J.E. Richter & N.J. Talley, et al (Eds.), The 
functional gastrointestinal disorders:  diagnosis, pathophysiology and treatment. (pp. 1-
23). McLean, VA: Degnon and Associates. 
5. 
Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. (1998). Quality of Life 
in Persons with Irritable Bowel Syndrome: Development and Validation of a New 
Measure. Digestive Diseases and Sciences, 43 (2), pp. 400-411. 
6. 
Patrick, D.L., & Erickson, P. (1993). Health status and health policy: allocating resources 
to health care. New York: Oxford University Press. 
7. 
McKenna, S.P. (1994). A new theoretical approach to the measurement of quality of life. 
Drug Inf J, 28, pp. 13-18. 
8. 
Szabo, S. (1995). The World Health Organization Quality of Life (WHOQOL) 
Assessment Instrument. In Spilker (Ed.), Quality of life and pharmacoeconomics in 
clinical trials. 2nd ed (pp. 355-362). Philadelphia, PA: Lippincott-Raven Publishers. 
9. 
The WHOQOL Group. (1994). The Development of the World Health Organization 
Quality of Life Assessment Instrument (the WHOQOL). In J. Orley & W. Kuyken (Eds.), 
Quality of Life Assessment: International Perspectives (pp. 41-57). Berlin, Germany: 
Springer-Verlag. 
10. 
Patrick, D.L., Wild, D.J., Johnson, E.S., Wagner, T.H., & Martin, M.A. (1994). Cross-
cultural validation of quality of life measures. In J. Orley, & W. Kuyken (eds.), Quality 
of life assessment: international perspectives, (pp. 19-32) Berlin, Germany: Springer-
Verlag. 
11. 
Wagner, T.H., Patrick, D.L., Bavendam, T.G., Martin, M.L., & Buesching, D.P. (1996). 
Quality of life of persons with urinary incontinence: development of a new measure. 
Urology, 47 (1), pp. 67-72. 
60 of 79


IBSMAN.doc, 11/3/2005, 9:32:51 AM 
29
 
12. 
Thompson, W.G., Dotevall, G., Drossman, D.A., Heaton, K.W., & Kruis, W. (1989). 
Irritable bowel syndrome: guidelines for the diagnosis. Gastroenterology International, 2, 
pp. 92-95. 
13. 
Patrick, D.L., Deyo, R.A., Atlas, S.J., Singer, D.E., Chapin, A., & Keller, R.B. (1995). 
Assessing health-related quality of life in patients with sciatica. Spine, 20 (17), pp. 1899-
908, discussion 1909. 
14. 
Drossman, D.A., Li, Z., Toner, B.B., Diamant, N.E., Creed, F.H., Thompson, D., Read, 
N.W., Babbs, C., Barreiro, M., Bank, L., Whitehead, W.E., Schuster, M.M., & Guthrie, 
E.A. (1995). Functional bowel disorders: a multi-center comparison of health status and 
development of illness severity index. Dig Dis Sci, 40 (5), pp. 986-995. 
15. 
Ware, J.E., & Sherbourne, C.D. (1992). The MOS 36-item Short Form Survey (SF-36): 1. 
Conceptual framework and item selection. Med Care, 30, pp. 473-483. 
16. 
Dupuy, H.J. (1984). The psychological well-being (PGWB) index. In Wenger NK, 
Mattson ME, Furberg CD, Elinson J, (Eds.), Assessment of quality of life in clinical trials 
of cardiovascular therapies (170-183). New York: Le Jacq,. 
17. 
Derogatis, L.R. (1983). SCL-90R: Administration, scoring and procedure manual II - for 
the (Revised) version.  Towson: Clinical Psychometric Research. 
18. 
Guyatt, G.H., Feeny, D.H., & Patrick, D.L. (1993). Measuring health-related quality of  
life. Ann Intern Med, 118, pp. 622-629. 
19. 
MOT Scientific Advisory Committee Instrument Review Criteria. (1995). MOT Bulletin 
II: I-V. Boston, MA: MOT Committee. 
20. 
Norusis, M, & J/SPSS Inc. (1993). SPSS Advanced Statistics Release 6.0. Chicago, IL: 
Spss Inc. 
21. 
Guyatt, G., Mitchell, A., Irvine, E.J., Singer, J., Williams, N., Goodacre, R., & Tompkins, 
C. (1989). A new measure of health status for clinical trials in inflammatory bowel 
disease. Gastroenterology, 96, pp. 804-810. 
22. 
Drossman, D.A. (1996). Inflammatory Bowel Disease. In Spilker, B. (Eds.), Quality of 
life and pharmacoeconomics in clinical trials 2nd ed. (pp. 925-935). New York: Raven 
Press 
23. 
Drossman, D.A., Li, Z., Andruzzi, E., Temple, R., Talley, N.J., Thompson, W.G., 
Whitehead, W.E., Janssens, J., Funch-Jensen, P., Coraziari, E., Richter, J.E., & Koch, 
G.G. (1993). U.S. householder survey of functional gastrointestinal disorders: 
prevalence, sociodemography, and health impact. Digestive Diseases and Sciences, 38 
(9), pp. 1569-1580. 
61 of 79


  
 
 
 
   IBSMAN.doc, 11/3/2005, 9:32:51 
AM 
30 
 
24. 
Talley, NJ., Gabriel, S.E., Harmsen, W.S., Zinsmeister, A.R., & Evans, R.W. (1995). 
Medical costs in community subjects with irritable bowel syndrome. Gastroenterology, 
109, pp. 1736-41. 
25. 
Whitehead, W.E., Burnett, C.K., Cook, E. III, & Taub, E. (1994). Health related quality 
of life in IBS: patients compared to IBS non-consulters and asymptomatic individuals. 
Am J Gastroenterology, 89, pp. 1700. (Abstract). 
26. 
Drossman, D.A., McKee, D.C., Sandler, R.S., Mitchell, C.M., Cramer, E.M., Lowman, 
B.C., & Burger, A.L. (1988). Psychosocial factors in the irritable bowel syndrome. A 
multivariate study of patients and non-patients with irritable bowel syndrome. 
Gastroenterology, 95, pp. 701-708. 
27. 
Whitehead, W.E., Bosmajian, L., Zonderman, A.B., Costa, P.T.J., & Schuster, M.M. 
(1988). Symptoms of psychologic distress associated with irritable bowel syndrome. 
Comparison of community and medical clinic samples. Gastroenterology, 95, pp. 709-
714. 
28. 
Dancey, C.P., & Backhouse, S. (1993). Towards a better understanding of patients with 
irritable bowel syndrome. J Adv Nurs,18 (9), pp. 1443-1450. 
29. 
Corney, R.H., & Stanton, R. Physical symptom severity, psychological and social 
dysfunction in a series of outpatients with irritable bowel syndrome. J Psychosom Res 
1990, 34 (5): pp. 483-491. 
30. 
Eypasch, E., Wood-Dauphinee, S., Williams, JI., Ure, B., Neugebauer, E., & Troidl, H. 
(1993). The Gastrointestinal quality of life index. A clinical index for measuring patient 
status in gastroenterologic surgery. Chirurg, 64 (4) pp. 264-74. 
31. 
Cella, D.F., Skeel, R.D., & Bonomi, A.E. (1994). Policies and Procedures Manual for the 
Eastern Cooperative Oncology Group. Chicago, IL. 
62 of 79


IBSMAN.doc, 11/3/2005, 9:34:02 AM 
31
APPENDIX A 
Screening Questionnaire 
based on Rome Criteria 
and 
Algorithm for Classification of IBS by Type 
Screening Questions 
 
Q1. 
For at least six months, have you had continuous or repeated discomfort or pain in your lower abdomen? 
 
 
1 
YES 
 
 
2 
NO  
(if no, skip to Q5) 
Q2. 
Is this discomfort or pain relieved by a bowel movement? 
 
 
1 
YES 
 
 
2 
NO 
Q3. 
Is this discomfort or pain associated with a change in the frequency of bowel movements, that is, having 
more or fewer bowel movements? 
 
 
1 
YES 
 
 
2 
NO 
Q4. 
Is this discomfort or pain associated with a change in consistency of the stool, that is, softer or harder? 
 
 
1 
YES 
 
 
2 
NO 
Q5. 
Would you say that at least one fourth (1/4) of the occasions or days in the last three months you have had 
any of the following? 
 
 
 
1YES 
2NO 
 
 
A. 
Fewer than three bowel movements a week (0-2)  
 
 
 
B. 
More than three bowel movements a day (4 or more) 
 
 
C. 
Hard or lumpy stools 
 
 
D. 
Loose or watery stools 
 
 
E. 
Straining during a bowel movement 
 
 
F. 
Urgency, that is having to rush to the bathroom for a bowel movement 
 
 
G. 
Feeling of incomplete bowel movement 
 
 
H. 
Passing mucus (white material) during a bowel movement 
 
 
I. 
Abdominal fullness, bloating or swelling 
Q6. 
Have you had any of the above symptoms for at least two days out of each week? 
 
 
1 
YES 
 
 
2 
NO 
63 of 79


 
 
 
 
IBSMAN.doc, 11/3/2005, 9:34:02 
AM 
32 
Scoring Algorithm for Diagnosis of IBS 
Q1=YES  
+ 
 
Q2=YES or Q3=YES or Q4=YES + 
YES to two or more of the following: 
Q5=A or B 
Q5=C or D 
Q5=E or F 
Q5=G 
Q5=H 
Q5=I 
Trial Classification of IBS Type 
Constipation predominant (Type A):  YES to Q5 A, C, and E  and NO to Q5 B, D, and F 
Diarrhea predominant (Type C): YES to Q5 B, D, and F and NO to Q5 A, C, and E 
Mixed Constipation and Diarrhea (Type B): YES to two or more of Q5 A, C, E and two or more of Q% B, 
D, and F or YES to Q5 A or C or E and YES to Q5 B or D or F or response patterns that did not 
fulfill any of these criteria but YES to two or more of Q5 G, H, or I 
64 of 79


IBSMAN.doc, 11/3/2005, 9:34:02 AM 
33
APPENDIX B 
Quality of Life in Persons with Irritable Bowel Syndrome (IBS-QOL) 
 
PARTICIPANT ID: 
SITE: 
PLEASE WRITE IN  
TODAY'S DATE:    _____  ______  _____ 
DAY       MONTH     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. 
 
HOW DID YOU HEAR ABOUT THIS STUDY? (CIRCLE ONE) 
 
1 
ADVERTISEMENT 
2 
MEDICAL CENTERS 
3 
PRIMARY CARE PRACTICE 
4 
COMMUNITY GI SPECIALIST 
5 
OTHER (SPECIFY) ____________________ 
 
 
IF YOU HAVE ANY QUESTIONS, PLEASE CONTACT: 
 
**SITE ADDRESS AND PHONE 
 NUMBER TO BE PLACED HERE** 
(final US version to be used in clinical trials) 
 
 
 
Copyright, 1997, Novartis Corporation.  All Rights Reserved. 
65 of 79


 
 
 
 
IBSMAN.doc, 11/3/2005, 9:34:02 
AM 
34 
About How You Feel 
Please think about your life over the past month (30 days), and look at the statements below.  Each statement has 
five possible 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 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 
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 
66 of 79


IBSMAN.doc, 11/3/2005, 9:34:02 AM 
35
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 
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) 
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 
67 of 79


 
 
 
 
IBSMAN.doc, 11/3/2005, 9:34:02 
AM 
36 
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 
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 
68 of 79


IBSMAN.doc, 11/3/2005, 9:34:02 AM 
37
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 
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 
A GREAT DEAL 
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 
69 of 79


 
 
 
 
IBSMAN.doc, 11/3/2005, 9:34:02 
AM 
38 
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 
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 
70 of 79


IBSMAN.doc, 11/3/2005, 9:34:02 AM 
39
Items Arranged According to Subscales 
Dysphoria 
1. 
I feel helpless because of my bowel problems. 
6. 
I feel like I’m losing control of my life because of my bowel problems.  
7. 
I feel my life is less enjoyable because of my bowel problems. 
9. 
I feel depressed about my bowel problems. 
10. 
I feel isolated from others because of my bowel problems. 
13. 
I feel angry that I have bowel problems. 
16. 
I feel irritable because of my bowel problems. 
30. 
My life revolves around my bowel problems. 
Interference with activity:  
3. 
I am bothered by how much time I spend on the toilet. 
18. 
I feel I get less done because of my bowel problems. 
19. 
I have to avoid stressful situations because of my bowel problems. 
22. 
I have to avoid strenuous activity because of my bowel problems. 
27. 
Long trips are difficult for me because of my bowel problems. 
29. 
It is important to be near a toilet because of my bowel problems. 
31. 
I worry about losing control of my bowels. 
Body image: 
5. 
I feel fat because of my bowel problems. 
21. 
My bowel problems limit what I can wear. 
25. 
I feel sluggish because of my bowel problems. 
26. 
I feel unclean because of my bowel problems. 
Health worry: 
4. 
I feel vulnerable to other illnesses because of my bowel problems. 
15. 
I worry that my bowel problems will get worse. 
32. 
I fear that I won’t be able to have a bowel movement. 
Food avoidance: 
11. 
I have to watch the amount of food I eat because of my bowel problems. 
23. 
I have to watch the kind of food I eat because of my bowel problems. 
28. 
I feel frustrated that I can not eat when I want because of my bowel problems. 
Social reaction: 
2. 
I am embarrassed by the smell caused by my bowel problems. 
14. 
I feel like I irritate others because of my bowel problems.  
17. 
I worry that people think I exaggerate my bowel problems. 
34. 
I feel that no one understands my bowel problems. 
Sexual: 
12. 
Because of my bowel problems, sexual activity is difficult for me. 
20. 
My bowel problems reduce my sexual desire. 
71 of 79


 
 
 
 
IBSMAN.doc, 11/3/2005, 9:34:02 
AM 
40 
Relationships: 
8. 
I feel uncomfortable when I talk about my bowel problems. 
24. 
Because of my bowel problems, I have difficulty being around people I do not know well. 
33. 
My bowel problems are affecting my closest relationships. 
 
Items Eliminated in Validation Study 
I am worried that my bowel problems hide a more serious illness. 
I feel responsible for bringing on my bowel problems. 
I feel bad about myself because of my bowel problems. 
I worry about not being able to get to the toilet on time. 
I worry about my health in general because of my bowel problems. 
It is difficult for me to control my weight because of my bowel problems. 
I feel rejected because of my bowel problems. 
72 of 79


IBSMAN.doc, 11/3/2005, 9:34:02 AM 
41
APPENDIX C 
IBS Symptom Frequency Questionnaire 
How often in the past month (30 days) did you have any of the following symptoms? (Please circle one number 
for each symptom) 
 
Symptoms 
 
Never 
Almost 
Never 
 
Seldom 
 
Sometimes 
 
Often 
Almost 
Always 
 
Always 
Abdominal discomfort, pain or cramps 
0 
1 
2 
3 
4 
5 
6 
Hard or lumpy stools 
0 
1 
2 
3 
4 
5 
6 
Loose or watery stools 
0 
1 
2 
3 
4 
5 
6 
Straining during a bowel movement 
0 
1 
2 
3 
4 
5 
6 
Urgency- having to rush to the toilet for a 
bowel movement 
0 
1 
2 
3 
4 
5 
6 
Feeling of incomplete bowel movement 
0 
1 
2 
3 
4 
5 
6 
Passing mucus (white material) during a 
bowel movement 
0 
1 
2 
3 
4 
5 
6 
Abdominal fullness, bloating or swelling 
0 
1 
2 
3 
4 
5 
6 
Passing gas 
0 
1 
2 
3 
4 
5 
6 
Heartburn or chest pain 
0 
1 
2 
3 
4 
5 
6 
Feeling full soon after starting a meal 
0 
1 
2 
3 
4 
5 
6 
Passing urine more frequently 
0 
1 
2 
3 
4 
5 
6 
Nausea 
0 
1 
2 
3 
4 
5 
6 
73 of 79


 
 
 
 
IBSMAN.doc, 11/3/2005, 9:34:02 
AM 
42 
IBS Symptom Bothersomeness Questionnaire 
On a 0 to 6 point scale, please rate the following symptoms according to how bothersome they were in the 
past month (30 days).  (Please circle one number for each symptom) 
Symptoms 
Not 
Bothersome 
  
 ➜ 
  ➜  
 
Somewhat 
Bothersome 
  
 ➜ 
  ➜  
 
Extremely 
Bothersome 
Abdominal discomfort, pain 
or cramps 
0 
1 
2 
3 
4 
5 
6 
Hard or lumpy stools 
0 
1 
2 
3 
4 
5 
6 
Loose or watery stools 
0 
1 
2 
3 
4 
5 
6 
Straining during a bowel 
movement 
0 
1 
2 
3 
4 
5 
6 
Urgency- having to rush to 
the toilet for a bowel 
movement 
0 
1 
2 
3 
4 
5 
6 
Feeling of incomplete 
bowel movement 
0 
1 
2 
3 
4 
5 
6 
Passing mucus (white 
material) during a bowel 
movement 
0 
1 
2 
3 
4 
5 
6 
Abdominal fullness, 
bloating or swelling 
0 
1 
2 
3 
4 
5 
6 
Passing gas 
0 
1 
2 
3 
4 
5 
6 
Heartburn or chest pain 
0 
1 
2 
3 
4 
5 
6 
Feeling full soon after 
starting a meal 
0 
1 
2 
3 
4 
5 
6 
Passing urine more 
frequently 
0 
1 
2 
3 
4 
5 
6 
Nausea 
0 
1 
2 
3 
4 
5 
6 
74 of 79


IBSMAN.doc, 11/3/2005, 9:34:02 AM 
43
APPENDIX D 
Demographic Questions 
About You 
A1. 
What is your gender?  (Please circle one number) 
1 
MALE 
2 
FEMALE 
A2. 
When were you born?  (Please write the numbers on the lines provided) 
 
 
/
 
/
 
 
MONTH 
 
DAY 
 
YEAR 
A3. 
What is the highest level of education you have completed? (Please circle one number) 
1 
NONE, PRIMARY OR ELEMENTARY SCHOOL 
2 
SECONDARY OR HIGH SCHOOL 
3 
APPRENTICESHIP 
4 
UNIVERSITY OR NON-UNIVERSITY HIGHER EDUCATION 
5 
POSTGRADUATE DEGREE 
A4. 
What is your current marital status?  (Please circle one number) 
1 
MARRIED OR LIVING AS MARRIED 
2 
WIDOWED 
3 
SEPARATED 
4 
DIVORCED 
5 
NEVER MARRIED 
A5. 
Please indicate the group that describes you best. (Please circle one number) 
1 
WHITE (NON-HISPANIC) 
2 
BLACK / AFRICAN-AMERICAN 
3 
AMERICAN INDIAN / ALASKAN NATIVE 
4 
ASIAN / PACIFIC ISLANDER 
5 
HISPANIC / LATINO 
6 
PLEASE SPECIFY _____________________________ 
A6. 
Which of these income categories comes closest to the total yearly income for your household, from all 
sources? (Please circle one number) 
1 
UNDER $5,000 
2 
$5,000 
TO 
$9,999 
3 
$10,000 
TO 
$14,999 
4 
$15,000 
TO 
$24,999 
5 
$25,000 
TO 
$34,999 
6 
$35,000 
TO 
$49,999 
7 
$50,000 
TO 
$74,999 
8 
$75,000 
AND OVER 
(If all you know is your monthly income, please write it here)  _____________ 
75 of 79


 
 
 
 
IBSMAN.doc, 11/3/2005, 9:34:02 
AM 
44 
76 of 79


IBSMAN.doc, 11/3/2005, 9:34:02 AM 
45
APPENDIX E 
SPSS Scoring Syntax from Diskette Labeled: 
IBS-QOL Instruments SPSS Scoring Diskette 
IBS-QOL 
FILENAME IN ‘A:\IBSQOLDL.SPS’; 
DATA LIST 
  FILE='a:\ibsqol.dat' FIXED RECORDS=1 Table /1 id 1-4 ibs01 5 
  -5 ibs02 6-6 ibs03 7-7 ibs04 8-8 ibs05 9-9 ibs06 10-10 ibs07 11-11 ibs08 12-12 
  ibs09 13-13 ibs10 14-14 ibs11 15-15 ibs12 16-16 ibs13 17-17 ibs14 18-18  
  ibs15 19-19 ibs16 20-20 ibs17 21-21 ibs18 22-22 ibs19 23-23 ibs20 24-24 
  ibs21 25-25 ibs22 26-26 ibs23 27-27 ibs24 28-28 ibs25 29-29 ibs26 30-30 
  ibs27 31-31 ibs28 32-32 ibs29 33-33 ibs30 34-34 ibs31 35-35 ibs32 36-36 
  ibs33 37-37 ibs34 38-38 . 
EXECUTE. 
FILENAME IN ‘A:\IBSQOL.SPS’; 
* SYNTAX FILE USED TO SCORE THE IBS-QOL 
* Filename="ibsqol.sps" 
* Written in SPSS for Windows 
* Last edited: 3/31/97 
* Irritable Bowel Syndrome Quality Of Life Group, Seattle, Washington, USA 
* This file creates 9 variables:  
*      9 total 100-point scale transformed scores: 
*          IBS_DY = DYSPHORIA SCORE (8 ITEM)                       
*          IBS_IN = INTERFERENCE WITH ACTIVITY SCORE (7 ITEM)  
*          IBS_BI = BODY IMAGE SCORE (4 ITEM)                       
*          IBS_HW = HEALTH WORRY SCORE (3 ITEM)                       
*          IBS_FA = FOOD AVOIDANCE SCORE (3 ITEM)                       
*          IBS_SR = SOCIAL REACTION SCORE (4 ITEM) 
*          IBS_SX = SEXUAL SCORE (2 ITEM)                       
*          IBS_RL = RELATIONSHIPS SCORE (3 ITEM)                       
*          IBS_OV = OVERALL SCORE (34 ITEM) 
* Labeling all variables  
VARIABLE LABELS 
 
IBS01 "I feel helpless"  
 
IBS02 "I am embarrassed by the smell" 
 
IBS03 "I am bothered by how much time I spend on the toilet"  
 
IBS04 "I feel vulnerable to other illnesses"  
 
IBS05 "I feel fat"  
 
IBS06 "I feel like I'm losing control of my life"  
 
IBS07 "I feel my life is less enjoyable"  
 
IBS08 "I feel uncomfortable when I talk about my bowel problems"  
 
IBS09 "I feel depressed about my bowel problems"  
 
IBS10 "I feel isolated from others"  
 
IBS11 "I have to watch the amount of food I eat"  
 
IBS12 "Sexual activity is difficult for me"  
 
IBS13 "I feel angry that I have bowel problems"  
 
IBS14 "I feel like I irritate others"  
 
IBS15 "I worry that my bowel problems will get worse"  
 
IBS16 "I feel irritable"  
 
IBS17 "I worry that people think I exaggerate about my bowel problems"  
 
IBS18 "I feel I get less done"  
77 of 79


 
 
 
 
IBSMAN.doc, 11/3/2005, 9:34:02 
AM 
46 
 
IBS19 "I have to avoid stressful situations"  
 
IBS20 "My bowel problems reduce my sexual desire"  
 
IBS21 "My bowel problems limit what I can wear"  
 
IBS22 "I have to avoid strenuous activity"  
 
IBS23 "I have to watch the kind of food I eat"  
 
IBS24 "I have difficulty being around people I do not know well"  
 
IBS25 "I feel sluggish because of my bowel problems"  
 
IBS26 "I feel unclean because of my bowel problems"  
 
IBS27 "Long trips are difficult for me"  
 
IBS28 "I feel frustrated that I cannot eat when I want"  
 
IBS29 "It is important to be near a toilet"  
 
IBS30 "My life revolves around my bowel problems"  
 
IBS31 "I worry about losing control of my bowels"  
 
IBS32 "I fear that I won't be able to have a bowel movement"  
 
IBS33 "My bowel problems are affecting my closest relationships"  
 
IBS34 "I feel no one understands my bowel problems" . 
EXECUTE . 
* Re-coding all variables so low score equals worse quality of life 
* Change out-of-range values to missing values 
RECODE IBS01 IBS02 IBS03 IBS04 IBS05 IBS06 IBS07 IBS08 IBS09 IBS10 IBS11 
       IBS12 IBS13 IBS14 IBS15 IBS16 IBS17 IBS18 IBS19 IBS20 IBS21 IBS22  
       IBS23 IBS24 IBS25 IBS26 IBS27 IBS28 IBS29 IBS30 IBS31 IBS32 IBS33  
       IBS34 (1=5) (2=4) (3=3) (4=2) (5=1) (ELSE=SYSMIS) . 
EXECUTE . 
* Labeling values of each item 
VALUE LABEL  
   IBS01 TO IBS34  
       5 'NOT AT ALL'  
       4 'SLIGHTLY'  
       3 'MODERATELY'  
       2 'QUITE A BIT'  
       1 'EXTREMELY'.  
EXECUTE . 
* Adding up item totals for each subscale  
COMPUTE TOT_DY = IBS01 + IBS06 + IBS07 + IBS09 + IBS10 + IBS13 + IBS16 + IBS30 . 
COMPUTE TOT_IN = IBS03 + IBS18 + IBS19 + IBS22 + IBS27 + IBS29 + IBS31 . 
COMPUTE TOT_BI = IBS05 + IBS21 + IBS25 + IBS26 . 
COMPUTE TOT_HW = IBS04 + IBS15 + IBS32 . 
COMPUTE TOT_FA = IBS11 + IBS23 + IBS28 . 
COMPUTE TOT_SR = IBS02 + IBS14 + IBS17 + IBS34 . 
COMPUTE TOT_SX = IBS12 + IBS20 . 
COMPUTE TOT_RL = IBS08 + IBS24 + IBS33 . 
COMPUTE TOT_OV = IBS01 + IBS02 + IBS03 + IBS04 + IBS05 + IBS06 + IBS07 + IBS08 + 
IBS09 +  IBS10 + IBS11 + IBS12 + IBS13 + IBS14 + IBS15 + IBS16 + IBS17 + IBS18 
+  IBS19 + IBS20 + IBS21 + IBS22 + IBS23 + IBS24 + IBS25 + IBS26 + IBS27 +  
IBS28 + IBS29 + IBS30 + IBS31 + IBS32 + IBS33 + IBS34 . 
* Computing all subscales scores (transformed 0 to 100 scale)  
COMPUTE IBS_DY=((tot_dy - 8)/(32))*100  
COMPUTE IBS_IN=((tot_in - 7)/(28))*100  
COMPUTE IBS_BI=((tot_bi - 4)/(16))*100  
COMPUTE IBS_HW=((tot_hw - 3)/(12))*100  
COMPUTE IBS_FA=((tot_fa - 3)/(12))*100  
COMPUTE IBS_SR=((tot_sr - 4)/(16))*100  
COMPUTE IBS_SX=((tot_sx - 2)/(8))*100  
COMPUTE IBS_RL=((tot_rl - 3)/(12))*100  
78 of 79


IBSMAN.doc, 11/3/2005, 9:34:02 AM 
47
COMPUTE IBS_OV=((tot_ov -34)/(136))*100  
EXECUTE . 
* Labeling all scored subscales   
VARIABLE LABELS  
IBS_DY 'DYSPHORIA SCORE (8 ITEM-TRANSFORMED)'/  
IBS_IN 'INTERFERENCE WITH ACTIVITY SCORE (7 ITEM-TRANSFORMED)'/  
IBS_BI 'BODY IMAGE SCORE (4 ITEM-TRANSFORMED)'/  
IBS_HW 'HEALTH WORRY SCORE (3 ITEM-TRANSFORMED)'/  
IBS_FA 'FOOD AVOIDANCE SCORE (3 ITEM-TRANSFORMED)'/  
IBS_SR 'SOCIAL REACTION SCORE (4 ITEM-TRANSFORMED)'/  
IBS_SX 'SEXUAL SCORE (2 ITEM-TRANSFORMED)'/  
IBS_RL 'RELATIONSHIPS SCORE (3 ITEM-TRANSFORMED)'/  
IBS_OV 'OVERALL SCORE (34 ITEM-TRANSFORMED)' .  
EXECUTE . 
79 of 79