Conditions: Constipation Predominant Irritable Bowel Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 312
Healthy volunteers: no

Brief summary:
This phase 3, open label study will evaluate the safety of tenapanor 50 mg BID in subjects with constipation-predominant irritable bowel syndrome (IBS-C) defined by the ROME III criteria. Subjects who have completed either TEN-01-301 (16 weeks) or TEN-01-302 (26 weeks) studies may be enrolled. Subjects will take tenapanor for approximately 52-55 weeks total based on previous protocol and this study.

Detailed description:
During the treatment period of up to 39-weeks, subjects will return for study visits approximately every 13 weeks. 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.

Arms:
arm 1: Tenapanor, 50 mg BID (100 mg total)

Interventions: intervention 1: Tenapanor
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
16.1 
Study Information 
16.1.1 
Protocol and protocol amendments 
The following documents are included: 
• Final protocol, dated 29 Jan 2016. 


Ardelyx, Inc. 
 
Clinical Study Protocol  
 
Protocol No. TEN-01-303 
 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 1 of 34 
Supersedes Date: NA 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol No. TEN-01-303 
 
An Open Label Long-Term Safety Study of Tenapanor for the Treatment of Constipation-
Predominant Irritable Bowel Syndrome (IBS-C) 
 
29 January 2016 
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. 


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 2 of 34 
Supersedes Date: NA 
PROTOCOL SUMMARY 
Study Title 
An Open Label Long-Term Safety Study of Tenapanor for the 
Treatment of Constipation-Predominant Irritable Bowel Syndrome 
(IBS-C) 
Sponsor 
Ardelyx, Inc. 
Study Phase 
3 
Treatment 
Groups  
Single treatment group; approximately 300 subjects total  
No. of Sites 
Approximately 50-60 
Dose Form and 
Frequency 
Tablet(s) 
Twice daily (BID)  
Doses 
Tenapanor 50 mg BID (total daily dose 100 mg) 
Methodology 
This is an open label study to evaluate the safety of tenapanor 50 mg 
BID in subjects with IBS-C (Rome III criteria). Subjects who have 
completed either the TEN-01-301 (16 weeks) or TEN-01-302 (26 
weeks) studies may be enrolled. Subjects will take tenapanor for up 
to 52 weeks total based on previous protocol and this study. 
Duration 
For each subject, the entire exposure to tenapanor will last for a total 
of approximately 52 to 55 weeks; including completion of either the 
TEN-01-301 or TEN-01-302 studies. For subjects completing studies 
TEN-01-301 or TEN-01-302, TEN-01-303 treatment duration will be 
39 and 26 weeks, respectively. 
 


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Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 3 of 34 
Supersedes Date: NA 
Treatment Period 
During the treatment period of up to 39-weeks subjects will return 
for study visits approximately every 13 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.   
Inclusion/Exclusion 
Criteria 
Inclusion Criteria 
Subjects meeting all of the following inclusion criteria will be 
eligible for enrollment: 
1. Subjects completed all 16 weeks of TEN-01-301 or all 26 
weeks of TEN-01-302. 
2. In the opinion of the investigator, the subject demonstrated 
adequate compliance with the study procedures during 
either the TEN-01-301 or TEN-01-302 studies preceding 
this long term safety study. 
3. 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) 
as determined in either TEN-01-301 or TEN-01-302 
studies. If of child-bearing potential, must have negative 
pregnancy test at last visit for TEN-01-301 or TEN-01-302 
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 study, or 
• Double barrier method,  
• Sterilization of one or both partner(s).   
4. Males must agree to use an appropriate method of barrier 
contraception (e.g., latex condom with a spermicidal 
agent) or have documented surgical sterilization 


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Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 4 of 34 
Supersedes Date: NA 
5. The subject has signed the informed consent and is willing 
to comply with all trial visits and assessments 
Exclusion Criteria 
Subjects meeting one or more of the following exclusion 
criteria are not to be enrolled in the study: 
1. The subject has been withdrawn or discontinued 
prematurely from either TEN-01-301 or TEN-01-302 
2. The subject reports using any prohibited medication and is 
not willing to abide by the restrictions for intake 
3. Pregnant or lactating women. 
4. 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. 
Statistical 
Considerations 
Summary tabulations will be presented that will display 
descriptive statistics at each visit for each treatment cohort and for 
all subjects in the safety analysis set. 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 receive at least one dose of study drug will be 
included in all analyses of safety.  
 
Safety analyses will include summaries for treatment emergent 
adverse events, clinical laboratory tests, vital signs, 12-lead ECGs, 
and physical exams. Study drug exposure, compliance and 
concomitant medications will also be summarized. 
 


Ardelyx, Inc. 
 
Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 5 of 34 
Supersedes Date: NA 
TABLE OF CONTENTS 
PROTOCOL SUMMARY ................................................................................................... 2	  
TABLE OF CONTENTS .................................................................................................... 5	  
1.	  
LIST OF ABBREVIATIONS ....................................................................................... 7	  
2.	  
INTRODUCTION AND STUDY RATIONALE ........................................................ 9	  
2.1.	  
Scientific Background .................................................................................. 9	  
2.2.	  
Description of Investigational Drug ............................................................. 9	  
3.	  
STUDY OBJECTIVES .............................................................................................. 10	  
3.1.	  
Primary Objective ....................................................................................... 10	  
4.	  
INVESTIGATIONAL PLAN ..................................................................................... 10	  
5.	  
STUDY POPULATION ............................................................................................. 11	  
5.1.	  
General Considerations .............................................................................. 11	  
5.2.	  
Inclusion Criteria ........................................................................................ 11	  
5.3.	  
Exclusion Criteria ....................................................................................... 11	  
5.4.	  
Rescue Medication ..................................................................................... 12	  
5.5.	  
Prohibited Concurrent Medications ............................................................ 12	  
5.6.	  
Removal of Subjects from Therapy or Assessment ................................... 12	  
6.	  
TREATMENTS .......................................................................................................... 13	  
6.1.	  
Identity of Investigational Product ............................................................. 13	  
6.2.	  
Packaging, Storage, and Labeling .............................................................. 13	  
6.3.	  
Treatments to be Administered .................................................................. 13	  
6.4.	  
Randomization and Blinding ...................................................................... 13	  
7.	  
SCHEDULE OF ASSESSMENTS ............................................................................. 14	  
8.	  
STUDY EVALUATIONS .......................................................................................... 15	  
8.1.	  
Evaluations and procedures at Visit 1 (Day 1) ........................................... 15	  
8.2.	  
Safety Assessments .................................................................................... 16	  
8.3.	  
Total Blood Volume Required for Study ................................................... 17	  
8.4.	  
Data Quality Assurance .............................................................................. 17	  
9.	  
ADVERSE EVENTS .................................................................................................. 18	  
9.1.	  
Adverse Event ............................................................................................ 18	  
9.2.	  
Severity ....................................................................................................... 18	  
9.3.	  
Unexpected Adverse Drug Experience ...................................................... 19	  
9.4.	  
Causality ..................................................................................................... 19	  
9.5.	  
Serious Adverse Event ............................................................................... 19	  
9.6.	  
Procedures for Recording and Reporting AEs and SAEs .......................... 20	  
9.7.	  
Monitoring of Adverse Events and Period of Observation ........................ 21	  
9.8.	  
Pregnancy ................................................................................................... 22	  
10.	  
STATISTICAL CONSIDERATIONS ..................................................................... 23	  


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Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
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Supersedes Edition: NA 
Edition Date: 29 January 2016 
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10.1.	   Determination of Sample Size .................................................................... 23	  
10.2.	   Randomization and Stratification ............................................................... 23	  
10.3.	   Analysis Sets .............................................................................................. 23	  
10.4.	   Procedures for Handling Missing Data ...................................................... 23	  
10.5.	   Methods of Pooling Data ............................................................................ 23	  
10.6.	   Visit Windows ............................................................................................ 23	  
10.7.	   Statistical Analyses ..................................................................................... 23	  
11.	  
ADMINISTRATIVE REQUIREMENTS ................................................................ 27	  
11.1.	   Good Clinical Practice ................................................................................ 27	  
11.2.	   Ethical Considerations ................................................................................ 27	  
11.3.	   Subject Informed Consent and Information ............................................... 27	  
11.4.	   Subject Confidentiality ............................................................................... 28	  
11.5.	   Protocol Compliance .................................................................................. 28	  
11.6.	   Study Monitoring and On-site Audits ........................................................ 28	  
11.7.	   Case Report Form Completion ................................................................... 29	  
11.8.	   Drug Accountability/Retention .................................................................. 29	  
11.9.	   Study Completion or Premature Closure .................................................... 30	  
11.10.	  Record Retention ........................................................................................ 30	  
12.	  
USE OF INFORMATION AND PUBLICATION .................................................. 31	  
13.	  
SIGNATURES ......................................................................................................... 32	  
13.1.	   Investigator Signature ................................................................................. 32	  
13.2.	   Sponsor Signature ....................................................................................... 33	  
14.	  
APPENDIX A: Clinical Laboratory Tests ................................................................ 34	  


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Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 7 of 34 
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1. 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransaminase 
AST 
Aspartate aminotransaminase 
BM 
Bowel movement 
BMI 
Body mass index 
BSFS 
Bristol stool form scale 
BUN 
Blood urea nitrogen 
CIC 
Chronic idiopathic constipation 
CKD 
Chronic kidney disease 
CO2 
Carbon dioxide 
CRC 
Child resistant closure 
CRF 
Case report form;  
CRO 
Contract research organization 
CSBM 
Complete spontaneous bowel movement 
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 
GI 
Gastrointestinal 
H+ 
Hydrogen 
HDPE 
High density polyethylene 
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 


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Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
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IRB 
Institutional review board 
ITT 
Intent to treat 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
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 
OBD 
Opioid bowel dysfunction 
QA 
Quality assurance 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBM 
Spontaneous bowel movement 
SOP 
Standard operating procedure 
TEAE 
Treatment emergent adverse event 
WBC 
White blood cell count 
WHO 
World health organization 
 
 
 
 


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Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 9 of 34 
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 open label long-term safety study will evaluate the safety of tenapanor in 
subjects with constipation predominant IBS (IBS-C) who have completed either study 
TEN-01-301 (16 weeks) or TEN-01-302 (26 weeks).  Subjects who qualify will 
receive tenapanor 50 mg BID for up to 52 weeks total based on previous protocols 
and this study. For subjects completing studies TEN-01-301 or TEN-01-302, 
treatment duration will be 39 and 26 weeks, respectively. 
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 
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 C50H68Cll6N8O10S2.  
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 


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Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 10 of 34 
Supersedes Date: NA 
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. 
 
3. 
STUDY OBJECTIVES 
3.1. Primary Objective 
The primary objective of this study is to assess the safety of tenapanor 50 mg for the 
treatment of IBS-C when administered twice daily (BID) for up to 52 weeks.  
4. 
INVESTIGATIONAL PLAN 
This is an open label long-term safety study of tenapanor in subjects with IBS-C.  
Subjects who have completed either study TEN-01-301 or TEN-01-302 will be 
eligible to enroll in this study.   
During the open label treatment period, subjects will return for study visits 
approximately every 13 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. 
 
 
 
 
 
 
 
 


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Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
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Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 11 of 34 
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5. 
STUDY POPULATION 
5.1. General Considerations 
Approximately three-hundred (300) subjects who have completed TEN-01-301 or 
TEN-01-302 and meet all of the inclusion criteria, and none of the exclusion criteria 
will be enrolled into the study at approximately 50 to 60 US clinical centers.   
5.2. Inclusion Criteria 
Subjects meeting all of the following inclusion criteria will be eligible for enrollment: 
1. Subjects completed all 16 weeks of TEN-01-301 or all 26 weeks of TEN-01-302. 
2. In the opinion of the investigator, the subject demonstrated adequate compliance 
with the study procedures during either TEN-01-301 or TEN-01-302 studies 
preceding this long term safety study. 
3. 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) as determined in either TEN-01-301 or TEN-
01-302 studies. If of child-bearing potential, must have negative pregnancy test at 
last visit for TEN-01-301 or TEN-01-302 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 study, or 
• Double barrier method,  
• Sterilization of one or both partner(s).   
4. Males must agree to use an appropriate method of barrier contraception (e.g., 
latex condom with a spermicidal agent) or have documented surgical sterilization 
5. The subject has signed the informed consent and is willing to comply with all 
trial visits and assessments 
5.3. Exclusion Criteria 
Subjects meeting one or more of the following exclusion criteria are not to be enrolled 
in the study: 
1. The subject has been withdrawn or discontinued prematurely from either TEN-01-
301 or TEN-01-302 


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Clinical Study Protocol                                    
 
Protocol No. TEN-01-303 
Edition No.: 1 
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Edition Date: 29 January 2016 
 Page 12 of 34 
Supersedes Date: NA 
2. The subject reports using any prohibited medication and is not willing to abide by 
the restrictions for intake 
3. Pregnant or lactating women. 
4. 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.. 
 
5.4. Rescue Medication 
Rescue medications are allowed for severe constipation (i.e, at least 72 hours after the 
subject’s previous BM or when symptoms become intolerable).  Bisacodyl (5 mg 
tablet or 10 mg suppository) is the preferred rescue medication; however, other rescue 
medications prescribed by a physician as standard of care are allowed. 
 
5.5. Prohibited Concurrent Medications 
The following medications are specifically prohibited from use during the study, 
unless specified as a rescue medication. 
All prescription and/or over the counter medications used to treat constipation and/or 
IBS-C  (e.g., linzess, amitiza, miralax, dulcolax, lactulose, bisacodyl). 
Narcotics either alone or in combination (e.g., tramadol, codeine, morphine, 
propoxyphene, loperamide, diphenoxylate, paregoric) if they are being used 
chronically and are expected to be taken indefinitely in the future. 
Patient is planning to receive an investigational drug (other than study drug) or 
investigational device at any time during this study (any investigational or imported 
drugs that have not been approved for human use by the FDA) 
 
5.6. Removal of Subjects from Therapy or Assessment 
Subjects will be discontinued from the study if a subject experiences a study drug 
related serious adverse event.   
Subjects will be informed that they can 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 4 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. 
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.  


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Clinical Study Protocol                                    
 
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Edition No.: 1 
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Edition Date: 29 January 2016 
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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.  
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) tenapanor 50 mg tablets. 
Tenapanor tablets should be stored in the original packaging between 2°C and 30°C. 
Temperature excursions are allowed from -30°C to 50°C for a maximum of 1 week.   
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).  All eligible subjects will receive 
tenapanor 50 mg BID. Subjects will take one tenapanor tablet twice daily, 
immediately prior to breakfast or the first meal of the day and immediately prior to 
dinner.  
Subjects will receive three bottles of drug at Visit 1 (Day 1) and Visit 2 (Week 13 ± 
2).  If the subject was previously in study TEN-01-301, they will also receive three 
bottles of drug at Visit 3 (Week 26 ± 2).  At each visit the subject will be asked to 
return their unused drug and bottles. Study drug compliance will be monitored by the 
clinical site staff and will be verified by the study monitor during on-site monitoring 
visits. 
6.4. Randomization and Blinding 
This is an open label study.  There is no randomization and all subjects and study 
personnel are unblinded.  All subjects that enroll in this study will receive tenapanor 
50 mg BID.


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Edition No.: 1 
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Edition Date: 29 January 2016 
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7. 
SCHEDULE OF ASSESSMENTS 
The study flow chart, including all procedures to be performed during the study is 
presented below.  Prior to engaging in any study procedure, each subject must sign and 
date an informed consent form.  In addition, a telephone contact will take place as 
footnoted below to find out if any treatment related problems have occurred. Additional 
telephone calls to the subjects for treatment follow-ups of AEs will be made as needed. 
 
Evaluation 
Enrolla 
Treatment Periode 
Site Visith 
1 
2 
3b 
4/ETc 
Study Week(s) 
1 
13±2 
26±2 
39±2 
Informed Consenta 
X 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
Concurrent Medications 
 
X 
Xb# 
X 
Physical Exam 
 
 
Xb 
X 
Vital Signsd 
 
X 
Xb# 
X 
Safety Laboratoriesf 
 
 
Xb 
X 
Urine Pregnancy testfg 
 
X 
Xb 
X 
Urinalysisf 
 
 
Xb 
X 
12-lead electronic ECG 
 
 
Xb 
X 
Drug Dispensed/returned 
D 
D/R 
D#/Rb# 
R 
Adverse Event Assessments 
 
X 
Xb# 
X 
aThe Informed Consent Form (ICF) must be signed before any protocol procedures are 
performed. 
bThis is the final visit for subjects that enrolled from Protocol TEN-01-302 and only 
procedures with this footnote are performed on subjects from TEN-01-302. Procedures 
for subjects enrolled from Protocol TEN-01-301 are marked with a # 
cThis is the final visit for subjects that enrolled from Protocol TEN-01-301. It is also used 
as an early termination (ET) visit. 
dVital signs include systolic and diastolic blood pressure (seated), heart rate, respiratory 
rate, temperature and body weight. 
eWhen a subject discontinues early, procedures performed at Visit 4 should be performed 
at the subject’s last visit. 
fLaboratory assessments are detailed in Appendix A 
g If the urine pregnancy test is positive, it will be confirmed with a serum pregnancy test. 
hTelephone calls will be made to subjects monthly during the two months prior to a site 
visit to ascertain if there have been any treatment related problems (Weeks 5±1, 9±1, 
17±1, 22±1 for subjects from TEN-01-301 and TEN-01-302 and for subjects from TEN-
01-301 also Weeks 30±1 and 35±1). 


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8. 
STUDY EVALUATIONS 
The assessments to be performed during the study are outlined by visit and study 
day/week below.  The day of enrollment begins the clock for all subsequent visit days 
and dates.   
8.1. Evaluations and procedures at Visit 1 (Day 1) 
The following procedures will be conducted at Visit 1: 
• Informed Consent  
• Inclusion/Exclusion Criteria 
• Drug Dispensed 
8.1.1 Telephone contacts (Weeks 5±1, 9±1, 17±1, 22±1, for subjects from TEN-01-
301 also Weeks 30±1 and 35±1) 
• Concurrent Medications (changes since last visit) 
• Adverse Events 
8.1.2 Evaluations and procedures at Visit 2 (Week 13 ±2) 
• Concurrent Medications (changes since last visit) 
• Vital signs 
• Urine Pregnancy test 
• Adverse Events 
• Drug Returned 
• Drug Dispensed 
8.1.3 Evaluations and procedures at Visit 3 (Week 26 ±2)  
 
This is the end of treatment visit for those subjects from study TEN-01-302 
• Concurrent Medications (changes since last visit) 
• Vital Signs 
• Physical Exam (only TEN-01-302 subjects) 
• Serum Chemistry and Hematology (only TEN-01-302 subjects) 
• Urine Pregnancy Test 
• Urinalysis (only TEN-01-302 subjects) 
• ECG (only TEN-01-302 subjects) 


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• Adverse Events 
• Drug Returned 
• Drug Dispensed (only TEN-01-301 subjects) 
8.1.4 Evaluations and procedures at Visit 4 (Week 39 ±2) 
This is the end of treatment visit for those subjects from study TEN-01-301 
• Concurrent Medications (changes since last visit) 
• Vital Signs 
• Physical Exam 
• Serum Chemistry and Hematology 
• Urine Pregnancy Test 
• Urinalysis  
• ECG 
• Adverse Events 
• Drug Returned 
8.2. Safety Assessments 
8.2.1 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.   
8.2.1.1 Adverse events 
Monitoring of treatment emergent adverse events will be conducted throughout the 
study beginning on Day 1.  Adverse events, including serious adverse events will be 
recorded in the eCRFs through the end of the study.  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.   
8.2.1.2 Physical examination 
A complete physical examination will be conducted during either Visit 3 (TEN-01-
302) or Visit 4 (TEN-01-301) (and at any early termination visit).   


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8.2.1.3 Electrocardiogram 
A 12-lead electrocardiogram will be obtained during either Visit 3 (TEN-01-302) or 
Visit 4 (TEN-01-301) (and at any early termination visit).   
8.2.1.4 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 Visits 2, 3 
and 4 (subjects from TEN-01-301 and early terminations only).   
8.2.1.5 Clinical laboratory tests 
A central laboratory will perform clinical laboratory tests.  Blood samples will be 
drawn from subjects for serum chemistries and hematology at either Visit 3 (TEN-01-
302) or Visit 4 (TEN-01-301) (and at any early termination visit).  Urine will be taken 
for urinalysis at either Visit 3 (TEN-01-302) or Visit 4 (TEN-01-301) (and at any 
early termination visit).  A urine pregnancy test will be performed at Visits 2, 3 and 4 
(TEN-01-301 only). If the urine pregnancy test is positive, it will be confirmed with a 
serum pregnancy test.  See Appendix A for specific laboratory tests.   
Clinical laboratory test values that are considered abnormal will be noted as clinically 
significant or not 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.   
 
8.3. Total Blood Volume Required for Study 
Table 8-1 
Approximate Blood Volume per Subject 
Test 
Number of Samples 
Volume (mL) 
Total (mL) 
Hematology (blood) 
1 
3 
3 
Chemistry (serum) 
1 
7 
7 
Total 
2 
-- 
10 
8.4. 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 
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 


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source documents available, provide missing or corrected data and sign the eCRFs. 
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) are 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 
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.   


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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.  
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 


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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 
(Enrollment) and the final visit (up to Weeks 26 or 39, Visits 3 or 4).   
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. 
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 


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report within 24 hours 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 
Ardelyx will assume responsibility for appropriate reporting of adverse events to 
regulatory authorities.  Ardelyx will report Suspected Unexpected Serious Adverse 
Reactions (SUSARs) to all investigational sites.   
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 (either Visit 3 (TEN-01-302) or Visit 4 (TEN-01-301)).  
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 
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.   


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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.   


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10. 
STATISTICAL CONSIDERATIONS 
This open label long-term safety study will evaluate the safety of tenapanor in 
subjects with constipation predominant IBS (IBS-C) who have completed either study 
TEN-01-301 or TEN-01-302.  Approximately, 300 subjects who qualify will be 
enrolled at approximately 50-60 US clinical centers and receive tenapanor 50 mg BID 
for up to 52 weeks total (previous protocol and this study). 
. A statistical analysis plan (SAP) will be developed, finalized, and signed-off on 
prior to the database lock. 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 analyses.  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 
Based on the two Phase 3 studies (TEN-01-301 and TEN-01-302) and the different 
treatment arms, 300 subjects entered into this open label long-term safety study 
should produce approximately 150 subjects with at least 52 weeks exposure to 
tenapanor 50 mg BID and an additional 150 subjects with 26 to 39 weeks of exposure 
to tenapanor 50 mg BID. 
10.2. Randomization and Stratification 
This is an open-label study. All subjects will receive tenapanor 50 mg BID.  
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.   
10.4. Procedures for Handling Missing Data 
      The safety analysis will be based on the observed data. No imputations or carried 
forward analyses will be done. 
10.5. Methods of Pooling Data 
      No data will be pooled for purposes of analyses.  
10.6. Visit Windows 
      Observed data will be used for the safety analyses. No visit windows will be applied.  
10.7. Statistical Analyses 
      Summary tabulations will be presented that will display descriptive statistics by visit 
for four treatment cohorts and for all subjects in the safety analysis set.  These cohorts 
are identified below. 
 
Table 10-1 Treatment Cohorts for Summary Tabulations 


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Protocol 301 
Protocol 303 
Cohort 
12-weeks 
4-weeks 
39-weeks 
1 
Tenapanor 50 mg BID 
Tenapanor 50 mg BID 
Tenapanor 50 mg BID 
2 
Tenapanor 50 mg BID 
Placebo 
Tenapanor 50 mg BID 
3 
Placebo 
Tenapanor 50 mg BID 
Tenapanor 50 mg BID 
 
 
 
 
 
Protocol 302 
 
 
26-weeks 
26-weeks 
4 
Tenapanor 50 mg BID 
Tenapanor 50 mg BID 
5 
Placebo 
Tenapanor 50 mg BID 
 
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.   
 
As this is an open label study of only treatment with tenapanor 50 mg BID, no 
statistical testing will be done.  
10.7.1 Subject Disposition 
      Subject disposition information will be summarized by treatment cohort and all 
subjects overall. The number and percent of subjects who are enrolled, 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 enrolled 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 the safety analysis set will also be tabulated. 
10.7.2 Demographic and Background Characteristics 
      Demographic and background characteristics from TEN-01-301 and TEN-01-302 will 
be summarized by treatment cohort and all subjects overall. 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).  
   
      Medical history and gastrointestinal (GI) history from TEN-01-301 and TEN-01-302 
will be summarized for the number and percentage of subjects for each body system. 
Medical history includes verbatim terms recorded for the subjects. GI history includes 
duration (years) since IBS symptoms began before enrollment, duration (months) 
since last colonoscopy before enrollment, and whether colonoscopy findings are not 
significant. Medical and GI history will also be listed. 
10.7.3 Prior/Concomitant Medication 
All medications administered during this study will be considered concomitant. These 
medications will be coded using the latest available version of the World Health 


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Organization (WHO) Drug Reference List. The number and percentage of subjects 
taking concomitant medications will be summarized by Anatomical Therapeutic 
Chemical (ATC) class and preferred name by treatment cohort and all subjects 
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 cohort and all subjects overall. Summary statistics will also be presented for 
percent compliance to study drug. 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 treatment, then multiplied 
by 100. 
10.7.5 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 for each 
treatment cohort and overall, 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 (Visit 3 for subjects from TEN-01-302 and Visit 4 for subjects from 
TEN-01-301), 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 (including 
urinalysis) will be summarized at each visit collected during the study for each 
treatment cohort and overall. The frequency of clinically significant abnormal 
laboratory test values will be tabulated by treatment cohort and overall. Shift tables 
will be derived for changes in laboratory tests from the last values obtained during 
TEN-01-301 or TEN-01-302 to Visit 3 or 4. 
Vital signs will be summarized descriptively for actual values and change from 
baseline values by visit and treatment cohort as well as overall. Vital signs are 
collected at study visits 2, 3 and 4, as applicable. Baseline for the vital signs will be 
the last values obtained during TEN-01-301 or TEN-01-302. 
 
12-lead electrocardiogram (ECG) results will be summarized descriptively for actual 
values and change from baseline values by treatment cohort and overall for each visit 
(Visit 3 or Visit 4 as applicable). Baseline for the ECG will be the last values 
obtained during TEN-01-301 or TEN-01-302. The overall interpretation will be 


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summarized with number of subjects and percentages for the normal and abnormal 
ECG result categories. 
 
All vital signs and electrocardiogram results will be listed. Abnormal or clinically 
significant results will be flagged. 
Physical examinations are collected at Visit 3 and Visit 4, as applicable.  The number 
and percentage of subjects in each category will be presented for each visit by 
treatment cohort and overall. 
All physical examination results will be listed. Abnormal physical exam results will 
be flagged. 
 


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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 
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.   


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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 
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 


Ardelyx, Inc. 
 
Clinical Study Protocol 
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 29 of 34 
Supersedes Date: NA 
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 screened and 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 consent for 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 
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 


Ardelyx, Inc. 
 
Clinical Study Protocol 
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 30 of 34 
Supersedes Date: NA 
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 
circumstances shall the Investigator re-locate or dispose of any trial documents before 
having obtained written approval from Ardelyx.  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.  
  


Ardelyx, Inc. 
 
Clinical Study Protocol 
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
 Page 31 of 34 
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12. USE OF INFORMATION AND PUBLICATION 
All information regarding tenapanor supplied by Ardelyx to the Investigator or 
generated by the Investigator in accordance with the conduct of the study is 
privileged and confidential information of Ardelyx.  The Investigator agrees to use 
this information to accomplish the study and will not use it for other purposes without 
written consent from Ardelyx.  It is understood that there is an obligation to provide 
Ardelyx with complete data obtained during the study.  The information obtained 
from the clinical trial will be used by Ardelyx in connection with the development of 
tenapanor and may be disclosed by Ardelyx to regulatory authority(ies), other 
Investigators, potential corporate partners, or consultants as required.   
The Investigator’s right and obligations with respect to publishing or otherwise 
presenting information regarding the study are detailed in the Publication provisions 
of the Clinical Study Agreement among the Investigator, the clinical site and Ardelyx.  
The Investigator shall comply with such provisions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Clinical Study Protocol 
Protocol No. TEN-01-303
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
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13.
SIGNATURES
13.1. Investigator Signature 
I have read Clinical Protocol TEN-01-303, Edition 1, dated 29 January 2016, An 
Open Label Long Term Safety Study to Evaluate the 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) 




Ardelyx, Inc. 
 
Clinical Study Protocol 
 
Protocol No. TEN-01-303 
Edition No.: 1 
CONFIDENTIAL 
Supersedes Edition: NA 
Edition Date: 29 January 2016 
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Supersedes Date: NA 
14. 
APPENDIX A: 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 
 
Urine β-hCG 
Appearance 
 
 
Specific Gravity 
 
 
pH 
 
 
Protein 
 
 
Glucose 
 
 
Ketones 
 
 
Blood 
 
 
Nitrite 
 
 
Microscopic 
 
 
 
 
 
 
 



SAP_001.pdf: 
 
 
 
 
 
 
 
16.1.9 
Documentation of statistical methods 
The following documents are included: 
• Final Statistical Analysis Plan, dated 08 Mar 2016 


Ardelyx, Inc. 
Clinical Study Protocol TEN-01-303  
CONFIDENTIAL 
Version V1.1 Final 
Statistical Analysis Plan 
8 March 2016 
 
Page 1 of 12 
 
STATISTICAL ANALYSIS PLAN 
 
An Open Label Long-Term Safety Study of Tenapanor for the Treatment 
of Constipation-Predominant Irritable Bowel Syndrome (IBS-C) 
 
 
 
 
Investigational 
Product: 
Tenapanor 
Protocol Number: 
TEN-01-303 
Development Phase: 
Phase 3 
Sponsor: 
Ardelyx, Inc. 
34175 Ardenwood Blvd.  
Fremont, CA 94555 
 
 
 
 
 
SAP Version V1.1 Final 
SAP Date:  8 March 2016 
 
Original Protocol:  29 January 2016 
 
 
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. 
 
 




Ardelyx, Inc. 
Clinical Study Protocol TEN-01-303  
CONFIDENTIAL 
Version V1.1 Final 
Statistical Analysis Plan 
8 March 2016 
 
Page 3 of 12 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................. 2	  
TABLE OF CONTENTS ...................................................................................................... 3	  
LIST OF ABBREVIATIONS ............................................................................................... 4	  
1.	  
INTRODUCTION ..................................................................................................... 5	  
2.	  
STUDY CHARACTERISTICS ................................................................................ 5	  
2.1	  
Primary Objective ..................................................................................................... 5	  
2.2	  
Study Design and Duration ....................................................................................... 5	  
2.2.1	  
Treatments Administered ................................................................................... 5	  
2.2.2	  
Randomization and Blinding .............................................................................. 6	  
2.2.3	  
Duration of Study ............................................................................................... 6	  
2.3	  
Safety Variables ........................................................................................................ 7	  
3.	  
STATISTICAL METHODOLOGY ......................................................................... 7	  
3.1	  
Determination of Sample Size ................................................................................... 7	  
3.2	  
Analysis Sets ............................................................................................................. 7	  
3.3	  
Procedures for Handling Missing Data ..................................................................... 7	  
3.4	  
Methods of Pooling Data ........................................................................................... 7	  
3.5	  
Visit Windows ........................................................................................................... 7	  
3.6	  
Statistical Analyses ................................................................................................... 7	  
3.6.1	  
Subject Disposition ............................................................................................. 8	  
3.6.2	  
Demographic and Background Characteristics .................................................. 8	  
3.6.3	  
Concomitant Medication .................................................................................... 9	  
3.6.4	  
Study Drug Exposure and Compliance .............................................................. 9	  
3.7	  
Safety Analyses ......................................................................................................... 9	  
3.7.1	  
Adverse Events ................................................................................................... 9	  
3.7.2	  
Clinical Laboratory Tests ................................................................................. 10	  
3.7.3	  
Vital Signs and 12-lead Electrocardiogram ...................................................... 11	  
3.7.4	  
Physical Examination ....................................................................................... 11	  
4.	  
PROGRAMMING SPECIFICATIONS .................................................................. 12	  
 
 


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Clinical Study Protocol TEN-01-303  
CONFIDENTIAL 
Version V1.1 Final 
Statistical Analysis Plan 
8 March 2016 
 
Page 4 of 12 
 
LIST OF ABBREVIATIONS  
AE 
ATC 
Adverse event 
Anatomical therapeutic chemical 
BID 
twice per day 
BMI 
Body mass index 
ECG 
GI 
HEENT 
12-Lead Electrocardiogram 
Gastrointestinal 
Head, ears, eyes, nose, and throat 
IBS  
Irritable bowel syndrome 
IBS-C 
ICF 
Constipation-predominant irritable bowel syndrome 
Informed consent form 
n, N 
 
PR 
PT 
Number of subjects with observations or number of subjects in an 
analysis set 
ECG interval 
Preferred term 
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 
SOC 
Serious adverse event 
System organ class 
TEAE 
WHO 
 
 
 
 
 
 
 
 
Treatment-emergent adverse event 
World Health Organization 
 
 
 
 
 
 
 


Ardelyx, Inc. 
Clinical Study Protocol TEN-01-303  
CONFIDENTIAL 
Version V1.1 Final 
Statistical Analysis Plan 
8 March 2016 
 
Page 5 of 12 
 
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-01-303. 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 
Primary Objective 
The primary objective of this study is to assess the safety of tenapanor 50 mg for the treatment of 
constipation-predominant irritable bowel syndrome (IBS-C) when administered twice daily (BID) 
for up to 52 weeks.  
This SAP will address the primary objective for this study. If other objectives are identified 
or the usage of the data collected for the purposes of this study change, these objectives will 
be addressed at a later time through a separate analysis plan and/or report. 
2.2 
Study Design and Duration 
This is an open label long-term safety study of tenapanor in subjects with IBS-C.  Subjects 
who have completed either study TEN-01-301 or TEN-01-302 will be eligible to enroll in 
this study.   
During the open label treatment period, subjects will return for study visits approximately 
every 13 weeks (see schedule of events).  Subjects will undergo safety assessments at these 
visits, which may include a physical exam, 12-lead electrocardiogram (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. 
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).  All eligible subjects will receive tenapanor 50 
mg BID. Subjects will take one tenapanor tablet twice daily, immediately prior to breakfast 
or the first meal of the day and immediately prior to dinner.  
Subjects will receive three bottles of drug at Visit 1 (Day 1), and Visit 2 (Week 13 ± 2); if the 
subject was previously in study TEN-01-301, they will also receive three bottles of drug at 
Visit 3 (Week 26 ± 2).  At each visit the subject will be asked to return their unused drug and 
bottles. Study drug compliance will be monitored by the clinical site staff and will be verified 
by the study monitor during on-site monitoring visits. 


Ardelyx, Inc. 
Clinical Study Protocol TEN-01-303  
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Version V1.1 Final 
Statistical Analysis Plan 
8 March 2016 
 
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2.2.2 
Randomization and Blinding 
This is an open label study.  There is no randomization and all subjects and study personnel 
are unblinded.  All subjects who enroll in this study will receive tenapanor 50 mg BID. 
2.2.3 
Duration of Study 
For each subject, the entire study will last for a total of approximately 52 to 55 weeks; 
including completion of either the TEN-01-301 or TEN-01-302 studies. For subjects 
completing studies TEN-01-301 or TEN-01-302, TEN-01-303 treatment duration will be 39 
and 26 weeks, respectively.  The study flow chart, including all procedures to be performed 
during the study is presented below.  
 
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. In addition, a telephone contact will take place as footnoted below to 
find out if any treatment related problems have occurred. Additional telephone calls to the 
subjects for treatment follow-ups of AEs will be made as needed. 
 
Evaluation 
Enrolla 
Treatment Period 
Site Visith 
1 
2 
3b 
4/ETc 
Study Week 
1 
13±2 
26±2 
39±2 
Informed Consenta 
X 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
Concurrent Medications 
 
X 
Xb# 
X 
Physical Exam 
 
 
Xb 
X 
Vital Signsd 
 
X 
Xb# 
X 
Clinical Laboratory Testsf 
 
 
Xb 
X 
Urine Pregnancy testfg 
 
X 
Xb# 
X 
Urinalysisf 
 
 
Xb 
X 
12-lead ECG 
 
 
Xb 
X 
Drug Dispensed/returned 
D 
D/R 
D#/Rb# 
R 
Adverse Event Assessments 
 
X 
Xb# 
X 
 
a The Informed Consent Form (ICF) must be signed before any protocol procedures are 
performed. 
b This is the final visit for subjects who enrolled from Protocol TEN-01-302 and only 
procedures with this footnote are performed. Procedures for subjects enrolled from Protocol 
TEN-01-301 are marked with a #. 
c This is the final visit for subjects who enrolled from Protocol TEN-01-301. 
d Vital signs include systolic and diastolic blood pressure (seated), heart rate, respiratory rate, 
temperature and body weight. 


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Statistical Analysis Plan 
8 March 2016 
 
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e When a subject discontinues early, procedures performed at Visit 4 should be performed at 
the subject’s last visit. 
f Laboratory assessments are detailed in Appendix A of the protocol. 
g If the urine pregnancy test is positive, it will be confirmed with a serum pregnancy test. 
h Telephone calls will be made to subjects monthly during the two months prior to a site visit 
to ascertain if there have been any treatment related problems (Weeks 5±1, 9±1, 17±1, 22±1, 
for subjects from TEN-01-301 and TEN-01-302 and for subjects from TEN-01-301 also 
Weeks 30±1 and 35±1). 
2.3 
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 body mass index [BMI]), 12-lead ECGs, and physical examinations.  
3. 
STATISTICAL METHODOLOGY 
3.1 
Determination of Sample Size 
Based on the two Phase 3 studies (TEN-01-301 and TEN-01-302) and the different treatment 
arms, 300 subjects entered into this open label long-term safety study should produce 
approximately 150 subjects with at least 52 weeks exposure to tenapanor 50 mg BID and an 
additional 150 subjects with 26 to 39 weeks of exposure to tenapanor 50 mg BID. 
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.  
3.3 
Procedures for Handling Missing Data 
The safety analysis will be based on the observed data. Except for provisions for estimating 
the date of the last dose (Section 3.6.4), no imputations or carried forward analyses will be 
performed.  
3.4 
Methods of Pooling Data 
Other than the treatment cohorts described below, no data will be pooled for purposes of 
analyses.  
3.5 
Visit Windows 
Observed data will be used for the safety analyses. No visit windows will be applied.  
3.6 
Statistical Analyses 
Summary tabulations will be presented which will display descriptive statistics by visit for 
five treatment cohorts and for all subjects in the safety analysis set. These treatment cohorts 
are identified below. 
 


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Statistical Analysis Plan 
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Treatment Cohorts for Summary Tabulations 
 
Protocol 301 
Protocol 303 
Cohort 
12-Weeks 
4-Weeks 
39-Weeks 
1 
Tenapanor 50 mg BID 
Tenapanor 50 mg BID 
Tenapanor 50 mg BID 
2 
Tenapanor 50 mg BID 
Placebo 
Tenapanor 50 mg BID 
3 
Placebo 
Tenapanor 50 mg BID 
Tenapanor 50 mg BID 
 
 
 
 
 
Protocol 302 
 
 
26-Weeks 
26-Weeks 
4 
Tenapanor 50 mg BID 
Tenapanor 50 mg BID 
5 
Placebo 
Tenapanor 50 mg BID 
 
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.  
As this is an open label study of only treatment with tenapanor 50 mg BID, no statistical 
testing will be performed.  
3.6.1 Subject Disposition 
Subject disposition information will be summarized by treatment cohort and all subjects 
overall. The number and percent of subjects who are enrolled, 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 enrolled 
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 the safety analysis set will also be tabulated. 
3.6.2 Demographic and Background Characteristics 
Demographic and background characteristics from TEN-01-301 and TEN-01-302 will be 
summarized by treatment cohort and all subjects overall. 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).  
Medical history and gastrointestinal (GI) history from TEN-01-301 and TEN-01-302 will be 
summarized for the number and percentage of subjects for each body system. Medical history 
includes verbatim terms recorded for the subjects. GI history includes duration (years) since 
IBS symptoms began before enrollment, duration (months) since last colonoscopy before 
enrollment, and whether colonoscopy findings are not significant. Medical and GI history 
will also be listed. 


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Statistical Analysis Plan 
8 March 2016 
 
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3.6.3 Concomitant Medication 
All medications administered during this study will be considered concomitant. These 
medications will be coded using the latest available version of the World Health 
Organization (WHO) Drug Reference List. The number and percentage of subjects taking 
concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
class and preferred name by treatment cohort and all subjects overall. 
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 study drug will be summarized with descriptive statistics by treatment 
cohort and all subjects overall. In addition, a contingency table will be provided to display 
the number and percentage of subjects in each treatment cohort and overall with exposure in 
the following categories:  ≤13 weeks, >13 to ≤26 weeks, and >26 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. 
Summary statistics will also be presented for percent compliance to study drug. 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 
cohort and overall. The count and percentage of subjects with overall compliance <80%, 
80%-100%, and >100% will also be tabulated by treatment cohort and overall. 
3.7 
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. 
3.7.1 
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 for each treatment cohort and overall. A 
treatment-emergent AE (TEAE) is any AE that starts on or after the first dose of study drug 
through the final visit (Visit 3 for subjects from TEN-01-302 and Visit 4 for subjects from 
TEN-01-301), 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 or is 


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Version V1.1 Final 
Statistical Analysis Plan 
8 March 2016 
 
Page 10 of 12 
 
subsequently considered drug-related by the investigator. 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 (SAEs) 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 
• SAEs 
• Drug-related SAEs 
• Death due to AEs 
• TEAEs leading to study drug discontinuation 
• Drug-related TEAEs leading to study drug discontinuation 
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 
cohort and overall 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 closest relationship of the TEAE to the study drug will be used for the 
analyses.  
TEAEs related to study drug, severe TEAEs, 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. 
3.7.2 
Clinical Laboratory Tests 
The list of clinical laboratory tests collected during this study is presented in Appendix A of 
the protocol. Serum chemistry, hematology, and urinalysis results will be summarized with 
descriptive statistics at Enrollment (based on the last values obtained during TEN-01-301 or 
TEN-01-302), and Visit 3 (for subjects enrolled from TEN-01-302) or Visit 4 (for subjects 
enrolled from TEN-01-301) by treatment cohort and overall. For continuous tests, actual 
values and change from enrollment 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, 


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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 cohort and overall. 
Shift tables classifying normal range results (low out of normal range, normal, or high out of 
normal range) between enrollment and the final visit will be tabulated by treatment cohort 
and overall. Missing results for each pairwise summary will be tabulated.  
Data listings of clinical laboratory tests will include flags for abnormal results. 
3.7.3 
Vital Signs and 12-lead Electrocardiogram 
Vital signs (body weight, heart rate, respiratory rate, sitting systolic blood pressure, sitting 
diastolic blood pressure, and temperature) will be summarized descriptively for actual values 
and change from enrollment values by treatment cohort and overall by visit. Enrollment 
values for the vital signs will be the last values obtained during TEN-01-301 or TEN-01-302. 
Electrocardiogram results (heart rate, PR interval, QRS duration, QT, QTcB and QTcF 
intervals) will be summarized descriptively for actual values and change from enrollment 
values by treatment cohort, overall, and visit. Enrollment values will be obtained in a similar 
manner as for the vital signs. 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. 
3.7.4 
Physical Examination 
Physical examinations (general appearance, HEENT, respiratory, cardiovascular, abdomen, 
skin, lymph nodes, musculoskeletal, extremities, and neurological) will be summarized at 
enrollment (last values collected for TEN-01-301 or TEN-01-302), and at Visit 3 or Visit 4. 
The number and percentage of subjects in each category will be presented for each visit by 
treatment cohort and overall. 
All physical examination results will be listed. Abnormal physical exam results will be 
flagged. 


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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.