Clinical trial NCT03988920
Conditions: Hyperphosphatemia End Stage Renal Disease
Sponsor: Ardelyx
Start date: 2019-06-15; Completion date: 2021-07-31
Enrollment: 172 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is designed to evaluate the ability of tenapanor alone or in combination with sevelamer to achieve serum phosphorus concentration (sP) within the population reference range (sP \>2.5 and ≤4.5 mg/dL) in patients with end-stage renal disease (ESRD) on dialysis with hyperphosphatemia (\>4.5 mg/dL).

Detailed description:
Patients who complete the TEN-02-301 study (PHREEDOM) may be eligible to enroll into TEN-02-401 (NORMALIZE).

Patients from the TEN-02-301 tenapanor arm will either receive only tenapanor or be given sevelamer in addition to tenapanor based on their sP. Patients from the TEN-02-301 sevelamer arm will be given tenapanor in addition to their sevelamer dose and the sevelamer dose will then be adjusted based on their sP following a protocol-specified dose titration schedule. Patients will be monitored for safety and efficacy with in-office and telephone visits for up to an additional 18 months.

Laboratory assessments will be measured at every visit (Weeks 1, 2, 3, 4, 6 and 8 and Months 3, 6, 9, 12, 15 and 18) using a central laboratory.

Safety assessments will be performed during the study and will include physical examinations, vital signs (blood pressure and pulse), body weights, clinical laboratory evaluations, 12-lead electrocardiograms (ECGs), and adverse event (AE) monitoring.

Arms: arm 1: Tenapanor will be administered QD or BID and sevelamer can be added to achieve desired serum phosphorus level arm 2: Sevelamer will be administered QD, BID or TID and tenapanor will be added to achieve desired serum phosphorus level and sevelamer dose will be decreased as needed
Interventions: intervention 1: Tenapanor intervention 2: Sevelamer Carbonate
Intervention descriptions: intervention 1: NHE3 Inhibitor intervention 2: Phosphate binder

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
 
A Long-Tern, Open Label Study to Evaluate the Ability of Tenapanor Alone or in Combination 
with Sevelamer to Treat to Goal Serum Phosphorus in Patients with End-Stage Renal Disease on 
Dialysis (NORMALIZE) 
Protocol No.: TEN-02-401 
15April 2019 
NCT03988920 


CLINICAL STUDY PROTOCOL 
Study TEN-02-401 
A Long-Tenn, Open Label Study to Evaluate the Ability ofTenapanor Alone or in 
Combination with Sevelamer to Treat to Goal Semm Phosphoms in Patients with End-Stage 
Renal Disease on Dialysis (NORMALIZE) 
Protocol No.: TEN-02-401 
Edition No.: 1 
15 April 2019 
Sponsor: 
Ardelyx, Inc. 
34175 Ardenwood Blvd. 
Fremont, CA 94555 


Ardelyx, Inc. 
Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL 
Page 2 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................ 2 
IN-TEXT TABLES .................................................................................................................. 4 
1 
GENERAL INFORMATION ................................................................................ 5 
1.1 
Study Administrative Structure ..................................................................... 5 
1.2 
Synopsis............................................................................................................. 6 
1.3 
Schedule of Events ......................................................................................... 12 
1.4 
List of Abbreviations ..................................................................................... 13 
2 
INTRODUCTION AND BACKGROUND ......................................................... 15 
2.1 
Introduction .................................................................................................... 15 
2.2 
Description of Investigational Product ........................................................ 16 
2.3 
Description of Phosphate Binder .................................................................. 16 
2.4 
Study Rationale .............................................................................................. 17 
2.5 
Risk-Benefit Assessment................................................................................ 17 
3 
STUDY OBJECTIVES ......................................................................................... 18 
3.1 
Primary Objectives ........................................................................................ 18 
3.2 
Secondary Objectives .................................................................................... 19 
3.3 
Exploratory Objectives.................................................................................. 19 
4 
STUDY DESIGN ................................................................................................... 19 
4.1 
Design Summary ............................................................................................ 19 
4.1.1 
Treatments Administered ............................................................................ 21 
4.1.2 
Duration of Study ........................................................................................ 22 
5 
SELECTION AND WITHDRAWAL OF PATIENTS ..................................... 22 
5.1 
Inclusion Criteria ........................................................................................... 23 
5.2 
Exclusion Criteria .......................................................................................... 23 
5.3 
Patient Withdrawal........................................................................................ 24 
5.4 
Early Termination of Study .......................................................................... 24 
6 
TREATMENT OF PATIENTS ........................................................................... 24 
6.1 
Administration of Investigational Product .................................................. 24 
6.1.1 
Identity of Investigational Product(s) ......................................................... 24 
6.1.2 
Treatments Administered ............................................................................ 25 
6.1.3 
Dose Adjustments ....................................................................................... 25 
6.1.4 
Method of Assigning Patients to Treatment Groups ................................... 27 
6.2 
Investigational Product Storage and Accountability .................................. 27 
6.2.1 
Storage Conditions ...................................................................................... 27 
6.2.2 
Drug Accountability .................................................................................... 27 
6.3 
Packaging and Labeling ................................................................................ 28 
6.3.1 
Study Drug .................................................................................................. 28 


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Protocol No.: TEN-02-401 
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6.3.2 
Blinding Methods ........................................................................................ 28 
6.4 
Concomitant Medications ............................................................................. 28 
6.4.1 
Concomitant Therapy .................................................................................. 28 
7 
COLLECTION OF STUDY VARIABLES ........................................................ 28 
7.1 
Recording of Data .......................................................................................... 28 
7.2 
Data Collection Prior to Enrollment ............................................................ 28 
7.2.1 
Safety Variables .......................................................................................... 29 
7.2.2 
Physical Examination .................................................................................. 29 
7.2.3 
Vital Signs (blood pressure and heart rate) ................................................. 29 
7.2.4 
Electrocardiograms ..................................................................................... 29 
7.2.5 
Clinical Laboratory Tests ............................................................................ 30 
7.2.6 
Analysis of Clinical Laboratory Tests ........................................................ 30 
7.2.7 
Adverse Events ........................................................................................... 32 
7.3 
Efficacy Variables .......................................................................................... 36 
7.4 
Exploratory Variables ................................................................................... 36 
8 
METHODOLOGY/STUDY VISITS ................................................................... 37 
8.1 
Baseline, Visit 1 .............................................................................................. 37 
8.2 
Weeks 1, 2, 3, 4, 6, and 8, Visits 2, 3, 4, 5, 6, and 7 ...................................... 38 
8.3 
Months 3, 6, 9, 12, and 15, Visits 8, 9, 10, 11, and 12 .................................. 38 
8.4 
Months 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, Telephone Visit T1, T2, 
T3, T4, T5, T6, T7, T8, T9, T10 .................................................................... 38 
8.5 
Month 18, Visit 13; End of Treatment Visit ................................................ 39 
8.6 
Unscheduled Visits ......................................................................................... 39 
8.7 
Withdrawal Procedures ................................................................................ 39 
8.8 
Total Blood Volume Required for Study ..................................................... 40 
8.9 
Protocol Deviations ........................................................................................ 40 
9 
STATISTICAL CONSIDERATIONS ................................................................ 41 
9.1 
Statistical Analysis Plan ................................................................................ 41 
9.2 
Determination of Sample Size ....................................................................... 41 
9.3 
Analysis Sets ................................................................................................... 41 
9.4 
Statistical Methods ......................................................................................... 41 
9.4.1 
General Approach ....................................................................................... 41 
9.4.2 
Baseline Descriptive Statistics .................................................................... 42 
9.4.3 
Efficacy Analysis ........................................................................................ 42 
9.4.4 
Procedures for Handling Missing Serum Phosphorus Data ........................ 42 
9.4.5 
Methods of Pooling Data ............................................................................ 42 
9.4.6 
Visit Windows ............................................................................................ 43 
9.4.7 
Safety Analyses ........................................................................................... 43 
10 
ACCESS TO SOURCE DATA/DOCUMENTS ................................................. 43 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .................................. 44 
11.1 
Conduct of Study ........................................................................................... 44 


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Protocol No.: TEN-02-401 
Edition No.: 1 
 
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11.2 
Protocol Amendments ................................................................................... 44 
11.3 
Monitoring of Study....................................................................................... 45 
11.4 
Ethics ............................................................................................................... 45 
11.5 
Institutional Review Board/Independent Ethics Committee 
Approval ......................................................................................................... 45 
11.5.1 
Ethics Review Prior to Study ...................................................................... 45 
11.5.2 
Ethics Review of other Documents ............................................................. 45 
11.6 
Written Informed Consent ............................................................................ 45 
12 
DATA HANDLING AND RECORD KEEPING ............................................... 46 
12.1 
Data Reporting and Case Report Forms ..................................................... 46 
12.1.1 
Case Report Forms ...................................................................................... 46 
12.1.2 
Laboratory Data .......................................................................................... 46 
12.1.3 
Retention of Source Documents ................................................................. 46 
12.2 
Retention of Essential Documents ................................................................ 46 
13 
ADMINISTRATIVE INFORMATION .............................................................. 47 
13.1 
Financing and Insurance ............................................................................... 47 
13.2 
Publication Policy .......................................................................................... 47 
14 
REFERENCES ...................................................................................................... 47 
15 
SIGNATURES ....................................................................................................... 48 
15.1 
Investigator Signature ................................................................................... 48 
15.2 
Sponsor Signature .......................................................................................... 49 
 
In-Text Tables 
Table 7-1: Clinical Laboratory Tests....................................................................................... 31 
Table 8-1: Approximate Blood Volume per Completed Patient ............................................. 40 




Ardelyx, Inc. 
Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL 
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1.2 
Synopsis 
Protocol Title: 
A Long-Term, Open Label Study to Evaluate the Ability of Tenapanor 
Alone or in Combination with Sevelamer to Treat to Goal Serum 
Phosphorus in Patients with End-Stage Renal Disease on Dialysis 
(NORMALIZE). 
Sponsor: 
Ardelyx, Inc. 
Study Phase: 
Phase 3 
Objectives: 
The primary objective of this study is: 
• To evaluate the ability of tenapanor alone or in combination with 
sevelamer to achieve serum phosphorus concentration (sP) within 
the population reference range (sP >2.5 and ≤4.5 mg/dL) in 
patients with end-stage renal disease on dialysis with 
hyperphosphatemia (>4.5 mg/dL).  
The secondary objectives of this study are: 
• To compare the phosphorus lowering effect of tenapanor and 
sevelamer alone in patients with sP >4.5 mg/dL to patients treated 
with a combination of tenapanor and sevelamer. 
• To evaluate the effect of tenapanor alone and in combination with 
sevelamer on the proportion of patients reaching serum 
phosphorus targets defined as ≤4.5 mg/dL. 
• To evaluate the effect of the addition of tenapanor to patients 
taking sevelamer on the percentage reduction in the sevelamer 
dose. 
• To evaluate the effect of tenapanor alone and in combination with 
sevelamer on intact fibroblast growth factor 23 (iFGF23). 
• To evaluate the effect of tenapanor alone and in combination with 
sevelamer on the Kidney Disease Quality of Life (KDQoL) 
survey. 
• To evaluate the effect of tenapanor alone and in combination with 
sevelamer on the Dialysis Symptom Index (DSI) survey 
(for English speakers only). 
• To compare the long-term safety of tenapanor alone and in 
combination with sevelamer. 
The exploratory objectives of this study are: 
• To evaluate the effect of tenapanor alone and in combination with 
sevelamer on PTH, CRP, aldosterone and other cardio-renal 
biomarkers (These data may not be part of the study report.) 
• To collect and store plasma/serum for future exploratory research 
into serum/plasma biomarkers related to cardio-renal disease 
and/or mineral metabolism or that may influence the response 


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Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
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(i.e. distribution, metabolism, safety, tolerability, and efficacy) to 
tenapanor. (These data will not be part of the study report.) 
Number of Sites: 
40-60 clinical sites in the US 
Number of Patients Approximately 150-200 patients with ESRD on hemodialysis (HD) or 
peritoneal dialysis (PD). 
Study Design  
Patients who complete the TEN-02-301 study (PHREEDOM) may be 
eligible to enroll into TEN-02-401 (NORMALIZE).  
Patients will be required to sign an ICF and meet all inclusion/exclusion 
criteria. No baseline assessments will be performed as part of this 
protocol; all baseline data for TEN-02-401 will be taken from the 
TEN-02-301 End of Treatment (EOT) visit. Patients from the 
TEN-02-301 tenapanor arm will either receive only tenapanor or be 
given sevelamer in addition to tenapanor based on their sP. Patients 
from the TEN-02-301 sevelamer arm will be given tenapanor in 
addition to their sevelamer dose and the sevelamer dose will then be 
adjusted based on their sP following a protocol-specified dose titration 
schedule. Patients will be monitored for safety and efficacy with in-
office and telephone visits for up to an additional 18 months.  
All study visits must be scheduled after a short dialysis interval (only 
for HD patients; e.g., Wednesday or Friday for patients on a MWF 
schedule and Thursday or Saturday for patients on a TThS schedule). 
Body weight and blood collections for laboratory assessments must be 
performed pre-dialysis. All other assessments may be performed pre-, 
during, or post-dialysis but should be performed at the same time at 
each visit. For patients receiving PD, visits should be performed on the 
same day each week, if possible.  
Tenapanor Arm 
The dosing regimens described below for sevelamer are for guidance to 
the Investigators. Investigators have flexibility to dose sevelamer, TID, 
BID or QD based on their experience with each patient or as per 
package insert. Dosing regimens can be adjusted based on the most 
recent sP laboratory data (central laboratory data or standard of care 
local laboratory data). 
 
If patients are in the tenapanor arm (from the TEN-02-301 study), 
sevelamer will be added  as described below: 
• sP >2.5 and ≤4.5 mg/dL: no addition of sevelamer. 
• sP >4.5 and ≤5.0 mg/dL: add one 800 mg tablet QD. 
• sP >5.0 and ≤5.5 mg/dL: add one 800 mg tablet BID. 
• sP >5.5 mg/dL: add one 800 mg tablet TID. 


Ardelyx, Inc. 
Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL 
Page 8 
If sP is still greater than or becomes >4.5 mg/dL at a subsequent visit, 
sevelamer dose can be increased in a stepwise manner as described 
below: 
 sP >4.5 and ≤5.0 mg/dL: add one 800 mg tablet to the existing 
regimen. 
 sP >5.0 and ≤5.5 mg/dL: add two 800 mg tablets to the existing 
regimen. 
 sP >5.5 mg/dL: add three 800 mg tablets each day (800 mg TID) 
to the existing regimen. 
The maximum dose of sevelamer should be based on standard of care, 
the sevelamer package insert, and the Investigator’s experience with 
each patient.  
If sP <2.5 mg/dL at any visit 
 Sevelamer dose can be lowered by one 800 mg tablet TID, or as 
appropriate, based on current regimen; Investigators have 
flexibility to dose sevelamer BID or QD based on their 
experience with each patient or as per package insert. 
 If patient is not taking sevelamer then tenapanor dose can be 
lowered by one 10 mg tablet BID, unless already at tenapanor 
10 mg BID, then can dose tenapanor 10 mg QD 
Sevelamer Arm 
If patients are from the TEN-02-301 sevelamer arm, tenapanor dose will 
be added based on their baseline sP as described below. Investigators 
may decrease or increase the tenapanor dose based on sP levels and/or 
GI tolerability in 10 mg increments to a minimum of 10 mg QD or a 
maximum of 30 mg BID, not more than once daily. Dosing regimens 
can be adjusted based on the most recent sP laboratory data (central 
laboratory data or standard of care local laboratory data). 
 sP >2.5 and ≤3.5 mg/dL: add three 10 mg tablets of tenapanor QD 
and Sevelamer dose can be lowered by one 800 mg tablet TID. 
 sP >3.5 and ≤4.5 mg/dL: add three 10 mg tablets of tenapanor QD
 sP >4.5: add three 10 mg tablets of tenapanor BID 
If sP >4.5 mg/dL at next visit  
 If on QD tenapanor, add three 10 mg tenapanor tablets to a 
maximum of 30 mg tenapanor BID. If on 30 mg tenapanor BID 
follow sevelamer dose regimen changes described below 
 Sevelamer dose can be increased by at least one 800 mg tablet at 
the largest meal and up to one 800 mg tablet TID; Investigators 
have flexibility to dose sevelamer BID or QD based on their 
experience with each patient or as per package insert. 


Ardelyx, Inc. 
Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL 
Page 9 
If sP <2.5 mg/dL at any visit 
 Sevelamer dose can be lowered by one 800 mg tablet TID; 
Investigators have flexibility to dose sevelamer BID or QD 
based on their experience with each patient or as per package 
insert. 
 If patient is not taking sevelamer then tenapanor dose can be 
lowered by one 10 mg tablet BID, unless already at tenapanor 
10 mg BID, then can dose tenapanor 10 mg QD 
For all subjects enrolled in TEN-02-401, tenapanor will be taken either 
once (QD; just prior to dinner or largest meal of the day) or twice daily 
(BID; just prior to breakfast and dinner. Patients on HD should not take 
tenapanor at the meal immediately preceding dialysis; in this case, 
patients will take tenapanor prior to the previous or next meal after 
dialysis. Sevelamer will be taken as per package insert. 
Investigators may decrease or increase the tenapanor dose based on sP 
levels and/or GI tolerability in 10 mg increments to a minimum of 
10 mg BID or a maximum of 30 mg BID not more than once daily. 
Laboratory assessments will be measured at every visit (Weeks 1, 2, 3, 
4, 6 and 8 and Months 3, 6, 9, 12, 15 and 18) using a central laboratory.  
Safety assessments will be performed during the study and will include 
physical examinations, vital signs (blood pressure and pulse), body 
weights, clinical laboratory evaluations, 12-lead electrocardiograms 
(ECGs), and adverse event (AE) monitoring. 
Patient Selection 
Criteria: 
Inclusion Criteria: 
1. Signed and dated informed consent prior to any study specific 
procedures. 
2. Completion of TEN-02-301(PHREEDOM) 
3. Women must be non-pregnant, non-lactating and fulfilling one of the 
following: 
a. Post-menopausal defined as amenorrhea for at least 12 months 
following cessation of all exogenous hormonal treatments and 
with follicle stimulating hormone (FSH) levels in the laboratory 
defined post-menopausal range (from TEN-02-301 study), or 
60 years of age or greater. 
b. Documentation of irreversible surgical sterilization by 
hysterectomy, bilateral oophorectomy or bilateral salpingectomy 
but not tubal ligation. 


Ardelyx, Inc. 
Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL 
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c. Use of acceptable contraceptive method: IUD with spermicide, a 
female condom with spermicide, contraceptive sponge with 
spermicide, an intravaginal system (e.g., NuvaRing®), a 
diaphragm with spermicide, a cervical cap with spermicide, or 
oral, implantable, transdermal, or injectable contraceptives, sexual 
abstinence, or a sterile sexual partner. 
d. Male partner who is sterile or using a condom with spermicide. 
4. Male participants must agree to avoid fathering a child (or donating 
sperm), and therefore be either sterile (documented) or agree to use, 
from the time of enrollment until 30 days after end of study, one of 
the following approved methods of contraception: a male condom 
with spermicide, a sterile sexual partner, use of an IUD with 
spermicide by female sexual partner, a female condom with 
spermicide, contraceptive sponge with spermicide, an intravaginal 
system (e.g., NuvaRing®), a diaphragm with spermicide, a cervical 
cap with spermicide, or oral, implantable, transdermal, or injectable 
contraceptives. 
5. Able to understand and comply with the protocol. 
Exclusion Criteria: 
1. Scheduled for living donor kidney transplant, plans to change to a 
different method of dialysis, home HD or plans to relocate to another 
center during the study period. 
2.  Life expectancy <12 months. 
3. If, in the opinion of the Investigator, the patient is unable or 
unwilling to fulfill the requirements of the protocol or has a 
condition which would render the results uninterpretable. 
Study Drug: 
Tenapanor 10 mg tablets, and 800 mg sevelamer carbonate tablets. 
Statistical 
Analyses: 
Analysis Populations: 
Safety Analysis Set: 
All patients who receive at least one dose of study drug (tenapanor or 
sevelamer) in the study. The safety analysis set will be used for the 
analysis of safety variables.  
Full Analysis Set (FAS): 
All patients who meet the study entry inclusion/exclusion criteria, 
receive at least one dose of study drug (tenapanor or sevelamer), and have 
at least one post-baseline sP assessment in the study. The FAS will be 
used for the analysis of efficacy variables. 


Ardelyx, Inc. 
Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL 
Page 11 
Efficacy Analyses: 
All efficacy variables will be descriptively summarized at each visit for 
the FAS and each TEN-02-301 treatment arm (tenapanor or sevelamer). 
Descriptive summaries of sP variables will also be repeated for FAS 
subjects with a baseline sP >4.5 mg/dL.  
For response endpoints, the response rate at each post-baseline visit will 
be estimated with asymptotic 95% confidence interval (CI) for each 
TEN-02-301 treatment arm. Inferential analyses of sP endpoints will be 
performed for comparisons of phosphorus-lowering effect between 
monotherapy (tenapanor and sevelamer alone) and combination therapy 
(tenapanor combined with sevelamer) unless the sample size in each 
monotherapy treatment group is less than 15. Inferential analyses of 
other endpoints may be performed as suggested by the data.  
Analyses are described in Section 9 and will be detailed in the statistical 
analysis plan (SAP).  
Safety Analyses: 
All safety measures will be descriptively summarized for the Safety 
Analysis Set and each TEN-02-301 treatment arm (tenapanor or 
sevelamer).  
Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and will be summarized by system 
organ class and preferred term.  
Actual values and change from baseline values for clinical laboratory 
tests, vital signs, body weights, and ECGs will be descriptively 
summarized by visit. The number and percentage of patients in each 
physical examination category will be presented by visit.  


Ardelyx, Inc. 
Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL  
Page 12 
1.3 
Schedule of Events 
Study Day 
Base-
line* 
W1 
± 2 
days 
W2 
± 2 
days 
W3 
± 2 
days 
W4 
± 2 
days 
W6 
± 2 
days 
W8 
± 2 
days 
M 3 
± 2 
weeks 
M 4 
± 2 
weeks 
M 5 
± 2 
weeks 
M 6 
± 2 
weeks 
M 7 
± 2 
weeks 
M 8 
± 2 
weeks 
M 9 
± 2 
weeks 
M 10 
± 2 
weeks 
M 11 
± 2 
weeks 
M 12 
± 2 
weeks 
M 13 
± 2 
weeks 
M 14 
± 2 
weeks 
M 15 
± 2 
weeks 
M 16 
± 2 
weeks 
M 17 
± 2 
weeks 
M 18 
EOT 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
T1 
T2 
V9 
T3 
T4 
V10 
T5 
T6 
V11 
T7 
T8 
V12 
T9 
T10 
V13 
ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med Historym 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BW, Ht, Kt/Vl 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signsa 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
ECG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clin Lab Testsb 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pregnancy Testc  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Drug Dispensej 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Drug Returnk 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
KDQoL/DSId 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
s-Phosphoruse 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
FGF23 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Exploratory 
Biomarkersf 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
AE Assessg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ConMedsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* All baseline procedures, except informed consent and I/E criteria will come from the TEN-02-301 EOT visit; V= visit at office or dialysis center; T= telephone visit;  
W= week, weekly visits are after a short dialysis interval and have a ± window of 2 days ; M= month; monthly visits have a ± window of 2 weeks. 
a If collected as part of standard of care, that data can be used and includes blood pressure and pulse. 
b Clinical laboratory tests: All blood collections are performed pre-dialysis.. See Table 7-1 for list of tests. 
c Pregnancy tests (serum) will only be performed on women of child-bearing potential. 
d KDQoL (KDQoL™-36), Kidney Disease and Quality of Life survey. DSI, Dialysis Symptom Index survey is for English speakers only and is not validated in other languages. 
e Serum phosphorus will be measured by a central laboratory. 
f Serum and plasma samples will be collected at the same time as the clinical laboratory evaluation and sent to the central laboratory for storage.  
g AEs and SAEs will be collected from consenting to the end of study. 
h Guidelines will be provided to limit the amount of concomitant medication information collected. 
j 
Investigators can adjust doses of tenapanor or sevelamer between visits via telephone. Sevelamer can be re-dispensed at Visits 2, 3, 4, 5, and 8 if dose permits. 
k Sevelamer can be re-dispensed, if enough drug is left until the next visit. Drug accountability is also performed. 
l 
Body weight is for HD patients only, height from TEN-02-301, and Kt/V can be taken from most recent standard-of-care assessment. 
m Major medical conditions taken from TEN-02-301.


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Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL  
Page 13 
1.4 
List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransaminase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransaminase 
BID 
bis in die, twice per day 
BMI 
Body mass index 
CKD 
Chronic kidney disease 
eCRF 
CRP 
Electronic case report form 
c-reactive protein 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
ESRD 
End-stage renal disease 
ESRD-PD 
End-stage renal disease on peritoneal dialysis 
FDA 
US Food and Drug Administration 
iFGF23 
Intact Fibroblast growth factor 23 
FSH 
Follicle-stimulating hormone level 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
H+ 
Hydrogen 
HD 
Hemodialysis 
IB 
Investigational Brochure 
IBS 
Irritable bowel syndrome 
IBS-C 
Constipation-predominant irritable bowel syndrome 
IBS-D 
Diarrhea-predominant irritable bowel syndrome 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
min 
Minimum (e.g., min, max) 
n 
Number of observed patients 
N 
Number of patients in the applicable analysis set 
Na+ 
Sodium 


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Abbreviation 
Definition 
NHE3 
Na/hydrogen antiporter  3 
p 
Probability; p-value 
PD 
Peritoneal dialysis 
PK 
Pharmacokinetic 
PTH 
Parathyroid hormone 
QD 
quaque die, once per day 
RBC 
Red blood cell 
s 
serum 
SAP 
Statistical Analysis Plan 
SAE 
Serious adverse event 
SOP 
Standard operating procedure 
TID 
ter in die, three times per day 
WBC 
White blood cell 


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2 
INTRODUCTION AND BACKGROUND 
2.1 
Introduction 
Chronic kidney disease (CKD) affects 5-10% of the population globally and the numbers of 
patients suffering from end-stage renal disease (ESRD) are increasing (Eknoyan 2004). With 
progressing impairment of renal function, the ability of the kidneys to appropriately excrete 
phosphorus is reduced and hyperphosphatemia is a nearly universal complication of ESRD. 
Hyperphosphatemia is also part of the CKD Bone Mineral Disorder, which is associated with a 
disruption of normal serum and tissue concentrations of phosphorus and calcium, and changes in 
circulating levels of hormones such as parathyroid hormone (PTH) and vitamin D. Left 
untreated, hyperphosphatemia can lead to vascular and tissue calcifications, bone pain, fractures 
and worsening secondary hyperparathyroidism and is associated with increased cardiovascular 
morbidity and mortality. Observational data show that treatment with phosphate binders to 
reduce hyperphosphatemia is independently associated with improved survival (Waheed 2013), 
and a meta-analysis of randomized clinical trials demonstrate that non-calcium based binders 
have a lower mortality as compared to calcium-based binders. Experimental studies provide 
support for the epidemiologic findings: phosphorus excess promotes vascular calcification, 
induces endothelial dysfunction and may contribute to other emerging chronic kidney 
disease-specific mechanisms of cardiovascular toxicity (Waheed 2013). Hence, clinical treatment 
guidelines for patients with advanced kidney disease suggest maintaining serum phosphorus 
within 3.5 to 5.5 mg/dL, which is close to the normal range (KDIGO guideline 2009). 
In addition to dietary phosphorus restrictions and dialysis, 80-90% of ESRD patients need 
treatment with oral phosphate binders. However, a significant proportion of ESRD patients still 
don’t achieve adequate phosphorus control (DOPPS Annual Report 2010). An important barrier 
for a successful treatment is the pill burden associated with all phosphate binders, which have to 
be dosed in several grams per day and taken with each meal to bind dietary phosphorus. The side 
effect profile with poor gastro-intestinal tolerability and concerns for long-term negative effects 
such as tissue calcification and potential metal accumulation toxicity from calcium-based and 
metal-based binders, respectively, further impair an effective phosphorus control in ESRD 
patients. There is, therefore, a rationale to develop oral phosphorus-lowering drugs with new 
mechanisms of action, a more convenient dosing and improved risk-benefit profile. 
Tenapanor is an oral, minimally absorbed compound that inhibits the NHE3 (sodium hydrogen 
exchanger) transporter locally in the gastrointestinal tract, which leads to reduced sodium (and 
fluid) absorption. Data from pre-clinical studies and results in healthy volunteers show that 
tenapanor also reduces the uptake of phosphorus from the gut.  


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Tenapanor reduces intestinal phosphorus absorption, predominantly through reduction of passive 
paracellular phosphorus influx, the most important overall mechanism of intestinal phosphorus 
absorption. Tenapanor modulates tight junctions to increase TEER, thereby reducing paracellular 
phosphorus permeability; this effect is mediated exclusively via on-target NHE3 inhibition.  
Tenapanor has been administered to approximately 400 healthy subjects at single doses up to 
900 mg, and in repeated doses up to 180 mg/day for 7 days, and to approximately 1350 IBS-C 
patients at doses up to 100 mg/day for up to one year and to >900 CKD patients (CKD stages 3b, 
4 and 5D) for up to one year at doses up to 120 mg/day.  
2.2 
Description of Investigational Product 
Tenapanor is a GI-acting, minimally systemic, NHE3 inhibitor. Tenapanor is administered as the 
hydrochloride salt and is chemically described as: (S)-N,N’-(10,17-dioxo-3,6,21,24-tetraoxa-
9,11,16,18-tetraazahexacosane-1,26-diyl)bis(3-((S)-6,8-dichloro-2-methyl-1,2,3,4-
tetrahydroisoquinolin-4-yl) benzenesulfonamide) dihydrochloride. Its empirical formula is 
C50H68Cl6N8O10S2. 
 
 
 
 
Dosing consists of one to three 10 mg tablets, taken in conjunction with breakfast and dinner.  
 
 
 Tablets of tenapanor 
should be stored in the original packaging according to the labeling. 
2.3 
Description of Phosphate Binder 
The phosphate binder used in this study will be sevelamer carbonate and will be supplied as 
commercially available (270 tablet count bottles) by the sponsor. Sevelamer carbonate must be 
stored in the original packaging as described on the label. 


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2.4 
Study Rationale 
Reduction of phosphorus uptake is an established treatment approach for hyperphosphatemia in 
ESRD-HD patients and a number of drugs that bind dietary phosphorus in the gut lumen are part 
of the standard of care for patients with advanced kidney disease on dialysis. Results from both 
Phase 2b and Phase 3 studies in ESRD-HD patients with hyperphosphatemia, showed that 
tenapanor produced a statistically significant decrease in serum phosphorus; these results suggest 
that tenapanor has the potential to provide phosphorus control comparable to existing 
phosphorus-lowering agents and improved dosing with reduced pill burden, which merits further 
clinical development. 
A nonclinical study in Sprague-Dawley rats demonstrated that the administration of tenapanor in 
combination with sevelamer produced a synergistic effect on the excretion of phosphorus in the 
feces and therefore had a greater effect in inhibhiting the absorption of dietary phosphorus than 
either drug alone. Based on this data and the inability of phosphate binders alone to get a 
majority of patients’ serum phosphorus below 4.6 mg/dL, this study is designed to investigate the 
long term potential of the combination of tenapanor and sevelamer to normalize ESRD patient’s 
serum phosphorus levels. 
2.5 
Risk-Benefit Assessment 
This risk-benefit assessment is based on the nonclinical toxicology, safety, and pharmacology 
studies as well as the 21 clinical trials performed with tenapanor; the results from this research 
are described in the Investigator’s Brochure. 
Pre-clinical toxicological studies up to 9 months have been performed in rodents and dogs. The 
toxicological profile includes soft stools and/or diarrhea and findings secondary to dehydration; 
these findings are an expected manifestation of the compound’s exaggerated pharmacologic 
activity and findings were reversible during the recovery period without drug. A two-year 
carcinogenicity study in Sprague-Dawley rats was negative. 
The safety, tolerability, pharmacodynamics and efficacy of tenapanor have been evaluated in 347 
healthy subjects at single doses up to 900 mg, and in repeated doses up to 180 mg/day for 7 days, 
and to 1020 IBS-C patients at doses up to 100 mg/day for up to 12 weeks and to 477 CKD 
patients (CKD stages 3b, 4 and 5D) for up to 12 weeks at doses up to 120 mg/day. 
Tenapanor has minimal systemic bioavailability. Less than 1% of plasma samples collected 
during human studies (>3000) have quantifiable tenapanor present in blood serum (lower limit of 
quantification = 0.5 ng/mL); all samples with tenapanor were below 1.5 ng/mL. 


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The reduction in sodium uptake results in an increase in net fluid volume in the intestinal tract. 
Based on this mechanism of action, tenapanor has the potential to produce softer/looser stools 
and increased stool frequency. Tenapanor has been generally safe and well tolerated in clinical 
studies and the safety profile with softening/loosening of stool consistency and gastro-intestinal 
adverse events have been consistent with its pharmacology.  
The theoretical adverse effects from tenapanor treatment in ESRD patients would be due to 
exaggerated pharmacological effects and may include electrolyte disturbances, metabolic 
acidosis, soft stools/diarrhea and reduced blood pressure. While a softening/loosening of the 
stool with an increased fluid loss via the intestine is an intended and desired effect of tenapanor 
in some patients, sensitive patients should be monitored for signs of dehydration in case of 
prolonged severe diarrhea. This study protocol includes clinical laboratory tests (including 
bicarbonate and electrolytes) and vital signs as well as specific discontinuation criteria related to 
phosphorus control to mitigate risks to study participants as well as to reduce the risk for severe 
hyper- or hypophosphatemia during the study and limit the period with risk for suboptimal 
phosphorus control. All patients will re-start their pre-study treatment with phosphate binders 
when their participation in the study ends. ESRD-HD patients are dialyzed three times per week 
and their health status is checked at each visit as part of standard of care. See the Investigator’s 
Brochure for details on non-clinical and clinical results with tenapanor. 
Patients will be informed both verbally and in writing about these aspects before taking part in 
any study-specific examination and the study will be conducted under conditions that ensure a 
high probability for the early detection of untoward events and for appropriate intervention. 
In summary, the risks to the participants in this up to 18 month study are considered acceptable 
and the study results will be important for the development of a potential new drug, which could 
improve the treatment of hyperphosphatemia in this patient group. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
The primary objective of this study is: 
• To evaluate the ability of tenapanor alone or in combination with sevelamer to achieve 
serum phosphorus concentration (sP) within the population reference range (sP >2.5 and 
≤4.5 mg/dL) in patients with end-stage renal disease on dialysis with hyperphosphatemia 
(>4.5 mg/dL).  


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3.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To compare the phosphorus lowering effect of tenapanor and sevelamer alone in patients 
with sP >4.5 mg/dL to patients treated with a combination of tenapanor and sevelamer. 
• To evaluate the effect of tenapanor alone and in combination with sevelamer on the 
proportion of patients reaching serum phosphorus targets defined as ≤4.5 mg/dL. 
• To evaluate the effect of the addition of tenapanor to patients taking sevelamer on the 
percentage reduction in the sevelamer dose. 
• To evaluate the effect of tenapanor alone and in combination with sevelamer on intact 
fibroblast growth factor 23 (iFGF23). 
• To evaluate the effect of tenapanor alone and in combination with sevelamer on the 
Kidney Disease Quality of Life (KDQoL) survey. 
• To evaluate the effect of tenapanor alone and in combination with sevelamer on the 
Dialysis Symptom Index (DSI) survey (for English speakers only). 
• To compare the long-term safety of tenapanor alone and in combination with sevelamer. 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To evaluate the effect of tenapanor alone and in combination with sevelamer on PTH, 
CRP, aldosterone and other cardio-renal biomarkers (These data may not be part of the 
study report.) 
• To collect and store plasma/serum for future exploratory research into serum/plasma 
biomarkers related to cardio-renal disease and/or mineral metabolism or that may 
influence the response (i.e. distribution, metabolism, safety, tolerability, and efficacy) to 
tenapanor. (These data will not be part of the study report.). 
4 
STUDY DESIGN 
4.1 
Design Summary 
Patients who complete the TEN-02-301 study (PHREEDOM) at Visit 23, may be eligible to 
enroll into TEN-02-401 (NORMALIZE).  
Patients will be required to sign an ICF and meet all inclusion and no exclusion criteria. No 
baseline assessments will be performed as part of this protocol; all baseline data for TEN-02-401 
will be taken from the TEN-02-301 End of Treatment (EOT) visit. Patients from the 


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TEN-02-301 tenapanor arm will either receive only tenapanor or be given sevelamer in addition 
to tenapanor based on their sP following a protocol-specified dose titration schedule. Patients 
from the TEN-02-301 sevelamer arm will be given tenapanor in addition to their sevelamer dose 
and the sevelamer dose will then be adjusted based on their sP following a protocol-specified 
dose titration schedule. Patients will be monitored for safety and efficacy with in-office and 
telephone visits for up to an additional 18 months.  
All study visits must be scheduled after a short dialysis interval (only for HD patients; e.g., 
Wednesday or Friday for patients on a MWF schedule and Thursday or Saturday for patients on 
a TThS schedule). Body weight and blood collections for laboratory assessments must be 
performed pre-dialysis. All other assessments may be performed pre-, during, or post-dialysis but 
should be performed at the same time at each visit. For patients receiving PD, visits should be 
performed on the same day each week, if possible. 
Investigators may decrease or increase the dose of tenapanor based on sP levels and/or GI 
tolerability. The changes must be made in 10 mg increments to a minimum of 10 mg BID or a 
maximum of 30 mg BID. The dose of sevelamer carbonate may be adjusted based on the 
guidance provided in Section 4.1.1 or the sevelamer package insert. Investigators have flexibility 
to dose sevelamer, TID, BID or QD based on their experience with each patient or as per 
package insert. 
Laboratory efficacy endpoints will be assessed at various times throughout the study; sP will be 
measured at every visit.  
Safety assessments will be performed during the study and will include physical examination, 
vital signs (blood pressure and pulse), body weights, clinical laboratory tests, 12-lead 
electrocardiograms (ECGs), and adverse event (AE) monitoring. Blood samples will be collected 
and stored, as appropriate, for the potential evaluation of exploratory biomarkers related to 
cardio-renal disease or bone metabolism or that may influence the response 
(i.e. pharmacokinetics, metabolism, distribution, safety, tolerability, and efficacy) to tenapanor. 
Details of study assessments and the schedule of events for this study are in Section 1.3. 


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4.1.1 
Treatments Administered 
Patients who complete the TEN-02-301 study and enroll into TEN-02-401 study will enter the 
study from either the tenapanor arm or the sevelamer arm.  
Tenapanor Arm 
The dosing regimens described below for sevelamer are for guidance to the Investigators. 
Investigators have flexibility to dose sevelamer, TID, BID or QD based on their experience with 
each patient or as per package insert. Dosing regimens can be adjusted based on the most recent 
sP laboratory data (central laboratory data or standard of care local laboratory data). 
If patients are in the tenapanor arm (from the TEN-02-301 study), sevelamer will be added as 
described below: 
• sP ≥2.5 and ≤4.5 mg/dL: no addition of sevelamer. 
• sP >4.5 and ≤5.0 mg/dL: add one 800 mg tablet QD. 
• sP >5.0 and ≤5.5 mg/dL: add one 800 mg tablet BID. 
• sP >5.5 mg/dL: add one 800 mg tablet TID. 
If sP is still greater than or becomes >4.5 mg/dL at a subsequent visit, sevelamer dose can be 
increased in a stepwise manner as described below: 
• sP >4.5 and ≤5.0 mg/dL: add one 800 mg tablet to the existing regimen. 
• sP >5.0 and ≤5.5 mg/dL: add two 800 mg tablets to the existing regimen. 
• sP >5.5 mg/dL: add three 800 mg tablets each day  (800 mg TID) to the existing regimen. 
The maximum dose of sevelamer should be based on standard of care,  the sevelamer package 
insert, and the Investigator’s experience with each patient.  
If sP <2.5 mg/dL at any visit 
• Sevelamer dose can be lowered by one 800 mg tablet TID, or as appropriate, based on 
current regimen; Investigators have flexibility to dose sevelamer BID or QD based on 
their experience with each patient or as per package insert. 
• If patient is not taking sevelamer then tenapanor dose can be lowered by one 10 mg tablet 
BID, unless already at tenapanor 10 mg BID, then can dose tenapanor 10 mg QD 


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Sevelamer Arm 
If patients are from the TEN-02-301 sevelamer arm, tenapanor dose will be added based on their 
baseline sP as described below. Investigators may decrease or increase the tenapanor dose based 
on sP levels and/or GI tolerability in 10 mg increments to a minimum of 10 mg QD or a 
maximum of 30 mg BID, not more than once daily. Dosing regimens can be adjusted based on 
the most recent sP laboratory data (central laboratory data or standard of care local laboratory 
data). 
•
sP >2.5 and ≤3.5 mg/dL: add three 10 mg tablets of tenapanor QD and Sevelamer dose
can be lowered by one 800 mg tablet TID.
•
sP >3.5 and ≤4.5 mg/dL: add three 10 mg tablets of tenapanor QD
•
sP >4.5: add three 10 mg tablets of tenapanor BID
If sP >4.5 mg/dL at next visit 
•
add three 10 mg tenapanor tablets, if on QD regimen to a maximum of 30 mg tenapanor 
BID. If on 30 mg tenapanor BID follow sevelamer dose regimen changes described 
below.
Sevelamer dose can be increased by at least one 800 mg tablet at the largest meal and up to one 
800 mg tablet TID; Investigators have flexibility to dose sevelamer BID or QD based on their 
experience with each patient or as per package insert. If sP <2.5 mg/dL at any visit: 
•
Sevelamer dose can be lowered by one 800 mg tablet TID; Investigators have flexibility
to dose sevelamer BID or QD based on their experience with each patient or as per
package insert.
•
If patient is not taking sevelamer then tenapanor dose can be lowered by one 10 mg tablet
BID, unless already at tenapanor 10 mg BID, then can dose tenapanor 10 mg QD
4.1.2 
Duration of Study 
The expected duration of each patient’s participation in the study will be up to 18 months. 
5 
SELECTION AND WITHDRAWAL OF PATIENTS 
Investigator(s) will record who sign the informed consent form for entry into the study. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  


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5.1 
Inclusion Criteria 
A patient will be eligible for study participation if he/she meets the following criteria: 
1. Signed and dated informed consent prior to any study specific procedures. 
2. Completion of TEN-02-301 (Visit 23). 
3. Women must be non-pregnant, non-lactating and fulfilling one of the following: 
a. Post – menopausal defined as amenorrhea for at least 12 months following cessation of 
all exogenous hormonal treatments and with follicle stimulating hormone (FSH) levels in 
the laboratory defined post-menopausal range (from TEN-02-301 study), or 60 years of 
age or greater.. 
b. Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy, but not tubal ligation. 
c. Use of acceptable contraceptive method: IUD with spermicide, a female condom with 
spermicide, contraceptive sponge with spermicide, an intravaginal system (e.g., 
NuvaRing®), a diaphragm with spermicide, a cervical cap with spermicide, or oral, 
implantable, transdermal, or injectable contraceptives, sexual abstinence, or a sterile 
sexual partner. 
d. Male partner who is sterile or using a condom with spermicide. 
4. Male participants must agree to avoid fathering a child (or donating sperm), and therefore be 
either sterile (documented) or agree to use, from the time of enrollment until 30 days after 
end of study, one of the following approved methods of contraception: a male condom with 
spermicide, a sterile sexual partner, use of an IUD with spermicide by female sexual partner, 
a female condom with spermicide, contraceptive sponge with spermicide, an intravaginal 
system (e.g., NuvaRing®), a diaphragm with spermicide, a cervical cap with spermicide, or 
oral, implantable, transdermal, or injectable contraceptives.  
5. Able to understand and comply with the protocol. 
5.2 
Exclusion Criteria 
A patient will not be eligible for study participation if he/she meets any of the exclusion criteria, 
or will be discontinued at the discretion of the Investigator if he/she develops any of the 
following exclusion criteria during the study: 
1. Scheduled for living donor kidney transplant, plans to change to a different method of 
dialysis, home HD or plans to relocate to another center during the study period. 


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2. Life expectancy <12 months. 
3. If, in the opinion of the Investigator, the patient is unable or unwilling to fulfill the 
requirements of the protocol or has a condition which would render the results 
uninterpretable. 
5.3 
Patient Withdrawal 
Patients are free to discontinue the study at any time, for any reason, and without prejudice to 
further treatment. The Investigator may remove a patient if, in the Investigator’s judgment, 
continued participation would pose unacceptable risk to the patient or to the integrity of the study 
data. 
A patient who discontinues will always be asked about the reason(s) for discontinuation and the 
presence of any AEs. The Investigator will record the reason for early withdrawal in the eCRF. 
If a patient discontinues the study, all visit procedures for Visit 13 (EOT) will be completed, if 
possible. 
5.4 
Early Termination of Study 
The study may be terminated at any time by the Sponsor for reasons including but not limited to 
the following (i) if serious side effects occur, (ii) if the Investigator does not adhere to the 
protocol, (iii) if, in the Sponsor’s judgment, there are no further benefits to be achieved from the 
study, or (iv) for administrative reasons. In the event that the clinical development of the 
investigational product is discontinued, Ardelyx, Inc. shall inform all Investigators / institutions 
and IRBs overseeing the trial. 
6 
TREATMENT OF PATIENTS 
6.1 
Administration of Investigational Product 
6.1.1 
Identity of Investigational Product(s) 
6.1.1.1 
Tenapanor 
Tenapanor hydrochloride is an amorphous, off-white to white powder. 
 
 
. 
 
 
  




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•
sP >4.5 and ≤5.0 mg/dL: add one 800 mg tablet to the existing regimen.
•
sP >5.0 and ≤5.5 mg/dL: add two 800 mg tablets to the existing regimen.
•
sP >5.5 mg/dL: add three 800 mg tablets each day (800 mg TID) to the existing regimen.
The maximum dose of sevelamer should be based on standard of care,  the sevelamer package 
insert, and the Investigator’s experience with each patient.  
If sP <2.5 mg/dL at any visit 
•
Sevelamer dose can be lowered by one 800 mg tablet TID, or as appropriate, based on
current regimen; Investigators have flexibility to dose sevelamer BID or QD based on
their experience with each patient or as per package insert.
•
If patient is not taking sevelamer then tenapanor dose can be lowered by one 10 mg tablet
BID, unless already at tenapanor 10 mg BID, then can dose tenapanor 10 mg QD
Sevelamer Arm 
If patients are from the TEN-02-301 sevelamer arm, tenapanor dose will be added based on their 
baseline sP as described below. Investigators may decrease or increase the tenapanor dose based 
on sP levels and/or GI tolerability in 10 mg increments to a minimum of 10 mg QD or a 
maximum of 30 mg BID, not more than once daily. Dosing regimens can be adjusted based on 
the most recent sP laboratory data (central laboratory data or standard of care local laboratory 
data). 
•
sP >2.5 and ≤3.5 mg/dL: add three 10 mg tablets of tenapanor QD and Sevelamer dose
can be lowered by one 800 mg tablet TID.
•
sP >3.5 and ≤4.5 mg/dL: add three 10 mg tablets of tenapanor QD
•
sP >4.5: add three 10 mg tablets of tenapanor BID
If sP >4.5 mg/dL at next visit 
•
add three 10 mg tenapanor tablets, if on QD regimen to a maximum of 30 mg tenapanor
BID. If on 30 mg tenapanor BID follow sevelamer dose regimen changes described
below
Sevelamer dose can be increased by at least one 800 mg tablet at the largest meal and up to one 
800 mg tablet TID; Investigators have flexibility to dose sevelamer BID or QD based on their 
experience with each patient or as per package insert. If sP <2.5 mg/dL at any visit: 


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Protocol No.: TEN-02-401 
Edition No.: 1 
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
Sevelamer dose can be lowered by one 800 mg tablet TID; Investigators have flexibility
to dose sevelamer BID or QD based on their experience with each patient or as per
package insert.

If patient is not taking sevelamer then tenapanor dose can be lowered by one 10 mg tablet
BID, unless already at tenapanor 10 mg BID, then can dose tenapanor 10 mg QD.
6.1.3.1 
Discontinuation Criteria 
See Section 5.3 Patient Withdrawal 
6.1.4 
Method of Assigning Patients to Treatment Groups 
Patients will enter the TEN-02-401 study into the same group as from the TEN-02-301 study. 
6.2 
Investigational Product Storage and Accountability 
6.2.1 
Storage Conditions 
The Investigator will ensure that all the study drugs are stored and dispensed in accordance with 
Food and Drug Administration (FDA) regulations concerning the storage and administration of 
investigational drugs. 
Tablets of tenapanor should be stored in the original packaging according to the labeling. 
Sevelamer should also be stored in the original packaging according to the labeling. 
6.2.2 
Drug Accountability 
The Investigator must ensure that all drug supplies are kept in a secure locked area with access 
limited to those authorized by the Investigator. The Investigator or the Investigator’s designee 
must maintain accurate records of the receipt of all study drug shipped by the Sponsor or its 
representative, including but not limited to the date received, lot number, expiration date, amount 
received, and the disposition of all study drug. Current dispensing records will also be 
maintained, including the date, bottle number (for tenapanor), and amount of study drug 
dispensed, and the patient receiving the drug, to be recorded both on the Master IP log and 
Subject IP log. All remaining study drug not required by regulations to be held by the clinical 
facility must be returned to Sponsor or its representative at the last IMV or the COV using the 
study drug return form provided. 


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6.3 
Packaging and Labeling 
6.3.1 
Study Drug 
 
 
 Tablets of tenapanor should be stored in the original packaging 
according to the labeling. 
6.3.2 
Blinding Methods 
The study is open labeled and study drug will not be blinded. 
6.4 
Concomitant Medications 
6.4.1 
Concomitant Therapy 
The use of concomitant medications during the study, will only be recorded in this study if it is a 
major change from the medications used at entry into the TEN-02-401 study. 
A major change is defined as the addition of a new drug used to treat a serious adverse event 
(SAE) or the removal of a drug due to the improvement of a disease/condition (i.e., blood 
pressure improvement) 
7 
COLLECTION OF STUDY VARIABLES 
7.1 
Recording of Data 
The Investigator will ensure that data are recorded in the electronic Case Report Form (eCRF) 
for this study. The Investigator ensures accuracy, completeness, and timeliness of the data 
recorded and of the provision of answers to data queries. The Investigator will sign the 
completed eCRF and a copy of the completed eCRF will be archived. 
7.2 
Data Collection Prior to Enrollment 
No baseline assessments will be performed as part of this protocol; all baseline data for 
TEN-02-401 will be taken from the TEN-02-301 End of Treatment (EOT) visit, if available, 
and include the following: 
• Date of birth, gender, and race 
• Weight (pre-dialysis) and height (kg and cm, respectively)  
• Kt/V – most recent value prior to enrolling into TEN-02-401 


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• KDQoL survey 
• DSI survey (for English speakers only) 
• Medical history (major medical conditions taken from TEN-02-301) 
• Physical examination 
• Vital signs (pre-dialysis) 
• Electrocardiogram (ECG) evaluation 
• Blood sample for clinical laboratory tests 
• Pregnancy test, if applicable 
• Blood sample for FGF23 and exploratory biomarkers 
• Concomitant medications 
7.2.1 
Safety Variables 
Safety assessments will be performed during the study and will include physical examinations, 
vital signs, body weights, clinical laboratory tests, electrocardiograms, and adverse event 
recording. Body weight, vital signs and blood collections for laboratory assessments must be 
perfomed predialysis. All other assessments may be perfomed pre-, during, or post-dialysis but 
should be performed at the same time at each visit. See Section 8 (Methodology/Study Visits) for 
a detailed schedule of procedures. 
7.2.2 
Physical Examination 
The physical examination will include an assessment of the following items: general appearance, 
skin (including any pitting edema in lower legs / feet), cardiovascular, respiratory, abdomen. 
Any findings or absence of findings relative to each patient’s physical examination will be 
carefully documented in the patient’s eCRF. 
7.2.3 
Vital Signs (blood pressure and heart rate) 
Blood pressure and heart rate will be obtained at all patient visits (pre-dialysis). Blood pressure, 
sitting systolic and diastolic blood pressure (SSBP and SDBP) will be measured after the patient 
has been sitting for approximately 5 minutes. All measurements will be recorded on the source 
document and in the eCRF. 
7.2.4 
Electrocardiograms 
A 12-lead electrocardiogram (ECG) will be performed in the sitting or supine position (for at 
least 5 minutes). 


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The following ECG parameters will be recorded: heart rate, PR-interval, QRS (principal 
deflection in ECG)-duration, QT-interval (uncorrected), QTc-interval (corrected), RR-interval  
and PI’s conclusion on ECG profile.  
The Investigator will assess whether the ECG is normal or abnormal; abnormal will be further 
subdivided into clinically significant and not clinically significant. Electrocardiographic intervals 
and Investigator assessment of all abnormal ECGs will be recorded on the eCRF. 
Additional ECGs may be obtained if clinically indicated.  
7.2.5 
Clinical Laboratory Tests 
Samples must be obtained, pre-dialysis, for the clinical laboratory tests identified in Table 7-1. 
A coagulation profile will only be performed on patients taking warfarin.  
Other evaluations and tests performed during the study, specified in the Schedule of Events 
(Section 1.3) will include a pregnancy test, if applicable. 
7.2.6 
Analysis of Clinical Laboratory Tests 
A certified laboratory will be used to process and provide results for the clinical laboratory tests.  
For any laboratory test value outside the reference range that the Investigator considers clinically 
significant, the Investigator will: 
• Repeat the test to verify the out-of-range value. 
• Follow the out-of-range value to a satisfactory clinical resolution. 
• Record as an AE any laboratory test value that (1) is confirmed and the Investigator 
considers clinically significant, or (2) that requires a patient to be discontinued from the 
study, or (3) that requires a patient to receive treatment, or (4) fulfills one or more SAE 
criteria. 


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Table 7-1: 
Clinical Laboratory Tests 
Hematologya
Chemistryb
Coagulation Profilec,d
Othere 
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count 
White blood cell (WBC) 
count 
Neutrophils (%) 
Lymphocytes (%) 
Monocytes (%) 
Basophils (%) 
Eosinophils (%) 
Platelet count 
Albumin 
Alanine aminotransaminase (ALT)  
Aspartate aminotransaminase (AST) Alkaline 
phosphatase 
Bilirubin, total 
Bicarbonate
Blood urea nitrogen (BUN) 
Calcium, total 
Chloride  
Creatinine 
Creatine kinase 
Glucose 
Magnesium 
Phosphorusf 
Potassium 
Sodium 
Prothrombin time 
Activated partial thromboplastin 
time 
Serum 
pregnancyg 
FGF-23ch 
Parathyroid Hormone 
(PTH)e 
c-reactive protein e 
Aldosteronee 
a Whole blood. 
b Serum. 
c Plasma.  
d Only in people treated with Warfarin. 
e May be performed from the biomarker samples, if desired and will not be part of the clinical study report. 
f Serum phosphorus is also performed separately from standard clinical laboratory tests at protocol specified time points. 
g Serum pregnancy tests will only be performed on women of child-bearing potential. 
h Intact FGF-23 will be measured. 


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7.2.7 
Adverse Events 
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section. 
An AE is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product during the course of a clinical investigation. An AE can therefore be 
any unfavorable and unintended sign, symptom, or disease temporally associated with the use 
of an investigational product, whether or not thought to be related to the investigational 
product. 
Patients will be monitored throughout the study for AEs, from the enrollment visit through 
the end of treatment (Visit 13). All AEs spontaneously reported by the patient or reported in 
response to the open question from the study personnel: “Have you had any health problems 
since the previous visit?”, or revealed by observation will be collected and recorded in the 
eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. In instances of well-recognized symptoms, they can 
be recorded as the commonly used diagnosis (e.g., fever, runny nose, and cough can be 
recorded as “flu”). However, if a diagnosis is known, but there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom should be 
recorded separately. 
Adverse events that are identified at the last assessment Visit 13 (EOT) as specified in the 
protocol must be recorded on the AE eCRF with the status of the AE noted, and the AE must 
be followed until AE is resolved or stable. All events that are ongoing at this time will be 
recorded as ongoing on the eCRF. The procedures specified in Section 7.2.7.8 are to be 
followed for reporting SAEs. 
7.2.7.1 
Adverse Events Associated with Change in Stool Form and/or Frequency 
Based on tenapanor’s ability to inhibit the absorption of dietary sodium, it is known to alter 
stool form and frequency in some patients. For a change in stool form and/or frequency to be 
considered an adverse event the patient must consider the bowel movements to be 
“bothersome.”  
7.2.7.2 
Recording Adverse Events 
Adverse events are to be recorded on the AE page of the eCRF. Severity will be graded 
according to the following definitions: 


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• Mild: The patient experiences awareness of symptoms but these are easily tolerated or 
managed without specific treatment 
• Moderate: The patient experiences discomfort enough to cause interference with usual 
activity, and/or the condition requires specific treatment 
• Severe: The patient is incapacitated with inability to work or do usual activity, and/or the 
event requires significant treatment measures. 
Action taken will be categorized as dose not changed, dose reduced, drug interrupted, drug 
withdrawn, required concomitant medication, required concomitant procedure and/or other. 
Event outcome at resolution or time of last follow-up will be recorded as not recovered/not 
resolved, recovered/resolved, recovered/resolved with sequelae, recovering/resolving, fatal or 
unknown. 
7.2.7.3 
Assessment of Adverse Events 
The relationship of the event to the study drug should be determined by the Investigator 
according to the following criteria: 
• Not related: The event is most likely produced by other factors such as the patient’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 is possibly due to drug administration and cannot be reasonably 
explained by other factors such as the patient’s clinical condition, intercurrent illness, or 
concomitant drugs. 
• 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 patient’s clinical condition, intercurrent 
illness, or concomitant drugs. 
7.2.7.4 
Following Adverse Events 
All (both serious and non-serious) AEs must be followed until they are resolved or stabilized, 
or until all attempts to determine resolution of the event are exhausted. The Investigator 
should use his/her discretion in ordering additional tests as necessary to monitor the 
resolution of such events. 


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7.2.7.5 
Discontinuation due to Adverse Events 
Any patient who experiences an AE may be withdrawn at any time from the study at the 
discretion of the Investigator. Patients withdrawn from the study due to an AE, whether 
serious or non-serious, must be followed by the Investigator until the clinical outcome of the 
AE is determined. The AE(s) should be noted on the appropriate CRFs and the patient’s 
progress should be followed until the AE is resolved. A decision to discontinue a patient due 
to an AE should be discussed with the Medical Monitor. If the AE may relate to overdose of 
study treatment, the IB should be consulted for details regarding any specific actions to be 
taken. 
7.2.7.6 
Pregnancy 
Female patients must be instructed to discontinue tenapanor and inform the study Investigator 
immediately if they become pregnant during the study. 
The Investigator must report any pregnancy to 
 within 1 business 
day of becoming aware of it. The patient must be immediately discontinued from further 
treatment with tenapanor. An uncomplicated pregnancy will not be considered an AE or 
SAE, but all pregnancies will be followed through birth. 
Pregnancies are captured if they occur in female patients or in the sexual partners of male 
patients from the time the patient is first exposed to tenapanor until 30 days after last 
exposure. 
Any congenital abnormalities in the offspring of a patient who received study drug will be 
reported as an SAE. The outcome of any pregnancy and the presence or absence of any 
congenital abnormality will be recorded in the source documentation and reported to 
. 
7.2.7.7 
Serious Adverse Events 
An SAE is any AE occurring from Enrollment through final study visit (V13), at any dose 
that results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 




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alert notifications for onward submission to their local IRB/IEC as required. All reports sent 
to investigators will be blinded. 
Follow-Up Reports 
The Investigator must continue to follow the patient until the SAE has resolved or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment) or the 
patient dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE 
form electronically in the EDC system for the study and submit any supporting 
documentation (e.g., patient discharge summary or autopsy reports) to 
 
 via fax or e-mail. If it is not possible to access the EDC system, refer to the 
procedures outlined above for initial reporting of SAEs.  
7.3 
Efficacy Variables 
The following are the efficacy variables for this study: 
• Patients reaching serum phosphorus goal levels defined as sP>2.5 and ≤4.5 mg/dL 
• Patients reaching serum phosphorus goal levels defined as sP ≤4.5 mg/dL 
• Percent change from baseline in sevelamer dose 
• Change from baseline in iFGF23 (intact) 
• Change from baseline in Kidney Disease and Quality of Life survey (KDQoL) 
composite score and subscales 
o 
Kidney Disease and Quality of Life™ (KDQOL™-36) (Copyright© 2000 by RAND 
and the University of Arizona) 
• Change from baseline in Dialysis Symptom Index survey (DSI) overall symptom burden 
score and overall symptom severity score 
o 
The University of Pittsburgh Medical Center, VA Pittsburgh Healthcare System 
(Weisbord et al. J Pain Symptom Manage, 2004:27, 226-40.) 
7.4 
Exploratory Variables 
Plasma and serum samples will be collected at specified times and may be used to evaluate 
the effect of tenapanor alone and in combination with sevelamer on PTH, CRP, aldosterone 
and other cardio-renal biomarkers (These data may not be part of the study report.) 


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Future exploratory research on serum/plasma biomarkers may be performed related to 
cardio-renal disease and/or mineral metabolism or that may influence the response 
(i.e. distribution, metabolism, safety, tolerability, and efficacy) to tenapanor. (These data will 
not be part of the study report.). 
8 
METHODOLOGY/STUDY VISITS 
8.1 
Baseline, Visit 1  
Prior to enrollment, the Investigator will inform each prospective patient of the nature of the 
study, explain the potential risks, and obtain written informed consent from the patient prior 
to performing any study-related procedures.  
No baseline assessments will be performed as part of this protocol; all baseline data for 
TEN-02-401 will be taken from the TEN-02-301 End of Treatment (EOT) visit and will 
consist of the following: 
• Informed consent 
• Inclusion and exclusion criteria (Section 5) 
• Weight (pre-dialysis) 
• Kt/V (most recent measurement prior to enrolling into TEN-02-401) 
• Medical history (major medical conditions taken from TEN-02-301) 
• Phosphate binder used and dose 
• KDQoL survey 
• DSI survey (for English speakers only) 
• Physical examination (Section 7.2.2) 
• Vital signs (pre-dialysis) (Section 7.2.3)  
• ECG evaluation (Section 7.2.4) 
• Clinical laboratory tests (pre-dialysis) (Section 7.2.5) 
o Serum chemistry 
o Hematology 
o Coagulation profile (if applicable) 
• Serum pregnancy test, if applicable 
• FGF-23, and exploratory biomarker sample (pre-dialysis) 
• Dispense study drug 


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• Begin collecting adverse events 
• Review concurrent medications 
8.2 
Weeks 1, 2, 3, 4, 6, and 8, Visits 2, 3, 4, 5, 6, and 7 
• Serum phosphorus (pre-dialysis) 
• Return/accountability of study drug 
• Dispense study drug 
• Adverse event reporting 
• Review concurrent medications 
8.3 
Months 3, 6, 9, 12, and 15, Visits 8, 9, 10, 11, and 12 
• Weight (pre-dialysis) 
• Kt/V (most recent measurement prior to screening) 
• KDQoL survey (not Months 9 and 15, Visits 10 and 12) 
• DSI survey, for English speakers only (not Months 9 and 15, Visits 10 and 12) 
• Vital signs (pre-dialysis) (Section 7.2.3)  
• Clinical laboratory tests (pre-dialysis) (Section 7.2.5) 
o Serum chemistry 
o Hematology 
o Coagulation profile (if applicable) 
• FGF-23, and exploratory biomarker sample (pre-dialysis) 
• Return/accountability of study drug 
• Dispense study drug 
• Adverse event reporting 
• Review concurrent medications 
8.4 
Months 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, Telephone Visit T1, T2, T3, T4, T5, 
T6, T7, T8, T9, T10 
• Adverse event reporting 
• Review concurrent medications 


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8.5 
Month 18, Visit 13; End of Treatment Visit 
• Weight (pre-dialysis) 
• Kt/V (most recent measurement prior to screening) 
• KDQoL survey 
• DSI survey (for English speakers only) 
• Physical examination (Section 7.2.2) 
• Vital signs (pre-dialysis) (Section 7.2.3)  
• ECG evaluation (Section 7.2.4) 
• Clinical laboratory tests (pre-dialysis) (Section 7.2.5) 
o Serum chemistry 
o Hematology 
o Coagulation profile (if applicable) 
• Serum pregnancy test, if applicable 
• FGF-23, and exploratory biomarker sample (pre-dialysis) 
• Return/accountability of study drug 
• Adverse event reporting 
• Review concurrent medications 
8.6 
Unscheduled Visits 
Unscheduled visits, for missed scheduled visits or safety or tolerability related reasons are 
allowed. Procedures performed are at the discretion of the Investigator.  
8.7 
Withdrawal Procedures 
In the event of a patient’s withdrawal, the Investigator will make every effort to complete all 
assessments performed at End-of-treatment visit (Visit 13). Withdrawn patients will be 
followed until resolution of any AEs or until the unresolved AEs are judged by the 
Investigator to have stabilized. 
For the withdrawal criteria see Section 5.3. 


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8.8 
Total Blood Volume Required for Study 
Table 8-1: 
Approximate Blood Volume per Completed Patient 
Test 
No. of Samples 
Volume (mL) 
Total (mL) 
Hematology (blood) 
7 
3 
21 
Chemistry (serum) (includes serum pregnancy test) 
7 
7 
49 
Phosphorus (serum)# 
6 
5 
30 
iFGF-23 (plasma) 
7 
4 
28 
Exploratory biomarker sample (serum and plasma) 
7 
13 
91 
Coagulation (plasma) 
7 
3 
21 
Total Volume 
-- 
-- 
240 
# Separate sample is only taken at specified times when no chemistry sample is taken 
8.9 
Protocol Deviations 
Patients must fully meet the following criteria in order to enroll in the study. In keeping with 
regulatory requirements, Ardelyx does not grant protocol waivers to inclusion/exclusion 
criteria.  
A protocol deviation is defined as any intentional or unintentional change to, or 
noncompliance with, the approved protocol procedures or requirements. Deviations may 
result from the action or inaction of the patient, Investigator, or site staff. Examples of 
deviations include, but are not limited to: 
 Failure to adhere to study exclusion and inclusion criteria 
 Failure to comply with dispensing or dosing requirements 
 Missed or out-of-window visits 
 Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, medical history; either tests not done, incorrect tests done, or not done 
within the time frame specified in the protocol 
 Procedural deviations such as incorrect storage of study drug, failure to update the ICF 
when new risks become known, failure to obtain Institutional Review Board (IRB) 
approvals for the protocol and ICF revisions 
A process for defining and handling protocol deviations will be established. Protocol 
deviations that effect the safety of a patient require immediate notification of the Medical 


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Monitor and Sponsor. The Investigator is responsible for seeing that any known protocol 
deviations are recorded and handled as agreed. 
9 
STATISTICAL CONSIDERATIONS  
9.1 
Statistical Analysis Plan 
A formal statistical analysis plan (SAP) will be provided separately. If the language in this 
protocol and the language in the SAP differ, the SAP governs. If additional analyses are 
performed or changes are made to the planned analyses after unblinding of the study data, 
such deviations will be documented in the clinical study report. 
9.2 
Determination of Sample Size 
Approximately 150-200 patients with ESRD on hemodialysis (HD) or peritoneal dialysis 
(PD) will be enrolled in this study. The sample size of this study is not planned based on 
statistical considerations.  
9.3 
Analysis Sets 
Two analysis sets are defined for this study: Safety Analysis Set and Full Analysis Set (FAS).  
Safety Analysis Set: 
All patients who receive at least one dose of study drug (tenapanor or sevelamer) in the 
study. The safety analysis set will be used for the analysis of safety variables.  
Full Analysis Set: 
All patients who meet the study entry inclusion/exclusion criteria, receive at least one dose of 
study drug (tenapanor or sevelamer), and have at least one post-baseline sP assessment in 
TEN-02-401. The FAS will be used for the analysis of efficacy variables. 
9.4 
Statistical Methods 
9.4.1 
General Approach  
Unless specified otherwise, descriptive statistics including the number of observations, mean, 
standard deviation, median, minimum, and maximum will be presented for continuous 
variables. Frequency and percentage of patients will be presented for categorical variables.  


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9.4.2 
Baseline Descriptive Statistics 
Baseline characteristics, including demographics, disease characteristics, prior/concomitant 
medications, and medical/surgical history will be summarized by TEN-02-301 treatment arm 
and overall for each analysis set.  
9.4.3 
 Efficacy Analysis 
All efficacy variables will be descriptively summarized at each visit for the FAS and each 
TEN-02-301 treatment arm (tenapanor or sevelamer). Descriptive summaries of sP variables 
will also be repeated for FAS subjects with a baseline sP >4.5 mg/dL.  
For response endpoints, the response rate at each post-baseline visit will be estimated with 
asymptotic 95% confidence interval (CI) for each TEN-02-301 treatment arm. Inferential 
analyses of sP endpoints will be performed for comparisons of phosphorus-lowering effect 
between monotherapy (tenapanor and sevelamer alone) and combination therapy (tenapanor 
combined with sevelamer) unless the sample size in each monotherapy treatment group is 
less than 15. Detailed model specifications will be provided in the statistical analysis plan 
(SAP). Inferential analyses of other endpoints may be performed as suggested by the data.  
Analyses will be detailed in the statistical analysis plan (SAP).  
9.4.4 
Procedures for Handling Missing Serum Phosphorus Data 
Descriptive summaries of efficacy and safety measures will be based on observed data. 
No imputation of missing data will be implemented.  
Handling of missing data for each inferential analysis will be detailed in the SAP.  
9.4.5 
Methods of Pooling Data 
For the purpose of adjusting for investigator effects in statistical models, investigator sites 
may be pooled into groups based on geographic region and number of patients enrolled with 
an aim for comparable sample sizes among pooled investigator sites. The goal of the pooling 
strategy will be to avoid less than a minimum number of patients per pooled investigator site. 
The size of a pooled investigator site would generally depend on the enrollment size for each 
individual investigator site. The pooled investigator sites will be used in all applicable 
analyses where adjustment for investigator effect is desired.  


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9.4.6 
Visit Windows 
No analysis visit windows will be formally defined. The schedule of events in Section 1.3 
details the intended collection of study variables at specified visits. Should additional data be 
collected between scheduled visits, these data will be included in the patient data listings but 
ignored for analyses purposes, unless the additional data are the last data collected during 
each study period. 
9.4.7 
Safety Analyses 
Safety analyses include summaries for adverse events, clinical laboratory tests, vital signs, 
body weights, 12-lead ECGs, and physical examinations. These summaries will be provided 
for the Safety Analysis Set and each TEN-02-301 treatment arm (tenapanor or sevelamer).  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Summary tables and listings will be provided by system organ class and 
preferred term for treatment-emergent adverse events (TEAEs). Actual values and change 
from baseline values for clinical laboratory tests, vital signs, body weights, and ECGs will be 
descriptively summarized by visit. The number and percentage of patients in each physical 
examination category will be presented by visit. 
10 
ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator will provide direct access to source data and documents for the Sponsor or 
its designee conducting study-related monitoring and/or audits, IRB/ Independent Ethics 
Committee (IEC) review, and regulatory review. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents, to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP (Good Clinical Practice), guidelines of 
the International Conference on Harmonization (ICH), and any applicable regulatory 
requirements. The Investigator will contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at any clinical site. 
The Investigator must inform the study patient that his/her study-related records may be 
reviewed by the above individuals without violating the patient’s privacy of personal health 
information in compliance with regulations of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). 


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Attention is drawn to the regulations promulgated by the FDA under the Freedom of 
Information Act providing, in part, that information furnished to clinical Investigators and 
IRBs will be kept confidential by the FDA only if maintained in confidence by the 
Investigator and IRB. By signing this protocol, the Investigator affirms to the Sponsor that 
the Investigator will maintain, in confidence, information furnished to him or her by the 
Sponsor and will divulge such information to the IRB under an appropriate understanding of 
confidentiality with such board. 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor or its designee will implement and maintain quality control and quality 
assurance procedures with written SOPs to ensure the study is conducted and data are 
generated, documented, and reported in compliance with the protocol, GCP, and applicable 
regulatory requirements. 
11.1 
Conduct of Study 
This study will be conducted in accordance with the provisions of the Declaration of Helsinki 
and all revisions thereof, and in accordance with the FDA Code of Federal Regulations 
(21 CFR Parts 11, 50, 54, 56, 312) and the International Conference on Harmonization (ICH) 
Guidelines on good clinical practice (ICH E6 R2). Specifically, this study is based on 
adequately performed laboratory and animal experimentation; the study will be conducted 
under a protocol reviewed by an IRB or IEC; the study will be conducted by scientifically 
and medically qualified persons; the benefits of the study are in proportion to the risks; the 
rights and welfare of the patients will be respected; the physicians conducting the study do 
not find the hazards to outweigh the potential benefits; and each patient will give his or her 
written, informed consent before any protocol-driven tests or evaluations are performed. 
The Investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate IRB, except when necessary to 
eliminate immediate hazards to the patient. Any deviation may result in the patient having to 
be withdrawn from the study, and may render that patient non-evaluable. 
11.2 
Protocol Amendments 
Only the Sponsor may modify the protocol. All amendments that have an impact on patient 
risk or the study objectives, or require revision of the ICF, must receive approval from the 
IRB prior to their implementation. Should the protocol changes be significant i.e., where 
there are changes in the existing protocol that significantly affect safety of patients, scope of 


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the investigation, or scientific quality of the study, the Sponsor must submit the protocol to 
the FDA prior to the protocol amendment being implemented.  
11.3 
Monitoring of Study 
The Investigator will permit the site monitor to review study data as frequently as is deemed 
necessary to ensure data are being recorded in an adequate manner and protocol adherence is 
satisfactory. 
The Investigator will provide access to the source documents or provide certified copies of 
the medical records for the monitor to verify eCRF entries. The Investigator is expected to 
cooperate with the Sponsor/designee in ensuring the study adheres to GCP requirements. 
11.4 
Ethics 
11.5 
Institutional Review Board/Independent Ethics Committee Approval 
11.5.1 
Ethics Review Prior to Study 
The Investigator will ensure that the protocol and consent form are reviewed and approved by 
the appropriate IRB prior to the start of any study procedures. The IRB will be appropriately 
constituted and perform its functions in accordance with FDA regulations, ICH GCP 
guidelines, and local requirements as applicable. 
11.5.2 
Ethics Review of other Documents 
In addition, the IRB will approve all protocol amendments (except for Sponsor-approved 
logistical or administrative changes), written informed consent documents and document 
updates, patient recruitment procedures, written information to be provided to the patients, 
available safety information, information about payment and compensation available to 
patients, the Investigator’s curriculum vitae and/or other evidence of qualifications, and any 
other documents requested by the IRB and regulatory authority as applicable. 
11.6 
Written Informed Consent 
The nature and purpose of the study will be fully explained to each patient (or the patient’s 
legally responsible guardian). The patients must be given ample time and opportunity to 
inquire about details of the trial, to have questions answered to their satisfaction, and to 
decide whether to participate. Written informed consent must be obtained from each patient 
(or guardian) prior to any study procedures being performed. 


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12 
DATA HANDLING AND RECORD KEEPING 
12.1 
Data Reporting and Case Report Forms 
12.1.1 
Case Report Forms 
The Investigator will be provided with eCRFs, and will ensure all data from patient visits are 
promptly entered into the eCRFs in accordance with the specific instructions given. The 
Investigator must sign the eCRFs to verify the integrity of the data recorded. 
12.1.2 
Laboratory Data 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be distributed to all sites. The Investigator must maintain source documents 
such as laboratory reports and complete history and physical examination reports. 
12.1.3 
Retention of Source Documents 
The Investigator must maintain source documents such as laboratory reports, x-rays, ECGs, 
consultation reports, and complete history and physical examination reports. 
12.2 
Retention of Essential Documents 
Essential documents should be maintained for at least 11 years based upon the Sponsor’s 
requirements and may be required to be maintained longer based upon applicable regional 
regulatory requirements. The Investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. Should the Investigator/institution 
not be able to maintain the records for this period of time, or there is a change in site location, 
the Investigator/institution must inform the Sponsor in writing, via certified mail, at least 
90 days prior to the destruction of any study documents, so that the Sponsor has the option, at 
the Sponsor’s expense, to have the records stored for a longer period of time. It is the 
responsibility of Sponsor to inform the Investigator/institution as to when these documents no 
longer need to be retained. 


Ardelyx, Inc. 
Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL 
Page 47 
13 
ADMINISTRATIVE INFORMATION 
 
 
 
 
 
 
 
 
14 
REFERENCES 
DOPPS Annual Report of the Dialysis Outcomes and Practice Patterns Study: Hemodialysis 
Data 1999-2008. Arbor Research Collaborative for Health, Ann Arbor, MI. Available from: 
http://www.dopps.org/annualreport/archives/DOPPSAR2010/index.htm 
Eknoyan G, Lameire N, Barsoum R, Eckardt KU, Levin A, Levin N, Locatelli F, MacLeod 
A, Vanholder R, Walker R, Wang H. The burden of kidney disease: improving global 
outcomes. Kidney Int. 2004;66(4):1310–1314. 
Ericsson KA, Simon HA. Verbal reports as data. Psychological Review. 1980;87:215–250. 
KDIGO, Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and 
Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney 
International 2009;76(Suppl 113):S1-S130. 
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997;32:920–924. 
Lindsay RM, Heidenheim PA, Nesrallah G, Garg AX, Suri R. Minutes to recovery after a 
hemodialysis session: a simple health-related quality of life question that is reliable,valid, and 
sensitive to change. Clin J Am Soc Nephrol. 2006;1:952–959. 
Waheed AA, Pedraza F, Lenz O, Isakova T (2013) Phosphate control in end-stage renal 
disease: barriers and opportunities. Nephrology, Dialysis, Transplantation 2013;0:1-8. 
Weisbord SD, Fried LF, Arnold RM, Rotondi AJ, Fine MJ, Levenson DJ, Switzer GE. 
Development of a symptom assessment instrument for chronic hemodialysis patients: 
the dialysis symptom index. J Pain Symp Manage. 2004;27:226–240. 


Ardelyx, Inc. 
Protocol No.: TEN-02-401 
Edition No.: 1 
 
15 April 2019 
CONFIDENTIAL 
Page 48 
15 
SIGNATURES 
15.1 
Investigator Signature 
I agree to conduct the study outlined above according to the terms and conditions of the 
protocol, GCP guidelines, and with applicable regulatory requirements. All information 
pertaining to the study will be treated in a confidential manner. 
 
 
Investigator’s Signature _______________________________________________ 
 
Investigator's Printed Name 
 
Investigational Site or Name of Institution 
 
 
 
Date___________________________