Clinical trial NCT03390842
Conditions: Metabolic Acidosis
Keywords: blood bicarbonate, kidney disease
Sponsor: Tricida, Inc.
Start date: 2017-12-20; Completion date: 2019-02-22
Enrollment: 196 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a 40-week, blinded, placebo-controlled extension of Study TRCA-301 (NCT03317444). Eligible subjects who complete the 12-week treatment period in Study TRCA-301 have the option to participate in this extension study evaluating the long-term safety and durability of effect of TRC101 in subjects with non-dialysis dependent chronic kidney disease and metabolic acidosis. Eligible subjects will be treated with TRC101 or placebo once daily (QD) on an out-patient basis for the subsequent 40 weeks. Subjects will continue to receive the same blinded treatment (TRC101 or placebo) that they received in Study TRCA-301.

Detailed description:

Arms: arm 1: Administered once daily (QD) for 40 weeks arm 2: Administered once daily (QD) for 40 weeks
Interventions: intervention 1: TRC101 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral suspension intervention 2: Oral suspension

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
Study Title:  
 A Blinded, Placebo-Controlled Extension to Study TRCA- 
301 to Evaluate the Long-term Safety and Durability of Effect 
of TRC101 in Subjects with Chronic Kidney Disease and 
Metabolic Acidosis 
 
Study Number:  
TRCA-301E 
 
NCT Number:  
NCT03390842 
 
Document Date:  
17 October 2018 
 
  


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
Confidential 
 
Page 1 of 74 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Blinded, Placebo-Controlled Extension to Study TRCA-
301 to Evaluate the Long-term Safety and Durability of Effect 
of TRC101 in Subjects with Chronic Kidney Disease and 
Metabolic Acidosis 
Study Number: 
TRCA-301E 
Investigational Drug: 
TRC101 
IND Number: 
125,832 
Indication: 
Treatment of metabolic acidosis associated with chronic 
kidney disease  
Investigators: 
Multicenter 
EudraCT Number: 
2017-002562-42 
Sponsor: 
Tricida, Inc. 
7000 Shoreline Court, Suite 201 
South San Francisco, CA 94080, U.S.A. 
Lead Medical Monitor: 
, MD, FASN 
Telephone:  
 
Fax:  
 
Email:  
   
Regional Medical 
Monitor (Europe): 
, MD, PhD 
Telephone:  
 
Fax:  
 
Email:  
  
Original Protocol Date: 
September 05, 2017 
Amendment 1: 
December 11, 2017 
Amendment 2: 
May 31, 2018 
Amendment 3: 
October 17, 2018 
 
Confidential Information 
The information in this document is confidential and is not to be disclosed without the written consent of Tricida, Inc. except 
to the extent that disclosure would be required by law and for the purpose of evaluating and/or conducting a clinical study 
for Tricida, Inc.  You are allowed to disclose the contents of this document only to your Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) and study personnel directly involved with conducting this protocol.  Persons to whom 
the information is disclosed must be informed that the information is confidential and proprietary to Tricida, Inc. and that it 
may not be further disclosed to third parties. 




TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
Confidential 
 
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Principal Investigator’s Signature 
 
Study Title: 
A Blinded, Placebo-Controlled Extension to Study TRCA-301 to 
Evaluate the Long-term Safety and Durability of Effect of TRC101 
in Subjects with Chronic Kidney Disease and Metabolic Acidosis 
Study Number: 
TRCA-301E 
Final Date: 
October 17, 2018 
 
 
I agree to conduct the study as detailed herein and in compliance with this Protocol, ICH 
Guidelines for Good Clinical Practice, the Declaration of Helsinki, all applicable U.S. 
regulations (including Parts 11, 50, 54, 56, 312 and 314), the European Union Clinical Trials 
Directive and all other applicable local and/or national laws, regulations and requirements.  
 
 
Signed: 
 
 
Date:  
 
 
Name:  __________________________________________________________________ 
Title:  ___________________________________________________________________ 
Institution Address:  _______________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
 
 
 




TRC101 
 
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Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
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SYNOPSIS 
TITLE: 
A Blinded, Placebo-Controlled Extension to Study TRCA-301 to Evaluate the Long-term Safety and 
Durability of Effect of TRC101 in Subjects with Chronic Kidney Disease and Metabolic Acidosis 
PROTOCOL NUMBER: 
TRCA-301E 
INVESTIGATIONAL PRODUCT: 
TRC101 
INDICATION: 
TRC101 is an oral, non-absorbed hydrochloric acid binder for the treatment of metabolic acidosis associated 
with chronic kidney disease (CKD).   
OBJECTIVES: 
To evaluate the long-term safety and durability of effect of TRC101 in CKD patients with metabolic 
acidosis. 
POPULATION: 
Subjects with non-dialysis dependent CKD and blood bicarbonate value of ≥ 12 mEq/L who completed the 
12-week Treatment Period in Study TRCA-301. 
STUDY DESIGN AND DURATION: 
This study is a 40-week, blinded, placebo-controlled extension of Study TRCA-301 (a Phase 3, multicenter, 
double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of TRC101 in 
subjects with CKD and metabolic acidosis).  Study sites, other than a designated unblinded staff member, as 
well as study subjects will be blinded.  Tricida will be unblinded when the database for the parent study, 
TRCA-301, is locked.  Eligible subjects who complete the 12-week Treatment Period in Study TRCA-301 
may have the option to participate in this extension study.  Subjects who discontinue prematurely from Study 
TRCA-301 will not be eligible for entry in the extension study.   
Study periods are as follows: 
• 
Week 12 Visit (1-day screening visit). 
• 
Treatment Period (starting with the Week 12 Visit and continuing for 40 weeks until the Week 52 
Visit). 
• 
Follow-up Period (2 weeks after discontinuation of treatment). 
After the subject provides informed consent, the subject’s eligibility will be evaluated on the basis of 
laboratory values, vital signs, renal status and pregnancy test (if applicable).  Eligible subjects will be treated 
with TRC101 or placebo once daily (QD) on an out-patient basis for the subsequent 40 weeks (Treatment 
Period); subjects will continue to receive the same blinded treatment (TRC101 or placebo) that they received 
in Study TRCA-301.  Dosing of oral concomitant medications and study drug will be separated by at least 
4 hours.   
Study drug dose adjustment and use of oral alkali supplements (for those subjects who were taking them at 
the Week 12 Visit) is described in the titration algorithm (Appendix 2). Subjects with a confirmed blood 
bicarbonate level > 30 mEq/L will undergo an interruption of the study drug dose in accordance with the 
titration algorithm.  Subjects with a blood bicarbonate level below the normal range (< 22 mEq/L) may have 
a blinded adjustment of the study drug dose in accordance with the titration algorithm.  At any time during 
the study, the Investigator will evaluate subjects with a confirmed blood bicarbonate level < 12 mEq/L for 
new acute acidotic processes and discuss them with the Medical Monitor.  The Medical Monitor will 
determine whether the subject may continue in the study.   
No addition or dose changes of any other concomitant therapy to raise blood bicarbonate will be allowed.  
Subjects who enter the study at the Week 12 Visit on an oral alkali supplement will be taken off the 
supplement if their blood bicarbonate is within the normal range (22 to 29 mEq/L) or above it (> 29 mEq/L), 


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October 17, 2018 
 
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as described in Appendix 2.  If, after removal of alkali supplementation, blood bicarbonate falls below the 
normal range, the study drug dose will be increased in a step-wise fashion to the maximum daily dose (3 
packets).  If blood bicarbonate is still below the normal range, the oral alkali therapy the subject was taking 
at the Week 12 Visit will be re-instated at the same dose the subject was taking at the Week 12 Visit.  If the 
Investigator judges that re-starting alkali treatment poses a safety risk, the risk should be documented.  In this 
situation, alkali will not be re-started.   
Subjects will return to the study center for study visits at Weeks 14, 16, 20, 24, 28, 34, 40, 46, and 52 for 
assessments of safety and durability of effect.  Additional unscheduled study visits may be necessary 
following study drug dose adjustments.  Subjects who complete the Treatment Period will enter the 2-week 
Follow-up Period and return to the study site for two visits: Follow-up 1 (Week 53) and Follow-up 2 (Week 
54), for adverse event (AE) collection, fasting blood draws and safety assessments as outlined in the 
Schedule of Events (Appendix 1).   
Subjects who withdraw from the study prematurely (i.e., prior to the Week 52 Visit) will undergo an Early 
Termination (ET) Visit, during which all Week 52 Visit assessments will be performed, and will be asked to 
attend Follow-up 1 and 2 Visits in 1 and 2 weeks, respectively.  All subjects who discontinue study drug 
prior to the Week 52 Visit will be contacted by telephone 40 weeks after their Week 12 Visit to ascertain 
vital status and renal status (i.e., receiving renal replacement therapy or not).   
Blood draws for bicarbonate measurements will be performed when subjects are in a fasted state (at least 
4 hours) and at approximately the same time of day for each subject. 
The maximum study duration for a subject is anticipated to be 42 weeks, including the 40-week Treatment 
Period, and 2-week Follow-up Period.  Including the 12-week exposure to study drug in the parent study 
(TRCA-301), subjects randomized to TRC101 in Study TRCA-301, who complete the Treatment Period in 
Study TRCA-301E, will have a total of 1-year of exposure to TRC101. 
INCLUSION CRITERIA: 
1. 
Have provided written informed consent prior to participation in the study. 
2. 
Have completed the 12-week treatment period and attended the Week 12 Visit in the parent 
study TRCA-301. 
3. 
Have a blood bicarbonate value of ≥ 12 mEq/L at the Week 12 Visit in Study TRCA-301, based 
on onsite measurement using the i-STAT point-of-care device.  
4. 
Have adequate peripheral venous access for blood draws. 
5. 
Women who are of childbearing potential must have negative pregnancy test at the Week 12 
Visit and be willing to use an acceptable method of birth control until 1 month after study 
completion.  Acceptable methods include hormonal contraception (oral contraceptives, patch, 
implant, and injection), intrauterine devices, double barrier methods (e.g., vaginal diaphragm, 
vaginal sponge, condom, spermicidal jelly), sexual abstinence or a vasectomized partner.  
Women who are surgically sterile with documentation of such, or who are at least 1-year post-
last menstrual period and > 55 years of age, are considered not to be of childbearing potential.   
EXCLUSION CRITERIA: 
1. 
Have any level of low blood bicarbonate at the Week 12 Visit that, in the opinion of the 
Investigator, requires emergency intervention or evaluation for an acute acidotic process. 
2. 
Required dialysis for acute kidney injury or worsening CKD during the parent study  
TRCA-301. 
3. 
Planned initiation of renal replacement therapy (dialysis or transplantation) within 6 months 
following study entry. 
4. 
Have a history or current diagnosis of clinically significant diabetic gastroparesis (based on 
Investigator’s judgment) or a history of bariatric surgery. 
5. 
Have a history or current diagnosis of bowel obstruction, swallowing disorders, severe 
gastrointestinal (GI) disorders, inflammatory bowel disease, major GI surgery, or active 
gastric/duodenal ulcers. 


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6. 
Have a serum calcium ≤ 8.0 mg/dL at the Week 10 Visit in the parent study, TRCA-301. 
7. 
Have active cancer during the 1 year prior to the Week 12 Visit, other than non-melanoma skin 
cancer, or cancer that is currently being treated or will be treated during the study.  Subjects 
with cancers that are being treated with hormonal therapy only may be permitted with approval 
of the Medical Monitor. 
8. 
Inability to consume the study drug, known allergy to the study drug or otherwise comply with 
the protocol. 
9. 
Have, in the opinion of the Investigator, any medical condition, uncontrolled systemic disease 
or serious concurrent illness that would significantly decrease study compliance or jeopardize 
the safety of the subject or affect the validity of the study results. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Investigational product: TRC101. 
Placebo: 
 NF Grade. 
TRC101 or placebo (up to 3 packets per day) will be self-administered orally as an aqueous suspension, QD, 
with food, at approximately the same time each day.  Concomitant oral medications must be taken at least 4 
hours before or after study drug administration.  The last dose of study drug will be taken the day before the 
Week 52 Visit. 
SAFETY ASSESSMENTS: 
Safety assessments will include AEs, vital signs, physical examination (including body weight), safety 
laboratory measurements (blood and urine), coagulation (for subjects on vitamin K antagonists or factor Xa 
inhibitors only), pregnancy test (for woment of childbearing potential only), and electrocardiograms (ECGs).   
MAIN ASSESSMENT OF DURABILITY OF EFFECT: 
The durability of the effect observed at the end of treatment in the parent study, TRCA-301, will be assessed 
by blood bicarbonate values. 
ENDPOINTS: 
Primary Endpoint:  Incidence of AEs, SAEs, and AEs leading to withdrawal. 
Secondary Endpoints:   
1. Having a change from baseline (CFB) in blood bicarbonate ≥ 4 mEq/L or having blood bicarbonate 
in the normal range (22 to 29 mEq/L) at the end of treatment (Week 52 Visit). 
2. CFB in blood bicarbonate at the end of treatment (Week 52 Visit). 
3. CFB in the total score of the Kidney Disease and Quality of Life (KDQOL) Question 3 items (daily 
activities) at the end of treatment (Week 52 Visit). 
4. CFB in repeated chair stand test duration at the end of treatment (Week 52 Visit). 
STATISTICAL ANALYSES: 
This blinded, placebo-controlled extension to Study TRCA-301 will evaluate the long-term safety and 
durability of effect of TRC101 in subjects with CKD and metabolic acidosis.  This study will enroll eligible 
subjects who completed the 12-week Treatment Period in Study TRCA-301. 
The Safety Analysis Set is defined as all subjects who received any amount of TRC101 or placebo in this 
extension study.  A Modified-Intent-to-Treat analysis set is defined as subjects who rolled over to this 
extension study and had at least one blood bicarbonate assessment after the Week 12 Visit.  Time points will 
be derived based on the date of first dose of study drug in the parent study, TRCA-301.  Baseline values are 
defined as the Baseline values in the parent study, TRCA-301, unless stated otherwise in the Statistical 
Analysis Plan (SAP).   
Frequencies and percentages will be presented for categorical variables and standard descriptive statistics 
will be presented for continuous variables. 
Safety will be summarized as follows:  Treatment-emergent AEs (TEAEs) are defined as those occurring 
with onset at the Week 12 visit + 1 day.  Number and percentage of subjects with TEAEs classified by 


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system organ class (SOC) and preferred term (PT); number (%) of subjects experiencing TEAEs by severity, 
causality, seriousness and action taken with regard to study drug will be summarized by 12-week intervals 
and during the entire treatment period (Weeks 12 to 52) with the denominator as the number of subjects at 
risk at the beginning of each interval.  Number (%) of subjects with TEAEs leading to discontinuation of 
study treatment will be summarized similarly by 12-week interval and during the entire treatment period 
(Weeks 12 to 52).  Clinical laboratory test results, vital signs and ECG findings will be summarized using 
descriptive statistics by time point.  Categorical displays (e.g., frequencies, shift tables) and plots of 
laboratory values over time may also be used, as appropriate.  Study drug dosing and dose titration will be 
summarized by time point.  The incidence and frequency of subjects who meet the dose interruption criterion 
(confirmed blood bicarbonate value > 30 mEq/L) at any time during the Treatment Period will be 
summarized by 12-week interval with the denominator as the number of subjects at risk at the beginning of 
each interval. 
Durability of effect will be evaluated as follows:  The proportions of subjects who meet the responder 
definition at each protocol-specified time point will be summarized.  Responders are defined as having a 
CFB in blood bicarbonate ≥ 4 mEq/L or having blood bicarbonate in the normal range (22 to 29 mEq/L).  
The difference in proportion (between TRC101 and placebo subjects) and its exact (Clopper-Pearson) 95% 
confidence interval (CI), as well as the p-value from Fisher’s exact test comparing the TRC101 group and the 
placebo group will be reported by time point.  The proportion of subjects in each group who are responders, 
along with their exact (Clopper-Pearson) 95% CIs, will be summarized by treatment group and time point.  A 
comparison between the TRC101 group and placebo group with respect to the proportion of responders at 
Week 52 will be perfomed using Fisher’s exact test.  A longitudinal mixed-effect model for repeated 
measures (MMRM) will be used to assess the CFB in bicarbonate level between the TRC101 group and 
placebo group at each protocol specified time point.  A test comparing the least squares (LS) means of CFB 
in bicarbonate between the TRC101 group and placebo group at Week 52 will be conducted.  An analysis of 
covariance (ANCOVA) model will be used to assess the CFB in total score of KDQOL Question 3 items and 
in the repeated chair stand test.  Additional analyses for durability of effect will be specified in the SAP.  If 
the residuals from the above mentioned models (i.e., MMRM, ANCOVA) are not normally distributed, 
alternative analyses to deal with non-normality will be used instead.  The SAP will specify these analyses. 
Analyses will summarize demographic and baseline characteristics, exposure  to study drug, dosing 
compliance, and concomitant medications.  The number and percentage of subjects who used prior and/or 
concomitant medications will be summarized by Anatomic Therapeutic Chemical (ATC) classification 
levels.  Alkali use will be summarized by visit. 
 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................5 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF TABLES ...................................................................................................................12 
LIST OF FIGURES .................................................................................................................12 
LIST OF APPENDICES ..........................................................................................................12 
LIST OF ABBREVIATIONS AND ACRONYMS ................................................................13 
1 
INTRODUCTION .................................................................................................16 
 
Disease Background.........................................................................................16 
 
Description of Investigational Product ............................................................17 
 
Relevant Nonclinical Background ...................................................................17 
1.3.1 
Nonclinical Pharmacology ...................................................................17 
1.3.2 
Safety Pharmacology ...........................................................................18 
1.3.3 
Nonclinical ADME ..............................................................................18 
1.3.4 
Nonclinical Toxicology .......................................................................18 
 
Relevant Clinical Background .........................................................................20 
1.4.1 
Study TRCA-101 .................................................................................20 
1.4.1.1 
Safety ..........................................................................................20 
1.4.1.2 
Efficacy .......................................................................................21 
 
Description and Justification for Route of Administration, Dosage, Dosage 
Regimen and Treatment Period .......................................................................23 
 
Description of Population to be Studied ..........................................................24 
2 
STUDY OBJECTIVES ..........................................................................................25 
3 
INVESTIGATIONAL PLAN ................................................................................25 
 
Overall Study Design and Plan ........................................................................25 
 
Rationale for Study Design and Control Group ...............................................27 
3.2.1 
Study Design ........................................................................................27 
3.2.2 
Safety Monitoring ................................................................................27 
 
Study Duration .................................................................................................28 
4 
STUDY POPULATION SELECTION AND WITHDRAWAL ...........................29 
 
Study Population ..............................................................................................29 
 
Inclusion Criteria .............................................................................................29 
 
Exclusion Criteria ............................................................................................29 
 
Subject Withdrawal ..........................................................................................30 
5 
STUDY TREATMENT(S) ....................................................................................32 
 
Description of Treatment(s) .............................................................................32 
5.1.1 
Investigational Drug.............................................................................32 
5.1.2 
Placebo .................................................................................................32 


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5.1.3 
Study Drug Dispensing, Packing and Labeling ...................................32 
 
Treatment(s) Administered ..............................................................................32 
 
Dosing Regimen...............................................................................................33 
 
Missed Doses ...................................................................................................34 
 
Selection and Timing of Dose for Each Subject ..............................................34 
 
Method of Assigning Subjects to Treatment Groups .......................................34 
 
Blinding............................................................................................................34 
 
Concomitant Therapy.......................................................................................35 
 
Restricted Medications.....................................................................................35 
 
Restrictions ......................................................................................................36 
5.10.1 
Fluid and Food Intake ..........................................................................36 
5.10.2 
Management of Acidemia (Use of Alkali Therapy) ............................37 
 
Treatment Compliance .....................................................................................37 
 
Storage and Accountability ..............................................................................37 
6 
STUDY PROCEDURES .......................................................................................38 
 
Informed Consent.............................................................................................38 
 
Concomitant Medications ................................................................................38 
 
Vital Signs ........................................................................................................38 
 
Complete Physical Examination, Including Body Weight ..............................38 
 
Repeated Chair Stand Test ...............................................................................39 
 
KDQOL............................................................................................................39 
 
12-Lead Electrocardiograms ............................................................................39 
 
Clinical Laboratory Tests .................................................................................40 
6.8.1 
Laboratory Parameters .........................................................................40 
 
Dietary Counseling ..........................................................................................42 
 
Adverse Events ................................................................................................42 
6.10.1 
Definition of an Adverse Event ...........................................................42 
6.10.2 
Definition of a Serious Adverse Event ................................................44 
6.10.3 
Definition of a Suspected Adverse Reaction .......................................44 
6.10.4 
Procedures for Eliciting, Recording and Reporting Adverse Events ...44 
6.10.4.1 
Adverse Event Reporting Period ................................................44 
6.10.4.2 
Eliciting Adverse Events.............................................................45 
6.10.4.3 
Assessing Adverse Events ..........................................................45 
6.10.4.4 
Independent Data Monitoring Committee ..................................47 
6.10.4.5 
Recording Adverse Events ..........................................................47 
6.10.5 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments .........................................................................................47 
6.10.6 
Serious Adverse Events Reporting ......................................................48 
6.10.6.1 
SAE Expedited Reporting ...........................................................49 
6.10.6.2 
Unblinding Treatment Allocation ...............................................49 


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Procedures for Reporting Pregnancy Exposure and Birth Events ...................50 
7 
STUDY ACTIVITIES ...........................................................................................50 
 
Week 12 Visit ..................................................................................................50 
 
Week 14 Visit ..................................................................................................51 
 
Week 16 and Week 46 Visits ...........................................................................52 
 
Week 20 and Week 40 Visits ...........................................................................53 
 
Week 24 and Week 34 Visits ...........................................................................53 
 
Week 28 Visit ..................................................................................................54 
 
Week 52 or Early Termination (ET) Visit .......................................................55 
 
Follow-up 1 Visit (Week 53) ...........................................................................56 
 
Follow-up 2 Visit (Week 54) ...........................................................................56 
 
Unscheduled Visit ............................................................................................57 
 
End-of-Study ....................................................................................................57 
8 
PLANNED STATISTICAL METHODS ..............................................................58 
 
General Considerations ....................................................................................58 
 
Determination of Sample Size .........................................................................58 
 
Analysis Populations ........................................................................................58 
 
Reference Date and Baseline ...........................................................................58 
 
Demographics and Baseline Characteristics ....................................................59 
 
Statistical Analysis of Durability of Effect ......................................................59 
8.6.1 
Durability of Effect Variable ...............................................................59 
8.6.2 
Durability of Effect Endpoints .............................................................59 
8.6.3 
Analysis of Durability of Effect ...........................................................59 
 
Safety Analysis ................................................................................................60 
 
Other Assessments or Analyses .......................................................................61 
9 
DATA HANDLING AND RECORD KEEPING .................................................61 
 
Source Data ......................................................................................................61 
 
Case Report Forms / Electronic Data Record ..................................................62 
 
Data Handling ..................................................................................................62 
 
Deviations from the Protocol ...........................................................................62 
 
Record Retention and Archiving .....................................................................63 
10 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................63 
11 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ...............................64 
 
Good Clinical Practice .....................................................................................64 
 
Institutional Review Board / Independent Ethics Committee..........................64 
 
Ethical Conduct of the Trial .............................................................................65 
 
Subject’s Information and Informed Consent ..................................................65 
 
Protocol Approval and Amendment ................................................................66 


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Premature Termination of the Study ................................................................66 
 
Confidentiality .................................................................................................67 
 
Liability and Insurance ....................................................................................67 
 
Publication Policy ............................................................................................67 
12 
REFERENCE LIST ...............................................................................................67 
13 
APPENDICES .......................................................................................................71 
 
LIST OF TABLES 
Table 1 
Restricted Prior and Concomitant Medications .........................................36 
Table 2 
Laboratory Parameters ...............................................................................41 
 
LIST OF FIGURES 
Figure 1 
Mean Change in Serum Bicarbonate by Treatment Group Over Time .....23 
Figure 2 
Study TRCA-301E Study Design Schematic ............................................25 
Figure 3 
Serious Adverse Event Reporting Instructions if EDC System is Not 
Available ....................................................................................................48 
 
LIST OF APPENDICES 
Appendix 1: 
Schedule of Events .....................................................................................72 
Appendix 2: 
Study Drug and Oral Alkali Supplement Titration Algorithm ..................74 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
ADME 
absorption, distribution, metabolism, excretion 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
β−HCG 
beta human chorionic gonadotropin 
BE 
base excess 
BID 
twice daily 
BUN 
blood urea nitrogen 
CFB 
change from baseline 
CI 
confidence interval 
CK 
creatine kinase 
CKD 
chronic kidney disease 
CNS 
central nervous system 
CRO 
contract research organization 
CV 
cardiovascular 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GI 
gastrointestinal 
HCO3- 
bicarbonate 


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HDL 
high density lipoprotein 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISF 
Investigative Site File 
LDL 
low density lipoprotein 
LS 
least squares 
MCH 
mean corpuscular hemoglobin 
MCV 
mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
MMRM 
mixed-effect model repeated measures 
NOAEL 
no observed adverse effect level 
pCO2 
partial pressure of carbon dioxide 
pO2 
partial pressure of oxygen 
PT 
preferred term 
QD 
once daily 
RAAS 
renin-angiotensin-aldosterone system 
RBC 
red blood cell 
RDW 
red cell distribution width 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SE 
standard error 
SO2 
oxygen saturation 
SOC 
system organ class 


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SUSAR(s) 
suspected unexpected serious adverse reaction(s) 
TCO2 
total carbon dioxide 
TEAE(s) 
treatment emergent adverse event(s) 
US 
United States 
WHO 
World Health Organization 
 


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1 
INTRODUCTION 
 
Disease Background 
Patients with chronic kidney disease (CKD) continue to generate acid from metabolism but 
have a reduced ability to excrete acid via the kidney.  As a result, metabolic acidosis, 
characterized by a reduced blood bicarbonate concentration (i.e., below 22 mEq/L), can 
develop in advanced stages of CKD.  Chronic metabolic acidosis affects 13 to 39% of CKD 
Stage 3 – 5 patients (Eustace 2004; Raphael 2014; Moranne 2009).  Left untreated, chronic 
metabolic acidosis can lead to increased mortality, acceleration of kidney disease, 
acceleration of muscle breakdown, and the development or exacerbation of bone disease 
(Dobre 2015). 
Clinical outcomes for CKD patients with bicarbonate levels that are below normal (i.e., 
< 22 mEq/L) are significantly worse compared to patients with normal bicarbonate (i.e., 
22 to 29 mEq/L); this has been demonstrated in multiple large retrospective database 
analyses reported in the literature (Shah 2009; Dobre 2013; Raphael 2011; Tangri 2011; 
Kovesdy 2009; Navaneethan 2011; Raphael 2016).  The relationship between decreasing 
bicarbonate levels and clinical outcomes is believed to be a continuum (i.e., as bicarbonate 
decreases from normal levels the risk of adverse outcomes, such as death, progression of 
CKD and hospitalization, progressively increases).  Hazards for patients with bicarbonate 
levels in the range required for subjects in this study (i.e., 12 to 20 mEq/L) are significantly 
worse than for patients with bicarbonate levels indicative of more mild metabolic acidosis 
(i.e., > 20 to 22 mEq/L).  Correction of low bicarbonate levels in patients with CKD (i.e., 
with oral alkali supplementation or consumption of a less acidic diet) has been shown to 
result in slowing of progression of renal disease (de Brito-Ashurst 2009; Phisitkul 2010; 
Mahajan 2010; Goraya 2013; Goraya 2014; Garneata 2016), improvements in muscle 
mass/function (de Brito-Ashurst 2009; Abramowitz 2013) and improvement in bone health 
(Domrongkitchaiporn 2002). 
Currently, no approved therapies are available in the United States for controlling 
bicarbonate in patients who have chronic metabolic acidosis.  Use of unapproved oral alkali 
supplements (e.g., food additives such as oral sodium bicarbonate and off-label use of 
potassium citrate) is general clinical practice; however, these agents have been studied only 
in patients with mild metabolic acidosis.  Most prospective trials have limited doses of oral 
sodium bicarbonate to < 2 g per day resulting in modest increases in blood bicarbonate of 
2 to 3 mEq/L.  The daily doses of sodium bicarbonate required to increase blood bicarbonate 
levels by 3 to 4 mEq/L in patients with metabolic acidosis are prohibitively high (6 to 8 g per 
day introducing 1.6 to 2.2 g of sodium; Abramowitz 2013).  Combined with the sodium 
intake from diet, this would result in a total daily sodium load exceeding the guideline-
recommended limit of 2.4 g/day for CKD patients (KDOQI 2002) independent of underlying 
comorbidities.  Furthermore, common conditions accompanying CKD (e.g., hypertension, 
heart failure, edema) may be aggravated by the sodium load that alkali therapies deliver and 


TRC101 
 
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Clinical Study Protocol: TRCA-301E 
 
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efficacy of diuretics reduced.  As such, there is a clear unmet medical need for new 
treatments with demonstrated efficacy and safety to treat chronic metabolic acidosis. 
 
Description of Investigational Product 
TRC101 is being developed as a first-in-class, orally administered, counterion-free, 
insoluble, non-absorbed hydrochloric acid (HCl) binder for the treatment of metabolic 
acidosis in patients with CKD.  TRC101 is a free-flowing powder composed of low-swelling, 
spherical beads approximately 100 micrometers in diameter.  The TRC101 bead size is 
carefully controlled in order to restrict absorption of particles from the gastrointestinal (GI) 
tract, consistent with several literature reports that show particles larger than 0.5 micrometers 
are not systemically absorbed (Jung, 2000).  Nonclinical studies with radiolabeled TRC101 
conducted in rats and dogs confirmed the lack of systemic absorption of TRC101. 
TRC101 is insoluble in aqueous and nonaqueous solvents.  TRC101 has both high proton 
(H+) and chloride (Cl-) binding capacity and Cl- binding selectivity.  The high amine content 
of the polymer is responsible for its high H+ and Cl- binding capacity, and the polymer’s 
extensive crosslinking provides size exclusion properties and selectivity for binding Cl- over 
other  larger competing anions.  The TRC101 mechanism of action involves binding of H+ 
and Cl-, resulting in a net reduction and removal of HCl from the GI tract, which results in an 
increase in serum bicarbonate levels.   
The TRC101 drug substance is packaged in individual-dose packets without addition of any 
excipients to create the clinical study material, a powder for oral suspension also called 
TRC101 (i.e., drug product). 
 
Relevant Nonclinical Background 
1.3.1 
Nonclinical Pharmacology 
Nonclinical in vitro and in vivo studies have demonstrated robust proton and chloride 
binding and removal by the TRC101 polyamine polymer.  In vitro studies have demonstrated 
that TRC101 selectively binds and retains HCl under conditions that mimic the pH, exposure 
times, and ionic content of various compartments of the GI tract.  The marked binding 
capacity and selectivity for HCl observed with TRC101 in vitro translates into in vivo 
pharmacological effects.  When TRC101 was packaged in nylon sachets, fed to a single pig, 
and then recovered from collected feces, analysis of the anions bound to the recovered 
polymer revealed an in vivo binding of 2.6 mEq of chloride per gram of TRC101.  
Furthermore, removal of HCl by TRC101 results in a dose-dependent increase in mean serum 
bicarbonate, as observed in rats with adenine-induced nephropathy and metabolic acidosis 
compared to untreated controls.   


TRC101 
 
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1.3.2 
Safety Pharmacology 
The nonclinical Good Laboratory Practice (GLP) safety program for TRC101 includes three 
studies assessing safety pharmacology.  These assessments of the central nervous system 
(CNS), respiratory, cardiovascular (CV), and GI systems did not identify any TRC101-
related adverse effects in rats up to 2 g/kg/day (GI) or up to 4 g/kg/day (CNS, respiratory) 
and in dogs up to 2 g/kg/day (CV).  
1.3.3 
Nonclinical ADME 
Lack of TRC101 absorption from the GI tract was demonstrated in both rats and dogs 
administered a single oral dose of [14C]-TRC101.  The results of the radiolabeled TRC101 
absorption, distribution, metabolism, and excretion (ADME) studies demonstrating a lack of 
oral bioavailability are consistent with the physicochemical properties of TRC101 
(insolubility in aqueous and organic solvents, particle size averaging 100 micrometers in 
diameter, and particle stability). The studies demonstrated no radioactivity in tissues or 
organs other than within the GI tract lumen, no radiolabel detectable in the plasma and blood 
samples indicating absorption, and ≤ 0.02% of radiolabel appearing in the urine or expired air 
of rats or in the urine of dogs.  The level of radioactivity excreted in the urine and/or expired 
air was consistent with the level of unincorporated radiolabel measured in a water extraction 
of the radiolabeled polymer.  Given the variability of the retrieval method, nearly complete 
recovery of the radioactive dose from the feces was observed within the first 48 hours after 
dosing.  It can be concluded that TRC101 is not systemically absorbed following oral 
administration to rats and dogs. 
1.3.4 
Nonclinical Toxicology 
Nonclinical toxicology studies of TRC101 to date include non-GLP 7-day repeat dose oral 
toxicology studies in rats and dogs, a GLP 33-day and 28-day repeat dose oral toxicology 
study with a 2-week recovery in rats and dogs, respectively, and a GLP 26-week and 39-
week chronic repeat dose oral toxicology interim analysis in the rat and dog, respectively (4-
week recovery analysis pending); a screening non-GLP in vitro genotoxicity study (bacterial 
reverse mutation [Ames] assay) and two GLP in vitro genotoxicity studies (Ames assay and 
chromosomal aberration assay in human peripheral blood lymphocytes); non-GLP pilot and 
GLP definitive embryofetal development (EFD) studies in the rat and the rabbit.  No single 
dose studies were conducted.     
In the 26-week GLP study in male and female Wistar Han rats, the animals received oral 
doses (via dietary admixture) of TRC101 at total daily doses of 0, 0.5, 1 and 2 g/kg/day.  The 
26-week dosing period was followed by a 4-week post-dose observation period.  
Assessments were conducted in a cohort of the animals from each dose group after 13 weeks 
(interim) and 26 weeks (complete dosing period) of test article administration, as well as 
following the 4-week recovery period.  The assessments included all in-life data collected 
through Week 13 or 26 and postmortem evaluations associated with the necropsies.   


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No definitive TRC101-related changes were observed in mortality, clinical observations, 
body weight, or food consumption measurements; ophthalmologic evaluations; clinical 
pathology parameters (including serum chemistry, hematology, and blood gas); or organ 
weights, gross necropsy or histopathology at the end of the treatment.  TRC101-related 
findings were limited to minimal, reversible increases in urine pH at all collection intervals in 
both sexes at 2 g/kg/day in the 33-day study, with a similar but less pronounced trend in 
males at 0.5 and 1.0 mg/kg/day.  The urine pH observation lacked microscopic correlates, 
was not considered adverse, but was considered a normal homeostatic process to maintain 
acid base status in the normal rats.  The study results indicate that the rats were capable of 
compensating for the effects of TRC101 on Cl- excretion and increased bicarbonate levels 
through increased excretion of excess bicarbonate in the urine. 
Since no adverse TRC101-related effects occurred in rats following doses up to 2 g/kg 
administered for 26 weeks, this dose was identified as the no observed adverse effect level 
(NOAEL) in male and female rats.  This dose level provides a 13-fold safety margin for the 
highest proposed clinical dose (9 g/day TRC101), based on a 60-kg subject. In the 39-week 
oral toxicology study in dogs with a 4-week recovery period the animals were administered 
oral doses (via capsule) of TRC101 at total daily doses of 0, 0.5, 1, and 2 g/kg/day, divided 
BID.  An interim assessment, including all in-life data and postmortem evaluations collected 
through the 39-week dosing period, was conducted in a cohort of the animals from each dose 
group.  No TRC101-related changes were observed in mortality, clinical observations, body 
weight, or food consumption measurements; ECG and ophthalmologic evaluations; clinical 
pathology parameters (including serum chemistry, hematology, and blood gas); or organ 
weights, gross necropsy, or histopathology.  TRC101-related findings were limited to a mild 
non-adverse increase in urine pH in both males and females at 2 g/kg.  An increase in urine 
pH is consistent with the pharmacology of TRC101 when animals with normal acid-base 
balance are administered high doses of TRC101.  The high dose of 2 g/kg/day (13-fold safety 
margin for a 9 g/day human dose) was identified as the NOAEL in male and female dogs in 
the 13-week interim evaluation. 
Reproductive toxicology studies demonstrated no effects of TRC101 on embryo-fetal 
development or maternal reproductive indices; it was also non-teratogenic.  The NOAEL for 
maternal toxicity and embryo-fetal development was the high dose of 2 g/day for both the rat 
and rabbit.  Because TRC101 is not systemically absorbed, Tricida has received a waiver from 
the Food and Drug Administration (FDA) for the conduct of the in vivo micronucleous assay, 
the male and female fertility and early embryonic development study in rats, and the peri- and 
post-natal developmental study in rats.  No carcinogenicity studies of TRC101 have been 
conducted.   
In conclusion, the nonclinical toxicology studies demonstrate that TRC101 has a very low 
order of toxicity.  The repeat dose toxicology studies in the rat and dog assessed local tolerance; 
histopathological evaluation of the GI tract indicated that TRC101 was generally well tolerated.  
The genotoxicity studies demonstrate that TRC101 is neither mutagenic nor clastogenic.  The 
embryo-fetal development studies showed no adverse TRC101-related effects on maternal 


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
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reproductive function or embryo-fetal parameters, and showed no effects on male or female 
reproductive organs in the GLP repeat dose toxicology studies in rat and dog.   
 
Relevant Clinical Background 
For a summary of the known and potential risks and benefits of TRC101 to human subjects, 
see the TRC101 Investigator’s Brochure.   
Study TRCA-101 has been completed, and results are summarized in this section.  All 
subjects enrolled in this long-term safety extension study will have completed the 12-week 
Treatment Period of the double-blind, placebo-controlled, Phase 3 study TRCA-301. 
1.4.1 
Study TRCA-101 
Study TRCA-101 was conducted in subjects with CKD Stage 3 – 4 (estimated glomerular 
filtration rate [eGFR] 20 to < 60 mL/min/1.73m2) and baseline serum bicarbonate levels of 
12 to 20 mEq/L.  It was a double-blind, placebo-controlled, parallel-design, 6-arm, fixed dose 
study, evaluating the safety and efficacy of three doses of TRC101 (3, 6 and 9 g/day) and two 
dosing regimens (once daily [QD] and twice daily [BID]) versus placebo.  Subjects enrolled 
in Study TRCA-101 were treated for 2 weeks while in residence at the clinical research units, 
after which they were discharged and followed for up to an additional 2 weeks (off 
treatment).  While in residence during the treatment period, subjects ate a standardized study 
diet controlled for protein and caloric content, as well as anions, cations and fiber, in 
accordance with dietary recommendations for CKD patients (KDOQI 2002).  Care was taken 
to ensure the diet was neither acidic nor basic.  The specific foods selected for the menus 
were chosen to closely approximated the regions’ typical diet.  The primary objective of the 
study was to assess the safety and tolerability of TRC101.  The main efficacy endpoint was 
change from baseline (CFB) to end-of-treatment in serum bicarbonate level. 
The study population comprised 135 subjects (86 male and 49 female), with a mean age of 
60.3 years (range of 30 to 79 years), a mean baseline eGFR of 34.8 mL/min/1.73m2 (range of 
19 to 66 mL/min/1.73m2; 44.4% with CKD Stage 4) and a mean baseline serum bicarbonate 
level of 17.7 mEq/L (range of 14.1 to 20.4 mEq/L).  Subjects had baseline comorbidities 
common in CKD patients, including hypertension (93.3%), diabetes (69.6%), left ventricular 
hypertrophy (28.9%), and congestive heart failure (21.5%).  As would be expected in a CKD 
Stage 3 – 4 population, nearly all study subjects had indications for sodium restriction:  
hypertension (93.3%), congestive heart failure (21.5%), peripheral edema (14.1%) and use of 
diuretics (42.2%).  As discussed in Section 1.2, since TRC101 does not contain a counterion, 
TRC101 administration does not result in sodium load and therefore enrollment of such 
subjects was appropriate. 
1.4.1.1 
Safety 
A 14-day treatment with TRC101, at doses of 1.5, 3 or 4.5 g BID, or 6 g QD, appeared to be 
safe and generally well tolerated.  In the 135 subjects who participated (104 subjects in the 


TRC101 
 
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Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
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TRC101 combined group and 31 subjects in the placebo group), there were no deaths, 
adverse events resulting in treatment discontinuation, or serious adverse events (SAEs).  The 
overall incidence of treatment-emergent adverse events (TEAEs) was 53.8% in the TRC101 
combined group (26.9% assessed as related to study drug) and 45.2% in the placebo group 
(12.9% assessed as related to study drug).  The majority of reported TEAEs were mild in 
severity: 44.2% in the TRC101 combined group (26.0% assessed as related to study drug) 
and 35.5% in the placebo group (12.9% assessed as related to study drug).  Fewer TEAEs 
were reported as moderate: 9.6% in the TRC101 combined group (1.0% assessed as related 
to study drug) and 9.7% in the placebo group (none assessed as related).  No severe AEs 
were reported in either treatment group. 
The most common adverse events (≥ 5% incidence) in the TRC101-treated subjects were 
diarrhoea (20.2%), headache (7.7%), constipation (6.7%), and hyperglycaemia (6.7%).  The 
most common adverse events in the placebo-treated subjects were diarrhoea (12.9%), 
glomerular filtration rate decreased (6.5%), blood glucose increased (6.5%), and 
hypoglycaemia (6.5%).  No event appeared to be dose-related.  
GI adverse events were the most commonly reported in TRC101-treated subjects, which is 
consistent with a non-absorbed drug acting primarily within the GI tract; all GI events were 
mild or moderate in severity.  Diarrhoea was the most common adverse event; all events 
were mild, self-limited, of short duration, often resolving while study treatment was ongoing, 
and none required treatment or resulted in discontinuation of study drug or early withdrawal 
from the study.  Diarrhoea events exhibited no apparent dose response, occurring in 36.0%, 
12.0%, 23.1% of subjects in the 1.5, 3, and 4.5 g BID TRC101 dose groups, respectively, and 
in 10.7% of subjects in the 6 g QD TRC101 group.  In the pooled placebo group diarrhoea 
occurred in 12.9% of subjects.  Given the small numbers, there is likely no difference 
between the groups. 
No trends suggested an off-target effect of TRC101 on other electrolytes (i.e., sodium, 
potassium, magnesium, calcium or phosphate).  No treatment-related effect on serum 
chloride levels or any effect on urine electrolytes was observed.  No subject experienced 
increases in serum bicarbonate that resulted in metabolic alkalosis (i.e., serum bicarbonate 
> 29 mEq/L).  In addition, there were no trends suggesting an effect of TRC101 on renal 
function, liver function, lipids, vital signs or ECG intervals. 
For additional details regarding the safety data from Study TRCA-101, see the TRC101 
Investigator’s Brochure. 
1.4.1.2 
Efficacy 
Over a 2-week treatment period, TRC101 significantly increased serum bicarbonate levels in 
the study population of CKD patients with baseline serum bicarbonate levels ranging from 
14.1 to 20.4 mEq/L.  TRC101 had a rapid onset of action (i.e., statistically significant 
increase in mean within group CFB in serum bicarbonate; p < 0.0001) within the first 24 – 


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
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48 hours following the initiation of treatment for all TRC101 dose groups combined.  The 
onset of action for between-group differences (active vs. placebo) appeared to occur between  
48 – 72 hours after the initiation of treatment with TRC101.  At Day 4 (72 hours after the 
first dose of TRC101), the mean increase in serum bicarbonate from baseline for each 
TRC101 group was 1 – 2 mEq/L:  1.5 g BID (p = 0.0011); 3 g BID (p = 0.0001); 6 g QD (p = 
0.0003); 4.5 g BID (p < 0.0001).  
At Day 15, all active doses/dosing regimens evaluated (1.5, 3 and 4.5 g TRC101 BID, and 
6 g TRC101 QD) showed statistically significantly (p < 0.0001) increased mean serum 
bicarbonate levels from baseline by approximately 3 – 4 mEq/L and each TRC101 dose 
increased serum bicarbonate levels to a significantly (p < 0.0001) greater extent than placebo.  
The observed increase in serum bicarbonate in each TRC101 dose group did not appear to be 
dose- or dosing regimen-dependent, except for potentially earlier onset of action in the 
highest TRC101 group, 4.5 g BID. 
After 2 weeks of treatment, the TRC101 6 g QD dose group demonstrated a similar increase 
from baseline in serum bicarbonate compared to the TRC101 3 g BID dose group 
(3.51 mEq/L versus 2.98 mEq/L, respectively), and the difference between the QD and BID 
dosing regimens was not statistically significant (p = 0.3408). 
Figure 1 illustrates the steady increase in mean serum bicarbonate observed in all TRC101 
dose groups during the 14-day treatment period with a mean increase at the end of treatment 
of approximately 3 to 4 mEq/L across all active dose groups.  The slope of serum bicarbonate 
increase remained constant in all TRC101 dose groups, with no evidence of serum 
bicarbonate reaching a plateau at the end of 2-week treatment.  Therefore, the maximal effect 
of each TRC101 dose tested in Study TRCA-101 has not yet been determined.  Serum 
bicarbonate levels in the placebo group remained essentially unchanged throughout the study, 
suggesting that the diet with a controlled protein (0.66 g/kg/day on average) and cation/anion 
content administered in the clinical research unit matched well with what the subjects ate at 
home and, therefore, had no significant impact on their serum bicarbonate values. 
The 2-week treatment period in study TRCA-101 was followed by a 2-week follow-up 
period during which subjects were off treatment.  Following discontinuation of TRC101, 
serum bicarbonate levels decreased within 2 days and were near their baseline values within 
9 days (Figure 1).  These results underscore the rapid reversibility of TRC101 effect.  In 
addition, the data demonstrate that chronic nature of the underlying metabolic acidosis in 
these CKD patients and suggest that continued treatment with TRC101 would be needed to 
maintain elevated serum bicarbonate level. 


TRC101 
 
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Figure 1 
Mean Change in Serum Bicarbonate by Treatment Group Over Time 
 
BID = twice daily; BL = baseline; QD = once daily; SE = standard error 
 
For additional details regarding the efficacy data from Study TRCA-101, see the TRC101 
Investigator’s Brochure. 
 
Description and Justification for Route of Administration, Dosage, 
Dosage Regimen and Treatment Period 
In this study, TRC101 will be administered orally, as a powder suspended in water, QD, with 
food, at approximately the same time each day.  TRC101 is a high molecular weight, non-
absorbed polymer with a site of action in the GI tract; thus, oral administration is the 
appropriate route.  Since doses of 3, 6 and 9 g QD TRC101 will be used in the parent study, 
TRCA-301, these doses will also be used in this extension study.  Placebo QD will be used as 
a comparator.  At each study visit (see Schedule of Events, Appendix 1), blood bicarbonate 
will be evaluated, and dose(s) of study drug and/or oral alkali supplement (if applicable) will 
be adjusted as described in Appendix 2 to attempt to maintain bicarbonate in the normal 
range during the 40-week Treatment Period.   
A QD dosing regimen was chosen for this study for consistency with the parent study, 
TRCA-301.  This dosing regimen is more convenient for study subjects than a BID dosing 
regimen and therefore may result in greater compliance during the 40-week Treatment 
Period.  
The duration of the Treatment Period in this study is 40 weeks so as to provide up to 1 year 
of continuous exposure data from those subjects who received 12 weeks of treatment with 
TRC101 in the parent study, TRCA-301.   


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Additional details on the rationale for the doses, dosing regimen and treatment period are 
provided in Section 3.2.   
 
Description of Population to be Studied 
This study is a long-term, blinded, placebo-controlled extension of Study TRCA-301 (the 
parent study).  To have been enrolled in the parent study, subjects must have been non-
dialysis dependent CKD patients (eGFR 20 to 40 mL/min/1.73m2) with chronic metabolic 
acidosis (blood bicarbonate 12 to 20 mEq/L).  At least 50% of subjects must have had a 
blood bicarbonate level of 12 to 18 mEq/L.  Subjects who completed the 12-week Treatment 
Period in Study TRCA-301 and attended the Week 12 Visit in that study are eligible for 
enrollment in this extension study if their blood bicarbonate value at the Week 12 Visit is     
≥ 12 mEq/L and they meet all other eligbility criteria.  Subjects will continue blinded study 
drug (TRC101 or placebo) treatment in the extension study at a dose based on their blood 
bicarbonate level as described in Appendix 2.   
To make the study generalizable to the intended target population of CKD patients, this study 
allows the use of common “background” medications taken by patients with CKD and 
metabolic acidosis (e.g., oral alkali supplements, diuretics, renin angiotensin aldosterone 
system [RAAS] inhibitors).  Restrictions regarding the use of oral alkali therapy are different 
from those in the parent study, TRCA-301.  While both studies allow enrollment of subjects 
concurrently taking a stable dose of oral alkali, because the primary endpoint measure in 
Study TRCA-301 is blood bicarbonate level, no changes to concomitant oral alkali are 
allowed in that study.  In contrast, to minimize the long-term sodium load and to allow for 
management of subjects with eGFR 20 to 40 mL/min/1.73m2, subjects in this extension study 
will discontinue background alkali supplementation if their blood bicarbonate is above the 
lower limit of the normal range (≥ 22 mEq/L; see Appendix 2).  Neither Study TRCA-301 
nor Study TRCA-301E allows increase in oral alkali supplement dose or initiation of new 
oral alkali therapy.  Investigators will be advised to avoid changing RAAS inhibitor doses 
during this study, when possible; however, as in the parent study, dose changes necessary for 
the management of comorbidities or acute events (e.g., hyperkalemia, worsening 
hyperkalemia) are not prohibited.  In addition, Investigators will be advised to avoid 
changing diuretic doses when possible; however, dose changes necessary for the 
management of comorbidities or acute events (e.g., heart failure, acute kidney injury) are not 
prohibited.  The rationale for the above restriction on background concomitant medications 
that may affect eGFR in this study is to gain experience with this aspect of the study design 
which may be used in a future study of TRC101 evaluating the rate of eGFR decline.  This 
study allows the concomitant use of other binder drugs (e.g., lanthanum carbonate, 
colesevelam, cholestyramine or sodium or calcium polystyrene sulfonate, calcium acetate, 
sevelamer, patiromer, bixalomer, and other polymeric drugs) with a ≥ 4-hour separation from 
the study drug dose.    




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on a dose interruption.  Enrollment in Study TRCA-301E is defined by completion of the 
enrollment procedure in the interactive response technology (IRT) system.  The enrollment 
procedure in the IRT system will be performed once subjects have completed participation in 
Study TRCA-301, they have provided informed consent for the extension study, and the 
Investigator (or designee) has determined they have met all TRCA-301E eligibility criteria. 
The starting dose of blinded study drug, study drug dose titration, and use of oral alkali 
supplements (for those subjects who were taking them at the Week 12 Visit), are described in 
the titration algorithm (Appendix 2).  The starting dose of study drug in the 40-week 
Treatment Period will be the same as the ending dose of study drug in Study TRCA-301, 
unless the subject meets the criteria for a dose adjustment at the Week 12 visit as described in 
Appendix 2.  
Subjects will return to the study center for study visits at Weeks 14, 16, 20, 24, 28, 34, 40, 
46, and 52 for assessments.  Additional unscheduled study visits may be necessary following 
study drug dose adjustments.   
Subjects with a confirmed blood bicarbonate level < 12 mEq/L at any time during the study 
will be evaluated by the Investigator for new acute acidotic processes and discussed with the 
Medical Monitor.  The Medical Monitor will determine whether the subject may continue in 
the study.   
No addition or up-titration of any other concomitant therapy to raise blood bicarbonate will 
be allowed.  Subjects who enter the study at the Week 12 Visit on an oral alkali supplement 
will be taken off the supplement if their blood bicarbonate is within or above the normal 
range as described in Appendix 2.  If, after removal of alkali supplementation, blood 
bicarbonate falls below the normal range, the study drug dose will be increased in a step-wise 
fashion to the maximum dose of 3 packets QD and, if blood bicarbonate is still below 
normal, the oral alkali therapy the subject was taking at the Week 12 Visit will be re-instated 
at the same dose the subject was taking at the Week 12 Visit.   If the Investigator judges that 
re-starting alkali treatment poses a safety risk, the risk should be documented.  In this 
situation, alkali will not be re-started. 
Dosing of oral concomitant medications and study drug will be separated by at least 4 hours 
throughout the Treatment Period in this study.   
Subjects who complete the Treatment Period will enter the 2-week Follow-up Period and 
return to the study site for two visits:  Follow-up 1 (Week 53) and Follow-up 2 (Week 54), 
for adverse event (AE) collection, fasting blood draws and safety assessments as outlined in 
the Schedule of Events.  Subjects who withdraw from the study prematurely (i.e., prior to the 
Week 52 Visit) will undergo an Early Termination (ET) Visit, during which all Week 52 
Visit assessments will be performed, and will attend Follow-up 1 and 2 Visits in 1 and 
2 weeks, respectively.  Subjects who discontinue study drug prior to the Week 52 Visit will 


TRC101 
 
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Clinical Study Protocol: TRCA-301E 
 
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be contacted by telephone 40 weeks after their Week 12 Visit to ascertain vital status and 
renal status (i.e., receiving renal replacement therapy or not).   
Blood draws for bicarbonate measurements will be performed when subjects are in a fasted 
state (at least 4 hours) and at approximately the same time of day for each subject. 
Assessments will be performed at the time points indicated in the Schedule of Events 
(Appendix 1).  Safety assessments will include:  AEs, vital signs (blood pressure, heart rate, 
temperature and respiratory rate); physical examination (including body weight); clinical 
laboratory testing (Table 2), and 12-lead ECGs.  The main assessment to evaluate the 
durability of effect of TRC101 will be blood bicarbonate level. 
 
Rationale for Study Design and Control Group 
3.2.1 
Study Design 
The purpose of this study is to define the long-term safety profile of TRC101 and to evaluate 
the durability of its effect.  The study is a 40-week, blinded, placebo-controlled extension 
that will enroll subjects who complete the randomized, double-blind, placebo-controlled, 
Phase 3 study, TRCA-301 (the parent study).  After the last subject completes the parent 
study and the TRCA-301 clinical database is locked, Tricida personnel and the blinded 
statistical group (i.e., not associated with the Data Monitoring Committee [DMC]) will 
become unblinded to treatment assignment.  Importantly, all Investigators, subjects, site 
personnel and CRO personnel who were blinded in the parent study, TRCA-301, will remain 
blinded until the clinical database is locked for this extension study. 
Please see Section 1.5 for a discussion of the rationale for the starting study drug dose, study 
drug dose titration regimen and algorithm for discontinuing concomitant oral alkali 
supplements in subjects who are taking them at the Week 12 Visit.  Please see Section 1.6 for 
a discussion of the rationale for the blood bicarbonate inclusion criteria for this extension 
study. 
3.2.2 
Safety Monitoring 
The design and conduct of TRCA-301E includes appropriate monitoring for safety and risk 
mitigation.  The Medical Monitor will review safety data on an ongoing basis to identify 
potential adverse safety trends.  Central laboratory reports will contain flags that will alert 
investigators and Tricida personnel to abnormal, critical, and exclusionary laboratory values, 
and the Medical Monitor will routinely review these results. 
A DMC, established for the parent study, TRCA-301, will continue to review safety during 
this study.  The DMC will comprise, at a minimum, one biostatistician and two clinicians, at 
least one of whom is a nephrologist.  The responsibilities of the DMC will be defined in a 
written charter, which will include the frequency, format and structure of DMC meetings, 


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and the use of treatment codes.  Study enrollment and study activities will continue during 
DMC safety reviews.  The Chairperson of the DMC will be a nephrologist. 
The DMC will be supported by an independent statistical group which will prepare unblinded 
analyses for the DMC and will have no role in preparing the Statistical Analysis Plan (SAP) 
after the study has started enrolling subjects.  A separate, blinded statistical group (i.e., not 
associated with the DMC) will be responsible for producing and finalizing the SAP and 
executing final data analysis of the study (this group will become unblinded when the clinical 
database for parent study, TRCA-301, is locked).   
TRC101, which is a high molecular weight, counterion-free polymer, is not absorbed and 
does not circulate systemically.  Experience in Study TRCA-101 has shown that the 
anticipated risks of treatment with TRC101 are non-serious, mild to moderate, short-lived 
diarrhea or constipation, that generally resolves while treatment is ongoing.  Adverse events 
will be monitored throughout the study. 
Risks of TRC101 effects on non-target substances (e.g., serum potassium, magnesium, 
calcium, phosphate, lipids) were not evident in the clinical data from Study TRCA-101; 
nevertheless, close attention will be paid to electrolyte levels, which will be assessed at every 
study visit. 
No cases of alkalosis (i.e., serum bicarbonate > 29 mEq/L) were observed in Study 
TRCA-101.  However, an exaggerated pharmacological effect of TRC101 is theoretically 
possible, given the longer duration of treatment in this study.  While kidneys are generally 
efficient at excreting excess bicarbonate, the rapidity with which this can happen is impaired 
at low levels of renal function.  To avoid prolonged periods of blood bicarbonate above the 
normal range, blood bicarbonate levels will be measured at every study visit and the study 
drug dose will be interrupted if blood bicarbonate is confirmed to be > 30 mEq/L.  Study 
TRCA-101 has shown that the effects of TRC101 are rapidly reversible, with the majority of 
the effect lost within approximately 1 week of treatment discontinuation and with serum 
bicarbonate returning essentially back to baseline within approximately 2 weeks of treatment 
discontinuation.  In addition, the parent study, TRCA-301, excludes patients with higher risk 
of inhibition of respiratory response to metabolic acidosis (i.e., chronic obstructive 
pulmonary disease that is treated with chronic oral steroids, that requires the subject to be on 
oxygen, or that required hospitalization within the previous 6 months). 
Investigators are to evaluate subjects whose blood bicarbonate decreases to < 12 mEq/L for 
possible causes of acute-on-chronic acidosis and discuss these cases with the Medical 
Monitor regarding continuation of the subject in the study. 
 
Study Duration 
The maximum study duration is anticipated to be 42 weeks per subject, including the 40-
week Treatment Period and 2-week Follow-up Period.  Including the 12-week exposure to 
study drug in the parent study, TRCA-301, subjects randomized to TRC101 in Study TRCA-


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301 who complete the Treatment Period in Study TRCA-301E will have a total of 1-year of 
exposure to TRC101. 
4 
STUDY POPULATION SELECTION AND WITHDRAWAL 
 
Study Population 
This study will enroll subjects with non-dialysis dependent CKD and a blood bicarbonate 
value of ≥ 12 mEq/L who completed the 12-week Treatment Period in Study TRCA-301 (the 
parent study) and attended the Week 12 Visit.  Study TRCA-301 was designed to enroll 
approximately 210 male and female adult subjects with CKD (eGFR of 20 to 
40 mL/min/1.73 m2) and low blood bicarbonate (12 to 20 mEq/L).  At least half of the 
subjects enrolled in the parent study were required to have a blood bicarbonate level of 12 to 
18 mEq/L. 
 
Inclusion Criteria 
Each subject must meet ALL of the following criteria to be enrolled in this safety extension 
study. 
1. 
Have provided written informed consent prior to participation in the study. 
2. 
Have completed the 12-week treatment period and attended the Week 12 Visit in the 
parent study TRCA-301. 
3. 
Have a blood bicarbonate value of ≥ 12 mEq/L at the Week 12 Visit in Study TRCA-
301, based on onsite measurement using the i-STAT point-of-care device.  
4. 
Have adequate peripheral venous access for blood draws. 
5. 
Women who are of childbearing potential must have negative pregnancy test at the 
Week 12 Visit and be willing to use an acceptable method of birth control until 1 
month after study completion.  Acceptable methods include hormonal contraception 
(oral contraceptives, patch, implant, and injection), intrauterine devices, double 
barrier methods (e.g., vaginal diaphragm, vaginal sponge, condom, spermicidal jelly), 
sexual abstinence or a vasectomized partner.  Women who are surgically sterile with 
documentation of such, or who are at least 1-year post-last menstrual period and > 55 
years of age, are considered not to be of childbearing potential.   
 
Exclusion Criteria 
Subjects who meet ANY of the following criteria will be excluded from participation in this 
study. 
1. 
Have any level of low blood bicarbonate at the Week 12 Visit that, in the opinion 
of the Investigator, requires emergency intervention or evaluation for an acute 
acidotic process. 


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2. 
Required dialysis for acute kidney injury or worsening CKD during the parent 
study TRCA-301. 
3. 
Planned initiation of renal replacement therapy (dialysis or transplantation) within 
6 months following study entry. 
4. 
Have a history or current diagnosis of clinically significant diabetic gastroparesis 
(based on Investigator’s judgment) or a history of bariatric surgery. 
5. 
Have a history or current diagnosis of bowel obstruction, swallowing disorders, 
severe gastrointestinal (GI) disorders, inflammatory bowel disease, major GI 
surgery, or active gastric/duodenal ulcers. 
6. 
Have a serum calcium ≤ 8.0 mg/dL at the Week 10 Visit in the parent study, 
TRCA-301. 
7. 
Have active cancer during the 1 year prior to the Week 12 Visit, other than non-
melanoma skin cancer, or cancer that is currently being treated or will be treated 
during the study.  Subjects with cancers that are being treated with hormonal 
therapy only may be permitted with approval of the Medical Monitor. 
8. 
Inability to consume the study drug, known allergy to the study drug or otherwise 
comply with the protocol. 
9. 
Have, in the opinion of the Investigator, any medical condition, uncontrolled 
systemic disease or serious concurrent illness that would significantly decrease 
study compliance or jeopardize the safety of the subject or affect the validity of 
the study results. 
 
Subject Withdrawal 
Within the provisions of informed consent and good clinical judgment with respect to the 
subject’s safety, every attempt should be made to have subjects complete both the Treatment 
Period and Follow-up Period.  All subjects will be informed that they have the right to 
withdraw from the study at any time.  If a subject discontinues from the study prematurely 
the reason given must be fully evaluated, if possible, and recorded appropriately in source 
documents and the electronic case report form (eCRF).  Subjects withdrawn from the study 
prematurely, for reasons other than withdrawn consent, will be followed for safety for 
2 weeks after receiving the last dose of study drug.  All subjects who discontinue study drug 
dosing prior to the Week 52 Visit will be contacted by telephone 40 weeks after their Week 
12 Visit to ascertain vital status and renal status (receiving renal replacement therapy or not).  
If the subject is being withdrawn because of an AE, that AE should be indicated as the reason 
for withdrawal.  The Investigator and the Medical Monitor may exercise their medical 
judgment to discontinue a subject’s participation in the study at any time if medically 
necessary.  
Subjects who meet any of the following criteria at any time during the study must be 
withdrawn from the study and should be medically managed as per standard of care by the 
Investigator: 


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• 
Occurrence of any AE, intercurrent illness or abnormality in laboratory assessment 
results that, in the opinion of the Investigator or Medical Monitor, warrants the 
subject’s permanent discontinuation of the study drug treatment. 
• 
Treatment with a prohibited concomitant medication.  Subjects who require a 
prohibited concomitant medication for the treatment of an AE or for a short duration 
may continue on study drug treatment if approved by the Medical Monitor (see 
Section 5.9 for details). 
• 
Subject’s noncompliance, defined as refusal or inability to adhere to the study 
schedule, study drug self-administration or procedures, that cannot be rectified 
through additional training or other means. 
• 
At the request of Tricida, IRB/IEC or regulatory authority.  
• 
Withdrawal of consent by subject to participate in the study.  Subjects should be 
encouraged to complete an Early Termination Visit, even if they are withdrawing 
consent, to ensure adequate safety follow-up. 
• 
Subject is lost to follow-up (the subject did not return for visits and study personnel 
were unable to contact the subject after at least three documented attempts). 
• 
Received dialysis for more than 1 week or underwent renal transplantation. 
• 
Pregnancy.  These subjects will be followed until the outcome of pregnancy is known 
and if subject agrees (see Section 6.11). 
Subjects with a confirmed blood bicarbonate level < 12 mEq/L should be evaluated by the 
Investigator for new acute acidotic processes and discussed with the Medical Monitor.  The 
Medical Monitor will determine whether the subject may continue in the study.  Subjects 
should be maintained on their study drug dose pending discussion with Medical Monitor. 
Subjects who withdraw from the study prematurely prior to the Week 52 visit will undergo 
an ET Visit and will be asked to attend two follow-up visits.   
It is important to collect information explaining why subjects withdrew from the study.  This 
information, together with AEs occurring at those times, may be informative of the cause-
specific reasons for why some subjects remain in the study or on the assigned treatment 
while others do not.  Therefore, although subjects are not obliged to give their reason for 
withdrawing consent, the Investigator will make a reasonable effort to obtain the reason 
while fully respecting the subjects’ rights.  Reasons for withdrawal of consent, when 
provided by the subject, will be recorded in the eCRF.  The procedures described for ET 
from the study will be performed (Section 7.7) if possible.  Every reasonable effort will be 
made to contact a subject who fails to attend a Study Visit, or does not respond by telephone, 
to ensure that the subject is in satisfactory health.  The Investigator will immediately inform 
the Medical Monitor of removal or early withdrawal of a subject from the study. 
Subjects withdrawn from the study for any reason will not be replaced. 


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5 
STUDY TREATMENT(S) 
 
Description of Treatment(s) 
5.1.1 
Investigational Drug 
TRC101 is packaged in labeled packets.  Refer to the current version of the TRC101 
Investigator’s Brochure for a more detailed description of the investigational drug.  
5.1.2 
Placebo 
Placebo, which consists of 
, National Formulary (NF) Grade, is 
packaged in labeled packets. 
5.1.3 
Study Drug Dispensing, Packing and Labeling 
Study drug is shipped and dispensed in cartons (kits).  Each invidual kit of study drug has a 
unique number and contains either 8 labelled packets of TRC101 or placebo.  Each study 
drug kit is labeled and secured with a tamper evident seal.  TRC101 and placebo kits will be 
shipped to the study site where they will be stored at room temperature (15 to 25°C) in a 
secure location. 
Study drug will be dispensed by the unblinded Pharmacist or study staff member designated 
for this role by the Investigator (hereafter referred to as “the designated study staff member”) 
according to the subject’s treatment assignment in the parent study, TRCA-301.  The exact 
dispensing instructions will be provided to the designated study staff  member by the 
interactive response technology (IRT) system.   
The designated study staff member will be responsible for maintaining complete study drug 
dispensing, returning, and dosing records for each study subject enrolled at the site 
 
Treatment(s) Administered 
All subjects will initially receive TRC101 or placebo at a dose determined by their ending 
dose in the parent study, TRCA-301, and the subject’s blood bicarbonate level at the Week 
12 Visit (see Appendix 2).  The doses of TRC101 to be administered in this study are:  0, 3, 6 
and 9 g QD, corresponding to 0, 1, 2 and 3 packets of blinded study drug.  Placebo will also 
be administered in doses of 0, 1, 2 and 3 packets.  Either upon enrollent into the study or 
during the study, the blinded study drug may be interrupted per the titration algorithm. 
TRC101 or placebo will be self-administered orally as an aqueous suspension, QD, with 
food, at approximately the same time each day for 40 weeks.   
The Investigator will designate a study staff member to dispense and account for study drug.  
The first dose of study drug will be self-administered on the day of the Week 12 Visit. 


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Subjects will be instructed to take any oral concomitant treatment at least 4 hours before or 
after study drug administration.   
The last dose of study drug will be taken the day before the Week 52 Visit. 
 
Dosing Regimen 
The study drug dose titration algorithm is described in Appendix 2.  Dose titrations may only 
be performed during a clinic visit.  If the dose of study drug is changed, the subject will start 
the new dose at the time of the next dose.  Dose titrations should be performed on the basis of 
onsite i-STAT blood bicarbonate measurements only.  
Subjects who completed the 12-week Treatment Period in Study TRCA-301 and attended the 
Week 12 Visit may enroll in this extension study if their blood bicarbonate value at the 
Week 12 Visit is ≥ 12 mEq/L and they meet the other entry criteria for this study (see 
Sections 4.2 and 4.3).   Eligible subjects will start the extension study on a study drug dose 
based on their ending dose in the parent study, TRCA-301, and their blood bicarbonate level 
at the Week 12 Visit (see Appendix 2).   
Blood bicarbonate will be evaluated periodically (see Schedule of Events, Appendix 1), and 
dose(s) of study drug and/or oral alkali supplement (if applicable) adjusted as described in 
Appendix 2 to maintain blood bicarbonate in the normal range.  In general, the study drug 
dose will not be titrated if blood bicarbonate is in the normal range.  If blood bicarbonate is 
confirmed to be > 30 mEq/L at any time during the study, the study drug treatment will be 
interrupted, no study drug will be dispensed to the subject, and the subject will be invited for 
a visit in approximately 1 week to retest blood bicarbonate.  If blood bicarbonate decreases 
and the subject is still within the Treatment Period, study drug will be re-started at a lower 
dose in accordance with the titration algorithm (see Appendix 2).   
The Medical Monitor must be notified within 24 hours of confirmation of a bicarbonate value 
> 30 mEq/L.  Dose interruptions due to blood bicarbonate elevations should be performed on 
the basis of i-STAT measurements, except in unusual situations when they may be based on 
confirmed non-i-STAT blood bicarbonate values > 30 mEq/L, e.g., if  i-STAT values cannot 
be obtained because the subject is hospitalized. 
No addition or up-titration of any concomitant therapy to raise blood bicarbonate will be 
allowed.  Subjects who enter the study on an oral alkali supplement will be taken off the 
supplement if their blood bicarbonate is ≥ 22 mEq/L as described in Appendix 2.  If, after 
removal of alkali supplementation, blood bicarbonate falls below the normal range, the study 
drug dose will be increased in a step-wise fashion to the maximum dose of 3 packets QD and, 
if blood bicarbonate is still below normal, the same oral alkali therapy the subject was taking 
at the Week 12 Visit will be re-instated at the same dose the subject was taking at the Week 
12 Visit.  If the Investigator judges that re-starting alkali treatment poses a safety risk, the 
risk should be documented.  In this situation, alkali will not be re-started. 


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Missed Doses 
Contact the Medical Monitor if a subject has missed more than seven consecutive doses of 
study drug for any reason. 
 
Selection and Timing of Dose for Each Subject 
Subjects will continue to receive the study drug (TRC101 or placebo) to which they were 
randomized in the parent study, TRCA-301.  The dose of study drug will be adjusted in a 
blinded fashion based on blood bicarbonate level as described in Appendix 2.  Study drug 
will be administered as an oral suspension in water with food, QD, at approximately the same 
time each day, from the Week 12 Visit through 1 day prior to the Week 52 Visit.  If a dose of 
study drug is adjusted, the subject will start the new dose at the time of the next dose.  
 
Method of Assigning Subjects to Treatment Groups 
Subjects will remain in the same treatment group (TRC101 or placebo) to which they were 
assigned in Study TRCA-301. 
 
Blinding 
As in Study TRCA-301, in this study 
 
 
an unblinded study staff member for handling (dispensation and collection) of the study drug.  
These individuals will be responsible for dispensing study drug and collecting used and 
unused study drug containers.  If the study drug dose needs to be adjusted or interrupted per 
the titration algorithm (see Appendix 2), such adjustments will be performed in a blinded 
manner in both TRC101 and placebo treatment groups.  The unblinded study staff member 
will not have any other responsibilities for the study except for performing study drug 
dispensation and collection, assessing dosing compliance and performing drug accountability 
and entering related data in electronic case report forms (eCRFs).  The subjects, 
Investigators, site personnel (including all those involved in collection of safety and efficacy 
information) and CRO staff (except for those responsible for monitoring of unblinded data) 
will be blinded to the subject’s treatment assignment.  To avoid unblinding of blinded site 
personnel to treatment assignment, strict blinding procedures related to drug accountability 
will be adhered to at the site level for this study, similar to those utilized for the parent study. 
Specifically, designated site staff, who have no other responsibilities for the study, will be 
responsible for study drug accountability and collection of used and unused study drug. The 
division of responsibilities between the unblinded staff and other study staff (who are blinded 
to treatment assignment in the parent study, TRCA-301) are detailed in the study Blinding 
Plan. 
After the last subject completes the parent study and the TRCA-301 clinical database is 
locked, Tricida personnel and the blinded statistical group (i.e., not associated with the Data 
Monitoring Committee) will become unblinded to treatment assignments.  Importantly, all 


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Investigators, subjects, site personnel and CRO personnel who were blinded in the parent 
study, TRCA-301, will remain blinded until the clinical database is locked for this extension 
study.   
In case of a medical emergency, the Investigator may obtain the treatment assignment for the 
subject from the IRT system if it is considered important to the management of the 
emergency.  In such cases, the Investigator must submit a written report, including all 
pertinent details, to a Medical Monitor within 24 hours of the unblinding.  The Investigator 
should make every reasonable attempt to contact a Medical Monitor before unblinding the 
subject. 
 
Concomitant Therapy 
Information on concomitant medications (including prescription, over-the-counter, herbal 
and naturopathic remedies, etc.) will be collected for this extension study beginning at the 
Week 12 Visit and continuing for the duration of the study (including ET) through 2 weeks 
following Week 52 for subjects completing the study and through 2 weeks following the ET 
visit for subjects discontinuing study drug treatment prior to Week 52.  A therapy will be 
considered a concomitant medication if it is administered at any time after the Week 12 Visit 
and before the completion of the final study visit.   
Subjects will be instructed to take any oral concomitant treatment at least 4 hours before or 
after study drug administration. 
If a subject requires a medication, or a change in the dose of a current medication, for 
treatment of any condition or AE that occurs during the study (including the Treatment and 
Follow-up Periods), such medication(s), or the new doses, and the AE(s) will be recorded on 
the eCRF. 
 
Restricted Medications 
In general, subjects should continue on regular doses of their usual medications.  Subjects 
who are receiving or who have recently received restricted drugs or drug classes prior to the 
Week 12 Visit should adhere to restrictions as described in Table 1. The rationale for the 
restrictions on concomitant medications is provided in Section 1.6.   
Subjects who require a prohibited concomitant medication for the treatment of an AE or for a 
short duration may continue on study drug treatment if approved by the Medical Monitor. 
If a change in antihypertensive drug is required, the Investigator should, if possible, avoid 
adding or changing the doses of medications that cause changes in serum electrolytes 
(e.g., diuretics and RAAS inhibitors); however, dose changes of these types of medications 
necessary for the management of comorbidities or acute events (e.g., hyperkalemia or 
worsening hyperkalemia, heart failure, acute kidney injury) are not prohibited. 


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Table 1 
Restricted Prior and Concomitant Medications 
Drug or Drug Class 
Week 12 Visit 
During the Study 
Investigational medications 
Not allowed 
Not allowed 
Potassium binders (Veltassa 
[patiromer], Kaexalate (sodium 
polystyrene sulfonate]) 
Not allowed 
Use is allowed with dose separation 
window of ≥ 4 h from the study drug 
dose 
Other polymeric binder drugs a  
Not allowed 
Use is allowed with dose separation 
window of ≥ 4 h from the study drug 
dose 
Sodium bicarbonate, potassium 
citrate, sodium citrate or other 
alkali therapy 
Stable dose 
No initiation of new alkali therapy or 
alkali dose increases beyond the 
Week 12 Visit dose.  Instructions for 
discontinuation and re-starting the 
original dose is provided in Appendix 2 
Non-ophthalmic carbonic 
anhydrase inhibitors b 
Stable dose 
Keep dose stable, if possible 
Antacids, H2-blockers, proton 
pump inhibitors, calcium 
supplements c 
Stable dose 
Keep dose stable, if possible 
RAAS inhibitors d 
Stable dose 
Keep dose stable, if possible, but dose 
changes necessary for the management 
of comorbidities or acute events (e.g., 
hyperkalemia/worsening hyperkalemia) 
are not prohibited 
Diuretics e 
Stable dose 
Keep dose stable, if possible, but dose 
changes necessary for the management 
of comorbidities or acute events (e.g., 
heart failure, acute kidney injury) are not 
prohibited 
 “Stable dose” is defined as no starting or stopping of these medications and no change in dose.  For diuretics, 
dose changes of up to ± 50% relative to the Week 12 dose is considered “stable”.   
a  
Lanthanum carbonate, colesevelam, cholestyramine, sevelamer, bixalomer, and other polymeric drugs. 
b  
Examples of carbonic anhydrase inhibitors include acetazolamide, methazolamide, dorzolamide, 
brinzolamide, zonisamide, topiramate, dichlorphenamide. 
c  
Antacid medications include milk of magnesia, proton pump inhibitors (e.g., omeprazole, 
pantoprazole, esomeprazole, lansoprazole), and H2 receptor antagonists (e.g., cimetidine, ranitidine, 
famotidine). Calcium supplements (e.g., calcium carbonate, calcium citrate, calcium chloride). 
d  
Examples of RAAS inhibitors:  lisinopril, enalapril, perindopril, losartan, valsartan, candesartan, 
spironolactone, eplerenone. 
e  
Examples of diuretic drugs:  furosemide, torsemide, hydrochlorthiazide, metolazone. 
 
Restrictions 
5.10.1 
Fluid and Food Intake  
For laboratory measurements requiring fasting (including all measurements of blood 
bicarbonate), a minimum period of fasting (water allowed) should be at least 4 hours.  


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Subjects should be questioned about their most recent food intake at each visit and the 
information documented in the source documents. 
5.10.2 
Management of Acidemia (Use of Alkali Therapy) 
Subjects may be on a stable dose of oral alkali therapy in this study; however, this dose must 
be kept the same as at the Week 12 Visit and new oral alkali therapies may not be initiated 
during the study.  If the Investigator judges that a subject requires treatment for sustained, 
clinically-significant worsening of metabolic acidosis during the study, diet counseling (i.e., 
reduced protein intake, vegetarian/vegan protein sources) may be implemented as clinically 
appropriate and in agreement with the Medical Monitor.  Subjects with confirmed blood 
bicarbonate decrease < 12 mEq/L should be investigated for possible causes of acute-on-
chronic acidosis and the Investigator should discuss these cases with the Medical Monitor.  
The subject’s study drug dose should be maintained pending discussion with the Medical 
Monitor. 
 
Treatment Compliance 
The unblinded study staff member will assess subjects’ treatment compliance at every study 
visit during the 40-week Treatment Period to confirm that the subject is taking study drug 
according to the protocol instructions and to document compliance in the eCRF as detailed in 
the eCRF completion guidelines.  Compliance will be assessed on the basis of the assigned 
study drug dose, the duration of treatment, and the quantity of dispensed and returned 
containers (used and unused).  Subjects will be instructed to save their opened/empty (used) 
study drug containers and bring them to the next study visit for compliance assessment along 
with any unopened containers.  The unblinded study staff member will not share any 
potentially unblinding information with the subject or any other party as described in Section 
5.7. 
 
Storage and Accountability 
All study drug supplies must be stored in a secure location under the proper storage 
conditions, with access restricted to the designated study staff only.  Study drug  must be 
stored at room temperature (15 to 25 °C). 
Site personnel will verify and acknowledge receipt of study drug by signing and returning all 
required forms.  All study drug dispensed to subjects must be accurately captured in the drug 
accountability records (forms and/or logs) maintained at the study site.  A copy of these 
records must be returned to Tricida at study completion for drug reconciliation purposes.  
Study drug designated for this clinical study must not be administered to any subject other 
than those enrolled in this specific investigation, and may not be utilized for any laboratory 
or animal research.  Subjects should be instructed to return all study drug dispensed to them 
(including empty containers) at each study visit during the Treatment Period.  All study drug 
containers (including used, empty, unused, and expired) will be retained until the Study 


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Close-Out Visit unless requested earlier by Tricida.  Tricida will provide instructions on 
where to return all used and unused study drug containers. 
6 
STUDY PROCEDURES 
 
Informed Consent 
A signed informed consent form (ICF) must be obtained from each subject prior to any 
study-mandated procedure.  Week 12 study procedures that are outlined in the parent study 
protocol, TRCA-301, will be performed under the parent study ICF. 
 
Concomitant Medications 
Information on concomitant medications (including prescription, over-the-counter, herbal 
and naturopathic remedies, etc.) will be collected at the Week 12 Visit (as part of the parent 
study, TRCA-301) and will continue to be collected for the duration of this study.  The 
Investigator or qualified designee will record all findings in source documents and on the 
concomitant medications eCRF. 
 
Vital Signs 
The Investigator or qualified designee will measure vital signs (systolic/diastolic blood 
pressure, respiratory rate, heart rate and temperature) at time points specified in the Schedule 
of Events (Appendix 1).  The vital sign measurements performed at the Week 12 Visit will 
be conducted as part of the parent study, TRCA-301.  The same method for measurement of 
temperature (e.g, oral, tympanic, axillary) should be used throughout the study for an 
individual subject.  Subjects must be in a supine, semi-fowler’s (semi-recumbent) or seated 
position in a rested and calm state for at least 5 minutes before blood pressure assessments 
are conducted.  The same position must be used for blood pressure measurements for a given 
subject at each time point.  Respiratory rate will be assessed by a full minute count. 
All measurements will be recorded on the vital signs eCRF.  Abnormal measurements may 
be repeated at the discretion of the Investigator and must be recorded on the vital signs 
eCRF.  When collection of vital signs, ECG, and/or blood samples is required at the same 
visit, vital signs should be performed first, followed by ECG and collection of blood samples. 
 
Complete Physical Examination, Including Body Weight 
The Investigator or qualified designee will perform a complete physical examination 
(including CV, lungs and chest, head and neck, abdomen, musculoskeletal, skin and 
neurological systems; genitourinary examination not required) and record body weight at the 
time points indicated in the Schedule of Events (Appendix 1).  The physical examination 
performed at the Week 12 Visit will be conducted as part of the parent study, TRCA-301.  
Pre-dose abnormal physical examination findings will be reported in the source documents 
and in the medical history eCRF.  Additional examinations should be performed where 


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clinically appropriate.  Any new clinically significant physical examination abnormality 
identified during the study should be reported as an AE and documented on the AE eCRF. 
 
Repeated Chair Stand Test 
The Investigator or qualified designee will administer the repeated chair stand test 
(Guralnik; 1995) at the time points indicated in the Schedule of Events (Appendix 1).  The 
repeated chair stand test at the Week 12 Visit will be conducted as part of the parent study, 
TRCA-301.  The repeated chair stand test in this study will be used as a measure of lower 
extremity muscle strength.  Site staff will be trained to perform the testing in a consistent 
manner.  The procedure details are provided in the Study Reference Manual. 
 
KDQOL  
The Investigator or qualified designee will collect  subjects’ answers to the Kidney Disease 
and Quality of Life (KDQOL) Question 3 items (daily activities) at the time points indicated 
in the Schedule of Events (Appendix 1).  The KDQOL assessment at the Week 12 Visit will 
be conducted as part of the parent study, TRCA-301.  The procedure details are provided in 
the Study Reference Manual. 
 
12-Lead Electrocardiograms 
During the study, 12-lead ECGs will be performed at the time points indicated in the 
Schedule of Events (Appendix 1).  The ECG performed at the Week 12 Visit will be 
conducted as part of the parent study, TRCA-301.  If a subject has serum potassium 
≥ 6.0 mEq/L at any time, ECGs will be collected more often, as clinically needed, until 
serum potassium is < 6.0 mEq/L. 
The subject must be in supine position in a rested and calm state for at least 5 minutes before 
the ECG assessment is conducted.  Subjects who are unable to be in the supine position 
should be in the most recumbent position possible. 
All ECGs should be performed with a standardized method, in triplicate, and approximately 
30 seconds apart, prior to blood draws or other invasive procedures.  Each ECG reading must 
include the following measurements:  heart rate and QRS, QT, RR, and PR intervals.  All 
measurements will be recorded on the ECG eCRF. 
The Investigator or designated site physician will review all ECGs.  Once signed, the original 
ECG tracing will be retained with the subject’s source documents.  At the request of Tricida, 
a copy of the original ECG will be made available.  Clinically significant ECG abnormalities/ 
changes meeting a definition of an AE (see Section 6.10.1) should be recorded on the AE 
eCRF. 


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Clinical Laboratory Tests 
6.8.1 
Laboratory Parameters 
The tests listed in Table 2 will be conducted on samples collected and analyzed by standard 
laboratory procedures at the time points specified in the Schedule of Events (Appendix 1).  
Laboratory assessments performed at the Week 12 Visit will be conducted as part of the 
parent study, TRCA-301.  The blood bicarbonate test results will be recorded on the eCRF.  
Missed test(s) that are not done must be reported as such on the eCRFs.  Clinically 
significant laboratory abnormalities will be recorded on the AE eCRF. 
All blood draws for bicarbonate measurements must be done with subjects in a fasted state 
(i.e., no food or drink, other than water, for 4 hours).   
Blood bicarbonate assessment using the i-STAT device is mandatory at each study visit.  In 
addition, a secondary measurement of blood bicarbonate using either enzymatic assay or 
benchtop venous blood gas analysis will be conducted at each study visit at the local 
laboratory. 
Twenty-four hour urine specimens will be brought to the clinic at the visits specified in the 
Schedule of Events (Appendix 1).  Twenty-four hour urine collections will be done by 
subjects one day prior to the specified visits. The 24-hour urine test at the Week 12 Visit will 
be conducted as part of the parent study, TRCA-301.  
Some of the blood and urine samples taken as shown in the Schedule of Events (Appendix 1) 
will be stored for evaluation by one or more central laboratories.  Instructions for the 
processing, storage and shipment of the samples to the central laboratories will be provided 
in a separate laboratory manual. 


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Table 2 
Laboratory Parameters 
Test Type 
Analytes 
Comments 
Whole blood 
bicarbonate (venous) 
pH, pCO2, pO2 and the calculated values for 
HCO3, TCO2, BE, and O2 saturation 
Conducted with i-STAT point-
of-care device with a G3+ 
cartridge 
Venous Blood Gas 
bicarbonate – 
benchtop analyzer 
pH, pCO2, pO2 and the calculated values for 
HCO3, TCO2, BE, and O2 saturation if reported 
Either assay to be conducted at 
local laboratory or study site but 
consistent for each subject 
 
Serum Bicarbonate 
(venous) – enzymatic 
assay 
HCO3- 
Serum Chemistry 
  
Albumin, ALT, AST, alkaline phosphatase, 
bilirubin (total and direct), BUN, calcium, 
chloride, cholesterol (HDL, LDL, total, and 
triglycerides), CK, CK-MB (if CK is elevated), 
creatinine (including eGFR), cystatin C*, 
glucose, magnesium, phosphate, potassium, 
sodium. 
Conducted at central laboratory 
Biomarkers  
Parathyroid hormone, serum pre-albumin, 25-
hydroxy-vitamin D 
Urinary biomarkers of bone resorption:  N-
terminal telopeptide (NTX), C-terminal 
telopeptide (CTX) 
Serum biomarkers of bone resorption:  
tartate-resistant acid phosphatase 5b (TRAP 5b), 
bone-specific alkaline phosphatase (BSAP), and 
type 1 procollagen (P1NP) 
Blood biomarker of bone formation:  serum 
osteocalcin 
Renal biomarkers:  urine angiotensinogen to 
creatinine ratio (UAGT), urine aldosterone, 
urine endothelin-1 (ET-1) 
Conducted at central laboratory 
 
Serum samples and urine 
samples will be collected and 
stored in frozen conditions until 
analyzed 
Coagulation 
INR 
For subjects receiving vitamin K 
antagonists or factor Xa 
inhibitors only.  Vitamin K 
antagonists include warfarin and 
acenocoumaral.  Factor Xa 
inhibitors include apixaban, 
rivaroxaban, betrixaban, 
edoxaban and enoxaparin. 
Conducted at local laboratory 
Hematology 
Red blood cell (RBC) count, white blood cell 
count, white blood cell count differential, 
hemoglobin, hematocrit and platelet count, RBC 
indices (e.g., MCV, red cell distribution width 
[RDW], MCH) 
Conducted at central laboratory 
Hemoglobin A1c 
Glycated hemoglobin 
Conducted at central laboratory 
Urinalysis 
Bilirubin, glucose, ketones, blood, leukocyte 
esterase, nitrites, pH, protein, urobilinogen, and 
urine specific gravity.  
Conducted at central laboratory  
A reflex microscopic analysis 
will be performed if the dipstick 
test is abnormal. 
 


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Table 2 
Laboratory Parameters (cont’d) 
Test Type 
Analytes 
Comments 
Spot urine tests  
Sodium, potassium, chloride, creatinine, 
albumin. 
Conducted at central laboratory 
24-hour urine 
collection 
Volume 
Urea nitrogen, sulfate, uric acid, albumin, and 
creatinine (including albumin to creatinine ratio) 
Volume will be measured at 
study site. 
 
Assays will be conducted at 
central laboratory. 
Pregnancy test 
β-HCG 
Conducted at central laboratory 
(serum pregnancy test) 
Urine dipstick at study site at the 
Week 12 Visit only 
* Cystatin C will be measured at the Week 12 and Week 52/ET Visits only  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-HCG = beta human chorionic 
gonadotropin; BSAP = bone-specific alkaline phosphatase; BUN = blood urea nitrogen; BE = base excess; CK 
= creatine kinase; CTX = C-terminal telopeptide; eGFR = estimated glomerular filtration rate; ET-1 = urine 
endothelin-1; HCO3 = bicarbonate, HDL = high-density lipoprotein; HCG = human chorionic gonadotropin; 
INR = international normalized ratio; LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; 
MCV = mean cell volume; NTX = N-terminal telopeptide; O2 = oxygen, P1NP = type 1 procollagen; RBC = red 
blood cell; RDW = red cell distribution width; SO2 = oxygen saturation; TCO2 = total carbon dioxide; TRAP-5b 
= tartate-resistant acid phosphatase 5b; UAGT = urine angiotensinogen to creatinine ratio 
 
Dietary Counseling 
Dietary counseling will be provided to all study subjects in accordance with dietary 
recommendations for CKD patients (e.g., KDIGO 2013) at the time points indicated in the 
Schedule of Events (see Appendix 1).  In addition, if a subject requires treatment for 
sustained, clinically-significant worsening of metabolic acidosis during the study in the 
judgment of the Investigator, diet counseling (i.e., reduced protein intake, vegetarian/vegan 
protein sources) may be implemented as clinically appropriate and in agreement with the 
Medical Monitor.  
 
Adverse Events 
6.10.1 
Definition of an Adverse Event 
An AE is defined as: “Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment” (ICH E2A Guideline: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, October 1994).  An AE can therefore be 
any unfavorable or unintended sign (including a clinically significant abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  
This includes:  
• 
Any new medical condition, sign or symptom or newly diagnosed event that occurs 
during the AE reporting period, including signs or symptoms associated with an 


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underlying condition that were not present prior to the AE reporting period for Study 
TRCA-301 (see Section  6.10.4.1). 
• 
A previous condition that has worsened in severity or frequency or changed in 
character during the AE reporting period;  
• 
Complications that occur as a result of protocol-mandated interventions; 
• 
Signs, symptoms or the clinical sequelae of a suspected drug interaction; and 
• 
Signs, symptoms or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication. 
 
For the purposes of this protocol, events that are not considered AEs include: 
• 
Isolated decline in blood bicarbonate or blood pH, even if assessed as clinically 
significant by the Investigator; 
• 
Anticipated fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study unless judged by the Investigator to be more severe than 
expected for the subject’s underlying condition;  
• 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of an AE.  For 
example, an acute appendicitis that begins during the AE reporting period should be 
reported as the AE and the resulting appendectomy should be recorded as treatment 
of the AE; 
• 
Placement of a dialysis access 
- 
If the access placement was prompted by clinically significant renal function 
decline during the study, then the latter should be reported as an AE and the 
access placement should be reported as an action taken for the AE. 
• 
Overdose in the absence of other signs/symptoms will not be reported as an AE in its 
own right; and 
• 
Pregnancy; however, any pregnancy complication should be recorded as an AE. 
Out of range laboratory results and abnormal ECGs, vital signs and other safety assessments 
will be considered AEs if they meet at least one of the following criteria: 
• 
Associated with symptoms or lead to a diagnosis (in such case the symptom or 
diagnosis should be recorded as an AE);  
• 
Lead to discontinuation of study drug; or 
• 
The abnormality is deemed clinically significant in its own right (i.e., if some action 
or intervention or alteration of treatment is required or if the Investigator judges the 
change to be beyond the range of normal physiological fluctuation). 


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6.10.2 
Definition of a Serious Adverse Event 
A serious adverse event (SAE) is an untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening. (This refers to a subject who, in the view of the Investigator or 
Tricida, was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, with the 
exception of: 
– Visits to the emergency room or hospital department that do not result in a 
hospital admission lasting more than 24 hours 
– Elective surgery for a pre-existing condition that has not worsened 
– Routine health assessments requiring admission not associated with any 
deterioration in condition 
– Social admission (lack of housing, family circumstances, etc.) 
• 
Results in persistent or significant disability/incapacity.  
• 
Is a congenital anomaly or birth defect. 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes above (e.g., blood dyscrasias, 
convulsions). 
Either the Investigator or Tricida can determine that an AE meets the definition of serious.  If 
either believes that the event is serious, the event must be considered serious and evaluated 
by Tricida for expedited reporting. 
6.10.3 
Definition of a Suspected Adverse Reaction 
A suspected adverse reaction is an AE for which there is a reasonable possibility that the 
drug caused the AE.  For the purposes of Investigational New Drug (IND) safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
drug and the AE.   
All AEs judged by either the Investigator or Tricida as having a reasonable causal 
relationship to a study drug will be designated as suspected adverse drug reactions. 
6.10.4 
Procedures for Eliciting, Recording and Reporting Adverse Events 
6.10.4.1 
Adverse Event Reporting Period 
AEs, including SAEs, will be collected throughout the study period, beginning from the time 
of enrollment until the completion of the last study visit assessments (2 weeks after the Week 


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52 visit for subjects who complete the study and until 2 weeks after the ET visit for subjects 
who discontinue study drug prematurely).  For subjects who do not undergo an ET visit 
following early discontinuation of study drug, the AE reporting period will end 2 weeks after 
the last dose of study drug.  Any AE or SAE that is assessed by either the Investigator or 
Tricida as related to the investigational drug and is ongoing at the last study visit will be 
followed, whenever possible, until it resolves or becomes stable or the subject is lost to 
follow-up. 
All subjects who have been exposed to investigational product will be evaluated for AEs.  
Treatment-emergent adverse events (TEAEs) are defined as those that occur on or after the 
day after the Week 12 Visit .  
6.10.4.2 
Eliciting Adverse Events 
Information on AEs and SAEs will be elicited at each AE assessment time point specified in 
the Schedule of Events (Appendix 1) by asking the subject an open-ended question such as: 
"Since you were last asked, have you felt unwell or different from usual in any way?" The 
subject may report AEs spontaneously at any time.  
6.10.4.3 
Assessing Adverse Events 
The Investigator should follow the guidelines for rating severity of adverse events:  
Severity 
Definition 
Mild 
Awareness of signs or symptoms, but easily tolerated; no disruption 
of normal activities; symptoms are transient and would not require 
medication or medical evaluation 
Moderate 
Discomfort enough to cause interference with usual activities and 
treatment may be required 
Severe 
Incapacitating with inability to do work or do usual activities; may 
require medical evaluation and/or treatment; the investigational 
product may have been discontinued  
It is important to note the distinctions between severe AEs and serious AEs.  Severity is a 
classification of intensity of a specific event, whereas an SAE is an AE that meets any of the 
regulatory specified criteria required for designation as seriousness described in 
Section 6.10.2 (e.g., a headache may be severe [interferes significantly with subject's usual 
function] but would not be classified as serious unless it met one of the criteria for SAEs). 
The Investigator will assess relationship of the AE to the investigational drug, TRC101, 
using the following definitions.  A suspected relationship (related, probably, possibly) 
between the events and the study drug means, in general, that there are facts (evidence) or 
arguments to suggest a causal relationship.  If the relationship to the study drug is considered 


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to be unlikely or not related, an alternative suspected etiology should be provided if available 
(e.g., concomitant medications, intercurrent illness/events). 
Relationship 
Definition 
Example 
Related 
Causal relationship is 
certain 
The temporal relationship between drug exposure 
and the AE onset/course is reasonable, there is a 
clinically compatible response to de-challenge, 
other causes have been eliminated; the event must 
be definitive pharmacologically or 
phenomenologically, using a satisfactory 
rechallenge procedure if necessary.  
Probable 
High degree of certainty 
for causal relationship 
The temporal relationship between drug exposure 
and AE onset/course is reasonable; there is a 
clinically compatible response to dechallenge 
(re-challenge is not required); unlikely to be 
attributed to disease or other drugs. 
Possible 
Not reasonably related 
although a causal 
relationship cannot be 
ruled out 
The temporal relationship between drug exposure 
and the AE onset/course is reasonable or 
unknown; de-challenge information is either 
unknown or equivocal; could also be explained 
by disease or other drugs. 
Unlikely 
Not reasonably related 
although a causal 
relationship cannot be 
ruled out 
Disease or other drugs provide plausible 
explanation. 
Unrelated 
No possible relationship 
The temporal relationship between drug exposure 
and the AE onset/course is unreasonable or 
incompatible, or a causal relationship to study 
drug is impossible. 
The Investigator will use the following categories to assess the outcome of each AE:  
• 
Recovered/resolved;  
• 
Not recovered/ not resolved; 
• 
Recovered/resolved with sequelae;  
• 
Fatal; or  
• 
Unknown. 
“Fatal” should be recorded as an outcome when the AE results in death.  If more than one AE 
is possibly related to the subject's death, the outcome of death should be indicated for the AE 
that, in the opinion of the Investigator, is the most plausible cause of death.  All other 
ongoing AE/SAEs will be recorded as not recovered/not resolved at the time of death.  


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Although “fatal” is usually an outcome of an event, events such as sudden death or 
unexplained death should be reported as SAEs. 
The action taken with regard to study drug in response to each AE will be assessed by the 
Investigator using the following categories: 
• 
No action taken; 
• 
Study drug interrupted; 
• 
Study drug discontinued; or 
• 
Not applicable (e.g., subject was not receiving study drug at the time of the AE). 
 
6.10.4.4 
Independent Data Monitoring Committee 
An independent unblinded DMC will review the safety data during the study conduct.  The 
DMC Charter will describe the data review process and its frequency. 
 
6.10.4.5 
Recording Adverse Events 
All AEs and SAEs, whether spontaneously reported by the subject or elicited or noted by 
study staff, will be recorded in the subject’s medical record and on the appropriate AE eCRF 
page.  In addition, the SAE Report Form must record each SAE.  
All AEs should be recorded using the words of the subject (verbatim term) to describe the 
AE, with two exceptions: if the verbatim term is vague or ambiguous (e.g., cramps), the 
study staff should try to obtain clarification by asking a follow-up question (e.g., What kind 
of cramps?) and record the words the subject used to clarify the event (e.g., menstrual 
cramps, calf muscle cramps).  
If the subject reports a group of symptoms and the Investigator is comfortable with a 
unifying diagnosis, the diagnosis should be recorded (e.g., rhinopharyngitis instead of runny 
nose, cough, sore throat and sneezing).  If a diagnosis is recorded, signs and symptoms need 
not be recorded separately.  If the Investigator is unable to report a diagnosis, symptoms 
should be recorded on the AE eCRF. 
The following information should be captured for each AE: date of onset and resolution, 
outcome, severity, seriousness, relationship to the study drug, action taken with the study 
drug and treatments administered.  Any treatment administered as a result of an AE should be 
recorded on the concomitant medication eCRF. 
6.10.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Clinically significant new or clinically significantly worsening abnormal laboratory findings 
(e.g., serum chemistry, hematology, and urinalysis) or other abnormal assessments (e.g., 
ECGs, vital signs) after enrollment into this study must be recorded as AEs or SAEs.  




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• 
Date of resolution (when medically applicable) 
• 
Outcome 
• 
Action taken for the SAE 
• 
Concomitant medications 
• 
Relevant medical history 
• 
Criteria of seriousness (see Section 6.10.2) 
• 
Study drug name, or code if unblinded, and treatment start date 
• 
Severity of the event 
• 
Causality assessment 
Additional information must be provided when available including any relevant records 
(e.g., Hospital Discharge Summary, Autopsy Report/Death Certificate, diagnostic study 
reports, etc.).  Any supporting information provided should not reveal a subject’s identity 
beyond the agreed study identifier.  The Investigator should ensure that information reported 
is accurate and consistent. 
Isolated decline in blood bicarbonate or blood pH, even if assessed as clinically significant 
by the Investigator, will not be captured as an AE for the purpose of this protocol. 
All AEs will be evaluated on a regular basis by the Medical Monitor to monitor safety in the 
study population. 
6.10.6.1 
SAE Expedited Reporting 
For each AE assessed by either the Investigator or Tricida to be serious, Tricida will 
determine (1) if the event was unexpected (i.e., the nature or severity is not expected from the 
information provided in the Investigator's Brochure) and (2) if the event was a suspected 
adverse reaction.  If the event is determined to be a serious, unexpected suspected adverse 
reaction (SUSAR), Tricida will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority and Investigators.  The Investigator is 
responsible for notifying his/her respective IRB/IEC. 
6.10.6.2 
Unblinding Treatment Allocation 
Generally, Tricida should only report SUSARs for which the treatment allocation of the 
subject is unblinded to the pertinent regulatory authorities.  Investigators should only receive 
blinded information unless unblinded information is judged necessary for safety reasons. 
When an event may be a SUSAR, the blind should be broken only for that specific subject.  
Unblinded information should only be accessible to those who need to be involved in the 
safety reporting to pertinent regulatory authorities, IECs/IRBs, and the Medical Monitor 
(i.e., the individual performing ongoing safety evaluations during the study). 


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Procedures for Reporting Pregnancy Exposure and Birth Events 
Should a female subject become pregnant or be suspected of being pregnant while 
participating in this study, the study drug will be permanently discontinued, and the event 
must be reported to Tricida’s designee, 
, on the Pregnancy 
Notification Form within 24 hours of receipt of information by the study staff. 
The Investigator is also responsible for following up the pregnancy at 3 monthly intervals 
until delivery or termination.  Pregnancies should initially be reported in the Pregnancy 
Notification Form and sent by e-mail to the following address:  
. 
When the outcome of the pregnancy is known, study staff will complete the Pregnancy 
Outcome Form and e-mail it to the following address:  
. 
While pregnancy is not considered an AE or SAE, any pregnancy complication should be 
recorded as AEs or SAEs (if applicable).  Fatalities, elective or spontaneous abortions, and 
congenital abnormalities/birth defects must be reported as SAEs. 
7 
STUDY ACTIVITIES 
A complete schedule of study events is presented in Appendix 1.  See Table 2 for a 
description of the analytes measured in each laboratory panel.  Since Week 12 Visit values 
will be used to determine eligibility in this study, no re-screening is allowed. 
 
Week 12 Visit 
Following completion of the assessments required at the Week 12 Visit in the parent study, 
TRCA-301, subjects who meet eligibility criteria may be enrolled in this extension study.  
Subjects should present to the clinic in a fasted state (except water) to ensure that they will be 
fasted for at least 4 hours prior to blood draws during the visit. 
The following procedures will be performed: 
• Obtain informed consent if this has not already been done prior to this visit (must be 
done prior to any procedures required only for this extension study)  
• Evaluate eligibility (inclusion and exclusion) criteria 
• Obtain urine sample for urine dipstick pregnancy test (for women of childbearing 
potential only)  
• Determine whether any changes to oral alkali supplementation are required for 
subjects taking them using titration algorithm in Appendix 2 
• Dispense study drug per IRT assignment [to be done by the designated study staff 
only] 
• Schedule next study visit 


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The following Week 12 Visit assessments, procedures and laboratory tests will be performed 
for the parent study, TRCA-301: 
• Record concomitant medications 
• Collect vital signs (blood pressure [in triplicate], heart rate, temperature, and 
respiratory rate [in triplicate]).    
• Perform complete physical examination, including body weight  
• Perform repeated chair stand test 
• Collect answers to KDQOL questions 
• Record ECG (triplicate)  
• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic serum bicarbonate assay or venous blood gas bicarbonate 
assay, coagulation (for subjects receiving vitamin K antagonists or factor Xa 
inhibitors only) 
• Draw fasting blood for the following assessments at the central laboratory:  serum 
chemistry panel, hematology panel, blood biomarker panel, hemoglobin A1c, and 
serum pregnancy test (for women of childbearing potential only) 
• Obtain urine for the following assessments at the central laboratory:  spot urine, 
urinalysis and urine biomarker panel 
• Obtain 24-hour urine sample for assessment at central laboratory 
• Collect used and unused study drug containers since the previous visit, assess dosing 
compliance and perform drug accountability [to be done by the Pharmacist only] 
• Record AEs 
• Dietary counseling 
 
Week 14 Visit 
The allowed visit window is ± 4 days.  The following procedures and assessments will be 
performed.  Subjects must present to these visits in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic assay serum bicarbonate or venous blood gas bicarbonate 
assay, coagulation (for subjects receiving vitamin K antagonists or factor Xa 
inhibitors only) 
• Draw fasting blood for the following assessments at the central laboratory:  serum 
chemistry panel  


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• Determine whether any changes to oral alkali supplementation are required for 
subjects who were taking them at the Week 12 Visit using titration algorithm in 
Appendix 2 
• Dispense study drug per IRT assignment [to be done by the designated study staff 
only] 
• Collect used and unused study drug containers since the previous visit, assess dosing 
compliance and perform drug accountability [to be done by the designated study staff 
only] 
• Record AEs 
• Schedule the next study visit 
 
Week 16 and Week 46 Visits 
The allowed visit windows are:  ± 4 days for Week 16 and ± 7 days for Week 46.  The 
following procedures and assessments will be performed.  Subjects must present to these 
visits in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic assay serum bicarbonate or venous blood gas bicarbonate 
assay, coagulation (for subjects receiving vitamin K antagonists or factor Xa 
inhibitors only) 
• Draw fasting blood for the following assessments at the central laboratory:  serum 
chemistry panel and serum pregnancy test (for women of childbearing potential only).   
• At Week 46 Visit only:  provide instruction on collecting 24-hour urine sample 
starting one day prior to the Week 52 Visit and dispense necessary supplies 
• Determine whether any changes to oral alkali supplementation are required for 
subjects who were taking them at the Week 12 Visit using titration algorithm in 
Appendix 2 
• Dispense study drug per IRT assignment [to be done by the designated study staff 
only] 
• Collect used and unused study drug containers since the previous visit, assess dosing 
compliance and perform drug accountability [to be done by the designated study staff 
only] 
• Record AEs 
• Schedule the next study visit 


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Week 20 and Week 40 Visits 
The allowed visit windows are:  ± 4 days for Week 20 and ± 7 days for Week 40.  The 
following procedures and assessments will be performed.  Subjects must present to these 
visits in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
• At Week 40 Visit only:  perform repeated chair stand test 
• At Week 40 Visit only:  collect answers to KDQOL questions 
• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic assay serum bicarbonate or venous blood gas bicarbonate 
assay, coagulation (for subjects receiving vitamin K antagonists or factor Xa 
inhibitors only) 
• Draw fasting blood for the following assessments at the central laboratory:  serum 
chemistry panel, hematology panel, and serum pregnancy test (for women of 
childbearing potential only)  
• Obtain urine for the following assessments at the central laboratory:  spot urine and 
urinalysis 
• Determine whether any changes to oral alkali supplementation are required for 
subjects who were taking them at the Week 12 Visit using titration algorithm in 
Appendix 2 
• Dispense study drug per IRT assignment [to be done by the designated study staff 
only] 
• Collect used and unused study drug containers since the previous visit, assess dosing 
compliance and perform drug accountability [to be done by the designated study staff 
only] 
• Record AEs 
• Dietary counseling  
• Schedule the next study visit 
 
Week 24 and Week 34 Visits 
The allowed visit windows are:  ± 4 days for Week 24 and ± 7 days for Week 34.  The 
following procedures and assessments will be performed.  Subjects must present to these 
visits in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
• Record ECG (triplicate) 


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• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic assay serum bicarbonate or venous blood gas bicarbonate 
assay, coagulation (for subjects receiving vitamin K antagonists or factor Xa 
inhibitors only) 
• Draw fasting blood for the following assessments at the central laboratory:  serum 
chemistry panel and serum pregnancy test (for women of childbearing potential only)  
• Determine whether any changes to oral alkali supplementation are required for 
subjects who were taking them at the Week 12 Visit using titration algorithm in 
Appendix 2 
• Dispense study drug per IRT assignment [to be done by the designated study staff 
only] 
• Collect used and unused study drug containers since the previous visit, assess dosing 
compliance and perform drug accountability [to be done by the designated study staff 
only] 
• Record AEs 
• Schedule the next study visit 
 
Week 28 Visit 
The allowed visit window is ± 7 days.  The following procedures and assessments will be 
performed.  Subjects must present to these visits in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
• Perform complete physical examination, including body weight 
• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic assay serum bicarbonate or venous blood gas bicarbonate 
assay, coagulation (for subjects receiving vitamin K antagonists or factor Xa 
inhibitors only) 
• Draw fasting blood for the following assessments at the central laboratory:  serum 
chemistry panel, hematology panel, and serum pregnancy test (for women of 
childbearing potential only)   
• Obtain urine for the following assessments at the central laboratory:  spot urine and 
urinalysis 
• Determine whether any changes to oral alkali supplementation are required for 
subjects who were taking them at the Week 12 Visit using titration algorithm in 
Appendix 2 
• Dispense study drug per IRT assignment [to be done by the designated study staff 
only] 


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• Collect used and unused study drug containers since the previous visit, assess dosing 
compliance and perform drug accountability [to be done by the designated study staff 
only] 
• Record AEs 
• Schedule the next study visit 
 
Week 52 or Early Termination (ET) Visit 
The Week 52 visit will occur no earlier than the 1-year anniversary of the Day 1 Visit in the 
parent study TRCA-301.  The following assessments will be performed at the Week 52 Visit 
for subjects who completed the entire Treatment Period (allowed visit window is + 7 days) or 
the ET Visit for subjects who withdrew from the study early.  Subjects must present to this 
visit in a fasted state.  The last dose of study drug should be taken the day before the 
Week 52 Visit. 
• Record concomitant medications  
• Collect vital signs (blood pressure [in triplicate], heart rate, temperature, and 
respiratory rate [in triplicate]) 
• Perform complete physical examination, including body weight 
• Record ECG (triplicate) 
• Perform repeated chair stand test 
• Collect answers to KDQOL questions 
• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic assay serum bicarbonate or venous blood gas bicarbonate 
assay, coagulation (for subjects receiving vitamin K antagonists or factor Xa 
inhibitors only) 
• Draw fasting blood for the following assessments at the central laboratory:  serum 
chemistry panel, hematology panel, blood biomarker panel, hemoglobin A1c, and 
serum pregnancy test (for women of childbearing potential only) 
• Obtain urine for the following assessments at the central laboratory:  spot urine, 
urinalysis and urine biomarker panel 
• Obtain 24-hour urine sample for assessment at central laboratory 
• Collect used and unused study drug containers since the previous visit, assess dosing 
compliance and perform drug accountability [to be done by the designated study staff 
only] 
• Record AEs 
• Dietary counseling 
• Schedule the next study visit 


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• All subjects who discontinue study drug prior to Week 52 will be contacted by 
telephone 40 weeks after their Week 12 Visit to ascertain vital status and renal status 
(i.e., receiving renal replacement therapy or not). 
 
 Follow-up 1 Visit (Week 53) 
The allowed visit window is ± 2 days for all visits during the Follow-up Period.  The 
following assessments will be performed.  Subjects must present to this visit in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate)  
• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic assay serum bicarbonate or venous blood gas bicarbonate 
assay, coagulation (for subjects receiving vitamin K antagonists or factor Xa 
inhibitors only) 
• Draw fasting blood for the following assessments at the central laboratory:  serum 
chemistry panel  
• Record AEs 
• Schedule the next study visit 
 
Follow-up 2 Visit (Week 54) 
The allowed visit window is ± 2 days for all visits during the Follow-up Period.  The 
following assessments will be performed.  Subjects must present to this visit in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate)  
• Collect body weight 
• Record 12-lead ECG (triplicate) 
• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic assay serum bicarbonate or venous blood gas bicarbonate 
assay, coagulation (for subjects receiving vitamin K antagonists or factor Xa 
inhibitors only) 
• Draw fasting blood for the following assessments at the central laboratory:  serum 
chemistry panel, hematology panel, and serum pregnancy test (for women of 
childbearing potential only) 
• Obtain urine for the following assessments at the central laboratory:  spot urine and 
urinalysis 
• Record AEs 


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Unscheduled Visit 
An unscheduled visit may be performed at any point during the study if an adjustment of 
study drug dose is required or at the discretion of the Investigator to follow-up on an 
abnormal finding or adverse event, or for another reason.  The allowed visit window for a 
1-week visit required per the titration algorithm is -1 to +3 days.  In all cases, the reason for 
the unscheduled visit should be documented.  Procedures during the unscheduled visit should 
be determined by the reason for the visit but could include: 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate)  
• Perform a complete physical examination, including body weight 
• Record 12-lead ECG (triplicate) 
• Central or local laboratory testing:  In general, for laboratory tests that are being 
analyzed at the central laboratory, the unscheduled testing should be done through the 
central laboratory, however, if rapid results are needed, local laboratory testing may 
also be performed.  Blood bicarbonate testing should be performed using the i-STAT 
device. 
• Determine whether any changes to oral alkali supplementation are required for 
subjects who were taking them at the Week 12 Visit using titration algorithm in 
Appendix 2 
• Perform study drug accountability and dispensation per IRT assignment (if 
applicable) [to be done by the designated study staff only] 
• Record AEs 
• Dietary counseling 
 
 
End-of-Study 
End-of-Study is defined as completion of the Follow-up 2 (Week 54) Visit.  For those 
subjects who withdrew prematurely from the study, end-of-study and the premature 
termination date are defined as the date of the subject’s last data collection.  
Subjects who complete the 40-week Treatment Period (Week 52 Visit) are considered to 
have completed the study even if they did not return for the follow-up visits. 
Subjects who discontinue study drug treatment prior to Week 52 will be contacted by 
telephone to determine vital status and renal status (i.e., receiving renal replacement therapy 
or not).  AE, SAE and concomitant medication data collection will stop after the Follow-up 2 
Visit. 


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8 
PLANNED STATISTICAL METHODS 
 
General Considerations 
A statistical analysis plan (SAP) will provide details of planned analyses and summary 
documents, such as tables, listings, and figures.  This section presents an overview of the 
planned analyses.  Final analyses are not limited to the summaries described herein.  If 
circumstances arise during the study that make these analyses inappropriate or if improved 
statistical methods become available, the SAP may be revised.  The SAP will describe in 
detail the plans for dealing with subjects who drop out of the study.  If the methods of the 
SAP and those in this section do not agree, the SAP prevails.   
Any revisions (both alternative and additional methods) to the SAP, and reasons for such 
revisions, will be described in the final study report. 
All continuous study assessments will be summarized by time point, as applicable, using 
descriptive statistics (n, mean, median and appropriate percentiles, standard deviation, 
minimum, and maximum).  All categorical study assessments will be summarized by time 
point, as applicable, using frequency counts and percentages.   
 
Determination of Sample Size 
No sample size calculation was performed, since this is an extension to Study TRCA-301 
into which eligible patients who choose to participate will be enrolled. 
 
Analysis Populations 
Two populations will be analyzed in this study.  The SAP may define additional analysis 
set(s). 
Safety analysis set: 
All subjects who received any amount of study drug in this 
extension Study TRCA-301E. 
 
Modified intent-to-
treat (MITT) 
analysis set 
 
Subjects who rolled over to this extension Study TRCA-301E and 
had at least one blood bicarbonate assessment after the Week 12 
Visit. 
 
 
Reference Date and Baseline 
Time points will be based on the date of first dose of study drug in Study TRCA-301 (the 
parent study).  Baseline values are defined as the Baseline value in Study TRCA-301, unless 
stated otherwise in the SAP.   


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Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be listed, study site and subject, and will be 
summarized.  Frequencies and percentages will be presented for the categorical variables and 
descriptive statistics will be presented for continuous variables. 
 
Statistical Analysis of Durability of Effect  
Primary durability of effect will be evaluated using the MITT analysis set based on the 
randomized treatment group assignment.  Number and proportion (expressed in percentage) 
of subjects, along with exact (Clopper-Pearson) 95% confidence intervals (CI) of the 
percentage, will be provided for all scheduled time points when summarizing categorical 
efficacy variables.  Descriptive statistics will be provided for all scheduled time points when 
summarizing continuous efficacy variables.  Statistical significance will be declared at the 
two-sided significance level of 0.05. 
8.6.1 
Durability of Effect Variable 
The analysis for durability of effect will include blood bicarbonate results that will be 
collected at Week 12 Visit through the end of the 40-week treatment from the i-STAT 
device.  The i-STAT blood bicarbonate data will be used to determine the CFB in 
bicarbonate over time.  Baseline blood bicarbonate is defined as the mean of the bicarbonate 
values collected at Screening visits and on Day 1 pre-dose in Study TRCA-301 (the parent 
study).  CFB in blood bicarbonate will be calculated for each time point subsequent to the 
Week 12 Visit.  Descriptive statistics will be provided for all scheduled time points.  
8.6.2 
Durability of Effect Endpoints 
Durability of Effect Endpoints are:   
1. Having a CFB in blood bicarbonate ≥ 4 mEq/L or having a blood bicarbonate in the 
normal range (22 to 29 mEq/L) at the end of treatment (Week 52 Visit).  
2. CFB in blood bicarbonate at the end of treatment (Week 52 Visit). 
3. CFB in the total score of the KDQOL Question 3 items (daily activities) at the end of 
treatment (Week 52 Visit). 
4. CFB in repeated chair stand test duration at the end of treatment (Week 52 Visit). 
8.6.3 
Analysis of Durability of Effect 
The number and proportions (expressed as percentages) of subjects who are responders at 
each time point and at the end of treatment (Week 52) will be calculated.  Responders are 
defined as having a CFB in blood bicarbonate ≥ 4 mEq/L or having a blood bicarbonate in 
the normal range (22 to 29 mEq/L).  The difference in proportion of responders between 
TRC101 and placebo subjects and its exact (Clopper-Pearson) 95% CI, as well as the p-value 
from Fisher’s exact test comparing the TRC101 group and the placebo group will be reported 


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by time point.  The proportion of subjects who are responders and the exact 95% CIs of the 
proportion will also be presented by treatment group and time point.  A comparison between 
the the TRC101 group and the placebo group with respect of the proportion of responders at 
Week 52 will be perfomed using Fisher’s exact test. 
A longitudinal mixed-effect model for repeated measures (MMRM) will be used to analyze 
the CFB in bicarbonate.  The model will include the CFB in bicarbonate as the dependent 
variable, treatment, time point (Weeks 12, 14,…, 52), and treatment by time point interaction 
as fixed effects, subject as a random effect, and the baseline bicarbonate and baseline eGFR 
as continuous covariates.  An unstructured covariance structure will be used.  The least 
squares (LS) mean of CFB in bicarbonate, standard error of the LS mean, and two-sided 95% 
CIs of the LS mean from the mixed model will be reported by time point and treatment 
group.  The LS mean difference from placebo (i.e., TRC101 – placebo), standard error (SE) 
of the LS mean difference, 95% CIs of the LS mean difference, and p-values of the LS mean 
difference from the mixed model will be reported by time point.  A test comparing the LS 
means of CFB in blood bicarbonate between treatment groups will be conducted at the end of 
treatment (Week 52 Visit). 
An analysis of covariance (ANCOVA) model will be used to assess the CFB in total score of 
KDQOL and in the repeated chair stand test.  The model will include the CFB value as the 
dependent variable, treatment as a fixed effect, and the baseline value as a covariate.  The 
least squares (LS) mean of CFB value, standard error of LS mean, and two-sided 95% CIs of 
the LS mean from the ANCOVA model will be reported by treatment group.  The LS mean 
difference from placebo (i.e., TRC101 – placebo), SE of the LS mean difference, 95% CIs of 
the LS mean difference, and p-values of the LS mean difference from the ANCOVA model 
will be reported. 
In order to evaluate the potential effect of missing data on the durability of effect, sensitivity 
analyses for responders will be performed using multiple imputation models under a MNAR 
assumption for the MITT analysis set.  The SAP will describe these additional analyses. 
If the residuals from the above mentioned models (i.e., MMRM, ANCOVA) are not normally 
distributed, alternative analyses to deal with non-normality will be used instead.  The SAP 
will specify these analyses. 
 
Safety Analysis 
Safety will be summarized for subjects in the safety analysis set.  The following will be 
summarized by 12-week interval with denominator as the number of subjects at risk at the 
beginning of each interval:  number and percentage of subjects with treatment-emergent AEs 
(TEAEs) classified by system organ class (SOC) and preferred term (PT); number (%) of 
subjects experiencing TEAEs by severity, causality, seriousness and action taken with regard 
to study drug.  The number (%) of subjects with TEAEs leading to discontinuation of study 
treatment will also be summarized similarly by 12-week interval.  Subjects will be counted 


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only once at each interval, SOC and PT level of summary.  Clinical laboratory test results, 
vital signs and ECG findings will be summarized using descriptive statistics by time point.  
Categorical display methods (e.g., frequencies, shift tables) and plots of laboratory values 
over time may also be used, as appropriate.  Blood bicarbonate values and their change from 
Baseline values will be descriptively summarized by time point.  The incidence and 
frequency of subjects who meet the dose interruption criterion (confirmed blood bicarbonate 
> 30 mEq/L) at any time during the Treatment Period will be summarized by 12-week 
interval with the denominator as the number of subjects at risk at the beginning of each 
interval.  Worsening or newly observed clinically significant physical examination findings 
will be reported as adverse events.   
 
Other Assessments or Analyses 
Exposure to study drug, dosing compliance, and concomitant medications will be 
summarized.  Alkali use will be summarized by visit. The number and percentage of subjects 
who used prior and/or concomitant medications will be summarized by Anatomic 
Therapeutic Chemical (ATC) classification levels and 12-week interval with denominator as 
the number of subjects at risk at the beginning of each interval.  At each time interval and 
level of ATC classification, subjects will be counted once. 
9 
DATA HANDLING AND RECORD KEEPING  
 
Source Data 
Source documents are original documents, data, and records (e.g., case histories, progress 
notes of the physician, nurses’ notes, medical records, hospital records, clinical and office 
charts, laboratory notes, memoranda, or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, and records kept at the pharmacy or laboratories).  Source 
data are contained in source documents and must be adequate to reconstruct all data 
transcribed onto the eCRFs and to evaluate the study.  Examples of source data include 
clinical findings, observations, enrollment summary information and ICF procedures, 
assessment of clinical significance for laboratory results, AE severity and seriousness, and 
Investigator’s opinion of AE relatedness to study drug.  
The Investigator is required to prepare and maintain adequate and accurate case histories that 
record all observations and other data pertinent to the investigation for all subjects.   
Source documentation should be available at monitoring visits to verify entries made on 
eCRFs, as needed.  Source documentation should also be available for verification by 
auditors and/or inspectors, as needed. 


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Case Report Forms / Electronic Data Record 
An electronic case report form (eCRF) is designed to record all of the protocol-required 
information to be reported to Tricida on each study subject.  The Investigator is responsible 
for ensuring the accuracy, completeness, legibility, and timeliness of the data reported on 
subjects’ eCRFs.  Data reported on the eCRF, which are derived from source documents, 
should be consistent with the source documents or the discrepancies should be explained.  An 
explanation should be given for all missing data. 
All eCRF data and query resolutions must be completed only by the clinical study personnel 
designated by the Investigator.  All site staff will have proper training prior to accessing the 
electronic data capture (EDC) system. 
Any change or correction to an eCRF will be tracked via an audit trail within the EDC 
system.  The audit trail will contain the original data value, new data value, date changed, the 
user who made the change, and the reason(s) for the change.  
CRFs should be completed in a timely manner to support the study timeline (i.e., the site 
should not wait for a monitoring visit before entering data into the eCRF). 
Data from the eCRFs and queries will be tracked and entered into a 21 CFR Part 11 
compliant clinical database.  The database system will be a secured, password-protected 
system with full audit trail utility. 
Subject data will be reviewed through programmed quality checks and manually through 
review of data listings by Tricida and its designee.  Data that appear inconsistent, incomplete, 
or inaccurate will be queried for clarification be the site.  Data corrections will be updated to 
the database and tracked in the audit trail.  AEs and concomitant medications will be coded 
using industry standard dictionaries (e.g., Medical Dictionary for Regulatory Activities 
[MedDRA] and World Health Organization [WHO] Drug dictionary). 
The Investigator is responsible for reviewing, verifying, and approving all subject data 
(i.e., eCRFs and resolved queries). 
 
Data Handling 
The final data will be transferred to the SAS-system for data analyses in accordance with the 
SAP.  The MedDRA dictionary will be used for coding of AEs and concomitant diseases. 
Concomitant medication will be coded using the WHO Drug Dictionary ATC code. 
 
Deviations from the Protocol 
Deviations from the protocol will be judged during the study and/or when an individual 
subject’s eCRF is completed (monitored).  
The SAP will define important protocol deviations for use in the statistical analysis. 


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Record Retention and Archiving 
The Investigator must maintain adequate records for the study including completed CRFs, 
medical records, laboratory reports, signed ICFs, drug disposition records, adverse 
experience reports, information regarding subjects who discontinued, all correspondence 
with the IRB/IEC and Tricida, and other pertinent data.   
Before site initiation Tricida will provide an Investigative Site File (ISF)/Regulatory Binder 
to each site.  The ISF will include essential documents as defined by the ICH Good Clinical 
Practice (GCP) guideline and applicable local requirements. 
The Investigator will be responsible for the update and maintenance of the ISF, which will be 
reviewed periodically by Tricida or its designee.  If an audit occurs, these documents will be 
reviewed during an audit by Tricida or an inspection by the Regulatory Authorities. 
All study-related documents and records should be archived according to ICH guidelines for 
at least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product or such longer period as may otherwise be instructed by Tricida in 
writing or as otherwise required by applicable regulatory requirements. 
The Investigator is to retain all records until notified by Tricida.  The Investigator will notify 
Tricida in writing of the relocation of any study records away from the research facility after 
study closure.  The Investigator must receive Tricida’s consent in writing prior to the 
destruction of any study records, or in the event of loss of any study records. 
10 
QUALITY CONTROL AND QUALITY ASSURANCE 
The integrity and quality of subject data will be ensured by providing training and process 
instructions for the completion of the eCRFs, performing quality control checks, conducting 
ongoing clinical data review (including medical and safety reviews), and performing source 
data verification and data reconciliation. 
Tricida employees or designees will conduct site monitoring visits at regular intervals in 
accordance with FDA and International Conference on Harmonization (ICH) guidelines.  The 
Investigator will permit Tricida or designee monitors to review and inspect facilities, and all 
records relevant to this study.  
The Investigator will also permit Tricida or designee auditors, the IRB/IEC, FDA or other 
Regulatory Authority inspectors to review and inspect facilities, procedures, and all records 
relevant to this study.  These records include, but are not limited to:  subject signed ICFs, 
source documentation, regulatory and essential documents, CRFs, and drug accountability 
records.  The Investigator should notify the Medical Monitor immediately of any regulatory 
inquiries, investigations, site visits (whether announced or unannounced), correspondence or 


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communication that relates to the study, and shall consult and cooperate with Tricida in 
responding to any such event, including providing documents, information and access as 
requested by Tricida.   
The following steps will be taken to ensure that the study is conducted by the investigational 
site in compliance with the study protocol, GCP and other applicable regulatory 
requirements: 
• 
Investigator meeting and/or Investigator site initiation.  
• 
Routine site monitoring. 
• 
Documented protocol and GCP training.  
• 
eCRF and query review against source documents. 
• 
Collection of local laboratory normal ranges and laboratory documentation. 
 
11 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
 
Good Clinical Practice 
The study will be conducted in accordance with US FDA regulations, the ICH E6 guidelines 
for GCP, the Declaration of Helsinki, and IRB or IEC requirements.  The study will also be 
conducted in accordance with the European Union Clinical Trials Directive 2001/20/EC for 
sites in the European Union and all other applicable local and national laws and regulations 
governing the conduct of human clinical studies.  
 
Institutional Review Board / Independent Ethics Committee 
All Investigators participating in this study must be governed under an appropriate 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC).  The applicable 
IRB or IEC should review and approve this protocol, the ICF, the Investigator’s Brochure 
and any information to be given to the subject before a site can begin conducting any study-
related activities.  A copy of the IRB/IEC approval letter for the protocol and the ICF must be 
provided to Tricida prior to investigational product shipment.  The IRB/IEC must approve 
any subject recruitment materials before the material is used for subject recruitment.   
Subsequently, the Investigator is responsible for obtaining re-approval by the IRB/IEC 
annually or more frequently in accordance with the regulatory requirements and policies and 
procedures established by the IRB/IEC.  Copies of the Investigator’s annual report and other 
required reports to the IRB/IEC and copies of the IRB/IEC continuance of approval must be 
furnished to Tricida.  The Investigator must also inform the IRB/IEC of any protocol changes 
or amendments, changes to the Investigator’s Brochure, expedited reports of SAEs submitted 
to regulatory authorities, and other significant safety concerns according to the IRB/IEC 
policy.  Written documentation of IRB/IEC approval of protocol amendments must be 
received before the amendment is implemented.  After completion or termination of the 


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study, Investigators will notify their IRB/IECs.  The Investigator will comply with all 
IRB/IEC policies throughout the duration of the study.  
 
Ethical Conduct of the Trial 
The Investigator is responsible for assuring that the study is conducted in accordance with 
current local and national regulations, ICH GCP guidelines, and other applicable laws, 
regulations and requirements governing the conduct of human clinical trials.   
The Investigator will not deviate from the protocol without prior written approval from 
Tricida, except in medical emergencies.  In the event of a medical emergency, the 
Investigator must notify the Medical Monitor immediately.  Any other change to the protocol 
must be implemented by Tricida as an amendment to the protocol and must be approved by 
the IRB/IEC prior to implementation. 
The Investigator must inform the governing IRB/IEC of all protocol changes in accordance 
with the IRB/IEC’s established procedure.  No deviation from the protocol of any type will 
be permitted without complying with the established IRB/IEC procedures.   
If an Investigator chooses to advertise for subjects, whether in professional or consumer 
publications, radio, or television, all advertising must be approved by Tricida and the 
IRB/IEC prior to initiation. 
Financial details and insurance are covered in the Clinical Trial Agreement and Clinical Trial 
Insurance Policy. 
 
Subject’s Information and Informed Consent 
Individual subject’s medical information obtained as a result of this study is considered 
confidential and disclosure to unauthorized parties is prohibited.  Subject’s confidentiality 
will be assured by utilizing subject identification code numbers and/or initials, instead of 
names.  If results of this study are reported in medical journals or at meetings, the subject’s 
identity will not be disclosed. 
With the subject’s authorization, medical information may be provided to the subject’s 
personal physician or to other appropriate medical personnel responsible for the subject’s 
welfare. 
In compliance with GCP guidelines, all subjects will be informed of the purpose of the 
research, the possible risks, and their right to withdraw at any time from the study without 
prejudice and without jeopardy to their future medical care at the center.  Each subject must 
agree to cooperate in all aspects of the study and must give informed written 
acknowledgment (signed ICF) to the Investigator prior to participation in the study; such ICF 
shall be in a form that has been prior approved by Tricida and IRB/IEC.  If the ICF is revised 
during the study, active subjects must sign the new version in order to continue participating 


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in the study.  For any updated or revised ICF, the subject record should state that written 
informed consent was obtained for the updated/revised consent form for continued 
participation in the study.  The ICF should be revised whenever there are changes to 
procedures in the amended protocol associated with procedures in the ICF or when new 
information becomes available that may affect the willingness of the subject to participate; 
such revised ICF to be prior approved by Tricida and IRB/IEC.  Every subject will be given a 
copy of each version of the form that he/she signs before and during the study. 
No subject is to participate in study activities until informed consent has been obtained.  
Documentation of the informed consent process and subject information discussion must 
appear in the subject’s medical record, and include a statement that informed consent was 
obtained prior to participation in the study. Signed acknowledgments (ICFs) must remain in 
the subjects’ files and be available for verification by monitors, auditors, and/or regulatory 
agency inspectors at any time.  The final IRB/IEC-approved ICF must be provided to Tricida 
for regulatory purposes. 
 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IRB/IEC/Regulatory Authority, in accordance with local legal requirements. 
Tricida and the Investigator must ensure that all ethical and legal requirements have been met 
before the first subject is enrolled in the study at the investigational site. 
This protocol is to be followed exactly.  To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Regulatory Authority 
approval prior to implementation (if appropriate).  
All amendments will be distributed to all protocol recipients, with appropriate instructions. 
 
Premature Termination of the Study 
If Tricida or the Medical Monitor becomes aware of conditions or events that suggest a 
possible hazard to subjects if the study continues, the study may be terminated after 
appropriate consultation between the relevant parties.  The study may also be terminated 
early at Tricida’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• 
The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study 
• 
Failure to enroll subjects at an acceptable rate 
 


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
Confidential 
 
Page 67 of 74 
 
Confidentiality 
All study findings and documents shall be regarded as confidential information of Tricida.  
The Investigator and members of his/her research team must not disclose such information 
without prior written approval from Tricida. 
The anonymity of participating subjects must be maintained.  Subjects will be identified on 
eCRFs and other documents submitted to Tricida (or designee) by their subject number, not 
by name.  Documents not to be submitted to Tricida (or designee) that identify the subject 
(e.g., the signed ICF) must be maintained in confidence by the Investigator.   
Signed ICFs must be available for verification by monitors, auditors, and/or regulatory 
agency inspectors at any time. 
 
Liability and Insurance 
Prior to the start of the study, Tricida (or its designee) and the Investigator (or the institution, 
as applicable) will agree on costs necessary to perform the study.  This agreement will be 
documented in a Clinical Trial Agreement that will be signed by the institution and/or 
Investigator and Tricida (or its designee).  
The institution and Investigator are required to have adequate current insurance to cover any 
liabilities arising out of its conduct of the study, including insurance to cover claims for 
negligence and/or malpractice.  Tricida will provide insurance coverage for the research 
study as required by local and/or national regulations. 
 
Publication Policy 
By signing the study protocol, the Investigator agrees with Tricida’s use of results of the 
study for the purposes of national and international registration, publication and information 
for medical and pharmaceutical professionals.  In addition, the Investigator agrees that, if 
necessary, the authorities will be notified of the Investigator's name, address, qualifications 
and extent of involvement in this study. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with Tricida in advance and receiving Tricida’s prior written approval of such 
publication. 
12 
REFERENCE LIST 
Abramowitz MK, Melamed ML, Bauer C, Raff AC, Hostetter TH. 2013. "Effects of Oral 
Sodium Bicarbonate in Patients with CKD." Clin J Am Soc Nephrol. 8: 714-720. 
Binder H.  Intestinal fluid and electrolyte movement.  In: Medical Physiology. Philadelphia, 
PA. Elsevier, Inc. 2012: 933-948. 


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
Confidential 
 
Page 68 of 74 
Csuka M, McCarty DJ. 1985. “Simple method for measurement of lower extremity muscle 
strength.” Am J Med. 78:77-81. 
de Brito-Ashurst I, Varagunum M, Raftery MJ, Yaqoob MM. 2009. “Bicarbonate 
supplementation slows progression of CKD and improves nutritional status.”  J Am Soc 
Nephrol. 9(20): 2075-2084. 
Dobre M, Rahman M, Hostetter TH. 2015. "Current Status of Bicarbonate in CKD." J Am 
Soc Nephrol. 26(3): 515-523. 
Dobre M, Yang W, Chen J, Drawz P, Hamm LL, Horwitz E, Hostetter T, Jaar B, Lora CM, 
Nessel L, Ojo A, Scialla J, Steigerwalt S, Teal V, Wolf M, Rahman M and CRIC 
Investigators. 2013. "Association of Serum Bicarbonate With Risk of Renal and 
Cardiovascular Outcomes in CKD: A Report From the Chronic Renal Insufficiency Cohort 
(CRIC) Study." Am J Kidney Dis. 62(4): 670-678. 
Domrongkitchaiporn S, Pongskul C, Sirikulchayanont, V, Stitchantrakul W, Leeprasert V, 
Ongphiphadhanakul B, Radinahamed P, Rajatanavin R. 2002. "Bone Histology and Bone 
Mineral Density after Correction of Acidosis in Distal Renal Tubular Acidosis." Kidney Int. 
62(6): 2160-216. 
Eustace JA, Astor B, Muntner PM, Ikizler TA, Coresh J. 2004. "Prevalence of Acidosis and 
Inflammation and Their Association with Low Serum Albumin in Chronic Kidney Disease." 
Kidney Int. 65(3): 1031-1040. 
Garneata L, Stancu A, Dragomir D, Stefan G, Mircescu G. 2016. “Ketonalogue-
Supplemented Vegetarian Very Low-Protein Diet and CKD Progression.” J Am Soc 
Nephrol. 27: 2164-2176. 
Goraya N, Simoni J, Jo CH, Wesson DE. 2014. "Treatment of Metabolic Acidosis in Patients 
with Stage 3 Chronic Kidney Disease with Fruits and Vegetables or Oral Bicarbonate 
Reduces Urine Angiotensin and Preserves Glomerular Filtrate Rate." Kidney Int. 86(5): 
1031-1038. 
Goraya N, Wesson DE. 2013. "Does Correction of Metabolic Acidosis Slow Chronic Kidney 
Disease Progression?" Curr Opin Nephrol Hypertens. 22(2): 193-197. 
Jung T, Kamm W, Breitenbach A, Kaiserling E, Xiao JX, Kissel T. 2000. “Biodegradable 
nanoparticles for oral delivery of peptides:  is there a role for polymers to affect mucosal 
uptake?” Eur J Pharm Biopharm. 50(1): 147-160. 
Kidney Disease and Quality of LifeTM Short Form (KDQOL-SFTM). 
Kidney Disease Improving Global Outcomes (KDIGO) Blood Pressure Working Group 
2013. 2013. "KDIGO Clinical Practice Guideline for the Evaluation and Management of 
Chronic Kidney Disease." 


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
Confidential 
 
Page 69 of 74 
Kidney Disease Outcomes Quality I. 2003. "K/DOQI Clinical Practice Guidelines for Bone 
Metabolism and Disease in Chronic Kidney Disease." Am J Kidney Dis. 42(supple 3): 1-201. 
Kidney Disease Outcomes Quality I. 2002. "K/DOQI Clinical Practice Guidelines for 
Chronic Kidney Disease: Evaluation, Classification and Stratification." Am J Kidney Dis. 
39(2)(suppl 1): S1-S266. 
Kovesdy CP, Anderson JE, Kalantar-Zadeh K. 2009. "Association of serum bicarbonate 
levels with mortality in patients with non-dialysis-dependent CKD." Nephrol Dial 
Transplant. 24(4): 1232-1237. 
Mahajan A, Simoni J, Sheather SJ, Broglio KR, Rajab MH, Wesson DE. 2010. "Daily Oral 
Sodium Bicarbonate Preserves Glomerular Filtration Rate by Slowing its Decline in Early 
Hypertensive Nephropathy." Kidney Int. 78(3): 303-309. 
Moranne O, Froissart M, Rossert J, Gauci C, Boffa J-J, Haymann JP, M'rad MB, Jacquot C, 
Houillier P, Stengel B, Fouqueray B; NephroTest Study Group. 2009. "Timing of Onset of 
CKD-Related Metabolic Complications." J Am Soc Nephrol. 20(1): 164-171. 
Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Wehbe E, Raina R, Simon JF, Srinivas 
TR, Jain A, Schreiber MJ Jr and Nally JV Jr. 2011. "Serum bicarbonate and mortality in 
stage 3 and stage 4 chronic kidney disease." Clin J Am Soc Nephrol. 6(10): 2395-2402. 
Phisitkul S, Khanna A, Simoni J, Broglio K, Sheather S, Rajab MH, Wesson DE. 2010. 
"Amelioration of Metabolic Acidosis in Patients with Low GFR Reduced Kidney Endothelin 
Production and Kidney Injury, and Better Preserved GFR." Kidney Int. 77(7): 617-623. 
Raphael KL, Murphy RA, Shlipak MG, Satterfield S, Huston HK, Sebastian A, Sellmeyer 
DE, Patel KV, Newman AB, Sarnak MJ, Ix JH, Fried LF; Health ABC Study. 2016. 
"Bicarbonate Concentration, Acid-Base Status, and Mortality in the Health, Aging, and Body 
Composition Study." Clin J Am Soc Nephrol. 11(2): 308-316. 
Raphael KL, Zhang Y, Ying J, Greene T. 2014. "Prevalence of and risk factors for reduced 
serum bicarbonate in chronic kidney disease." Nephrology (Carlton). 19(10): 648-654. 
Raphael KL, Wei G, Baird BC, Greene T, Beddhu S. 2011. "Higher Serum Bicarbonate 
Levels Within the Normal Range are Associated with Better Survival and Renal Outcomes in 
African Americans." Kidney Int. 79(3): 356-362. 
Shah SN, Abramowitz M, Hostetter TH, Melamed ML. 2009. "Serum Bicarbonate Levels 
and the Progression of Kidney Disease: a Cohort Study." Am J Kidney Dis. 54(2): 270-277. 
Swartz, RD. 1996. "Fluid, Electrolyte, and Acid-Base Changes During Renal Failure." In 
Fluids and Electrolytes, edited by Kokko and Tannen, 487-532. Philadelphia, PA: WB 
Sunders Company. 


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Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
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Tangri N, Stevens LA, Griffith J, Tighiouart H, Djurdjev O, Naimark D, Levin A, Levey AS. 
2011. "A Predictive Model for Progression of Chronic Kidney Disease to Kidney Failure." 
JAMA. 305(15)15: 1553-1559. 
Toto RD, Alpern RJ. 1996. "Metabolic Acid-Base Disorders." In Fluids and Electrolytes, 
edited by Kokko and Tannen, 201-266. PA: WB Saunders. 
Turnberg L, Bieberdorf F, Morawski S et al. 1970. “Interrelationships of Chloride, 
Bicarbonate, Sodium, and Hydrogen Transport in the Human Ileum.  J Clin Invest. 
49(3):557-567. 
Weiner ID, Mitch WE, Sands JM. 2015. "Urea and Ammonia Metabolism and the Control of 
Renal Nitrogen Excretion." Clin J Am Soc Nephrol. 10(8): 1444-1458. 


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Clinical Study Protocol: TRCA-301E 
 
October 17, 2018 
 
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13 
APPENDICES 
 


TRC101 
 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
 
October 17, 2018 
 
Confidential 
 
Page 72 of 74 
Appendix 1: Schedule of Events 
Study Activity 
Period 
Screening 
Treatment 
Follow-up 
 
UNS 
Visit [q] 
Visit Name 
W12 
W14 
W16 
W20 
W24 
W28 
W34 
W40 
W46 
W52/ET [a] 
F1 
F2 
 
Timing 
Week  
12 
Week  
14 
Week 
16 
Week  
20 
Week  
24 
Week  
28 
Week 
34 
Week 
40 
Week 
46 
Week  
52/ET 
Week  
53 
Week 
54 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X [b] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs [c]  
X [b] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body Weight 
X [b] 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Physical Exam [d] 
X [b] 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Repeated Chair Stand Test 
X [b] 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
KDQOL Question 3 
X [b] 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
ECG [e] 
X [b] 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Fasting i-STAT Bicarbonate [f] 
L [b] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Fasting Blood Bicarbonate 
(Enzymatic Serum or Venous Blood 
Gas Assay) [g] 
L [b] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Fasting Serum Chemistry 
C [b] 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
C 
Coagulation [h] 
L [b] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Pregnancy Test [i] 
C [b], L 
 
C 
C 
C 
C 
C 
C 
C 
C 
 
C 
 
C 
Hematology 
C [b] 
 
 
C 
 
C 
 
C 
 
 
C 
 
C 
 
C 
Hemoglobin A1c 
C [b] 
 
 
 
 
 
 
 
 
C 
 
 
 
C 
Biomarkers (Blood and Urine) [j] 
C [b] 
 
 
 
 
 
 
 
 
C 
 
 
 
 
Urinalysis and Spot Urine Tests  
C [b] 
  
  
C 
 
C 
 
C 
 
C 
 
C 
 
C 
Training on 24-Hour Urine 
Collection and Dispensing Supplies 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
24-Hour Urine Collection [k] 
C [b] 
 
 
 
 
 
 
 
 
C 
 
 
 
 
Dispensation of Study Drug [l] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Discontinue/Re-start Oral Alkali 
Supplement for Subjects Taking it at 
Week 12 Visit per Appendix 2 [m] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Daily Self-Administration of Study 
Drug 
X [n] 
 
 
 
 
Study Drug Dosing Compliance and 
Accountability [o] 
X [b] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse Event Collection 
X [b,p] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dietary Counseling 
X [b] 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 


TRC101 
 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
 
October 17, 2018 
 
Confidential 
 
Page 73 of 74 
Notes:  All blood draws for bicarbonate measurements must be done with subjects in a fasted state (at least 4 hours, except water).  Allowed visit windows are:   
± 4 days for Week 14, 16, 20, 24 Visits;  ± 7 days for Week 28, 34, 40, 46 and 52 Visits (Week 52 Visit must not occur earlier than the 1-year anniversary of the 
Day 1 Visit in the parent study TRCA-301);  and ± 2 days for Follow-up 1 and 2 Visits. 
Abbreviations:  C = central laboratory assessment;  ECG = electrocardiogram;  L = local laboratory assessment;  UNS = unscheduled. 
a  
The Week 52 visit will occur no earlier than the 1 year anniversary of the Day 1 visit in study TRCA-301.  Subjects who discontinue the study prior to 
Week 52 are required to undergo an Early Termination Visit with all Week 52 Visit procedures to be performed.  All subjects who discontinue study 
drug prior to Week 52 will be contacted by telephone at the Week 52 Visit timepoint to ascertain vital status and renal status (i.e., receiving renal 
replacement therapy or not).   
b  
Data collected for the Week 12 Visit in Study TRCA-301 will serve as the Week 12 Visit data in this extension study. 
c  
Vital signs include:  blood pressure and respiratory rate (both in triplicate, measurements taken approximately 2 minutes apart at Week 12 and Week 52 
Visits; once at all other time points), heart rate, and temperature. 
d  
Complete physical examination will include an examination of cardiovascular, lungs and chest, head and neck, abdomen, musculoskeletal, skin and 
neurological systems (genitourinary examination not required). 
e  
ECG will be collected in triplicate, 30 seconds apart.  The subject must be in a supine position, or in the most recumbent position possible, in a rested 
and calm state for at least 5 minutes before the ECG assessment is conducted.  All ECGs should be performed prior to blood draws whenever possible.  
f  
The i-STAT G3+ cartridge must be used and measurement taken from a whole blood sample within 10 min of the blood draw. 
g  
Either enzymatic or venous blood gas assay but consistent for each subject as soon as possible in accordance with local laboratory requirements.   
h  
For subjects receiving vitamin K antagonists or factor Xa inhibitors only. Vitamin K antagonists include warfarin and acenocoumaral. Factor Xa 
inhibitors include apixaban, rivaroxaban, betrixaban, edoxaban and enoxaparin. 
i  
For women of childbearing potential, blood samples will be collected for serum pregnancy tests at the visits indicated.  At the Week 12 Visit, a urine 
sample will be collected for a urine dipstick pregnancy test conducted at the study site.   
j  
Blood and urine biomarker samples will be collected and stored under frozen conditions as specified in the laboratory manual. 
k  
Instruct subjects on collecting 24-hour urine samples and dispense necessary supplies.  Subjects should collect urine samples at home in accordance 
with the Urine Collection Instructions and return the collected specimens at the Week 12 and Week 52 Visits. 
l  
Dispense study drug per IRT instructions.  Instruct subject to take study drug with food at approximately the same time each day, at least 4 hours apart 
from all oral concomitant medications.   
m  
Oral alkali supplement (for subjects taking one at the Week 12 Visit only), should be discontinued or re-started based on blood bicarbonate level and 
study drug dose as described in Appendix 2. 
n  
The last dose of study drug shall be administered 1 day before the Week 52 Visit. 
o  
Instruct subject to bring all used and unused study drug containers to each visit.  Collect all study drug containers at the Week 52 Visit or at ET Visit. 
p  
Adverse events with a start date during the parent study, TRCA-301, that are ongoing at the time of enrollment in TRCA-301E and adverse events with 
an onset following enrollment in TRCA-301E will be recorded. 
q  
Possible procedures during the unscheduled visit are listed.  The actual procedures should be determined by the Investigator based on the reason for the 
unscheduled visit.  In all cases, reason for the visit and recording of adverse events and concomitant medications should be done.  


TRC101 
 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301E 
 
 
October 17, 2018 
Confidential 
 
Page 74 of 74 
Appendix 2: Study Drug and Oral Alkali Supplement Titration Algorithm 
Blood Bicarbonate 
(mEq/L) 
Study Drug 
Oral Alkali Supplementa 
< 12b 
At Week 12 Visit:  Do not enroll subject in Study TRCA-301E 
During Treatment Period:  Evaluate for new acute acidotic process, contact Medical Monitor.  Maintain dose(s) pending discussion 
with Medical Monitor. 
12 to < 22 
Increase the study drug dose by 1 packet/day 
(maximum dose is 3 packets/day). 
Only increase the dose if NO dose changes have 
been made during the previous 14 days. 
Retest blood bicarbonate at next scheduled visit. 
Maintain dose until next scheduled visit. 
22 to < 27 
Maintain dose until next scheduled visit. 
Discontinue oral alkali supplement until the next scheduled visit. If bicarbonate 
remains ≥ 22 mEq/L, do not re-instate oral alkali.  If bicarbonate is < 22 mEq/L at 
the next scheduled visit, increase study drug dose by one packet and retest 
bicarbonate at the next scheduled visit.  If a subject who was taking oral alkali at 
the Week 12 Visit had their oral alkali discontinued, AND they are receiving the 
maximum dose of study drug (i.e., 3 packets) AND their blood bicarbonate value 
is < 22 mEq/L, re-instate the same oral alkali supplement subject was taking at the 
Week 12 Visit at the same dose taken at the Week 12 Visitc.  If the Investigator 
judges that re-starting alkali treatment poses a safety risk, the risk should be 
documented.  In this situation, alkali will not be re-started. 
27 to 30 
Maintain dose.   
Invite subject for a visit in approximately 1 to 2 
weeks to retest blood bicarbonate. 
 
> 30b 
Interrupt (hold) study drug. 
Invite subject for a visit in approximately 1 week 
to retest blood bicarbonate.   
If blood bicarbonate at that visit is: 
≤ 30 mEq/L, restart study drug at a lower dose     
(1 packet/day less than before dose interruption) 
except for subjects on 1 packet/day prior to dose 
interruption, who will restart study drug at 1 
packet/day dose. 
> 30 mEq/L, continue to hold the dose and retest 
again in approximately 1 week. 
Discontinue oral alkali supplement. 
a For subjects taking an oral alkali supplement at Week 12 only. 
b Blood bicarbonate values of < 12 mEq/L or > 30 mEq/L must be confirmed by a repeated measurement from a separate blood draw.  
c The Week 12 dose is defined as the average daily dose prescribed during Week 12. 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title:  
 A Blinded, Placebo-Controlled Extension to Study TRCA- 
301 to Evaluate the Long-term Safety and Durability of Effect 
of TRC101 in Subjects with Chronic Kidney Disease and 
Metabolic Acidosis 
 
Study Number:  
TRCA-301E 
 
NCT Number:  
NCT03390842 
 
Document Date:  
12 February 2019 
 
  


 
 
STATISTICAL ANALYSIS PLAN 
Study Title: 
A Blinded, Placebo-Controlled Extension to Study TRCA-301 
to Evaluate the Long-term Safety and Durability of Effect of 
TRC101 in Subjects with Chronic Kidney Disease and 
Metabolic Acidosis 
Study Number: 
TRCA-301E 
Investigational Drug: 
TRC101 
IND Number: 
125,832 
Indication: 
Treatment of metabolic acidosis associated with chronic 
kidney disease  
Investigators: 
Multicenter 
EudraCT Number: 
2017-002562-42 
Sponsor: 
Tricida, Inc. 
7000 Shoreline Court, Suite 201 
South San Francisco, CA 94080, U.S.A. 
Plan Version: 
12 February 2019 (Version 1.0) 
Plan Prepared by: 
, MS 
Statistical Consultant 
 
 
CONFIDENTIAL 
This document is confidential and property of Tricida, Inc.  It may not be copied or 
provided to any other party without the express written consent of Tricida, Inc. 
2019 Tricida, Inc. 
 
 




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Table of Contents 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 8 
2 
REVISION HISTORY......................................................................................................... 11 
3 
RELEVANT DOCUMENTS: PROTOCOL, AMENDMENTS AND CASE REPORT 
FORMS ................................................................................................................................ 11 
4 
COMMITMENT TO GOOD STATISTICAL PRACTICE ................................................ 11 
 
Definition of Good Statistical Practice .................................................................... 11 
 
Use of Standards ...................................................................................................... 12 
5 
PURPOSE OF THE ANALYSIS PLAN ............................................................................. 12 
6 
STUDY OBJECTIVES ........................................................................................................ 12 
7 
STUDY DESIGN................................................................................................................. 13 
 
Overall Study Design ............................................................................................... 13 
 
Randomization and Blinding ................................................................................... 17 
 
Assessments in Study TRCA-301E ......................................................................... 17 
 
Safety Measurements ................................................................................... 17 
 
Efficacy Measurements ................................................................................ 17 
 
Other Measurements .................................................................................... 18 
8 
SAMPLE SIZE AND POWER ............................................................................................ 18 
9 
ANALYSIS SETS ............................................................................................................... 18 
 
TRCA-301E Safety Analysis Set ............................................................................. 18 
 
TRCA-301E Modified Intent-To-Treat Analysis Set .............................................. 18 
 
TRCA-301E Per Protocol Analysis Set ................................................................... 18 
 
Phase 3 Safety Analysis Set ..................................................................................... 19 
 
Randomized and Enrolled Subjects ......................................................................... 19 
10 
GENERAL CONSIDERATIONS ....................................................................................... 19 
 
Convention for Data Presentation ............................................................................ 19 
 
Definitions and Derived Variables ........................................................................... 20 
 
Baseline Values ............................................................................................ 20 
10.2.1.1 
Baseline Serum Bicarbonate Value Using i-STAT ...................... 20 
10.2.1.2 
Screening and Baseline Estimated Glomerular Filtration Rate 
Values ........................................................................................... 21 
10.2.1.3 
Baseline Serum Creatinine ............................................................ 21 
10.2.1.4 
Baseline Urine Albumin-to-Creatinine Ratio ............................... 21 
10.2.1.5 
Baseline Electrocardiogram Parameters ....................................... 22 
 
Change from Baseline Value ....................................................................... 22 
 
Responder .................................................................................................... 22 


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Study Day..................................................................................................... 22 
 
Age ............................................................................................................... 22 
 
Estimated Glomerular Filtration Rate .......................................................... 22 
 
Anion Gap .................................................................................................... 23 
 
Multiple Records at a Time Point ................................................................ 23 
 
Treatment-Emergent Adverse Events .......................................................... 23 
 
Prior and Concomitant Medications ............................................................ 24 
 
Alkali Therapy ............................................................................................. 24 
 
Acid Reducing Drug .................................................................................... 24 
 
Calcium Supplement Medication ................................................................. 25 
 
Antihypertensive Medication ....................................................................... 25 
 
Diuretic Medication ..................................................................................... 25 
 
KDQOL Physical Functioning Survey ........................................................ 25 
 
Repeated Chair Stand Test ........................................................................... 26 
 
Hemolysis .................................................................................................... 26 
 
Analysis Windows ................................................................................................... 26 
11 
STATISTICAL AND ANALYSIS ISSUES ....................................................................... 27 
 
Adjustments for Covariates...................................................................................... 27 
 
Handling Dropouts or Missing Data ........................................................................ 28 
 
General Considerations ................................................................................ 28 
 
Evaluating Missing Data .............................................................................. 28 
11.2.2.1 
Missing Data in Serum Bicarbonate ............................................. 28 
11.2.2.2 
Missing Data in KDQOL Physical Functioning Survey and 
Repeated Chair Stand Test ............................................................ 28 
 
Handling of Safety Data........................................................................................... 29 
 
Adverse Events ............................................................................................ 29 
 
Prior and Concomitant Medications ............................................................ 30 
 
Interim Analyses and Data Monitoring.................................................................... 30 
 
Multicenter Considerations ...................................................................................... 31 
 
Multiple Comparisons, Multiplicity......................................................................... 31 
 
Use of an “Efficacy Subset” of Subjects.................................................................. 31 
 
Active-Control Studies............................................................................................. 31 
 
Examination of Subgroups ....................................................................................... 32 
12 
STUDY PATIENTS ............................................................................................................ 33 
 
Subject Disposition .................................................................................................. 33 
 
Overall Summary ......................................................................................... 33 
 
Examination of Time to Early Discontinuation of the Study ...................... 34 


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Protocol Deviations .................................................................................................. 34 
 
Demographics and Baseline Characteristics ............................................................ 35 
 
Medical History ....................................................................................................... 35 
13 
STUDY DRUG AND OTHER MEDICATIONS ............................................................... 36 
 
Study Drug Exposure, Compliance, and Titration ................................................... 36 
 
Study Drug Exposure ................................................................................... 36 
 
Study Drug Compliance ............................................................................... 36 
 
Dose Titration .............................................................................................. 37 
 
Prior and Concomitant Medications ........................................................................ 38 
 
Restricted Medications............................................................................................. 38 
 
Medications Used for Certain Analyses .................................................................. 38 
 
Calcium Supplements and Selected Antihypertensive Medications ............ 38 
 
Diuretics ....................................................................................................... 39 
14 
EFFICACY ANALYSES .................................................................................................... 39 
 
Endpoints, Analyses, and Analysis Variables.......................................................... 39 
 
Main Durability of Effect Endpoints ........................................................... 39 
 
Additional Durability of Effect Analyses .................................................... 39 
 
Exploratory Analyses ................................................................................... 40 
14.1.3.1 
Individual Items from KDQOL Physical Functioning Survey ..... 40 
14.1.3.2 
Biomarkers .................................................................................... 40 
14.1.3.3 
Offset of Treatment Effect ............................................................ 41 
 
Efficacy Variables ........................................................................................ 41 
14.1.4.1 
Change from Baseline in Serum Bicarbonate ............................... 41 
14.1.4.2 
Categorical Change in Serum Bicarbonate ................................... 41 
14.1.4.3 
Other Change from Baseline Variables ........................................ 42 
 
Responder Analysis Method .................................................................................... 42 
 
Reporting Results ......................................................................................... 42 
 
Statistical Hypotheses .................................................................................. 42 
 
Statistical Testing ......................................................................................... 43 
 
Evaluating Interactions ................................................................................ 43 
 
Analysis Method for Change from Baseline in Serum Bicarbonate ........................ 44 
 
Mixed-effect Model for Repeated Measures ............................................... 44 
 
Reporting Results ......................................................................................... 44 
 
Using Ranked-Based Models ....................................................................... 45 
 
Analysis Method for Other Change from Baseline Variables ................................. 45 
 
Analysis of Covariance ................................................................................ 45 
 
Reporting Results ......................................................................................... 46 


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Hypothesis and Testing for Change from Baseline Analyses .................................. 46 
 
Statistical Hypothesis ................................................................................... 46 
 
Statistical Testing ......................................................................................... 46 
 
Categorical Analysis Methods ................................................................................. 47 
 
Individual Components of the Response ..................................................... 47 
 
Categorical Change in Serum Bicarbonate .................................................. 47 
 
Individual Items of the KDQOL Physical Functioning Survey ................... 47 
 
Analysis of Offset of Treatment Effect .................................................................... 47 
 
Sensitivity Analyses ................................................................................................. 48 
 
Serum Bicarbonate ....................................................................................... 48 
 
Time to Complete Repeated Chair Stand Test ............................................. 48 
15 
SAFETY ANALYSES......................................................................................................... 48 
 
Safety Variables ....................................................................................................... 49 
 
Adverse Events ........................................................................................................ 49 
 
TEAEs Occurring during Study TRCA-301E ............................................. 50 
 
Additional Analyses of Selected Adverse Events ........................................ 50 
 
Summary and Analyses of Death and Renal Disease Progression .......................... 51 
 
Survival Analysis ......................................................................................... 51 
 
Time-to-Event Analyses .............................................................................. 51 
 
Incidence of High Bicarbonate ................................................................................ 52 
 
Clinical Laboratory Evaluation ................................................................................ 52 
 
Analysis of Variables Reported as Ratio to Serum Creatinine .................... 53 
 
Out of Range Summary ............................................................................... 54 
 
Vital Signs ................................................................................................................ 55 
 
Body Weight ............................................................................................................ 56 
 
12-lead Electrocardiogram ....................................................................................... 56 
 
Physical Examination............................................................................................... 56 
16 
SUBGROUP ANALYSES .................................................................................................. 56 
17 
DEVIATIONS FROM THE PROTOCOL SPECIFIED ANALYSIS ................................ 58 
 
Analysis of Change from Baseline in Serum Bicarbonate....................................... 58 
18 
REFERENCES .................................................................................................................... 58 
19 
APPENDICES ..................................................................................................................... 58 
 
Anatomical Therapeutic Chemical Level 4 Terms for ACEi or ARB ..................... 58 
 
Anatomical Therapeutic Chemical Level 4 Terms for Potassium-Sparing Diuretics
.................................................................................................................................. 58 
 
Gastrointestinal Nonspecific Inflammation and Dysfunctional Conditions 
(Standardised MedDRA Queries) ............................................................................ 59 


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Hyperkalemia Events ............................................................................................... 63 
 
List of Tables 
Table 1 
Study TRCA-301E Schedule of Events (Protocol Amendment 3) ............................. 15 
Table 2 
Analysis Visit Windows ............................................................................................. 26 
Table 3 
Concomitant Medications in TRCA-301 and/or TRCA-301E ................................... 30 
Table 4 
Laboratory Parameters ................................................................................................ 53 
Table 5 
Pre-Specified Threshold Levels for Selected Laboratory Tests ................................. 54 
Table 6 
Pre-Specified Threshold Levels for Vital Signs ......................................................... 55 
Table 7 
Pre-Specified Threshold Levels for Electrocardiogram Parameters ........................... 56 
Table 8 
List of Pre-Specified Subgroup Analyses at Week 52 ................................................ 57 
 
 


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1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
AA 
aldosterone antagonist 
ACEi 
angiotensin-converting enzyme inhibitor 
ACR 
albumin to creatinine ratio 
ADaM 
analysis data model 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AR (1) 
first-order autoregressive structure 
ARB 
angiotensin II receptor blocker 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BSAP 
bone-specific alkaline phosphatase 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CFB 
change from baseline 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CM 
concomitant medication 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CRO 
clinical research organization 
CSR 
clinical study report 


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Abbreviation 
Description 
CTX 
C-terminal telopeptide 
DDD 
death, renal replacement therapy, or doubling of serum creatinine 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
eGFR(Cys) 
estimated glomerular filtration rate derived from serum cystatin C 
ET 
early termination 
FDA 
The Food and Drug Administration 
HR  
heart rate 
ICH 
International Council on Harmonisation  
IRT 
interactive response technology 
KDQOL 
kidney disease quality of life questionnaire 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
MMRM 
mixed-effect model repeated measures 
MRA 
mineralocorticoid receptor antagonist 
n 
number of subjects 
NTX 
N-terminal telopeptide 
PP 
per-protocol 
PT 
preferred term 
P1NP 
procollagen 1 N-terminal propeptide 
QTcF 
Corrected value of the interval between the Q and T waves on the 
electrocardiogram tracing, corrected using Fridericia’s formula 


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Abbreviation 
Description 
RAAS 
renin-angiotensin-aldosterone system 
REML 
restricted maximum likelihood 
RRT 
renal replacement therapy 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
standard error 
SF-36 
36-item Short Form Health Survey 
SMQ 
Standardised MedDRA Queries 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
TRAP 5b 
tartrate-resistant acid phosphatase 5b 
USA 
United States (of America) 
WHO DD 
World Health Organization drug dictionary 
 
 


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2 
REVISION HISTORY 
Version 
Date 
Document 
Owner 
Revision Summary 
1.0 
12Feb2019 
 
Original 
3 
RELEVANT DOCUMENTS: PROTOCOL, AMENDMENTS AND CASE REPORT 
FORMS 
Original Protocol (September 5, 2017) 
Protocol Amendment 1 (December 11, 2017) 
Protocol Amendment 2 (May 31, 2018) 
Protocol Amendment 3 (October 17, 2018) 
Case Report Form (CRF) Version 1.0 (December 14, 2017) 
CRF Version 2.0 (January 29, 2018) 
CRF Version 3.0 (June 29, 2018) 
4 
COMMITMENT TO GOOD STATISTICAL PRACTICE 
 
Definition of Good Statistical Practice 
Guidance on Statistical Principles for Clinical Trials from International Council on Harmonisation 
(ICH E9) implicitly defines good statistical practice.  Good statistical practice includes both 
appropriate statistical designs to minimize bias and maximize precision of analysis plus 
operational excellence to assure credibility of results.  The scientific design associated with any 
clinical trial is found in the protocol and a more detailed, pre-specified statistical analysis plan 
such as this one presents the final statistical methods.   
Tricida and 
 interpret the operational side of good statistical practice as a transparent, 
reproducible, and validated approach to acquiring and analyzing clinical trial data.  Reproducible 
research depends upon process transparency and also provides auditability of the statistical 
analysis.  Analysis transparency requires that a navigable electronic process chain exist from 
defining the objective of the analysis to creating the results. 


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Use of Standards 
Data standards are foundational for creating an environment where tools can be leveraged at 
different points in the analysis process.  Data standards for clinical development of drugs have 
been defined and are maturing under various initiatives through the Clinical Data Interchange 
Standards Consortium (CDISC).  Tricida uses Study Data Tabulation Model (SDTM) datasets and 
Analysis Data Model (ADaM) statistical analysis files for producing analysis results.  Other 
applicable standards include regulatory guidance from the Food and Drug Administration (FDA) 
and ICH: 
• ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3) 
• ICH Guidance for Good Clinical Practice (ICH E6 [R2]) 
• ICH Guidance for Statistical Principles for Clinical Trials (ICH E9) 
5 
PURPOSE OF THE ANALYSIS PLAN 
The purpose of this statistical analysis plan (SAP) is to pre-specify the statistical analysis methods 
for supporting the completion of the clinical study report (CSR) for Study TRCA-301E for 
investigational product TRC101.  This SAP will be used for data analysis and evaluation of the 
long-term safety and durability of TRC101 effect in chronic kidney disease (CKD) patients with 
metabolic acidosis.  The planned analyses identified in this SAP may be included in regulatory 
submissions, and/or future manuscripts.  The analysis methods described in this plan are 
considered a priori, in that they have been prospectively defined prior to clinical database lock.  
Exploratory analyses, which are not defined in this SAP, may be performed to support the clinical 
development program.  Any changes from the planned analyses as stated in the study protocol will 
be documented in the CSR. 
6 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the long-term safety and durability of effect of TRC101 
in CKD patients with metabolic acidosis. 
The durability of effect of TRC101 will primarily be evaluated through the following analyses: 


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• Responder at the end of treatment (Week 52 Visit) (see definition in Section 10.2.3 and 
analysis in Section 14.2) 
• Change from baseline in serum bicarbonate at the end of treatment (Week 52 Visit) (see 
definition in Section 10.2.2 and analysis in Sections 14.3) 
• Change from baseline in total score of kidney disease quality of life questionnaire 
(KDQOL) Physical Functioning Survey (Week 52 Visit) (see definition in Section 10.2.16 
and analysis in Sections 14.4) 
• Change from baseline in the duration of repeated chair stand test (Week 52 Visit) (see 
definition in Section 10.2.17 and analysis in Sections 14.4) 
7 
STUDY DESIGN 
 
Overall Study Design 
This study is a 40-week, blinded (Investigators and subjects), placebo-controlled extension of 
Study TRCA-301 (a Phase 3, multicenter, double-blind, randomized, placebo-controlled study to 
evaluate the efficacy and safety of TRC101 in subjects with CKD and metabolic acidosis).  Eligible 
subjects who completed the 12-week Treatment Period in Study TRCA-301 (the parent study) had 
the option to participate in this extension study.  The study periods are as follows: 
• Week 12 Visit (1-day screening visit). 
• Treatment Period (starting with Week 12 Visit and continuing for 40 weeks, until Week 52 
Visit or early termination [ET]). 
• Follow-up Period (2 weeks after discontinuation of treatment). 
After the subject provided informed consent, the subject’s eligibility was to be evaluated based on 
laboratory values, vital signs, renal status, and pregnancy test (if applicable).  Eligible subjects 
continued to be treated with the same study drug they received in the parent study (TRC101 or 
placebo, once daily [QD]), on an out-patient basis for the subsequent 40 weeks (Treatment Period).  
The first dose of study drug in this extension study was taken on the day of the Week 12 Visit.   
The maximum duration of Study TRCA-301E was anticipated to be 42 weeks per subject (i.e., 40-
week Treatment Period and 2-week Follow-up Period).  Assessments and procedures for 
evaluation of safety were conducted per the protocol-specified schedule (see Table 1 for details). 
Enrollment in Study TRCA-301E was defined by completion of the enrollment procedure in the 
interactive response technology (IRT) system.  The enrollment procedure in the IRT system was 


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performed once subjects had completed participation in Study TRCA-301, they had provided 
informed consent for the extension study, and the Investigator (or designee) had determined they 
met all TRCA-301E eligibility criteria.   


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Table 1 
Study TRCA-301E Schedule of Events (Protocol Amendment 3) 
Study Activity 
Period 
Screening 
Treatment 
Follow-up 
 
UNS 
Visit [q] 
Visit Name 
W12 
W14 
W16 
W20 
W24 
W28 
W34 
W40 
W46 
W52/ET [a] 
F1 
F2 
 
Timing 
Week  
12 
Week  
14 
Week 
16 
Week  
20 
Week  
24 
Week  
28 
Week 
34 
Week 
40 
Week 
46 
Week  
52/ET 
Week  
53 
Week 
54 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X [b] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs [c]  
X [b] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body Weight 
X [b] 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Physical Exam [d] 
X [b] 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Repeated Chair Stand Test 
X [b] 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
KDQOL Physical Functioning 
Survey 
X [b] 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
ECG [e] 
X [b] 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Fasting i-STAT Bicarbonate [f] 
L [b] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Fasting Blood Bicarbonate 
(Enzymatic Serum or Venous Blood 
Gas Assay) [g] 
L [b] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Fasting Serum Chemistry 
C [b] 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
C 
Coagulation [h] 
L [b] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Pregnancy Test [i] 
C [b], L 
 
C 
C 
C 
C 
C 
C 
C 
C 
 
C 
 
C 
Hematology 
C [b] 
 
 
C 
 
C 
 
C 
 
C 
 
C 
 
C 
Hemoglobin A1c 
C [b] 
 
 
 
 
 
 
 
 
C 
 
 
 
C 
Biomarkers (Blood and Urine) [j] 
C [b] 
 
 
 
 
 
 
 
 
C 
 
 
 
 
Urinalysis and Spot Urine Tests  
C [b] 
  
  
C 
 
C 
 
C 
 
C 
 
C 
 
C 
Training on 24-Hour Urine 
Collection and Dispensing Supplies 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
24-Hour Urine Collection [k] 
C [b] 
 
 
 
 
 
 
 
 
C 
 
 
 
 
Dispensation of Study Drug [l] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Discontinue/Re-start Oral Alkali 
Supplement for Subjects Taking it at 
Week 12 Visit per Appendix 2 [m] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Daily Self-Administration of Study 
Drug 
X [n] 
 
 
 
 
Study Drug Dosing Compliance and 
Accountability [o] 
X [b] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse Event Collection 
X [b,p] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dietary Counseling 
X [b] 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 


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Notes:  All blood draws for bicarbonate measurements must be done with subjects in a fasted state (at least 4 hours, except water).  Allowed visit windows are:   
± 4 days for Week 14, 16, 20, 24 Visits; ± 7 days for Week 28, 34, 40, 46 and 52 Visits (Week 52 Visit must not occur earlier than the 1-year anniversary of the 
Day 1 Visit in the parent study TRCA-301); and ± 2 days for Follow-up 1 and 2 Visits. 
Abbreviations:  C = central laboratory assessment; ECG = electrocardiogram; ET = early termination; F = follow-up; IRT = interactive response technology; 
KDQOL = kidney disease quality of life; L = local laboratory assessment; UNS = unscheduled; W = week. 
a  
The Week 52 visit will occur no earlier than the 1-year anniversary of the Day 1 visit in study TRCA-301.  Subjects who discontinue the study prior to 
Week 52 are required to undergo an Early Termination Visit with all Week 52 Visit procedures to be performed.  All subjects who discontinue study 
drug prior to Week 52 will be contacted by telephone at the Week 52 Visit timepoint to ascertain vital status and renal status (i.e., receiving renal 
replacement therapy or not).   
b  
Data collected for the Week 12 Visit in Study TRCA-301 will serve as the Week 12 Visit data in this extension study. 
c  
Vital signs include:  blood pressure and respiratory rate (both in triplicate, measurements taken approximately 2 minutes apart at Week 12 and Week 52 
Visits; once at all other time points), heart rate, and temperature. 
d  
Complete physical examination will include an examination of cardiovascular, lungs and chest, head and neck, abdomen, musculoskeletal, skin and 
neurological systems (genitourinary examination not required). 
e  
ECG will be collected in triplicate, 30 seconds apart.  The subject must be in a supine position, or in the most recumbent position possible, in a rested 
and calm state for at least 5 minutes before the ECG assessment is conducted.  All ECGs should be performed prior to blood draws whenever possible.  
f  
The i-STAT G3+ cartridge must be used and measurement taken from a whole blood sample within 10 min of the blood draw. 
g  
Either enzymatic or venous blood gas assay but consistent for each subject as soon as possible in accordance with local laboratory requirements.   
h  
For subjects receiving vitamin K antagonists or factor Xa inhibitors only. Vitamin K antagonists include warfarin and acenocoumaral. Factor Xa 
inhibitors include apixaban, rivaroxaban, betrixaban, edoxaban and enoxaparin. 
i  
For women of childbearing potential, blood samples will be collected for serum pregnancy tests at the visits indicated.  At the Week 12 Visit, a urine 
sample will be collected for a urine dipstick pregnancy test conducted at the study site.   
j  
Blood and urine biomarker samples will be collected and stored under frozen conditions as specified in the laboratory manual. 
k  
Instruct subjects on collecting 24-hour urine samples and dispense necessary supplies.  Subjects should collect urine samples at home in accordance 
with the Urine Collection Instructions and return the collected specimens at the Week 12 and Week 52 Visits. 
l  
Dispense study drug per IRT instructions.  Instruct subject to take study drug with food at approximately the same time each day, at least 4 hours apart 
from all oral concomitant medications.   
m  
Oral alkali supplement (for subjects taking one at the Week 12 Visit only), should be discontinued or re-started based on blood bicarbonate level and 
study drug dose as described in Protocol Appendix 2. 
n  
The last dose of study drug shall be administered 1 day before the Week 52 Visit. 
o  
Instruct subject to bring all used and unused study drug containers to each visit.  Collect all study drug containers at the Week 52 Visit or at ET Visit. 
p  
Adverse events with a start date during the parent study, TRCA-301, that are ongoing at the time of enrollment in TRCA-301E and adverse events with 
an onset following enrollment in TRCA-301E will be recorded. 
q  
Possible procedures during the unscheduled visit are listed.  The actual procedures should be determined by the Investigator based on the reason for the 
unscheduled visit.  In all cases, reason for the visit and recording of adverse events and concomitant medications should be done.


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Randomization and Blinding 
There is not a separate randomization for this extension study; subjects remained in the same 
treatment group (TRC101 or placebo) to which they were assigned in the parent study, Study 
TRCA-301. 
The subjects, Investigators, site personnel (including all those involved in collection of safety and 
efficacy information) and clinical research organization (CRO) staff (except for those responsible 
for monitoring of potentially unblinding data [i.e., drug accountability]) are blinded to the subject’s 
treatment assignment.  To avoid unblinding of blinded site personnel to treatment assignment, 
strict blinding procedures related to drug accountability are to be adhered to at the site level for 
this study, similar to those utilized for the parent study.  Specifically, designated site staff, with no 
other responsibilities for the study, are responsible for study drug accountability and collection of 
used and unused study drug.  The division of responsibilities between the unblinded staff and other 
study staff (who are blinded to treatment assignment in the parent study, TRCA-301) are detailed 
in the study Blinding Plan. 
 
Assessments in Study TRCA-301E 
Table 1 shows the schedule of events of this study.   
 Safety Measurements 
Safety is assessed by repeated clinical evaluation, including adverse events (AEs), serious adverse 
events (SAEs), vital signs, physical examination, 12-lead electrocardiograms (ECG), and clinical 
laboratory tests (chemistry, hematology, coagulation, spot urine, and urinalysis) from central 
laboratories. 
 Efficacy Measurements 
Efficacy is assessed by  
• i-STAT bicarbonate measurements at Weeks 14, 16, 20, 24, 28, 34, 40, 46, 52/ET, 53, and 
54.   
• KDQOL Physical Functioning Survey and repeated chair stand test results at Weeks 40 
and 52/ET. 


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 Other Measurements 
Blood and 24-hour urine samples for assessment of biomarkers are scheduled to be collected at 
Week 52/ET.  The 24-hour urine collections at Week 52/ET will also be used to characterize 
albumin, sulfate, uric acid and urea nitrogen excretion.   
8 
SAMPLE SIZE AND POWER 
No sample size and power calculation were performed since this is an extension to the parent study, 
TRCA-301. 
9 
ANALYSIS SETS 
TRCA-301E is an extension study in which all subjects continued on their original treatment 
assignment from the parent study, TRCA-301.  To facilitate review of the TRCA-301E data 
analysis results, some of the tables, listings and figures (TLFs) will include data from all visits 
since the start of the TRCA-301 study. 
 
TRCA-301E Safety Analysis Set 
The TRCA-301E Safety Analysis Set is defined as all subjects who received any amount of 
study drug (TRC101 or placebo) in Study TRCA-301E.   
 
TRCA-301E Modified Intent-To-Treat Analysis Set  
The TRCA-301E Modified Intent-To-Treat (MITT) Analysis Set is defined as all randomized 
subjects who had both baseline and at least one post-baseline serum bicarbonate value measured 
using the i-STAT device in the parent Study TRCA-301 and at least one serum bicarbonate value 
after the Week 12 Visit in Study TRCA-301E.  The TRCA-301E MITT Analysis Set will be the 
main evaluation for the durability of TRC101 efficacy, based on the randomized treatment 
assignment in Study TRCA-301. 
 
TRCA-301E Per Protocol Analysis Set 
The TRCA-301E Per-Protocol (PP) Analysis Set is defined as all subjects in the TRCA-301E 
MITT Analysis Set who completed both the 12-week Treatment Period of the parent Study 
TRCA-301 and the 40-week Treatment Period of Study TRCA-301E without important protocol 


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deviations, and who were treated with study drug and had ≥ 80% study drug dosing compliance 
in Study TRCA-301E.  The TRCA-301E PP Analysis Set will be supportive for evaluation of the 
primary durability of efficacy endpoints, based on the randomized treatment assignment in Study 
TRCA-301. 
 
Phase 3 Safety Analysis Set 
The Phase 3 Safety Analysis Set is defined as all subjects who received any amount of study drug 
(TRC101 or placebo) in the parent Study TRCA-301, regardless of subjects’ enrollment in the 
extension Study TRCA-301E.  All data collected during both studies (TRCA-301 and TRCA-
301E) will be included in the Phase 3 Safety Analysis Set.   
 
Randomized and Enrolled Subjects 
All randomized subjects are those 217 subjects who were randomized in the parent Study TRCA-
301.  Subjects enrolled in the extension Study TRCA-301E are those 196 subjects who completed 
Study TRCA-301 and rolled over into the extension study.  The disposition summary will include 
all randomized subjects.  Summaries for baseline characteristics and medical histories will consist 
of the TRCA-301E enrolled subjects. 
10 GENERAL CONSIDERATIONS 
The analysis sets as defined in Section 9 will be used for analyses of safety and durability of effect.  
Subject listings of all analysis data that support summary tables and/or figures will be provided.  
Measurements from subjects excluded from the pre-defined analysis sets or extra measurements 
(such as unscheduled or repeat assessments) will be included in the subject listings, but not 
included in summary tables, unless specified otherwise.  In general, subject listings will be sorted 
by treatment group, subject number, study ID, assessment date, and assessment time (as 
applicable).   
 Convention for Data Presentation 
For most summary statistics, data will be analyzed and displayed by treatment group, where 
applicable.  Unless otherwise specified, descriptive statistics for continuous variables will include 
the number of subjects with data to be summarized (n), mean, standard deviation (SD), median, 


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minimum and maximum.  The n will be presented as an integer; the same level of precision as in 
the observed/reported value will be presented when reporting minimum and maximum; 1 more 
level of precision than in the observed/reported value will be presented when reporting mean and 
median; and 2 more levels of precision than in the observed/reported value will be presented when 
reporting SD.   
All categorical/qualitative data will be presented using frequency counts and percentages.  All 
percentages will be presented to the nearest tenth, unless otherwise specified.  Percentages equal 
to 100 will be presented as 100% and percentages will not be presented for zero frequencies.  
Where individual variable values are missing, categorical data will be summarized based on 
reduced denominators (i.e., only subjects with available data will be included in the denominators).  
For summaries of AEs and concomitant medications (CMs), the percentages will be based on the 
number of subjects who received study drug (TRC101 or placebo). 
Results of statistical analyses will be reported using TLFs.  The ICH numbering convention will 
be used for all TLFs.  The following conventions will be followed: 
• Unless otherwise noted, all statistical testing will be two-sided and will be performed 
at the 0.05 significance level. 
• Tests will be declared statistically significant if the calculated p-value is < 0.05, 
unless otherwise specified. 
Final analyses and summaries will be produced using SAS® version 9.4.  Mock-shells of TLFs 
for the CSR are presented in Appendix 19.5. 
 Definitions and Derived Variables 
 Baseline Values  
Baseline values for all safety and efficacy variables are defined as the last non-missing assessment 
prior to the first dose of study drug in the parent Study TRCA-301, unless otherwise specified.   
10.2.1.1 
Baseline Serum Bicarbonate Value Using i-STAT 
Serum bicarbonate values are measured onsite using an i-STAT point-of-care device.  The 
Baseline Bicarbonate is defined as the average of the values of serum bicarbonate collected at the 
Screening 1 Visit, Screening 2 Visit, and Baseline Visit (i.e., Day 1 pre-dose) in the parent Study 


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TRCA-301.  This value will be used for derivation of change from baseline in serum bicarbonate 
and will serve as a covariate in statistical models, as appropriate. 
10.2.1.2 
Screening and Baseline Estimated Glomerular Filtration Rate Values 
The Screening estimated glomerular filtration rate (eGFR) value is defined as the average of the 
values of eGFR collected at the Screening 1 and Screening 2 Visits, based on serum creatinine 
measurements, in the parent study, Study TRCA-301.   
The Baseline eGFR value is defined as the average of the eGFR collected at the Screening 1 Visit, 
Screening 2 Visit, and Day 1 pre-dose, as measured by the central laboratory in the parent Study 
TRCA-301.  All available eGFR measurements from these three protocol-specified visits will be 
included in the baseline value calculation.  This value will be used for derivation of the change 
from baseline in eGFR and will serve as a covariate in statistical models, as appropriate. 
10.2.1.3 
Baseline Serum Creatinine 
The Baseline Creatinine value is defined as the average of the serum creatinine collected at the 
Screening 1 Visit, Screening 2 Visit, and Day 1 pre-dose, as measured by the central laboratory in 
the parent Study TRCA-301.  All available serum creatinine measurements from these three 
protocol-specified visits will be included in the baseline value calculation.  This value will be used 
for derivation of the change from baseline in serum creatinine. 
10.2.1.4 
Baseline Urine Albumin-to-Creatinine Ratio 
The baseline spot urine albumin-to-creatinine ratio (Baseline spot ACR) is defined as the 
geometric mean of the ACR measurements collected at the Screening 1 Visit and Day 1 Visit, as 
measured by the central laboratory in the parent Study TRCA-301.  All available ACR 
measurements from these two protocol-specified visits will be included in the baseline value 
calculation.  The baseline ACR from the 24-hour urine sample (Baseline 24-hour ACR) will be 
derived by the ratio of albumin and creatinine from a sample of that urine on or prior to the Day 1 
Visit.  


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10.2.1.5 
Baseline Electrocardiogram Parameters 
12-lead ECG parameters were collected in triplicate on Day 1 pre-dose in the parent Study 
TRCA-301.  The mean of the ECG intervals and heart rate measurements will be used as 
baseline and for derivation of the change from baseline values.   
 Change from Baseline Value 
The change from baseline value will be calculated as the measured value subsequent to the first 
dose of study drug in the parent Study TRCA-301 minus the baseline value. 
 Responder 
A responder is defined as a subject who, at a specified point in time, had a change from baseline 
in serum bicarbonate ≥ 4 mEq/L or had a serum bicarbonate in the normal range (22 - 29 mEq/L), 
as measured onsite using an i-STAT point-of-care device. 
 Study Day 
In Study TRCA-301E, Study Day, which follows the CDISC SDTM standard, is defined as 
(Assessment date – date of first study drug dosing in the parent Study TRCA-301) + 1.   
 Age 
Age (years) will be calculated as the number of years between date of birth and date of informed 
consent in the parent Study TRCA-301, expressed as an integer.   
 Estimated Glomerular Filtration Rate 
The eGFR value will be calculated using the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) formula from serum creatinine.  The primary analysis for change in eGFR will be 
based on serum creatinine reported by the central laboratory.  Because of the potential for changes 
in muscle mass related to bicarbonate correction, eGFR calculated from serum cystatin C levels 
(at the Week 52/ET Visit) will also be evaluated as an exploratory analysis.  
The CKD-EPI formula can be expressed as a single formula using serum creatinine (mg/dL): 
eGFR = 141 × minimum (Serum Creatinine /κ,1)α × maximum (Serum Creatinine /κ,1)-1.209 × 
0.993Age × 1.018 [if female] × 1.159 [if black] 


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Where κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min 
indicates the minimum of SCr/κ or 1 and max indicates the maximum of SCr/κ or 1. 
The CKD-EPI formula can be expressed as a single formula using serum cystatin C (mg/L): 
eGFR = 133 × minimum (Serum cystatin C/0.8,1)-0.499 × maximum (Serum cystatin C/0.8,1)-1.328 
× 0.996Age × 0.932 [if female]. 
 Anion Gap 
Serum anion gap will be derived as [serum sodium (mEq/L) + serum potassium (mEq/L)] – [serum 
chloride (mEq/L) + serum bicarbonate (mEq/L)].  Urine anion gap will be derived as urine sodium 
(mEq/L) + urine potassium (mEq/L) – urine chloride (mEq/L). 
 Multiple Records at a Time Point 
For analysis purposes, the mean value of multiple measurements collected from subjects in the 
same position (i.e., supine, standing, etc.) at a visit will be used for that time point.  Summary of 
the vital sign parameters will be presented by treatment and time point, regardless of the subjects’ 
position (e.g., supine, sitting) during recording of the vital signs.  All collected measurements and 
the mean values will be listed. 
 Treatment-Emergent Adverse Events  
Treatment-emergent adverse events (TEAEs) are defined as all AEs with an onset date or 
worsening in severity on or after the date of the first dose of study drug in the parent Study 
TRCA-301 (also in Section 11.3.1).  Related AEs are those reported by the investigator as having 
a relationship to study drug that is “related”, “probable” or “possible.”  TEAEs with onset date or 
worsening in severity after the enrollment in Study TRCA-301E (i.e., Week 12 Visit) will be 
identified as TRCA-301E TEAEs.  Ongoing AEs with an onset date during Study TRCA-301 that 
were ongoing when the subject enrolled in the extension study were reported as TEAEs in Study 
TRCA-301. 


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Prior and Concomitant Medications 
Prior medications are defined as all prescription and over-the-counter medications that were taken 
within 28 days (whether continuing or not) prior to the date of the first dose of study drug in the 
parent Study TRCA-301.  Concomitant medications are defined as all prescription and over-the-
counter medications that are used concurrently with study drug and through the post-treatment 
follow-up.  A prior medication can also be a CM (see also Section 11.3.2) if it continued after the 
first dose of study drug in the parent Study TRCA-301.  Medications with start date after the 
enrollment in Study TRCA-301E (Week 12 Visit) will be identified as CMs that were started in 
the extension study. 
Ongoing CMs with a start date during or prior to the first dose of study drug in the parent Study 
TRCA-301 and that were ongoing when the subject enrolled into TRCA-301E will be reported as 
CMs for both studies. 
Alkali Therapy 
Oral alkali therapies are medications containing bicarbonate or bicarbonate equivalents, such as 
sodium bicarbonate, potassium citrate or sodium citrate.  Baseline alkali therapies are those 
medications that were used at the start of study treatment in the parent Study TRCA-301.  Alkali 
dose change information was collected on the CRF at each visit.  These data will be used for 
analyses to determine if a dose change occurred.  Given that oral alkali treatment was 
algorithmically stopped and re-started in Study TRCA-301E, the number (%) of subjects who 
changed their oral alkali treatment, as well as reasons for such change, will be summarized by 
scheduled time point.  The dose changes will be indicated in the medication listing. 
Acid Reducing Drug 
An acid reducing drug is defined as a CM (Section 10.2.10) with coded text of Anatomic 
Therapeutic Chemical (ATC) class level 2 being “DRUGS FOR ACID RELATED DISORDERS” 
using the World Health Organization Drug Dictionary (WHO DD). 


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Calcium Supplement Medication 
Calcium supplement medications will be determined by the medical monitor through his/her 
review of the medication data.  Calcium supplement medications will be flagged in the medication 
listing. 
Antihypertensive Medication 
Antihypertensive medications will be determined by the medical monitor through his/her review 
of the medication data.  Antihypertensive medications will be flagged in the medication listing. 
Diuretic Medication 
The concomitant use of loop and thiazide-type diuretics (i.e., potassium-wasting diuretics) will be 
summarized.  Examples of loop diuretics include furosemide, piretanide, bumetanide and 
torasemide.  Examples of thiazide-type diuretics include chlorothiazide (e.g., Diuril®), 
chlorthalidone, hydrochlorothiazide (e.g., Microzide®), indapamide and metolazone.  Combination 
drugs that include a loop or thiazide diuretic will be include in the above counts.  A newly added 
diuretic is one of these medications started during Study TRCA-301E.  A subject will be 
considered to have received both types of diuretics if both medications started during TRCA-301E.  
Potassium-sparing diuretics include spironolactone, eplerenone and amiloride. 
KDQOL Physical Functioning Survey 
The KDQOL is a validated, kidney disease-specific measure of health-related quality of life 
(Hays 1997).  This instrument includes the 36-item Short Form Health Survey (SF-36) as a 
generic chronic disease core, as well as items relevant to patients with kidney disease, such as 
symptoms, burden of illness, social interaction, staff encouragement, and patient 
satisfaction.  For studies TRCA-301 and TRCA-301E, Item 3 of the KDQOL, also known as the 
SF-36 Physical Function subscale, was selected to measure physical functioning and is 
referenced herein as the KDQOL Physical Functioning Survey.  


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Repeated Chair Stand Test 
The repeated chair stand test was used as a measure of lower extremity muscle strength.  It is 
among the group of measures (gait speed, chair stand, and balance tests) comprising the Short 
Physical Performance Battery, which has been used as a predictive tool for possible disability 
and for monitoring physical functioning in older people (Guralnik 1995).  
Hemolysis 
Serum potassium results will be excluded from data analysis, if the test sample was hemolyzed.  
Hemolyzed results are defined as values > 50 mg/dL hemoglobin based on the LIH assay and 
these will be considered a “fail” for potassium. 
 Analysis Windows 
Clinic visits may occur outside protocol-specified windows.  Therefore, instead of relying solely 
on visit labels in the clinical database, analysis visits and their windows are defined using Study 
Day (Section 10.2.4).  For the purposes of data analysis and summary, assessments and/or 
measurements will be flagged based on the collection date/time that is closest to the scheduled 
time point (or target Study Day).  Analysis visit windows are presented in Table 2 by type of 
assessments and/or measurements.  For summary tables that present data for Week 52/ET, the 
data will include the last measurement or assessment that was collected at that visit. 
Table 2 Analysis Visit Windows 
Scheduled 
Time 
Point 
Target 
Study 
Day 
Analysis Visit Windows (Study Day) 
Bicarbonate, 
Serum 
Chemistry, 
Vital Signs 
Haematology, 
Urinalysis 
Spot Urine 
Repeated 
Chair Stand 
Test, 
KDQOL 
Physical 
Functioning 
Survey 
ECG 
Physical 
Examination, 
Body Weight 
Serum 
Cystatin C, 
Biomarkers, 
24-hour 
Urine 
Parameters 
Screening 1 
-14 
low to -8 
- 
- 
- 
- 
- 
Screening 2 
-7 
-7 to -1 
- 
- 
- 
- 
- 
Day 1 
1 
1 to 4 
-14 to 1 
-14 to 1 
-14 to 1 
-14 to 1 
-14 to 1 
Week 1 
8 
5 to 11 
2 to 24 
- 
- 
- 
- 
Week 2 
15 
12 to 22 
- 
- 
2 to 28 
- 
- 
Week 4 
29 
23 to 36 
- 
- 
- 
2 to 42 
- 
Week 6 
43 
37 to 50 
25 to 63 
- 
29 to 63 
- 
- 
Week 8 
57 
51 to 64 
- 
- 
- 
43 to 70 
- 


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Table 2 Analysis Visit Windows 
Scheduled 
Time 
Point 
Target 
Study 
Day 
Analysis Visit Windows (Study Day) 
Bicarbonate, 
Serum 
Chemistry, 
Vital Signs 
Haematology, 
Urinalysis 
Spot Urine 
Repeated 
Chair Stand 
Test, 
KDQOL 
Physical 
Functioning 
Survey 
ECG 
Physical 
Examination, 
Body Weight 
Serum 
Cystatin C, 
Biomarkers, 
24-hour 
Urine 
Parameters 
Week 10 
71 
65 to 78 
- 
- 
- 
- 
- 
Week 12 
85 
79 to 92 
64 to 91 
2 to 91 
64 to 91 
71 to 91 
2 to 91 
Week 14 
99 
93 to 106 
- 
- 
- 
- 
- 
Week 16 
113 
107 to 127 
- 
- 
- 
- 
- 
Week 20 
141 
128 to 155 
92 to 168 
- 
- 
- 
- 
Week 24 
169 
156 to 183 
- 
- 
92 to 203 
- 
- 
Week 28 
197 
184 to 218 
169 to 238 
- 
- 
92 to 280 
- 
Week 34 
239 
219 to 260 
- 
- 
204 to 301 
- 
- 
Week 40 
281 
261 to 302 
239 to 322 
92 to 322 
- 
- 
- 
Week 46 
323 
303 to 344 
- 
- 
 
- 
- 
Week 52 
365 
345 to 368 
323 to 371 
323 to 371 
302 to 367 
281 to 371 
92 to 371 
Week 53 
372 
369 to 375 
- 
- 
- 
- 
- 
Week 54 
379 
≥376 
≥372 
- 
≥368 
≥372 
- 
ECG = electrocardiogram; ET = early termination; KDQOL = kidney disease quality of life 
Note: ET Visit is not shown.  The summary for the visit will include the last measurement or assessment collected. 
11 STATISTICAL AND ANALYSIS ISSUES 
 Adjustments for Covariates 
The Baseline Bicarbonate and the Baseline eGFR, as continuous covariates, will be included in a 
statistical model, such as a mixed-model for repeated measures (MMRM) for analysis of change 
from baseline in serum bicarbonate.  Other baseline values of continuous variables will be included 
in the analysis of covariance (ANCOVA) models (Section 14.4) as covariates.   
Baseline Bicarbonate group (≤ 18 versus > 18 mEq/L) was a stratification variable for 
randomization in the parent Study TRCA-301 and will be used as a subgroup (Section 11.9) to 
evaluate safety and durability of effect in Study TRCA-301E.  Other baseline characteristics, such 
as age group (< 65 versus ≥ 65 years), sex, Screening eGFR group (< 30 versus 
≥ 30 mL/min/1.73m2), baseline alkali therapy (Yes versus No) and geographic region (Europe 
versus United States [USA]) may also be used as subgroups (Section 11.9). 


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 Handling Dropouts or Missing Data 
 General Considerations 
Missing data will not be imputed, unless otherwise specified.  Early termination visits will be 
mapped to the next scheduled visit for inclusion in summary tables, where appropriate.  For 
example, subjects who terminate after Week 20 (e.g., have assessments through Week 20) would 
have their early termination assessments mapped to the next scheduled visit (i.e., Week 24) based 
on the analysis window (Section 10.3).  A summary including data collected at the Week 52/ET 
Visit will be presented. 
Every effort will be made to ensure completeness of data collection.  If severity or relationship of 
an AE to study drug is not recorded, the severity or relationship will be imputed as “severe” or 
relationship as “possible”, for analysis purposes.  In the subject listing, both collected and imputed 
values will be presented. 
 Evaluating Missing Data 
11.2.2.1 
Missing Data in Serum Bicarbonate 
If serum bicarbonate data are missing from either treatment group, such data will be considered to 
be missing at random.  Missing data will not be imputed for the analysis of change from baseline 
in serum bicarbonate.  Serum bicarbonate data will be examined by treatment group and scheduled 
time point.  In order to evaluate the potential effect of missing data on the durability of effect, 
sensitivity analyses (Section 14.8.1) for responders and change from baseline in serum bicarbonate 
will be performed using multiple imputation models under a missing not at random (MNAR) 
assumption for the TRCA-301E MITT Analysis Set. 
11.2.2.2 
Missing Data in KDQOL Physical Functioning Survey and Repeated Chair Stand 
Test 
The reasons for missing time to complete repeated chair stand test results may include, but are 
not limited to: a) the subject was weak and thus unable to stand up from the chair once; b) the 
subject could stand up from the chair once, but was unable to do so five times as required for the 
repeated chair stand test; c) the subject was physically unable to perform the test, for example 


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due to below the knee amputation of both lower extremities; and d) the subject missed a visit.  
The reasons for missing data will be examined by treatment group and scheduled time point.   
For both analysis of the KDQOL Physical Functioning Survey and the repeated chair stand test, 
for subjects with no data after the Week 40 Visit, the Week 40 Visit value will be used in the 
analysis. 
For the purposes of the main analysis of change from baseline in time to complete the repeated 
chair stand test, the missing chair stand time for subjects who were unable to perform the chair 
stand test due to reasons (a) or (b) will be set to 60 seconds, which is the maximum time period 
allowed for the test.  The change from baseline value will be calculated after the imputed values 
at baseline and/or post baseline time point.  The rank-based ANCOVA model will be used for 
this analysis, by ranking the change from baseline values within each scheduled time point.  
A sensitivity analysis (Section 14.8.2) will be performed that excludes subjects who were unable 
to perform the chair stand test.  For subjects with no data after the Week 40 Visit, the Week 40 
Visit value will be used in the analysis. 
 Handling of Safety Data 
 Adverse Events 
All AE verbatim terms reported on the electronic CRFs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA® version 20.0).  TEAEs are defined as any AEs, regardless of 
relationship to study drug, that have an onset or worsening in severity on or after the first dose of 
study drug in the parent Study TRCA-301, Study Day 1.  In Study TRCA-301E, TEAEs are 
defined as those AEs with an onset or worsening in severity after the date of Week 12 Visit.  If it 
cannot be determined whether the AE is treatment-emergent because of a partial onset date, the 
event will be counted as a TEAE.  Adverse events with incomplete start dates will be considered 
TEAEs, if: 
• 
Onset time is missing but the onset date is on Study Day 1 (or after the date of Week 12 Visit, for 
TRCA-301E TEAE). 
• 
Day and month are missing, and the year is equal to or after the year of the first date of study drug 
dosing (or after the date of Week 12 Visit, for TRCA-301E TEAE);  


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• 
Day is missing, and the year is after the year of the first date of study drug dosing (or after year of 
the date of Week 12 Visit, for TRCA-301E TEAE);  
• 
Day is missing, and the year is equal to the year of the first date of study drug dosing and the 
month is equal to or after the month of the first date of study drug dosing (or after the date of 
Week 12 Visit, for TRCA-301E TEAE); or 
• 
Year is missing. 
Related AEs are those with relationship to study medication reported as “possible”, “probable” or 
“related”.   
 Prior and Concomitant Medications 
All medication verbatim terms reported on the electronic CRFs will be mapped according to the 
WHO DD (Enhanced version, March 1, 2017, B2 format).  The medication verbatim terms will be 
mapped to ATC class and preferred names.  Prior and concomitant medications are defined in 
Section 10.2.10.  Two CM flags will be used to identify medications taken in the parent Study 
TRCA-301 and/or in TRCA-301E (Table 3).   
Table 3 Concomitant Medications in TRCA-301 and/or TRCA-301E 
Study 
Definition of Concomitant Medication 
TRCA-301 
The CM was given anytime between the date of first study drug dosing in TRCA-301 and 
the date of last visit in TRCA-301 (either Week 12/ET or Week 14, whichever is the last) 
TRCA-301E 
The CM was given anytime between date after the Week 12 Visit in TRCA-301E and the 
date of last visit in TRCA-301E (either Week 52/ET or Week 54, whichever is the last) 
 
If start date is missing, the medication will be considered to have started prior to the study.  Such 
a medication may also be considered concomitant, depending on the stop date or lack thereof.  If 
the stop date of a CM is missing, then the medication will be treated as ongoing.  If the start date 
of a medication is missing, the stop date will be used to determine whether or not it is concomitant.  
Medications with other incomplete start dates will be identified as concomitant using the same 
algorithm as above for TEAEs, if the stop date information is insufficient for the determination.  
 Interim Analyses and Data Monitoring 
No interim analyses are planned. 


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 Multicenter Considerations 
A total of 25 study centers in Europe and 12 centers in the USA participated in Study TRCA-301, 
while 22 centers in Europe and 7 centers in the USA participated in Study TRCA-301E.  Data 
from all study centers will be pooled for safety and efficacy analyses, as well as for summaries.  
Because the number of subjects at each center is small, no analyses will be performed by study 
center.  Geographic region (i.e., Europe and USA) will be used for subgroup analyses. 
 Multiple Comparisons, Multiplicity  
In order to control family-wise error rate, formal statistical testing for the durability of effect 
endpoints (described in the protocol as secondary endpoints) will be performed sequentially:   
1. A formal comparison between the TRC101 and the placebo groups will be performed using 
Fisher’s exact test for the proportion of responders at the Week 52 Visit.   
2. Only when comparison No. 1 is statistically significant at the two-sided 0.05 level, will a formal 
test for the change from baseline in serum bicarbonate at the Week 52 Visit be performed.  A 
MMRM model will be used to compare the group least squares (LS) means of change from 
baseline in serum bicarbonate at Week 52.   
3. Only when both comparisons No. 1 and No. 2 are statistically significant at the two-sided 0.05 
level, will a formal test for the change from baseline in the total score of the KDQOL Physical 
Functioning Survey at the Week 52 Visit be performed.  A rank-based ANCOVA model will be 
used to compare the group means of change in the total score of the KDQOL Physical 
Functioning Survey at Week 52. 
4. Only when all aforementioned comparisons are statistically significant at the two-sided 0.05 
level, will a formal test for the change from baseline in the duration of the repeated chair stand 
test at the Week 52 Visit be performed.  A rank-based ANCOVA model will be used to compare 
the group means of change in the duration of the repeated chair stand test at Week 52. 
 Use of an “Efficacy Subset” of Subjects 
TRCA-301E PP Analysis Set will be used for supportive analyses for the primary durability of 
effect endpoints as outlined in Section 14.1.1.  
 Active-Control Studies 
There was no active control group.  The placebo group will serve as a comparator in this study. 


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 Examination of Subgroups 
Subjects will be categorized into the following subgroups for the purposes of evaluating the safety 
and the durability of TRC101 effect.  All subgroup analyses will be performed using data collected 
at Week 52.  
The subgroup analyses below will be performed for the responder analysis (Section 14.2) and the 
analysis of change from baseline in serum bicarbonate (Sections 14.3): 
• 
Baseline Bicarbonate (≤ 18 versus > 18 mEq/L) 
• 
Screening eGFR (< 30 versus ≥ 30 mL/min/1.73m2) 
• 
Age (< 65 versus ≥ 65 years) 
• 
Sex (Male versus Female) 
• 
Race (White versus Non-White) 
• 
Baseline alkali use (Yes versus No) 
• 
Geographic region (Europe versus USA) 
• 
Acid reducing drug (Section 10.2.13) (Yes versus No) 
The subgroup analyses below will be performed for the change from baseline in total score of 
KDQOL Physical Functioning Survey and change from baseline in time to complete the repeated 
chair stand test: 
• 
Baseline Bicarbonate (≤ 18 versus > 18 mEq/L) 
• 
Age (< 65 versus ≥ 65 years) 
• 
Sex (Male versus Female) 
• 
Baseline Score (above versus below median) for the respective test, KDQOL Physical 
Functioning Survey or repeated chair stand. 
 
The subgroup analyses below will be performed for the proportion of subjects with hyperkalemia 
AEs (Section 19.4): 
• Baseline Bicarbonate (≤ 18 versus > 18 mEq/L) 
• Screening eGFR (< 30 versus ≥ 30 mL/min/1.73m2) 
• Baseline potassium level (below normal range, within normal range, above normal range) 
• Diabetes mellitus (Yes versus No) 


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• Concomitant angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor 
blocker (ARB) use (Section 19.1) (Yes versus No) 
• Concomitant use of potassium-wasting diuretic (Section 10.2.15) (Yes versus No) 
• Concomitant use of potassium-sparing diuretic (Section 19.2) (Yes versus No) 
• Concomitant use of ACEi or ARB plus potassium-sparing diuretic (Yes versus No) 
• Mean daily dose of the study drug (< mean daily dose versus ≥ mean daily dose) (for 
events occurring in the TRC101 group only) 
12 STUDY PATIENTS 
 Subject Disposition 
 Overall Summary 
Enrollment and disposition will be summarized by treatment group and overall.  The subject 
disposition summary will include: 
• Number of subjects randomized in Study TRCA-301 
• Number (%) of subjects in the Phase 3 Safety Analysis Set 
• Number of subjects who completed the 12-week Treatment Period in Study TRCA-301 
• Number of subjects who discontinued early from Study TRCA-301  
o The primary reason for early discontinuation 
• Number of subjects who enrolled in Study TRCA-301E 
• Number (%) of subjects in the TRCA-301E Safety Analysis Set 
• Number (%) of subjects in the TRCA-301E MITT Analysis Set 
• Number (%) of subjects in the TRCA-301E PP Analysis Set 
• Number of subjects who completed the 40-week Treatment Period in Study TRCA-301E 
• Number of subjects who completed Study TRCA-301E (i.e., completed the Week 54 
Visit) 
• Number of subjects who discontinued early from Study TRCA-301E 
o The primary reason for early discontinuation 
 


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A listing of disposition will be provided for all randomized subjects.  Those subjects who did not 
enroll in the extension study will be noted with asterisk (*).  The dates of last treatment, 
completed/discontinued study and last contact for these subjects occurred in Study TRCA-301.  
 Examination of Time to Early Discontinuation of the Study 
Time to premature discontinuation will be examined using the Kaplan-Meier method.  Percentage, 
along with the 95% confidence interval (CI) of the percentage, of subjects who discontinued at 
specified time intervals will be provided.  The p-value from the log-rank test comparing the 
distributions of two treatment groups of early termination will be reported.  A Kaplan-Meier plot 
of the time to premature discontinuation will be provided.  This analysis will include all subjects 
who were randomized into Study TRCA-301.  Subjects who completed Study TRCA-301 and did 
not enroll in the extension study will be censored at their last visit in the parent study.  Similarly, 
subjects who completed Study TRCA-301E will be censored at their last visit in the extension 
study.  The duration is between Day 1 (in the parent Study TRCA-301) to the date of last visit in 
Study TRCA-301 if a subject did not enroll in the extension study or to the date of last visit in 
Study TRCA-301E if a subject enrolled in the extension study.  The incidence rate of early 
discontinuation will be calculated as 100% × number of discontinuations / total person-year in the 
study.  Total person-year is the sum of individual subject’s duration (year) in the study. 
 Protocol Deviations 
Protocol deviations that occurred during Study TRCA-301E (i.e., after the Week 12 Visit through 
Week 54 Visit) will be classified by deviation type (e.g., important or minor) and category (e.g., 
eligibility criteria, out of window visit, SAE reporting, missed or out of window procedures, etc.).  
All deviations will be identified and adjudicated prior to database lock.  Important protocol 
deviations are defined per ICH guidance.  They are described in detail in the Protocol Deviation 
Adjudication Memo.  Protocol deviation categories include: 
• Investigational product  
• Informed consent  
• Key eligibility criteria  
• SAE reporting  


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• Out of window procedure 
• Procedure - missed or not interpretable  
• Out of window visit 
• Missed visit 
• Restricted medications  
• Blinding  
• Other 
The important deviations that occurred during Study TRCA-301E will be presented in a subject 
listing and summarized by deviation category and treatment group.   
 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group for subjects 
who enrolled in Study TRCA-301E.  Demographic characteristics will include age, age group 
(< 65 or ≥ 65 years), sex, race, ethnicity and geographic region (Europe or USA).  The following 
baseline characteristics will be summarized: baseline oral alkali therapy use (Yes or No), baseline 
weight, height, body mass index (BMI), baseline systolic blood pressure (mmHg) and baseline 
systolic blood pressure group (≤ 135 or > 135 mmHg).  Selected baseline laboratory test results 
will be summarized: Screening eGFR, Screening eGFR group (< 30 or ≥ 30 mL/min/1.72m2), 
Baseline eGFR, baseline serum creatinine, Baseline Bicarbonate, Baseline Bicarbonate group 
(≤ 18 or > 18 mEq/L), baseline serum potassium, baseline potassium group (below, within, or 
above the limits of normal), baseline spot urine ACR, baseline spot urine ACR group (< 30, ≥ 30 
and ≤ 300, > 300 mg/g), baseline 24-hour urine ACR, and baseline 24-hour urine ACR group 
(< 30, ≥ 30 and ≤ 300, > 300 mg/g).  All of the above information will be listed by subject. 
 Medical History 
General medical history terms will be mapped to preferred terms (PTs) and system organ classes 
(SOCs) using MedDRA® version 20.0.  Additional medical history that may have come to light in 
the extension study was captured in an additional medical history electronic CRF.  General medical 
history, selected medical history terms, selected signs and symptoms experienced recurrently or 
continuously during the 3 months prior to Screening in the parent Study TRCA-301, as well as 


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primary cause of CKD will be summarized by treatment group for subjects who enrolled in Study 
TRCA-301E.  All medical histories will be listed.  
13 STUDY DRUG AND OTHER MEDICATIONS 
The following data analyses will be performed for the 54-week study duration. 
 Study Drug Exposure, Compliance, and Titration 
 Study Drug Exposure 
Study drug exposure during the 40-week Treatment Period in Study TRCA-301E will be 
descriptively summarized by the total number of packets dispensed, total number of packets 
consumed, total number of doses taken, total TRC101 dose (g) consumed, mean daily TRC101 
dose (g), study drug dosing compliance (%), and duration (days) of exposure.  Number (%) 
subjects taking study drug at different dose levels at any time during the study will be summarized 
by the number of study drug packets prescribed.   
The total number of packets consumed is defined as the total number of packets dispensed – the 
total number of unused packets returned.  Due to study drug titration, the assigned number of 
packets per day for a subject could change from one time interval to another.  The total number of 
packets expected to be taken is the sum of the number of prescribed number of packets in all time 
intervals.  The total number of doses taken is the sum of dosing days in all time intervals.  The 
total TRC101 dose (g) consumed is derived as 3 g × the total number of packets consumed.  The 
TRC101 mean daily dose is derived as the total TRC101 dose (g) / the total number of doses taken.  
The duration of study drug exposure in Study TRCA-301E is defined as the number of days on 
treatment from the date of the Week 12 Visit to the date of last dose.  A by-subject listing of 
exposure will be provided. 
 Study Drug Compliance 
Study drug compliance during the 40-week Treatment Period in Study TRCA-301E (expressed in 
percentage) is defined as the total number of packets consumed divided by the total number of 
packets expected to be taken.  A subject who completes the 40-week Treatment Period without 


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dose interruption is expected to take study drug for a total of 280 days.  Without dose titration and 
at 6 g TRC101/day, the total number of packets expected to be taken is 560 packets = 280 days × 
2 (i.e., 6 g per day divided by 3 g per packet).  Depending on dose titration, the total number of 
expected packets varies by subject.   
 Dose Titration 
Titration of study drug will be summarized by type (i.e., titration, up-titration, down-titration, dose 
interruption) and reason for each type of dose change during Study TRCA-301E (i.e., from the 
Week 12 Visit through the Week 52 Visit).  Specifically, the number (%) of subjects with the 
following information will be summarized by treatment group:  
• without any titration  
• with any titration 
• with an up-titration from 
o 0 to 1 packet  
o 1 to 2 packets  
o 2 to 3 packets  
• reason for up-titration 
• with a down-titration from 
o 2 to 1 packet  
o 3 to 2 packets  
• reason for down-titration 
• with a dose interruption from 
o 1 to 0 packets  
o 2 to 0 packets  
o 3 to 0 packets  
• reason for dose interruption 
• with only up-titration 
• with only down-titration 
• with both up and down titrations 


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• with 
o 0 titrations 
o 1 titration 
o 2 titrations 
o 3 titrations 
o 4 titrations 
o 5 or more titrations 
 Prior and Concomitant Medications 
Prior and concomitant medications (Section 11.3.2) will be summarized for the 42-week TRCA-
301E Study Period (i.e., 40-week Treatment Period and 2-week Follow-up Period) by treatment 
group using WHO DD ATC class and preferred name.  These summaries will present the number 
and percentage of subjects using each medication.  Subjects may have more than one medication 
within an ATC class and preferred name.  At each summary level subjects are counted once if they 
reported one or more medications at that level.  Each summary will be ordered by descending 
frequency of preferred name within each ATC class.  
 Restricted Medications 
The concomitant use of restricted medications during the 42-week TRCA-301E Study Period, as 
defined in the Study TRCA-301E Protocol Section 5.9 Table 1, will be summarized and listed 
separately, using the same dictionary mapping as described above.  Oral alkali therapy 
(Section 10.2.11) during the 42-week TRCA-301E Study Period will be summarized by category 
(stopped dosing or new/dose change) and by timepoint, with reasons for stopping or re-starting 
oral alkali also summarized. 
 Medications Used for Certain Analyses 
 Calcium Supplements and Selected Antihypertensive Medications 
Calcium supplements (Section 10.2.13) used during the 42-week TRCA-301E Study Period will 
be summarized by category (stopped dosing or new/dose change).a  Summary of new/dose 
changed antihypertensive medications will also be provided by treatment group using WHO DD 
ATC class and preferred name. 


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 Diuretics 
Prior use (i.e., before the first dose of study drug in the parent Study TRCA-301) and new use of 
loop and thiazide diuretics (Section 10.2.15) during the TRCA-301E 42-week Study Period will 
be summarized by treatment group.  Number (%) of subjects who used loop diuretics, thiazide-
type diuretics or both will be presented.  The medication listing will flag the two types of diuretics.  
14 EFFICACY ANALYSES 
All efficacy analyses will be performed using the TRCA-301E MITT Analysis Set.  The analyses 
of the main durability of effect endpoints (Section 14.1.1) will also be performed using the 
TRCA-301E PP Analysis Set.  The change from baseline values will be calculated as described 
in Section 10.2.2.  Baseline values are defined in Section 10.2.1. 
 Endpoints, Analyses, and Analysis Variables 
 Main Durability of Effect Endpoints 
The main durability of effect endpoints were defined as secondary endpoints in the Study TRCA-
301E protocol.   
1. Responder at the end of treatment (Week 52 Visit).   
2. Change from baseline in serum bicarbonate at the end of treatment (Week 52 Visit) 
3. Change from baseline in the total score of the KDQOL Physical Functioning Survey at 
the end of treatment (Week 52 Visit) 
4. Change from baseline in the duration of the repeated chair stand test at the end of 
treatment (Week 52 Visit) 
 Additional Durability of Effect Analyses 
Additional durability of effect analyses will be performed by scheduled time point (Table 1): 
1. Responder (number and percentage of subjects) at each visit 
2. Change from baseline in serum bicarbonate at each visit 
3. Individual components of response at each visit 
• Number and percentage of subjects having a change from baseline in serum 
bicarbonate ≥ 4 mEq/L 
• Number and percentage of subjects having a serum bicarbonate in the normal 
range (22 to 29 mEq/L) 
4. Categorical change from baseline in serum bicarbonate (number and percentage of 
subjects) at each visit 


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• ≥ 2 mEq/L 
• ≥ 3 mEq/L 
• ≥ 4 mEq/L 
• ≥ 5 mEq/L 
• ≥ 6 mEq/L 
• ≥ 7 mEq/L 
5. Change from baseline in the total score of the KDQOL Physical Functioning Survey at 
Week 12 and Week 40 
6. Change from baseline in the duration of the repeated chair stand test at Week 12 and 
Week 40 
In addition, the distribution and mean (SD) number of visits when the responder definition 
(change from baseline in serum bicarbonate ≥ 4 mEq/L or to a level within the normal range [22 
to 29 mEq/L]) was met will be summarized by treatment group. 
 Exploratory Analyses 
14.1.3.1 
Individual Items from KDQOL Physical Functioning Survey 
The change from baseline in individual items (i.e., items a – j) of the KDQOL Physical 
Functioning Survey will be analyzed at the Weeks 12, 40 and 52. 
14.1.3.2 
Biomarkers 
The change from baseline in the following biomarkers will be analyzed at the end of treatment 
(Week 52 Visit). 
• Parathyroid hormone 
• Serum prealbumin 
• 25-hydroxyvitamin D 
• Urinary biomarkers of bone resorption 
a. N-terminal telopeptide (NTX)  
b. C-terminal telopeptide (CTX)  
• Serum biomarkers of bone resorption 
a. Tartrate-resistant acid phosphatase 5b (TRAP 5b)  
b. Bone-specific alkaline phosphatase (BSAP) 
c. Procollagen 1 N-terminal propeptide (P1NP)  
• Serum osteocalcin 
• 24-Hour urine biomarkers 
a. Endothelin-1  


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b. Aldosterone 
c. Angiotensinogen 
d. Endothelin-1 to creatinine ratio 
e. Aldosterone to creatinine ratio 
f. Angiotensinogen to creatinine ratio 
14.1.3.3 
Offset of Treatment Effect 
Offset of treatment effect will be assessed using the serum bicarbonate data collected during the 
2-week post treatment period (i.e., Follow-up Period), when subjects will not receive study drug.  
The following analyses will be performed at Weeks 53 and 54: 
1. Responder  
2. Change from baseline in serum bicarbonate 
3. Change from the last on treatment serum bicarbonate value 
 Efficacy Variables 
14.1.4.1 
Change from Baseline in Serum Bicarbonate 
Serum bicarbonate values will be measured onsite using an i-STAT point-of-care device.  Change 
from baseline in serum bicarbonate is defined in Section 10.2.2.  A positive change will indicate 
an increase in serum bicarbonate relative to baseline.  The analysis methods for change from 
baseline in serum bicarbonate are described in Sections 14.3 and 14.6. 
14.1.4.2 
Categorical Change in Serum Bicarbonate 
Binary indicator variables will be used to identify the percentage of patients with increases in post-
baseline serum bicarbonate levels at each scheduled time point.  The components of the response 
are: 
• an increase in serum bicarbonate from baseline ≥ 4 mEq/L 
• serum bicarbonate value within the range 22 to 29 mEq/L 
As additional efficacy analyses, the following categories will be evaluated:  
• an increase in serum bicarbonate from baseline ≥ 2 mEq/L 
• an increase in serum bicarbonate from baseline ≥ 3 mEq/L 
• an increase in serum bicarbonate from baseline ≥ 4 mEq/L 
• an increase in serum bicarbonate from baseline ≥ 5 mEq/L 
• an increase in serum bicarbonate from baseline ≥ 6 mEq/L 


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• an increase in serum bicarbonate from baseline ≥ 7 mEq/L 
The analysis method for the above categorical variables is described in Section 14.6.2. 
14.1.4.3 
Other Change from Baseline Variables 
The following change from baseline variables will be calculated as the measured value subsequent 
to the first dose of study drug in the parent Study TRCA-301 minus the baseline value: 
• Change from baseline in the total score of the KDQOL Physical Functioning Survey 
(measured at Weeks 12, 40 and 52)  
• Change from baseline in the repeated chair stand test duration (measured at Weeks 
12, 40 and 52) 
• Change from baseline in biomarkers (measured at Week 52) 
The analysis methods for the above change from baseline variables are described in Sections 14.4 
and 14.6.   
Due to the fact that the change from baseline in the individual items of the KDQOL Physical 
Functioning Survey (i.e., items a – j) (measured at Weeks 12, 40 and 52) are discrete in nature, 
they will be summarized using counts and percentages. 
 Responder Analysis Method 
 Reporting Results 
The number and proportions (expressed as percentages) of responders (Section 10.2.2) at each 
scheduled time point and at the Week 52 Visit will be calculated.  These proportions, along with 
their exact (Clopper-Pearson) 95% CIs, will be summarized by treatment group and scheduled 
time point.  In addition, the difference in proportion between TRC101 and placebo subjects and its 
exact 95% CI and the p-value from Fisher’s exact test comparing the TRC101 group and the 
placebo group will be reported by scheduled time point (i.e., on or after Week 14).   
 Statistical Hypotheses 
The primary null hypothesis is that the proportion of subjects who are responders at the Week 52 
Visit is the same in the TRC101 and placebo groups: the TRC101 proportion (πTRC101) = the 
placebo proportion (πPlacebo).  The alternative hypothesis is that the proportion of subjects who are 


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responders at the Week 52 Visit differs in the TRC101 and the placebo groups: the TRC101 
proportion (πTRC101) ≠ the placebo proportion (πplacebo).  
 Statistical Testing 
Testing for the difference (TRC101 – placebo) in proportion (≠ 0) at the Week 52 Visit will be 
conducted using the Fisher’s exact test.  Durability of effect of TRC101 will be declared when the 
difference in proportions of responders between TRC101 and placebo at the Week 52 Visit is 
statistically significant at a two-sided alpha level of 0.05. 
 Evaluating Interactions  
As an exploratory analysis, the interactions between treatment and the following terms will be 
evaluated using logistic regression models for the responder analysis at the Week 52 Visit.   
• 
Baseline Bicarbonate ( ≤ 18 versus > 18 mEq/L) 
• 
Screening eGFR (< 30 versus ≥ 30 mL/min/1.73m2) 
• 
Age (< 65 versus ≥ 65 years) 
• 
Sex (Male versus Female) 
• 
Baseline alkali use (Yes versus No) 
• 
Geographic region (Europe versus USA) 
• 
Acid reducing drug (Section 10.2.12) (Yes versus No) 
 
A logistic regression model will include responder (Yes or No) as the dependent variable, 
treatment, and treatment × subgroup variable interaction term as independent variables.  The p-
value for testing the treatment × subgroup variable interaction term will be reported. 
A forest plot will be generated to include the main analysis and the above subgroups.  The p-
values of interactions between the treatment and the above subgroups will be presented on the 
forest plot. 


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 Analysis Method for Change from Baseline in Serum Bicarbonate 
 Mixed-effect Model for Repeated Measures 
The MMRM model will include the change from baseline in serum bicarbonate as the dependent 
variable; treatment, scheduled time point (i.e., Week 1 through Week 52), and treatment by 
scheduled time point interaction as fixed effects; subject as a random effect; and the Baseline eGFR 
and the Baseline Bicarbonate as continuous covariates.  Within-subject correlations will be 
modeled using an unstructured covariance structure.  Time ordering is a repeated measure within 
subjects.  Errors for different subjects are assumed independent with an unstructured covariance 
structure.  The estimation method for the model will be restricted maximum likelihood (REML).   
In the event the MMRM model with an unstructured covariance structure does not converge, the 
following covariance structures will be used as substitution in the order below.  Each subsequent 
covariance structure will be used only if each previous covariance structure was used and the 
model did not converge. 
1. Toeplitz covariance structure (assuming measurements from samples taken closer together 
in time are more highly correlated than those from samples taken farther apart) 
2. First order of auto-regressive [AR(1)] covariance structure (assuming measurements from 
samples taken closer together in time are more highly correlated than those from samples 
taken farther apart) 
3. Compound symmetry covariance structure (assuming equal correlation for measurements 
from a subject, regardless of how far apart in time when they were taken) 
 Reporting Results 
The LS mean of the change from baseline in serum bicarbonate, standard error (SE) of the LS 
mean, and two-sided 95% CI of the LS mean from the mixed model will be reported by treatment 
and scheduled time point.  The LS mean difference of the change from baseline in serum 
bicarbonate between the TRC101 group and the placebo (i.e., TRC101 – placebo), SE of the LS 
mean difference, 95% CI of the LS mean difference, and the p-values of the LS mean difference 
from the mixed model will be provided by scheduled time point.   
In addition, descriptive statistics for serum bicarbonate at baseline and at each scheduled post-
baseline time point, along with change from baseline in serum bicarbonate, will be summarized by 


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treatment and scheduled time point.  Graphic presentation of serum bicarbonate change over the 
52-week period will be plotted:  
• 
LS mean (95% CI of LS mean) of serum bicarbonate by treatment group, including Week 1 
through Week 52  
• 
LS mean (95% CI of LS mean) of change from baseline in serum bicarbonate by treatment group, 
including Week 1 through Week 52  
• 
Arithmetic mean ± SE (from descriptive statistics) of serum bicarbonate by treatment group, 
including scheduled time points of Screening 1, Screening 2, and Day 1 pre-dose, through 
Week 54.  
• 
Arithmetic mean ± SE of change from baseline in serum bicarbonate by treatment group, including 
scheduled time points from baseline to Week 54. 
 Using Ranked-Based Models 
After fitting the MMRM model, the distribution of residuals within each treatment group at a given 
time point will be tested for normality using the Anderson-Darling test.  If the distribution of 
residuals in both treatment groups at a given time point is normal (p > 0.05), then the original 
values (i.e., the change from baseline values) will be used in the analysis.  Methods described in 
Sections 14.3.1 will be followed.  If the distribution of residuals in either treatment group at a 
given time point is significantly non-normal (p < 0.05), then a rank-based model will be used.  In 
this case, only the P-values will be reported from the rank-based model.  The LS mean, 95% CI of 
LS mean, LS mean of group difference, and 95% CI of LS mean of the difference from the 
candidate model using the original values will be presented.   
 Analysis Method for Other Change from Baseline Variables 
 Analysis of Covariance 
Based on the exploratory analyses of residuals from the models using Study TRCA-301 KDQOL 
Physical Functioning Survey and repeat chair stand data, the normality assumption was violated.  
Therefore, the rank-based ANCOVA models will be used in data analysis of these endpoints.  The 
rank of the change from baseline value will be the dependent variable; the treatment group will be 
a fixed effect; and the baseline value of the parameter being analyzed (e.g., total score of the 


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KDQOL Physical Functioning Survey or the duration of the repeated chair stand test), the Baseline 
eGFR, and the Baseline Bicarbonate will be continuous covariates.   
 Reporting Results 
The p-value for testing the difference between treatment groups will be reported from the 
rank-based model at each scheduled post-baseline time point for each parameter.  The descriptive 
statistics of reported values at baseline and at each scheduled post-baseline time point, along with 
change from baseline values, will be summarized by treatment and scheduled time point.  The 95% 
CI of group means will also be provided.   
 Hypothesis and Testing for Change from Baseline Analyses 
The following hypothesis and testing will only apply to the following change from baseline variables: 
1. Change from baseline in serum bicarbonate at the end of treatment (Week 52 Visit) 
2. Change from baseline in the total score of the KDQOL Physical Functioning Survey at 
the end of treatment (Week 52 Visit) 
3. Change from baseline in the duration of repeated chair stand test at the end of treatment 
(Week 52 Visit) 
 Statistical Hypothesis 
Comparing TRC101 with placebo at the Week 52 Visit, the null hypothesis is the two group means 
of a change from baseline variable are equal (μ TRC101 = μ placebo).  The alternative hypothesis is the 
two group means of a change from baseline variable are not equal (μ TRC101 ≠ μ placebo). 
 Statistical Testing 
Using the above described MMRM or ANCOVA model for a change from baseline analysis, (LS) 
meanTRC101 = (LS) meanPlacebo at the Week 52 Visit will be tested for statistical significance.  
Gatekeeping procedures as described in Section 11.6 will be used in the following sequence:   
1. Responder (Week 52 Visit) 
2. Change from baseline in serum bicarbonate at the end of treatment (Week 52 Visit) 
3. Change from baseline in the total score of the KDQOL Physical Functioning Survey at 
the end of treatment (Week 52 Visit) 
4. Change from baseline in the duration of the repeated chair stand test at the end of 
treatment (Week 52 Visit) 


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For a given change from baseline endpoint above, the durability of effect will be declared if the 
current and all previous hypotheses are rejected.  A subsequent formal testing will not be 
performed if any of the current or previous tests is not rejected. 
 Categorical Analysis Methods 
 Individual Components of the Response 
In addition to the responder analysis (Section 14.2), the two individual components of the response 
(1) having a change from baseline in serum bicarbonate ≥ 4 mEq/L and (2) having a serum 
bicarbonate in the normal range (22 to 29 mEq/L) will also be assessed.  The proportion (expressed 
as percentages) of subjects with an individual component at each scheduled time point will be 
reported as described in Section 14.2.1. 
 Categorical Change in Serum Bicarbonate 
The proportions (expressed as percentages) of subjects with increases in their serum bicarbonate 
by ≥ 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6 and ≥ 7 mEq/L at each scheduled time point will be reported as described 
in Section 14.2.1.  
 Individual Items of the KDQOL Physical Functioning Survey 
Since the change from baseline in individual items of the KDQOL Physical Functioning Survey is 
categorical in nature, Cochran-Mantel-Haenszel (CMH) statistics will be used.  Number (%) of 
subjects in each category will also be displayed by scheduled time point and item. 
 Analysis of Offset of Treatment Effect 
The analysis of offset of treatment effect will be performed by scheduled time point (i.e., Weeks 
53 and 54).  The proportions (expressed as percentages) of responders will be reported as described 
in Section 14.2.1.  Descriptive statistics of the reported and change from baseline values of serum 
bicarbonate will be summarized.  In addition, the change from the last on-treatment serum 
bicarbonate value will be summarized descriptively by treatment group and scheduled time point. 


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 Sensitivity Analyses 
 Serum Bicarbonate 
In order to evaluate the potential effect of missing serum bicarbonate data, sensitivity analyses 
will be performed using control-based pattern imputation under the missing not at random 
assumption.  The method is based on the assumption that subjects who stop taking TRC101 will 
no longer benefit from it in the future, and thus will tend to have outcomes similar to those in the 
placebo group.  Although the scientific justification of the method seems reasonable, it is 
important to note that any such sensitivity analysis still relies on untestable assumptions about 
unobserved data; however, so does ignoring the missing data.  Based on the paper by Ratitch and 
O’Kelly[1], which describes an implementation of the pattern-mixture model approach using a 
control-based pattern imputation, the imputation model for the missing observations in the 
TRC101 group will be constructed not from the observed data in the treatment group but rather 
from the observed data in the placebo group.  This model will also be the imputation model that 
is used to impute missing observations in the placebo group. 
Multiple imputation inference involves the following three steps: 
1. The missing observations are filled in m times to generate m complete datasets using 
SAS® PROC MI based on the multiple imputation method[1].  We will set m to be 10. 
2. The analysis methods described in Sections 14.2, 14.3 will be applied to the m completed 
datasets.   
3. The results from the m completed datasets are combined using SAS® PROC 
MIANALYZE for confirmation of the analyses. 
 Time to Complete Repeated Chair Stand Test 
A sensitivity analysis will be performed that excludes subjects who were unable to perform the 
chair stand test at baseline or either at the Week 40 or Week 52 Visit due to any reason. 
15 SAFETY ANALYSES 
One of the study objectives is to assess the long-term safety of TRC101.  Safety will be evaluated 
by AEs, clinical laboratory test results, vital signs, body weight, ECG findings, and physical 
examination results.  Two safety analysis sets will be used.  The first (TRCA-301E Safety Analysis 


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Set [see Section 9.1]) will be used in the analyses of AEs, clinical laboratory test results, vital signs, 
body weight, and ECGs.  The second (Phase 3 Safety Analysis Set [see Section 9.4]) will be used 
for time to event analyses.  All descriptive statistics (described in Section 10.1) will be presented 
by treatment group. 
 Safety Variables 
Safety variables include: 
1. AEs, SAEs and withdrawal of study treatment due to AE 
2. Having a confirmed serum bicarbonate value > 30 mEq/L  
3. Laboratory test results, including 
a. Serum chemistry (Weeks 14, 16, 20, 24, 28, 34, 40, 46, 52/ET, 53, and 54) 
b. Coagulation (Weeks 14, 16, 20, 24, 28, 34, 40, 46, 52/ET, 53, and 54) 
c. Hematology (Weeks 20, 28, 40, 52/ET, 54) 
d. Urinalysis (Weeks 20, 28, 40, 52/ET, 54) 
e. Spot Urine (Weeks 20, 28, 40, 52/ET, 54) 
f. 24-hour urine (Week 52/ET Visit) 
g. Pregnancy test (Weeks 16, 20, 24, 28, 34, 40 ,46, 52/ET, 54) 
h. Cystatin C (Week 52) 
4. Vital signs (Weeks 14, 16, 20, 24, 28, 34, 40, 46, 52/ET, 53, and 54) 
5. Body weight (Weeks 28, 52/ET, 54) 
6. 12-lead ECG rhythm and intervals (Weeks 24, 34, 52/ET, 54) 
 Adverse Events 
TEAEs are defined in Section 11.3.1.  All reported AEs (including non-TEAEs) will be listed.  A 
separate listing will be provided for TEAEs leading to death (if any).  Additionally, listings will 
be provided for selected TEAEs: a) gastrointestinal nonspecific inflammation and dysfunctional 
conditions identified by the Standardised MedDRA Queries (SMQ, Section 19.3) and b) 
hyperkalemia (Section 19.4).  A listing of deaths and other serious adverse events will be 
prepared that includes deaths and SAEs that occurred in both Studies TRCA-301 and TRCA-
301E.  All TEAE summary tables will present the number and percentages of subjects reporting 
TEAEs. 


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 TEAEs Occurring during Study TRCA-301E 
An overall summary of TEAEs that occurred during the extension Study TRCA-301E will be 
presented by severity, seriousness, and relation to study drug.  The denominator will be the total 
number of subjects from the TRCA-301E Safety Analysis Set in each treatment group.  In addition, 
TEAEs will be summarized by MedDRA SOC and PT.  Subjects can have more than one TEAE 
per SOC and PT.  The following summaries will be presented for the TEAEs that occurred during 
Study TRCA-301E: 
• TEAEs by SOC and PT 
• TEAEs by worst severity, SOC and PT 
• Related TEAEs by SOC and PT 
• Serious TEAEs by SOC and PT 
• TEAEs leading to death (if any) by SOC and PT 
• TEAEs leading to study drug discontinuation (if any) by SOC and PT 
• TEAEs leading to study drug interruption (if any) by SOC and PT 
At each level of subject summarization, subjects are counted once if they reported at least one 
TEAE at that level.  If a subject reported the same TEAE on multiple occasions, the highest 
severity (severe > moderate > mild) or study drug relationship (related > probable > possible > 
unlikely > unrelated) recorded for the event will be summarized.  Each summary will be ordered 
by SOC alphabetically and by PT in descending order of the total incidence within each SOC. 
 Additional Analyses of Selected Adverse Events 
Selected TEAEs below that were reported from the date of first dose of study drug in Study 
TRCA-301E to Week 54 in TRCA-301E will be evaluated: 
• Gastrointestinal nonspecific inflammation and dysfunctional conditions that are 
identified using SMQ (Section 19.3) 
• Hyperkalemia events (Section 19.4) 
Number (%) of subjects with gastrointestinal nonspecific inflammation and dysfunctional 
conditions SMQ and hyperkalemia AEs will be summarized.  The number (%) of events by the 
study drug dose level being taken on the onset date of the event will also be summarized.  Placebo 


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is considered as a 0 g dose level.  TRC101 treated subjects could be receiving a 0, 3, 6, 9 g dose 
level. 
Hyperkalemia events will be further assessed by the association with the subgroups defined in 
Section 11.9. 
 Summary and Analyses of Death and Renal Disease Progression  
Ascertainment of survival status and renal replacement therapy (RRT) status (i.e., started dialysis 
or received a kidney transplant) will be done at the Week 52 Visit for all subjects enrolled in the 
TRCA-301E study, including those who discontinued study drug treatment prior to Week 52.  A 
subject listing will be provided. 
 Survival Analysis 
Survival analysis will be performed using data from the parent Study TRCA-301 and the extension 
Study TRCA-301E (i.e., the Phase 3 Safety Analysis Set).  Overall survival time is defined as the 
duration between the date of first dose of study drug in the parent Study TRCA-301 to the date of 
death, regardless of the cause of death.  Subjects will be censored to the date that the subject was 
last known to be alive as determined at the last study contact. The Kaplan-Meier method will be 
used for the analysis of survival.  Log-rank test will be used to compare the survival distributions 
between the treatment groups.  In addition, percentage, along with their 95% CI of the percentage, 
of subjects who were alive at specified time intervals will be provided.  A Kaplan-Meier plot of 
survival will be provided. 
 Time-to-Event Analyses 
Two time to event analyses will be performed in a manner similar to that of the survival analysis.  
In the first analysis (i.e., time to death or RRT analysis), the event is defined as the first event of 
death or RRT.  RRT is defined as either of the following: 
• Initiation of chronic dialysis defined as dialysis that was ongoing at the end of the 
study or at last follow-up for the study  
• Renal transplantation  


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In the second analysis (i.e., time to death, RRT or ≥ 50% decline in eGFR), the event is defined as 
the first occurrence of death, RRT, or ≥ 50% decline in eGFR.  The eGFR decline is defined as 
two consecutive qualifying eGFR values ≥ 28 days apart that meet the threshold, with no 
intervening values that do not meet the threshold. The event onset date is the first collection date 
of the two qualifying values.  A single qualifying value will also count: If there is at least one 
qualifying value < 28 days prior to the last eGFR value and the immediately preceding value 
represents a decline of ≥ 40%.  These two values must be ≥ 7 days apart.  In this case, the first of 
these 2 values representing a ≥ 50% decline in eGFR will be considered the start date of the event.  
The time to event is defined as the duration between the date of first dose of study drug in the 
parent Study TRCA-301 to the date of first occurrence of the event.  Subjects will be censored to 
the date at which the subject was last known to be  
• alive and free from RRT for time to death or RRT analysis  
• alive and free from RRT and event of ≥ 50% decline in eGFR for the second time to event 
analysis 
A listing of subject status on survival, RRT, renal function decline (i.e., ≥ 50% decline in eGFR 
from baseline) will be provided.  Kaplan-Meier plots will be provided. 
 Incidence of High Bicarbonate 
A summary table will be provided with the number and percentage of subjects who met the high 
bicarbonate dose interruption criterion (confirmed > 30 mEq/L) during the 40-week Study TRCA-
301E Treatment Period.  The table will also include the total number of subjects and total number 
of occurrences of any bicarbonate value > 30 mEq/L during the Treatment Period in Study 
TRCA-301E. 
 Clinical Laboratory Evaluation 
Continuous clinical laboratory test results from central laboratories (serum chemistry, hematology, 
spot urine, 24-hour urine and urinalysis) will be summarized using descriptive statistics at baseline 
and at each scheduled post-baseline time point during Study TRCA-301E.  Changes from baseline 
will also be summarized by treatment group and scheduled time point.  An additional summary 
will be provided for urine ACR (from a spot urine and from the 24-hour urine collection) from the 


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subset of subjects with a baseline value > 30 mg/g.  Categorical display methods (e.g., frequencies) 
and plots of laboratory values over time may also be used, as appropriate. Table 4 lists all the 
laboratory parameters to be summarized.  Box and whisker plots by treatment group and protocol 
scheduled time points will be provided for selected electrolytes (i.e., potassium, sodium, and 
chloride).  The graphs will include data from all subjects from the Phase 3 Safety Analysis Set. 
Descriptive statistics and out of range summaries for the eGFR derived from the central laboratory 
serum creatinine values will be presented separately from the chemistry test results described 
above. 
 Analysis of Variables Reported as Ratio to Serum Creatinine 
Variables such as 24-hour urine endothelin-1-to-creatinine ratio, aldosterone-to-creatinine ratio, 
angiotensinogen-to-creatinine ratio, 24-hour urine ACR, and spot urine ACR will be summarized 
descriptively by geometric mean, 95% CI of geometric mean, minimum and maximum.  The 
change from baseline will be reported as the geometric mean ratio (post-baseline/baseline) and 
95% CI of the geometric mean ratio. 
Table 4 Laboratory Parameters 
Test Type 
Parameter 
Assessment and Summary 
Whole serum bicarbonate 
(venous) 
pH, pCO2, pO2 and the calculated values 
for HCO3, BE, and O2 saturation 
Conducted with i-STAT:  
Descriptive statistics only 
Venous blood gas 
bicarbonate – benchtop 
analyzer 
pH, pCO2, pO2 and the calculated values 
for HCO3, BE, and O2 saturation if 
reported 
Either assay to be conducted at local 
laboratory or study site:  
Descriptive statistics only 
 
Serum bicarbonate (venous) 
– enzymatic assay 
HCO3 
Serum chemistry 
Albumin, ALT, AST, alkaline 
phosphatase, bilirubin (total and direct), 
BUN, calcium, chloride, cholesterol (HDL, 
LDL, total, and triglycerides), CK, CK-
MB (if CK is elevated), creatinine, eGFR 
(derived from creatinine and cystatin C), 
glucose, magnesium, phosphate, 
potassium, sodium, serum anion gap. 
Conducted at central laboratory: 
Descriptive statistics and categorical 
display (See Table 5) 
Coagulation 
INR 
For subjects receiving vitamin K 
antagonists or factor Xa inhibitors 
only.  Listing only 


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Table 4 Laboratory Parameters 
Test Type 
Parameter 
Assessment and Summary 
Hematology 
RBC count, white blood cell count, white 
blood cell count differential, hemoglobin, 
hematocrit and platelet count, RBC indices 
(e.g., MCV, RDW, MCH) 
Conducted at central laboratory: 
Descriptive statistics and categorical 
display (See Table 5) 
Hemoglobin A1c 
Glycated hemoglobin 
Conducted at central laboratory: 
Descriptive statistics only 
Urinalysis 
Bilirubin, glucose, ketones, blood, 
leukocyte esterase, nitrites, pH, protein, 
urobilinogen, and urine specific gravity.  
Conducted at central laboratory:  
Descriptive statistics only for pH 
and specific gravity. 
Spot urine tests  
Sodium, potassium, chloride, creatinine, 
anion gap, albumin, ACR. 
Conducted at central laboratory: 
Descriptive statistics only. 
24-hour urine collection 
Volume, urea nitrogen, sulfate, uric acid, 
albumin, and creatinine (including ACR) 
Conducted at central laboratory: 
Descriptive statistics only. 
Pregnancy test 
β-HCG 
Conducted at central laboratory 
(serum pregnancy test). 
Urine dipstick at study site at the 
Week 12 Visit only.  Listing only. 
ACR = albumin-to-creatinine ratio; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BE = 
base excess; BUN = blood urea nitrogen; CK = creatine kinase; CK-MB = creatine kinase-muscle/brain; eGFR = 
estimated glomerular filtration rate; HCO3 = bicarbonate; HDL = high-density lipoprotein; INR = international 
normalized ratio; LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; MCV = mean 
corpuscular volume; pCO2 = partial pressure of carbon dioxide; pO2 = partial pressure of oxygen; RBC = red 
blood cell; RDW = red cell distribution width; β-HCG = β-human chorionic gonadotropin. 
 Out of Range Summary 
The number (%) of subjects with any out of range chemistry and hematology values (i.e., above 
upper limit of normal, below lower limit of normal, above a pre-specified level or below a pre-
specified level) will be summarized by treatment group and scheduled time point.  For eGFR 
thresholds, the proportion of patients meeting the specified threshold at any post-baseline time 
point during the study will also be summarized by treatment group. Tricida chose these pre-
specified levels (Table 5) for laboratory tests because they are more appropriate for the study 
population than normal ranges for healthy subjects. 
Table 5 Pre-Specified Threshold Levels for Selected Laboratory Tests  
Laboratory Category 
Test Name 
Pre-Specified Level  
Chemistry 
Sodium 
< 132 mEq/L 
Chemistry 
Potassium 
< 3.0, < 3.5, > 5.0, > 5.5, > 6.0 mEq/L 
results from specimens reported as hemolyzed 
(Section 10.2.18) will be excluded.  


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Laboratory Category 
Test Name 
Pre-Specified Level  
Chemistry 
Serum bicarbonate 
< 10, < 12, > 30, > 32 mEq/L 
Chemistry 
Creatinine 
2-fold increase, confirmed or at last follow up (see 
Section 15.3.2) 
Chemistry 
eGFR (based on 
creatinine) 
≤ 10 mL/min/1.73m2, < 15 mL/min/1.73m2 
Chemistry 
Glucose 
> 250 mg/dL 
Hematology 
Hemoglobin 
< 9 g/dL 
Hematology 
Hematocrit 
< 27% 
Spot Urine and 
24-hour urine collection 
ACR 
> 30 mg/g, > 300 mg/g 
All laboratory results will be listed.  Laboratory results that are above or below normal limits will 
be flagged in the listings.  In addition, laboratory results that meet or exceed the pre-specified 
levels (i.e., are above [or below as appropriate] the pre-specified levels as shown in the above 
table) will be flagged.   
 Vital Signs 
Descriptive statistics for blood pressure (BP), heart rate (HR), respiratory rate, and temperature, 
including baseline values and change from baseline values, will be summarized by treatment group 
and scheduled time point.  In addition, number and percentage of subjects with any out of range 
values (i.e., above a pre-specified level or below a pre-specified level) will be summarized by 
scheduled time point.  Tricida chose these pre-specified levels for vital signs because they are more 
appropriate for the study population than normal ranges for healthy subjects.  The pre-specified 
threshold levels for vital signs are defined in Table 6.   
Table 6 Pre-Specified Threshold Levels for Vital Signs  
Vital Sign 
Pre-Specified Level  
Systolic blood pressure 
< 100, > 190 mmHg, > 30% increase or decrease from baseline 
Diastolic blood pressure 
> 95 mmHg, > 20% increase or decrease from baseline 
Heart rate 
< 40, > 100 beats/min 
Respiratory rate 
< 10, > 20 breaths/min, change from baseline by 
≥ 6 breaths/minute 
All vital signs parameters will be listed.  The listing will flag any vital signs that exceed the levels 
provided in the table above. 


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 Body Weight 
Descriptive statistics for body weight measurements, including baseline values and CFB values, 
will be summarized by treatment group and scheduled time point.  Body weight measurements 
will be listed along with vital signs. 
 12-lead Electrocardiogram 
Listings will present ECG data, such as clinical interpretation of ECGs, ECG rhythm and 
assessments of HR, and intervals of PR, QRS, QT, and QTcF.  The baseline and on-study cardiac 
rhythms (normal sinus rhythm, atrial fibrillation, other) will be descriptively summarized.  
Descriptive statistics for observed values and change from baseline at each scheduled time point 
will be presented for these 12-lead ECG intervals and HR assessments.  In addition, the number 
and percentage of subjects with any abnormal values (i.e., outside a pre-specified threshold) will 
be summarized by scheduled time point.  The pre-specified levels of ECG QTc thresholds are 
consistent with FDA guidance (See Table 7).   
Table 7 Pre-Specified Threshold Levels for Electrocardiogram Parameters 
ECG Parameter 
Pre-Specified Level 
PR 
> 200 msec 
QTcF 
> 450, > 480 or > 500 msec, > 30 or > 60 msec increase from 
baseline 
Heart rate 
< 40, > 100 beats/min 
 
ECG = electrocardiogram; QTcF = QT interval corrected by the method of Fridericia 
All ECG parameters will be listed.  The listing will flag any results that are outside the levels 
provided in the table above. 
 Physical Examination 
Abnormal clinically significant findings were reported as Medical History or Adverse Events 
depending on date of onset.  
16 SUBGROUP ANALYSES 
Subgroups defined in Section 11.9 will be used to explore the durability of the TRC101 effect by 
intrinsic and extrinsic factors or to further explore safety findings.  The variables to be analyzed 


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for the each of the subgroups are described in Table 8.  The analysis methods are described in the 
sections of the SAP indicated in the table.   
Table 8 List of Pre-Specified Subgroup Analyses at Week 52 
Type 
Variable 
Method 
Section 
Subgroup 
Efficacy 
Responders at 
Week 52 
14.2.1 
Baseline Bicarbonate (≤ 18 vs > 18 mEq/L) 
Screening eGFR (< 30 vs ≥ 30 mL/min/1.73m2) 
Age (< 65 vs ≥ 65 years) 
Sex (Male vs Female) 
Race (White vs Non-White) 
Baseline alkali use (Yes vs No) 
Geographic region (Europe vs USA) 
Acid reducing drug (Yes vs No) 
Efficacy 
Change from 
baseline in serum 
bicarbonate 
14.3 
Efficacy 
Change from 
baseline in total 
score of KDQOL 
Physical 
Functioning Survey 
at Week 52 
14.4 
Baseline Bicarbonate (≤ 18 vs > 18 mEq/L) 
Age (< 65 vs ≥ 65 years) 
Sex (Male vs Female) 
Baseline KDQOL Question 3 score (above vs below median 
baseline KDQOL Physical Functioning Survey score) 
Efficacy 
Time to complete 
repeated chair 
stand test at Week 
52 
14.4 
Baseline Bicarbonate (≤ 18 vs > 18 mEq/L) 
Age (< 65 vs ≥ 65 years) 
Sex (Male vs Female) 
Baseline time to complete repeated chair stand test (above vs below 
median baseline time) 
Safety 
Subjects reporting 
hyperkalemia 
events 
15.2.2.2 
Baseline Bicarbonate (≤ 18 vs > 18 mEq/L) 
Screening eGFR (< 30 vs ≥ 30 mL/min/1.73m2) 
Baseline potassium level (below normal range, within normal 
range, above normal range) 
Diabetes mellitus (Yes vs No) 
Concomitant ACEi or ARB use (Yes vs No) 
Concomitant use of potassium-wasting diuretic (Yes vs No) 
Concomitant use of potassium-sparing diuretics (Yes vs No) 
Concomitant use of ACEi or ARB plus potassium-sparing diuretics 
(Yes vs No) 
Mean daily dose (< median daily dose level vs ≥ median daily dose 
level) 
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ECG = electrocardiogram; 
ET = early termination; KDQOL = kidney disease quality of life 
 


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17 DEVIATIONS FROM THE PROTOCOL SPECIFIED ANALYSIS 
 Analysis of Change from Baseline in Serum Bicarbonate 
In the protocol Section 8.6.1, it stated “The analysis for durability of effect will include blood 
bicarbonate results that will be collected at Week 12 Visit through the end of the 40-week 
treatment from the i-STAT device.”  In order to fully evaluate the treatment effect, the planned 
analysis, uses an MMRM model that comprises serum bicarbonate data from Week 1 in the 
parent Study TRCA-301 through Week 52 in Study TRCA-301E.  The data from the Week 14 
Visit through the end of the 40-week Treatment Period will be included in the model. 
18 REFERENCES 
1. Ratitch, B. and O’Kelly, M. (2011), “Implementation of Pattern-Mixture Models Using 
Standard SAS/STAT Procedures,” in Proceedings of PharmaSUG 2011 (Pharmaceutical 
Industry SAS Users Group), SP04, Nashville. 
2. Allison, P. (2010), Survival Analysis Using SAS: A Practical Guide, Second Edition 
3. Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace RB. Lower-extremity 
function in persons over the age of 70 years as a predictor of subsequent disability. N 
Engl J Med. 1995;332(9):556-61. 
4. Hays RD, Kallich JD, Mapes D, Coons SJ, Amin N, Carter WB. Kidney Disease Quality 
of Life Short Form (KDQOL-SFtm), Version 1.3. A Manual for Use and Scoring. RAND 
corporation 1997. 
 
19 APPENDICES 
 Anatomical Therapeutic Chemical Level 4 Terms for ACEi or ARB 
The following is a list of ATC Level 4 terms for ACEi or ARB.  Other ATC level 4 terms may 
be added upon medical review. 
• ACE INHIBITORS AND CALCIUM CHANNEL BLOCKERS 
• ACE INHIBITORS AND DIURETICS 
• ACE INHIBITORS, PLAIN 
• ANGIOTENSIN II ANTAGONISTS, PLAIN 
 
 Anatomical Therapeutic Chemical Level 4 Terms for Potassium-Sparing Diuretics 
The following is a list of ATC Level 4 terms for potassium-sparing diuretics: 


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• aldosterone antagonists 
• amiloride 
• eplerenone 
• spironolactone 
• other potassium sparing agents 
 
 Gastrointestinal Nonspecific Inflammation and Dysfunctional Conditions (Standardised 
MedDRA Queries) 
The table below lists the PTs for gastrointestinal nonspecific inflammation and dysfunctional 
conditions using SMQ. 
SMQ  
Preferred Term 
Gastrointestinal nonspecific dysfunction 
Acid peptic disease 
Gastrointestinal nonspecific dysfunction 
Duodenogastric reflux 
Gastrointestinal nonspecific dysfunction 
Dyspepsia 
Gastrointestinal nonspecific dysfunction 
Gastrooesophageal reflux disease 
Gastrointestinal nonspecific dysfunction 
Gastrooesophageal sphincter insufficiency 
Gastrointestinal nonspecific dysfunction 
Cardiospasm 
Gastrointestinal nonspecific dysfunction 
Diverticulum intestinal 
Gastrointestinal nonspecific dysfunction 
Dyschezia 
Gastrointestinal nonspecific dysfunction 
Dyskinesia oesophageal 
Gastrointestinal nonspecific dysfunction 
Gastric atony 
Gastrointestinal nonspecific dysfunction 
Gastric dilatation 
Gastrointestinal nonspecific dysfunction 
Gastric emptying study 
Gastrointestinal nonspecific dysfunction 
Gastric fluid analysis abnormal 
Gastrointestinal nonspecific dysfunction 
Gastric hypermotility 
Gastrointestinal nonspecific dysfunction 
Gastric hypertonia 
Gastrointestinal nonspecific dysfunction 
Gastric hypomotility 
Gastrointestinal nonspecific dysfunction 
Gastric pH decreased 
Gastrointestinal nonspecific dysfunction 
Gastric pH increased 
Gastrointestinal nonspecific dysfunction 
Gastrointestinal hypermotility 
Gastrointestinal nonspecific dysfunction 
Gastrointestinal motility disorder 
Gastrointestinal nonspecific dysfunction 
Impaired gastric emptying 
Gastrointestinal nonspecific dysfunction 
Intestinal dilatation 
Gastrointestinal nonspecific dysfunction 
Intestinal transit time abnormal 
Gastrointestinal nonspecific dysfunction 
Intestinal transit time decreased 
Gastrointestinal nonspecific dysfunction 
Intestinal transit time increased 
Gastrointestinal nonspecific dysfunction 
Myochosis 


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SMQ  
Preferred Term 
Gastrointestinal nonspecific dysfunction 
Oesophageal achalasia 
Gastrointestinal nonspecific dysfunction 
Oesophageal dilatation 
Gastrointestinal nonspecific dysfunction 
Oesophageal hypomotility 
Gastrointestinal nonspecific dysfunction 
Oesophageal manometry 
Gastrointestinal nonspecific dysfunction 
Oesophageal pH increased 
Gastrointestinal nonspecific dysfunction 
Pancreatic enzyme abnormality 
Gastrointestinal nonspecific dysfunction 
Pancreatic failure 
Gastrointestinal nonspecific dysfunction 
Presbyoesophagus 
Gastrointestinal nonspecific dysfunction 
Pylorus dilatation 
Gastrointestinal nonspecific dysfunction 
Toxic dilatation of intestine 
Gastrointestinal nonspecific inflammation 
Chronic gastritis 
Gastrointestinal nonspecific inflammation 
Colitis 
Gastrointestinal nonspecific inflammation 
Duodenitis 
Gastrointestinal nonspecific inflammation 
Enteritis 
Gastrointestinal nonspecific inflammation 
Erosive duodenitis 
Gastrointestinal nonspecific inflammation 
Erosive oesophagitis 
Gastrointestinal nonspecific inflammation 
Feline oesophagus 
Gastrointestinal nonspecific inflammation 
Functional gastrointestinal disorder 
Gastrointestinal nonspecific inflammation 
Gastric mucosa erythema 
Gastrointestinal nonspecific inflammation 
Gastritis 
Gastrointestinal nonspecific inflammation 
Gastritis erosive 
Gastrointestinal nonspecific inflammation 
Gastroduodenitis 
Gastrointestinal nonspecific inflammation 
Gastrointestinal erosion 
Gastrointestinal nonspecific inflammation 
Gastrointestinal mucosa hyperaemia 
Gastrointestinal nonspecific inflammation 
Gastrointestinal mucosal exfoliation 
Gastrointestinal nonspecific inflammation 
Haemorrhagic erosive gastritis 
Gastrointestinal nonspecific inflammation 
Intestinal angioedema 
Gastrointestinal nonspecific inflammation 
Oesophageal mucosa erythema 
Gastrointestinal nonspecific inflammation 
Oesophagitis 
Gastrointestinal nonspecific inflammation 
Reactive gastropathy 
Gastrointestinal nonspecific inflammation 
Reflux gastritis 
Gastrointestinal nonspecific inflammation 
Remnant gastritis 
Gastrointestinal nonspecific inflammation 
Ulcerative gastritis 
Gastrointestinal nonspecific inflammation 
Allergic colitis 
Gastrointestinal nonspecific inflammation 
Anal inflammation 
Gastrointestinal nonspecific inflammation 
Colitis erosive 
Gastrointestinal nonspecific inflammation 
Colonoscopy abnormal 
Gastrointestinal nonspecific inflammation 
Diverticulitis 


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SMQ  
Preferred Term 
Gastrointestinal nonspecific inflammation 
Endoscopic ultrasound abnormal 
Gastrointestinal nonspecific inflammation 
Endoscopy abnormal 
Gastrointestinal nonspecific inflammation 
Endoscopy gastrointestinal abnormal 
Gastrointestinal nonspecific inflammation 
Endoscopy large bowel abnormal 
Gastrointestinal nonspecific inflammation 
Endoscopy upper gastrointestinal tract 
abnormal 
Gastrointestinal nonspecific inflammation 
Faecal calprotectin abnormal 
Gastrointestinal nonspecific inflammation 
Faecal calprotectin increased 
Gastrointestinal nonspecific inflammation 
Faecal elastase concentration abnormal 
Gastrointestinal nonspecific inflammation 
Faecal elastase concentration decreased 
Gastrointestinal nonspecific inflammation 
Gastric fibrosis 
Gastrointestinal nonspecific inflammation 
Gastrointestinal inflammation 
Gastrointestinal nonspecific inflammation 
Intrinsic factor antibody abnormal 
Gastrointestinal nonspecific inflammation 
Intrinsic factor antibody positive 
Gastrointestinal nonspecific inflammation 
Oesophageal irritation 
Gastrointestinal nonspecific inflammation 
Oesophagitis chemical 
Gastrointestinal nonspecific inflammation 
Oesophagogastroduodenoscopy abnormal 
Gastrointestinal nonspecific inflammation 
Oesophagogastroscopy abnormal 
Gastrointestinal nonspecific inflammation 
Oesophagoscopy abnormal 
Gastrointestinal nonspecific inflammation 
Pancreatitis chronic 
Gastrointestinal nonspecific inflammation 
Pepsinogen I decreased 
Gastrointestinal nonspecific inflammation 
Pepsinogen I increased 
Gastrointestinal nonspecific inflammation 
Proctitis 
Gastrointestinal nonspecific inflammation 
Proctoscopy abnormal 
Gastrointestinal nonspecific inflammation 
Proctosigmoidoscopy abnormal 
Gastrointestinal nonspecific inflammation 
Sigmoidoscopy abnormal 
Gastrointestinal nonspecific inflammation 
Stomach scan abnormal 
Gastrointestinal nonspecific inflammation 
Stool chymotrypsin abnormal 
Gastrointestinal nonspecific inflammation 
X-ray with contrast lower gastrointestinal 
tract abnormal 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Abdominal discomfort 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Abdominal distension 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Abdominal pain 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Abdominal pain lower 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Abdominal pain upper 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Abdominal symptom 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Abdominal tenderness 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Abnormal faeces 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Aerophagia 


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SMQ  
Preferred Term 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Anorectal discomfort 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Bowel movement irregularity 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Change of bowel habit 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Constipation 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Defaecation urgency 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Diarrhoea 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Discoloured vomit 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Epigastric discomfort 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Eructation 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Faecal volume decreased 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Faecal volume increased 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Faeces hard 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Faeces soft 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Flatulence 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Frequent bowel movements 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Gastrointestinal pain 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Gastrointestinal sounds abnormal 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Gastrointestinal toxicity 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Infrequent bowel movements 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Nausea 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Non-cardiac chest pain 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Oesophageal discomfort 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Oesophageal pain 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Premenstrual cramps 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Vomiting 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Anorectal swelling 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Antacid therapy 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Antidiarrhoeal supportive care 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Antiemetic supportive care 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Breath odour 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Chest pain 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Colonic lavage 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Dysphagia 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Early satiety 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Gastritis prophylaxis 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Gastrointestinal disorder therapy 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Gastrointestinal tract irritation 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Gastrooesophageal reflux prophylaxis 


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SMQ  
Preferred Term 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Glycogenic acanthosis 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Hypovolaemia 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Laxative supportive care 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Malabsorption 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Mucous stools 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Pernicious anaemia 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Post procedural constipation 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Post procedural diarrhoea 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Post-tussive vomiting 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Probiotic therapy 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Procedural nausea 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Procedural vomiting 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Prophylaxis against diarrhoea 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Prophylaxis of nausea and vomiting 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Regurgitation 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Retching 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Steatorrhoea 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Vomiting projectile 
 
 Hyperkalemia Events 
There are two preferred terms for hyperkalemia: 
• Blood potassium increased 
• Hyperkalaemia