Conditions: Metabolic Acidosis
Keywords: blood bicarbonate, kidney disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 217
Healthy volunteers: no

Brief summary:
This is a multicenter, double-blind, placebo-controlled, parallel-design study. The study will enroll approximately 210 adult male and female subjects with stage 3 or 4 chronic kidney disease and metabolic acidosis. The study dosing (TRC101 or placebo) will continue for 12 weeks once daily.

The maximum study duration is anticipated to be up to 16 weeks.

Detailed description:

Arms:
arm 1: Administered once daily (QD) for 12 weeks arm 2: Administered once daily (QD) for 12 weeks

Interventions: intervention 1: TRC101 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral suspension intervention 2: Oral suspension

Protocol document:
Prot_000.pdf: 
 
 
 
 
Protocol for Study TRCA-301 
 
 
Official Study Title: 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo- 
Controlled Study to Evaluate the Efficacy and Safety of 
TRC101 in Subjects with Chronic Kidney Disease and 
Metabolic Acidosis 
 
 
ClinicalTrials.gov Identifier:  
NCT03317444   
 
 
Document Date: 
November 27, 2017 


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301 
 
November 27, 2017 
 
Confidential 
 
Page 1 of 80 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
TRC101 in Subjects with Chronic Kidney Disease and 
Metabolic Acidosis 
Study Number: 
TRCA-301 
Investigational Drug: 
TRC101 
IND Number: 
125,832 
Indication: 
Treatment of metabolic acidosis associated with chronic 
kidney disease  
Investigators: 
Multicenter 
EudraCT Number: 
2016-003825-41 
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: 
March 02, 2017 
Amendment 1: 
June 05, 2017 
Amendment 2: 
August 03, 2017 
Amendment 3: 
November 27, 2017 
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-301 
 
November 27, 2017 
 
Confidential 
 
Page 3 of 80 
Principal Investigator’s Signature 
 
Study Title: 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of TRC101 in 
Subjects with Chronic Kidney Disease and Metabolic Acidosis 
Study Number: 
TRCA-301 
Final Date: 
November 27, 2017 
 
 
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 EU Clinical Trials Directive 
and all other applicable local and/or national laws, regulations and requirements.  
 
 
Signed: 
 
 
Date:  
 
 
Name:  __________________________________________________________________ 
Title:  ___________________________________________________________________ 
Institution Address:  _______________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
 




TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301 
 
November 27, 2017 
 
Confidential 
 
Page 5 of 80 
SYNOPSIS 
TITLE: 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of TRC101 in Subjects with Chronic Kidney Disease and Metabolic Acidosis 
PROTOCOL NUMBER: 
TRCA-301 
INVESTIGATIONAL PRODUCT: 
TRC101 
INDICATION: 
Treatment of metabolic acidosis associated with chronic kidney disease (CKD) 
OBJECTIVES: 
Efficacy:  To evaluate the efficacy of TRC101 in CKD patients with metabolic acidosis (blood bicarbonate 
12 to 20 mEq/L) 
Safety:     To evaluate the safety of administration of TRC101 in CKD patients with metabolic acidosis 
(blood bicarbonate 12 to 20 mEq/L) 
POPULATION: 
This study will enroll approximately 210 male and female subjects, 18 to 85 years of age with CKD (an 
estimated glomerular filtration rate [eGFR] of 20 to 40 mL/min/1.73m2) and low blood bicarbonate (12 to 
20 mEq/L).  At least half of the subjects enrolled will have a blood bicarbonate level of 12 to 18 mEq/L.  
STUDY DESIGN AND DURATION: 
This is a double-blind, placebo-controlled, parallel-design, 2-arm study.  Approximately 210 subjects will be 
randomized in a 4:3 ratio into one of the two arms (6 g TRC101 or placebo administered once daily [QD] 
with lunch). 
Study periods are the following: 
• 
Screening Period (up to 2 weeks). 
• 
Treatment Period (12 weeks) starting with Baseline Visit (Day 1).  At the end of 12-week Treatment 
Period eligible subjects may enroll into a 40-week extension study. 
• 
Follow-up Period (2 weeks after discontinuation of treatment, whether subject completes treatment or 
discontinues early) for subjects who do not enroll in the extension study. 
After providing informed consent, the eligibility of potential subjects will be evaluated based on laboratory 
values, medical history, concomitant medications, vital signs, pregnancy test (if applicable), and physical 
examination.  Three qualifying fasting blood bicarbonate values (obtained at Screening 1, Screening 2, and 
Baseline Visits based on onsite measurement using an i-STAT point-of-care device) are required to establish 
subject’s eligibility.  Both Screening blood bicarbonate values and the average of two Screening and Day 1 
values (i.e., baseline bicarbonate) must be within the range 12 to 20 mEq/L.  Two qualifying eGFR values of 
20 to 40 mL/min/1.73m2 at the Screening 1 and Screening 2 Visits are required to establish subject’s 
eligibility.  The Screening 1 and Screening 2 Visits must be at least 5 days apart.   
Qualified subjects will be randomized on the morning of the Baseline Visit (Day 1), which is the first day of 
the 12-week Treatment Period.  A collection of baseline venous blood and urine samples will be performed 
in a fasting state pre-dose.  Following randomization, designated unblinded site staff will assist the subject in 
administering the first dose of study drug, which will be taken onsite in the morning with food (light meal or 
snack) after collection of baseline laboratory specimens.  Subjects will be given a dosing diary in which to 
record the time of study drug dosing. 
Subjects will continue dosing on an out-patient basis for the subsequent 12 weeks (Treatment Period).  
Dosing of oral concomitant medications and study drug will be separated by at least 4 hours.  The study drug 
dose will be fixed during the first 4 weeks of the Treatment Period, except for subjects with blood 


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301 
 
November 27, 2017 
 
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Page 6 of 80 
bicarbonate ≥ 27 mEq/L.  Subjects with a blood bicarbonate level of 27 to 30 mEq/L will have their dose of 
study drug decreased per the titration algorithm (see 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 (see Appendix 2).  Beginning at the Week 4 Visit, subjects with a blood bicarbonate level 
below the normal range (< 22 mEq/L) will have a blinded adjustment of the study drug dose in accordance 
with the titration algorithm (see Appendix 2).  At any time during the study, subjects with a confirmed blood 
bicarbonate level < 12 mEq/L 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.  During the 12-week Treatment Period, subjects will attend eight study visits (Day 1, Weeks 1, 
2, 4, 6, 8, 10, and 12) for efficacy and safety assessments.   
Subjects who complete the Treatment Period will be offered participation in a 40-week extension study 
(TRCA-301E).  Subjects who are not willing to participate in the extension study or who are not eligible will 
enter the 2-week Follow-up Period and return to the study site for two visits: Follow-up 1 (Week 13) and 
Follow-up 2 (Week 14), for adverse event (AE) collection, fasting blood draws and safety assessments as 
outlined in the Schedule of Events (see Appendix 1).  Subjects who withdraw from the study prematurely 
(i.e., prior to the Week 12 Visit) will undergo an Early Termination (ET) Visit, during which all Week 12 
Visit assessments will be performed, followed by Follow-up 1 and 2 Visits in 1 and 2 weeks, respectively.  
Blood draws for bicarbonate measurements will be done 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 is anticipated to be 16 weeks per subject, including the Screening Period (up to 
2 weeks), 12-week Treatment Period, and 2-week Follow-up Period.  The maximum TRCA-301 study 
duration for subjects who continue into the extension Study TRCA-301E will be 14 weeks (excluding the 2-
week Follow-up Period). 
INCLUSION CRITERIA: 
1. 
Have provided written informed consent prior to participation in the study. 
2. 
Male or female subjects 18 to 85 years of age at Screening 1 Visit. 
3. 
Have a blood bicarbonate value of 12 to 20 mEq/L at Screening 1 and Screening 2 Visits AND 
an average value for Screening 1, Screening 2, and Baseline Visits (i.e., baseline blood 
bicarbonate) within the range 12 to 20 mEq/L based on onsite measurement using an i-STAT 
point of care device. 
Screening 1 and Screening 2 Visits must be at least 5 days apart. 
Note:  Subjects with baseline blood bicarbonate values of 12 to 18 mEq/L are eligible without 
restriction.  Once 105 subjects with baseline blood bicarbonate values of > 18 to 20 mEq/L have 
been enrolled, randomization may be closed to additional subjects with baseline blood 
bicarbonate in this range.   
4. 
At both Screening Visits have an eGFR value of 20 to 40 mL/min/1.73m2 calculated using the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation as reported by the 
central laboratory.  If a central laboratory eGFR value from Screening 2 Visit is not available, 
eGFR can be calculated using CKD-EPI equation based on onsite serum creatinine 
measurement at the Baseline Visit to establish subject’s eligibility.  
Screening 1 and Screening 2 Visits must be at least 5 days apart. 
5. 
Have stable renal function as defined by eGFR values at both Screening Visits that are not 
different by more than 20% (the higher of the two Screening eGFR values will be used as the 
denominator to calculate the 20% allowable difference). 
6. 
At both Screening Visits have systolic blood pressure < 170 mmHg (all three replicates). 
7. 
Have a hemoglobin A1c (HbA1c) value of ≤ 9.0% at the Screening 1 Visit based on central 
laboratory measurement. 
8. 
Have adequate peripheral venous access for blood draws. 
9. 
Women who are of childbearing potential must have negative pregnancy tests at the Screening 1 
Visit and Day 1 and be willing to use an acceptable method of birth control from the Screening 


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301 
 
November 27, 2017 
 
Confidential 
 
Page 7 of 80 
1 Visit 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 either Screening Visit that, in the opinion of the 
Investigator, requires emergency intervention or evaluation for an acute acidotic process. 
2. 
Have had anuria, dialysis, acute kidney injury, history of acute renal insufficiency or known ≥ 30% 
increase in serum creatinine or known ≥ 30% acute or chronic decrease in eGFR in the 3 months 
prior to the Screening 1 Visit. 
3. 
Have chronic obstructive pulmonary disease (COPD) that is treated with chronic oral steroids, that 
requires the subject to be on oxygen, or that required hospitalization within the previous 6 months. 
4. 
Had heart failure with maximum New York Heart Association (NYHA) Class IV symptoms, or that 
required hospitalization with a primary cause of heart failure, during the preceding 6 months (see 
Appendix 3). 
5. 
Have had a heart or kidney transplant. 
Note:  Patients on the cadaveric transplant list or being evaluated for a future living donor 
transplant may be enrolled. 
6. 
Planned initiation of renal replacement therapy (dialysis or transplantation) within 12 weeks 
following randomization. 
7. 
Have had a stroke or transient ischemic attack (TIA) within the 6 months prior to randomization. 
8. 
Have had a cardiac event within 12 weeks prior to randomization, including:  myocardial 
infarction, acute coronary syndrome, coronary bypass grafting, percutaneous coronary intervention, 
valve procedure, inpatient or outpatient treatment for acute decompensated heart failure. 
9. 
Have been hospitalized for any reason during the 2 months prior to the Screening 1 Visit, other than 
for pre-planned diagnostic or minor invasive procedures.   
Note: Subjects who had major cardiovascular procedures or percutaneous cardiac procedures 
during this time frame are excluded, even if the procedures were pre-planned. 
10. 
Have a history or current diagnosis of clinically significant diabetic gastroparesis (based on 
Investigator’s judgment) or a history of bariatric surgery. 
11. 
Have a history or current diagnosis of bowel obstruction, swallowing disorders, severe 
gastrointestinal (GI) disorders, inflammatory bowel disease, major GI surgery, frequent diarrhea or 
active gastric/duodenal ulcers. 
12. 
Have liver enzyme (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) or total 
bilirubin values > 3 × the upper limit of normal (ULN) at Screening based on central laboratory 
measurements. 
13. 
Have a serum calcium ≤ 8.0 mg/dL at the Screening 1 Visit based on central laboratory 
measurement. 
14. 
Have a serum potassium value < 3.8 mEq/L or > 5.9 mEq/L at the Screening 1 or Screening 2 Visit. 
15. 
Have active cancer during the 1 year prior to Screening, 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. 


TRC101 
 
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Clinical Study Protocol: TRCA-301 
 
November 27, 2017 
 
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Page 8 of 80 
16. 
Have received any investigational medication during the last month (28 days or ≥ 5 half-lives [if 
known], whichever is longer) preceding the Screening 1 Visit. 
17. 
Have used any of the following in the 14 days prior to the Screening 1 Visit:  lanthanum carbonate, 
colesevelam, cholestyramine, sodium or calcium polystyrene sulfonate, calcium acetate, sevelamer, 
bixalomer, patiromer, and other polymeric binder drugs. 
18. 
Have had a change in doses (including starting or stopping treatment) in the 2 weeks prior to the 
Screening 1 Visit or during Screening Period to the following:  calcium-containing supplements, 
such as calcium carbonate and calcium citrate; antacids; H2-blockers; proton pump inhibitors.  See 
Section 5.9 for examples of specific drugs.  
19.  Have had a change in doses (including starting or stopping treatment) in the 4 weeks prior to the 
Screening 1 Visit or during Screening Period to the following: sodium bicarbonate, potassium 
citrate, sodium citrate or other alkali therapy; diuretics; renin-angiotensin-aldosterone system 
[RAAS] inhbitors, such as angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor 
blockers [ARBs], aldosterone antagonists [AAs], mineralocorticoid receptor antagonists [MRAs]; 
non-ophthalmic carbonic anhydrase inhibitors.  See Section 5.9 for examples of specific drugs. 
Note:  For diuretics, dose changes of up to ± 50% relative to the average dose during the Screening 
Period are considered “stable”, and a dose change up to ± 50% between the Screening 1 Visit and 
the Baseline Visit is considered “stable”. 
20. 
Have a known allergy to placebo 
  
21. 
Inability to consume the study drug or otherwise comply with the protocol. 
22. 
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. 
23. 
Have participated in a previous clinical study of TRC101. 
24. 
Currently breastfeeding. 
 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Investigational product: TRC101. 
Placebo: 
, NF Grade. 
Approximately 210 subjects will be randomized in a 4:3 ratio to one of the following treatments: 
• 
6 g TRC101 QD (n~120) 
• 
Placebo (n~90) 
TRC101 or placebo will be administered orally as an aqueous suspension, QD with lunch, for 12 weeks.  
Concomitant oral medications must be taken at least 4 hours before or after study drug administration.  The 
first dose of study drug will be given at the study site on Day 1 in the morning with food.  The last dose of 
study drug will be taken the day before the Week 12 Visit unless the subject is enrolled in the extension 
Study TRCA-301E. 
MAIN EFFICACY ASSESSMENT: 
Efficacy will be assessed by blood bicarbonate values. 
SAFETY ASSESSMENTS: 
Safety assessments will include AEs, vital signs, physical examination (including body weight), safety 
laboratory measurements, coagulation (for subjects on vitamin K antagonists or factor Xa inhibitors only), 
spot urine, urinalysis, and electrocardiograms (ECGs).   


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Clinical Study Protocol: TRCA-301 
 
November 27, 2017 
 
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ENDPOINTS: 
Primary Efficacy:   
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 12 Visit). 
Secondary Efficacy: 
CFB in blood bicarbonate at the end of treatment (Week 12 Visit).  
Exploratory Efficacy: 
1. 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 12 Visit). 
2. CFB in repeated chair stand test duration at the end of treatment (Week 12 Visit). 
Safety: 
1. AEs, SAEs and withdrawal of study treatment due to AE. 
2. Having met the high bicarbonate dose interruption criterion (confirmed > 30 mEq/L) at any time 
during the Treatment Period. 
STATISTICAL ANALYSES: 
This is a double-blind, placebo-controlled, parallel-design, 2-arm, study.  Subjects will be randomized in a 
4:3 ratio into one of the two arms (6 g TRC101 or placebo administered QD with lunch).  Randomization 
will be stratified by baseline blood bicarbonate (≤ 18 mEq/L vs. > 18 mEq/L) and screening eGFR 
(< 30 mL/min/1.73m2 vs. ≥ 30 mL/min/1.73m2), which represents an average of two eGFR values obtained at 
Screening 1 and Screening 2 Visits. 
Two populations will be analyzed in this study: 
1. Modified intent-to-treat (MITT) analysis set:  All randomized subjects who had baseline and at least 
one post-baseline bicarbonate values. 
2. Safety analysis set:  All subjects who received any amount of study drug (TRC101 or placebo). 
Frequencies and percentages will be presented for the categorical variables and descriptive statistics will be 
presented for continuous variables.   
Efficacy:  Efficacy data will be summarized by treatment group for subjects in the MITT analysis set based 
on the randomized treatment group assignment.  The bicarbonate results read from the i-STAT device will be 
the basis for efficacy evaluations.  
The primary efficacy analysis will compare TRC101 and placebo with respect to the proportions of subjects 
who are responders at the end of treatment (Week 12 Visit).  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) at the end of 
treatment (Week 12 Visit).  The primary endpoint analysis will include: 
1. The difference in proportion (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 by time point; and   
2. 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.   
The secondary efficacy analysis will compare the least squares (LS) means CFB in bicarbonate level between 
the TRC101 group and placebo group at the end of treatment (Week 12 Visit).  The secondary endpoint will 
be assessed using a longitudinal mixed model for repeated measures (MMRM).   
Exploratory efficacy analyses will be specified in the statistical analysis plan (SAP). 
Statistical significance will be declared with a two-sided test at the 0.05 level.  In order to control family-
wise error rate, statistical testing for the primary and secondary efficacy endpoints will be performed 
sequentially.  At the Week 12 Visit, Fisher’s exact test will be used to compare the group proportions.   If 
this formal test is statistically significant, a second formal test for the proportion of TRC101 responders at 
Week 12 will be conducted.  Only when the primary efficacy result is statistically significant will a formal 


TRC101 
 
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Clinical Study Protocol: TRCA-301 
 
November 27, 2017 
 
Confidential 
 
Page 10 of 80 
test for the secondary efficacy endpoint (CFB in blood bicarbonate at Week 12 Visit) be performed.   
Safety:  Safety will be summarized by treatment group for subjects in the safety analysis set.  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 will be summarized by treatment group.  Number (%) of subjects with 
TEAEs leading to discontinuation of study treatment will also be summarized by treatment group. Clinical 
laboratory test results, vital signs and ECG findings will be summarized using descriptive statistics by 
treatment group and time point. The primary analysis for change in eGFR will be based on serum creatinine 
(a supportive analysis will use serum cystatin C, due to the potential for changes in muscle mass related to 
bicarbonate correction).  Categorical display methods (e.g., frequencies, shift tables) and plots of laboratory 
values over time may also be used, as appropriate.  Newly observed, clinically significant physical 
examination findings will be listed.   
Other Analyses:  Demographic and baseline characteristics will be summarized by treatment group.  
Exposure to study drug, dosing compliance, and concomitant medications will be summarized by treatment 
group.  The number and percentage of subjects who used prior and/or concomitant medications will be 
summarized by Anatomic Therapeutic Chemical (ATC) classification levels and treatment group.   
SAMPLE SIZE DETERMINATION: 
Primary efficacy endpoint:  A sample size of 120 subjects in the TRC101 group and 90 subjects in the 
placebo group will have high power to detect differences between the TRC101- and placebo-treated groups.   
The sample size calculation is based on the data from the Phase 1/2 Study TRCA-101, where 3% of placebo 
and 46% of TRC101 treated subjects had an increase in blood bicarbonate of ≥ 4 mEq/L or had blood 
bicarbonate in the normal range at Week 2.  We assume the full TRC101 treatment effect had not been 
reached during this short treatment period.  In Study TRCA-301, we expect to observe that 50 to 55% of 
TRC101-treated and 10% of placebo-treated subjects will have an increase of ≥ 4 mEq/L or have blood 
bicarbonate in the normal range at the end of treatment (Week 12 Visit).  A Fisher's exact test with a 0.05 
two-sided significance level will have over 99% power to detect this difference when 90 placebo subjects 
and 120 TRC101 subjects are enrolled.  If the true proportion of TRC101 subjects who respond at the Week 
12 Visit is indeed between 50% and 55% and if no more than 5% of subjects have missing data at Week 12, 
the study will have roughly 90% power to result in a 95% confidence limit with a lower bound of at least 
35% and 40%, respectively.   
The sample size calculation for the secondary efficacy endpoint will be documented in the SAP. 
 
 


TRC101 
 
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Clinical Study Protocol: TRCA-301 
 
November 27, 2017 
 
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Page 11 of 80 
 
TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................5 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF TABLES ...................................................................................................................14 
LIST OF FIGURES .................................................................................................................14 
LIST OF APPENDICES ..........................................................................................................14 
LIST OF ABBREVIATIONS AND ACRONYMS ................................................................15 
1 
INTRODUCTION .................................................................................................18 
1.1 
Disease Background.........................................................................................18 
1.2 
Description of Investigational Product ............................................................19 
1.3 
Relevant Nonclinical Background ...................................................................19 
1.3.1 
Nonclinical Pharmacology ...................................................................19 
1.3.2 
Safety Pharmacology ...........................................................................19 
1.3.3 
Nonclinical ADME ..............................................................................20 
1.3.4 
Nonclinical Toxicology .......................................................................20 
1.4 
Relevant Clinical Background .........................................................................21 
1.4.1 
Study TRCA-101 .................................................................................21 
1.4.1.1 
Safety ..........................................................................................21 
1.4.1.2 
Efficacy .......................................................................................22 
1.5 
Description and Justification for Route of Administration, Dosage, Dosage 
Regimen and Treatment Period .......................................................................24 
1.6 
Description of Population to be Studied ..........................................................24 
1.7 
Description of Assay Methodology for Measurement of Blood/Serum 
Bicarbonate Concentration...............................................................................26 
2 
STUDY OBJECTIVES ..........................................................................................26 
2.1 
Efficacy ............................................................................................................26 
2.2 
Safety ...............................................................................................................26 
3 
INVESTIGATIONAL PLAN ................................................................................27 
3.1 
Overall Study Design and Plan ........................................................................27 
3.2 
Rationale for Study Design and Control Group ...............................................29 
3.2.1 
Study Design ........................................................................................29 
3.2.2 
Safety Monitoring ................................................................................29 
3.3 
Study Duration .................................................................................................31 
4 
STUDY POPULATION SELECTION AND WITHDRAWAL ...........................31 
4.1 
Study Population ..............................................................................................31 
4.2 
Inclusion Criteria .............................................................................................31 
4.3 
Exclusion Criteria ............................................................................................32 
4.4 
Subject Withdrawal ..........................................................................................34 


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November 27, 2017 
 
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5 
STUDY TREATMENT(S) ....................................................................................35 
5.1 
Description of Treatment(s) .............................................................................35 
5.1.1 
Investigational Drug.............................................................................35 
5.1.2 
Placebo .................................................................................................36 
5.1.3 
Study Drug Dispensing, Packing and Labeling ...................................36 
5.2 
Treatment(s) Administered ..............................................................................36 
5.3 
Dosing Regimen...............................................................................................37 
5.4 
Missed Doses ...................................................................................................37 
5.5 
Selection and Timing of Dose for Each Subject ..............................................38 
5.6 
Method of Assigning Subjects to Treatment Groups .......................................38 
5.7 
Blinding............................................................................................................38 
5.8 
Concomitant Therapy.......................................................................................39 
5.9 
Restricted Medications.....................................................................................39 
5.10 
Restrictions ......................................................................................................41 
5.10.1 
Prior Therapy .......................................................................................41 
5.10.2 
Fluid and Food Intake ..........................................................................41 
5.10.3 
Management of Acidemia (Use of Alkali Therapy) ............................41 
5.11 
Treatment Compliance .....................................................................................41 
5.12 
Storage and Accountability ..............................................................................42 
6 
STUDY PROCEDURES .......................................................................................42 
6.1 
Informed Consent.............................................................................................42 
6.2 
Demographics and Medical History ................................................................42 
6.3 
Prior and Concomitant Medications ................................................................42 
6.4 
Vital Signs ........................................................................................................42 
6.5 
Complete Physical Examination, Including Body Weight and Height............43 
6.6 
Repeated Chair Stand Test ...............................................................................43 
6.7 
KDQOL............................................................................................................43 
6.8 
12-Lead Electrocardiograms ............................................................................44 
6.9 
Clinical Laboratory Tests .................................................................................44 
6.9.1 
Laboratory Parameters .........................................................................44 
6.10 
Dietary Counseling ..........................................................................................46 
6.11 
Adverse Events ................................................................................................46 
6.11.1 
Definition of an Adverse Event ...........................................................46 
6.11.2 
Definition of a Serious Adverse Event ................................................48 
6.11.3 
Definition of a Suspected Adverse Reaction .......................................48 
6.11.4 
Procedures for Eliciting, Recording and Reporting Adverse Events ...49 
6.11.4.1 
Adverse Event Reporting Period ................................................49 
6.11.4.2 
Eliciting Adverse Events.............................................................49 
6.11.4.3 
Assessing Adverse Events ..........................................................49 


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6.11.4.4 
Independent Data Monitoring Committee ..................................51 
6.11.4.5 
Recording Adverse Events ..........................................................51 
6.11.5 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments .........................................................................................52 
6.11.6 
Serious Adverse Events Reporting ......................................................52 
6.11.6.1 
SAE Expedited Reporting ...........................................................54 
6.11.6.2 
Unblinding Treatment Allocation ...............................................54 
6.12 
Procedures for Reporting Pregnancy Exposure and Birth Events ...................54 
7 
STUDY ACTIVITIES ...........................................................................................55 
7.1 
Screening 1 Visit (Week -2) ............................................................................55 
7.2 
Screening 2 Visit (Week -1) ............................................................................55 
7.3 
Laboratory Re-Testing and Subject Re-Screening ..........................................56 
7.4 
Baseline Visit (Day 1) ......................................................................................56 
7.5 
Week 1, Week 2, and Week 10 Visits .............................................................57 
7.6 
Week 4 and Week 8 Visits ...............................................................................58 
7.7 
Week 6 Visit ....................................................................................................59 
7.8 
Week 12 or Early Termination Visit (ET) .......................................................59 
7.9 
Follow-up 1 Visit (Week 13) ...........................................................................60 
7.10 
Follow-up 2 Visit (Week 14) ...........................................................................61 
7.11 
Unscheduled Visit ............................................................................................61 
7.12 
End-of-Study ....................................................................................................62 
8 
PLANNED STATISTICAL METHODS ..............................................................62 
8.1 
General Considerations ....................................................................................62 
8.2 
Determination of Sample Size .........................................................................62 
8.3 
Analysis Populations ........................................................................................63 
8.4 
Demographics and Baseline Characteristics ....................................................63 
8.5 
Statistical Analysis of Efficacy ........................................................................63 
8.5.1 
Efficacy Variable .................................................................................64 
8.5.2 
Efficacy Endpoints ...............................................................................64 
8.5.3 
Efficacy Analysis .................................................................................64 
8.5.3.1 
Primary Efficacy Analysis ..........................................................64 
8.5.3.2 
Secondary Efficacy Analyses .....................................................65 
8.5.3.3 
Sensitivity Analyses and Exploratory Efficacy Endpoint 
Analyses ......................................................................................65 
8.6 
Safety Analysis ................................................................................................65 
8.7 
Other Assessments or Analyses .......................................................................66 
9 
DATA HANDLING AND RECORD KEEPING .................................................66 
9.1 
Source Data ......................................................................................................66 
9.2 
Case Report Forms / Electronic Data Record ..................................................66 
9.3 
Data Handling ..................................................................................................67 


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9.4 
Deviations from the Protocol ...........................................................................67 
9.5 
Record Retention and Archiving .....................................................................67 
10 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................68 
11 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ...............................69 
11.1 
Good Clinical Practice .....................................................................................69 
11.2 
Institutional Review Board / Ethics Committee ..............................................69 
11.3 
Ethical Conduct of the Trial .............................................................................69 
11.4 
Subject’s Information and Informed Consent ..................................................70 
11.5 
Protocol Approval and Amendment ................................................................71 
11.6 
Premature Termination of the Study ................................................................71 
11.7 
Confidentiality .................................................................................................71 
11.8 
Liability and Insurance ....................................................................................72 
11.9 
Publication Policy ............................................................................................72 
12 
REFERENCE LIST ...............................................................................................73 
13 
APPENDICES .......................................................................................................76 
 
LIST OF TABLES 
Table 1 
Restricted Prior and Concomitant Medications .........................................40 
Table 2 
Laboratory Parameters ...............................................................................45 
 
LIST OF FIGURES 
Figure 1 
Mean Change in Serum Bicarbonate by Treatment Group Over Time .....24 
Figure 2 
Study TRCA-301 Study Design Schematic ...............................................27 
Figure 3 
Serious Adverse Event Reporting Instructions if EDC System is Not 
Available ....................................................................................................53 
 
LIST OF APPENDICES 
Appendix 1: 
Schedule of Events .....................................................................................77 
Appendix 2: 
Study Drug Titration Algorithm ................................................................79 
Appendix 3: 
New York Heart Association (NYHA) Classification of Heart Failure ....80 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AA 
aldosterone antagonist 
ACE 
angiotensin-converting enzyme 
ADME 
absorption, distribution, metabolism, excretion 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ARB 
angiotensin II receptor blocker 
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 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CK 
creatine kinase 
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 
EU 
European Union 
EUCTD 
European Union Clinical Trials Directive 


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FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GI 
gastrointestinal 
HbA1c 
hemoglobin A1c 
HCO3- 
bicarbonate 
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 
KDQOL 
Kidney Disease and Quality of Life 
LDL 
low density lipoprotein 
LLN 
lower limit of normal 
LS 
least square 
MCH 
mean corpuscular hemoglobin 
MCV 
mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
MRA 
mineralocorticoid receptor antagonist 
NF 
National Formulary 
NOAEL 
no observed adverse effect level 
NYHA 
New York Heart Association 
pCO2 
partial pressure of carbon dioxide 


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pO2 
partial pressure of oxygen 
PT 
preferred term 
PTH 
parathyroid hormone 
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 
SO2 
oxygen saturation 
SOC 
system organ class 
SUSAR(s) 
suspected unexpected serious adverse reaction(s) 
TCO2 
total carbon dioxide 
TEAE(s) 
treatment emergent adverse event(s) 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 


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1 
INTRODUCTION 
1.1 
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 – 39% of CKD 
Stage 3 – 5 patients (Eustace, 2004; Raphael, 2014; Moranne, 2009).  If chronic metabolic 
acidosis is left untreated, the consequences include 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 – 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).  Hazard ratios 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 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 limited doses of oral sodium bicarbonate to < 2 g 
per day resulting in modest increases in blood bicarbonate of 2 – 3 mEq/L.  The daily doses 
of sodium bicarbonate required to increase blood bicarbonate levels by 3 – 4 mEq/L in 
patients with metabolic acidosis are prohibitively high (6 – 8 g per day introducing 
1.6 – 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 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. 


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1.2 
Description of Investigational Product 
TRC101 is being developed as a first-in-class, orally administered, counterion-free, 
insoluble, non-absorbed hydrochloric acid binder for the treatment of metabolic acidosis in 
patients with CKD.  It 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 H+ and Cl- 
binding capacity and Cl- binding selectivity.  The high amine content of the polymer is 
responsible for the high H+ and Cl- binding capacity of TRC101 and the polymer’s extensive 
crosslinking provides size exclusion properties and selectivity for binding Cl- over other 
potential interfering anions.  The TRC101 mechanism of action involves binding of H+ and 
Cl-, resulting in a net reduction and removal of hydrochloric acid from the GI tract which 
results in an increase in serum bicarbonate levels.  Binding Cl- in addition to H+  reduces 
exchange of Cl- with bicarbonate in the GI lumen, preventing a subsequent decrease in serum 
bicarbonate. 
The TRC101 drug substance is packaged in individual-dose packets without addition of any 
excipients to create the clinical study material (i.e., drug product), a powder for oral 
suspension also called TRC101. 
1.3 
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.   
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 


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(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 
TRC101 is insoluble in both aqueous and organic solvents.  Due to its insolubility, stability, 
and size (averaging 100 micrometers in diameter), the polymer is not anticipated to be 
absorbed from the lumen of the GI tract.  To confirm lack of absorption following oral 
administration, the absorption, distribution, metabolism and excretion (ADME) of 
radiolabeled TRC101, in both rats and dogs, were characterized after a single oral dose of 
[14C]-TRC101.  The studies demonstrated no radioactivity in tissues or organs other than the 
GI tract, no detectable radiolabel in the plasma, approximately 95 – 99% of the radioactive 
dose excreted in the feces with most recovered within the first 48 hours after dosing, and 
≤ 0.02% of radiolabel excreted in the urine of dogs and rats.  The level of radioactivity 
excreted in urine was consistent with the level of unincorporated radiolabel measured in a 
water extraction of the radiolabeled polymer, [14C]-TRC101.  Therefore, it can be concluded 
that TRC101 is not systemically absorbed following oral administration in rats and dogs. 
1.3.4 
Nonclinical Toxicology 
Nonclinical toxicology studies of TRC101 to date include non-Good Laboratory Practice 
(GLP) 7-day repeat dose toxicology studies in rats and dogs; a GLP 33-day repeat dose 
toxicology study with a 2-week recovery in rats; a GLP 28-day repeat dose toxicology study 
with a 2-week recovery in dogs; GLP 13-week repeat dose toxicology interim analyses in the 
rat and the dog as part of the chronic toxicology studies, 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 embryo-fetal development (EFD) studies in the rat and 
the rabbit; no single dose studies were conducted.  The oral route of exposure was selected 
for the repeat dose toxicology and EFD studies in rats, rabbits, and/or dogs because this is the 
intended route of human exposure.  These studies demonstrate that TRC101 has a very low 
order of toxicity; the genotoxicity studies demonstrate that TRC101 is neither mutagenic nor 
clastogenic; the pilot EFD studies suggest that there are no adverse TRC101-related effects 
on maternal reproductive function or embryo-fetal parameters.  There were no effects on male 
or female reproductive organs in the GLP repeat dose toxicology studies in rat and dog.  The no 
observed adverse effect levels (NOAELs) for the 13-week repeat dose toxicology interim 
analyses were the highest doses tested, i.e., 2 g/kg/day in rats and dogs, providing support for 
up to 12 weeks of dosing in humans with TRC101 doses up to 9 g/day.  In the same studies, 
local tolerance was assessed, and histopathological evaluation of the GI tract indicated that 
TRC101 was generally well tolerated.  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.   


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1.4 
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. 
1.4.1 
Study TRCA-101 
To date, TRC101 has been studied in one Phase 1/2 clinical trial, Study TRCA-101, 
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.  Study 
TRCA-101 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 – 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%).  Because TRC101 does not result in sodium load as discussed in 
Section 1.2, 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 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) of 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) 


TRC101 
 
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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 or SAEs 
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.  
Gastrointestinal (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, 
and all 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).  There were also 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 – 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).  


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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 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. 
1.5 
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.  TRC101 is a high molecular weight, nonabsorbed polymer with a site of action in the 
GI tract; thus, oral administration is the appropriate route.  A dose of 6 g QD TRC101 was 
chosen as the starting dose for this study since it was shown to be safe, well tolerated, and 
efficacious in Study TRCA-101 (along with the 1.5 g BID, 3 g BID and 4.5 g BID TRC101 
doses).  A starting dose of 6 g provides the option of bidirectional dose adjustment (i.e., up or 
down titration), thus potentially allowing greater flexibility in controlling blood bicarbonate 
levels compared to a 3 g or 9 g starting dose.  A QD dosing regimen is more convenient for 
study subjects than a BID dosing regimen and therefore may result in greater compliance 
during a 12-week treatment period.  Placebo QD will be used as a comparator.  Additional 
details on the rationale for the doses, dosing regimen and treatment period are provided in 
Section 3.2. 
1.6 
Description of Population to be Studied 
In the completed Study TRCA-101, the allowable ranges for eGFR and blood bicarbonate 
were 20 to < 60 mL/min/1.73m2 and 12 to 20 mEq/L, respectively.  The population studied in 
this clinical study is CKD patients with chronic metabolic acidosis who have eGFR from 20 


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to 40 mL/min/1.73m2 and blood bicarbonate levels from 12 to 20 mEq/L.  At least half of the 
subjects enrolled will have blood bicarbonate level of 12 to 18 mEq/L. 
This study is designed to provide significant overlap with the population investigated in 
Study TRCA-101 and in future investigational studies of TRC101. 
The lower limit of the bicarbonate range is intended to exclude patients who are acutely 
acidotic as their management is largely aimed at rapid treatment of the underlying etiology of 
the acidosis.  Whereas clinical practice guidelines also recommend treating milder acidosis 
(serum bicarbonate > 20 to 22 mEq/L) (KDIGO 2013; KDOQI 2003), the population for the 
current study will include only those with blood bicarbonate 12 to 20 mEq/L.  This is to 
ensure that all subjects have significant metabolic acidosis. 
To make the study more generalizable to the intended target population of CKD patients, this 
study will be conducted in outpatients whose dietary intake is not mandated by the study 
protocol, unlike the in-unit TRCA-101 study which used a controlled diet.  Additionally, 
compared with the TRCA-101 study, exclusions for common concomitant medications such 
as H2 blockers and proton pump inhibitors have been removed from this protocol, and 
subjects with more severe heart failure (i.e., NYHA Class III) may be enrolled  
(see Appendix 3). 
This protocol allows the use of “background” medications that can affect eGFR and blood 
bicarbonate (e.g., oral alkali, calcium supplements, diuretics, renin angiotensin aldosterone 
system [RAAS] inhibitors) with some restrictions.   Doses of alkali medications may not be 
changed and new oral alkali therapies must not be initiated during the study.  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.  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 rationale for 
allowance of alkali treatment is to avoid significantly worsening acidosis among the placebo 
subjects; however, maintaining a stable dose of such treatments is necessary to avoid 
confounding of the primary efficacy measurement.  Subjects may be, but are not required to 
be, on RAAS inhibitor(s) at Baseline.  Investigators will be advised to avoid changing RAAS 
inhibitor doses during the study, when possible, but dose changes necessary for the 
management of comorbidities or acute events (e.g., hyperkalemia/worsening hyperkalemia) 
are not prohibited.  Investigators will be advised to avoid changing diuretic doses when 
possible, but dose changes necessary for the management of comorbidities or acute events 
(e.g., heart failure, acute kidney injury) are not prohibited. 
 


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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 evaluating the rate of eGFR decline. 
1.7 
Description of Assay Methodology for Measurement of Blood/Serum 
Bicarbonate Concentration 
Bicarbonate concentrations in venous blood will be assessed in this study using the i-STAT 
System (handheld blood analyzer with G3+ cartridge manufactured by Abbott Point of Care, 
Princeton, NJ) in all subjects.  In addition, either a clinical chemistry analyzer performing 
enzymatic measurement of bicarbonate in serum or a benchtop venous blood gas analyzer for 
measuring bicarbonate will be used consistently for each subject.  These assays (with the i-
STAT assay and one of two other assays being mandatory) will be conducted at the local 
laboratory or at the study site. 
All efficacy analyses will be conducted using bicarbonate concentrations collected from the 
i-STAT devices.  The i-STAT measurements of blood bicarbonate levels will be the basis of 
study drug dose adjustment decisions.  Data from the other assay methodology (either 
enzymatic or venous blood gas bicarbonate analysis) will be evaluated in an exploratory 
manner. 
The two blood gas analysis methods (benchtop and i-STAT) provide a calculated bicarbonate 
concentration from measurement of pH and pCO2 in a whole blood sample.  The enzymatic 
assay method used in most clinical laboratories directly measures the total CO2 (bicarbonate 
+ dissolved CO2) concentration in a serum sample using an assay that relies upon the 
conversion of dissolved CO2 to HCO3- with base, followed by a series of enzymatic reactions 
resulting in a decrease in the 380/410 nm absorbance of the reaction mixture. 
2 
STUDY OBJECTIVES 
2.1 
Efficacy 
This study is intended to evaluate the efficacy of TRC101 in CKD patients with metabolic 
acidosis (blood bicarbonate 12 to 20 mEq/L). 
2.2 
Safety 
This study is intended to evaluate the safety of administration of TRC101 in CKD patients 
with metabolic acidosis (blood bicarbonate 12 to 20 mEq/L). 




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urine samples will be performed in a fasting state pre-dose.  Following randomization, 
designated unblinded site staff will assist the subject in administering the first dose of study 
drug, which will be taken onsite in the morning with food (light meal or snack) after 
collection of baseline laboratory specimens.  Subjects will be given a dosing diary in which 
to record the time of study drug dosing. 
Subjects will continue dosing on an out-patient basis for the subsequent 12 weeks (Treatment 
Period).  Dosing of oral concomitant medications and study drug will be separated by at least 
4 hours.  The study drug dose will be fixed during the first 4 weeks of the Treatment Period, 
except for subjects with blood bicarbonate ≥ 27 mEq/L.  Subjects with a blood bicarbonate 
level of 27 to 30 mEq/L will have their dose of study drug decreased per the blinded titration 
algorithm (see Appendix 2).  Subjects with a confirmed blood bicarbonate level of 
> 30 mEq/L will undergo an interruption of the study drug dose in accordance with the 
titration algorithm (see Appendix 2).  Beginning at the Week 4 Visit, subjects with a blood 
bicarbonate level below the normal range (< 22 mEq/L) will have a blinded adjustment of the 
study drug dose in accordance with the titration algorithm (see Appendix 2).  At any time 
during the study, subjects with confirmed blood bicarbonate level < 12 mEq/L 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. 
During the 12-week Treatment Period, subjects will attend eight study visits (Day 1, 
Weeks 1, 2, 4, 6, 8, 10, and 12) for efficacy and safety assessments.  Subjects will be fasted 
(other than water) for at least 4 hours prior to blood draws.  Assessments will be performed at 
the time points indicated in the Schedule of Events (Appendix 1).  Safety assessments will 
include:  adverse events (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.  Efficacy will be assessed by examining changes in blood 
bicarbonate. 
Subjects who complete the Treatment Period will be offered participation in a 40-week 
extension study (TRCA-301E).  Subjects who are not willing to participate in the extension 
study or who are not eligible will enter the 2-week Follow-up Period and return to the study 
site for two visits: Follow-up 1 (Week 13) and Follow-up 2 (Week 14), for adverse event 
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 12 
Visit) will undergo an Early Termination (ET) Visit during which all Week 12 Visit 
assessments will be performed, followed by Follow-up 1 and 2 Visits in 1 and 2 weeks, 
respectively.  Blood draws for bicarbonate measurements will be done when subjects are in a 
fasted state and at approximately the same time of day for each subject. 
See Appendix 1, Schedule of Events, for further information on the conduct of the study. 


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3.2 
Rationale for Study Design and Control Group 
3.2.1 
Study Design 
This study is randomized to reduce bias.  Because no approved treatment is available for 
chronic metabolic acidosis, placebo was chosen as the comparator.  Furthermore, a 
comparison to placebo allows for better characterization of the efficacy and safety of new 
chemical entities.  However, due to the chronicity and severity of the baseline metabolic 
acidosis in this 12-week study, subjects receiving oral alkali treatment at baseline will be 
allowed to continue on this treatment at stable doses to avoid significant worsening of 
acidosis in the placebo-treated subjects. 
The Investigators, site personnel (except for designated unblinded staff responsible for study 
drug dispensing and accountability), subjects, Tricida, contract research organization (CRO) 
personnel (except for those responsible for unblinded monitoring) will be blinded to reduce 
bias.  The data monitoring committee (DMC) members and the statisticians responsible for 
reporting to the DMC will be unblinded during the study.  A blinding plan will describe the 
specific requirements for maintaining the blind at the site and sites will be trained on these 
requirements. 
In the completed Study TRCA-101, treatment with TRC101 for 2 weeks resulted in a 
significant increase in serum bicarbonate in all three doses studied (3, 6 and 9 g/day) 
(Section 1.4.1.2); however, the maximum effect of each of these fixed doses was not 
determined.  At the end of 2 weeks, all three BID dosing regimens (1.5 g, 3 g, and 4.5 g) as 
well as the QD dosing regimen (6 g) appeared to be similarly effective based on mean 
changes from baseline in serum bicarbonate after 2 weeks.  However, a greater proportion of 
subjects receiving 3 g BID and 4.5 g BID achieved larger increases in blood bicarbonate 
(e.g., ≥ 4 mEq/L) than the lowest 1.5 g BID dose.  Based on these findings, the mid-dose 
(i.e., 6 g QD) was selected as the starting dose for this study.  The subjects whose blood 
bicarbonate is below the normal range after 4 weeks of fixed-dose treatment will have their 
dose up-titrated to 9 g QD while the blind is maintained.  Given that no dose-related adverse 
events occurred in Study TRCA-301, this dosing regimen was chosen to optimize efficacy 
while examining the plateau effect of 6 g QD TRC101 over 4 weeks, the sustained efficacy 
of TRC101 over 12 weeks, and the effects of dose adjustment. 
A QD dosing regimen was selected to simplify administration of concomitant medications 
and to enhance compliance and convenience.  Study drug will be administered in the middle 
of the day, with lunch, so as to facilitate maintaining at least a 4-hour interval between dosing 
with study drug and oral concomitant medications. 
3.2.2 
Safety Monitoring 
The design and conduct of TRCA-301 includes appropriate monitoring for safety and risk 
mitigation.  The Medical Monitor will review blinded safety data on an ongoing basis to 
identify potential adverse safety trends.  Central laboratory reports will contain flags that will 


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alert investigators and Tricida personnel to abnormal, critical, and exclusionary laboratory 
values, and the Medical Monitor will routinely review these results on an ongoing basis. 
A DMC, which will be established for this study, will review safety during the 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 meeting schedule, format and structure, 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 the 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. 
TRC101 is a high molecular weight, counterion-free polymer.  It 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 study drug 
dose will be blindly decreased if blood bicarbonate level is 27 to 30 mEq/L and interrupted if 
blood bicarbonate is confirmed to be > 30 mEq/L.  It is known from Study TRCA-101 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, patients with higher risk of inhibition of respiratory response to metabolic acidosis 
(i.e., COPD that is treated with chronic oral steroids, that requires the subject to be on 
oxygen, or that required hospitalization within the previous 6 months) will be excluded from 
this study. 


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Among subjects randomized to placebo, in particular, a decrease in bicarbonate during the 
12-week Treatment Period is a possibility, particularly if dietary acid load increases or renal 
function deteriorates.  This protocol requires that the Investigator 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. 
3.3 
Study Duration 
The maximum study duration is anticipated to be up to 16 weeks per subject, including the 
Screening Period (up to 2 weeks), 12-week Treatment Period, and 2-week Follow-up Period.  
The maximum TRCA-301 study duration for subjects who continue into the extension Study 
TRCA-301E will be 14 weeks (excluding 2-week Follow-up Period). 
4 
STUDY POPULATION SELECTION AND WITHDRAWAL 
4.1 
Study Population 
This study will enroll approximately 210 male and female subjects, 18 to 85 years of age 
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 will have a blood bicarbonate level of 12 to 18 mEq/L. 
4.2 
Inclusion Criteria 
Each subject must meet ALL of the following criteria to be enrolled in this study. 
1. 
Have provided written informed consent prior to participation in the study. 
2. 
Male or female subjects 18 to 85 years of age at the Screening 1 Visit. 
3. 
Have a blood bicarbonate value of 12 to 20 mEq/L at Screening 1 and Screening 2 
Visits AND an average value for Screening 1, Screening 2, and Baseline Visits (i.e., 
baseline blood bicarbonate) within the range 12 to 20 mEq/L based on onsite 
measurement using an i-STAT point of care device. 
Screening 1 and Screening 2 Visits must be at least 5 days apart. 
Note:  Subjects with baseline blood bicarbonate values of 12 to 18 mEq/L are eligible 
without restriction.  Once 105 subjects with baseline blood bicarbonate values of > 18 
to 20 mEq/L have been enrolled, randomization may be closed to additional subjects 
with baseline blood bicarbonate in this range. 
4. 
At both Screening Visits have an eGFR value of 20 to 40 mL/min/1.73m2 calculated 
using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
as reported by the central laboratory.  If a central laboratory eGFR value at Screening 
2 Visit is not available, eGFR can be calculated using CKD-EPI equation based on 
onsite serum creatinine measurement at the Baseline Visit to establish subject’s 
eligibility. 


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Screening 1 and Screening 2 Visits must be at least 5 days apart. 
5. 
Have stable renal function as defined by eGFR values at both Screening Visits that 
are not different by more than 20% (the higher of the two Screening eGFR values 
will be used as the denominator to calculate the 20% allowable difference).  
6. 
At both Screening Visits have systolic blood pressure < 170 mmHg (all three 
replicates). 
7. 
Have a hemoglobin A1c (HbA1c) value of ≤ 9.0% at the Screening 1 Visit based on 
central laboratory measurement. 
8. 
Have adequate peripheral venous access for blood draws. 
9. 
Women who are of childbearing potential must have negative pregnancy tests at the 
Screening 1 Visit and Day 1 and be willing to use an acceptable method of birth 
control from the Screening 1 Visit 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. 
4.3 
Exclusion Criteria 
Subjects who meet ANY of the following criteria will be excluded from participation in the 
study. 
1. 
Have any level of low blood bicarbonate at either Screening Visit that, in the 
opinion of the Investigator, requires emergency intervention or evaluation for an 
acute acidotic process. 
2. 
Have had anuria, dialysis, acute kidney injury, history of acute renal insufficiency 
or known ≥ 30% increase in serum creatinine or known ≥ 30% acute or chronic 
decrease in eGFR in the 3 months prior to the Screening 1 Visit. 
3. 
Have chronic obstructive pulmonary disease (COPD) that is treated with chronic 
oral steroids, that requires the subject to be on oxygen, or that required 
hospitalization within the previous 6 months. 
4. 
Had heart failure with maximum New York Heart Association (NYHA) Class IV 
symptoms, or that required hospitalization with a primary cause of heart failure, 
during the preceding 6 months (see Appendix 3). 
5. 
Have had a heart or kidney transplant. 
Note:  Patients on the cadaveric transplant list or being evaluated for a future 
living donor transplant may be enrolled. 


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6. 
Planned initiation of renal replacement therapy (dialysis or transplantation) within 
12 weeks following randomization. 
7. 
Have had a stroke or transient ischemic attack (TIA) within the 6 months prior to 
randomization. 
8. 
Have had a cardiac event within 12 weeks prior to randomization, including:  
myocardial infarction, acute coronary syndrome, coronary bypass grafting, 
percutaneous coronary intervention, valve procedure, inpatient or outpatient 
treatment for acute decompensated heart failure. 
9. 
Have been hospitalized for any reason during the 2 months prior to the Screening 
1 Visit, other than for pre-planned diagnostic or minor invasive procedures.  Note: 
Subjects who had major CV procedures or percutaneous cardiac procedures during 
this time frame are excluded, even if the procedures were pre-planned. 
10. 
Have a history or current diagnosis of clinically significant diabetic gastroparesis 
(based on Investigator’s judgment) or a history of bariatric surgery. 
11. 
Have a history or current diagnosis of bowel obstruction, swallowing disorders, 
severe GI disorders, inflammatory bowel disease, major GI surgery, frequent 
diarrhea or active gastric/duodenal ulcers. 
12. 
Have liver enzyme (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST]) or total bilirubin values > 3 × the upper limit of normal (ULN) at 
Screening based on central laboratory measurements. 
13. 
Have a serum calcium ≤ 8.0 mg/dL at the Screening 1 Visit based on central 
laboratory measurement. 
14. 
Have a serum potassium value < 3.8 mEq/L or > 5.9 mEq/L at the Screening 1 or 
Screening 2 Visit. 
15. 
Have active cancer during the 1 year prior to Screening, 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. 
16. 
Have received any investigational medication during the last month (28 days or 
≥ 5 half-lives [if known], whichever is longer) preceding the Screening 1 Visit. 
17. 
Have used any of the following in the 14 days prior to the Screening 1 Visit:  
lanthanum carbonate, colesevelam, cholestyramine or sodium or calcium 
polystyrene sulfonate, calcium acetate, sevelamer, bixalomer, patiromer, and other 
polymeric binder drugs. 
18. 
Have had a change in doses (including starting or stopping treatment) in the 
2 weeks prior to the Screening 1 Visit or during Screening Period to the following: 
calcium-containing supplements, such as calcium carbonate and calcium citrate; 
antacids; H2-blockers; proton pump inhibitors.  See Section 5.9 for examples of 
specific drugs. 
19. 
Have had a change in doses (including starting or stopping treatment) in the 
4 weeks prior to the Screening 1 Visit or during Screening Period to the following: 


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sodium bicarbonate, potassium citrate, sodium citrate or other alkali therapy; 
diuretics; renin-angiotensin-aldosterone system [RAAS] inhibitors, such as 
angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers 
[ARBs], aldosterone antagonists [AAs], mineralocorticoid receptor antagonists 
[MRAs]; non-ophthalmic carbonic anhydrase inhibitors.  See Section 5.9 for 
examples of specific drugs.  
Note:  For diuretics, dose changes of up to ± 50% relative to the average dose 
during the Screening Period are considered “stable”, and a dose change up to ± 
50% between the Screening 1 Visit and the Baseline Visit is considered “stable”. 
20. 
Have a known allergy to placebo (
).  
21. 
Inability to consume the study drug or otherwise comply with the protocol. 
22. 
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. 
23. 
Have participated in a previous clinical study of TRC101. 
24. 
Currently breastfeeding. 
4.4 
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 and recorded appropriately in source documents and 
the electronic case report form (eCRF).  Subjects withdrawn from the study prematurely will 
be followed for safety for 2 weeks after receiving the last dose of study drug.  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 his or her 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: 
• Occurrence of any AE, intercurrent illness or abnormality in laboratory assessment 
results which, 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). 


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• 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 or underwent renal transplantation. 
• Pregnancy.  These subjects will be followed until the outcome of pregnancy is known and 
if subject agrees (see Section 6.12). 
Subjects with confirmed bicarbonate < 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.  The subject should be 
maintained on their study drug dose pending discussion with Medical Monitor. 
Subjects who withdraw from the study treatment prematurely prior to the Week 12 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 very 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 (Section 7.8) will be performed if possible.  Every effort will be made to 
contact a subject who fails to attend a Study Visit, or does not respond by telephone, in order 
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. 
5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Investigational Drug 
TRC101 is packaged in labeled packets and dispensed in cartons containing eight (8) packets 
each.  Refer to the current version of the TRC101 Investigator’s Brochure for a more detailed 
description of the investigational drug. 


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5.1.2 
Placebo 
Placebo consists of 
, National Formulary (NF) Grade, and is 
packaged in labeled packets and dispensed in cartons containing eight (8) packets each.   
5.1.3 
Study Drug Dispensing, Packing and Labeling 
Labelled cartons of TRC101 and placebo 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 Pharmacist”) according to the 
subject’s treatment assignment.  The exact dispensing instructions will be provided to the 
Pharmacist by the interactive response technology (IRT) system.   
The Pharmacist will be responsible for maintaining complete study drug dispensing, 
returning, and dosing records for each study subject enrolled at the site.  
5.2 
Treatment(s) Administered 
Randomization will be performed using the IRT system.  Approximately 210 subjects will be 
randomized in a 4:3 ratio to one of the following treatments: 
• 6 g TRC101 QD (n~120) 
• Placebo QD (n~90) 
Subjects with blood bicarbonate values of 12 to 18 mEq/L will be randomized without 
restriction.  Once 105 subjects with blood bicarbonate values of > 18 to 20 mEq/L at baseline 
(i.e., average of Screening Visit 1, Screening Visit 2, and pre-dose Day 1 values) have been 
enrolled, randomization may be closed to additional subjects with baseline blood bicarbonate 
in this range. 
TRC101 or placebo will be administered orally as an aqueous suspension, QD with lunch, for 
12 weeks.   
The Investigator will designate an unblinded Pharmacist to dispense and account for study 
drug and to train subjects on study drug preparation and administration.  The first dose of 
TRC101 or placebo will be administered at the study site in the morning with food (light 
meal or snack) and under the supervision of the Pharmacist after the baseline blood samples 
have been drawn.  The Pharmacist will train the subject on how to administer the study drug 
in accordance with the subject dosing instructions. 
Subjects will record the timing of study drug dosing in a dosing diary.  Subjects will be 
instructed to take any oral concomitant treatment at least 4 hours before or after study drug 
administration.  Subjects will be instructed to bring the completed dosing diary with them to 
each visit to the study site. 


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The last dose of study drug will be taken the day before the Week 12 Visit (subjects who 
continue into the extension Study TRCA-301E will continue study drug dosing per the 
extension study protocol). 
5.3 
Dosing Regimen 
The study drug dose titration algorithm is described in Appendix 2.  Dose titrations can only 
be performed during a clinic visit.  If the dose of study drug is changed, the subject will start 
the new dose at lunch time on the titration day.  Dose titrations should be performed on the 
basis of onsite i-STAT blood bicarbonate measurements only.  
The study drug dose will be fixed for the first 4 weeks of the Treatment Period (during this 
time each subject will receive the study drug dose assigned at randomization [Baseline 
Visit]); no study drug dose adjustments will be permitted before the Week 4 Visit, except for 
subjects with elevation of blood bicarbonate ≥ 27 mEq/L.  If the blood bicarbonate level is 27 
to 30 mEq/L at any time during the Treatment Period through Week 11, the study drug dose 
will be decreased by 1 packet/day (minimum dose is 0 packets/day).  Beginning at the Week 
4 Visit, subjects with a blood bicarbonate level below the normal range (< 22 mEq/L) will 
have a blinded adjustment of the study drug dose in accordance with the titration algorithm 
(see Appendix 2).  The study drug dose will only be titrated if NO dose changes have been 
made during the previous 14 days.  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 to < 27 mEq/L and the subject is 
still within the Treatment Period, study drug should be re-started at a lower dose in 
accordance with the titration algorithm (see Appendix 2).  If blood bicarbonate is 
≥ 27 mEq/L, the study drug dosing should be withheld until blood bicarbonate is 
< 27 mEq/L. 
No dose titration will be allowed after Week 11 (i.e., 77 days after the day of the first dose).  
Dose titrations are blinded. 
The Medical Monitor must be notified within 24 hours of confirmation of a bicarbonate value 
> 30 mEq/L or < 12 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. 
5.4 
Missed Doses 
Contact the Medical Monitor if a subject has missed more than three consecutive doses of 
study drug for any reason. 


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5.5 
Selection and Timing of Dose for Each Subject 
Subjects will be randomly assigned by the IRT system to one of the available treatment 
regimens at the Baseline Visit.  The dose of study drug may be uptitrated at or after the 
Week 4 Visit and throughout the Treatment Period until Week 11 (77 days after the first dose 
of study drug) for blood bicarbonate levels (refer to Appendix 2).  Study drug will be 
administered as an oral suspension in water with lunch, QD from the Baseline Visit through 
1 day prior to the Week 12 Visit.  If a dose of study drug is adjusted, the subject will start the 
new dose at lunch time on the titration day.  
Dosing times for study drug will be collected by the subject on the dosing diary and recorded 
on the eCRF. 
5.6 
Method of Assigning Subjects to Treatment Groups 
When a subject who has met all eligibility criteria for the study is identified, the subject will 
be randomized using the IRT system at the Baseline Visit (Day 1).  The IRT system will 
randomly assign the subject to one of the two treatment groups (placebo or 6 g TRC101) with 
stratification by baseline blood bicarbonate (≤ 18 mEq/L vs. > 18 mEq/L) and screening 
eGFR (< 30 mL/min/1.73m2 vs. ≥ 30 mL/min/1.73m2), which represents an average of two 
eGFR values obtained at Screening 1 and Screening 2 Visit.   
The randomization treatment assignment will be performed by the IRT system in a blinded 
manner and the treatment randomization codes for the study will be maintained by the 
IRT system. 
5.7 
Blinding 
In this study, 
 
 an unblinded 
Pharmacist or designated unblinded study staff member (the “Pharmacist”) for handling 
(dispensation and collection) of the study drug.  These individuals will be responsible for 
dispensing study drug (including supervision of administration of the first dose of study 
drug) and collecting used and unused study drug containers and dosing diaries.  If 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 active and placebo treatment 
groups.  The Pharmacist must 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 eCRF.  The subjects, 
Investigators, Medical Monitors, Tricida, 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 remain blinded to the subject’s treatment assignment.  The 
DMC members and the statisticians responsible for reporting to the DMC will be unblinded 
during the study. 


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The Pharmacist must not inform the subjects, Investigators, Medical Monitors, Tricida, or 
other site or CRO personnel about the subjects’ treatment assignment.  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 a medical 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. 
5.8 
Concomitant Therapy 
Information on prior and concomitant medications (including prescription, over-the-counter, 
herbal and naturopathic remedies, etc.) will be collected beginning at the Screening 1 Visit 
and continuing for the duration of the study (including ET) until the last study visit.  A 
therapy will be considered a concomitant medication if it is administered at any time after 
randomization (Day 1) and before the completion of the final study visit.  A therapy will be 
considered a prior medication if it is administered at any time during the 28 days prior to the 
Screening 1 Visit and during the Screening Period (until randomization). 
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 Screening, 
Treatment and Follow-up Periods), such medication(s), or the new doses, and the adverse 
event(s) [AE(s)] will be recorded on the eCRF. 
5.9 
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 
Screening 1 Visit should adhere to restrictions as described in Table 1.  The rationale for the 
restrictions on concomitant medications is provided in Section 1.6.   
Changes to alkali treatment are not allowed.   
Investigators will be advised to avoid changing doses of RAAS inhibitors or diuretics when 
possible.  However, RAAS inhibitor dose decreases or discontinuation necessary for the 
management of comorbidities or acute events (e.g., hyperkalemia/worsening hyperkalemia) 
and diuretic dose increases necessary for the management of comorbidities or acute events 
(e.g., heart failure, acute kidney injury) are not prohibited.   
The use of polymer binder drugs is not allowed during the study; however, use of a 
potassium binder (e.g., Veltassa or Kayexalate) for a short duration (e.g., up to 4 days on up 
to two separate occasions) for the management of hyperkalemia is permitted without 


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interruption of study drug treatment with a dose separation from study drug of at least 
4 hours.   
Table 1 
Restricted Prior and Concomitant Medications 
Drug or Drug Class 
28 Days or 5 Drug 
Half-lives (Whichever 
is Longer) through 15 
Days Prior to the 
Screening 1 Visit 
14 Days Prior to the 
Screening 1 Visit and 
during the Screening 
Period 
During the 
Study 
Investigational 
medications 
Not allowed 
Not allowed 
Not allowed 
Potassium binders (e.g., 
Veltassa, Kayexalate) 
Allowed 
Not allowed 
Not allowed a 
Other polymer binder 
drugs b  
Allowed 
Not allowed 
Not allowed 
Sodium bicarbonate 
potassium citrate, 
sodium citrate or other 
alkali therapy 
Stable dose 
Stable dose 
Keep dose stable 
Non-ophthalmic 
carbonic anhydrase 
inhibitors c 
Stable dose 
Stable dose 
Keep dose stable, 
if possible 
Antacids, H2-blockers, 
proton pump inhibitors, 
calcium supplements d 
Allowed 
Stable dose 
Keep dose stable, 
if possible 
RAAS inhibitors e 
Stable dose 
Stable dose 
Keep dose stable, 
if possible 
Diuretics f 
Stable dose 
Stable dose 
Keep dose stable, 
if possible 
Note:  If a dose change or addition or discontinuation of prohibited or restricted drug(s) is unavoidable for 
clinical management of the subject, contact a Medical Monitor for approval unless medical urgency precludes 
this. In all cases, notify a Medical Monitor within 24 hours of the change.  “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 average dose during the Screening Period are considered “stable”.  A dose change up to ± 50% 
between the Screening 1 Visit and the Baseline Visit is considered “stable”. 
a  
Short-term treatment (up to 4 days on up to 2 separate occasions) is allowed during the study for 
treatment of hyperkalemia in consultation with the Medical Monitor.  Dose separation window of at 
least 4 hours from study drug required in these instances. 
b  
Lanthanum carbonate, colesevelam, cholestyramine or sodium or calcium polystyrene sulfonate, 
calcium acetate, sevelamer, bixalomer, and other polymeric drugs. 
c  
Examples of carbonic anhydrase inhibitors include acetazolamide, methazolamide, dorzolamide, 
brinzolamide, zonisamide, topiramate, dichlorphenamide. 
d  
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). 
e  
Examples of RAAS inhibitors:  lisinopril, enalapril, perindopril, losartan, valsartan, candesartan, 
spironolactone, eplerenone.  
f  
Examples of diuretic drugs:  furosemide, torsemide, hydrochlorthiazide, metolazone.   


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5.10 
Restrictions 
5.10.1 
Prior Therapy 
Restrictions regarding prior therapy are as described under Exclusion Criteria (Section 4.3) 
and in Table 1. 
5.10.2 
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.  
Subjects should be questioned about their most recent food intake at each visit and the 
information documented in the source documents. 
5.10.3 
Management of Acidemia (Use of Alkali Therapy) 
Subjects may be on a stable dose of oral alkali therapy at Baseline; however, this dose must 
be kept constant 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. 
5.11 
Treatment Compliance 
The Pharmacist will assess subjects’ treatment compliance at every study visit during the 
12-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).  The dosing diary data collected from the study subjects will be used as a 
secondary means for assessing compliance.  Supervised study drug dosing on Day 1 at the 
study site will occur to ensure subject compliance with dosing instructions.  Subjects will be 
provided with a dosing diary and will be requested to record the time when study drug was 
taken and the number of packets taken.  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 Pharmacist will not share 
any potentially unblinding information with the subject or any other party as described in 
Section 5.7. 


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5.12 
Storage and Accountability 
All study drug supplies must be stored in a secure location under the proper storage 
conditions, with access restricted to the Pharmacist only.  Study drug must be stored at room 
temperature (15 to 25 °C). 
The Pharmacist 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 post-baseline study visit during the Treatment Period.  
All used, unused, and expired medication and empty study drug containers will be retained 
until the Study 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 
6.1 
Informed Consent 
A signed informed consent form (ICF) must be obtained from each subject prior to any 
study-mandated procedure.  
6.2 
Demographics and Medical History 
The Investigator or qualified designee will collect subject’s demographics information and a 
complete medical and surgical history (including neurologic and psychiatric) at the Screening 
1 Visit.  Medical history will include information on the subject’s prior and concurrent 
medical conditions and methods of birth control, if applicable.  The Investigator or qualified 
designee will record all findings in source documents, on the medical history eCRF and the 
concomitant medications eCRF, if applicable. 
6.3 
Prior and Concomitant Medications 
At the Screening 1 Visit the Investigator or qualified designee will collect information 
regarding the subject’s prior prescription and non-prescription medications and nutritional 
supplements taken within 28 days.  The information on concomitant medications will be 
collected at all subsequent visits during the study.  The Investigator or qualified designee will 
record all findings in source documents and on the concomitant medications eCRF. 
6.4 
Vital Signs 
The Investigator or qualified designee will measure vital signs (systolic/diastolic blood 
pressure and respiratory rate [in triplicate with measurements recorded approximately 


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2 minutes apart at the Screening 1, Screening 2, and Week 12 Visits; once for all other time 
points], heart rate, and temperature) at time points specified in the Schedule of Events 
(Appendix 1).  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. 
6.5 
Complete Physical Examination, Including Body Weight and Height 
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).  Height will be measured at the 
Screening 1 Visit only.  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 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. 
6.6 
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 Screening 1 Visit will be performed for subject’s training 
purposes only, without collecting the data.  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. 
6.7 
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 procedure details are provided in the Study 
Reference Manual. 


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6.8 
12-Lead Electrocardiograms 
During the study, 12-lead ECGs will be performed at the time points indicated in the 
Schedule of Events (Appendix 1).  If a subject has serum potassium ≥ 6.0 mEq/L at any time 
post-Screening, ECGs will be collected more often, as clinically needed, until serum 
potassium is < 6.0 mEq/L. 
The subject must be in a 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 electronic case report form (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 6.11.1) should be recorded 
on the AE eCRF. 
6.9 
Clinical Laboratory Tests 
6.9.1 
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). 
The 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 collections will be done by subjects one day prior to the Baseline 
Visit and on the day prior to the Week 12 visit.  The specimens will be brought to the next 
clinic visit. 


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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. 
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 
(mandatory) 
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 (PTH), 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 
* Cystatin C will be measured at the Baseline and Week 12/ET Visits only. 
 
 


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Table 2 
Laboratory Parameters (Cont’d) 
Test Type 
Analytes 
Comments 
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 
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. 
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 
Hemoglobin A1c 
HbA1c 
Conducted at central laboratory 
Pregnancy test 
β-HCG 
Conducted at central laboratory (serum 
pregnancy test) 
Urine dipstick at study site at the 
Baseline Visit only 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-HCG = beta human chorionic 
gonadotropin; BUN = blood urea nitrogen; BE = base excess; CPK = creatine phosphokinase; 
eGFR = estimated glomerular filtration rate; 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; O2 = oxygen, RBC = red blood cell; 
RDW = red cell distribution width; SO2 = oxygen saturation; TCO2 = total carbon dioxide 
6.10 
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.  
6.11 
Adverse Events 
6.11.1 
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 


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(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 
underlying condition that were not present prior to the AE reporting period (from the time 
the subject signs the ICF until the completion of the last study visit assessments);  
• 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 


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• 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). 
6.11.2 
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. 
6.11.3 
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. 


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6.11.4 
Procedures for Eliciting, Recording and Reporting Adverse Events 
6.11.4.1 
Adverse Event Reporting Period 
AEs, including SAEs, will be collected throughout the study period, beginning from the time 
the subject signs the ICF until the subject’s last study visit.  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 
date of the first dose of investigational product.  Non-treatment emergent adverse events 
(e.g., events occurring during Screening) should be recorded as medical history unless related 
to a study procedure, in which case, they should be recorded as adverse events. 
6.11.4.2 
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.  
6.11.4.3 
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 6.11.2 (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) 


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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 
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 


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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.  
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). 
 
6.11.4.4 
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.  
6.11.4.5 
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. 


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6.11.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Clinically significant abnormal laboratory tests, vital signs, ECG abnormalities, and physical 
examination findings before the administration of the first dose of study drug should not be 
reported as AEs, but rather, as medical history, unless they are expected findings from 
medical history that has already been reported (e.g., elevated phosphate in a patient with a 
history of hyperparathyroidism). 
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 the first dose of study drug must be recorded as AEs or SAEs.  
Abnormalities resulting in study drug discontinuation, those associated with clinical signs or 
symptoms, or requiring treatment should be reported as AEs. 
6.11.6 
Serious Adverse Events Reporting  
The Investigator has the obligation to report each SAE to Tricida’s designee, 
 
, within 24 hours of knowledge of the occurrence.  This includes events that 
occur during the Follow-up Period.  Additionally, if the Investigator learns of any SAE that 
occurred after the Follow-up Period for which there is a reasonable possibility of relatedness 
to the investigational drug, that event must be reported within 24 hours.   
SAEs must be reported by entering the SAE information into the SAE CRF in the electronic 
data capture (EDC) system.  
 Drug Safety will receive notification of the initial SAE via 
an e-mail alert generated from the EDC system. 
If the event meets seriousness criteria and it is not possible to access the EDC, SAE reporting 
via a paper form will be required.  Submit SAE information via paper form as described in 
Figure 3.  The SAE information must be entered onto the SAE eCRF as soon as the EDC 
system becomes accessible.  All SAEs should be followed until they are resolved or 
stabilized and all relevant information is compiled.  Follow-up information must be handled 
in the same way and reported within the same time frame as the initial report. 




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All AEs will be evaluated on a regular basis by the Medical Monitor to monitor safety in the 
study population. 
6.11.6.1 
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. 
6.11.6.2 
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.  
The blind should be maintained for individuals responsible for the ongoing conduct of the 
study (e.g., management, monitors and investigators) and those responsible for data analysis 
and interpretation of results at the conclusion of the study (e.g., biometrics personnel). 
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). 
6.12 
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. 


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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. 
7.1 
Screening 1 Visit (Week -2) 
The Screening 1 Visit will occur within 2 weeks of the Baseline Visit.  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 (must be done prior to any of the following procedures 
including asking subjects to discontinue any prohibited medications) 
• Assign a unique subject identification number using the IRT system 
• Evaluate eligibility (inclusion/exclusion criteria) 
• Record demographic data (including sex, age, race, and ethnicity) and medical history 
• Record all prescription and non-prescription medications taken within 28 days 
• Collect vital signs (blood pressure [in triplicate], heart rate, temperature, and respiratory 
rate [in triplicate]) 
• Record body weight and height 
• 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 central laboratory:  serum chemistry 
panel, hematology panel, hemoglobin A1c, serum pregnancy test (for women of 
childbearing potential only) 
• Obtain urine for spot urine and urinalysis assessments at central laboratory  
• Record AEs 
 
7.2 
Screening 2 Visit (Week -1) 
Subjects who meet eligibility criteria based on the results of the Screening 1 Visit will return 
for confirmatory bicarbonate and eGFR measurements at the Screening 2 Visit.  Screening 1 
and Screening 2 Visits must be at least 5 days apart.  
• Evaluate eligibility (blood bicarbonate, eGFR, systolic blood pressure) 
• Record prior medications 
• Collect vital signs (blood pressure [in triplicate], heart rate, temperature, and respiratory 
rate [in triplicate]) 


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• Perform a complete physical examination 
• Train subject on the repeated chair stand test without collecting the data 
• Draw fasting blood for the following assessments at local laboratory:  i-STAT 
bicarbonate, enzymatic assay serum bicarbonate or venous blood gas bicarbonate assay  
• Draw fasting blood for assessment of serum chemistry panel at central laboratory 
• Provide instructions on collecting 24-hour urine sample starting one day prior to the 
Baseline Visit and dispense necessary supplies   
• Record AEs 
 
7.3 
Laboratory Re-Testing and Subject Re-Screening 
The Investigator may repeat a failed Screening blood or urine laboratory assessment once per 
analyte during the Screening Period (including Screening 2 and Baseline Visits) if he/she 
feels the original result was unexpected (e.g., due to a lab error, etc.).  When Screening 
laboratory values required for study eligibility are repeated, eligibility should be determined 
based on the most recent value. 
If a central laboratory eGFR value from Screening 2 Visit is not available, eGFR can be 
calculated using CKD-EPI equation based on onsite serum creatinine measurement at the 
Baseline Visit to establish subject’s eligibility.  For eGFR, the most recent creatinine at the 
Screening 1 Visit and the most recent creatinine from Screening 2 Visit should be used.  If a 
central laboratory eGFR value and a local eGFR value are both available at the time of 
randomization, the central laboratory value should be used for eligibility determination. 
For blood bicarbonate, the most recent value available from each of the three visits 
(Screening 1, Screening 2, Day 1) should be used for eligibility determination. 
Re-screening of subjects who fail to meet eligibility criteria will be allowed provided the 
Medical Monitor approves, the subject repeats the Informed Consent process and all 
Screening evaluations are repeated; a new subject identification number will be assigned 
each time a subject is re-screened. 
7.4 
Baseline Visit (Day 1) 
Following completion of the Screening Period, subjects who meet eligibility criteria based on 
the results of the Screening 1 and 2 Visits will return to the study site for the Baseline Visit 
on Day 1 (within 2 weeks of Screening 1 Visit) for confirmatory blood bicarbonate 
measurement.  Subjects must present to the site in a fasted state. 
The following procedures will be performed: 
• Evaluate eligibility (blood bicarbonate and eGFR) 


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• Record prior/concomitant medications 
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate) up to 
1 hour prior to administration of the first dose of study drug  
• Collect body weight any time prior to administration of the first dose of study drug 
• Perform repeated chair stand test 
• Collect answers to KDQOL questions 
• Record ECG (triplicate) any time prior to administration of study drug 
• 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 central laboratory:  serum chemistry 
panel, hematology panel, and biomarker panel 
• Obtain urine sample for urine dipstick pregnancy test (women of childbearing potential 
only)  
• Obtain urine for the following assessments at central laboratory any time prior to 
administration of first dose of study drug:  spot urine, urinalysis, and urine biomarker 
panel  
• Obtain 24-hour urine sample for assessment at central laboratory 
• Randomize subject using the IRT system 
• Dispense study drug per IRT assignment and drug dosing diary [to be done by the 
Pharmacist only] 
• Instruct subject on study drug dosing and diary completion procedures and supervise 
administration of the first dose [to be done by the Pharmacist only] 
• Record AEs 
• Dietary counseling 
• Schedule next study visit 
 
7.5 
Week 1, Week 2, and Week 10 Visits 
The allowed visit window is ± 1 day for all visits during the Treatment Period.  The 
following procedures and assessments will be performed at the Week 1, Week 2, and Week 
10 Visits.  Subjects must present to these visits in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate)  


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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 assessment of serum chemistry panel at central laboratory 
• At Week 2 Visit only:  record 12-lead ECG 
• At Week 10 Visit only:  provide instructions on collecting 24-hour urine sample starting 
one day prior to the Week 12 Visit and dispense necessary supplies   
• Dispense the study drug per IRT assignment and dosing diary [to be done by the 
Pharmacist only] 
• Collect used and unused study drug containers since the previous visit and corresponding 
dosing diary, assess dosing compliance and perform drug accountability [to be done by 
the Pharmacist only] 
• Record AEs 
• Schedule the next study visit 
 
7.6 
Week 4 and Week 8 Visits 
The allowed visit window is ± 1 day for all visits during the Treatment Period.  The 
following procedures and assessments will be performed at the Week 4 and Week 10 Visits.  
Subjects must present to these visits in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate)  
• Collect body weight  
• Perform a complete physical examination 
• 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 assessment of serum chemistry panel at central laboratory 
• Dispense the study drug per IRT assignment and dosing diary [to be done by the 
Pharmacist only] 
• Collect used and unused study drug containers since the previous visit and corresponding 
dosing diary, assess dosing compliance and perform drug accountability [to be done by 
the Pharmacist only] 
• Record AEs 
• Schedule the next study visit 
 


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7.7 
Week 6 Visit 
The allowed visit window is ± 1 day for all visits during the Treatment Period.  The 
following procedures and assessments will be performed at the Week 6 Visit.  Subjects must 
present to this visit in a fasted state. 
• Record concomitant medications  
• Collect vital signs (blood pressure, heart rate, temperature, and respiratory rate)  
• Record 12-lead ECG 
• 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 central laboratory:  serum chemistry 
panel, hematology panel, hemoglobin A1c, and serum pregnancy test (for women of 
childbearing potential only) 
• Obtain urine for the following assessments at central laboratory:  spot urine, urinalysis, 
and urine biomarker panel  
• Dispense the study drug per IRT assignment and dosing diary [to be done by the 
Pharmacist only] 
• Collect used and unused study drug containers since the previous visit and corresponding 
dosing diary, assess dosing compliance and perform drug accountability [to be done by 
the Pharmacist only] 
• Record AEs 
• Dietary counseling 
• Schedule the next study visit 
 
7.8 
Week 12 or Early Termination Visit (ET) 
The following assessments will be performed at the Week 12 Visit for subjects who 
completed the entire Treatment Period or 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 on Day 84 of the study, regardless of the date of the Week 12 visit; however, every 
effort should be made to conduct the Week 12 visit on Day 85, which is in exactly 12 weeks 
from Day 1 (Baseline Visit). 
• Record concomitant medications  
• Collect vital signs (blood pressure [in triplicate], heart rate, temperature, and respiratory 
rate [in triplicate])  
• Collect body weight 


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• Perform a complete physical examination 
• Perform repeated chair stand test 
• Collect answers to KDQOL questions 
• 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 central laboratory:  serum chemistry 
panel, hematology panel, hemoglobin A1c, biomarker panel and serum pregnancy test 
(for women of childbearing potential only) 
• Obtain urine for the following assessments at 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 and corresponding 
dosing diary, assess dosing compliance and perform drug accountability [to be done by 
the Pharmacist only] 
• Record AEs 
• Dietary counseling 
• Schedule the next study visit 
 
7.9 
Follow-up 1 Visit (Week 13) 
The allowed visit window is ± 1 day for all visits during the Follow-up Period.  The 
following assessments will be performed at the Week 13 Visit.  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 assessment of serum chemistry panel at central laboratory 
• Record AEs 
• Schedule the next study visit 
 


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7.10 
Follow-up 2 Visit (Week 14) 
The allowed visit window is ± 1 day for all visits during the Follow-up Period.  The 
following assessments will be performed at the Week 14 Visit.  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 central laboratory:  serum chemistry 
panel and hematology panel 
• Obtain urine sample for central laboratory assessment of spot urine and urinalysis 
• Record AEs 
 
7.11 
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 day.  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 
• Record 12-lead ECG 
• 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. 
• Perform study drug accountability and dispensation per IRT assignment (if applicable) 
[to be done by the Pharmacist only] 
• Record AEs 


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7.12 
End-of-Study 
Subjects who complete the 12-week Treatment Period will be offered participation in a 40-
week extension study (TRCA-301E).  For subjects who are enrolled in the extension study, 
end-of-study in Study TRCA-301 is defined as completion of the Week 12 Visit.   
For subjects who are not willing to participate in, or who are not eligible for, the extension 
study, end-of-study in Study TRCA-301 is defined as completion of the Follow-up 2 (Week 
14) Visit.   
For those subjects who withdrew from Study TRCA-301 prematurely, end-of-study is 
defined as the time of the subject’s last data collection. 
8 
PLANNED STATISTICAL METHODS 
8.1 
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 
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. 
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 treatment group (6 g TRC101 or 
placebo) and 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 treatment group and time point, as applicable, using 
frequency counts and percentages.  Two-sided 95% confidence intervals will be reported for 
the efficacy estimates. 
8.2 
Determination of Sample Size 
Primary efficacy endpoint:  A sample size of 120 subjects in the TRC101 group and 90 
subjects in the placebo group will have high power to detect differences between the 
TRC101- and placebo-treated groups.  The sample size calculation is based on the data from 
the Phase 1/2 Study TRCA-101, where 3% of placebo and 46% of TRC101 treated subjects 
had an increase in blood bicarbonate of ≥ 4 mEq/L or had blood bicarbonate in the normal 
range at Week 2.  We assume the full TRC101 treatment effect had not been reached during 
this short treatment period.  In Study TRCA-301, we expect that 50 to 55% of TRC101-
treated and 10% of placebo-treated subjects will have an increase of ≥ 4 mEq/L or have 


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blood bicarbonate in the normal range at the end of treatment (Week 12 Visit).  A Fisher's 
exact test with a 0.05 two-sided significance level will have over 99% power to detect this 
difference when 90 placebo subjects and 120 TRC101 subjects are enrolled.  If the true 
proportion of TRC101 subjects who respond at the Week 12 Visit is indeed between 50% 
and 55% and if no more than 5% of subjects have missing data at Week 12, the study will 
have roughly 90% power to result in a 95% confidence limit with a lower bound of at least 
35% and 40%, respectively.   
Sample size calculation for the secondary efficacy endpoint will be documented in the SAP. 
8.3 
Analysis Populations 
Two populations will be analyzed in this study.  The SAP may define additional analysis 
set(s). 
Modified intent-
to-treat (MITT) 
analysis set: 
All randomized subjects who had both baseline and at least one post-
baseline blood bicarbonate value.  Post-baseline is defined as a blood 
bicarbonate value obtained after the first dose of study drug. 
 
Safety analysis 
set: 
 
All subjects who received any amount of study drug (TRC101 or 
placebo) 
 
8.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be listed by treatment group, study site and 
subject, and will be summarized by treatment group.  Frequencies and percentages will be 
presented for the categorical variables and descriptive statistics will be presented for 
continuous variables. 
8.5 
Statistical Analysis of Efficacy  
Efficacy data will be summarized by treatment group for subjects in the MITT analysis set 
based on the randomized treatment group assignment.  Number and 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 0.05 level with a two-sided test.  In order to 
control family-wise error rate, formal statistical testing for the primary and secondary 
endpoints will be performed sequentially.  At Week 12, Fisher’s exact test will be used to 
compare the group proportions for the primary efficacy endpoint.  Only when the primary 
efficacy result is statistically significant will the formal test be performed using an MMRM 
model to compare the group means at Week 12 for the secondary efficacy endpoint.   


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8.5.1 
Efficacy Variable 
The efficacy analysis will include bicarbonate results that will be collected at baseline 
through the end of the 12-week treatment from the i-STAT device.  The i-STAT bicarbonate 
data will be used to determine the CFB in bicarbonate over time.  Baseline bicarbonate is 
defined as the mean of the bicarbonate values collected at Screening visits and on Day 1 
pre-dose.  CFB in bicarbonate will be calculated for each time point subsequent to the first 
dose of study drug.  Descriptive statistics of efficacy data will be provided for all scheduled 
time points.  
8.5.2 
Efficacy Endpoints 
Primary Efficacy:   
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 12 Visit).  
Secondary Efficacy: 
CFB in blood bicarbonate at the end of treatment (Week 12 Visit). 
Exploratory Efficacy: 
1. CFB in the total score of the KDQOL Question 3 items (daily activities) at the end of 
treatment (Week 12 Visit). 
2. CFB in repeated chair stand test duration at the end of treatment (Week 12 Visit). 
 
8.5.3 
Efficacy Analysis  
Efficacy data will be summarized by treatment group for subjects in the MITT analysis set 
based on the randomized treatment group assignment.   
8.5.3.1 
Primary Efficacy Analysis  
The number and proportions (expressed as percentages) of subjects who are responders at 
each time point and at the end of treatment 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 by 
time point.  The exact 95% CIs of the proportions will also be summarized by treatment 
group and time point.  A formal test for the difference (TRC101 – placebo) in proportion (= 
0) will be conducted at Week 12 using the Fisher’s exact test.  If this formal test is 
statistically significant, a second formal test for the proportion of TRC101 responders at 
Week 12 will be conducted.   


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8.5.3.2 
Secondary Efficacy Analyses 
The secondary efficacy analysis will compare the TRC101 group with the placebo group in 
LS mean CFB in blood bicarbonate at the end of treatment (Week 12 Visit).  The null 
hypothesis is that there is no mean difference between the TRC101 group and the placebo 
group.  The alternative hypothesis is that the means differ.  The secondary efficacy endpoint 
will be assessed using a longitudinal mixed-effect model for repeated measures (MMRM).  
The model will include the CFB in bicarbonate as the dependent variable, treatment, time 
point (Weeks 1, 2, …, 12), and treatment by time point interaction as fixed effects, subject as 
a random effect, the baseline bicarbonate and baseline eGFR as continuous covariates.  An 
unstructured covariance structure will be assumed.  The least squares (LS) mean of CFB in 
bicarbonate, standard error of 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), 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.  Only when the primary efficacy endpoint is statistically significant 
will formal testing be performed for the secondary efficacy endpoint.  Meeting the secondary 
endpoint will be declared if the two-sided p-value at Week 12 is <0.05 and the primary 
efficacy endpoint is statistically significant.   
8.5.3.3 
Sensitivity Analyses and Exploratory Efficacy Endpoint Analyses 
In order to evaluate the potential effect of missing data on the primary and secondary 
efficacy results, sensitivity analyses will be performed using multiple imputation models 
under a MNAR assumption for the MITT analysis set.  These analyses will be described in 
the SAP. 
The SAP will also describe the analysis methods for the exploratory efficacy endpoints.   
8.6 
Safety Analysis 
Safety will be summarized by treatment group for subjects in the safety analysis set.  The 
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 will be 
summarized by treatment group.  The number (%) of subjects with TEAEs leading to 
discontinuation of study treatment will also be summarized by treatment group.  Subjects will 
be counted only once at each SOC and PT level of summary.  Clinical laboratory test results, 
vital signs and ECG findings will be summarized using descriptive statistics by treatment 
group and time point.  Categorical display methods (e.g., frequencies, shift tables) and plots 
of laboratory values over time may also be used, as appropriate.  Worsening or newly 
observed, clinically significant physical examination findings will be reported as adverse 
events.   


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8.7 
Other Assessments or Analyses 
Exposure to study drug, dosing compliance, and concomitant medications will be 
summarized by treatment group.  The number and percentage of subjects who used prior 
and/or concomitant medications will be summarized by Anatomic Therapeutic Chemical 
(ATC) classification levels and treatment group.  At each level of ATC classification, 
subjects will be counted once.   
9 
DATA HANDLING AND RECORD KEEPING  
9.1 
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 TRC101.  
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. 
9.2 
Case Report Forms / Electronic Data Record 
An 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 
EDC system. 


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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 via programmed quality checks and manually via data listings 
review by Tricida and its designee.  Data that appear inconsistent, incomplete, or inaccurate 
will be queried for site clarification.  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). 
9.3 
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. 
9.4 
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 major and minor protocol deviations for use in the statistical analysis, if 
applicable. 
9.5 
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. 


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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 
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. 


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• 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 
11.1 
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 
(EUCTD) for sites in the European Union (EU) and all other applicable local and national 
laws and regulations governing the conduct of human clinical studies.  
11.2 
Institutional Review Board / Ethics Committee 
All Investigators participating in this study must be governed under an appropriate 
Institutional Review Board (IRB) or 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 
study, Investigators will notify their IRB/IECs.  The Investigator will comply with all 
IRB/IEC policies throughout the duration of the study.  
11.3 
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.   


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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. 
11.4 
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 
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. 


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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. 
11.5 
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. 
11.6 
Premature Termination of the Study 
If Tricida, DMC, 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 
 
11.7 
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.   


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Signed ICFs must be available for verification by monitors, auditors, and/or regulatory 
agency inspectors at any time. 
11.8 
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. 
11.9 
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. 
 


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12 
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Sodium Bicarbonate in Patients with CKD." Clin J Am Soc Nephrol. 8: 714-720. 
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PA. Elsevier, Inc. 2012: 933-948. 
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 
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Domrongkitchaiporn S, Pongskul C, Sirikulchayanont, V, Stitchantrakul W, Leeprasert V, 
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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. 
Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace RB. 1995. “Lower-Extremity 
Function in Persons Over the Age of 70 Years as a Predictor of Subsequent Disability.” N 
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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 
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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." 
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 
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Kovesdy CP, Anderson JE, Kalantar-Zadeh K. 2009. "Association of serum bicarbonate 
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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. 
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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 
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Raphael KL, Wei G, Baird BC, Greene T, Beddhu S. 2011. "Higher Serum Bicarbonate 
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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. 
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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13 
APPENDICES 
 


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Appendix 1: Schedule of Events 
Study Activity 
Period 
Screening 
Treatment 
Follow-up 
 
UNS 
Visit [v] 
Visit Name 
S1 
S2 
D1 
W1 
W2 
W4 
W6 
W8 
W10 
W12 [a] 
F1 
F2 
 
Timing 
Week 
-2 [b] 
Week 
-1 [c] 
Day  
1 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week  
12 
Week  
13 
Week 
14 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject ID Number Assignment in IRT  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medications [d] 
X 
X 
X [t] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs [e]  
X 
X 
X [t] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body Weight and Height [f]  
X [f] 
 
X [t] 
 
 
X 
 
X 
 
X 
 
X 
 
 
Physical Exam [g] 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Repeated Chair Stand Test 
 
X [u] 
X 
 
 
 
 
 
 
X 
 
 
 
 
KDQOL  
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
ECG [h] 
 
X [t] 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Fasting i-STAT Bicarbonate [i] 
L 
L 
L [t] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Fasting Blood Bicarbonate (Enzymatic 
Serum or Venous Blood Gas Assay) [j] 
L 
L 
L [t] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Coagulation [k] 
L 
 
L [t] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Fasting Serum Chemistry 
C 
C [l] 
C [t] 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
C 
Hematology 
C 
 
C [t] 
 
 
 
C 
 
 
C 
 
C 
 
 
Hemoglobin A1c 
C 
 
 
 
 
 
C 
 
 
C 
 
 
 
 
Pregnancy Test [m] 
C 
 
L [t] 
 
 
 
C 
 
 
C 
 
 
 
 
Biomarkers (Blood and Urine) [n] 
 
 
C [t] 
 
 
 
 
 
 
C 
 
 
 
 
Urinalysis and Spot Urine Tests  
C 
 
C [t] 
 
 
 
C 
 
 
C 
 
C 
 
 
Training on 24-Hour Urine Collection 
and Dispensing Supplies  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
24-Hour Urine Collection [o] 
 
 
C [t] 
 
 
 
 
 
 
C 
 
 
 
 
Randomization in IRT 
 
 
X [t] 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of Study Drug and 
Dosing Diary [p, q, r, s] 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Onsite Study Drug Dosing [q] 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing Compliance and 
Accountability [r, s] 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse Event Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dietary Counseling 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Notes:  (1)  All blood draws for bicarbonate measurements must be done with subjects in a fasted state (at least 4 hours, except water).  (2) Weekly visits should 
be targeted to occur on the same day of the week as Day 1 (e.g., always on Wednesday).  Allowed visit windows are ± 1 day for all study visits during the 
Treatment and Follow-up Periods. 


TRC101 
 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301 
 
 
November 27, 2017 
 
Confidential 
 
Page 78 of 80 
Abbreviations: C = central laboratory assessment;  ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c;  ID = 
identification;  KDQOL = kidney disease quality of life;  L = local laboratory assessment;  UNS = unscheduled. 
a  
Subjects who terminate the study early are required to undergo an Early Termination Visit with all Week 12 Visit procedures to be performed. 
b  
Screening 1 Visit must occur within 2 weeks of Baseline Visit. 
c  
Screening 1 and Screening 2 Visits must occur  at least 5 days apart. 
d  
At Screening 1 Visit, record all prescription and non-prescription medications and nutritional supplements taken within 28 days. 
e  
Vital signs include:  blood pressure and respiratory rate (both in triplicate, measurements taken approximately 2 minutes apart at Screening 1, Screening 
2, and Week 12 Visits; once at all other time points), heart rate, and temperature. 
f  
Height will only be collected at the Screening 1 Visit. 
g  
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). 
h  
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.  
i  
The i-STAT G3+ cartridge must be used and measurement taken from a whole blood sample within 10 min of the blood draw.   
j  
Either enzymatic or venous blood gas assay but consistent for each subject as soon as possible in accordance with local laboratory requirements.  
 
k  
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. 
l  
If necessary, at the Screening 2 Visit, eGFR may be assessed based on local serum creatinine measurement to confirm eligibility. 
m  
For women of childbearing potential, blood samples will be collected for serum pregnancy tests at the Screening 1, Week 6, and Week 12 Visits, and a 
urine sample will be collected for a urine dipstick pregnancy test at the Baseline Visit. 
n  
Blood and urine samples will be collected and stored under frozen conditions as specified in the laboratory manual. 
o  
Instruct subjects on collecting 24-hour urine samples prior to Baseline and Week 12 Visits 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 Baseline and Week 12 Visits.  
p  
Dispense study drug per IRT instructions and provide the dosing diary.  Instruct subject to take study drug with lunch, at least 4 hours apart from all oral 
concomitant medications.   
q  
Administer the first dose of study drug on the morning of Day 1, with a snack, while the subject is at the site. 
r  
Instruct the subject to bring the dosing diary to each visit.  Review dosing diary vs. study drug supplies and assess dosing compliance.  Record dosing 
diary information at each visit in eCRF.  Collect the dosing diary at the Week 12 or at the ET Visit. 
s  
Instruct subject to bring all used and unused study drug to each visit.  Collect all used and unused study drug at the Week 12 Visit or at the ET Visit. 
t  
Procedure to be performed prior to administration of the first dose of study drug. 
u  
Train the subjects on repeated chair stand test at the Screening 2 Visit.  No eCRF data will be collected. 
 
v  
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-301 
 
November 27, 2017 
 
Confidential 
 
Page 79 of 80 
Appendix 2: Study Drug Titration Algorithm 
Blood Bicarbonate 
(mEq/L) 
Before Week 4 Visit 
Week 4 through Week 11 
< 12* 
Evaluate for new acute acidotic 
process, contact Medical 
Monitor.  Maintain dose 
pending discussion with 
Medical Monitor 
Evaluate for new acute acidotic 
process, contact Medical 
Monitor.  Maintain dose 
pending discussion with 
Medical Monitor. 
12 to < 22 
Maintain dose until next 
scheduled visit. 
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. 
22 to < 27 
Maintain dose until next scheduled visit. 
27 to 30 
Decrease the study drug dose by 1 packet/day (minimum dose is 0 
packets/day). 
Invite subject for a visit in approximately 1 week to retest blood 
bicarbonate. 
Only decrease the dose if NO dose changes have been made during 
the previous 14 days. 
> 30* 
Interrupt (hold) study drug. 
Invite subject for a visit in approximately 1 week to retest blood 
bicarbonate.   
If blood bicarbonate at that visit is: 
• < 27 mEq/L, restart study drug at a lower dose (1 packet/day 
less than before dose interruption). 
• ≥ 27 mEq/L, continue to hold the dose and retest again in 
approximately 1 week. 
* Blood bicarbonate value of < 12 mEq/L or > 30 mEq/L must be confirmed by a repeated measurement from a 
separate blood draw.  
 
 


TRC101 
 
Tricida, Inc. 
Clinical Study Protocol: TRCA-301 
 
November 27, 2017 
 
Confidential 
 
Page 80 of 80 
Appendix 3: New York Heart Association (NYHA) Classification of Heart Failure 
Class 
Patient Symptoms 
Class I 
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea (shortness of breath). 
Class II 
Slight limitation of physical activity.  Comfortable at rest.  Ordinary 
physical activity results fatigue, palpitation, dyspnea (shortness of 
breath). 
Class III 
Marked limitation of physical activity.  Comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV 
Unable to carry out any physical activity without discomfort.  
Symptoms of heart failure at rest.  If any physical activity is 
undertaken, discomfort increases. 
Source:  www.heart.org, accessed 30September2015 
 

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan for Study TRCA-301 
 
 
Official Study Title: 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo- 
Controlled Study to Evaluate the Efficacy and Safety of 
TRC101 in Subjects with Chronic Kidney Disease and 
Metabolic Acidosis 
 
 
ClinicalTrials.gov Identifier:  
NCT03317444   
 
 
Document Date: 
May 23, 2018 


 
 
STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
TRC101 in Subjects with Chronic Kidney Disease and 
Metabolic Acidosis 
Study Number: 
TRCA-301 
Investigational Drug: 
TRC101 
Indication: 
Treatment of metabolic acidosis associated with chronic 
kidney disease 
Investigators: 
Multicenter 
IND Number: 
125,832 
EudraCT Number: 
2016-003825-41 
Sponsor: 
Tricida, Inc. 
7000 Shoreline Court, Suite 201 
South San Francisco, CA 94080, U.S.A. 
Plan Version: 
23 May 2018 (Final Version 2.0) 
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. 
2018 Tricida, Inc. 
 
 




Tricida, Inc.  
23 May 2018 
SAP TRCA-301 Final Version 2.0 
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Table of Contents 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 7 
2 
REVISION HISTORY........................................................................................................... 9 
3 
RELEVANT DOCUMENTS: PROTOCOL, AMENDMENTS AND CASE REPORT 
FORMS .................................................................................................................................. 9 
4 
COMMITMENT TO GOOD STATISTICAL PRACTICE .................................................. 9 
4.1 
Definition of Good Statistical Practice ......................................................................... 9 
4.2 
Use of Standards ......................................................................................................... 10 
5 
PURPOSE OF THE ANALYSIS PLAN ............................................................................. 10 
6 
STUDY OBJECTIVES ........................................................................................................ 11 
6.1 
Primary Objective ....................................................................................................... 11 
6.2 
Secondary Objective ................................................................................................... 11 
7 
STUDY DESIGN................................................................................................................. 11 
7.1 
Overall Study Design .................................................................................................. 11 
7.2 
Randomization and Blinding ...................................................................................... 15 
7.3 
Assessments ................................................................................................................ 16 
 
Efficacy Measurements ................................................................................. 16 
 
Safety Measurements .................................................................................... 16 
 
Other Measurements ...................................................................................... 16 
8 
SAMPLE SIZE AND POWER ............................................................................................ 16 
8.1 
Primary Efficacy Endpoint ......................................................................................... 16 
8.2 
Secondary Efficacy Endpoint ..................................................................................... 17 
9 
ANALYSIS SETS ............................................................................................................... 19 
9.1 
Modified Intent-To-Treat ............................................................................................ 19 
9.2 
Per-Protocol ................................................................................................................ 19 
9.3 
Safety Analysis Set ..................................................................................................... 19 
10 
GENERAL CONSIDERATIONS ....................................................................................... 19 
10.1 
Definitions and Derived Variables .............................................................................. 21 
 
Age ................................................................................................................ 21 
 
Study Day ...................................................................................................... 21 
 
Estimated Glomerular Filtration Rate ........................................................... 21 
 
Anion Gap ..................................................................................................... 21 
 
Multiple Records at a Time Point .................................................................. 22 
 
Baseline Values ............................................................................................. 22 
 
Baseline Blood Bicarbonate Value Using i-STAT ........................................ 22 
 
Baseline Blood Bicarbonate Subgroups ........................................................ 22 


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Screening and Baseline eGFR Value ............................................................ 22 
 
Screening eGFR Subgroups .......................................................................... 22 
 
Baseline Blood pH and Base Excess Values Using i-STAT ......................... 23 
 
24-hour Urine Excretion of Uric Acid, Sulfate, Creatinine, Albumin, and 
Urea Nitrogen ................................................................................................ 23 
 
24-hour Creatinine Clearance ........................................................................ 23 
 
Baseline Electrocardiogram Parameters ........................................................ 23 
 
Treatment-Emergent Adverse Events ........................................................... 23 
 
Concomitant Medications and Concurrent Procedures ................................. 23 
 
Alkali Therapy ............................................................................................... 24 
10.2 
Analysis Windows ...................................................................................................... 24 
11 
STATISTICAL AND ANALYSIS ISSUES ....................................................................... 25 
11.1 
Adjustments for Covariates......................................................................................... 25 
11.2 
Handling Dropouts or Missing Data ........................................................................... 25 
11.3 
Handling of Efficacy Data .......................................................................................... 25 
11.4 
Handling of Safety Data.............................................................................................. 26 
 
Adverse Events .............................................................................................. 26 
 
Concomitant Medications .............................................................................. 26 
11.5 
Interim Analyses and Data Monitoring....................................................................... 27 
11.6 
Multicenter Considerations ......................................................................................... 27 
11.7 
Multiple Comparisons, Multiplicity............................................................................ 28 
11.8 
Use of an “Efficacy Subset” of Subjects..................................................................... 29 
11.9 
Active-Control Studies................................................................................................ 29 
11.10 Examination of Subgroups .......................................................................................... 29 
12 
STUDY PATIENTS ............................................................................................................ 29 
12.1 
Subject Disposition ..................................................................................................... 29 
12.2 
Protocol Deviations ..................................................................................................... 30 
12.3 
Demographics and Baseline Characteristics ............................................................... 31 
12.4 
Medical History .......................................................................................................... 31 
13 
STUDY DRUG AND OTHER MEDICATIONS ............................................................... 32 
13.1 
Prior and Concomitant Medications ........................................................................... 32 
13.2 
Restricted Medications................................................................................................ 32 
13.3 
Exposure to Study Drug, Study Treatment Compliance, and Dose Titration ............. 32 
14 
EFFICACY ANALYSES .................................................................................................... 33 
14.1 
Efficacy Endpoints ...................................................................................................... 33 
 
Primary Efficacy Endpoint ............................................................................ 33 
 
Secondary Efficacy Endpoint ........................................................................ 34 


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SAP TRCA-301 Final Version 2.0 
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Exploratory Efficacy Endpoints .................................................................... 34 
14.2 
Efficacy Variables ....................................................................................................... 34 
 
Change from Baseline in Blood Bicarbonate ................................................ 34 
 
Categorical Change in Blood Bicarbonate .................................................... 35 
 
Additional Change from Baseline Variables ................................................. 35 
14.3 
Primary Efficacy Analysis .......................................................................................... 35 
 
Reporting Results .......................................................................................... 36 
 
Statistical Hypotheses .................................................................................... 36 
 
Statistical Testing .......................................................................................... 36 
14.4 
Secondary Efficacy Analysis ...................................................................................... 37 
 
Statistical Hypothesis .................................................................................... 37 
 
Statistical Model ............................................................................................ 37 
 
Reporting Results .......................................................................................... 38 
 
Statistical Testing .......................................................................................... 38 
14.5 
Sensitivity Analyses for Primary and Secondary Efficacy Endpoints ........................ 39 
14.6 
Subgroup Analyses of the Primary and Secondary Efficacy Endpoints ..................... 39 
14.7 
Exploratory Efficacy Analyses - KDQOL and Repeated Chair Stand Test ............... 39 
14.8 
Other Efficacy Analyses ............................................................................................. 40 
 
Individual Components of the Primary Endpoint .......................................... 40 
 
Categorical Change in Blood Bicarbonate .................................................... 40 
 
Change from Baseline in Biomarkers at Week 12 ........................................ 41 
 
Subgroup Analysis of Change in i-STAT Blood Bicarbonate Over Time .... 41 
15 
SAFETY ANALYSES......................................................................................................... 42 
15.1 
Safety Variables .......................................................................................................... 42 
15.2 
Adverse Events ........................................................................................................... 42 
15.3 
Incidence of High Bicarbonate ................................................................................... 43 
15.4 
Clinical Laboratory Evaluation ................................................................................... 43 
 
Summary of Change from Baseline in eGFR ................................................ 45 
 
Summary of Change from Baseline in Blood pH and Base Excess .............. 45 
 
Bicarbonate Measurements from Local Laboratory ...................................... 45 
15.5 
Vital Signs ................................................................................................................... 45 
15.6 
Body Weight ............................................................................................................... 46 
15.7 
12-lead Electrocardiograms ........................................................................................ 46 
15.8 
Physical Examination.................................................................................................. 47 
15.9 
Safety Monitoring ....................................................................................................... 47 
16 
CHANGES RELATIVE TO THE PROTOCOL-SPECIFIED ANALYSIS ....................... 47 
16.1 
Other Efficacy Analyses ............................................................................................. 47 


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23 May 2018 
SAP TRCA-301 Final Version 2.0 
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17 
Reference ............................................................................................................................. 48 
 
List of Tables 
Table 1 
Study TRCA-301 Protocol Schedule of Events ......................................................... 13 
Table 2 
Analysis Visit Windows ............................................................................................ 24 
Table 3 
Country Code and Geographic Region Category ...................................................... 27 
Table 4 
Pre-Specified Threshold Levels for Selected Laboratory Tests ................................ 44 
Table 5 
Pre-Specified Threshold Levels for Vital Signs ........................................................ 46 
Table 6 
Pre-Specified Threshold Levels for ECG Parameters ............................................... 47 
 
 


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23 May 2018 
SAP TRCA-301 Final Version 2.0 
Page 7 of 48 
 
 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
ADaM 
analysis data model 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BP 
blood pressure 
CBC 
complete blood count 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CFB 
change from baseline 
CrCL 
creatinine clearance 
CKD 
chronic kidney disease 
CM 
concomitant medication 
CRF 
case report form 
CRU 
clinical research unit 
CSR 
clinical study report 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EU 
European Union  
FDA 
The Food and Drug Administration 
K+ 
potassium 
KDQOL 
kidney disease quality of life questionnaire 
HR  
heart rate 
LDL 
low density lipoprotein 
LS 
least squares 
ICH 
International Council for Harmonisation  
IRT 
interactive response technology 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 


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23 May 2018 
SAP TRCA-301 Final Version 2.0 
Page 8 of 48 
 
 
Abbreviation 
Description 
MMRM 
mixed-effect model repeated measures 
MNAR 
missing not at random 
PT 
preferred term 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
standard error 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
UAGT 
urine angiotensinogen to creatinine ratio 
WHO 
World Health Organization 
 
 


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23 May 2018 
SAP TRCA-301 Final Version 2.0 
Page 9 of 48 
 
 
2 
REVISION HISTORY 
Version 
Date 
Document 
Owner 
Revision Summary 
Draft 1.0 
2 March 2017 
 
First version 
Draft 2.0 
5 June 2017 
 
Incorporated comments from the FDA’s 
responses dated 24 May 2017. 
Final 1.0 
04 August 2017 
 
Updates to be in sync with Protocol 
Amendment 2.  Editorial changes made for 
clarification. 
Final 2.0 
23 May 2018 
 
Added analyses to describe the population 
baseline renal risk, to further explore threshold 
bicarbonate responses, to explore effects of the 
starting dose and dose titration, to further 
specify handling of protocol deviations, and to 
update the per-protocol population definition. 
This revision also includes minor re-wording 
to enhance clarity and/or internal consistency.  
3 
RELEVANT DOCUMENTS: PROTOCOL, AMENDMENTS AND CASE REPORT 
FORMS 
Original Protocol (2 March 2017) 
Protocol Amendment 1 (05 June 2017) 
Protocol Amendment 2 (03 August 2017) 
Protocol Amendment 3 (27 November 2017) 
Case Report Form (CRF) Final Version 1.0 (August 2017) 
Case Report Form (CRF) Version 2.0 (February 2018) 
 
4 
COMMITMENT TO GOOD STATISTICAL PRACTICE 
4.1 
Definition of Good Statistical Practice 
Guidance on Statistical Principles for Clinical Trials from International Conference 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 


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SAP TRCA-301 Final Version 2.0 
Page 10 of 48 
 
 
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.   
We 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. 
4.2 
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) data sets 
and Analysis Data Model (ADaM) statistical analysis files for producing analysis results.  Other 
applicable standards include regulatory guidances from FDA and ICH: 
• ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3) 
• ICH Guidance for Good Clinical Practice (ICH E6) 
5 
PURPOSE OF THE ANALYSIS PLAN 
This statistical analysis plan (SAP) pre-specifies the statistical analysis methods for supporting the 
completion of the clinical study report (CSR) of Study TRCA-301 for investigational product 
TRC101.  This SAP will be used to analyze the efficacy and safety data collected during the study.  
The planned analyses identified in this SAP may be included in regulatory submissions, and/or 
future manuscripts.  The analyses described in this plan are considered a priori, in that they have 
been defined prior to clinical database lock and authorized unblinding of treatment assignment.  
Exploratory analyses, which are not defined in this SAP, may be performed to support the clinical 
development program.  Any post-hoc or unplanned analyses that are performed for the CSR but 
not defined in this SAP, will be documented in the CSR, as will any changes from the planned 
analyses as stated in the study protocol.   


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23 May 2018 
SAP TRCA-301 Final Version 2.0 
Page 11 of 48 
 
 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of TRC101 in chronic kidney disease 
(CKD) patients with metabolic acidosis (blood bicarbonate 12 to 20 mEq/L). 
6.2 
Secondary Objective 
The secondary objective of the study is to assess the safety of administration of TRC101 in CKD 
patients with metabolic acidosis (blood bicarbonate 12 to 20 mEq/L). 
7 
STUDY DESIGN 
7.1 
Overall Study Design 
This is a double-blind, placebo-controlled, parallel-design, 2-arm study.  Approximately 210 
subjects will be randomized in a 4:3 ratio to receive 6 g TRC101 or placebo once daily (QD).  
Approximately 55 study centers will participate in this study. 
Screening Period: Eligible subjects will be enrolled into the study if they: are 18 to 85 years of 
age; have a blood bicarbonate value of 12 to 20 mEq/L at Screening 1 and Screening 2; have an 
average value of blood bicarbonate from Screening 1, Screening 2, and Day 1 pre-dose (i.e., 
baseline blood bicarbonate) within the 12 to 20 mEq/L range; and have an estimated glomerular 
filtration rate (eGFR) of 20 to 40 mL/min/1.73m2 at both the Screening 1 and Screening 2 visits.  
Additional inclusion and exclusion criteria can be found in the TRCA-301 protocol, Section 4.  
Randomization of eligible subjects will be based on their baseline blood bicarbonate strata (≤18 
versus >18 mEq/L) and Screening eGFR strata (<30 versus ≥30 mL/min/1.73m2, where Screening 
eGFR is defined as the average of Screening Visit 1 and Screening Visit 2 values). 
Treatment Period: Randomized subjects will receive study drug (placebo or TRC101) for 12 weeks 
(Treatment Period) on an outpatient basis.  The dose of the study drug will be fixed for the first 4 
weeks of the Treatment Period, except for subjects with a blood bicarbonate level ≥ 27 mEq/L.  
Subjects with a blood bicarbonate level of 27 to 30 mEq/L will have their dose of study drug 
decreased per the titration algorithm (see TRCA-301 protocol, Appendix 2).  Subjects with a 
confirmed blood bicarbonate level of > 30 mEq/L will undergo an interruption of the study drug 


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SAP TRCA-301 Final Version 2.0 
Page 12 of 48 
 
 
dose in accordance with the titration algorithm (see TRCA-301 protocol, Appendix 2).  Beginning 
at the Week 4 Visit, subjects with a blood bicarbonate level below the normal range (12 to < 
22 mEq/L) will have an adjustment of the study drug dose in accordance with the titration 
algorithm (see Protocol Appendix 2).  At any time during the study, subjects with a confirmed 
blood bicarbonate level < 12 mEq/L will be evaluated by the Investigator for new acute acidotic 
processes and discussed with the Medical Monitor.  During the 12-week Treatment Period, 
subjects will attend eight study visits (Day 1, Weeks 1, 2, 4, 6, 8, 10, and 12) for efficacy and 
safety assessments (See Table 1 for details).   
Follow-up Period: Subjects who complete the Treatment Period will be offered participation in a 
40-week extension study (Study TRCA-301E).  Subjects who are not willing to participate in the 
extension study or who are not eligible for it will enter the 2-week Follow-up Period of Study 
TRCA-301, which consists of Follow-up 1 Visit (Week 13) and Follow-up 2 Visit (Week 14), for 
adverse event (AE) collection, fasting blood draws and safety assessments (See Table 1 for 
details).   
The maximum duration of Study TRCA-301 is anticipated to be 14 weeks per subject for those 
who continue into the TRCA-301E extension study (i.e., up to 2-week Screening Period and 12-
week Treatment Period).  For subjects who do not participate in the TRCA-301E extension study, 
the maximum duration of Study TRCA-301 is anticipated to be 16 weeks (i.e., up to 2-week 
Screening Period, 12-week Treatment Period and 2-week Follow-up Period).  Assessments and 
procedures for evaluation of efficacy and safety will be conducted per the protocol-specified 
schedule (see Table 1 for details). 
 


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SAP TRCA-301 Final Version 2.0 
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Table 1 Study TRCA-301 Protocol Schedule of Events 
Study Activity 
Period 
Screening 
Treatment 
Follow-up 
 
UNS 
Visit [v] 
Visit Name 
S1 
S2 
D1 
W1 
W2 
W4 
W6 
W8 
W10 
W12 [a] 
F1 
F2 
 
Timing 
Week 
-2 [b] 
Week 
-1 [c] 
Day  
1 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week  
12 
Week  
13 
Week 
14 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject ID Number Assignment in IRT  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medications [d] 
X 
X 
X [t] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs [e]  
X 
X 
X [t] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body Weight and Height [f]  
X [f] 
 
X [t] 
 
 
X 
 
X 
 
X 
 
X 
 
 
Physical Exam [g] 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Repeated Chair Stand Test 
 
X [u] 
X 
 
 
 
 
 
 
X 
 
 
 
 
KDQOL  
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
ECG [h] 
 
X [t] 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Fasting i-STAT Bicarbonate [i] 
L 
L 
L [t] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Fasting Blood Bicarbonate (Enzymatic 
Serum or Venous Blood Gas Assay) [j] 
L 
L 
L [t] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Coagulation [k] 
L 
 
L [t] 
L 
L 
L 
L 
L 
L 
L 
L 
L 
 
L 
Fasting Serum Chemistry 
C 
C [l] 
C [t] 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
C 
Hematology 
C 
 
C [t] 
 
 
 
C 
 
 
C 
 
C 
 
 
Hemoglobin A1c 
C 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test [m] 
C 
 
L [t] 
 
 
 
C 
 
 
C 
 
 
 
 
Biomarkers (Blood and Urine) [n] 
 
 
C [t] 
 
 
 
 
 
 
C 
 
 
 
 
Urinalysis and Spot Urine Tests  
C 
 
C [t] 
 
 
 
C 
 
 
C 
 
C 
 
 
Training on 24-Hour Urine Collection 
and Dispensing Supplies  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
24-Hour Urine Collection [o] 
 
 
C [t] 
 
 
 
 
 
 
C 
 
 
 
 
Randomization in IRT 
 
 
X [t] 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of Study Drug and Dosing 
Diary [p, q, r, s] 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Onsite Study Drug Dosing [q] 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing Compliance and 
Accountability [r, s] 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse Event Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dietary Counseling 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Notes:  (1)  All blood draws for bicarbonate measurements must be done with subjects in a fasted state (at least 4 hours, except water).  (2) Weekly visits should be targeted to occur 
on the same day of the week as Day 1 (e.g., always on Wednesday).  Allowed visit windows are ± 1 day for all study visits during the Treatment and Follow-up Periods. 


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Abbreviations: C = central laboratory assessment; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ET = early termination; HbA1c = hemoglobin A1c; ID = 
identification; IRT = interactive response technology; KDQOL = kidney disease quality of life; L = local laboratory assessment; UNS = unscheduled. 
a  
Subjects who terminate the study early are required to undergo an Early Termination Visit with all Week 12 Visit procedures to be performed. 
b  
Screening 1 Visit must occur within 2 weeks of Baseline Visit. 
c  
Screening 1 and Screening 2 Visits must occur at least 5 days apart. 
d  
At Screening 1 Visit, record all prescription and non-prescription medications and nutritional supplements taken within 28 days. 
e  
Vital signs include:  blood pressure and respiratory rate (both in triplicate, measurements taken approximately 2 minutes apart at Screening 1, Screening 2, and Week 12 
Visits; once at all other time points), heart rate, and temperature. 
f  
Height will only be collected at the Screening 1 Visit. 
g  
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). 
h  
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.  
i  
The i-STAT G3+ cartridge must be used and measurement taken from a whole blood sample within 10 min of the blood draw.   
j  
Either enzymatic or venous blood gas assay but consistent for each subject as soon as possible in accordance with local laboratory requirements.  
 
k  
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. 
l  
If necessary, at the Screening 2 Visit, eGFR may be assessed based on local serum creatinine measurement to confirm eligibility. 
m  
For women of childbearing potential, blood samples will be collected for serum pregnancy tests at the Screening 1, Week 6, and Week 12 Visits, and a urine sample will 
be collected for a urine dipstick pregnancy test at the Baseline Visit. 
n  
Blood and urine samples will be collected and stored under frozen conditions as specified in the laboratory manual. 
o  
Instruct subjects on collecting 24-hour urine samples prior to Baseline and Week 12 Visits 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 Baseline and Week 12 Visits.  
p  
Dispense study drug per IRT instructions and provide the dosing diary.  Instruct subject to take study drug with lunch, at least 4 hours apart from all oral concomitant 
medications.   
q  
Administer the first dose of study drug on the morning of Day 1, with a snack, while the subject is at the site. 
r  
Instruct the subject to bring the dosing diary to each visit.  Review dosing diary vs. study drug supplies and assess dosing compliance.  Record dosing diary information 
at each visit in eCRF.  Collect the dosing diary at the Week 12 or at the ET Visit. 
s  
Instruct subject to bring all used and unused study drug to each visit.  Collect all used and unused study drug at the Week 12 Visit or at the ET Visit. 
t  
Procedure to be performed prior to administration of the first dose of study drug. 
u  
Train the subjects on repeated chair stand test at the Screening 2 Visit.  No eCRF data will be collected. 
 
v  
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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7.2 
Randomization and Blinding 
Eligible subjects will be randomized in a 4:3 ratio to receive TRC101 or placebo, stratified by their 
baseline blood bicarbonate value (≤18 versus >18 mEq/L) and screening eGFR value (<30 versus 
≥30 mL/min/1.73m2): 
• 6 g TRC101 administered QD for 12 weeks (n≈120) 
• placebo administered QD for 12 weeks (n≈90)  
At least half of the subjects enrolled in the study will have a baseline blood bicarbonate value of 
12 to 18 mEq/L.   
In this study, 
 
 each study site must have an unblinded Pharmacist 
or designated unblinded study staff member (the “Pharmacist”) for handling (dispensation and 
collection) of the study drug.  These individuals will be responsible for dispensing study drug 
(including supervision of administration of the first dose of study drug) and collecting used and 
unused study drug containers and dosing diaries.  If study drug dose needs to be adjusted or 
interrupted per the titration algorithm (see TRCA-301 protocol, Appendix 2), such adjustments 
will be performed in a blinded manner in both active and placebo treatment groups.  The designated 
unblinded study staff member(s) 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 the electronic case report forms (eCRFs).  The 
subjects, Investigators, Medical Monitors, Tricida, site personnel (including all those involved in 
collection of safety information) and CRO staff (except for those responsible for monitoring of 
unblinded data) will remain blinded to the subject’s treatment assignment throughout the study 
until after the database is locked and access to the randomized treatment codes has been authorized.  
The DMC members and the statisticians responsible for reporting to the DMC will be unblinded 
during the study. 
The Pharmacist must not inform the subjects, Investigators, Medical Monitors, Tricida, or other 
site or CRO personnel about the subjects’ treatment assignment.  In case of a medical emergency, 


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the Investigator may obtain the treatment assignment for the subject from the interactive response 
technology (IRT) system if such information is considered important to the management of a 
medical 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.  
Additional details on study blinding are described in the Blinding Plan. 
7.3 
Assessments 
Table 1 shows the schedule of events of the study.   
 
Efficacy Measurements 
Fasting blood bicarbonate levels measured onsite with an i-STAT point-of-care device will be used 
to determine the primary and secondary efficacy endpoints for this study.  Exploratory efficacy 
measurements include: repeated chair stand test, and kidney disease quality of life questionnaire 
(KDQOL) Question 3.  Other efficacy measurements include blood and urine biomarkers related 
to bone and kidney health. 
 
Safety Measurements 
Safety will be assessed by repeated clinical evaluation, including adverse events, serious adverse 
events (SAEs), vital signs, physical examination, 12-lead electrocardiograms (ECGs), and clinical 
laboratory tests (chemistry, hematology, coagulation, and urinalysis) from central laboratories. 
 
Other Measurements 
Spot urine will be used to evaluate urine electrolytes. 24-hour urine collections will be used to 
characterize albumin, sulfate, uric acid and urea nitrogen excretion. 
8 
SAMPLE SIZE AND POWER 
8.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is 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 12 Visit).  This outcome is termed a “response”. 


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The sample size in this study is based on the efficacy results observed in the Phase 1/2 Study 
TRCA-101.  The table below shows 46% of TRC101-treated subjects and 3% of placebo-treated 
subjects had an increase of ≥4 mEq/L or had blood bicarbonate in the normal range (22 to 
29 mEq/L) after 2 weeks of treatment.  We assume the full TRC101 treatment effect had not been 
reached during the short (2-week) treatment period.   
Results from Study TRCA-101 
Blood Bicarbonate (mEq/L) 
Pooled TRC101 
(n=104) 
Pooled Placebo 
(n=31) 
Number (%) of Subjects at Week 2 (Day 15) 
 
 
CFB ≥4 
41 (39.4%) 
1 (3.2%) 
Normal (22 - 29) 
37 (35.6%) 
0 
Composite (CFB ≥4 or Normal) 
48 (46.2%) 
1 (3.2%) 
95% Exact CI of Composite 
36.3%, 56.2% 
<0.1%, 16.7% 
CFB = Change from baseline; CI = confidence interval. 
 
In Study TRCA-301, we expect that 50 to 55% of TRC101-treated and 10% of placebo-treated 
subjects will have an increase of ≥4 mEq/L or have blood bicarbonate in the normal range at the 
end of treatment (Week 12 Visit).  A Fisher's exact test with a 0.05 two-sided significance level 
will have over 99% power to detect this difference if the study has 90 placebo and 120 TRC101 
subjects.  If the true proportion of TRC101 subjects who respond at the Week 12 Visit is indeed 
between 50% and 55% and if no more than 5% of subjects have missing data at Week 12, the study 
will have roughly 90% power to result in a 95% confidence limit with a lower bound of at least 
35% and 40%, respectively. 
8.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is change from baseline in blood bicarbonate at the end of 
treatment (Week 12 Visit). 
In the Phase 1/2 Study TRCA-101 after 2 weeks of treatment, we observed the following with 
regard to the change from baseline in blood bicarbonate level: 


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Results from Study TRCA-101 
 
TRC101 
Placebo 
Mean CFB at Week 1 (Day 8) 
2.3 
0.83 
Mean CFB at Week 2 (Day 15) 
3.3 
-0.18 
Common SD 
2.5 
Treatment × Time effect 
P = 0.2248 
Baseline blood bicarbonate (Covariate) 
P <0.0001 
Correlation between Week 1 and Week 2 
0.667 
0.333 
CFB = change from baseline; SD = standard deviation 
 
In Study TRCA-301, we expect to observe the following mean change from baseline in blood 
bicarbonate over time for each group, with between group variance of 1.871, between time point 
variance of 0.08, and time point × treatment variance of 0.23. 
 
Time Point 
Treatment 
Week 1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Placebo 
0.85 
0.75 
0.65 
0.55 
0.45 
0.35 
0.25 
TRC101 
2.00 
2.50 
3.00 
3.50 
3.75 
4.00 
4.25 
 
We assume a constant standard deviation to be 3.0 mEq/L and correlation as shown in the table 
below: 
 
Week 1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 1 
1 
0.6 
0.399 
0.265 
0.176 
0.117 
0.078 
Week 2 
0.6 
1 
0.6 
0.399 
0.265 
0.176 
0.117 
Week 4 
0.399 
0.6 
1 
0.6 
0.399 
0.265 
0.176 
Week 6 
0.265 
0.399 
0.6 
1 
0.6 
0.399 
0.265 
Week 8 
0.176 
0.265 
0.399 
0.6 
1 
0.6 
0.399 
Week 10 
0.117 
0.176 
0.265 
0.399 
0.6 
1 
0.6 
Week 12 
0.078 
0.117 
0.176 
0.265 
0.399 
0.6 
1 
 
We calculated power and sample size for the mixed-effect repeated measures (MMRM) model 
based on (nQuery Advisor software) a univariate two-group repeated measures analysis of 
variance using the Greenhouse-Geisser correction to nominal degrees of freedom.  This study will 
have 99% power to detect a variance among the group marginal means of 1.871 mEq/L, will have 
85% power to detect a variance of 0.08 among the means of the 7 time points (i.e., Weeks 1, 2, 4, 
6, 8, 10, and 12), and will have 99% power to detect an interaction between groups and time points 
with a variance of 0.23, assuming that the between groups error term is 5.32, the within groups 


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error term is 2.4, the measure of "sphericity" of the covariance matrix, epsilon, is 0.69, (its estimate, 
the Greenhouse-Geisser correction, has an expected bias of about g1/(2n-2) where g1 is -2.38) 
when the significance level is 0.05 and the sample size in each of the two groups is 104 subjects 
(approximation to 90 placebo and 120 TRC101 subjects, respectively). 
9 
ANALYSIS SETS 
9.1 
Modified Intent-To-Treat 
The modified intent-to-treat (MITT) analysis set is defined as all randomized subjects who had 
both baseline and at least one post-baseline blood bicarbonate value measured using the i-STAT 
device.  The MITT analysis set will be used for evaluation of efficacy, based on planned treatment 
assignment. 
9.2 
Per-Protocol 
The per-protocol (PP) analysis set is defined as MITT subjects, who completed the 12-week 
treatment period without important protocol deviations (See Section 12.2) and with ≥80% study 
drug dosing compliance.  The PP analysis set, which will be based on the planned treatment 
assignment, will be used for evaluation of efficacy. 
9.3 
Safety Analysis Set 
The safety analysis set is defined as all subjects who received any amount of study drug (TRC101 
or placebo).  The safety analysis set, which will be based on the actual treatment received, will be 
used for evaluation of safety.  Placebo-treated subjects who received any amount of TRC101 
during the treatment period will be assigned to the TRC101 treatment group from the time when 
TRC101 was received. 
10 GENERAL CONSIDERATIONS 
The analysis sets as defined in Section 9 will be used for efficacy and safety analyses.  Subject 
listings of all analysis data that support summary tables and/or figures will be provided along with 
their source data from the eCRFs.  Measurements from subjects excluded from the pre-defined 
analysis sets or extra measurements (such as unscheduled or repeat assessments) will not be 
included in summary tables unless specified otherwise but will be included in the subject listings.  


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In general, subject listings will be sorted by treatment group, subject number, assessment date 
(time, and parameter, as applicable).   
For most summary statistics, data will be analyzed and displayed by treatment group.  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, minimum and 
maximum.  The same number of decimal places as in the observed value will be presented when 
reporting minimum and maximum; 1 more decimal place than in the observed value will be 
presented when reporting mean and median; and 2 more decimal places than in the observed 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 1 decimal place, 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. 
Results of statistical analyses will be reported using summary tables, listings, and figures (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. 
All analyses and summaries will be produced using SAS® version 9.4 or higher. 
Note that while the SAP predominantly uses the term ‘blood bicarbonate’ the TLFs will use ‘serum 
bicarbonate’. 


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10.1 Definitions and Derived Variables 
 
Age 
Age (years) will be calculated as the number of years between date of birth and date of informed 
consent, expressed as an integer. 
 
Study Day 
Study Day, which follows the CDISC SDTM standard, is defined as (Assessment date – date of 
first study drug dosing) + 1, where the assessment date is on or after the date of first study drug 
dosing; (Assessment date – date of first study drug dosing), where the assessment date is before 
the date of first study drug dosing.   
 
Estimated Glomerular Filtration Rate 
eGFR data will be used in data analysis.  The eGFR value will be calculated using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) formula from both serum creatinine and 
serum cystatin C that will be reported from the central laboratory.  The primary analysis for change 
in eGFR will be based on serum creatinine.  Because of the potential for changes in muscle mass 
related to bicarbonate correction, eGFR calculated from serum cystatin C levels will be evaluated 
at baseline and Week 12.  
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] 
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). 


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Multiple Records at a Time Point 
For analysis purposes, the mean value of multiple measurements collected at the same position 
(i.e., supine, standing, etc.) on the same visit day will be summarized for the corresponding 
protocol defined time point.  All collected measurements and the mean values will be listed. 
 
Baseline Values  
Baseline values for all efficacy and safety variables are defined as the last non-missing assessment 
prior to the first dose of study drug, unless otherwise specified.   
 
Baseline Blood Bicarbonate Value Using i-STAT 
Blood bicarbonate values are measured onsite using an i-STAT point-of-care device.  Baseline 
blood bicarbonate is defined as the average of the values of blood bicarbonate collected at the 
Screening 1 Visit, Screening 2 Visit, and Baseline Visit (i.e., Day 1 pre-dose).   
 
Baseline Blood Bicarbonate Subgroups 
For exploratory efficacy analysis, subjects will be classified according to their baseline blood 
bicarbonate stratum (≤ 18 mEq/L or >18 mEq/L). 
 
Screening and Baseline eGFR Value 
The Screening eGFR value is defined as the average of the values of eGFR used to determine 
eligibility and calculated from the serum creatinine at the Screening 1 and Screening 2 Visits using 
the CKD-EPI formula.  The creatinine measurements used for determining eligibility may have 
been analyzed at the central or local laboratory.  This Screening eGFR value will be used for the 
randomization strata.   
The Baseline eGFR value is defined as the average of values of eGFR collected at the Screening 
1 Visit, Screening 2 Visit, and Baseline Visit (i.e., Day 1 pre-dose), based on serum creatinine 
measured by the central laboratory.  This value will be used for derivation of change from baseline 
and will serve as a covariate in statistical models. 
 
Screening eGFR Subgroups 
For exploratory efficacy analysis and/or safety analysis, subjects will be classified according to 
their Screening eGFR stratum.  The Screening eGFR subgroups are:  


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• <30 mL/min/1.73m2 
• ≥30 mL/min/1.73m2 
 
Baseline Blood pH and Base Excess Values Using i-STAT 
Blood pH and base excess are measured onsite using an i-STAT point-of-care device.  The 
baseline value of each of these two parameters is defined as the average of the measurements 
collected at the Screening 1 Visit, Screening 2 Visit, and Baseline Visit (i.e., Day 1 pre-dose). 
 
24-hour Urine Excretion of Uric Acid, Sulfate, Creatinine, Albumin, and Urea 
Nitrogen 
If timed urine was collected for more or less than 24 hours, the daily excretion will be 
normalized and reported as weight unit of the analyte during a 24-hour period.  
 
24-hour Creatinine Clearance 
The 24-hour creatinine clearance (mL/min) will be calculated as (urine concentration of 
creatinine in mg/dL × urine volume over 24 hours in mL)/(serum creatinine in mg/dL × 1440). 
 
Baseline Electrocardiogram Parameters 
12-lead ECG parameters will be collected in triplicate on Day 1 pre-dose.  The average of the 
ECG intervals and heart rate measurements will be used as baseline.  Screening values will be 
used as baseline for subjects who did not have any ECG measurements on Day 1 pre-dose. 
 
Treatment-Emergent Adverse Events  
Treatment-emergent adverse events (TEAEs) are defined as all AEs that begin on or after the time 
of the first dose of study drug (also see Section 11.4.1).  Related AEs are those reported by 
investigators as possibly related, probably related, or related to study drug.   
 
Concomitant Medications and Concurrent Procedures 
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 study drug administration.  Concomitant 
medications are defined as all prescription and over-the-counter medications that are used 
concurrently (from Day 1 to Week 14).  A prior medication can also be a concomitant medication 
if it continued after the first dose of study drug.  


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Alkali Therapy 
Oral alkali therapies are medications containing active ingredients of sodium bicarbonate, 
potassium bicarbonate, potassium citrate, or sodium citrate.  Baseline alkali therapies are those 
medications that were used at the start of study treatment. 
10.2 Analysis Windows 
Clinical 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 (See Section 10.1.2).  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 
protocol-scheduled time point (or target Study Day).  Analysis visit windows are presented in 
Table 2 by type of assessments and/or measurements.   
Table 2 Analysis Visit Windows 
Protocol 
Scheduled 
Time Point 
Target 
Study 
Day 
Analysis Visit Windows (Study Day) 
All Other 
Assessments 
Hematology 
Urinalysis 
Spot Urine 
Pregnancy 
Tests 
Repeated Chair 
Stand 
KDQOL 
Biomarkers 
24-Hour Urine 
Collection 
ECG 
Body 
Weight 
Screening 1 
-14 
≤ -8* 
≤ -8* 
- 
- 
- 
Screening 2 
-1 
-7 to -1* 
- 
- 
- 
- 
Day 1 
1 
1* 
-7 to 1* 
-14 to 1* 
-14 to 1* 
≤ 1* 
Week 1 
8 
2 to 11 
- 
- 
- 
- 
Week 2 
15 
12 to 22 
- 
- 
2 to 28 
- 
Week 4 
29 
23 to 36 
- 
- 
- 
2 to 42 
Week 6 
43 
37 to 50 
2 to 63 
- 
29 to 63 
- 
Week 8 
57 
51 to 64 
- 
- 
- 
43 to 70 
Week 10 
71 
65 to 78 
- 
- 
- 
- 
Week 12 
85 
79 to 90 
64 to 91 
≥2 
64 to 91 
71 to 91 
Week 13 
92 
91 to 97 
- 
- 
- 
- 
Week 14 
99 
≥98 
≥92 
- 
≥92 
≥92 
* Use visit designation for scheduled visits; otherwise use the visit window.  


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11 STATISTICAL AND ANALYSIS ISSUES 
11.1 Adjustments for Covariates 
The baseline blood bicarbonate and baseline eGFR, as continuous covariates, will be included in 
an MMRM model for analysis of change from baseline in blood bicarbonate.  Other baseline values 
of continuous efficacy variables will be included in MMRM models (see Section 14.4.2) or 
analysis of covariance (ANCOVA) models (see Section 14.7) as covariates.   
Two stratification variables, Baseline blood bicarbonate (≤18 versus >18 mEq/L) and Screening 
eGFR (<30 versus ≥30 mL/min/1.73m2), are utilized in the randomization.  They will be used as 
subgroups (see Section 11.10) to evaluate primary and secondary efficacy variables.  Other 
baseline characteristics, such as age, sex, race, baseline alkali therapy, and geographic region, may 
also be used as subgroups (see Section 11.10). 
11.2 Handling Dropouts or Missing Data 
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 11 (e.g., have assessments through Week 11) would 
have their early termination assessments mapped to the next scheduled visit (i.e. Week 12) based 
on the analysis window (See Section 10.2).   
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 “possibly related”, for analysis purposes.  In the subject listing, both collected and 
imputed values will be presented. 
11.3 Handling of Efficacy Data 
The primary analysis will not impute missing (blood bicarbonate) data.  For the primary analysis, 
missing data in both placebo and TRC101 will be assumed to be missing at random (MAR).  
Subject withdrawal patterns in the placebo and TRC101 groups will be assessed.  Sensitivity 
analyses for the primary and secondary efficacy endpoints (Section 14.5) will use multiple 
imputation models assuming the data are missing not at random (MNAR). 


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11.4 Handling of Safety Data 
 
Adverse Events 
All AE verbatim terms reported on the eCRFs 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.  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 Day 0 or Study Day 1. 
• Day and month are missing and the year is equal to or after the year of the first date of 
study drug dosing;  
• Day is missing and the year is after the year of the first date of study drug dosing;  
• 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 
• Year is missing. 
Related AEs are those with relationship to study drug reported as “possible”, “probable” or 
“related”.   
 
Concomitant Medications 
All medication verbatim terms reported on the eCRFs will be mapped according to the World 
Health Organization (WHO) Drug Dictionary (WHO DD Enhanced version, March 1st, 2017, B2 
format).  The medications will be mapped to Anatomical/Therapeutic/Chemical (ATC) class and 
preferred names.  A prior medication is considered to be any medication that is taken prior to the 
first study drug dosing.  A concomitant medication is considered to be any medication taken after 
the start of study drug dosing.  Specifically, concomitant medications are medications: 
• that are continued from Screening and continued after the first study drug dosing,  
• with start dates or stop dates within the Treatment Period 
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 concomitant medication 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 


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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.  
During the study, alkali dose will be monitored; the protocol specifies that the dose of oral alkali, 
if any, should not change during the study.  Any change in equivalent dose during the study when 
the type of alkali has changed (e.g. sodium citrate to sodium bicarbonate) will be identified. 
11.5 Interim Analyses and Data Monitoring 
There will be no interim analyses of efficacy.  Safety data monitoring is described in Section 15.9. 
11.6 Multicenter Considerations 
Thirty-seven (37) study centers in Europe and the United States randomized at least 1 subject in 
the study as follows:  European Union (EU) countries (8 sites with 82 subjects); Non-EU countries 
(17 sites with 108 subjects); and the United States (12 sites with 27 subjects).  Data from all study 
centers will be pooled for efficacy and safety analyses as well as for summaries.  Because the 
number of subjects at each center is likely to be small, no analyses will be performed by center.  
Geographic region (i.e., EU, Non-EU, and US), in which study sites in certain geographic locations 
will be pooled together, will be used for subgroup analyses.  The table below lists these study 
centers with their site identification number, country and geographic region category. 
Table 3 Country Code and Geographic Region Category 
Site 
Identification 
Number 
Country 
Code 
Country Name 
Geographic 
Region 
11 
BGR 
Bulgaria 
EU 
21 
HRV 
Croatia 
EU 
41 
HUN 
Hungary 
EU 
44 
HUN 
Hungary 
EU 
46 
HUN 
Hungary 
EU 
49 
HUN 
Hungary 
EU 
71 
SVN 
Slovenia 
EU 
72 
SVN 
Slovenia 
EU 
31 
GEO 
Georgia 
Non-EU 
32 
GEO 
Georgia 
Non-EU 
33 
GEO 
Georgia 
Non-EU 


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Table 3 Country Code and Geographic Region Category 
Site 
Identification 
Number 
Country 
Code 
Country Name 
Geographic 
Region 
34 
GEO 
Georgia 
Non-EU 
35 
GEO 
Georgia 
Non-EU 
36 
GEO 
Georgia 
Non-EU 
37 
GEO 
Georgia 
Non-EU 
61 
SRB 
Serbia 
Non-EU 
64 
SRB 
Serbia 
Non-EU 
65 
SRB 
Serbia 
Non-EU 
81 
UKR 
Ukraine 
Non-EU 
83 
UKR 
Ukraine 
Non-EU 
84 
UKR 
Ukraine 
Non-EU 
85 
UKR 
Ukraine 
Non-EU 
86 
UKR 
Ukraine 
Non-EU 
87 
UKR 
Ukraine 
Non-EU 
88 
UKR 
Ukraine 
Non-EU 
52 
USA 
United States 
USA 
53 
USA 
United States 
USA 
54 
USA 
United States 
USA 
55 
USA 
United States 
USA 
56 
USA 
United States 
USA 
57 
USA 
United States 
USA 
58 
USA 
United States 
USA 
59 
USA 
United States 
USA 
91 
USA 
United States 
USA 
92 
USA 
United States 
USA 
93 
USA 
United States 
USA 
95 
USA 
United States 
USA 
 
11.7 Multiple Comparisons, Multiplicity 
In order to control family-wise error rate, formal statistical testing for the primary and secondary 
endpoints will be performed sequentially.  At the Week 12 Visit, a formal comparison between the 
TRC101 and the placebo groups will be performed using Fisher’s exact test for the proportion of 
subjects having a CFB in blood bicarbonate ≥4 mEq/L or having blood bicarbonate in the normal 
range.  Only when this comparison is statistically significant at the two-sided 0.05 level, will a 


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formal test for the secondary efficacy endpoint (CFB in blood bicarbonate at the Week 12 Visit) 
be performed.  A MMRM model will be used to compare the group least squares (LS) means of 
change in blood bicarbonate at Week 12.     
11.8 Use of an “Efficacy Subset” of Subjects 
All efficacy analyses will be performed using the MITT analysis set, based on the assigned 
treatment group.  In addition, the primary and secondary efficacy analyses will use the PP analysis 
set as a supportive evaluation of efficacy of TRC101.   
11.9 Active-Control Studies 
The placebo group will serve as a comparator in this study. 
11.10 Examination of Subgroups 
Subjects will be categorized into the following subgroups for the purposes of exploring primary 
and secondary efficacy endpoints.  These subgroups may also be used for safety evaluations.  
Forest plots will be generated to display the primary and secondary results from the above 
subgroups, along with the overall results. 
• Baseline blood 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 (EU, Non-EU, US) 
• Dose titration status during the study (no titration, any up-titration, any down-titration)  
 
12 STUDY PATIENTS 
12.1 Subject Disposition 
Enrollment and disposition will be summarized by treatment group and overall for all randomized 
subjects.  All enrolled subjects are defined as those who signed the informed consent form.  The 
subject disposition summary will include: 


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• Number of randomized subjects 
• Number of subjects randomized but not dosed 
• Number of subjects in the MITT analysis set 
• Number of subjects in the safety analysis set 
• Number of subjects in the PP analysis set 
• Number of subjects who completed the 12-week treatment period 
• Number of subjects who completed the study (i.e., completed the Week 14 visit or rolled 
over to Study TRCA-301E) 
• Number of subjects who prematurely discontinued from the study 
o The primary reason for withdrawal from the study 
• Number of subjects who entered in Study TRCA-301E  
A listing of disposition will be provided for all enrolled subjects.  Subjects who are excluded from 
MITT or PP analysis sets will be listed, along with reasons for the exclusions.   
12.2 Protocol Deviations 
Protocol deviations will be classified by deviation type (i.e., important) and category (e.g., 
eligibility criteria, out of window visit, SAE reporting, missed or out of window procedures, etc.).  
All deviations will be identified prior to database lock and important deviations will be presented 
in listing(s).  Important protocol deviations (referred to in the protocol as “major protocol 
deviations”) are defined per ICH guidance.  Important deviations will be summarized by deviation 
category and treatment group.  Important protocol deviations will be defined for this study prior 
to database lock and are described in detail in the Protocol Deviation Adjudication Memo.  
Protocol deviation categories include: 
• Investigational product  
• Informed consent  
• Key eligibility criteria  
• Other eligibility criteria  
• SAE reporting  
• Out of window procedure 
• Procedure - missed or not interpretable  
• Out of window visit 
• Missed visit 


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• Restricted medications  
• Randomization  
• Stratification  
• Blinding  
• Other 
12.3 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for all randomized subjects.  
Demographic characteristics will include age, age group (< 65 or ≥ 65 years), sex, race, and 
ethnicity.  The following baseline characteristics will be summarized: baseline alkali use (Yes or 
No), geographic region, baseline weight, height, body mass index (BMI), baseline systolic blood 
pressure (SBP) and baseline SBP group (≤ 135 or > 135 mmHg).  In addition, the following 
selected baseline laboratory test results will be summarized: Screening eGFR, Screening eGFR 
group (< 30 or ≥ 30 mL/min/1.73m2), baseline eGFR, baseline blood bicarbonate, baseline blood 
bicarbonate group (≤ 18 or > 18 mEq/L), baseline serum potassium, baseline urine albumin to 
creatinine (ACR) ratio, baseline urine ACR group (< 30 mg/g; or ≥ 30 mg/g and ≤ 300 mg/g; or 
> 300 mg/g), baseline serum albumin, baseline serum phosphate, and baseline serum calcium.  
Furthermore, baseline 5-year and 2-year kidney failure risk (%) will be calculated using the 8-
variable kidney failure risk prediction equation (Tangri, et al. JAMA. 2011;305(15):1553-1559).  
All of the above information will be listed by subject in the following categories: demographic 
information, baseline characteristics, and selected baseline laboratory test results.  A listing will 
compare the randomization stratification variables in the IRT system with the Screening eGFR 
group (< 30 or ≥ 30 mL/min/1.73m2) and Baseline blood bicarbonate group (≤ 18 or > 18 mEq/L). 
12.4 Medical History 
Medical history will be mapped to preferred terms and system organ classes using the Medical 
Dictionary for Regulatory Activities (MedDRA®) Dictionary (version 20.0).  Selected medical 
history items (by preferred term), CKD etiology, and selected recurrent signs and symptoms will 
be summarized by treatment group.  Medical history, selected medical history terms, and kidney 


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disease history (primary cause and recurring signs and symptoms) will be summarized for all 
randomized subjects and listed by treatment group and subject identification number.   
13 STUDY DRUG AND OTHER MEDICATIONS 
13.1 Prior and Concomitant Medications 
Prior and concomitant medications (see definition in Section 11.4.2) will be summarized 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 incidence of ATC class and preferred name within each ATC class.  
13.2 Restricted Medications 
The concomitant use of restricted medications as defined in the Study TRCA-301 protocol, Section 
5.9 Table 1 will be summarized and listed separately, using the same dictionary mapping as 
described above or based on manual medical review.  Number (%) of subjects who used new or 
changed dose of oral alkali and calcium supplements will be summarized.  Summary of certain 
new/dose changed antihypertensive medications given systemically (i.e., diuretics and renin-
angiotensin-aldosterone system [RAAS] inhibitors, such as angiotensin-converting enzyme [ACE] 
inhibitors, angiotensin II receptor blockers [ARBs], aldosterone antagonists [AAs], renin 
inhibitors, mineralocorticoid receptor antagonists [MRAs], β-blockers, calcium channel blockers, 
alpha-adrenergic antagonists drugs, and direct vasodilators) regardless of stated indication will 
also be provided. Calcium supplements are defined as orally administered calcium carbonate, 
calcium acetate, calcium citrate, and other calcium salts taken for any indication. 
13.3 Exposure to Study Drug, Study Treatment Compliance, and Dose Titration 
Summaries will include the total number of packets dispensed, total number of packets consumed, 
total dose (g) consumed, study drug compliance, and duration (days) of exposure during the study 
treatment period.   


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Total dose (g) consumed is derived as the sum of the assigned dose level (i.e., subjects assigned to 
the TRC101 treatment group consumed 3 g TRC101 per packet) for all empty packets returned. 
Study drug compliance (expressed in percentage) will be derived in the following way: 
• Using the drug accountability data, the compliance is defined as 100%×the total number 
of empty packets returned divided by the total number of packets dispensed.   
If a subject terminated from the study early and did not return packets, the packets dispensed at 
the last visit prior to termination will not be included in the calculations for study drug dosing or 
compliance. 
The duration of study drug exposure is defined as the number of days on treatment from the first 
dose of study drug until the last dose of study drug.  Study drug exposure will be summarized with 
descriptive statistics by treatment group.   
Furthermore, number (%) of subjects with and without dose titration of study drug and those with 
dose uptitration, dose downtitration, and dose interruption during the treatment period will be 
summarized by treatment group and overall using subject counts, percentages and the exact 95% 
CI of the percentages.  Number (%) of subjects who were dispensed a minimum and a maximum 
0, 1, 2 or 3 study drug packets per day over various time intervals will be summarized by treatment 
group.  Mean daily dose of study drug dispensed will also be summarized by treatment group and 
time interval.  Denominators for percentages will be based on the number of subjects who remained 
active in the study during each time interval of interest.   
The drug accountability information, including reasons or comments for incomplete or missed 
doses, will be listed in a patient listing.  Subject dosing diary information will also be listed. 
14 EFFICACY ANALYSES 
14.1 Efficacy Endpoints 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint is having a change from baseline in blood bicarbonate ≥ 4 mEq/L 
or having a blood bicarbonate level in the normal range (22 to 29 mEq/L) at the end of treatment 
(Week 12 Visit).  This outcome is termed “response”. 


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Secondary Efficacy Endpoint 
The secondary efficacy endpoint is CFB in blood bicarbonate at the end of treatment (Week 12 
Visit). 
 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints identified in the study protocol are: 
1. 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 12 Visit) 
2. CFB in repeated chair stand test duration at the end of treatment (Week 12 Visit) 
Additional exploratory efficacy endpoints (not specified in the study protocol) include: 
1. CFB in parathyroid hormone (PTH) 
2. CFB in serum pre-albumin 
3. CFB in 25-hydroxy-vitamin D 
4. CFB in urinary biomarkers of bone resorption:  
a. N-terminal telopeptide (NTX)  
b. C-terminal telopeptide (CTX)  
5. CFB in serum biomarkers of bone resorption: 
a. Tartrate-resistant acid phosphatase 5b (TRAP 5b)  
b. Bone-specific alkaline phosphatase (BSAP) 
c. Type 1 procollagen (P1NP)  
6. CFB in urine renal biomarkers: 
a. Urine angiotensinogen to creatinine ratio (UAGT)  
b. Urine aldosterone  
c. Uric acid 
d. Sulfate 
e. Urine endothelin-1 (ET-1) 
7. CFB in serum osteocalcin (biomarker of bone formation)  
If any biomarker samples have not been analyzed by the time of database lock, these assessments 
will be deferred and samples analyzed with those from the TRCA-301E study. 
14.2 Efficacy Variables 
 
Change from Baseline in Blood Bicarbonate 
Blood bicarbonate values will be measured onsite using an i-STAT point-of-care device.  Change 
from baseline in blood bicarbonate will be calculated as the measured value minus the baseline 


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value (see definition in Section 10.1.7) subsequent to the first dose of study drug.  In other words, 
a positive change will indicate an increase in blood bicarbonate relative to baseline.  
 
Categorical Change in Blood Bicarbonate 
Binary indicator variables will be used to identify the frequencies of increases in post-baseline 
blood bicarbonate levels at each time point.  The categories for the primary efficacy analysis are: 
• an increase in blood bicarbonate from baseline ≥ 4 mEq/L 
• blood bicarbonate value within 22 to 29 mEq/L 
As additional exploratory efficacy analyses, the following categories will be evaluated:  
• an increase in blood bicarbonate from baseline ≥2 mEq/L  
• an increase in blood bicarbonate from baseline ≥3 mEq/L  
• an increase in blood bicarbonate from baseline ≥5 mEq/L 
• an increase in blood bicarbonate from baseline ≥6 mEq/L 
• an increase in blood bicarbonate from baseline ≥7 mEq/L 
 
Additional Change from Baseline Variables 
As exploratory and other efficacy analyses, the following change from baseline variables will be 
calculated as the measured value minus the baseline value subsequent to the first dose of study 
drug.  They will be measured once at baseline and once post baseline. 
• CFB in the total score of the KDQOL Question 3 items (daily activities)  
• CFB in repeated chair stand test duration  
• CFB in parathyroid hormone 
• CFB in serum pre-albumin 
• CFB in 25-hydroxy-vitamin D 
• CFB in urinary biomarkers of bone resorption (NTX and CTX) 
• CFB in serum biomarkers of bone resorption (TRAP 5b, BSAP, and P1NP)  
• CFB in urine renal biomarkers (UAGT, aldosterone, and ET-1)  
• CFB in serum osteocalcin  
14.3 Primary Efficacy Analysis  
The primary analysis will be performed on the MITT analysis set, with the PP analysis set as 
supportive.   


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Reporting Results 
The number and proportions (expressed as percentages) of subjects who are responders at each 
time point and at the end of treatment will be calculated.  A responder is defined as a subject who 
has a change from baseline in blood bicarbonate ≥ 4 mEq/L or has 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 two-sided 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 by time 
point.  The exact 95% CIs will also be presented by treatment group and time point.     
 
Statistical Hypotheses 
The two hypothesis tests will be used to evaluate the primary efficacy endpoint:  
1. The null hypothesis is that there is no difference between treatment groups in proportion 
of subjects who are responders at Week 12.  The alternative hypothesis is that there is a 
difference between treatment groups in proportion at Week 12 
H0: πTRC101 – πplacebo = 0; 
H1: πTRC101 – πplacebo ≠ 0. 
2. The null hypothesis is that the proportion of TRC101 treated subjects who are responders 
at Week 12 is less than or equal to U (0.35 or 35%).  The alternative hypothesis is that the 
TRC101 proportion at Week 12 is greater than U. 
H0: πTRC101 ≤ U;  
H1: πTRC101 > U.  
 
Statistical Testing 
Statistical testing for the above hypotheses will be performed in the following sequence.  The first 
formal test for the difference (TRC101 – placebo) in proportion (≠ 0) will be conducted at the 
Week 12 Visit using the Fisher’s exact test.  With successful rejection of the null hypothesis #1 
(Section 14.3.2), the second formal test for TRC101 proportion ≤ 0.35 will be conducted at the 
Week 12 visit, using the two-sided 95% confidence lower limit.  If the lower limit of the 95% CI 
for TRC101 treated subjects is above U (0.35 or 35%), the null hypothesis #2 (Section 14.3.2) will 
be rejected.  


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14.4 Secondary Efficacy Analysis 
The secondary analysis will be performed on the MITT analysis set, with the PP analysis set as 
supportive.  All scheduled blood bicarbonate values collected through the Week 12 visit will 
contribute to the analysis.  The efficacy variable, the change from baseline in blood bicarbonate 
value, will be calculated for each time point after the first dose through the Week 12 visit (i.e., 
Weeks 1, 2, … , 12).  Missing data will not be imputed for the main analysis but will be imputed 
for the sensitivity analysis (Section 14.5).  The analysis will test the difference in LS means 
between TRC101 and placebo at Week 12.   
 
Statistical Hypothesis 
For the secondary efficacy endpoint (i.e., the CFB in blood bicarbonate at Week 12 comparing 
TRC101 with placebo), the null hypothesis is the two means of CFB in blood bicarbonate are equal 
(μ TRC101 = μ placebo).  The alternative hypothesis is the two means of CFB in blood bicarbonate are 
not equal (μ TRC101 ≠ μ placebo). 
 
Statistical Model 
The MMRM model will define the CFB in blood bicarbonate as the dependent variable, set 
treatment, time point, and treatment by time point interaction as fixed effects, subject as a random 
effect, and the baseline eGFR and baseline blood 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) 


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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 least squares (LS) mean of CFB in blood bicarbonate, standard error (SE) of the LS mean, 
two-sided 95% CI of the LS mean, and p-value from the mixed model will be reported by treatment 
group and time point.  The LS mean difference of the CFB in blood 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-value of the LS mean difference from the mixed model will 
be provided by time point.   
In addition, descriptive statistics for blood bicarbonate at baseline and at each scheduled post-
baseline time point, along with CFB in blood bicarbonate, will be summarized by treatment and 
time point.  Graphs will be produced to show:  
• LS mean ± 95% CI of change from baseline in blood bicarbonate (from the mixed model) 
by treatment group over time  
• Arithmetic mean ± SE of change from baseline in blood bicarbonate (from descriptive 
statistics) by treatment group over time 
• LS mean ± 95% CI of blood bicarbonate (from the mixed model) by treatment group over 
time  
• Arithmetic mean ± SE of blood bicarbonate (from descriptive statistics) by treatment 
group over time 
 
Statistical Testing 
Using the above described mixed model (Section 14.4.2), LS meanTRC101 = LS meanplacebo at the 
Week 12 Visit will be formally tested for statistical significance, only when the primary efficacy 
endpoint is statistically significant.  In order to maintain the family-wise error rate, a statistically 
significant TRC101 effect (LS mean difference >0) will be declared if the two-sided p-value at 
Week 12 is <0.05 and the primary efficacy endpoint is statistically significant. 


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14.5 Sensitivity Analyses for Primary and Secondary Efficacy Endpoints 
In order to evaluate the potential effect of missing data on the primary and secondary efficacy 
results, sensitivity analyses will be performed using multiple imputation models under a MNAR 
assumption for the MITT analysis set.  We will use a multiple imputation method with Copy 
Reference (CR) method using estimated means in the placebo group.  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, so does ignoring 
the missing data as the primary outcome.   
Multiple imputation inference involves the following three steps: 
1. The missing bicarbonate data are filled in m times to generate m complete datasets using 
SAS® PROC MI based on multiple imputation method CR.  We will set m to be 100. 
2. The analysis methods described in Sections 14.3.1 and 14.4.2 will be applied to the m 
completed datasets.   
3. The results from the m completed datasets are combined using SAS® PROC 
MIANALYZE for confirmatory of the primary and secondary efficacy analyses. 
 
14.6 Subgroup Analyses of the Primary and Secondary Efficacy Endpoints 
Subgroups defined in Section 11.10 will be used to explore the effect of the primary and secondary 
efficacy endpoints by intrinsic and extrinsic factors.  The subgroup analyses for the primary 
efficacy endpoint will be analyzed as described in Section 14.3.1.  The subgroup analyses for the 
secondary efficacy endpoint will be analyzed as described in Sections 14.4.2 and 14.4.3.  
14.7 Exploratory Efficacy Analyses - KDQOL and Repeated Chair Stand Test 
The exploratory efficacy variables, the total score of the KDQOL Question 3 items (daily 
activities) and the repeated chair stand test duration (time, in seconds, to complete five stands), 
will be collected at baseline and once at the Week 12 Visit or early termination; ANCOVA models 
will be used for the analyses.  The KDQOL Short Form (version 1.3) Question 3 individual item 
scores (i.e., item a-j) will be transformed as described in the KDQOL Short Form scoring manual 


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(Hays, 1997).  Scores of 1, 2, and 3 will be recoded to 0, 50, and 100, respectively.  The total score 
of the KDQOL Question 3 items is defined as the average of recoded item (i.e., item a-j) scores.  
The ANCOVA models will comprise the CFB value (i.e., total score of the KDQOL Question 3 
items [daily activities] or repeated chair stand test duration, accordingly) as the dependent variable; 
treatment group as a fixed effect; and the baseline value, the baseline eGFR, and baseline blood 
bicarbonate as continuous covariates.  The LS mean of CFB values, SE of the LS mean, two-sided 
95% CI of the LS mean, and p-value from the ANCOVA model will be reported by treatment 
group.  The LS mean difference of the CFB values 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-value of the LS mean difference will also be provided.   
Individual items of the KDQOL Question 3, the total score, and change from baseline in total score 
will be presented in a subject listing.  Repeated chair stand time to complete five stands, change 
from baseline in duration, reason for failed test, single chair stand result (with or without help, 
without or without using arm to stand) will be provided in subject listing. 
14.8 Other Efficacy Analyses 
 
Individual Components of the Primary Endpoint 
In addition to assessing the primary efficacy for subjects in MITT and PP analysis sets (Section 
14.3.1), we will also assess the components of the primary efficacy endpoint (1) having CFB in 
blood bicarbonate ≥4 mEq/L and (2) having a blood bicarbonate in the normal range (22 to 
29 mEq/L).  The proportion (expressed as percentages) of MITT subjects with a component at 
each time point and at the end of treatment will be reported as described in the previous Section 
14.3.1. 
 
Categorical Change in Blood Bicarbonate 
The proportions (expressed as percentages) of subjects with increases in their blood bicarbonate 
by ≥ 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, and ≥ 7 mEq/L at each time point and at the end of treatment will be 
reported as described in the Section 14.3.1 for MITT subjects.  


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Change from Baseline in Biomarkers at Week 12 
Efficacy variables, such as parathyroid hormone, serum pre-albumin, 25-hydroxy-vitamin D, 
urinary biomarkers of bone resorption (NTX and CTX), serum biomarkers of bone resorption 
(TRAP 5b, BSAP, and P1NP), urine renal biomarkers (aldosterone, uric acid, sulfate, and ET-1), 
and serum osteocalcin, all collected at baseline and once post baseline (at Week 12 Visit or early 
termination) will be analyzed using ANCOVA models similar to those described in Section 14.7, 
except for UAGT.  Aldosterone, uric acid, sulfate, CTX, NTX, endothelin-1, and angiotensinogen 
are measured in the 24-hour urine collection. 
For UAGT, geometric mean and 95% CI of the geometric mean, along with n, min and max, will 
be presented by treatment group and time point.  The ANCOVA models will comprise the natural 
logarithm of the post baseline UAGT value as the dependent variable; treatment group as a fixed 
effect; and the natural logarithm of baseline value, the baseline eGFR, and baseline blood 
bicarbonate as continuous covariates.  The geometric LS mean and two-sided 95% CI of the 
geometric LS mean from the ANCOVA model will be reported by treatment group.  The geometric 
LS mean ratio (TRC101/placebo), 95% CI of the geometric LS mean ratio, and the p-value will 
also be provided.  The geometric (LS) mean and its 95% CI will be obtained by exponentiating the 
(LS) mean and 95% CI on the natural log-scale. 
 
Subgroup Analysis of Change in i-STAT Blood Bicarbonate Over Time 
The treatment effect on i-STAT blood bicarbonate in subjects from different randomization strata 
(i.e., baseline blood bicarbonate ≤18 versus >18 mEq/L and screening eGFR <30 versus 
≥30 mL/min/1.73m2) and dose titration status (i.e., receiving only 2 packets throughout entire 
study, up-titrated to 3 packets at any time, and down-titrated to 1 or 0 packet at any time) will be 
evaluated. The blood bicarbonate values, as measured by an i-STAT point-of-care device, along 
with change from baseline values, will be summarized by treatment and time point for each stratum 
and each titration status.   


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15 SAFETY ANALYSES 
One of the study objectives is to assess the safety of TRC101.  Safety will be evaluated by adverse 
events, clinical laboratory test results, vital signs, body weight, ECG findings, and physical 
examination and by the incidence of blood bicarbonate values > 30 mEqL.  All analyses of the 
safety data will be performed using the safety analysis set, based on the actual treatment a subject 
received.  All descriptive statistics (described in Section 10) will be presented by treatment group 
in the safety analysis set. 
15.1 Safety Variables 
Safety variables include: 
1. AEs, SAEs and withdrawal of study drug due to AE 
2. Having met the high bicarbonate dose interruption criterion (confirmed > 30 mEq/L) at 
any time during the Treatment Period 
3. Laboratory test results 
4. Vital signs 
5. Body weight 
6. Findings from 12-lead ECG 
15.2 Adverse Events 
TEAEs are defined in Section 11.4.1.  All reported AEs (including non-TEAEs) will be listed.  All 
TEAE summary tables will present the number and percentages of subjects reporting TEAEs.  A 
summary of TEAEs by severity, seriousness, and relation to study drug will be tabulated.  In 
addition, TEAEs will be summarized by MedDRA system organ class and preferred term.  
Subjects can have more than one TEAE per system organ class and preferred term.  These 
summaries will include the following: 
• All TEAEs 
• TEAEs by worst severity 
• Study drug related TEAEs 
• Serious TEAEs 
• TEAEs leading to study drug discontinuation (if any) 
• Death (if any) 
 


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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 descending incidence of system organ class and preferred term within each system organ class, 
based on the Total column.  
15.3 Incidence of High Bicarbonate 
A summary table will be provided with number and percentage of subjects who had a 
bicarbonate > 30 mEq/L by time interval during the Treatment Period.  The table will also include 
total number of subjects and total number of occurrences during the Treatment Period. 
15.4 Clinical Laboratory Evaluation 
Clinical laboratory test results from central laboratories (serum chemistry, hematology, 
coagulation, spot urine, 24-hour urine and urinalysis) will be summarized using descriptive 
statistics at baseline and at each scheduled post-baseline time point, unless otherwise specified.  
Changes from baseline will also be summarized by time point.  Serum anion gap values from 
serum chemistry and urine anion gap from spot urine (Section 10.1.4) will be derived and 
summarized descriptively, in a similar way as collected laboratory results.   
For urine albumin to creatinine ratio (from spot urine), the geometric mean and 95% CI of the 
geometric mean, along with n, min and max, will be presented by treatment group and time point.  
At post baseline time point, geometric mean fold rise and 95% CI of geometric mean fold rise will 
also be presented.  The geometric mean and its 95% CI will be obtained by exponentiating the 
mean and 95% CI on the natural logarithm of urine albumin to creatinine ratio.  The geometric 
mean fold rise and its 95% CI will be obtained by exponentiating the mean and 95% CI on the 
difference in natural logarithm of urine albumin to creatinine ratio from baseline. 
Categorical display methods (e.g., frequencies, shift tables) for laboratory values over time may 
also be used, as appropriate.  The number and percentage of subjects with any out of range 
chemistry and hematology values (i.e., above upper limit of normal, below lower limit of normal, 


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above a pre-specified level or below a pre-specified level) will be summarized by time point.  
Tricida chose these pre-specified levels for laboratory tests because they are more appropriate for 
the study population than normal ranges for healthy subjects (See Table 4 below).   
Table 4 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, > 6.0 mEq/L 
Chemistry 
Blood bicarbonate 
< 10, < 12, > 30, > 32 mEq/L 
Chemistry 
Creatinine 
> 25% increase from baseline 
Chemistry 
eGFR (based on 
creatinine and 
Cystatin C) 
< 10 mL/min/1.73m2, < 15 mL/min/1.73m2 (among 
those with eGFR > 18 mL/min/1.73m2 at baseline) 
> 30%, > 40%, and > 50% decrease from baseline 
Chemistry 
Glucose 
> 250 mg/dL 
Hematology 
Hemoglobin 
< 9 g/dL 
Hematology 
Hematocrit 
< 27% 
 
Furthermore, in order to examine possible off-target effects of TRC101, the following descriptive 
summary statistics will be generated: 
• CFB in serum potassium for the subset of subjects whose baseline serum potassium is >5.0 
mEq/L, any time during the study treatment,  
• CFB in serum phosphate for the subset of subjects whose baseline serum phosphate is >5.5 
mg/dL, any time during the study treatment, and  
• CFB in low density lipoprotein (LDL) for the subset of subjects whose baseline LDL is 
> 120 mg/dL, any time during the study treatment 
Urinalysis results (other than pH and specific gravity), urine microscopic findings, and pregnancy 
test results will be listed, but not summarized.   
From the 24-hour urine collection, the following data will be summarized and listed: 
• Change in creatinine clearance (CrCL in mL/min), defined as [24-hour urine volume (mL) 
* 24 urine Cr (mg/dL)]/[Serum Cr (mg/dL)*1440] 
• Change in 24-hour urea nitrogen excretion 
• Change in 24-hour albumin excretion 
• Change in 24-hour sulfate excretion 
• Change in 24-hour uric acid excretion 
 


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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 appropriated] the pre-specified levels as shown in the above 
table) will be flagged.   
 
Summary of Change from Baseline in eGFR 
The eGFR values are derived from the central laboratory serum creatinine using the CKD-EPI 
formula (Section 10.1.3).  The eGFR values, CFB and percent CFB will be summarized 
descriptively by treatment group and time point.  Graphs will be produced to show:  
• Arithmetic mean ± SE of CFB in eGFR by treatment group over time  
• Arithmetic mean ± SE of eGFR by treatment group over time 
Because treatment of acidosis may increase muscle over time, a cystatin based eGFR will be used 
to evaluate eGFR changes independent of muscle mass changes.  The eGFR derived from the 
central laboratory serum cystatin C values, using the CKD-EPI formula (Section 10.1.3), were 
measured at baseline and once post baseline.  The eGFR values will be summarized at baseline 
and post baseline along with the CFB and percent CFB in eGFR will be summarized by treatment 
group. 
 
Summary of Change from Baseline in Blood pH and Base Excess 
This analysis will evaluate blood pH and base excess measured by the i-STAT point-of-care 
device.  The blood pH and base excess values and CFB in blood pH and base excess will be 
summarized by treatment group and time point.  All measurements from the i-STAT point-of-care 
device will be listed. 
 
Bicarbonate Measurements from Local Laboratory 
Blood bicarbonate concentrations from the local laboratory, using either the enzymatic assay or a 
benchtop venous blood gas analyzer, will be listed by subject.  Other parameters measured by the 
benchtop venous blood gas analyzer will also be included in the listing. 
15.5 Vital Signs 
Descriptive statistics for blood pressure, heart rate, respiratory rate, and temperature, including 
baseline values and change from baseline values, will be summarized by treatment group and time 


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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 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 thresholds levels for vital signs (See 
Table 5 below).   
Table 5 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/minute, increase or decrease 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. 
15.6 Body Weight 
Descriptive statistics for body weight measurements, including baseline values and change from 
baseline values, will be summarized by treatment group and time point.  Body weight 
measurements will be listed along with vital signs. 
15.7 12-lead Electrocardiograms 
Listings will present ECG data, such as clinical interpretation of ECGs, ECG rhythm and 
assessments of heart rate (HR), and intervals of QRS, QT, and PR.  The baseline cardiac rhythm 
will be descriptively summarized.  Descriptive statistics for observed values and change from 
baseline at each time point will be presented for these 12-lead ECG interval 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 treatment and time point.  The pre-specified levels of 
ECG QTc thresholds are consistent with FDA guidance (See Table 6 below).   


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Table 6 Pre-Specified Threshold Levels for ECG 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/minute 
 
All ECG parameters will be listed.  The listing will flag any results that outside the above levels 
provided in the table above. 
15.8 Physical Examination 
Abnormal clinically significant findings are reported as Medical History or Adverse Events 
depending on date of onset.  Abnormal non-clinically significant findings from physical 
examinations will be listed.  
15.9 Safety Monitoring  
The Medical Monitor will review blinded safety data on an ongoing basis to identify potential 
adverse safety trends.  The Medical Monitor will routinely review central laboratory results on an 
ongoing basis.  The Data Monitoring Committee (DMC) will review safety data periodically.  
Details of the DMC safety data review can be found in the Data Safety Monitoring Committee 
charter. 
16 CHANGES RELATIVE TO THE PROTOCOL-SPECIFIED ANALYSIS 
16.1 Other Efficacy Analyses 
SAP Section 14.8 contains additional efficacy and dosing analyses that were not described in the 
protocol as follows:  
• Additional categorical thresholds of bicarbonate increase (>2 mEq/L and >3 mEq/L) was 
added to further understand potential treatment effect on bicarbonate increase in lower 
ranges. 
• Baseline descriptor of kidney failure risk at 2 and 5 years (i.e., Kidney Failure Risk 
Equation score) was added to describe baseline kidney failure risks in the study 
population. 


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• Analyses exploring the effects of starting dose and dose titration. 
While the protocol specified one of the safety endpoints as “Having met the high bicarbonate dose 
interruption criterion (confirmed > 30 mEq/L) at any time during the Treatment Period.”, SAP 
Section 15.3 describes summaries of subjects who had a bicarbonate > 30 mEq/L event.  Removing 
the “confirmed” qualifier should capture any subjects potentially meeting the high bicarbonate 
dose interruption criterion at any time during the Treatment Period. 
17 Reference 
1. Yuan Y.  Sensitivity Analysis in Multiple Imputation for Missing Data, SAS Institute Inc. 
http://support.sas.com/resources/papers/proceedings14/SAS270-2014.pdf  
2. Tangri, et al. A predictive model for progression of chronic kidney disease to kidney 
failure JAMA. 2011;305(15):1553-1559 
3. Hays RD, et al. Kidney Disease Quality of Life Short Form (KDQOL-SFtm), Version 1.3: 
A Manual for Use and Scoring. Rand, 1997.