Clinical trial NCT03071263
Conditions: Hyperkalemia Resistant Hypertension
Keywords: Treatment of Hyperkalemia Hyperkalemia Potassium Chronic Kidney Disease Hypertension Resistant Hypertension Spironolactone
Sponsor: Relypsa, Inc.
Start date: 2017-01-23; Completion date: 2018-11-27
Enrollment: 295 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if patiromer treatment in chronic kidney disease (CKD) subjects receiving spironolactone for the treatment of resistant hypertension will result in more persistent use of spironolactone through prevention of hyperkalemia and lead to improved blood pressure control compared with treatment with spironolactone alone (placebo).

Detailed description:
Approximately 290 eligible participants with \[chronic kidney disease (CKD) on stable doses of medication\] will be randomly assigned to receive a patiromer or placebo starting dose of two packets a day, once a day.

All eligible participants will undergo a screening/run-in period (up to 4 weeks) to determine eligibility for study entry. Eligible participants will be randomized and treated for 12 weeks (Treatment Period) and followed for 2 weeks after completing the patiromer or placebo treatment. There are 8 planned clinic visits during the Treatment Period and one planned visit two weeks after the last dose of patiromer or placebo (Follow-up Period).

The dose of patiromer or placebo may be increased or decreased (titrated) based on participants' individual potassium response.

Arms: arm 1: spironolactone + blinded patiromer arm 2: spironolactone + blinded placebo
Interventions: intervention 1: Patiromer intervention 2: Placebo intervention 3: Spironolactone
Intervention descriptions: intervention 1: 2 packets/day starting dose, administered orally intervention 2: 2 packets/day starting dose, administered orally intervention 3: 25 mg tablet/day starting dose, administered orally

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
Title: 
A Randomized, Double-Blind, 
Placebo-controlled, Parallel Group Study of 
Patiromer for the Enablement of Spironolactone 
Use for Blood Pressure Control in Patients with 
Resistant Hypertension and Chronic Kidney 
Disease:  Evaluation of Safety and Efficacy 
(AMBER) 
Investigation Drug: 
Patiromer for Oral Suspension 
US IND #: 
75,615 
Protocol Number: 
RLY5016-207 
EudraCT: 
2016-002657-38 
Sponsor: 
Relypsa, Inc. 
100 Cardinal Way 
Redwood City, CA 94063 
USA 
+1.650.421.9500 Phone 
+1.650.421.9700 Fax 
Relypsa Medical Monitor: 
 
 
 
+1.650.421.9700 Fax 
Original Protocol Date: 
14 July, 2016 
Amendment 1 Date: 
18 October, 2016 
Amendment 2 (Administrative) 
Date: 
4 November, 2016 
CONFIDENTIAL INFORMATION 
Not to be copied, distributed, quoted, or otherwise disclosed or used 
without prior written permission from 
Relypsa, Inc. 


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PROTOCOL SIGNATURE FORM 
 
Protocol Title: 
A Randomized, Double-Blind, 
Placebo-controlled, Parallel Group Study of 
Patiromer for the Enablement of Spironolactone 
Use for Blood Pressure Control in Patients with 
Resistant Hypertension and Chronic Kidney 
Disease:  Evaluation of Safety and Efficacy 
(AMBER) 
Protocol Number: 
RLY5016-207 
Original Protocol Date: 
14 July, 2016 
Amendment 1 Date: 
18 October, 2016 
Amendment 2 (Administrative) 
Date: 
4 November, 2016 
I agree to conduct the study as detailed herein and in compliance with the protocol, ICH 
Guidelines for Good Clinical Practice (GCP) and other applicable regulatory requirements. 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
Principal Investigator Name (print) 
 
 
 
 
 




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RLY5016-207 
PROTOCOL AMENDMENT 2 
SUMMARY AND RATIONALE FOR CHANGES 
 
The following is a summary of the changes made in this protocol amendment, the sections 
affected, and the rationale for each change.  
 
 
 
 
No. 
Section(s) 
Description of Changes 
Rationale 
1 
All 
Global Change: 
 Updated title page, Protocol and Review 
Signature Form, footers and text to 
reflect amended protocol version and 
date 
 Updated the Table of Contents 
 
Punctuation changes 
Typographical 
/Administrative 
2 
Synopsis,  
Section 4.2 
The term ‘untreated’ is added to the 
exclusion that subjects with secondary 
causes of hypertension should be excluded. 
Clarifies that it is 
subjects with 
untreated secondary 
causes of 
hypertension that 
should be excluded 
3 
Synopsis, 
Sections 3.1.2, 
5.5, 6.1 
 
Instructions to the subject to delay taking 
their BP medications on the morning of the 
study visits until after office BP 
measurements have been completed 
Clarifies that blood 
pressure 
measurements 
should be done 
before BP 
medications are 
administered on the 
morning of the visit  
4 
Sections 6.1.2, 
6.1.3, 6.1.4, 
6.2.2, 6.2.3, 
7.3.2.2, 
The order of the visit activities specifies that 
BP measurements should be conducted 
before other scheduled activities (except for 
S4 and Week 12 Visits where EQ-5D-5L 
will be the first assessment) 
Clarifies the order of 
visit activities 


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STUDY SYNOPSIS 
Title: 
A Randomized, Double-Blind, Placebo-controlled, Parallel Group Study of Patiromer 
for the Enablement of Spironolactone Use for Blood Pressure Control in Patients with 
Resistant Hypertension and Chronic Kidney Disease:  Evaluation of Safety and Efficacy 
(AMBER) 
Protocol Number: 
RLY5016-207 
Phase: 
2 
Description of Agent 
or Intervention: 
Patiromer for Oral Suspension (patiromer) is a polymeric drug designed to bind and 
remove potassium from the gastrointestinal tract leading to removal of potassium from 
the body and lowering of serum potassium levels.  Patiromer (Veltassa®) is approved by 
the Food and Drug Administration (FDA) for the treatment of hyperkalemia in adult 
patients. 
Study Objective: 
To determine if patiromer treatment in chronic kidney disease (CKD) subjects receiving 
spironolactone for the treatment of resistant hypertension will result in more persistent 
use of spironolactone through prevention of hyperkalemia and lead to improved blood 
pressure control compared with treatment with spironolactone alone (placebo) 
Study Outcomes 
Primary Endpoint: 
Treatment group difference (spironolactone plus patiromer vs. spironolactone plus 
placebo) in proportion of subjects remaining on spironolactone at Week 12. 
Secondary Endpoint: 
Treatment group difference in change in systolic blood pressure (SBP) by automated 
office blood pressure (AOBP) measurements from baseline to Week 12 or last available 
AOBP measurement prior to addition of any new blood pressure (BP) medications or 
changes to any baseline BP medications. 
Other Endpoints: 
Other endpoints include: 
 
Change in AOBP SBP from baseline to Week 12 
 
Potassium levels over time (measured both centrally and locally) 
 
Proportion of subjects with serum K+ ≥ 5.5 mEq/L 
 
Average daily dose and cumulative dose of spironolactone 
 
Time to discontinuation of spironolactone 
 
Change in albuminuria (urine albumin to creatinine ratio [ACR]) from baseline to 
Week 12 
 
EQ-5D-5L questionnaire results at Baseline and Week 12/Early Termination (ET) 
Safety: 
Safety endpoints will consist of adverse events ([AEs]) including newly observed 
clinically significant physical examination abnormalities), clinical laboratory tests, vital 
signs, clinically significant electrocardiogram (ECG) findings and reasons for 
discontinuing study drugs. 
Study Design 
Description: 
This is a randomized, double-blind, placebo-controlled, parallel group study of 
patiromer or placebo treatment (patiromer/placebo) in conjunction with spironolactone 
in subjects with resistant hypertension and CKD.  The study will consist of a 
Screening/Run-in Period (up to 4 weeks), a 12-week Double-Blind Treatment Phase and 
a Follow-up Visit 2 weeks after Week 12 or ET Visit. 
Screening/Run-in Period (up to 4 weeks): 
The purpose of the Screening/Run-in Period is to ensure that all enrolled subjects are on 
stable doses of baseline medications, do not have “white coat” hypertension, can 
demonstrate proper and reliable use of the home BP (HBP) monitoring device prior to 
study drug treatment, and meet all study inclusion/exclusion criteria. 


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The Screening/Run-in Period will consist of 4 Screening Visits (S1, S2, S3, and S4) that 
are approximately 7 days (at least 4 days but no more than 10 days) after the prior 
Screening Visit (Appendix A).  Subjects will be instructed to delay taking their blood 
pressure medications on the morning of their subsequent study visits until after office 
blood pressure measurements have been completed. 
Visit S1:  Each subject will be issued a HBP monitor and provided with training on 
device use.  Subjects will be instructed to measure HBP in triplicate twice daily after 
Visit S1 (Section 7.3.2.1). 
Visits S2, S3 and S4:  Two types of office BP measurements will be performed before 
other scheduled activities (except for S4 where the EQ-5D-5L will be the first 
assessment).  Both measurements will be performed with the subject alone after 
5 minutes of seated rest (Section 7.3.2.2): 
1. 
Performed by an automatic oscillometric BP monitoring device that can 
measure BP in triplicate (automated office BP, AOBP) 
2. 
Performed by the subject using their issued HBP monitoring device in 
triplicate (subject-measured BP, SMBP) 
Note:  Study staff should not be present while both office BP measurements are being 
performed.  Subjects will be instructed to bring their issued HBP device to every visit. 
 
To be eligible for this study, subjects will be required to meet all of the following 
criteria: 
1. AOBP SBP 135 to 160 mmHg at each Screening Visit; however, AOBP SBP 
may be < 135 mmHg at either S2 or S3 Visits 
2. Estimated glomerular filtration rate (eGFR) of 25 – ≤ 45 mL/min/1.73 m2 
(mean [calculated by the Interactive Web Response System – IWRS] of two 
values measured at S1 and S3 (or 7 to 28 days apart) during the 
Screening/Run-in Period) 
3. Local laboratory measurements of K+ level of 4.3 – 5.1 mEq/L obtained at 
Visits S1, S3 and S4 (all measurements must be within range) 
4. Does not meet any exclusion criteria 
If hemolysis of the local sample is detected or suspected (see Section 7.1.1) at 
Screening Visits (S1 and S3), a repeat of the potassium measurement from a separate 
blood draw will be performed within 1 day.  If the repeated potassium level does not 
meet entry criteria, then the subject is considered a Screen Failure. 
For Visit S4, if hemolysis of the local sample is detected or suspected, the subject is not 
randomized and a repeat of the potassium measurement from a separate blood draw will 
be performed within 1 day.  If the subject qualifies, the subject will be randomized on 
the same day.  All assessments performed at Visit S4, aside from the hemolyzed 
potassium level, will be considered baseline assessments, and the day the repeat 
potassium measurement was obtained will be designated the Randomization/Baseline 
(Day 0) Visit.  If the repeated potassium level does not meet entry criteria, then the 
subject is considered a Screen Failure. 
If a subject fails any qualifying criteria at any of the Screening Visits, the subject will 
be considered a Screen Failure at that Visit.  Subjects who meet all study entry criteria 
except for eGFR and/or serum potassium will be screen failures but may be rescreened 
once at least 2 weeks after initial screen failure (Section 6.1.5). 
Double-Blind Treatment Period (12 weeks): 
Randomization Visit (Baseline/Day 0):   
Subjects who meet all eligibility criteria at Visit S4 will be randomized on the same day 
to either patiromer or placebo treatment (1:1) with stratification based on the local 
potassium level at Visit S4 (4.3 – < 4.7 or 4.7 – 5.1 mEq/L) and history of Type 1 or 2 


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diabetes mellitus (Yes or No).  The S4 assessments will become the baseline 
assessments.  A combined visit (S4/Randomization [Baseline/Day 0]) will be recorded 
for all randomized subjects. 
All randomized subjects will be provided with detailed instructions regarding when to 
take spironolactone, patiromer/placebo, and other baseline medications after 
considering the subject’s current medication regimen, patiromer/placebo instructions 
regarding administration, and subject preference (see Section 5.5.1).  The subject will 
be instructed to begin taking study drugs (spironolactone and patiromer/placebo) on the 
day following randomization (Day 1) and on the morning of their subsequent study 
visits to delay taking their blood pressure medications until office blood pressure 
measurements have been completed. 
Treatment Period Visits (refer to Appendix A):   
During the Double-Blind Treatment Period, study visits will occur at Week 1 
(Day 8 ± 3 days), Week 2 (Day 15 ± 3 days), Week 3 (Day 22 ± 3 days), Week 4 
(Day 29 ± 3 days), Week 6 (Day 43 ± 7 days), Week 8 (Day 57 ± 7 days), Week 10 
(Day 71 ± 7 days), and Week 12 (Day 85 ± 7 days). 
Patiromer/placebo treatment:   
Patiromer/placebo will be taken at a starting dose of two packets once daily (QD).  
Based upon the treatment algorithm, patiromer/placebo will be increased in two-packet 
per day increments for local K+ > 5.1 mEq/L in intervals of at least 1 week up to a 
maximum dose of six packets QD.  For subjects with K+ < 4.0 mEq/L, 
patiromer/placebo dose will be decreased by at least two packets per day.  The 
minimum dose of patiromer/placebo is 0 packets.  Patiromer/placebo should be taken 
with food, at least 3 hours before or 3 hours after administration of other oral 
concomitant medications including spironolactone.  Refer to Appendix B 
(Patiromer/Placebo Titration) for complete dosing and monitoring instructions. 
Throughout the Double-Blind Treatment Period, subjects who develop K+ ≥ 5.5 mEq/L 
that cannot be managed with blinded patiromer/placebo escalation according to the 
treatment algorithm (refer to Appendix B) will discontinue spironolactone and 
patiromer/placebo, but will remain in the study (refer to Appendix C, Spironolactone 
Dosing) and complete all remaining scheduled visits.  After discontinuation of 
spironolactone and patiromer/placebo, hyperkalemia may be treated using the standard 
of care per the Investigator’s judgment. 
Spironolactone treatment:   
Spironolactone will be initiated for all randomized subjects on Day 1, at a dose of 
25 mg taken orally QD.  At Week 3, for subjects with AOBP SBP ≥ 120 mmHg and 
K+ ≤ 5.1 mEq/L, spironolactone will be increased to 50 mg QD.  For subjects with 
AOBP SBP ≥ 120 mmHg and K+ > 5.1 mEq/L at Week 3, the 25 mg daily dose of 
spironolactone will be continued until the first subsequent visit when K+ is ≤ 5.1 mEq/L 
(and AOBP SBP is ≥ 120 mmHg) at which time spironolactone will be increased to 
50 mg QD. 
Subjects with AOBP SBP < 120 mmHg at the Week 3 Visit will continue 
spironolactone at 25 mg per day. 
If a subject has an AOBP SBP < 100 mmHg or experiences symptoms of hypotension 
with AOBP SBP < 120 mmHg, the spironolactone dose may be reduced (e.g., 25 mg 
every other day) or discontinued at the discretion of the Investigator (Appendix C, 
Spironolactone Dosing).  If spironolactone is discontinued, patiromer/placebo must be 
discontinued at the same time.  These subjects will remain in the study and be followed 
per protocol. 
Blood pressure management:   
When spironolactone has been discontinued and AOBP SBP is ≥ 165 to < 200 mmHg, 
alternative antihypertensive medication may be added to the blood pressure regimen 
(Appendix D, Blood Pressure Management and Alternative BP Medication 


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Suggestions).  Baseline antihypertensive medication doses should not be changed 
except for AE-related reasons where changes to baseline medications can be justified by 
the Investigator (e.g., increases in loop diuretics for new edematous states or 
discontinuation of baseline medication for drug-related AEs). 
For subjects on spironolactone 25 mg QD (before Week 3), spironolactone may be 
increased to 50 mg QD before the Week 3 Visit for persistent SBP ≥ 180 mmHg 
(AOBP), at the investigator’s discretion.  For subjects on spironolactone 50 mg QD, an 
additional BP medication may be added to control persistent SBP ≥ 165 mmHg AOBP) 
at the discretion of the Investigator.  This decision may reflect the degree of blood 
pressure elevation, the time since last spironolactone dose adjustment, and the level of 
urgency to lower blood pressure, in the Investigator’s judgment.  Baseline medication 
doses should not be changed except for AE-related reasons where changes to baseline 
medications can be justified by the Investigator (e.g., increases in loop diuretics for new 
edematous states or discontinuation of baseline medication for drug-related AEs). 
For all subjects (on or off spironolactone) with AOBP SBP ≥ 200 mmHg, subjects 
should be treated in accordance with the standard of care for BP management per the 
Investigator’s judgment (i.e., additional medications or change in baseline medication 
dose are permitted, Appendix D).  Note:  All subjects will remain in the study and 
complete all study assessments in accordance with the protocol. 
Unscheduled Visits:   
For subjects with study drug (spironolactone or patiromer/placebo) modifications based 
on BP assessments or potassium levels, an Unscheduled Visit should be conducted 
within 1 week after this modification unless the next scheduled visit is within 1 week of 
the study drug modification, in which case the subject will return at the next scheduled 
visit. 
Upon completion of all Double-Blind Treatment Period assessments at the Week 12 
Visit (or ET Visit), subjects will discontinue all study drugs that they are receiving 
(patiromer/placebo/spironolactone).  After study drug discontinuation, the treatment of 
hypertension should proceed in accordance with the standard of care for BP 
management per the Investigator’s judgment. 
Follow-up Visit (2 Weeks after Week 12 or ET Visit + up to 7 Days Window): 
All subjects will be instructed to return for a Follow-up Visit 2 weeks after the Week 12 
Visit or after ET Visit (+ up to 7 days).  The Investigator may request the subject to 
return to the study site prior to the Follow-up Visit to evaluate potassium levels, BP, or 
AEs, at his/her discretion.  If a subject arrives at the Follow-up Visit prior to 2 Weeks, 
subjects will receive a Follow-up Phone Call at 2 weeks (+ up to 7 days) after Week 12 
or ET Visit. 
Data Safety 
Monitoring 
Committee: 
A Data and Safety Monitoring Committee (DSMC) will review laboratory and blood 
pressure data, all reports of AEs (including deaths from any cause), discontinuations 
from spironolactone and patiromer/placebo, withdrawals from the study, and other data 
as described in the DSMC Charter.  The DSMC Charter will include a description of the 
scope of planned reviews.  When reviewing data, including individual data, the DSMC 
may be unblinded to treatment assignment (patiromer or placebo). 
Study Duration: 
Up to 18 weeks:  Screening/Run-in Period (up to 4 weeks), Double-Blind Treatment 
Period (12 weeks), and a Follow-up Visit 2 weeks after the Week 12 Visit. 
Study Sites: 
Approximately 60 sites. 
Study Population: 
Approximately 290 subjects will be randomized. 
Study Treatments 
Dose and Route of 
Administration: 
Investigational Products: 
Patiromer for Oral Suspension:  Patiromer will be provided blinded as a powder for oral 
suspension in packets of 4.2 g each.  In the Double-Blind Treatment Period, the starting 
dose of patiromer will be 8.4 g (two packets, 4.2 g each) QD, taken orally with food.  


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Patiromer QD doses for the study will be adjusted as needed (Appendix B) and will be 
0 packets (minimum dose), two packets, four packets, or six packets (maximum dose). 
Placebo:  Placebo (microcrystalline cellulose) will be provided blinded as a powder for 
oral suspension in packets identical in appearance to patiromer packets.  In the 
Double Blind Treatment Period, the starting dose will be two packets QD, taken orally 
with food.  The number of packets for titration and instructions for use will be the same 
as for patiromer (Appendix B). 
Spironolactone:  Spironolactone will be administered orally to all subjects at a starting 
dose of 25 mg QD (at least 3 hours before or after patiromer/placebo) and increased to 
50 mg QD at Week 3 (or after) for all subjects with AOBP SBP ≥ 120 mmHg and 
K+ ≤ 5.1 mEq/L (Appendix C). 
Eligibility Criteria 
Inclusion Criteria: 
Eligible subjects must meet all the following criteria: 
1. 
Provide written informed consent prior to participation in the study 
2. 
Age ≥ 18 years 
3. 
Taking at least three antihypertensive medications, one of which is a diuretic, 
for at least 28 days at a stable dose.  Angiotensin-converting enzyme (ACE) 
inhibitors or angiotensin receptor blockers (ARBs) should be included among 
these three antihypertensive medications, unless previously not tolerated or 
contraindicated. 
4. 
Uncontrolled hypertension as documented by AOBP SBP 135 to 160 mmHg at 
each Screening Visit; however, AOBP SBP may be < 135 mmHg at either S2 
or S3 Visits (see Section 7.3.2.2)  
5. 
eGFR of 25 – ≤ 45 mL/min/1.73 m2 (mean [calculated by the IWRS] of two 
values measured at Visits S1 and S3 (or 7 to 28 days apart) during the 
Screening/Run-in Period and calculated using CKD Epidemiology 
Collaboration [CKD-EPI] formula)  
6. 
Qualifying local laboratory K+ measurements of 4.3 – 5.1 mEq/L obtained at 
Visits S1, S3 and S4 (all measurements must be within range) 
7. 
Females of child-bearing potential must be non-lactating, must have a negative 
serum pregnancy test at screening, must use a medically acceptable form of 
birth control from 28 days prior to screening through the study and for 28 days 
after completion of the study 
Exclusion Criteria: 
Subjects must not meet any of the following: 
1. 
History of untreated secondary causes of hypertension (other than CKD) 
including but not limited to Cushing’s syndrome, primary hyperaldosteronism, 
renal vascular stenosis, or coarctation of the aorta 
2. 
Inability to measure BP (e.g., the largest sized arm BP cuff is inadequate given 
the circumference of the subject’s arm) 
3. 
Noncompliance with antihypertensive medications, in the investigator’s 
judgment 
4. 
Change in renal function requiring hospitalization or dialysis within 3 months 
prior to screening 
5. 
Renal transplant or anticipated need for renal transplantation during planned 
study participation 
6. 
History of malignancy within the previous 12 months except for cured 
non-melanocytic skin cancer 
7. 
Recent cardiovascular event (within the last 3 months):  myocardial infarction, 
unstable angina, hospitalization for heart failure, revascularization, or stroke 
(or transient ischemic attack) 


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8. 
Clinically significant ventricular arrhythmia 
9. 
Atrial fibrillation with HR > 100 beats per minute (bpm) 
10. 
Previous use of patiromer in a clinical study 
11. 
Any current use of spironolactone or other mineralocorticoid antagonists (e.g., 
eplerenone) 
12. 
Hypersensitivity to patiromer, spironolactone, or any of their components 
13. 
Use of any of the following permitted potassium-altering chronic medications 
if doses have not been stable for at least 28 days prior to screening or if doses 
are anticipated to change during study participation:  bronchodilators, 
theophylline, heparin, and canagiflozin 
14. 
Use of the following prohibited medications within 7 days prior to Screening:  
calcium acetate or calcium carbonate supplements (unless for occasional 
antacid use, at the discretion of the Investigator), digoxin, direct renin 
inhibitors (e.g., aliskiren), lanthanum carbonate, lithium, sevelamer, quinidine, 
sodium polystyrene sulfonate or calcium polystyrene sulfonate, colesevelam, 
colestipol, cholestyramine, drospirenone, potassium supplements, bicarbonate 
or baking soda (unless for occasional antacid use, at the discretion of the 
Investigator), triamterene, amiloride, trimethoprim, tacrolimus, cyclosporine, 
systemic glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs) or 
COX-2 inhibitors (with the exception of low dose aspirin), sympathomimetics 
15. 
Use of any investigational product within 30 days or 5 half-lives, whichever is 
longer, prior to screening 
16. 
History of bowel obstruction, swallowing disorders, clinically significant 
gastroparesis, severe gastrointestinal disorders or major gastrointestinal 
surgery (e.g., large bowel resection)  
17. 
Inability to take the study medications or comply with the protocol, in the 
opinion of the Investigator  
18. 
History of alcohol or drug abuse within 1 year of screening 
19. 
Any medical condition, uncontrolled systemic disease, or serious intercurrent 
illness that would significantly decrease study compliance or jeopardize the 
safety of the subject or affect the validity of the trial results, in the opinion of 
the Investigator 
Statistical Methods 
Determination of 
Sample Size: 
This study will randomize approximately 290 subjects, to ensure that at least 
280 subjects will be available for the primary analysis.  This allows for the possibility 
that up to 10 subjects are randomized but never take study medication.  A sample size 
of 280 subjects has 90% power to detect a difference between treatment groups of 20% 
or more in the proportion of subjects remaining on spironolactone at Week 12, at α = 
0.05. 
Randomization: 
Eligible subjects will be randomized 1:1 to either spironolactone + patiromer or 
spironolactone + placebo.  The randomization will be stratified using the locally 
measured potassium at Visit S4 (4.3 to < 4.7 mEq/L or 4.7 to 5.1 mEq/L) and history of 
Type 1 or 2 diabetes mellitus (Yes or No). 
Efficacy Analysis: 
Primary Efficacy 
Endpoint: 
The proportion of subjects remaining on spironolactone at Week 12 will be compared 
between treatment groups (spironolactone/patiromer vs. spironolactone/placebo) using 
the Cochran-Mantel-Haenszel test, stratified by baseline serum potassium category 
(K+ 4.3 – < 4.7 mEq/L or 4.7 – 5.1 mEq/L). 
Secondary Endpoint: 
AOBP SBP change from baseline to Week 12 or last available assessment prior to 
addition of any new BP medications or changes to any baseline BP medications will be 
analyzed using analysis of covariance (ANCOVA) methods. 


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Other Endpoints: 
Change in AOBP SBP at Week 12 will be analyzed using repeated measures as well as 
ANCOVA methods. 
Average daily dose and cumulative dose of spironolactone, and change in albuminuria 
(ACR) from baseline to Week 12, will be compared between treatment groups using 
ANCOVA methods. 
Kaplan-Meier methods will be used to analyze the time to discontinuation of 
spironolactone. 
Potassium levels will be summarized for local and central values at each time point.  
Counts (%) of subjects who have experienced no potassium measurement ≥ 5.5 mEq/L 
will be presented at each time point. 
The EQ-5D-5L questionnaire results will be summarized at Baseline and Week 12/ET. 
Safety Analysis 
Safety variables will consist of all AEs (including newly observed clinically significant 
physical examination abnormalities and events of interest, such as allergic reactions and 
gastrointestinal events), renal events (e.g., worsening renal failure, acute kidney injury, 
changes in eGFR), clinical laboratory test results (including serum potassium 
< 3.0 mEq/L, < 3.5 mEq/L, > 5.0 mEq/L, and clinically significant changes in serum 
calcium, magnesium, phosphorus), vital signs (including blood pressure), clinically 
significant ECG findings, potassium-related ECG changes and reasons for discontinuing 
patiromer/placebo/spironolactone. 
 


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TABLE OF CONTENTS 
STUDY SYNOPSIS ..................................................................................................................5 
1 
INTRODUCTION .................................................................................................18 
1.1 
Effects of Study Drugs in Humans ............................................................19 
1.1.1 
Patiromer ..............................................................................................19 
1.1.2 
Spironolactone .....................................................................................20 
1.2 
Rationale for the Clinical Study RLY5016-207 ........................................22 
2 
TRIAL OBJECTIVES ...........................................................................................23 
3 
TRIAL DESIGN ....................................................................................................24 
3.1 
Description .................................................................................................24 
3.1.1 
Screening/Run-in Period (Up to 4 weeks) ...........................................26 
3.1.2 
Double-Blind Treatment Period (12 weeks) ........................................27 
3.1.3 
Follow-up Visit (2 Weeks after Week 12 or ET Visit + up to 7 day 
window) ...............................................................................................30 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................30 
4.1 
Inclusion Criteria .......................................................................................30 
4.2 
Exclusion Criteria ......................................................................................30 
4.3 
Subject Withdrawal from Study .................................................................32 
5 
STUDY TREATMENTS .......................................................................................32 
5.1 
Treatment Blinding ....................................................................................32 
5.1.1 
Breaking the Blind ...............................................................................33 
5.2 
Allocation to Treatments............................................................................33 
5.3 
Investigational Product Supplies................................................................33 
5.3.1 
Formulation and Packaging .................................................................33 
5.3.2 
Preparation and Dispensing of Patiromer/Placebo ..............................33 
5.3.3 
Dosing and Administration of Patiromer/Placebo and Spironolactone34 
5.3.4 
Study Drug Adherence .........................................................................34 
5.4 
Investigational Product Storage and Accountability..................................35 
5.5 
Concomitant Medications ..........................................................................35 
5.5.1 
Timing of Oral Drug Administration ...................................................36 
5.5.2 
Permitted Medications .........................................................................36 
5.5.2.1 
Permitted Antihypertensive Medications ....................................36 
5.5.3 
Permitted Medications for Heart Failure .............................................37 
5.5.4 
Prohibited Medications ........................................................................37 
6 
TRIAL PROCEDURES .........................................................................................38 
6.1 
Screening/Run-in Period (up to 4 Weeks): ................................................38 
6.1.1 
S1 .........................................................................................................38 
6.1.2 
S2 (1 week [a least 4 days but no more than 10 days] after S1) ..........39 


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6.1.3 
S3 (1 week [at least 4 days but no more than 10 days] after S2) .........40 
6.1.4 
S4 (1 week [a least 4 days but no more than 10 days] after S3) ..........41 
6.1.5 
Rescreening of Subjects .......................................................................42 
6.2 
Double-Blind Treatment Period (12 Weeks) .............................................42 
6.2.1 
Randomization (Baseline, Day 0) Visit ...............................................42 
6.2.2 
Week 1 – Week 4 (± 3 days); Week 6, Week 8, and Week 10 
(± 7 days) .............................................................................................43 
6.2.3 
Week 12 Visit (± 7 days) .....................................................................44 
6.3 
Follow-up Visit (2 weeks after Week-12 or ET Visit, + up to 7 day 
window) .....................................................................................................45 
6.3.1 
Follow-up Phone Call ..........................................................................46 
6.4 
Early Termination Visit .............................................................................46 
6.5 
Unscheduled Visits ....................................................................................46 
7 
ASSESSMENTS ....................................................................................................47 
7.1 
Potassium ...................................................................................................47 
7.1.1 
Preventing, Identifying and Handling Hemolyzed Samples ................48 
7.2 
Laboratory Tests ........................................................................................48 
7.2.1 
NT-proBNP ..........................................................................................48 
7.2.2 
Spironolactone Level (Mass Spectrometry Analysis) ..........................48 
7.3 
Vital Signs ..................................................................................................49 
7.3.1 
Heart Rate ............................................................................................49 
7.3.2 
Blood Pressure .....................................................................................49 
7.3.2.1 
Home Blood Pressure .................................................................49 
7.3.2.2 
Office Blood Pressure .................................................................49 
7.4 
Physical Examination.................................................................................50 
7.5 
Diet .............................................................................................................50 
7.6 
ECG Assessment ........................................................................................50 
7.7 
Urine Collection for ACR ..........................................................................50 
7.8 
24-Hour Urine Collection for Sodium, Potassium, Creatinine, Albumin 
(for ACR) ...................................................................................................51 
7.9 
EQ-5D-5L Questionnaire ...........................................................................51 
8 
ADVERSE EVENT REPORTING........................................................................51 
8.1 
Definition of an Adverse Event .................................................................51 
8.1.1 
Definition of Serious Adverse Event ...................................................52 
8.2 
Procedures for Eliciting, Recording and Reporting Adverse Events .........53 
8.2.1 
Adverse Event Reporting Period .........................................................53 
8.2.2 
Eliciting Adverse Events......................................................................53 
8.2.3 
Assessing Adverse Events ...................................................................53 
8.2.4 
Causality Assessments .........................................................................54 


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8.2.5 
Recording Adverse Events ...................................................................55 
8.2.6 
Data and Safety Monitoring Committee ..............................................55 
8.3 
Serious Adverse Events Reporting ............................................................55 
8.3.1 
SAE Notification ..................................................................................55 
8.3.2 
SAE Expedited Reporting ....................................................................56 
8.4 
Procedures for Reporting Pregnancy Exposure and Birth Events .............57 
9 
DATA ANALYSIS / STATISTICAL METHODS ...............................................57 
9.1 
Sample Size Determination........................................................................57 
9.1.1 
Interim Analysis ...................................................................................57 
9.2 
Randomization ...........................................................................................57 
9.3 
General Considerations ..............................................................................58 
9.4 
Subject Disposition ....................................................................................58 
9.5 
Demography and Baseline Characteristics ................................................59 
9.6 
Efficacy Analyses ......................................................................................59 
9.6.1 
Primary Efficacy ..................................................................................59 
9.6.2 
Secondary Efficacy ..............................................................................59 
9.6.3 
Other Endpoints ...................................................................................59 
9.6.4 
Subgroups of Interest ...........................................................................60 
9.6.5 
Safety Analysis ....................................................................................60 
9.6.5.1 
Adverse Events ...........................................................................60 
9.6.5.2 
Deaths .........................................................................................61 
9.6.5.3 
Laboratory Assessments .............................................................61 
9.6.5.4 
Concomitant Medications ...........................................................61 
9.6.5.5 
Vital Signs ...................................................................................61 
9.7 
Handling of Missing Data ..........................................................................62 
10 
DATA HANDLING AND RECORDKEEPING ..................................................62 
10.1 
Case Report Forms / Electronic Data Record ............................................62 
10.2 
Record Retention .......................................................................................63 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................63 
12 
ETHICS..................................................................................................................64 
12.1 
Institutional Review Board / Independent Ethics Committee....................64 
12.2 
Ethical Conduct of the Trial .......................................................................64 
12.3 
Subject’s Information and Informed Consent ............................................65 
13 
RELYPSA DISCONTINUATION CRITERIA ....................................................66 
14 
PUBLICATION OF TRIAL RESULTS ................................................................66 
15 
REFERENCES ......................................................................................................66 
 
 
 


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LIST OF FIGURES 
Figure 1: 
Study Schema.............................................................................................25 
Figure 2: 
Patiromer/Placebo Titration .......................................................................72 
Figure 3: 
Spironolactone Titration ............................................................................74 
LIST OF APPENDICES 
Appendix A: Schedule of Events .....................................................................................68 
Appendix B: Patiromer/Placebo Titration .......................................................................71 
Appendix C: Spironolactone Dosing ...............................................................................73 
Appendix D: Blood Pressure Management and BP Medication Suggestions .................76 
Appendix E: List of Central Laboratory Assays .............................................................78 
 
 
 


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GLOSSARY OF ABBREVIATIONS 
ABPM 
ambulatory blood pressure monitoring 
ACE 
angiotensin-converting enzyme 
ACR 
albumin to creatinine ratio 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AOBP 
automated office blood pressure 
ARBs 
angiotensin receptor blockers 
ASCOT-BPLA 
Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm 
BID 
twice daily 
BP 
blood pressure 
BPM 
beats per minute 
CI 
confidence interval 
CKD 
chronic kidney disease 
CKD-EPI 
CKD Epidemiology Collaboration 
D 
day 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
DSMC 
data safety monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HBP 
home blood pressure 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 


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ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
K+ 
potassium 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRA 
mineralocorticoid receptor antagonists 
NSAID 
nonsteroidal anti-inflammatory drugs 
QD 
once daily 
R 
randomization 
RALES 
Randomized Aldactone Evaluation Study 
S1 
Screening 1 
S2 
Screening 2 
S3 
Screening 3 
S4 
Screening 4 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error 
SMBP 
subject-measured blood pressure 
TEAE 
treatment-emergent adverse event 
TID 
three times daily 
W 
week 
WBC 
white blood cell count 
US 
United States 
 


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1 
INTRODUCTION 
Treatment resistant hypertension (defined as blood pressure above goal despite treatment with 
optimally tolerated doses of three antihypertensive agents of different classes, including a 
diuretic) (Calhoun, 2008) remains a significant problem, affecting up to 8% of hypertensive 
patients identified from registry data using 24-hour ambulatory blood pressure monitoring 
(ABPM) (de la Sierra, 2011).  Other sources estimate the prevalence as significantly greater in 
specific cohorts, for example, CKD with albuminuria, in which rates reach nearly 50% 
(Tanner, 2013, Wolley, 2016).  The true prevalence of this condition is unknown, however, since 
most studies have not included information regarding key diagnostic criteria for determining true 
resistant hypertension rather than apparent resistant hypertension.  Key diagnostic criteria 
include antihypertensive medication doses (often suboptimal), treatment adherence (a frequent 
cause of apparent resistant hypertension), systematic exclusion of measurement artifacts 
including poor measurement technique and exclusion of “white-coat hypertension”, adherence to 
dietary sodium restriction, and exclusion of secondary causes of hypertension (Rossignol, 2015). 
Observational studies have shown a significant positive association between greater plasma 
aldosterone levels and blood pressure in both nonhypertensive and hypertensive populations 
(Vasan, 2004, Rossi, 2006), as well as a greater prevalence of primary hyperaldosteronism in 
those with treatment resistant hypertension (Calhoun 2002).  Although there are likely multiple 
causes for resistant hypertension, one potential mechanism among patients treated with 
angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is 
abnormal sodium retention mediated by aldosterone breakthrough despite blockade of the 
renin-angiotensin-aldosterone system with ACE inhibitors or ARBs.  This occurs in 10% of 
patients treated with ACE inhibitors/ARBs over 6 months, and > 50% over 1 year, leading to 
excess sodium retention, hypertension and other adverse cardiovascular effects (Bomback, 
2007).  Accordingly, there has been much interest in the use of mineralocorticoid receptor 
antagonists (MRAs) to treat resistant hypertension (Narayan, 2016). 
A recently published review (Narayan, 2016) evaluated new evidence of MRA use in the 
treatment of resistant hypertension, and included results from the PATHWAY 2 study 
(Williams, 2015).  In PATHWAY 2, the average reduction in home systolic blood pressure 
(SBP) by spironolactone was superior to placebo (-8.7 mmHg, 95% CI:  9.72 to -7.69; 
p < 0.0001), superior to the mean of the other two active treatments (doxazosin and 
bisoprolol, -4.2, 95% CI:  -5.13 to -3.38; p < 0.0001), and superior when compared with the 
individual treatments.  Spironolactone was the most effective blood pressure-lowering treatment, 
irrespective of baseline plasma renin levels.  Lower renin levels, however, were most predictive 
of the greatest BP response.  Narayan, et al. concluded that there is sufficient evidence to 
recommend MRAs, in particular spironolactone, as the first choice medication to treat resistant 
hypertension in large part because of the PATHWAY 2 findings (Narayan, 2016). 
Most studies in resistant hypertension to date (including PATHWAY 2) have largely been 
limited to patients with either normal or only mildly impaired renal function, although resistant 
hypertension is common in patients with chronic kidney disease (CKD) (Horowitz, 2015).  The 
prevalence of resistant hypertension is twice as high in patients with CKD compared to patients 
without CKD, and the prevalence increases with both decreased estimated glomerular filtration 


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rate (eGFR) and raised albuminuria.  In the CRIC study, 42% of 3612 patients with established 
CKD had apparent treatment-resistant hypertension (Rossignol, 2015, Muntner 2010). 
Due to the risks of hyperkalemia and acute kidney injury, MRA use has been limited in advanced 
CKD.  In patients with resistant hypertension and CKD Stage 3, MRAs raised serum potassium 
levels by an average of 0.4 mEq/L and serum creatinine concentrations increased from a mean of 
1.5 to 1.8 mg/dL.  In a Cochrane review (Bolignano, 2014), MRAs added to ACE or ARB 
therapy increased the risk of hyperkalemia twofold (95% CI:  1.25 – 3.0) in patients with mild to 
moderate CKD, dependent on baseline GFR, potassium, the dose of the drug, and concomitant 
medications.  In CKD with proteinuria and hypertension, spironolactone effectively reduced both 
BP and urine protein levels.  However, caution has been advised when starting spironolactone in 
patients who have a baseline serum potassium greater than 4.6 mEq/L (Judd, 2015).  In the 
Kholsa, et al. observational study, where patients had aldosterone antagonists added to a diuretic 
and renin-angiotensin system drug regimen, similar findings were reported.  Kholsa et al. defined 
the patient cohort in their study at the greatest risk for developing hyperkalemia as those with a 
serum potassium level of > 4.5 mEq/L and eGFR of ≤ 45 mL/min/1.73m2, and whose kidney 
function was further decreased by approaching goal BP (Khosla, 2009).  Therefore, despite the 
potential benefit of MRA treatment for resistant hypertension in patients with CKD, the risk of 
hyperkalemia has often limited their use.  More recently, though, the development of potassium 
binders with the potential for chronic use may now provide new options for the treatment of this 
patient population. 
Veltassa® (patiromer) for Oral Suspension (also known as RLY5016 for Oral Suspension) is 
approved by the Food and Drug Administration (FDA) for the treatment of hyperkalemia 
(Veltassa PI, 2016).  Patiromer contains a new chemical entity (the drug substance, RLY5016S) 
belonging to the pharmacologic class of Potassium Binders.  The drug substance consists of the 
polymer anion (the active moiety, patiromer) and a calcium-sorbitol counterion complex.  
Patiromer is a nonabsorbed, cation-exchange polymer that binds potassium predominantly in the 
lumen of the colon where potassium is the most abundant cation.  This increases fecal potassium 
excretion, leading to removal of potassium from the body and lowering of serum potassium 
levels in the hyperkalemic patient. 
The hypothesis of this study is that the concomitant use of spironolactone and patiromer in 
patients with resistant hypertension and CKD will prevent or manage hyperkalemia and allow 
the use of spironolactone for the management of blood pressure. 
1.1 
Effects of Study Drugs in Humans 
1.1.1 
Patiromer 
The clinical development program for patiromer included 20 completed clinical studies:  three 
Phase 1 studies, four Phase 2 studies, one two-part Phase 3 study (RLY5016-301), and 12 drug-
drug interaction (DDI) clinical studies.  Subjects who participated in these clinical studies 
included patients with hyperkalemia, CKD, HF, diabetes mellitus, hypertension and/or patients 
on hemodialysis, and healthy volunteer subjects.  A total of 1099 subjects received at least one 
dose of patiromer and the duration of dosing ranged from a single dose to up to 1 year. 


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The pivotal Phase 3 study (RLY5016-301) evaluated the treatment of hyperkalemia in subjects 
with CKD at two starting doses, 4.2 g patiromer BID or 8.4 g patiromer BID (subjects with 
screening serum potassium [K+] of > 5.0 to < 5.5 mEq/L were assigned the lower starting dose 
and subjects with screening serum K+ of 5.5 to < 6.5 mEq/L were assigned the higher starting 
dose) (Weir, 2015).  The study consisted of two parts (Part A, a 4-week treatment phase, and 
Part B, an 8-week, placebo-controlled, randomized withdrawal phase).  In Part A, the mean (SE) 
change in serum potassium from baseline (mean [SD] 5.58 [0.51] mEq/L) to Week 4 
was -1.01 (0.031) mEq/L (95% CI:  [-1.07, -0.95]); this mean reduction in serum potassium was 
statistically and clinically significant.  The proportion of subjects with a serum potassium level in 
the Part A target range of target range of 3.8 to < 5.1 mEq/L at Week 4 was 76% overall.  The 
proportion of subjects in the target range was similar in both starting dose groups, which had 
been assigned according to severity of starting serum potassium level.  Randomized withdrawal 
of the drug in the second part (Part B) confirmed the efficacy observed in Part A and provided 
evidence of the benefit of continued treatment with patiromer once serum potassium is 
controlled. 
A comprehensive assessment of safety of patiromer for the treatment of hyperkalemia was 
conducted.  A total number of 1099 subjects were exposed to at least one dose of patiromer and a 
pooled safety analysis was conducted in 666 subjects receiving patiromer and 49 subjects 
receiving placebo.  Data from the overall safety population demonstrated that patiromer was 
well-tolerated.  Adverse events (AEs) and serious adverse events (SAEs) were reported in 60.8% 
and 8.3% of subjects, respectively, of the overall safety population receiving patiromer for up to 
52 weeks.  Approximately 20% of subjects receiving patiromer experienced AEs considered 
related to study drug but no SAEs were considered drug related.  The proportion of subjects 
discontinuing study drug due to an AE was relatively low at 9%, indicating the therapy was 
generally well tolerated in subjects, including those who were treated for up to 1 year in the 
long-term efficacy and safety Phase 2 Study RLY5016-205.  Overall, the most common reported 
AEs were gastrointestinal in nature and predominantly were events of constipation and diarrhea.  
These events tended to occur early after treatment initiation, were mild to moderate in nature, 
occurred in less than 10% of subjects, were self-limited and typically did not require dose 
reductions or discontinuations.  Hypokalemia AEs and measured potassium levels < 3.5 mEq/L 
did occur but were infrequent and none of these events were serious or associated with 
electrocardiogram (ECG) changes.  AEs of chronic renal failure, acute renal failure and cardiac 
disorders events were also observed, however these events generally were not assessed as being 
attributable to patiromer but consistent with AEs expected in study population with a high 
burden of CKD, diabetes mellitus, HF, and coronary artery disease. 
Refer to the current version of the Investigator’s Brochure for a more detailed summary of these 
clinical studies (Investigator’s Brochure, 2016). 
1.1.2 
Spironolactone 
Spironolactone is a potent, nonselective, steroidal MRA that competitively inhibits aldosterone 
binding to the mineralocorticoid receptor (MR) and renders it transcriptionally inactive, thus 
antagonizing the genomic effects of aldosterone.  It does not antagonize aldosterone-induced 
nongenomic renal and extrarenal effects (Tamargo, 2014). 


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Activation of MRs by aldosterone promotes multiple renal, cardiac, and vascular deleterious 
effects, including endothelial dysfunction, hypertension, neurohumoral activation, cardiovascular 
(CV) and renal remodeling (hypertrophy, fibrosis, and apoptosis), decreases arterial compliance, 
increases expression of cell adhesion molecules, platelet activation, plasminogen activator 
inhibitortype1 (PAI-1) activity, and oxidative stress, and exerts proarrhythmic and 
proinflammatory effects (Tamargo, 2014).  In addition, activation of central MRs increases 
central sympathetic tone to the kidneys, heart, and vascular smooth muscles, increases 
vasopressin release, and decreases baroreceptor sensitivity.  These effects are reported to be 
genomic (i.e., dependent on transcription and translation).  Additionally, aldosterone produces 
rapid, translation- and transcription-independent effects (nongenomic effects).  Nongenomic 
effects also occur independently of hemodynamic factors and play an important role in the 
mechanisms by which aldosterone contributes to endothelial dysfunction, vasoconstriction, 
resistant arterial hypertension, CV and renal remodeling, inflammation, heart failure, insulin 
resistance, and chronic renal disease (CKD) (Tamargo, 2014).  Endothelial MR activation has 
been linked to enhanced vasoconstrictor and/or impaired vasodilator responses, as well. 
Spironolactone was introduced into clinical use in the early 1960’s as a potassium-sparing 
diuretic for the treatment of hypertension, primary hyperaldosteronism, volume-overload states, 
and hypokalemia.  Its mode of action was thought to be complementary to that of the diuretics 
used for the treatment of these conditions at the time, mediated at the aldosterone-dependent 
sodium-potassium exchange site in the distal convoluted renal tubule where it caused increased 
amounts of sodium and water to be excreted, while potassium was retained.  It was thought to act 
both as a diuretic and as an antihypertensive by this mechanism.  Early studies demonstrated 
efficacy for blood pressure reduction.  Spironolactone has also been indicated as a diuretic in 
patients with cirrhosis and ascites, in whom secondary hyperaldosteronism is present, and 
hypokalemia is a hazard (Aldactone®, 2014). 
Since that time, the extrarenal effects of aldosterone have become more widely appreciated and 
the potential benefits of MRAs more extensively studied.  More recently, MRAs as 
antihypertensive drugs have been preferentially indicated in the treatment of primary and 
secondary hyperaldosteronism.  They have been increasingly recommended in hypertensive 
patients with metabolic syndrome or target organ damage represented by left ventricular (LV) 
hypertrophy or albuminuria (Tarmargo, 2014) and spironolactone has most recently been 
recommended as add-on therapy in patients with resistant hypertension in whom MRAs have 
shown positive results.(Tamargo, 2014, Williams, 2015)  Spironolactone is indicated in patients 
with chronic congestive HF (NYHA Class II-IV) with reduced ejection fraction to improve 
survival and reduce hospitalization for heart failure when added to standard therapy 
(Tamargo, 2014). 
Until recently, MRAs had received little attention in patients with CKD because of the risk of 
hyperkalemia.  However, low doses of MRAs may offer additional antihypertensive and 
anti-inflammatory benefits in selected CKD populations.  Spironolactone (and eplerenone) 
reduce aldosterone induced renal damage and decrease proteinuria in hypertensive patients.  In 
patients with CKD, the addition of MRAs to ACE inhibitors or ARBs significantly reduced BP 
and glomerular filtration rate (GFR) and decreased proteinuria.  However, a meta-analysis of 
11 RCTs using MRAs, alone or in combination with ACE inhibitors/ARBs for preventing the 
progression of CKD in patients with albuminuria and diabetic or nondiabetic nephropathy, found 


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that MRAs reduce 24-hour proteinuria and BP, but this did not translate into an improvement in 
end-of-treatment GFR.  Therefore, long-term effects of MRAs on renal outcomes, mortality, and 
safety remains uncertain (Tamargo, 2014). 
Due to the lack of receptor selectivity, spironolactone also blocks androgen receptors and 
activates progesterone receptors, causing progestogenic and antiandrogenic adverse effects.  
Long-term use has been associated with gynecomastia and other endocrine-adverse effects, such 
as breast tenderness, impotence, loss of libido and menstrual irregularities which has limited its 
use.  Gynecomastia is a dose-dependent reversible AE reported in 13% of men prescribed 
spironolactone, alone or in combination with other antihypertensives; at doses of 50mg/d or less 
the incidence was 6.9% in a hypertension study.  In large clinical outcome studies, (the 
Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm [ASCOT–BPLA] 
and RALES trials), gynecomastia was reported in 6 to 10% of men and was the reason for 
spironolactone discontinuation in 3% of patients in the ASCOT–BPLA (Tamargo, 2014). 
Oral spironolactone is absorbed rapidly but has a short half-life (1.4 h) because it is metabolized 
rapidly and extensively into active metabolites including canrenone, which is marketed as a 
MRA in some countries and has a half-life of 16 – 35 h in healthy volunteers).  These active 
metabolites explain a peak response which occurs after 48 or more hours.  The steady-state effect 
of spironolactone is consequently not reached until after 6 weeks of treatment.  This 
pharmacokinetic profile allows for once-daily or alternate-day administration of spironolactone.  
Also, the slow clearance of the active metabolites may explain why the duration of the natriuretic 
and antikaliuretic effects of spironolactone differ, the latter often persisting for several days after 
drug discontinuation.  The persistence of hyperkalemia is important in patients treated with ACE 
inhibitors or ARBs, especially in patients with CKD.  The half-life of spironolactone is 
prolonged significantly (24 – 58h) in patients with cirrhotic ascites or heart failure.  
Spironolactone and its metabolites are highly bound (> 90%) to plasma proteins, mainly to 
albumin.  Because spironolactone does not rely on GFR or tubular secretion to reach its site of 
action it remains effective even in patients with advanced CKD (Tamargo, 2014). 
1.2 
Rationale for the Clinical Study RLY5016-207  
The use of patiromer to prevent hyperkalemia associated with the treatment of resistant 
hypertension with spironolactone has not been evaluated.  The hypothesis of this study is that the 
concomitant use of spironolactone and patiromer in patients with resistant hypertension and 
CKD will prevent or manage hyperkalemia and allow the use of spironolactone for the 
management of blood pressure. 
In the PEARL-HF study (Pitt, 2011), heart failure patients on at least one ACE inhibitor, ARB, 
or β blocker, and eligible for spironolactone treatment, received placebo or patiromer in addition 
to spironolactone.  Among subjects with eGFR ≤ 45 mL/min/1.73m2 and baseline serum 
potassium 4.3 to ≤ 5.1 mEq/L, 56% of subjects receiving placebo compared with 0% of subjects 
receiving patiromer developed a serum potassium > 5.5 mEq/L.  These data suggest that 
patiromer may prevent hyperkalemia in other cohorts treated with spironolactone with risk 
factors for hyperkalemia. 


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The aim of this study is to evaluate whether the use of patiromer to prevent and manage 
hyperkalemia in subjects with CKD and resistant hypertension treated with spironolactone will 
result in more persistent use of spironolactone compared to subjects treated with spironolactone 
without patiromer.  We anticipate that this will lead to greater reduction of blood pressure in the 
group treated with patiromer compared with the group treated with spironolactone alone, in 
whom discontinuation of spironolactone may occur due to hyperkalemia. 
Since there are substantial differences in international guideline recommendations for target BP 
in CKD, Rossignol, et al. (Rossignol, 2015) recommend BP levels for defining resistant 
hypertension that are consistent with those of the general population (ie, office SBP 
≥ 140 mmHg or diastolic blood pressure [DBP] ≥ 90 mmHg).  Out of office blood pressure 
measurements have been shown to be more accurate compared with office BP measurements and 
can exclude white coat hypertension and masked hypertension, both common in patients with 
CKD.  However, more recently, data suggest that automated office BP (AOBP) using an 
automatic oscillometric monitoring device without study staff present may have less variability; 
therefore, AOBP measurements will be used in this study for subject selection, treatment 
decisions, and the primary evaluation of BP effects, and target blood pressure for these patients 
will be 135/85 mmHg.  Home blood pressure (HBP) measurements and subject-measured blood 
pressure (SMBP) performed at the study site by the patient using the HBP monitor will also be 
performed.  Home blood pressure measurements may also improve adherence to medications by 
increasing patient involvement (Wolley, 2016). 
In this study, the BP comparison of greatest interest will be the between group difference in 
change from baseline blood pressure which theoretically should reflect the difference in 
proportion of subjects remaining on spironolactone at Week 12.  It is anticipated that a larger 
proportion of subjects in the placebo plus spironolactone group will meet spironolactone 
discontinuation thresholds for potassium during the treatment period.  To insure the safety of 
these subjects without confounding the between group comparisons unduly, subjects randomized 
to the study will be limited to those with systolic AOBP from 135 to < 160 mmHg, who are less 
likely to require urgent treatment of hypertension should spironolactone be discontinued.  All 
subjects who experience persistent systolic BP of 165 mmHg or greater may be treated with 
additional antihypertensive therapy chosen by the investigator. 
2 
TRIAL OBJECTIVES 
To determine if patiromer treatment of CKD subjects receiving spironolactone for the treatment 
of resistant hypertension will result in: 
• More persistent use of spironolactone through prevention of hyperkalemia 
• Improved blood pressure control through more persistent use of spironolactone 


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3 
TRIAL DESIGN 
3.1 
Description 
This study is a randomized, double-blind, placebo-controlled, parallel group study of patiromer 
or placebo treatment (patiromer/placebo) in conjunction with spironolactone in subjects with 
resistant hypertension and CKD.  Approximately 290 subjects will be randomized. 
The study will consist of (Figure 1):  Screening/Run-in Period (up to 4 weeks); Double-Blind 
Treatment Period (12 weeks); Follow-up Visit 2 weeks after Week-12 Visit or Early Termination 
(ET) Visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1: 
Study Schema 
 
AOBP = automated office blood pressure; BP = blood pressure; eGFR = estimated glomerular filtration rate; K+ = potassium measurement; R = Randomization/Baseline (Day 0) 
Visit; S = Screening Visit; SBP = systolic blood pressure; SMBP = subject-measured blood pressure; W = week 
a 
Receiving at least three antihypertension drugs including diuretic.  ACE inhibitors or ARBs should be included among these three antihypertensive medications, unless 
previously not tolerated or contraindicated (see Inclusion Criteria, Section 4.1). 
b 
Performed by an oscillometric BP monitoring device that will automatically measure subject’s BP in triplicate after 5 minutes of sitting quietly without the aid of study staff, 
AOBP (Section 7.3.2.2). 
c 
Mean (calculated by the IWRS) of two values measured at Visits S1 and S3 (or 7 to 28 days apart) during the Screening/Run-in Period. 
d 
Qualifying local laboratory K+ measurements of 4.3 – 5.1 mEq/L obtained at Visits S1, S3 and S4 (all measurements must be within range) 
e 
Subjects who develop hyperkalemia (K+ ≥ 5.5 mEq/L) that cannot be managed with blinded patiromer/placebo escalation according to the treatment algorithm (Appendix B) 
will discontinue spironolactone and patiromer/placebo, but still remain in the study (Appendix C).  Thereafter, hyperkalemia may be treated using standard of care. 
f 
Two (2) weeks after the Week 12 (+ 7 days) or ET Visit.  Subjects who complete the Follow-up Visit prior to 2 Weeks will receive a Follow-up Phone Call at 2 weeks 
(+ up to 7 days) after Week 12 or ET Visit. 
Note:  For subjects with study drug (spironolactone or patiromer/placebo) modifications based on BP assessments or potassium levels, an Unscheduled Visit will be conducted 
within 1 week after this modification unless the next scheduled visit is within 1 week of the study drug modification, in which case, the subject will return at the next scheduled 
visit.  For all study visit windows, refer to the Schedule of Events (Appendix A).  For all visits except for S1 and the Follow-up Visit, SMBP measurements will be performed (see 
Section 7.3.2.1).


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3.1.1 
Screening/Run-in Period (Up to 4 weeks) 
The purpose of the Screening/Run-in Period is to ensure that all enrolled subjects are on stable 
doses of baseline medications, do not have “white coat” hypertension, can demonstrate proper 
and reliable use of the BP monitoring device prior to study drug treatment, and meet all study 
inclusion/exclusion criteria. 
The Screening/Run-in Period will consist of four Screening Visits (S1, S2, S3, and S4) that are 
approximately 7 days (at least 4 days but no more than 10 days) after the prior screening Visit 
(Appendix A). 
Visit S1:  Each subject will be issued a HBP monitor and provided with training on device use.  
Subjects will be instructed to measure HBP in triplicate twice daily after Visit S1 
(Section 7.3.2.1). 
Visits S2, S3 and S4:  Two types of office BP measurements will be performed before other 
scheduled activities (except for S4 where the EQ-5D-5L will be the first assessment).  Both 
measurements will be performed with the subject alone after 5 minutes of seated rest 
(Section 7.3.2.2): 
1. Performed by an automatic oscillometric BP monitoring device that can measure BP in 
triplicate (automated Office BP, AOBP)  
2. Performed by the subject using their issued HBP monitoring device in triplicate 
(subject-measured BP, SMBP) 
Note:  Study staff should not be present while both office BP measurements are being performed.  
Subjects will be instructed to bring their issued HBP device to every visit. 
To be eligible for this study, subjects will be required to meet all of the following criteria (see 
Section 4 for complete criteria): 
1. AOBP SBP 135 to 160 mmHg at each Screening Visit; however, AOBP SBP may be 
< 135 mmHg at either S2 or S3 Visits 
2. eGFR of 25 – ≤ 45 mL/min/1.73 m2 (mean [calculated by the Interactive Web Response 
System – IWRS] of two values measured at S1 and S3 (or 7 to 28 days apart) during the 
Screening/Run-in Period) 
3. Local laboratory measurements of K+ level of 4.3 – 5.1 mEq/L obtained at Visits S1, S3 and 
S4 (all measurements must be within range) 
4. Does not meet any exclusion criteria 
If hemolysis of the local sample is detected or suspected (see Section 7.1.1) at Screening Visits 
(S1 and S3), a repeat of the potassium measurement from a separate blood draw will be 
performed within 1 day.  If the repeated potassium level does not meet entry criteria, then the 
subject is considered a Screen Failure. 
For Visit S4, if hemolysis of the local sample is detected or suspected, the subject is not 
randomized and a repeat of the potassium measurement from a separate blood draw will be 


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performed within 1 day.  If the subject qualifies, the subject will be randomized on the same day.  
All assessments performed at Visit S4, aside from the hemolyzed potassium level, will be 
considered baseline assessments, and the day the repeat potassium measurement was obtained 
will be designated the Randomization/Baseline (Day 0) Visit.  If the repeated potassium level 
does not meet entry criteria, then the subject is considered a Screen Failure. 
If a subject fails any qualifying criteria, at any of the Screening Visits, the subject will be 
considered a Screen Failure at that Visit.  Subjects who meet all study entry criteria except for 
eGFR and/or serum potassium will be screen failures but may be rescreened once at least 
2 weeks after initial screen failure (Section 6.1.5). 
3.1.2 
Double-Blind Treatment Period (12 weeks) 
Randomization (Baseline – Day 0) Visit: 
Subjects who meet all eligibility criteria at Visit S4 will be randomized on the same day to either 
patiromer or placebo treatment (1:1) with stratification based on the local potassium level at 
Visit S4 (4.3 – < 4.7 or 4.7 – 5.1 mEq/L) and history of Type 1or 2 diabetes mellitus (Yes or 
No).  The S4 assessments will become the baseline assessments.  A combined visit 
(S4/Randomization [Baseline/Day 0]) will be recorded for all randomized subjects. 
All randomized subjects will be provided with detailed instructions for when to take 
spironolactone, patiromer/placebo, and other baseline medications after considering the subject’s 
current medication regimen, patiromer/placebo instructions regarding administration, and subject 
preference (see Section 5.5.1).  The subject will be instructed to begin taking study drugs 
(spironolactone and patiromer/placebo) on the following day (Day 1) and on the morning of their 
subsequent study visits to delay taking their blood pressure medications until office blood 
pressure measurements have been completed. 
 
Treatment Period Visits (refer to Appendix A): 
During the Double-Blind Treatment Period, study visits will occur at Week 1 (Day 8 ± 3 days), 
Week 2 (Day 15 ± 3 days), Week 3 (Day 22 ± 3 days), Week 4 (Day 29 ± 3 days), 
Week 6 (Day 43 ± 7 days), Week 8 (Day 57 ± 7 days), Week 10 (Day 71 ± 7 days), and Week 12 
(Day 85 ± 7 days). 
Patiromer/placebo treatment: 
Patiromer/placebo will be taken at a starting dose of two packets once daily (QD).  Based upon 
the treatment algorithm, patiromer/placebo will be increased in two-packet per day increments 
for local K+ > 5.1 mEq/L in intervals of at least 1 week up to a maximum dose of six packets 
QD.  For subjects with K+ < 4.0 mEq/L, patiromer/placebo dose will be decreased by at least 
two packets per day.  The minimum dose of patiromer/placebo is 0 packets.  Patiromer/placebo 
should be taken with food, at least 3 hours before or 3 hours after administration of other 
concomitant medications including spironolactone.  Refer to Appendix B for complete dosing 
and monitoring instructions. 


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Throughout the Double-Blind Treatment Period, subjects who develop K+ ≥ 5.5 mEq/L that 
cannot be managed with blinded patiromer/placebo escalation according to the treatment 
algorithm (refer to Appendix B) will discontinue spironolactone and patiromer/placebo, but will 
remain in the study (refer to Appendix C) and complete all remaining scheduled visits.  After 
discontinuation of spironolactone and patiromer/placebo, hyperkalemia may be treated using the 
standard of care per the Investigator’s judgment. 
Spironolactone treatment: 
Spironolactone will be initiated for all randomized subjects on Day 1, at a dose of 25 mg taken 
orally QD.  At Week 3, for subjects with AOBP SBP ≥ 120 mmHg and K+ ≤ 5.1 mEq/L, 
spironolactone will be increased to 50 mg QD.  For subjects with K+ > 5.1 mEq/L, 25 mg daily 
dose of spironolactone will be continued until the first subsequent visit when K+ is ≤ 5.1 mEq/L 
(and AOBP SBP ≥ 120 mmHg), at which time spironolactone will be increased to 50 mg QD. 
Subjects with AOBP SBP < 120 mmHg at the Week 3 Visit will continue their 25 mg daily dose, 
unless symptoms of hypotension are present with SBP < 120 mmHg, or if SBP is < 100 mmHg 
(Appendix C), in which case the spironolactone dose may be reduced to 25 mg every other day 
or discontinued altogether, at the discretion of the Investigator.  Spironolactone may be reduced 
or discontinued for SBP < 100 mmHg.  If spironolactone is discontinued, patiromer/placebo 
must be discontinued at the same time.  These subjects will remain in the study and be followed 
per protocol. 
Note:  During all study visits, if a subject experiences symptoms of hypotension with AOBP 
SBP < 120 mmHg, or if SBP < 100 mmHg, spironolactone dose may be reduced (e.g., 25 mg 
every other day) or discontinued at the discretion of the Investigator. 
Throughout the treatment period, creatinine will be measured at each study visit (and may be 
measured at Unscheduled Visits).  Subjects should be monitored for changes in renal function, 
especially during periods of medication changes or adjustments.  Acute reductions in GFR have 
been seen with the initiation of spironolactone, similar to those seen with initiation of ACE 
inhibitors and ARBs that have been attributed to transient changes in glomerular hemodynamics 
(Bianchi, 2015, KDIGO, 2012).  These changes typically do not impact long-term renal function.  
In this study, use of the KDOQI recommendations for the detection and management of early 
decrease in GFR (when initiating ACE inhibitors/ARBs) for monitoring the initiation of 
spironolactone (NKF, 2004) should be considered. 
Based on KDOQI guidelines: 
• An early decline in eGFR is defined as > 15% reduction from baseline within 4 weeks of 
initiation of spironolactone 
• For decreases in eGFR up to 30%, no changes to spironolactone dosing need to be made, and 
eGFR may be followed routinely 
• Decreases in eGFR > 30%, however, should prompt a search for other etiologies of abrupt 
renal function decline, including prerenal and postrenal causes, toxic reactions, and renal 
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• For a decline in eGFR from 30 to 50%, the spironolactone dose should be decreased and the 
eGFR followed weekly.  If the eGFR does not return to within 30% of baseline within 
4 weeks, spironolactone should be discontinued 
• Spironolactone should be discontinued for a decline in eGFR > 50% and eGFR should be 
followed at least weekly until eGFR has returned to within 15% of the baseline value, and 
biweekly thereafter through the end of the study 
Blood pressure management should proceed as outlined below. 
Blood pressure management: 
When spironolactone has been discontinued and AOBP SBP is ≥ 165 to < 200 mmHg, 
alternative antihypertensive medication may be added to the blood pressure regimen (Appendix 
D).  Baseline medication doses should not be changed except for AE-related reasons where 
changes to baseline medications can be justified by the Investigator (e.g., increases in loop 
diuretics for new edematous states or discontinuation of baseline medication for drug-related 
AEs). 
For subjects on spironolactone 25 mg QD (before Week 3), spironolactone may be increased to 
50 mg QD before the Week 3 Visit for persistent SBP ≥ 180 mmHg (assessed by AOBP), at the 
investigator’s discretion.  For subjects on spironolactone 50 mg QD, additional BP medication 
may be added to control persistent SBP ≥ 165 mmHg (assessed by AOBP) at the discretion of 
the investigator.  This decision may reflect the degree of blood pressure elevation, the time since 
last spironolactone dose adjustment, and the level of urgency to lower blood pressure, in the 
investigator’s judgment.  Baseline medication doses should not be changed except for AE-related 
reasons where changes to baseline medications can be justified by the Investigator (e.g., 
increases in loop diuretics for new edematous states or discontinuation of baseline medication for 
drug-related AEs). 
For all subjects (on or off spironolactone) with AOBP ≥ 200 mmHg, subjects should be treated 
in accordance with the standard of care for BP management and the Investigator’s judgment (i.e., 
additional medications or change in baseline medication dose are permitted, Appendix D).  
Note:  All subjects will remain in the study and complete all study assessments in accordance 
with the protocol. 
Unscheduled Visits: 
For subjects with study drug (spironolactone or patiromer/placebo) modifications based on BP 
assessments or potassium levels, an Unscheduled Visit should be conducted within 1 week after 
this modification unless the next scheduled visit is within 1 week of the study drug modification, 
in which case the subject will return at the next scheduled visit. 
Upon completion of all Double-Blind Treatment Period assessments at the Week 12 Visit (or 
ET Visit), subjects will discontinue all study drugs that they are receiving 
(patiromer/placebo/spironolactone).  After study drug discontinuation, the treatment of 
hypertension should proceed in accordance with the standard of care for BP management and the 
Investigator’s judgment. 


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3.1.3 
Follow-up Visit (2 Weeks after Week 12 or ET Visit + up to 7 day window) 
All subjects will return for a Follow-up Visit, 2 weeks after the Week 12 Visit (+ up to 7 days, if 
necessary).  The Investigator may request the subject to return to the study site prior to the 
2-week Follow-up Visit to evaluate potassium levels, AOBP, or AEs, at his/her discretion.  In the 
case where a subject completes the Follow-up Visit prior to 2 Weeks, the subject will receive a 
Follow-up Phone Call at 2 weeks (+ up to 7 days) after Week 12 or ET Visit. 
Subjects who terminate early from the study will complete the ET Visit assessments and return 
for a Follow-up Visit 2 weeks (+ up to 7 days) after the ET Visit. 
4 
SUBJECT SELECTION AND WITHDRAWAL 
All potential study subjects will be evaluated using the inclusion and exclusion criteria, described 
below. 
4.1 
Inclusion Criteria 
Eligible subjects must meet all the following criteria: 
1. Provide written informed consent prior to participation in the study 
2. Age ≥ 18 years 
3. Taking at least three antihypertensive medications, one of which is a diuretic, for at least 
28 days at a stable dose.  ACE inhibitors or ARBs should be included among these three 
antihypertensive medications, unless previously not tolerated or contraindicated. 
4. Uncontrolled hypertension as documented by AOBP SBP 135 to 160 mmHg at each 
Screening Visit; however, AOBP SBP may be < 135 mmHg at either S2 or S3 Visits (see 
Section 7.3.2.2) 
5. eGFR of 25 – ≤ 45 mL/min/1.73 m2 (mean [calculated by the IWRS] of two values measured 
at S1 and S3 or 7 to 28 days apart during the Screening/Run-in and calculated using CKD 
Epidemiology Collaboration [CKD-EPI] formula)  
6. Qualifying local laboratory K+ measurements of 4.3 – 5.1 mEq/L obtained at Visits S1, S3 
and S4 (all measurements must be within range) 
7. Females of child-bearing potential must be non-lactating, must have a negative serum 
pregnancy test at screening, must use a medically acceptable form of birth control from 
28 days prior to screening through the study and for 28 days after completion of the study 
4.2 
Exclusion Criteria 
Subjects must not meet any of the following criteria: 
1. History of untreated secondary causes of hypertension (other than CKD) including but not 
limited to Cushing’s syndrome, primary hyperaldosteronism, renal vascular stenosis, or 
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2. Inability to measure BP (e.g., the largest sized arm BP cuff is inadequate given the 
circumference of the subject’s arm) 
3. Noncompliance with antihypertensive medications, in the investigator’s judgment  
4. Change in renal function requiring hospitalization or dialysis within 3 months prior to 
screening 
5. Renal transplant or anticipated need for renal transplantation during planned study 
participation 
6. History of malignancy within the previous 12 months except for cured non-melanocytic skin 
cancer 
7. Recent cardiovascular event (within the last 3 months):  myocardial infarction, unstable 
angina, hospitalization for heart failure, revascularization, or stroke (or transient ischemic 
attack) 
8. Clinically significant ventricular arrhythmia 
9. Atrial fibrillation with HR > 100 bpm 
10. Previous use of patiromer in a clinical study 
11. Any current use of spironolactone or other mineralocorticoid antagonists (e.g., eplerenone) 
12. Hypersensitivity to patiromer, spironolactone, or any of their components 
13. Use of any of the following permitted potassium-altering chronic medications if doses have 
not been stable for at least 28 days prior to screening or if doses are anticipated to change 
during study participation:   bronchodilators, theophylline, heparin, and canagiflozin 
14. Use of the following prohibited medications within 7 days prior to Screening:  calcium 
acetate or calcium carbonate supplements (unless for occasional antacid use, at the discretion 
of the Investigator), digoxin, direct renin inhibitors (e.g., aliskiren), lanthanum carbonate, 
lithium, sevelamer, quinidine, sodium polystyrene sulfonate or calcium polystyrene 
sulfonate, colesevelam, colestipol, cholestyramine, drospirenone, potassium supplements, 
bicarbonate or baking soda (unless for occasional antacid use, at the discretion of the 
Investigator), triamterene, amiloride, trimethoprim, tacrolimus, cyclosporine, systemic 
glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors (with 
the exception of low dose aspirin), sympathomimetics 
15. Use of any investigational product within 30 days or 5 half-lives, whichever is longer, prior 
to screening 
16. History of bowel obstruction, swallowing disorders, clinically significant gastroparesis, 
severe gastrointestinal disorders or major gastrointestinal surgery (e.g., large bowel 
resection)  
17. Inability to take the study medications or comply with the protocol, in the opinion of the 
Investigator  
18. History of alcohol or drug abuse within 1 year of screening 


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19. Any medical condition, uncontrolled systemic disease, or serious intercurrent illness that 
would significantly decrease study compliance or jeopardize the safety of the subject or 
affect the validity of the trial results, in the opinion of the Investigator 
4.3 
Subject Withdrawal from Study 
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 Double-Blind 
Treatment Period and the Follow-up Visit.  Subjects will be informed that they will be free to 
withdraw from the study at any time.  However, should a subject withdraw, every effort will be 
made to determine the reason why the subject has withdrawn his/her consent.  Although subjects 
will not be obliged to give a reason for withdrawing consent, the Investigator will make an effort 
to obtain the reason, while fully respecting the subject’s rights.  Reasons for withdrawal of 
consent, when provided by the subject, will be recorded in the electronic case report form 
(eCRF), and the procedures described for ET (Sections 6.4 and 6.2.3) 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 and/or the Medical Monitor may exercise his or her medical judgment to 
terminate a subject’s participation in the study if they determine that the subject’s continued 
participation in the study is a potential safety concern.  The Investigator will immediately inform 
the Medical Monitor of removal or early withdrawal of a subject from the study.  All subjects 
withdrawn early from the study for any reason will complete the procedures described for ET 
and be followed for safety for at least 2 weeks after receiving the last dose of study medications.  
Subjects withdrawn from the study for any reason will not be replaced. 
In addition to other protocol specified discontinuations of study drugs for hyperkalemia and 
hypotension (Appendix B and Appendix C), spironolactone and patiromer/placebo treatment will 
be discontinued for subjects who require maintenance dialysis, become pregnant, or who 
experience a treatment-related SAE during the study.  These subjects will remain in the study 
until study completion and will be treated with in accordance with the standard of care per the 
Investigator’s judgment. 
5 
STUDY TREATMENTS 
5.1 
Treatment Blinding 
To minimize the potential for bias, treatment randomization information will be kept confidential 
by the unblinded biostatistician and will not be released to the investigator or investigator site 
personnel until the study database has been locked.  The blind will be maintained for subjects, 
site personnel, and all Relypsa and vendor staff, with the exception of unblinded staff required 
for the development of the final randomization schedule and for production of unblinded 
materials for the Data Safety Monitoring Committee (DSMC) in addition to Relypsa Drug Safety 
staff in situations where unblinding is necessary to comply with Regulatory requirements. 
The Relypsa staff who may be unblinded will be identified prior to the start of study enrollment.  
If the Investigator, site study staff, or site Investigational Pharmacist becomes aware of a 
subject’s study treatment assignment, efforts should be made to not disclose treatment 


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assignments to other study staff, subjects, or their care-givers.  Blinded Relypsa staff will also 
remain blinded to treatment assignment. 
Subjects should refrain from discussion of their study drugs with the site staff or other subjects, 
and any questions regarding the physical properties or appearance of the study drugs should be 
directed to the dispensing Investigational Pharmacist only. 
5.1.1 
Breaking the Blind 
In the case of a medical emergency, the Investigator may request that the blind be broken if it is 
considered important to the management of the medical emergency.  In such cases, the 
Investigator will be unblinded via the IWRS.  The Investigator should make every reasonable 
attempt to notify the study Medical Monitor before breaking the blind.  The investigator may 
inform the subject and/or his/her treating physician of the treatment assignment. 
5.2 
Allocation to Treatments 
All subjects will begin treatment with spironolactone 25 mg QD on the day after randomization 
to patiromer/placebo (Day 1).  Subsequent dosing decisions will be made in accordance with 
Appendix C. 
Randomization to patiromer or placebo (Day 0) will be 1:1, stratified by baseline potassium level 
(4.3 – < 4.7 and 4.7 – 5.1 mEq/L) based on the potassium value measured by the local laboratory 
at Visit S4 and history of Type 1 or 2 diabetes mellitus (Yes or No), will be performed at the 
Randomization Visit using the IWRS. 
5.3 
Investigational Product Supplies 
5.3.1 
Formulation and Packaging 
Patiromer or placebo will be provided to the subject blinded, as a powder for oral suspension in 
packets.  The individual packets will be assembled as a kit for dispensing containing 20 packets 
each.  Each packet will contain patiromer (4.2g) or placebo (microcrystalline cellulose).  
Patiromer or placebo will be shipped to and stored at the study site refrigerated (2 – 8°C).  Study 
subjects will be instructed to store patiromer or placebo refrigerated (2 – 8°C) for the duration of 
the study. 
Spironolactone 25 mg tablets will be provided to all subjects for oral administration and should 
be stored below 77 degrees Fahrenheit (25 degrees Celsius) (Aldactone PI, 2014). 
5.3.2 
Preparation and Dispensing of Patiromer/Placebo 
Patiromer/placebo are for oral administration only.  Each dose should be prepared immediately 
prior to administration. 
Patiromer/placebo suspension should not be heated (e.g., microwaved) or added to heated foods 
or liquids.  Patiromer or placebo should not be taken in its dry form but mixed with water only.  
Patiromer or placebo doses should be prepared following the steps below: 


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• Measure 1/3 cup (approximately 80 mL) of water.  Pour half of the water into a glass, then 
add patiromer and stir.  Add the remaining half of the water and stir thoroughly.  The powder 
will not dissolve and the mixture will look cloudy.  Add more water to the mixture as needed 
for desired consistency. 
• Drink the mixture immediately.  If powder remains in the glass after drinking, add more 
water, stir and drink immediately.  Repeat as needed to ensure the entire dose is 
administered. 
The Investigational Pharmacist(s) or qualified designee will be responsible for dispensing the 
investigational product and documenting the dispensation.  The Investigational Pharmacist(s) or 
qualified designee will be someone who does not perform any other study assessments. 
At each Double-Blind Treatment Period Visit, subjects should return all empty packets and 
unopened packets in their closed, original box.  Drug accountability will be performed by the 
drug dispensing Investigational Pharmacist or qualified designee. 
5.3.3 
Dosing and Administration of Patiromer/Placebo and Spironolactone 
The starting dose of patiromer/placebo will be two packets QD taken with food for randomized 
subjects.  Patiromer/placebo should be taken at least 3 hours before or 3 hours after 
administration of other orally administered medications, including spironolactone (see 
Section 5.5.1 and Investigator’s Brochure for additional information). 
Based upon the patiromer/placebo treatment algorithm (Section 3.1.2 and Appendix B), 
patiromer/placebo will be increased in two-packet per day increments for serum K+ > 5.1 mEq/L 
in intervals of at least 1 week.  Doses of patiromer/placebo will be two packets, four packets, and 
six packets (maximum dose).  Patiromer/placebo will be decreased by at least two packets per 
day for serum K+ < 4.0 mEq/L.  The minimum daily dose of patiromer/placebo will be 0 packets. 
All subjects will initiate spironolactone 25 mg QD on Day 1.  At the Week 3 visit (or after), the 
spironolactone dose will be increased to 50 mg QD for subjects with AOBP SBP ≥ 120 mmHg 
and K+ ≤ 5.1 mEq/L.  For subjects with K+ > 5.1 mEq/L, 25 mg daily dose of spironolactone will 
be continued until the first subsequent visit when K+ is ≤ 5.1 mEq/L (and AOBP SBP 
≥ 120 mmHg), at which time spironolactone will be increased to 50 mg QD (see Appendix C). 
Note:  During all study visits, if a subject experiences symptoms of hypotension with 
SBP < 120 mmHg, or if SBP < 100 mmHg, spironolactone dose may be reduced to 25 mg every 
other day or discontinued at the discretion of the Investigator. 
5.3.4 
Study Drug Adherence 
At Randomization on Day 0, subjects will be instructed on proper dosing of study drugs with 
detailed instructions on when to take study drugs and all concomitant medications after 
considering the subject’s current medication regimen, patiromer/placebo instructions regarding 
administration, and subject preference.  The subject will be instructed to follow the agreed 
dosing instructions for the remainder of the study to encourage compliance.  The Investigator 


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will determine if the dosing instruction requires changes at each visit and any changes will be 
communicated to the subject. 
Subjects will also be instructed to return any unused spironolactone tablets and to save their 
empty/used patiromer or placebo packets and bring them together with any unopened packets to 
the next visit for compliance assessment.  Subjects will be instructed to return empty/used 
patiromer or placebo packets in the box or containers in which originally provided.  In order to 
minimize the potential of study staff unblinding, the Investigational Pharmacist or the qualified 
designee who is not involved in subject study procedures will assess compliance based on 
returned empty and unopened packets and returned spironolactone tablets during the 12-week 
Double-Blind Treatment Period to confirm that the subject is taking patiromer or placebo and 
spironolactone according to the protocol instructions. 
Compliance will be documented in the eCRF as detailed in the electronic data capture (EDC) 
completion guidelines.  Compliance will be assessed on the basis of the prescribed 
patiromer/placebo and spironolactone doses, the duration of treatment, and the quantity of 
dispensed and returned kits/packets (used and unused) and returned tablets.  The Investigational 
Pharmacist will inform the study personnel if any compliance issues are identified so that the 
subject can be retrained on proper dosing and administration. 
5.4 
Investigational Product Storage and Accountability 
The Investigational Pharmacist or designee will verify and acknowledge receipt of each shipment 
of patiromer/placebo and spironolactone.  Patiromer/placebo will be shipped and stored under 
refrigeration (2 – 8 degrees Celsius).  Spironolactone should be shipped and stored at 
temperatures less than 77 degrees Fahrenheit (25 degrees Celsius) (Aldactone PI, 2014).  All 
study drugs will be stored in a secure location.  No subject other than those enrolled in this 
specific clinical study shall take patiromer/placebo or spironolactone provided for this study.  
Patiromer/placebo or spironolactone provided for this study may not be utilized for any 
laboratory or animal research.  All investigational product dispensed to subjects must be 
accurately recorded on the Investigational Product Accountability Record maintained at the 
Study Site by the Investigational Pharmacist or the qualified designee.  Subjects should be 
instructed to return all investigational product dispensed to them (including empty containers) at 
each study visit.  All investigational product and empty containers will be retained at the site by 
the Investigational Pharmacist/qualified designee for the Study Monitor’s verification.  
Investigational Product accountability and compliance for all investigational products will be 
performed by the site Investigational Pharmacist or the qualified designee at each scheduled 
study visit starting at the Baseline Visit and ending on the Week 12 or ET Visit. 
5.5 
Concomitant Medications 
Information on concomitant medication (prescription, over-the-counter, herbal and naturopathic 
remedies, etc.) will be collected beginning at the Screening Visit and continuing for the duration 
of the study (including ET Visit) until the Follow-up visit or Follow-up Phone Call. 
In general, subjects should continue on the same medications and regimens that were ongoing at 
the study entry. Subjects should be instructed to delay taking their blood pressure medications on 


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the morning of study visits until after office blood pressure measurements have been completed.  
Doses of these medications should be kept as stable as possible during the study.  Medications 
that the Investigator deems indicated for treatment of any intercurrent illness or a pre-existing 
condition that are not on the prohibited medication list or do not form an exclusion criterion for 
participation in this study will generally be allowed.  If new medications for mild to moderate 
pain relief are required, NSAIDs and COX-2 inhibitors should be avoided, as they are prohibited 
medications due to their effects on BP and serum potassium, and alternatives such as 
acetaminophen should be used. 
5.5.1 
Timing of Oral Drug Administration 
Based on data from human in vivo DDI studies, patiromer/placebo should be taken at least 3 
hours before or 3 hours after administration of other orally administered medications 
(see Investigator’s Brochure and Section 5.3.3 for further details).  Each subject will be provided 
with individualized instructions for when to take spironolactone, patiromer/placebo, and other 
medications after consideration of the subject’s current medication regimen and subject’s 
preference.  The instructions will be updated during the study if any changes to the subject’s 
medication regimen occurs during the study. 
For subjects taking medications with a narrow therapeutic index, careful monitoring is advised. 
5.5.2 
Permitted Medications 
The following potassium-altering chronic medications will be permitted provided that the 
treatment doses are stable for at least 28 days prior to screening and no changes are anticipated 
during the study: 
• bronchodilators 
• theophylline 
• heparin 
• canagliflozin 
5.5.2.1 
Permitted Antihypertensive Medications 
All antihypertensive drugs (except spironolactone, eplerenone, or other MRAs, and aliskiren or 
other direct renin inhibitors) will be permitted at screening and baseline if the subject has been 
on a stable dose for at least 28 days prior to screening.  During subject’s participation in the 
study, no new antihypertensive medications will be initiated, except as outlined in the protocol 
(Section 3.1.2 and Appendix D).  Baseline antihypertensive medication doses will not be 
changed and new ACE inhibitors or ARBs will not be initiated during the study except in the 
management of AOBP > 200 mmHg (see Appendix D).  Spironolactone may not be reinitiated if 
it has been discontinued during the study.  Treatment of hypertension in these subjects should be 
standard of care, in accordance with the clinical judgment of the Investigator. 


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5.5.3 
Permitted Medications for Heart Failure 
The following medications will be permitted at screening and baseline for the management of 
heart failure as long as doses have remained stable for 28 days prior to screening:  thiazide and 
loop diuretics, ACE inhibitors, ARBs, beta-adrenergic blockers, hydralazine and long-acting 
nitrates. 
During the study, no new ACE inhibitors or ARBs will be initiated except as described in the 
protocol (see Appendix D) and every effort will be made to keep the doses of all these 
medications stable. 
5.5.4 
Prohibited Medications 
During the entire study, the following medications will be prohibited while being treated with 
patiromer/placebo: 
• calcium acetate or calcium carbonate supplements (unless for occasional antacid use, at the 
discretion of the Investigator)  
• digoxin 
• eplerenone or other MRAs 
• lanthanum carbonate 
• sevelamer 
• quinidine 
• sodium polystyrene sulfonate or calcium polystyrene sulfonate 
• colesevelam 
• colestipol 
• cholestyramine 
• drospirenone 
• therapeutic potassium supplements 
• bicarbonate or baking soda (unless for occasional antacid use, at the discretion of the 
Investigator) 
• trimethoprim 
• tacrolimus 
• cyclosporine 
• systemic glucocorticoids 


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• NSAIDs or COX-2 inhibitors, except low dose aspirin 
• sympathomimetics 
• lithium 
• aliskiren or any direct renin inhibitor 
• potassium sparing diuretics such as triamterene and amiloride 
6 
TRIAL PROCEDURES 
Refer to the Schedule of Events (Appendix A) for the frequency and timing of the required study 
assessments and activities.  For dietary counseling refer to Section 7.5. The following 
chronology of events should be adhered to at each visit: 
1. EQ-5D-5L Questionnaire (S4 and Week 12 Visits only) 
2. AOBP 
3. SMBP 
4. Other procedures 
6.1 
Screening/Run-in Period (up to 4 Weeks): 
Before any study-specific procedures are performed, the subject will receive an explanation of all 
study procedures and must sign and date a written informed consent form (ICF) approved by an 
institutional review board (IRB) (see Section 12.2 for additional requirements).  The timing of 
the Screening Visit (and all subsequent visits) must take into account planned absences at the 
research facility and the need for study visits according to the Schedule of Events (Appendix A). 
The subjects will be instructed to arrive at the scheduled time for each Screening Visit to allow 
for completion of all assessments including measurement of the potassium level by the local 
laboratory.  At the first Screening Visit, subjects will be assigned a unique subject identification 
number, which will be generated during Screening Visit registration in IWRS. On the morning of 
all study visits after S1, the subjects will be instructed to delay taking their BP medications until 
office BP measurements have been completed. 
The Screening/Run-in Period will consist of 4 Screening Visits (S1, S2, S3, and S4) that will 
occur approximately 7 days (at least 4 days but no more than 10 days) after the prior Screening 
Visit (Appendix A). 
6.1.1 
S1  
The following activities will be performed (Appendix A): 
• Subject signs informed consent  


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• IWRS registration  
• Review inclusion and exclusion criteria  
• Collect demographic information 
• Review medical history  
• Measure height and weight 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes  
• Perform physical examination 
• Perform 12-lead ECG 
• Record AOBP (Section 7.3.2.2) performed using automatic oscillometric office device with 
the capability of performing automatic multiple measurements after the study staff has left 
the room (unwitnessed measurement after the subject has been sitting quietly for 5 minutes) 
• Issue HBP monitor and appropriate size blood pressure cuff 
• Train subject on use of HBP monitor and collection of twice daily measurements (see 
Section 7.3.2.1)  
• Collect blood samples for evaluation of (see Appendix E): 
- 
Potassium level (measured locally and by central laboratory) 
- 
Serum chemistry including creatinine, eGFR (central laboratory) 
- 
Hematology (central laboratory) 
- 
Pregnancy (central laboratory) 
• Collect urine sample for urinalysis (central laboratory)  
• Dietary counselling  
• AE assessment 
• Record concomitant medications  
6.1.2 
S2 (1 week [a least 4 days but no more than 10 days] after S1)  
At each study visit beginning with S2, the office blood pressure (AOBP and SMBP) should be 
performed before other scheduled activities. The following activities will be performed 
(Appendix A): 
• IWRS registration 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 


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• Record AOBP (Section 7.3.2.2) performed using automatic oscillometric office device with 
the capability of performing automatic multiple measurements after the study staff has left 
the room (unwitnessed measurement after the subject has been sitting quietly for 5 minutes) 
• Record SMBP (Section 7.3.2.2) performed onsite using the subject’s HPB monitor.  If a 
subject does not bring their issued HBP monitor to the visit, the SMBP will be missing for 
that Visit 
• Train subject on use of HBP monitor and collection of twice daily measurements as 
necessary (see Section 7.3.2.1)  
• Dietary counselling  
• AE assessment 
• Record concomitant medications 
6.1.3 
S3 (1 week [at least 4 days but no more than 10 days] after S2) 
The office blood pressure (AOBP and SMBP) should be performed before other scheduled 
activities.  The following activities will be performed (Appendix A): 
• IWRS registration 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes  
• Record AOBP (Section 7.3.2.2) performed using automatic oscillometric office device with 
the capability of performing automatic multiple measurements after the study staff has left 
the room (unwitnessed measurement after the subject has been sitting quietly for 5 minutes) 
• Record SMBP (Section 7.3.2.2) performed onsite using the subject’s HPB monitor.  If a 
subject does not bring their issued HBP monitor to the visit, the SMBP will be missing for 
that Visit 
• Train subject on use of HBP monitor and collection of twice daily measurements as 
necessary (see Section 7.3.2.1)  
• Collect blood samples for evaluation of: 
- 
Potassium level (measured locally and by central laboratory) 
- 
Serum chemistry including creatinine, eGFR (central laboratory; see Appendix E) 
• Dispense 24-hour urine collection container for urine sodium, potassium, creatinine, and 
albumin (for ACR) (to be collected for 24 hours beginning at least 24 hours before the 
S4 Visit) 
• Train subject on 24-hour urine collection.  The 24-hour urine collection should begin 
immediately after the first morning void at least 24 hours before the S4 visit. 


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• Dispense urine collection cups for S4 urine ACR determination (total of 2 urine specimens to 
be collected on the morning of the second and third days before the S4 visit).  These samples 
will be sent to the central laboratory on day of S4. 
• Train subject for ACR collection 
• Dietary counselling  
• AE assessment 
• Record concomitant medications  
6.1.4 
S4 (1 week [a least 4 days but no more than 10 days] after S3) 
The EQ-5D-5L assessment should be performed first, then the office blood pressure (AOBP and 
SMBP) second, and all other scheduled activities should be performed after.  The following 
activities will be performed (Appendix A): 
• IWRS registration 
• Review inclusion and exclusion criteria 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Record AOBP (Section 7.3.2.2) performed using automatic oscillometric office device with 
the capability of performing automatic multiple measurements after the study staff has left 
the room (unwitnessed measurement after the subject has been sitting quietly for 5 minutes) 
• Record SMBP (Section 7.3.2.2) performed onsite using the subject’s HPB monitor.  If a 
subject does not bring their issued HBP monitor to the visit, the SMBP will be missing for 
that Visit 
• Train subject on use of HBP monitor and collection of twice daily measurements as 
necessary (see Section 7.3.2.1) 
• Collect blood samples for evaluation of (see Appendix E): 
- 
Potassium level (measured locally, and central laboratory if subject meets all eligibility 
criteria) 
- 
Serum chemistry including creatinine, eGFR (send to central laboratory only if subject 
meets all eligibility criteria) 
- 
Hematology (send to central laboratory only if subject meets all eligibility criteria) 
- 
NT-proBNP (see Section 7.2.1, send to central laboratory only if subject meets all 
eligibility criteria) 
- 
Aldosterone and plasma renin activity (send to central laboratory only if subject meets all 
eligibility criteria) 
• Collect 24-hour urine specimen for sodium, potassium, creatinine and albumin (for ACR) 
(collected for 24 hours prior to Visit S4) 


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• Collect ACR urine specimens (samples from first morning voids on the second and third day 
before S4, see Appendix A). 
• Perform urine pregnancy test for women of child bearing potential 
• AE assessment 
• Record concomitant medications 
Discard all central laboratory samples for subjects who do not meet study entry criteria. 
6.1.5 
Rescreening of Subjects 
Subjects who meet all study entry criteria except for eGFR and/or serum potassium will be 
screen failures but may be rescreened once at least 2 weeks after initial screen failure. 
To rescreen a subject: 
• The Medical Monitor must be contacted for rescreening approval 
• The subject must be re-consented 
• The subject must receive a new subject identification number assigned by IWRS 
• All Screening Visits (S1-S4) and assessments must be repeated (see Section 6.1) 
6.2 
Double-Blind Treatment Period (12 Weeks) 
Subjects who meet all eligibility criteria at Visit S4 will be randomized on the same day, and S4 
assessments will be considered the baseline assessments and will not be repeated.  For these 
subjects, Visit S4 will be designated as the S4/Randomization (Baseline, Day 0) Visit. 
6.2.1 
Randomization (Baseline, Day 0) Visit 
The following activities will be performed at Randomization (Baseline, Day 0) Visit in addition 
to those performed for the S4 Visit (Section 6.1.4 and Appendix A): 
• Confirm subject meets all entry criteria 
• IWRS randomization to patiromer or placebo (assignment blinded) 
• Measure weight 
• Send urine samples for baseline urinalysis (central laboratory)  
• Establish dosing schedule for study drugs and all concomitant medications in collaboration 
with the subject; instruct the subject to begin study medications on the following day (Day 1) 


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• Investigational Pharmacist or qualified designee dispenses spironolactone and blinded 
patiromer/placebo based on kit number assigned by IWRS and instructs subject to begin 
taking medications on Day 1 (see Section 3.1.2) 
• Subject completes EQ-5D-5L Questionnaire 
• Dietary counselling  
6.2.2 
Week 1 – Week 4 (± 3 days); Week 6, Week 8, and Week 10 (± 7 days) 
At all scheduled or unscheduled study visits during the Double-Blind Treatment Period after 
Day 1, the local potassium level will be used for adjustments to patiromer/placebo dose and 
spironolactone administration in accordance with the study patiromer/placebo and spironolactone 
dosing algorithms (see Appendix B and Appendix C).  AOBP will also be assessed and 
adjustments to spironolactone administration or BP management will be made in accordance 
with Section 3.1.2, Appendix C and Appendix D.  Modification of baseline antihypertensive 
medications will not be allowed, except in subjects with SBP ≥ 200 mmHg or for AE-related 
reasons where changes to baseline medications can be justified by the Investigator (e.g., 
increases in loop diuretics for new edematous states or discontinuation of baseline medication for 
drug-related AEs), as described in Section 3.1.2 and Appendix D. 
The office blood pressure measurements (AOBP and SMBP) should be performed before other 
scheduled activities.  The following activities will be performed (Appendix A): 
• IWRS registration 
• Measure resting heart rate after the subject has been sitting quietly for 5 minutes 
• Record AOBP (Section 7.3.2.2) performed using automatic oscillometric office device with 
the capability of performing automatic multiple measurements after the study staff has left 
the room (unwitnessed measurement after the subject has been sitting quietly for 5 minutes) 
• Record SMBP (Section 7.3.2.2) performed onsite using the subject’s HPB monitor.  If a 
subject does not bring their issued HBP monitor to the visit, the SMBP will be missing for 
that Visit 
• Review HBP measurement procedure with subject, as necessary 
• Collect blood samples for evaluation of: 
- 
Potassium level (measured locally and by central laboratory) 
- 
Serum chemistry including creatinine, eGFR (central laboratory; see Appendix E)  
- 
Hematology, (central laboratory; Week 4 only; see Appendix E) 
- 
Spironolactone level (at Week1, Week 4 and Week 8 only, see Section 7.2.2) 
• Dispense urine ACR collection cups and train subject regarding ACR collection at Week 3, 
Week 6 and Week 10 (for Week 12 Visit) visits.  Instruct the subject to collect three first 
morning void urine samples for evaluation of urine ACR (central laboratory; Week 4 and 


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Week 8 only; see Appendix A).  Urine specimens will be collected at home from first 
morning void for the days specified below, and sent to the central laboratory with the visit 
samples; see Section 7.7) 
- 
Week 4 samples (3 separate samples) 
◦ 
2 days before the visit 
◦ 
1 day before the visit 
◦ 
Day of the visit 
- 
Week 8 samples (3 separate samples) 
◦ 
2 days before the visit 
◦ 
1 day before the visit 
◦ 
Day of the visit 
• Investigational Pharmacist or qualified designee dispenses blinded patiromer/placebo based 
on kit number assigned by IWRS in accordance with Section 3.1.2 (see Appendix B) 
• Investigational Pharmacist or qualified designee dispenses spironolactone in accordance with 
instructions in Section 3.1.2 (Appendix C) 
• Investigational Pharmacist or qualified designee performs drug accountability 
• Review potassium measured locally and AOBP results and adjust study medications 
according to Section 3.1.2 and Appendix B, Appendix C, and Appendix D. 
• Dietary counselling 
• AE assessment 
• Record concomitant medications 
6.2.3 
Week 12 Visit (± 7 days) 
The Week 12 Visit is the last visit for the Double-Blind Treatment Period of the study.  At the 
Week 12 Visit, all study drug treatments will be discontinued.  Investigators may prescribe out of 
study (i.e., standard of care) antihypertensive medication if needed. 
The EQ-5D-5L assessment should be performed first, then the office blood pressure (AOBP and 
SMBP) second, and all other scheduled activities should be performed after.  The following 
activities will be performed (Appendix A):  
• IWRS registration 
•  Record AOBP (Section 7.3.2.2) performed using automatic oscillometric office device with 
the capability of performing automatic multiple measurements after the study staff has left 
the room (unwitnessed measurement after the subject has been sitting quietly for 5 minutes) 


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• Record SMBP (Section 7.3.2.2) performed onsite using HPB monitor.  If a subject does not 
bring their issued HBP monitor to the visit, the Subject-measured Office BP will be missing 
for that Visit 
• Measure resting heart rate after the subject has been sitting quietly for 5 minutes 
• Measure weight 
• Perform physical examination 
• Perform 12-Lead ECG 
• Collect HBP monitors 
• Collect blood samples for evaluation of: 
- 
Potassium level (measured locally and by central laboratory) 
- 
Serum chemistry including creatinine, eGFR (central laboratory; (see Appendix E) 
- 
Hematology, (central laboratory; see Appendix E) 
- 
Pregnancy (central laboratory; see Appendix E) 
- 
NT-proBNP (see Section 7.2.1) 
- 
Spironolactone level (see Section 7.2.2) 
• Collect urine sample for evaluation of urinalysis (central laboratory; see Appendix E) 
• Collect subject’s three first morning void urine samples for evaluation of urine ACR 
(central laboratory) Week 12 (see Section 7.7) 
- 
Week 12 samples (3 separate samples) 
◦ 
2 days before the visit 
◦ 
1 day before the visit 
◦ 
Day of the visit 
• Subject completes EQ-5D-5L Questionnaire 
• Investigational Pharmacist or qualified designee performs drug accountability 
• AE assessment 
• Dietary counselling 
• Record concomitant medications 
6.3 
Follow-up Visit (2 weeks after Week-12 or ET Visit, + up to 7 day window) 
The office blood pressure (AOBP) should be performed before other schedule activities.  The 
following activities will be performed (Appendix A): 


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• IWRS registration 
• Measure resting heart rate after the subject has been sitting quietly for 5 minutes 
• Record AOBP (Section 7.3.2.2) performed using automatic oscillometric office device with 
the capability of performing automatic multiple measurements after the study staff has left 
the room (unwitnessed measurement after the subject has been sitting quietly for 5 minutes) 
• Collect blood samples for evaluation of: 
- 
Potassium level (measured locally and by central laboratory) 
- 
Serum chemistry including creatinine, eGFR (central laboratory; see Appendix E)  
• AE assessment 
• Record concomitant medications  
The Investigator may request the subject to return to the study site for unscheduled visits prior to 
the Follow-up Visit to evaluate potassium levels, blood pressure, or AEs (see Section 6.5). 
6.3.1 
Follow-up Phone Call 
Only for subjects with a Follow-up Visit < 2 weeks after Week-12 or ET Visit or those who did 
not attend the Follow-up Visit will receive a Follow-up Phone call 2 weeks after Week-12 or ET 
Visit (+ up to 7 days window). 
Assessments performed over the phone call: 
• AE assessment  
• Concomitant medication assessment for any drugs used to treat an AE 
6.4 
Early Termination Visit 
Subjects who withdraw prematurely from the study before the Week 12 Visit will complete the 
ET Visit, which will be performed on the day of the withdrawal or as soon as possible.  All 
assessments (aside from those that require activities prior to the ET Visit; i.e., urine collections 
for ACR) applicable to the Week 12 Visit (Section 6.2.3) will be performed at the ET Visit. 
6.5 
Unscheduled Visits 
At any study visit, if a hyperkalemia event (K+ ≥ 5.5 mEq/L) and/or modification of study 
drug(s) occurs, an Unscheduled visit will be conducted within 1 week after modification of study 
drugs (Appendix B and Appendix C) unless the next scheduled visit is within 1 week of the 
study drug modification, in which case, the subject will return at the next scheduled visit. 
Additional Unscheduled Visits may be conducted during the study as needed, at the discretion of 
the Investigator. 
The following activities will occur any time an Unscheduled Visit is performed during the study:  


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The office blood pressure (AOBP and SMBP) should be performed before other scheduled 
activities. 
• IWRS registration  
• Measure resting heart rate  
• Measure AOBP using automatic oscillometric office device with the capability of performing 
automatic multiple measurements after the study staff has left the room (unwitnessed 
measurement after the subject has been sitting quietly for 5 minutes; Section 7.3.2.2) 
• Potassium level (measured locally and by central laboratory) 
• Dietary counselling  
• AE assessment 
• Record concomitant medications  
The following activities are optional during an Unscheduled Visit: 
• Measure weight 
• Perform physical exam and/or ECG as indicated 
 
• Dispense blinded patiromer or placebo according to the kit number assigned by IWRS 
(except for Unscheduled Visits after Week 12 or ET Visit) 
• Collect blood samples for evaluation of the following (central laboratory; see Appendix E): 
- 
Serum chemistry including creatinine, eGFR 
- 
Hematology 
• Dispense spironolactone, as necessary (see Appendix B and Appendix C) (except for 
Unscheduled Visits after Week 12 or ET Visit) 
• Investigational Pharmacist or qualified designee performs drug accountability  
7 
ASSESSMENTS 
7.1 
Potassium 
Serum potassium levels will be assessed locally and by central laboratory at all study visits 
including unscheduled visits (Appendix A).  Screen Failure subjects who meet all other study 
entry criteria except for potassium level and/or eGFR may be rescreened once (see 
Section 6.1.5).  Detailed instructions on how to draw blood and prepare specimens for analysis 
are provided in the Laboratory Manual. 


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7.1.1 
Preventing, Identifying and Handling Hemolyzed Samples 
Hemolysis of blood specimens may result in spuriously high potassium levels, potentially 
leading to inappropriate up-titrating of patiromer/placebo or inappropriate discontinuations of 
spironolactone in this study 
The Laboratory Manual provides detailed descriptions of the recommended phlebotomy, sample 
preparation and transportation procedures to minimize hemolysis.  Upon receipt of each blood 
sample for potassium analysis, the central laboratory will perform a semiquantitative test to 
assess for evidence of hemolysis.  Predefined criteria will be established for determining whether 
the test result is indicative of potential hemolysis.  These criteria and the criteria for removing 
serum potassium value from the efficacy analyses on the basis of hemolysis are described in the 
Laboratory Manual.  When a central laboratory sample has been identified as hemolyzed after it 
has been received and processed by the central laboratory, the blood draw will not be repeated by 
the site personnel.  The statistical analysis plan (SAP) summarizes how the data analyses will 
account for the missing central laboratory potassium value.  If the central laboratory blood 
sample has been identified as hemolyzed by the site personnel (i.e., visual inspection) before it 
has been sent to the central laboratory, a repeat blood draw can be performed if the subject is still 
at the site. 
When a blood sample, which will be used by the site for study drug titration and subject 
management, has hemolyzed (e.g., by visual inspection of the local laboratory serum sample), 
the site will repeat the potassium measurement from a separate blood draw within 1 day in order 
to ensure accurate decision-making regarding patiromer/placebo titration. 
7.2 
Laboratory Tests 
All laboratory assessments will be performed by central laboratory unless specified in the 
Schedule of Events (Appendix A).  All central laboratory assessments are detailed in Appendix 
E. 
7.2.1 
NT-proBNP 
Blood samples collected at the S4/Baseline (Day 0) Visit and Week-12 visit or ET Visit will be 
analyzed for NT-proBNP levels.  Please refer to the Laboratory Manual for additional 
information. 
7.2.2 
Spironolactone Level (Mass Spectrometry Analysis) 
Blood samples collected at Week 1, Week 4, Week 8, and Week 12 or ET Visit from subjects 
who are still receiving spironolactone at the indicated visit will be analyzed for spironolactone 
levels using mass spectrometry.  Please refer to the Laboratory Manual for additional 
information. 


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7.3 
Vital Signs 
The subject should avoid eating, smoking, or exercising for 30 minutes before vital sign 
measurements are taken.  The subject should rest, sitting quietly, for approximately 5 minutes 
prior to the measurements. 
7.3.1 
Heart Rate 
Heart rate should be measured after the subject has been sitting quietly for 5 minutes prior to BP 
measurement, and should be measured for a full 60 seconds. 
7.3.2 
Blood Pressure 
7.3.2.1 
Home Blood Pressure  
At the first Screening Visit (S1), subjects will be issued a HBP monitor and an appropriate size 
BP cuff by the study site personnel and will be trained on use of the device.  Subjects will be 
asked to measure their BP at home twice daily during the Screening/Run-in Period and during 
the 12-Week Double-Blind Treatment Period. 
Subjects will be instructed to perform HBP measurements twice daily (morning and evening) at 
approximately the same times each day (e.g., at 8:00 [morning] and 20:00 in the [evening]) in 
triplicate (see HBP Training Materials and Manual of Operations; Mancia, 2013). 
Note:  Subjects will be instructed to bring their issued monitors to each scheduled visit.  If a 
subject does not bring their issued monitor, only an automatic oscillometric Office BP will be 
measured (Section 7.3.2.2).  The site will be notified regarding out-of-range HBP and subject 
noncompliance.  
7.3.2.2 
Office Blood Pressure 
AOBP measurements will be performed by an automatic oscillometric BP measurement device 
that can measure BP in triplicate and with no study staff present.  See Manual of Operations for 
complete instructions.  At all scheduled visits except for Visit S1, two types of BP measurements 
will be performed onsite.  Both measurements will be performed before other scheduled 
activities (except for S4 and Week 12 Visits where EQ-5D-5L will be the first assessment) with 
the subject alone with no study staff present after the subject has been seated quietly for 
5 minutes: 
1. Performed by an automatic oscillometric BP measurement device that can measure BP in 
triplicate (automated office BP, AOBP) 
2. Performed by the subject using their issued HBP monitoring device in triplicate 
(subject-measured BP, SMBP) 
For subjects who do not bring their issued HBP monitor to the study visit, the onsite SMBP data 
will be missing for that Visit. 


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7.4 
Physical Examination 
Physical examination will be performed as indicated in the Schedule of Events (see Appendix 
A).  The following body systems are to be examined: 
• Cardiovascular 
• Lungs and chest, including respirations 
• Head and neck 
• Abdomen 
• Musculoskeletal 
• Skin 
• Neurological 
Any new clinically significant physical examination abnormality identified during the study will 
be reported as an AE. 
7.5 
Diet 
Hypertension in subjects with CKD is often accompanied by a decrease in the kidney’s ability to 
excrete salt.  Addressing this salt sensitivity is critical for the management of hypertension in 
CKD.  Dietary counseling will be conducted at each visit in accordance with the standard 
practices of the Investigator and should address all the dietary requirements of the subject (e.g., 
diabetes mellitus), as appropriate.  The dietary intake of potassium containing foods should not 
be changed during the study. 
7.6 
ECG Assessment 
If the Investigator is concerned regarding any potassium value, a retest of potassium level and/or 
ECG evaluation for electrophysiological manifestations can be initiated by the Investigator at 
their discretion. 
The subject should be resting quietly for a minimum of 5 minutes prior to obtaining the ECG.  
If a new potassium-related ECG change is observed, the Investigator should apply the 
appropriate standard of care to evaluate and treat hyperkalemia.  Any subject with new 
potassium-related ECG changes and local K+ ≥ 5.5 mEq/L will discontinue spironolactone and 
patiromer/placebo immediately but will remain in the study and complete all remaining study 
visits while receiving appropriate therapy as indicated.  BP management will proceed in 
accordance with Section 3.1.2 and Appendix D. 
7.7 
Urine Collection for ACR 
Urine samples will be collected at the S4/Baseline, Week 4, Week 8, Week 12 (or ET Visit), in 
order to calculate the ACR.  Section 6 and Appendix A describe the visits at which urine sample 
containers will be dispensed.  Urine collection for this purpose will be collected by the subject at 


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home.  Urine specimens will be collected from the first morning void for the 2 days prior to and 
the morning of the Visit (see Section 6 and Appendix A) for the Week 4, Week 8, and Week 12 
collections.  For the S4/Baseline (Day 0) Visit, urine from the first morning void will be 
collected on the second and third days before the Visit.  After the first morning void sample is 
collected on the second day before the Visit, the 24-hour urine sample collection will begin and 
should be completed on the morning of the S4/Baseline Visit (see Section 7.8).  At an ET Visit, a 
single spot urine specimen may be collected at the clinic if time permits.  Detailed description of 
the urine collection process for ACR measurements is provided in the Laboratory Manual. 
7.8 
24-Hour Urine Collection for Sodium, Potassium, Creatinine, Albumin (for ACR) 
A single 24-hour urine collection will be performed beginning at least 24 hours prior to the 
S4/Baseline (Day 0) Visit to assess the baseline urine sodium, potassium, albumin, and creatinine 
levels (for baseline ACR).  These urine albumin and creatinine measurements will be used in 
addition to those from first morning void samples for assessment of baseline ACR (section 7.7).  
Detailed description of the urine collection process for 24-hour urine sodium, potassium, 
albumin, creatinine measurements (for ACR) is provided in the Laboratory Manual. 
7.9 
EQ-5D-5L Questionnaire 
Subject reported outcome will be assessed using the EQ-5D-5L questionnaire, comprised of five 
questions each with five levels (e.g., no problems, slight problems, moderate problems, severe 
problems and extreme problems) representing five health domains:  mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression.  The EQ-5D-5L also includes a visual analog 
scale (VAS) that records the subject’s self-rated health status on a graduated scale that ranges 
from 0–100, with higher scores indicating higher health-related quality of life. 
Subjects will complete the EQ-5D-5L questionnaire at the Baseline (Day 0) and Week-12 or 
ET Visits.  Subjects will complete the EQ-5D-5L questionnaire before study staff performs any 
clinic or study assessments to avoid biasing the subjects’ responses.  The study coordinators will 
review the subject’s responses to the EQ-5D-5L questionnaire immediately after completion by 
subject to ensure that all questions are answered with a single response. 
8 
ADVERSE EVENT REPORTING 
8.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment (Clinical Safety Data Management, 1995).  An AE can therefore be any unfavorable or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  This includes:  1) any new medical condition, sign or 
symptom, clinically significant physical examination abnormality or newly diagnosed event that 
occurs during the AE reporting period (see Section 8.2.1), including signs or symptoms 
associated with an underlying condition that were not present prior to the AE reporting period; 
2) a preexisting condition that has worsened in severity or frequency or changed in character 
after the subject signs the informed consent during the AE reporting period; and 3) complications 


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that occur as a result of protocol-mandated interventions.  An AE can arise from any use of the 
investigational drug (e.g., off-label use, use in combination with another drug) and from any 
route of administration, formulation, or dose, including an overdose.  It also includes any side 
effects, injury, toxicity or sensitivity reactions that may be experienced by a subject in this 
clinical trial. 
Out of range laboratory results, 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 will 
be recorded as an AE) 
• Lead to discontinuation of patiromer 
• Required treatment or subject referral for further testing outside the protocol (repeat testing 
or titration are within protocol procedures) 
• The Investigator or Relypsa considered the abnormality as clinically significant in its own 
right (e.g., asymptomatic creatinine kinase > 5000 IU/L) 
For the purposes of this protocol, events that will not be considered AEs include: 
• Anticipated fluctuating signs or symptoms of a pre-existing medical condition (e.g., tremor in 
a subject with Parkinson’s disease; migraine episodes) that have not worsened in severity or 
frequency or changed in character during the AE reporting period 
• Surgeries or medical procedures are not AEs, however, the medical condition (new or 
worsened) that led to the surgery or medical procedure is the reported AE (e.g., for 
appendicitis resulting in appendectomy, appendicitis would be reported as the AE). 
• Overdose without clinical signs or symptoms 
• Pregnancy (see Section 8.4 for reporting obligations) 
8.1.1 
Definition of Serious Adverse Event 
An SAE is an AE that meets one or more of the following criteria: 
• Death 
• Life threatening experience defined as any AE that in the view of the Investigator or 
Relypsa, places the subject at immediate 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 an overnight 
hospital admission 
- 
Elective surgery for a pre-existing condition that has not worsened 


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- 
Routine health assessments requiring admission 
- 
Social admission (lack of housing, family circumstances, etc.) 
• Results in persistent or significant disability/incapacity (i.e.:  a substantial disruption of 
the ability to conduct normal life functions/ normal activities of daily living) 
• Is a congenital anomaly or birth defect in an offspring of a female subject taking patiromer 
or a congenital anomaly or birth defect in the female partner of a male subject taking 
patiromer during the conduct of the clinical study 
• Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization but based upon medical judgment, jeopardizes the subject and may 
require medical or surgical intervention to prevent one of the outcomes above (e.g., blood 
dyscrasias; convulsions) 
Either the Investigator or Relypsa 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 
Relypsa for expedited reporting 
8.2 
Procedures for Eliciting, Recording and Reporting Adverse Events 
8.2.1 
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 (normally Follow-up Visit).  Any AE or 
SAE will be followed until the event or its sequelae resolves or becomes stable or otherwise 
justified by the Investigator in agreement with Relypsa.  The Investigator must report any AEs 
that occur after the protocol specified reporting period if according to the Investigator’s 
assessment there was a reasonable possibility that the AE was related to patiromer or any study 
procedures. 
8.2.2 
Eliciting Adverse Events 
Information on AEs and SAEs will be elicited at each AE assessment time point specified in the 
Schedule of Events 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. 
8.2.3 
Assessing Adverse Events 
The Investigator will follow the guidelines for rating severity of AEs: 


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Mild: 
No disruption to normal activities.  Awareness of signs or symptoms, but 
easily tolerated; symptoms are transient and would not require medication or 
medical evaluation. 
Moderate: 
Some disruption to normal activities.  May lead to discomfort, treatment may 
be required. 
Severe: 
Significant disruption to normal activities.  May be incapacitating; may require 
medical evaluation and/or treatment. 
The term “severe” is often used to describe the intensity of a specific event; the event itself, 
however, may be of relatively minor medical significance, such as severe headache.  Severity of 
the event is not the same as seriousness, which is a regulatory definition.  Regardless of the 
severity, an AE is serious if it meets seriousness criteria (see Section 8.1.1). 
8.2.4 
Causality Assessments 
The Investigator will provide a causality assessment for all AEs using his/her best clinical 
judgment based upon the available medical information of the event that is being reported.  The 
causality assessment will be re-assessed as new medical information becomes available.  If the 
Investigator’s causality assessment is not reported it will be considered as “related” until it is 
received.  The Investigator and Relypsa will each assess relatedness of the AE to the 
investigational drugs, patiromer/placebo and spironolactone, using the following definitions: 
Not Related:  There is no reasonable possibility that patiromer caused or contributed to the AE. 
• The event is related to an etiology other than the investigational such as underlying disease, 
study or non-study procedures, concomitant medications, or the subject’s clinical state 
• The time of the occurrence of the AE is not reasonably related to the administration of the 
study drug 
Related:  There is a reasonable possibility that patiromer caused or contributed to the AE. 
• There is a compatible temporal association between the event and the administration of 
investigational drug 
• There is a biologically plausible mechanism for the study treatment to cause or contribute to 
the AE 
• The event improves or diminishes upon withdrawal of the study drug without the initiation of 
any specific treatments for the event (dechallenge), and/or the event recurs or worsens with 
the rechallenge of the study therapy 
• The event cannot be reasonably attributed to concurrent or underlying illness, other drugs or 
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For causality assessment purposes “reasonable possibility” is meant to convey that, based on the 
Investigator’s medical judgment of the available information, there are facts or arguments to 
suggest a positive causal relationship. 
8.2.5 
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 case report form 
(CRF) or eCRF page.  In addition, the SAE Report Form must be completed for each SAE. 
For AEs related to an etiology other than the investigational drug, the alternative etiology, such 
as underlying disease, study or non-study procedures, concomitant medications, or the subject’s 
clinical state, must be documented in the study subject's medical record and provided in the AE 
eCRF and, if applicable, the SAE report. 
All AEs will be recorded using the words of the subject (verbatim term) to describe the AE 
whenever possible.  However, if the verbatim term is vague or ambiguous (e.g., cramps), the 
study staff will 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).  Additionally, if the subject reports a group of symptoms that the Investigator 
uses to make a unifying diagnosis, the diagnosis will be recorded instead of the symptoms (e.g., 
rhinopharyngitis instead of runny nose, cough, sore throat and sneezing).  If a diagnosis is 
unknown, signs and symptoms need to be recorded separately until a diagnosis is determined, at 
which time the diagnosis will be reported in lieu of the symptoms. 
The following information will be captured for each AE:  date of onset and resolution, outcome, 
severity (as defined in Section 8.2.3), seriousness criteria, Investigator’s causality assessment for 
the relatedness of the AE to the investigational drug, action taken with the investigational drug 
and treatments administered.  Any treatment administered as a result of an AE will be recorded 
on the Concomitant Medication CRF and/or Surgical and Medical Procedure CRF as applicable. 
8.2.6 
Data and Safety Monitoring Committee 
A Data and Safety Monitoring Committee (DSMC) will review laboratory and blood pressure 
data, all reports of AEs (including deaths from any cause), discontinuations from spironolactone 
and patiromer/placebo, withdrawals from the study, and other data as described in the DSMC 
Charter.  The DSMC Charter will include a description of the scope of planned reviews.  When 
reviewing data, including individual data, the DSMC may be unblinded to treatment assignment 
(patiromer or placebo).  The DSMC will advise the Steering Committee regarding the need for 
changes in the conduct of the study as outlined in the DSMC Charter. 
8.3 
Serious Adverse Events Reporting 
8.3.1 
SAE Notification 
The Investigator has the obligation to report each SAE to Relypsa or designee within 24 hours of 
knowledge of the occurrence.  Follow-up reports must be submitted in a timely fashion as 
additional information becomes available.  If the Investigator learns of any SAE that occurred 


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after the Follow-up Period for which there is a reasonable possibility of relatedness to the 
investigational drugs, that event and subsequent follow-up information must be reported within 
24 hours. 
Cause of death is required whenever known.  If an autopsy was performed, an autopsy report will 
be provided.  If an autopsy was not conducted, a Death Certificate will be provided if obtainable.  
Death will be reported as an outcome and not as an event. 
SAEs must be reported by entering the SAE information into the AE CRF in the EDC system.  If 
the event meets seriousness criteria, SAE reporting via the paper SAE Report Form will also be 
required.  The Investigator must complete a paper copy of SAE report form, scan and e-mail or 
fax it to the contact provided in the SAE or Pregnancy and Lactation Reporting Form 
Completion Guidelines.  All SAEs should be followed until they are resolved, stabilized or 
otherwise justified by the Investigator in agreement with Relypsa and all relevant information is 
compiled. 
The SAE Form will be completed with the following information at a minimum: 
• Trial number/ trial site 
• Name of reporter/Investigator 
• Subject identification number 
• SAE term 
• Date of onset 
• Date of outcome or resolution (when medically applicable) 
• Outcome 
• Criteria of seriousness 
• Severity of the event 
• Relatedness to patiromer/placebo and spironolactone 
Additional information that is medically pertinent to the SAE must be provided when available, 
or as requested by the Sponsor (hospital Discharge Summary, Autopsy Report/Death Certificate, 
diagnostic study reports, etc.). 
8.3.2 
SAE Expedited Reporting 
Relypsa will notify all Investigators of all SAEs requiring expedited reporting to Regulatory 
Authorities. 
The Investigator is responsible for notifying the IRB in accordance with local regulations of all 
SAEs that occur.  The Investigator must review and file the safety report with the Investigator’s 
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Relypsa is responsible for notifying the applicable Health Authorities of SAEs in accordance 
with applicable laws and regulations. 
8.4 
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 investigational product will be permanently discontinued, and the event must be 
reported to Relypsa upon receipt of information by the study staff.  Pregnancies must be reported 
throughout the conduct of the study including two weeks following the last dose of study drug 
received.  Pregnancy reporting includes exposure of the female partner of a male subject.  While 
pregnancy is not considered an SAE, it must be reported to Relypsa within 24 hours of becoming 
aware on the Pregnancy Monitoring Form.  Pregnancy complications are reported as AEs or 
SAEs (if applicable).  Any pregnancy will be followed through delivery for the observation of 
any SAEs.  Fatalities, elective or spontaneous abortions, congenital abnormalities/birth defects 
and AEs/SAEs occurring in the newborn must be reported as SAEs.  Newborns potentially 
exposed to study drug via maternal or paternal sources who experience a SAE before, during, or 
after delivery (including lactation by the maternal subject) will be followed until resolution of the 
event or for a minimum of 1 year). 
9 
DATA ANALYSIS / STATISTICAL METHODS 
This section briefly describes the planned statistical methods for this study.  A Statistical 
Analysis Plan (SAP) will describe the methods in detail.  If there is a difference between the 
language of this protocol and the language of the SAP, the SAP will take precedence over the 
protocol. 
9.1 
Sample Size Determination 
This study will randomize approximately 290 subjects, to ensure that at least 280 subjects will be 
available for the primary analysis.  This allows for the possibility that up to 10 subjects are 
randomized but never take study medication.  A sample size of 280 subjects has 90% power to 
detect a difference between treatment groups of 20% or more in the proportion of subjects 
remaining on spironolactone at Week 12, at α = 0.05. 
9.1.1 
Interim Analysis 
An interim analysis has been planned after approximately 50% of the subjects have completed 
Week 12 to evaluate the assumptions used to determine the sample size.  The DSMC will 
determine if additional subjects are required to meet the primary endpoint.  Relypsa will 
determine if the protocol will be amended to allow additional subject enrollment.  The study will 
not be stopped early based on the interim analysis. 
9.2 
Randomization 
Eligible subjects will be randomized 1:1 to either spironolactone + patiromer or spironolactone + 
placebo.  The randomization will be stratified by the Visit S4 locally measured potassium at 
baseline (4.3 to < 4.7 mEq/L or 4.7 to 5.1 mEq/L) and history of Type 1 or 2 diabetes mellitus 
(Yes or No). 


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Treatment group assignments will be kept blinded until database lock.  The blind will be 
maintained for subjects, site personnel, and all Relypsa and vendor staff, with the exception of 
unblinded staff required for the development of the final randomization schedule, for production 
of unblinded materials for the DSMC, and Relypsa Drug Safety staff in situations where 
unblinding is necessary to comply with Regulatory requirements.  The Relypsa staff who may be 
unblinded will be identified prior to the start of study enrollment. 
The study populations planned for analysis are described below. 
• Safety Population:  The Safety Population consists of all subjects who have received at least 
one dose of spironolactone, patiromer or placebo. 
• Intent-to-Treat Population (ITT):  The ITT Population consists of all subjects who have been 
randomized and have received at least one dose of spironolactone and at least one dose of 
blinded study medication (patiromer or placebo). 
• Blood Pressure Analysis Population (BPA Population):  The BPA Population consists of all 
subjects who have non-missing Baseline and Week 12 AOBP-assessed SBP. 
Additional study populations may be defined in the SAP if needed. 
9.3 
General Considerations 
Local potassium values will be used for randomization/stratification, titration of the blinded 
study medication (patiromer/placebo), and discontinuation of spironolactone.  Central serum 
potassium values will be used for the analysis of change in potassium over time. 
Subjects will be screened for eligibility at Screening Visits 1 – 4 (S1, S2, S3, and S4).  If a 
subject meets all eligibility criteria at Visits S1 – S4, the subject will be randomized at the 
S4/Baseline (Day 0) Visit (Appendix A).  The subject will take his or her first dose of 
spironolactone and first dose of blinded study medication (patiromer/placebo) on the day after 
this visit (Day 1). 
Tables will be presented by treatment group and overall, unless otherwise specified in the SAP. 
9.4 
Subject Disposition 
Summaries will be presented for the number and percentage of subjects who were randomized, 
received study drug, completed Week 12, and participated in the scheduled Follow-up Visit.  For 
subjects who terminated early, a summary of reasons will be provided. 
Counts of subjects will be presented for each analysis population, by study site and overall. 
A listing of subject disposition will be provided, including membership in each analysis 
population. 


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9.5 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for the ITT Population, the Safety 
Population (if it differs from the ITT Population), and the BPA Population. 
Demographic and baseline characteristics to be summarized include, but are not limited to:  age, 
gender, race, ethnicity, vital signs, height, weight and BMI, baseline concomitant medications of 
special interest, and relevant comorbidities. 
Summaries of continuous variables will include the mean, standard deviation (SD), standard 
error (SE), median, 25th and 75th percentiles, and the maximum and minimum.  Summaries of 
categorical variables will include counts and percentages. 
Listings for demographics and baseline characteristics will be provided. 
9.6 
Efficacy Analyses 
9.6.1 
Primary Efficacy 
The proportion of subjects remaining on spironolactone at Week 12 will be compared between 
treatment groups (spironolactone/patiromer versus spironolactone/placebo) using the 
Cochran-Mantel-Haenszel test, stratified by baseline potassium category (4.3 to < 4.7 mEq/L or 
4.7 to 5.1 mEq/L).  Additionally, a sensitivity analysis will include stratification by study site 
(small sites will be pooled). 
The primary efficacy analysis will be performed using the ITT Population. 
Subjects who terminate from the study early or discontinue study spironolactone early, for any 
reason, will be considered as not having remained on spironolactone. 
9.6.2 
Secondary Efficacy 
The secondary efficacy variable for this study is change from Baseline in AOBP SBP at Week 12 
or last available assessment prior to addition of any new BP medications or changes to any 
baseline BP medications. 
The secondary efficacy endpoint will be analyzed using an analysis of covariance (ANCOVA) 
model, with baseline AOBP SBP as a covariate and baseline serum potassium as a categorical 
factor (K+ 4.3 – < 4.7 or 4.7 – 5.1 mEq/L).  The analysis will use the ITT Population. 
9.6.3 
Other Endpoints 
Additional end-points will be compared between treatment groups including (please refer to the 
statistical analysis plan for further information): 
• Change in AOBP SBP from Baseline to Week 12 
• Potassium levels over time (measured both centrally and locally) 


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• Proportion of subjects with serum K+ ≥ 5.5 mEq/L 
• Average daily dose and cumulative dose of spironolactone 
• Time to discontinuation of spironolactone  
• Change from baseline to Week 12 in albuminuria (ACR) 
• EQ-5D-5L questionnaire results at Baseline and at Week 12/ET 
Change in AOBP at Week 12 will be analyzed with an ANCOVA model using the BPA 
Population.  Additionally, change at Week 12 will be analyzed using a repeated measures mixed 
model that will include all ITT subjects with at least one measurement of AOBP SBP at Week 1 
or later.  Models will include baseline AOBP SBP as a covariate and baseline serum potassium 
as a categorical factor (K+ 4.3 – < 4.7 or 4.7 – 5.1 mEq/L). 
Potassium levels will be summarized for local and central values at each time point.  Counts (%) 
of subjects who have experienced no potassium measurement ≥ 5.5 mEq/L will be presented at 
each time point. 
Kaplan-Meier methods will be used to analyze the time to discontinuation of spironolactone.  
Treatment groups will be compared using the log-rank test. 
Average daily dose and cumulative dose of spironolactone, and change in albuminuria (ACR) 
from Baseline to Week 12, will be analyzed using ANCOVA methods. 
The EQ-5D-5L questionnaire results will be summarized at Baseline and Week 12/ET. 
9.6.4 
Subgroups of Interest 
Primary and secondary efficacy analyses will be produced for the subgroups specified below.  
Subgroup analyses will also be done for selected efficacy or safety endpoints, as appropriate. 
Subgroups to be analyzed include: 
• Gender 
• Age < 65 versus ≥ 65 years 
• Type 1 or Type 2 diabetes mellitus (presence versus absence at baseline) 
• Any additional subgroups of interest will be described in the SAP 
9.6.5 
Safety Analysis 
9.6.5.1 
Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as any AE that begins or worsens at the 
time of or after the first dose of any study medication (spironolactone, patiromer, or placebo). 


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All AEs and serious AEs (SAEs) will be coded using MedDRA (version will be specified in the 
SAP). 
Summaries will be provided by SOC, PT and severity for: 
• All TEAEs 
• TEAEs related to study medication (separately for spironolactone and for patiromer/placebo) 
• TEAEs leading to study medication discontinuation (separately for spironolactone and for 
patiromer/placebo 
• SAEs 
• TEAEs of special interest (e.g. allergic reactions, gastrointestinal events, renal events) 
A listing of AEs will be provided, to include verbatim term, PT, SOC, severity, relationship to 
study medications, whether serious, onset/end date, action taken and outcome of event. 
9.6.5.2 
Deaths 
A listing of deaths will be provided. 
9.6.5.3 
Laboratory Assessments 
Laboratory parameters will be summarized at each visit at which the parameter is scheduled to 
be collected.  Summaries will also be provided for the change from baseline at each of these 
visits. 
Tables will be provided to summarize counts and percentages of subjects experiencing clinically 
significant levels of, or change in, serum potassium (< 3.0, < 3.5, and > 5.1 mEq/L), calcium, 
magnesium and phosphorus. 
Shift tables will be provided for change from baseline to end of treatment in serum potassium, 
serum calcium, and serum magnesium, and for change in CKD stage as defined by eGFR level. 
9.6.5.4 
Concomitant Medications 
Summaries will be provided of concomitant medication use during the study, by ATC4 and 
preferred drug name. 
9.6.5.5 
Vital Signs 
Clinic assessments of SBP, DBP, resting heart rate, and weight will be summarized at each 
scheduled visit at which they are assessed.  Summaries will also be provided for change from 
baseline at each of these visits. 
Height is collected only at Screening Visit 1.  Height will be provided in the listing of vital signs, 
but will not otherwise be summarized. 


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9.7 
Handling of Missing Data 
Missing central serum potassium laboratory values may be imputed using local laboratory values 
collected on the same day.  Details regarding imputation methods will be provided in the SAP. 
Procedures for managing any other missing data will be provided in the SAP. 
10 DATA HANDLING AND RECORDKEEPING 
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, records kept at the pharmacy or laboratories, and subject logs).  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 patiromer. 
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. 
10.1 
Case Report Forms / Electronic Data Record 
An eCRF is designed to record all of the protocol-required information to be reported to Relypsa 
on each trial 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 trial personnel 
designated by the Investigator.  All site staff will have proper training prior to accessing the EDC 
system. 
Any change or correction to an eCRF will be tracked via an audit trail within the EDC system.  
The audit trail will contain the original data value, new data value, date changed, the user who 
made the change, and the reason(s) for the change. 
CRFs should be completed in a timely manner to support the study timeline (i.e., the site should 
not wait for a monitoring visit before entering data into the eCRF). 


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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 Relypsa 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). 
10.2 
Record Retention 
The Investigator must maintain adequate records for the study including completed eCRFs, 
medical records, laboratory reports, signed ICFs, drug disposition records, adverse experience 
reports, information regarding subjects who discontinued, all correspondence with the IRB/IEC 
and Relypsa, and other pertinent data. 
The Investigator is to retain all records until notified by Relypsa.  The Investigator will notify 
Relypsa in writing of the relocation of any study records away from the research facility after 
study closure.  The Investigator must contact Relypsa in writing prior to the destruction of any 
study records, or in the event of loss of any study records. 
11 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. 
Relypsa employees or designee will conduct site monitoring visits at regular intervals in 
accordance with FDA and International Conference on Harmonisation (ICH) guidelines.  The 
Investigator will permit Relypsa or designee monitors to review and inspect facilities, and all 
records relevant to this study. 
The Investigator will also permit Relypsa 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.  If 
the FDA or other regulatory agency should schedule an inspection, the Investigator should notify 
the Medical Monitor immediately. 
The following steps will be taken to ensure that the trial is conducted by the investigational site 
in compliance with the study protocol, Good Clinical Practices (GCP), and other applicable 
regulatory requirements: 


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• Investigator meeting and/or Investigator site initiation 
• Routine site monitoring 
• Documented protocol and GCP training 
• eCRF and query review against source documents 
• Collection of local laboratory normal ranges 
12 ETHICS 
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 EU and all other applicable local and national laws and regulations 
governing the conduct of human clinical studies. 
12.1 
Institutional Review Board / Independent Ethics Committee 
All Investigators participating in this study must be governed under an appropriate 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 Relypsa prior to investigational product shipment.  The IRB/EC 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 Relypsa.  
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 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. 
12.2 
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 requirements 
governing the conduct of human clinical trials. 
The Investigator will not deviate from the protocol without prior written approval from Relypsa, 
except in medical emergencies.  In the event of a medical emergency, the Investigator must 
notify the Medical Monitor as soon as possible.  Any other change to the protocol must be 
implemented as an amendment to the protocol and must be approved by the IRB/IEC prior to 
implementation. 


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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 Relypsa and the IRB/IEC 
prior to initiation. 
Financing and insurance are covered in the Clinical Trial Agreement and Clinical Trial Insurance 
Policy. 
12.3 
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.  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 trial.  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.  Every subject will be given a copy of each version of 
the form that he/she signs before and during the study.  In the United States, each ICF may also 
include authorization allowing the institution, Investigator and Relypsa to use and disclose 
personal health information in compliance with the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). 
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 Relypsa for regulatory 
purposes. 


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13 RELYPSA DISCONTINUATION CRITERIA 
Based on their data review, the DSMC may provide recommendations to stop the study as per 
guidance within the DSMC Charter.  Relypsa will determine whether the study should be 
stopped early. 
14 PUBLICATION OF TRIAL RESULTS 
The Clinical Trial Agreement describes Relypsa’s publication terms. 
15 REFERENCES  
1. Aldactone PI.  Aldactone (Spironolactone) [Package Insert], Revised Oct-2014.  G.D.  Searle 
LLC, 2008. 
2. Bianchi S, Batini V, Bigazzi R.  The Renal Effects of Mineralocorticoid Receptor 
Antagonists.  Int J Cardiol, 200, 20-24, 2015. 
3. Bolignano D, Palmer SC, Navaneethan SD, Strippoli GF.  Aldosterone Antagonists for 
Preventing the Progression of Chronic Kidney Disease.  Cochrane Database Syst Rev, 4, 
CD007004, 2014. 
4. Bomback AS, Klemmer PJ.  The Incidence and Implications of Aldosterone Breakthrough.  
Nat Clin Pract Nephrol, 3[9], 486-492, 2007. 
5. Calhoun DA, Jones D, Textor S, et al. Resistant Hypertension:  Diagnosis, Evaluation, and 
Treatment:  a Scientific Statement From the American Heart Association Professional 
Education Committee of the Council for High Blood Pressure Research.  Circulation, 
117[25], e510-e526, 2008. 
6. De la Sierra A, Segura J, Banegas JR, et al. Clinical Features of 8295 Patients With Resistant 
Hypertension Classified on the Basis of Ambulatory Blood Pressure Monitoring.  
Hypertension, 57[5], 898-902, 2011. 
7. Horowitz B, Miskulin D, Zager P.  Epidemiology of Hypertension in CKD.  Adv Chronic 
Kidney Dis, 22[2], 88-95, 2015. 
8. Judd E, Calhoun DA.  Management of Hypertension in CKD:  Beyond the Guidelines.  Adv 
Chronic Kidney Dis, 22[2], 116-122, 2015. 
9. KDIGO.  Kidney Disease:  Improving Global Outcomes (KDIGO) Blood Pressure Work 
Group.  KDIGO Clinical Practice Guideline for the Management of Blood Pressure in 
Chronic Kidney Disease.  Kidney Inter Suppl, 2[5], 337-414, 2012. 
10. Khosla N, Kalaitzidis R, Bakris GL.  Predictors of Hyperkalemia Risk Following 
Hypertension Control With Aldosterone Blockade.  Am J Nephrol, 30[5], 418-424, 2009. 
11. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Practice Guidelines for the 
Management of Arterial Hypertension.  Eur Heart J, 2013[34], 2159-2219, 2013. 
12. Muntner P, Anderson A, Charleston J, et al. Hypertension Awareness, Treatment, and 
Control in Adults With CKD:  Results From the Chronic Renal Insufficiency Cohort (CRIC) 
Study.  Am J Kidney Dis, 55[3], 441-451, 2010. 


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13. Narayan H, Webb DJ.  New Evidence Supporting the Use of Mineralocorticoid Receptor 
Blockers in Drug-Resistant Hypertension.  Curr Hypertens Rep, 18[5], 34, 2016. 
14. NKF.  KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in 
Chronic Kidney Disease.  Guideline 11:  Use of Angiotensin-Converting Enzyme Inhibitors 
and Angiotensin Recptor Blockers in CKD.  2004 [Accessed on:  6-29-2016]; Available 
from:  URL:  http://www2.kidney.org/professionals/KDOQI/guidelines_bp/guide_11.htm. 
15. Patiromer for oral suspension. Investigator’s Brochure. Relypsa, Inc.  Version 9. July 2015. 
16. Pitt B, Anker SD, Bushinsky DA, et al. Evaluation of the Efficacy and Safety of RLY5016, a 
Polymeric Potassium Binder, in a Double-Blind, Placebo-Controlled Study in Patients With 
Chronic Heart Failure (the PEARL-HF) Trial.  Eur Heart J, 32[7], 820-828, 2011. 
17. Robles, N. R.  Home Blood Pressure Monitoring, Reproducibility and Prognostic Aspects - 
Third in Series.  2015 [Accessed on:  7-7-2016]; Available from:  URL:  
https://www.escardio.org/Guidelines-&-Education/Journals-and-publications/ESC-journals-
family/E-journal-of-Cardiology-Practice/Volume-13/Home-blood-pressure-monitoring-
reproducibility-and-prognostic-aspects-third-i. 
18. Rossi GP, Bernini G, Caliumi C, et al. A Prospective Study of the Prevalence of Primary 
Aldosteronism in 1,125 Hypertensive Patients.  J Am Coll Cardiol, 48[11], 2293-2300, 2006. 
19. Rossignol P, Massy ZA, Azizi M, et al.  The Double Challenge of Resistant Hypertension 
and Chronic Kidney Disease.  Lancet, 386[10003], 1588-1598, 2015. 
20. Tamargo J, Solini A, Ruilope LM.  Comparison of Agents That Affect Aldosterone Action.  
Semin Nephrol, 34[3], 285-306, 2014. 
21. Tanner RM, Calhoun DA, Bell EK, et al. Prevalence of Apparent Treatment-Resistant 
Hypertension Among Individuals With CKD.  Clin J Am Soc Nephrol, 8[9], 1583-1590, 
2013. 
22. Vasan RS, Evans JC, Larson MG, et al. Serum Aldosterone and the Incidence of 
Hypertension in Nonhypertensive Persons.  N Engl J Med, 351[1], 33-41, 2004. 
23. Veltassa PI.  Veltassa (Patiromer) [Package Insert], Revised May-2016.  Relypsa, Inc., 2016. 
24. Williams B, MacDonald TM, Morant S, et al. Spironolactone Versus Placebo, Bisoprolol, 
and Doxazosin to Determine the Optimal Treatment for Drug-Resistant Hypertension 
(PATHWAY-2):  a Randomised, Double-Blind, Crossover Trial.  Lancet, 386[10008], 2059-
2068, 2015. 
25. Wolley MJ, Stowasser M.  Resistant Hypertension and Chronic Kidney Disease:  a 
Dangerous Liaison.  Curr Hypertens Rep, 18[5], 36, 2016. 
 
 


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Appendix A: Schedule of Events 
Study Period 
Screening/Run-in 
Period 
Screening/ 
Randomization 
Double-Blind Treatment 
Follow-
Upa 
Unscheduled 
Visit 
Visit/Day/Week 
S1 
S2 
S3 
S4/BL(D0)b 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 
or ET 
Visit 
2W after 
W12 or 
ET Visit 
 
Window 
1 week (≥ 4 d but ≤ 10 d) apart 
±3 d 
±3 d 
±3 d 
±3 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
 
Study Activity 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IWRS Entry 
X 
X 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion Exclusion Criteria 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heart Rate (resting for 5 
minutes) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xd 
 
 
 
 
 
 
 
X 
 
X, optional 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X, optional 
12-lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X, optional 
AOBP performed onsite             
(triplicate measurements)e 
X 
X 
X 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
X 
X 
SMBP performed onsite and 
HBP training, as necessary         
(triplicate measurements)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X, if 
available 
SMBP performed at home          
(triplicate measurements)h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X, if 
available 
Potassiumi 
L&C 
 
L&C 
L&Cd 
Lj&C 
Lj&C 
Lj&C 
Lj&C 
Lj&C 
Lj&C 
Lj&C 
L&C 
L&C 
L&C 
Serum Chemistry (including 
creatinine, eGFR) 
C 
 
C 
Cd 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C, optional 
Hematology 
C 
 
 
Cd 
 
 
 
C 
 
 
 
C 
 
C, optional 
Serum Pregnancy 
C 
 
 
 
 
 
 
 
 
 
 
C 
 
 
NT-proBNP 
 
 
 
Cd 
 
 
 
 
 
 
 
C 
 
 


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Appendix A: Schedule of Events (Cont’d) 
Study Period 
Screening/Run-in 
Period 
Screening/ 
Randomization 
Double-Blind Treatment 
Follow-
Upa 
Unscheduled 
Visit 
Visit/Day/Week 
S1 
S2 
S3 
S4/BL(D0)b 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 
or ET 
Visit 
2W after 
W12 or 
ET Visit 
 
Window 
1 week (≥ 4 d but ≤ 10 d) apart 
±3 d 
±3 d 
±3 d 
±3 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
 
Study Activity 
Aldosterone and plasma renin 
activity 
 
 
 
Cd 
 
 
 
 
 
 
 
 
 
 
Spironolactone Level 
 
 
 
 
C 
 
 
C 
 
C 
 
C 
 
 
Urinalysis 
C 
 
 
Cd 
 
 
 
 
 
 
 
C 
 
 
24 hr urine collection container 
(dispense and train) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
24 hr urine for sodium, 
potassium, creatinine, albumin 
(for ACR) 
 
 
 
Cd 
 
 
 
 
 
 
 
 
 
 
ACR urine sample collection 
cups (dispense and train) 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Urine ACR (3 first morning 
void samples) 
 
 
 
Cd,k 
 
 
 
C 
 
C 
 
C 
 
 
Urine pregnancy test 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L Questionnairel 
 
 
 
Xd 
 
 
 
 
 
 
 
X 
 
 
IWRS Randomization to 
Patiromer / Placebo 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
Patiromer/placebo Dispensingm  
 
 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
 
 
X, optional 
Spironolactone Dispensingn  
 
 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
 
 
X, optional 
Drug Accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X, optional 
Dietary Counselling 
X 
X 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 


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Appendix A: Schedule of Events (Cont’d) 
Study Period 
Screening/Run-in 
Period 
Screening/ 
Randomization 
Double-Blind Treatment 
Follow-
Upa 
Unscheduled 
Visit 
Visit/Day/Week 
S1 
S2 
S3 
S4/BL(D0)b 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 
or ET 
Visit 
2W after 
W12 or 
ET Visit 
 
Window 
1 week (≥ 4 d but ≤ 10 d) apart 
±3 d 
±3 d 
±3 d 
±3 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
 
Study Activity 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AOBP = automated office blood pressure; ACR = albumin to creatinine ratio; AE = adverse event; BP = blood pressure; C = central laboratory; D (or d) = day; D0 = Day 0; ET = Early Termination 
Visit; hr = hour; IWRS = Interactive Web Response System; L = local; R = Randomization; S = Screening Visit; SMBP = subject-measured blood pressure.  
a 
If a subject completes the Follow-up Visit prior to 2 Weeks, the subject will receive a Follow-up Phone Call at 2 weeks after Week 12 or ET Visit (+ up to 7 days) (Section 6.3.1). 
b 
If hemolysis of the local sample is detected or is suspected (see Section 7.1.1), subject is not randomized at S4, and a repeat of the potassium measurement from a separate blood draw will be 
performed within 1 day.  If subject qualifies they will be randomized and this Visit will be the Randomization/Baseline (Day0) Visit.  All assessments at S4, aside from the repeat potassium 
level, will be considered the baseline. 
c 
For subjects who meet all inclusion criteria, this Visit becomes the Randomization/Baseline Visit (Day0).  For subjects who screen fail at this visit, this is Visit S4. 
d 
Assessment or event will occur only if subject meets all inclusion criteria (Section 4.1). 
e 
Measured automatically using office device (while unobserved by the study staff) after 5 minutes of quiet seating prior to triplicate measures (Section 7.3.2.2). 
f 
Review AOBP results and adjust study medications according to Section 3.1.2 and Appendix C, and Appendix D. 
g 
HBP device issued on Visit S1 and measured by subject using their issued HBP device (while unobserved by the study staff) after 5 minutes of quiet seating prior to triplicate measures 
(Section 7.3.2.2).  HBP monitors are collected from subjects at the Visit Week-12.  
h 
HBP will be measured by subject twice daily (Section 7.3.2.1) (e.g., at approximately 08:00 hrs and 20:00 hrs) after sitting quietly for at least 5 minutes.  The subject will perform triplicate 
measures, 1 minute apart.  HBP training will be performed at the first screening visit and retraining can be performed at any Visit, as needed.  HBP monitors are collected from subjects at the 
Visit Week-12. 
i 
If hemolysis of the local sample is detected or is suspected (see Section 7.1.1), the sample must repeated within 1 .day for reassessment of potassium. 
j 
Review potassium results and adjust study medications according to Section 3.1.2 and Appendix B. 
k 
One of the ACR measurements will be from the 24-hour urine collection (see Section 7.7). 
l 
Subjects will complete the EQ-5D-5L questionnaire before study staff performs any clinic or study assessments to avoid biasing the subjects’ responses. 
m 
On Day1 patiromer/placebo two packets QD will be taken at home with food and at least 3 hours before or 3 hours after other oral medications including spironolactone.  See Appendix B for 
dosing/titration algorithm. 
n 
On Day 1 spironolactone (25 mg QD) will be taken at home and increased to 50 mg at Week 3 for subjects with blood pressure ≥ 120 mmHg See Appendix C for dosing instructions. 


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Appendix B: Patiromer/Placebo Titration 
Patiromer/placebo will be taken at a starting dose of two packets once daily (QD).  Based 
upon the treatment algorithm, patiromer/placebo will be increased in two-packet per day 
increments for local K+ > 5.1 mEq/L in intervals of at least 1 week up to a maximum dose of 
six packets QD.  For subjects with K+ < 4.0 mEq/L, patiromer/placebo dose will be decreased 
by at least two packets.  The minimum dose of patiromer/placebo is 0 packets. 
Throughout the Double-Blind Treatment Period, subjects who develop K+ ≥ 5.5 mEq/L that 
cannot be managed with blinded patiromer/placebo escalation according to the treatment 
algorithm (refer to Figure 2) will discontinue spironolactone and patiromer/placebo, but will 
remain in the study (refer to Appendix C, Spironolactone Dosing) and complete all remaining 
scheduled visits.  After discontinuation of spironolactone and patiromer/placebo, 
hyperkalemia may be treated using standard of care per the Investigator’s judgment. 
Figure 2 describes patiromer/placebo dosing adjustments by Visit and level of potassium. 
 
 


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Figure 2: 
Patiromer/Placebo Titration 
 
K+ = potassium; max = maximum; QD = once daily. 
a 
After discontinuation of spironolactone and patiromer/placebo, hyperkalemia may be treated using standard of care per the Investigator’s judgment. 
NOTE:  All patiromer/placebo dose increases should be made no less than 1 week apart.  At Week 12 all study treatments (patiromer/placebo and spironolactone) 
will be discontinued. 


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Appendix C: Spironolactone Dosing 
Spironolactone will be initiated for all randomized subjects on Day 1, at a dose of 25 mg 
taken orally QD.  At Week 3, for subjects with AOBP SBP ≥ 120 mmHg and K+ 
≤ 5.1 mEq/L, spironolactone will be increased to 50 mg QD.  For subjects with K+ 
> 5.1 mEq/L, 25 mg daily dose of spironolactone will be continued until the first subsequent 
visit when K+ is ≤ 5.1 mEq/L (and AOBP SBP ≥ 120 mmHg), at which time spironolactone 
will be increased to 50 mg QD. 
Subjects with AOBP SBP < 120 mmHg at the Week 3 Visit will continue their 25 mg daily 
dose, unless symptoms of hypotension are present in which case the spironolactone dose may 
be reduced to 25 mg every other day or discontinued altogether, at the discretion of the 
Investigator.  Spironolactone may be reduced or discontinued for AOBP SBP < 100 mmHg.  
If spironolactone is discontinued, patiromer/placebo must be discontinued at the same time.  
These subjects will remain in the study and be followed per protocol.  Note:  At any study 
visit spironolactone dose may be reduced or discontinued for AOBP SBP < 120 mmHg with 
symptoms of hypotension, or for AOBP SBP < 100 mmHg at the direction of the 
investigator.  Figure 3 describes spironolactone dosing adjustments by Visit and level of SBP 
(AOBP). 
 
 


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Figure 3: 
Spironolactone Titration 
 
AOBP = automated office blood pressure; K+ = potassium; PI = Investigator; QD = once daily; 
QOD = once every other day; SBP = systolic blood pressure.  
a 
If spironolactone is discontinued, patiromer/placebo must be discontinued at the same time.  These subjects 
will remain in the study and be followed per protocol.  After study drug discontinuation, the treatment of 
hypertension should proceed in accordance with the standard of care for BP management and the 
Investigator’s judgment. 
NOTE:  At Week 12 all subjects will discontinue all study medications (spironolactone and patiromer/placebo). 
 
 


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Changes in Spironolactone Dosing Based on eGFR 
Throughout the treatment period, creatinine will be measured at each study visit (and may be 
measured at Unscheduled Visits).  Subjects should be monitored for changes in renal 
function, especially during periods of medication changes or adjustments.  Acute reductions 
in GFR have been seen with the initiation of spironolactone, similar to those seen with 
initiation of ACE inhibitors and ARBs that have been attributed to transient changes in 
glomerular hemodynamics (Bianchi, 2015, KDIGO, 2012).  These changes typically do not 
impact long-term renal function.  In this study, use of the KDOQI recommendations for the 
detection and management of early decrease in GFR (when initiating ACE inhibitors/ARBs) 
for monitoring the initiation of spironolactone (NKF, 2004) should be considered. 
Based on KDOQI guidelines: 
• An early decline in GFR is defined as > 15% reduction from baseline within 4 weeks of 
initiation of spironolactone 
• For decreases in eGFR up to 30%, no changes to spironolactone dosing need to be made, 
and eGFR may be followed routinely 
• Decreases in eGFR > 30%, however, should prompt a search for other etiologies of 
abrupt renal function decline, including prerenal and postrenal causes, toxic reactions, 
and renal artery disease 
• For a decline in eGFR from 30 to 50%, the spironolactone dose should be decreased and 
the eGFR followed weekly.  If the eGFR does not return to within 30% of baseline within 
4 weeks, spironolactone should be discontinued 
• Spironolactone should be discontinued for a decline in eGFR > 50% and eGFR should be 
followed at least weekly until eGFR has returned to within 15% of the baseline value, and 
biweekly thereafter through the end of the study 
 
 


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Appendix D:  Blood Pressure Management and Additional BP Medication Suggestions 
Prior to addition of new antihypertensive blood pressure medications please consider: 
• The degree of blood pressure elevation 
• Whether or not the subject is still receiving spironolactone 
• The time since last spironolactone dose adjustment 
• The level of urgency to lower blood pressure  
The following are recommendations, but the investigator’s best clinical judgment should 
guide the final decision.  Baseline medication doses should not be changed except for 
AE-related reasons where changes to baseline medications can be justified by the 
Investigator (e.g., increases in loop diuretics for new edematous states or discontinuation of 
baseline medication for drug-related AEs) or for AOBP ≥ 200 mmHg, where possible. 
AOBP SBP ≥ 200 mmHg 
Baseline antihypertensive medication doses may be increased and new ACE inhibitors or 
ARB medications may be initiated during the study only for management of AOBP SBP 
≥ 200 mmHg (whether or not on spironolactone).  These subjects may continue 
spironolactone if discontinuation reasons (see Appendix B and Appendix C) have not been 
met, but spironolactone may not be reinitiated if it has been discontinued during the study.  
Treatment of hypertension in these subjects should be standard of care, in accordance with 
the clinical judgment of the Investigator. 
AOBP SBP ≥ 165 mmHg and < 200 mmHg and Spironolactone has been Discontinued 
At any time after spironolactone discontinuation, alternative BP medications may be added to 
control persistent SBP ≥ 165 mmHg (assessed by AOBP) through the end of the treatment 
period (Week 12). 
Subjects may be treated with additional BP medication (excluding ACE inhibitors and 
ARBs) selected by the Investigator, according to standard of care practices.  Doses of 
baseline antihypertensive medications may not be increased and spironolactone may not be 
reinitiated if it has been discontinued during the study. 
Baseline antihypertensive medication doses should not be changed except for AE-related 
reasons where changes to baseline medications can be justified by the Investigator (e.g., 
increases in loop diuretics for new edematous states or discontinuation of baseline 
medication for drug-related AEs). 
AOBP SBP ≥ 165 mmHg and < 200 mmHg and Spironolactone Ongoing 
For subjects on spironolactone 25 mg QD (before Week 3) and K+ ≤ 5.1 mEq/L, 
spironolactone may be increased to 50 mg before the Week 3 visit for persistent SBP 
≥ 180 mmHg (assessed by AOBP), at the investigator’s discretion. 


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For subjects on spironolactone 50 mg QD (for most subjects will usually be after Week 3) or 
on spironolactone < 50 mg QD and K+ > 5.1 mEq/L,  additional BP medication may be 
added to control persistent SBP ≥ 165 mmHg (assessed by AOBP) at the discretion of the 
investigator.  This decision may reflect the degree of blood pressure elevation, the time since 
last spironolactone dose adjustment and the level of urgency to lower blood pressure, in the 
investigator’s judgment.  Baseline medication doses should not be changed except for 
AE-related reasons where changes to baseline medications can be justified by the 
Investigator (e.g., increases in loop diuretics for new edematous states or discontinuation of 
baseline medication for drug-related AEs. 
Suggestions for BP medications which may be added are listed below (Rossignol, 2015): 
• β blockers, preferably one with an hepatic elimination route (i.e., metoprolol, carvedilol, 
nebivolol, and propranolol) to avoid drug accumulation, which could lead to an increased 
risk of bradyarrhythmias 
• α blockers (e.g., doxazosin) 
• Centrally acting α agonists that do not require dose adjustments (e.g., clonidine) 
• Direct vasodilators (i.e., hydralazine or minoxidil) may sometimes be used, but could 
induce severe ﬂuid retention and tachycardia (especially minoxidil, which has other side 
effects such as hirsutism and pericardial effusion). 
 


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Appendix E: List of Central Laboratory Assays 
Serum Chemistry Panel: 
Hematology: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (total) 
Blood Urea Nitrogen 
Calcium 
Creatine kinase  
Creatinine (with eGFR) 
Glucose 
Inorganic phosphate 
Iron 
Lactate dehydrogenase 
Magnesium 
Potassium  
Sodium 
Total cholesterol 
Total protein 
Uric acid 
White blood cell count (WBC) 
Red blood cell count  
Hemoglobin 
Hematocrit (Packed Cell Volume) 
Mean cell volume  
Mean cell hemoglobin  
Mean cell hemoglobin concentration  
Platelet count 
Differential WBC 
Urine: 
Specific gravity 
pH 
Protein 
Glucose 
Creatinine 
Ketones 
Blood 
Urobilinogen 
Leukocytes 
Leukocyte esterase 
Nitrites 
Bilirubin 
24-hour urine collection for sodium, creatinine, 
albumin (for ACR) 
Spot urine for albumin and creatinine (for ACR) 
Urine pregnancy 
Other: 
Serum pregnancy  
NT-proBNP 
Aldosterone and plasma renin activity 
Spironolactone level  
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 


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STATISTICAL ANALYSIS PLAN 
Title: 
A Randomized, Double-Blind, Placebo-controlled, 
Parallel Group Study of Patiromer for the Enablement of 
Spironolactone Use for Blood Pressure Control in 
Patients with Resistant Hypertension and Chronic Kidney 
Disease:  Evaluation of Safety and Efficacy (AMBER) 
Investigational Drug: 
Patiromer for Oral Suspension 
US IND #: 
075615 
Protocol Number: 
RLY5016-207 
Protocol Version and Date: 
Amendment 2, 4 November, 2016 
Sponsor: 
Relypsa, Inc. 
100 Cardinal Way 
Redwood City, CA 94063 
USA. 
+1.650.421.9500 Phone 
+1.650.421.9700 Fax 
Original SAP Date: 
07 FEB 2017 
Updated SAP Date: 
11 December 2018  
Version: 
1.2 
 
 
CONFIDENTIAL INFORMATION 
Not to be copied, distributed, quoted, or otherwise disclosed or used  
without prior written permission from Relypsa, Inc. 


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TABLE OF CONTENTS 
1 
INTRODUCTION ...................................................................................................6 
2 
STUDY OBJECTIVES AND STUDY DESIGN ....................................................6 
2.1 
Study Objectives ..........................................................................................6 
2.2 
Study Design ................................................................................................6 
2.3 
Sample Size Determination..........................................................................9 
3 
RANDOMIZATION AND BLINDING..................................................................9 
4 
INTERIM ANALYSES ...........................................................................................9 
5 
ANALYSIS SETS ...................................................................................................9 
5.1 
Intent-to-treat Population (ITT) ...................................................................9 
5.2 
Per-protocol Population (PP) .....................................................................10 
5.3 
Safety Population (SAF) ............................................................................10 
5.4 
Protocol Deviations ....................................................................................10 
6 
ENDPOINTS AND VISIT WINDOWS ................................................................10 
6.1 
Efficacy Endpoints .....................................................................................10 
6.1.1 
Primary Efficacy Endpoint ..................................................................10 
6.1.2 
Secondary Efficacy Endpoint ..............................................................11 
6.1.3 
Other Efficacy Endpoints .....................................................................11 
6.1.4 
Exploratory Efficacy Endpoint ............................................................11 
6.2 
Safety Endpoints ........................................................................................11 
6.3 
Study Day and Visit Windows ...................................................................12 
6.3.1 
Study Day.............................................................................................12 
6.3.2 
Visit Windows .....................................................................................12 
6.3.3 
Baseline ................................................................................................12 
6.4 
Key Considerations for Blood Pressure .....................................................13 
7 
HANDLING OF DROPOUTS AND MISSING DATA .......................................14 
7.1 
Dropouts .....................................................................................................14 
7.2 
Missing AOBP ...........................................................................................14 
7.3 
Missing Information for Adverse Events ...................................................14 
7.4 
Missing Dates or Partially Missing Dates ..................................................14 
8 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ............14 
8.1 
General Considerations and Statistical Methods .......................................14 
8.2 
Subject Disposition ....................................................................................15 
8.3 
Demographics and Baseline Characteristics ..............................................15 
8.4 
Medical History .........................................................................................16 
8.5 
Prior and Concomitant Medications ..........................................................16 
8.6 
Exposure to Study Drug .............................................................................16 
8.7 
Compliance ................................................................................................16 


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8.8 
Protocol Deviations ....................................................................................17 
8.9 
Efficacy Analyses ......................................................................................17 
8.9.1 
Primary Efficacy Analysis ...................................................................17 
8.9.2 
Secondary Efficacy Analysis ...............................................................17 
8.9.3 
Additional Efficacy Analyses ..............................................................18 
8.9.4 
Subgroups ............................................................................................20 
8.9.5 
Exploratory Efficacy Analysis .............................................................21 
8.10 
Safety Analyses ..........................................................................................21 
8.10.1 
Adverse Events ....................................................................................21 
8.10.2 
Emergency Room Visits and Revascularization Procedures ...............22 
8.10.3 
Death ....................................................................................................22 
8.10.4 
Clinical Laboratory Tests .....................................................................22 
8.10.5 
Vital Signs ............................................................................................24 
8.10.6 
Physical Examination...........................................................................25 
8.10.7 
12-lead Electrocardiogram (ECG) .......................................................25 
8.10.8 
Pregnancy Test .....................................................................................25 
9 
REFERENCES ......................................................................................................25 
APPENDIX A: 
SCHEDULE OF EVENTS ........................................................................26 
APPENDIX B: 
IMPUTATION OF DATES .......................................................................29 
1 
Imputation of Missing/Partially Missing Adverse Event Dates ................29 
1.1 
Incomplete Start Date: ...............................................................................29 
1.2 
Incomplete Stop Date:................................................................................29 
2 
Imputation of Dates for Prior/Concomitant Medications/Procedures .......30 
3. 
Imputation of Dates for Pre-specified Medical History .............................30 
APPENDIX C: 
LIST OF CENTRAL LABORATORY ASSAYS .....................................32 


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GLOSSARY OF ABBREVIATIONS 
ACEI 
angiotensin-converting enzyme inhibitor 
ACR 
albumin to creatinine ratio 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AOBP 
automated office blood pressure 
ARB 
angiotensin II receptor blocker 
BID 
twice daily 
BP 
blood pressure 
CBC 
complete blood count 
BPM 
beats per minute 
CI 
confidence interval 
CKD 
chronic kidney disease 
 
 
DBP 
diastolic blood pressure 
DSMC 
data safety monitoring committee 
EDC 
electronic data capture 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
FU 
Follow-up Visit 
FDA 
Food and Drug Administration 
FGF23 
fibroblast growth factor 23 
GCP 
good clinical practices 
HbA1c 
hemoglobin A1c 
HBP (7dHBP) 
home blood pressure (seven-day home blood pressure) 
HF 
heart failure 
HR 
heart rate 


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ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
K+ 
potassium 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRA 
mineralocorticoid receptor antagonist 
NSAIDs 
non-steroidal anti-inflammatory drugs 
QD 
once daily 
RAASi 
renin-angiotensin aldosterone system (inhibitor) 
S1 
Screening Visit 1 
S2 
Screening Visit 2 
S3 
Screening Visit 3 
S4 
Screening Visit 4 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error 
SMBP 
subject-measured blood pressure performed at the study site using the 
HBP monitor 
TEAE 
treatment-emergent adverse event 
TID 
three times daily 
WBC 
white blood cell count 


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1 
INTRODUCTION 
This document presents the statistical analysis plan (SAP) for protocol RLY5016-207,  entitled 
“A Randomized, Double-Blind, Placebo-controlled, Parallel Group Study of Patiromer for the 
Enablement of Spironolactone Use for Blood Pressure Control in Patients with Resistant 
Hypertension and Chronic Kidney Disease:  Evaluation of Safety and Efficacy (AMBER)”.   
Results obtained from the analyses outlined in this document will provide the basis of the 
Clinical Study Report (CSR) for this study. The statistical rationale and analysis methods 
specified in this document take precedence over those described in the protocol, should there 
be any differences.   
2 
STUDY OBJECTIVES AND STUDY DESIGN 
2.1 
Study Objectives 
The objective of the study is to determine whether patiromer treatment of CKD subjects 
receiving spironolactone for the treatment of resistant hypertension will result in: 
• More persistent use of spironolactone through prevention of hyperkalemia 
• Improved blood pressure control through more persistent use of spironolactone 
 
2.2 
Study Design 
This study is a randomized, double-blind, placebo-controlled, parallel group study of 
patiromer or placebo treatment (patiromer/placebo) in conjunction with spironolactone in 
subjects with resistant hypertension and CKD.  Approximately 290 subjects will be 
randomized. 
Screening for this study includes 4 visits and lasts up to 4 weeks.  Subjects who meet all 
eligibility criteria are randomized to receive either spironolactone and patiromer or 
spironolactone and placebo.  The active treatment period runs for 12 weeks.  A follow-up 
visit is scheduled 2 weeks after completion of the Week 12 or Early Termination (ET) Visit. 
Study periods are as follows:  
• Screening Period (4 Visits)   
Screening Visit 1 (S1), Screening Visit 2 (S2), Screening Visit 3 (S3) and Screening 
Visit 4 (S4) occur one week apart (at least 4 days but no more than 10 days).  If the 
subject meets all eligibility criteria at the final screening visit (S4), the visit becomes 
the Randomization/Baseline Visit. 
• Double-Blind Treatment/Observation Period (12 weeks) 
 At the Randomization/Baseline Visit, each subject is randomized to either 
spironolactone + patiromer or spironolactone + placebo, and is instructed to begin 
study drug on the following day, which then becomes Day 1 of the study. 


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The Double-Blind Treatment/Observation Period consists of 8 scheduled visits at 
Weeks 1, 2, 3, 4, 6, 8, 10, and 12. The intent is to observe all subjects for the entire 12 
weeks of this period, whether or not they have discontinued study drug. 
• Follow-up Period  
Two weeks after the subject has completed either the Week 12 Visit or ET Visit, the 
subject returns for a Follow-up (FU) Visit. 
The Schedule of Events for this study is presented in Appendix A.  
The initial dose of spironolactone will be 25 mg QD for all subjects, and the initial dose of 
patiromer/placebo will be 2 packets QD.  If a subject’s blood pressure and potassium 
assessments allow, the dose of spironolactone will be increased to 50 mg QD at Week 3.  
Detailed titration rules for spironolactone and patiromer/placebo are specified in the protocol 
in Appendix B (patiromer/placebo) and Appendix C (spironolactone). 
The overall design of the study is presented schematically below in Figure 1. 


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Figure 1. Study Schema 
 
AOBP = automated office blood pressure; HBP = home blood pressure; eGFR = estimated glomerular filtration rate; K+ = potassium measurement; R = Randomization/Baseline 
(Day 0) Visit; S = Screening Visit; SBP = systolic blood pressure; W = week 
a 
Receiving at least three antihypertension drugs including diuretic.  ACE inhibitors or ARBs should be included among these three antihypertensive medications, unless 
previously not tolerated or contraindicated (see Inclusion Criteria).. 
b 
Mean (calculated by the IWRS) of two values measured at Visits S1 and S3 (or 7 to 28 days apart) during the Screening/Run-in Period. 
c 
Qualifying local laboratory K+ measurements of 4.3 – 5.1 mEq/L obtained at Visits S1, S3 and S4 (all measurements must be within range) 
d 
Subjects who develop hyperkalemia (K+ ≥ 5.5 mEq/L) that cannot be managed with blinded patiromer/placebo escalation according to the treatment algorithm will 
discontinue spironolactone and patiromer/placebo, but still remain in the study. Hyperkalemia may be treated using standard of care 
e
Performed both by a designated oscillometric BP monitoring device that will automatically measure subject’s BP in triplicate after 5 minutes of sitting quietly without the aid 
of study staff, AOBP, and by the subject using their issued HBP device (triplicate measurements). 
f 
Two (2) weeks after the Week 12 (+ 7 days) or ET Visit (note, no subject measured office BP at this Visit).  Subjects who complete the Follow-up Visit prior to 2 Weeks will 
receive a Follow-up Phone Call at 2 weeks (+ up to 7 days) after Week 12 or ET Visit. 
Note: The reference to Appendix C for dosing is referring to the Protocol Appendix C. For subjects with study drug (spironolactone or patiromer/placebo) modifications based on 
BP assessments or potassium levels, an Unscheduled Visit will be conducted within 1 week after this modification unless the next scheduled visit is within 1 week of the study 
drug modification, in which case, the subject will return at the next scheduled visit.  For all study visit windows, refer to the Schedule of Events.


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2.3 
Sample Size Determination 
This study will randomize approximately 290 subjects, to ensure that at least 280 subjects 
will be available for the primary analysis.  This allows for the possibility that up to 10 
subjects are randomized but never take study medication.  A sample size of 280 subjects has 
90% power to detect a difference between treatment groups of 20% or more in the proportion 
of subjects remaining on spironolactone at Week 12, at α = 0.05. 
3 
RANDOMIZATION AND BLINDING 
At Screening Visit 4, eligible subjects will be randomized 1:1 to spironolactone + patiromer 
or spironolactone + placebo.  Randomization will be stratified by the Visit S4 locally 
measured potassium value (4.3 to < 4.7 mEq/L or 4.7 to 5.1 mEq/L) and by history of Type 1 
or 2 diabetes mellitus (Yes or No). 
To minimize the potential for bias, subjects, site personnel, and sponsor and vendor staff will 
remain blinded to treatment assignments, with the exception of unblinded staff required for 
the development of the final randomization schedule and for production of unblinded 
materials for the Data Safety Monitoring Committee (DSMC).  Drug safety staff may also be 
unblinded where this is necessary to comply with regulatory requirements. 
For production of DSMC materials, an unblinded sponsor biostatistician and unblinded 
sponsor programmer(s) will be identified.     
The final randomization schedule will be produced by unblinded staff at Endpoint, the IWRS 
vendor for this study, and will be reviewed by the sponsor DSMC unblinded biostatistician. 
The study will be unblinded after database lock. 
4 
INTERIM ANALYSES 
No interim efficacy analysis is planned for this study. Safety will be evaluated by the DSMC 
on an ongoing basis.    
5 
ANALYSIS SETS 
5.1 
Intent-to-treat Population (ITT) 
The Intent-to-Treat (ITT) Population includes all subjects who have been randomized and 
have taken at least one dose of spironolactone and at least one dose of patiromer/placebo.  
All efficacy analyses will be performed on the ITT population, analyzed by planned 
treatment group assignment.  In addition, the primary and secondary endpoints will also be 
performed using the Per-protocol Population. 


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5.2 
Per-protocol Population (PP) 
The per-protocol population includes ITT subjects who have been compliant with dosing of 
both spironolactone and patiromer/placebo and who do not have any important protocol 
deviations (see Section 5.4).   
Dosing compliance is defined as having taken 80-120% of the prescribed dose. 
The primary and secondary endpoints will be performed using the PP Population, in addition 
to the ITT Population. 
5.3 
Safety Population (SAF) 
The safety population will include all randomized subjects who have taken at least one dose 
of spironolactone or patiromer/placebo, analyzed according to the actual treatment received. 
All safety analyses will be performed on the SAF population. 
5.4 
Protocol Deviations 
Prior to database lock, all protocol deviations will be compiled.  Important protocol 
deviations will be identified and used to determine, prior to database lock, the per protocol 
population. 
The following deviations are considered, a priori, to be important protocol deviations: 
• Violations of initial informed consent 
• Enrolled in violation of the entry criteria 
• Site errors in randomization assignment 
• Administration of a prohibited medication to a study subject potentially affecting the 
primary and secondary efficacy endpoints 
• Study subjects not discontinuing study medication when they met protocol criteria for 
stopping study treatment 
• Dosing with study drug after a study subject’s withdrawal from the study 
 
6 
ENDPOINTS AND VISIT WINDOWS 
6.1 
Efficacy Endpoints 
6.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is the proportion of subjects remaining on 
spironolactone at Week 12. 


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Subjects who terminate from the study early or discontinue study spironolactone prior to 
Week 12, for any reason, will be considered as not having remained on spironolactone until 
Week 12. 
6.1.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is change from Baseline in AOBP SBP at Week 12 or last 
available AOBP SBP prior to addition of any new BP medications or increase from any 
baseline BP medications.  
6.1.3 
Other Efficacy Endpoints 
The following other efficacy endpoints were specified by the protocol: 
• Change in AOBP SBP from baseline to Week 12 
• Potassium levels over time (measured both centrally and locally) 
• Proportion of subjects with serum K+ ≥ 5.5 mEq/L 
• Average daily dose and cumulative dose of spironolactone 
• Time to discontinuation of spironolactone 
• Change in albuminuria (urine albumin to creatinine ratio [ACR]) from baseline to 
Week 12 
• EQ-5D-5L questionnaire results at Baseline and Week 12/ET  
In addition to the endpoints specified in the protocol, the following additional endpoints will 
be examined: 
• Change in AOBP SBP from baseline to Week 12 in the subgroup of patients 
remaining on spironolactone at Week 12  
• Change in AOBP SBP/DBP over time 
6.1.4 
Exploratory Efficacy Endpoint 
• Change in 7dHBP SBP/DBP over time 
6.2 
Safety Endpoints 
Safety endpoints will consist of: 
• Adverse events, including newly observed clinically significant physical examination 
abnormalities and events of interest (e.g. gastrointestinal events, renal events) 
• Clinical laboratory test results and changes over time, including Spironolactone level 
and NT-pro-BNP. 


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• Vital signs 
• ECG findings and changes 
• Reasons for discontinuing patiromer/placebo/spironolactone 
• Deaths 
Adverse events will be coded using MedDRA 18.1. 
6.3 
Study Day and Visit Windows 
6.3.1 
Study Day 
The first date of dosing with any study medication (either spironolactone or 
patiromer/placebo) will be used as the Reference Date for Study Day calculation.   
The Study Day for date of first dosing is Day 1.  The Study Day for all other study events is 
defined as follows: 
• If a date is prior to the Reference Date, Study Day is defined as [date] - [Reference 
Date], so the Study Day for the day before date of first dose (typically the 
randomization day) is defined as Day -1.  
• If a date is on or after the Reference Date, Study Day is defined as [date] - [date of 
randomization] +1; hence, the Study Day for the day after first dose is defined as Day 
2.  
6.3.2 
Visit Windows 
The protocol specified windows for scheduled visits are shown in the Schedule of Events 
(Appendix A).   
Unless otherwise specified, analyses by visit will use the visit weeks reported in the database 
and include results collected at scheduled visits.   
Analyses not limited to visits (e.g. incidence of laboratory test values within a given range, 
and time to event analyses), will include all available values of the variable of interest, 
irrespective of whether it was collected at a scheduled or unscheduled visit.  
For central laboratory data, the visit information from the central laboratory will be used to 
determine whether a visit is scheduled or unscheduled.   
6.3.3 
Baseline 
For all analysis variables, unless otherwise specified, baseline is the last non-missing value of 
the variable on or before the first dose of any study medication. 


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6.4 
Key Considerations for Blood Pressure 
Blood pressure is measured in three ways in this study: 
• AOBP:  Automated Office Blood Pressure 
• SMBP:  Subject-Measured Blood Pressure (performed at the study site using the HBP 
monitor) 
• 7dHBP: 7-day Home Blood Pressure 
The AOBP is an unwitnessed measurement taken at the clinic using an automatic office 
device that collects 3 measures of SBP/DBP.  The mean of the three values is used for 
titration of study medication, and is the value that will be used for most analyses. 
The SMBP is an unwitnessed measurement taken at the clinic using the subject’s home blood 
pressure device.  The home blood pressure device takes 3 readings automatically, and the 
mean of the three is used.  If an AOBP is unavailable at a visit, for whatever reason, the 
SMBP will be used in its place to determine titration of study medications.   
The HBP device is used by the subject outside the clinic to take measurements twice a day.  
At each sitting, 3 readings are taken automatically and uploaded to the Bioclinica database. 
The 7-day home blood pressure (7dHBP) is calculated from these measurements as follows: 
1. Morning average = average of all measurements with time stamp midnight to before 
noon on given day 
2. Evening average = average of all measurements with time stamp noon to before 
midnight on given day 
3. Daily average = average of morning and evening averages 
4. 7-day HBP (7dHBP) = average of daily averages for prior 7 days 
The morning/evening averages include all values within the specified timeframes.  If there 
are no valid readings during the morning time period, the morning average is missing, and 
the daily average will be based on the available values during the evening period, and 
similarly if there are no valid readings in the evening period.  If there are no valid readings in 
either the morning or evening period, the daily average will be missing for that day. The 
7dHBP is calculated using as many daily averages as are available for the previous 7 days.   
A valid 7dHBP requires that there be, at an absolute minimum, at least one valid reading for 
each of the prior 3 days.  Readings taken with the HBP device while at the clinic are 
excluded from the calculation of the 7dHBP.  Because the calculation requires averages of 
averages, rounding should not be done until the final 7dHBP result has been calculated.  
 
For summaries of the 7dHBP by visit, the value of the 7dHBP at a visit will be calculated 
using the 7 days prior to the visit, and will not include any readings taken on the day of the 
visit. 


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7 
HANDLING OF DROPOUTS AND MISSING DATA 
7.1 
Dropouts 
In this study, every effort is made to retain all subjects through Week 12, whether or not they 
are still on study medication. 
For the primary endpoint (percentage of subjects remaining on spironolactone at Week 12), 
any subject who terminates early is defined as not having remained on spironolactone. All 
ITT subjects will be included in the analysis. 
7.2 
Missing AOBP 
If the AOBP SBP is missing at a scheduled visit, the SMBP SBP for that visit will be used in 
analysis. 
 
7.3 
Missing Information for Adverse Events 
For subjects with the missing information for adverse events, the following imputation rules 
will be applied: 
• An adverse event with onset date equivalent to the first dosing date will be considered to 
be treatment-emergent unless there is evidence to conclude that it is not. 
• An adverse event with missing severity will be assigned to the highest severity observed 
for the subject, among all events with the same preferred term; if there are no other AEs 
with same preferred term and non-missing severity, the adverse event will be counted as 
severe. 
• An adverse event with missing relationship to study drug (patiromer/placebo or 
spironolactone) will be assigned to possible relationship (i.e. related). 
7.4 
Missing Dates or Partially Missing Dates 
Missing or partially missing dates will be imputed conservatively for concomitant 
medications, procedures and adverse events (AEs).  Specific rules for handling missing or 
partially missing dates are provided in the Appendix B. 
No imputations for other missing safety data will be undertaken. 
8 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1 
General Considerations and Statistical Methods 
Efficacy analyses will be performed by planned treatment (i.e. as randomized), and safety 
analyses by actual treatment received.   


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For continuous variables, descriptive statistics will include the number of subjects, mean, 
standard deviation (SD), standard error (SE), median, 25th, 75th percentiles, minimum and 
maximum. 
For categorical variables, descriptive statistics will include frequencies and percentages in 
each category. 
For time-to-event variables, the descriptive statistics will include the median, 95% CI, 
25th/75th percentiles, minimum and maximum.  Counts of events and of number censored will 
also be provided. 
When mean change from baseline is summarized, subjects will be included in the analysis if 
they have both a baseline value and a post-baseline value at the time point of interest. 
All statistical tests will be conducted at a two-sided alpha level of 0.05, and 95% confidence 
intervals will be utilized, unless otherwise stated. 
Detailed statistical methods are specified in sections below.   
8.2 
Subject Disposition 
The number and percentage of subjects randomized, subjects who receive study drug, and 
subjects who complete study (or are terminated early) will be summarized by treatment 
group and overall.  The number and percentage of subjects terminating from the study early 
will be presented by reason. The ITT, PP, and Safety Populations will also be summarized by 
treatment group and overall.  If populations do not differ (e.g. ITT and Safety Populations) 
then the summary will be presented only once. 
In addition, the number and percentage of subjects who signed informed consent, screen 
failures and screen failure reasons will be summarized. 
Listings of subject disposition and screening will be provided. 
8.3 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the ITT, PP and Safety 
Populations (if they differ from ITT), by treatment group and overall. 
The summary of demographic information will include age, sex, race and ethnicity.  The 
summary of patient characteristics at baseline will include, but is not limited to, weight, 
height, BMI, baseline medical history (including chronic kidney disease, diabetes types, 
hypertension, heart failure including NYHA class, ejection fraction (EF), myocardial 
infarction, baseline serum potassium and eGFR). 
Listings of demographics and baseline characteristics will be provided. 


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8.4 
Medical History 
General medical history will be coded in accordance with MedDRA 18.1 and will be 
summarized by body system (or procedure), for each treatment group and overall. 
A listing of general medical history will be provided. 
8.5 
Prior and Concomitant Medications 
All prior and concomitant medications will be coded using the current version of the World 
Health Organization Drug dictionary (WHO Drug Sep2016). 
Prior medications are defined as medications with start date before the date of first dose of 
study medication.  Concomitant medications are those taken during the study period, and are 
defined as medications with start date on or before the date of last dose of study medication  
and end date on or after the date of first dose of study medication, or no end date.  
Prior and concomitant medications will be separately summarized by treatment and overall.  
Additional summaries will be provided for concomitant medications of interest, including all 
antihypertensive agents and medications for diabetes mellitus (Type 1 or 2).  Summaries will 
be presented by treatment group and overall. 
Listings of all prior and concomitant medications will be provided. 
8.6 
Exposure to Study Drug 
Exposure to study drug will be summarized separately for spironolactone and 
patiromer/placebo.  Summaries will be provided, by treatment group, for: 
• Duration: calculated as [last dose date]-[first dose date]+1.  
• Total dose: calculated for each subject as the total dosage received  
• Mean daily dose: calculated for each subject as the total dose divided by the duration 
of study drug exposure  
• Number and type of titrations (up or down)  
In addition, for patiromer/placebo, the number of non-zero dose days will be summarized. 
Separate listings will be provided for spironolactone and patiromer/placebo exposure. 
8.7 
Compliance 
Study drug compliance will be assessed separately for spironolactone and patiromer/placebo.  
Summaries will be presented by treatment group. 


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Dose compliance will be derived from the total dose of study drug taken by a subject divided 
by the prescribed total dose over the treatment period, multiplied by 100. 
Descriptive statistics will be provided for dose compliance.  In addition, counts (%) will be 
provided for compliance categories 80-120%, < 80%, and > 120%. 
A listing of compliance for each study drug by subject will be provided. 
8.8 
Protocol Deviations 
The number and percentage of subjects with protocol deviations will be summarized by 
category of deviation, for each treatment group and overall.  A listing of important protocol 
deviations will be provided. 
8.9 
Efficacy Analyses 
8.9.1 
Primary Efficacy Analysis 
The primary efficacy endpoint for this study is the proportion of subjects remaining on 
spironolactone at Week 12.  
A subject is defined as having remained on spironolactone until Week 12 if the End of Study 
Treatment eCRF confirms the subject has completed the full 12-week course of study 
treatment and the subject had not discontinued spironolactone early.  Subjects who terminate 
from the study early or discontinue spironolactone early, for any reason, will be defined as 
not having remained on spironolactone until Week 12. The number and percentage of 
subjects remaining on spironolactone at Week 12, and the 95% CI, will be provided by 
treatment group.  Confidence intervals will be obtained using the exact (Clopper-Pearson) 
method. 
The percentage of subjects remaining on spironolactone at Week 12 will be compared 
between treatment groups (spironolactone + patiromer versus spironolactone + placebo) 
using a Cochran-Mantel-Haenszel (CMH) test, at α-level 0.05.  The test will be stratified by 
baseline potassium category (4.3 to < 4.7 mEq/L or 4.7 to 5.1 mEq/L) and Type 1 or 2 
diabetes mellitus (Yes or No).   
The primary analysis will be performed using the ITT and PP Populations.   
8.9.2 
Secondary Efficacy Analysis 
The secondary efficacy endpoint is change from Baseline in AOBP SBP at Week 12 or last 
available AOBP SBP on or prior to the first date of addition of any new BP medications or 
increases from any baseline BP medications. 
Baseline AOBP is defined as the latest available AOBP on or before the date of first dose 
date. 


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Changes/additions to baseline BP medications are recorded on the Antihypertensive 
Medications eCRF.  The earliest date of any recorded increase/addition will be compared to 
the date of the Week 12 AOBP, and the rules below will be applied.  Note that only dates of 
BP medication increases/additions with start date on or before the upper limit of the Week 12 
window will be considered. 
• If the earliest date of  BP medication increase/addition is on or after the date of the 
Week 12 AOBP, or there is no record of any increase/addition, the Week 12 AOBP 
SBP will be used for analysis. 
• If the earliest date of BP medication increase/addition is prior to the Week 12 AOBP, 
or when the Week 12 visit should have occurred if there is no Week 12 AOBP, then 
the AOBP on or before and closest to the earliest date of change will be used for 
analysis. 
• If a subject has no Week 12 AOBP and no record of any BP medication 
changes/additions, the subject will not be included in this analysis. 
In above rules, the SMBP, if available, may be used in place of a missing AOBP at the same 
visit. 
The secondary efficacy endpoint will be analyzed using an analysis of covariance 
(ANCOVA) model, with baseline AOBP SBP as a continuous covariate and factors for 
treatment group, baseline serum potassium (K+ 4.3 – < 4.7 or 4.7 – 5.1 mEq/L), and Type 1 
or 2 diabetes mellitus (Yes or No).   
The analysis will be performed using the ITT and PP Populations. A sensitivity analysis will 
be performed using the last observation carried forward, when a subject has no Week 12 
AOBP and no record of any BP medication changes/additions. 
8.9.3 
Additional Efficacy Analyses 
Additional analyses will be provided for blood pressure, potassium, spironolactone exposure 
and quality of life measures as outlined in subsections below. 
8.9.3.1 
Blood Pressure 
Change in AOBP SBP from baseline to Week 12  
Treatment groups will be compared for change in AOBP SBP at Week 12 regardless of 
increase in antihypertensives by using both ANCOVA and repeated measures methods.   
An ANCOVA analysis will be carried out using a model that includes baseline AOBP SBP 
as a continuous covariate and factors for treatment group, baseline serum potassium (K+ 4.3 
to < 4.7 or 4.7 to 5.1 mEq/L), and Type 1 or diabetes mellitus (Yes or No).  This analysis will 
include only ITT subjects who have AOBP SBP (or SMBP if AOBP is missing) at both 
Baseline and Week 12.  


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In addition, a repeated measures mixed model analysis will be performed using all ITT 
subjects who have an AOBP SBP (or SMBP if AOBP is missing) assessment at Baseline and 
at least one post-baseline assessment at Week 1 or later.  The model will include baseline 
AOBP SBP as a continuous covariate and factors for treatment group, time, baseline serum 
potassium (K+ 4.3 to < 4.7 or 4.7 to 5.1 mEq/L), and Type 1 or 2 diabetes mellitus (Yes or 
No).   
AOBP over time 
Summaries of AOBP SBP/DBP will be provided at each visit and for change from Baseline, 
by treatment group.  SMBP SBP/DBP may be used for missing AOBP SBP/DBP. Summaries 
of change at each post-baseline time point will include only subjects who have non-missing 
values at baseline and at the post-baseline time point of interest.  
Mean SBP/DBP and mean change from baseline will be presented graphically.  
The change from Baseline in AOBP SBP over time prior to the first date of addition of any 
new BP medications or increases from any baseline BP medications will also be presented 
for the subjects who remained on spironolactone through Week 12. 
8.9.3.2 
Potassium  
Central serum potassium levels and change from Baseline will be summarized, by treatment 
group, at each scheduled visit.     
Central serum potassium over time will be presented graphically. 
Number and percentage of subjects who have experienced no K+ ≥ 5.5 mEq/L will be 
presented by visit. All central laboratory potassium values will be used for this analysis.  
Local laboratory potassium values from serum samples will be included in listings. 
8.9.3.3 
Spironolactone 
Treatment groups will be compared for spironolactone duration, total dose and mean daily 
dose using ANCOVA models with baseline AOBP as a continuous covariate, and including 
factors for treatment group, baseline serum potassium (K+ 4.3 to < 4.7 or 4.7 to 5.1 mEq/L), 
and history of Type 1 or 2 diabetes mellitus (Yes or No). 
The number and percentage of subjects at each spironolactone dose will be presented by 
treatment group and visit.  Dose at a visit is defined to be the investigator prescribed dose at 
that visit. 
Time to discontinuation of spironolactone will be estimated using Kaplan-Meier methods, 
and will be compared between treatment groups using the log rank test. 


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8.9.3.4 
Change in albuminuria (urine albumin to creatinine ratio [ACR]) from 
Baseline to Week 12 (ET) 
Albuminuria will be summarized, by treatment group, at Baseline and Week 12, as well as 
change in albuminuria from Baseline to Week 12. The analysis will also be conducted for the 
subgroup of subjects whose ACR was elevated at baseline. 
8.9.3.5 
EQ-5D-5L Quality of Life questionnaire results at Baseline and Week 12/ET  
The EQ-5D-5L Quality of Life (QOL) instrument is collected at Randomization/Baseline and 
Week 12/ET. 
The EQ-5D-5L QOL instrument consists of 5 dimensions of quality of life (mobility, self 
care, usual activities, pain/discomfort, and anxiety/depression) and the EQ visual analogue 
(EQ VAS) measure of “how good or bad your health is today”.   
For each of the 5 dimensions, subjects choose between 5 levels (no problems, slight 
problems, moderate problems, severe problems, and extreme problems).  Answers are scored 
from 1 (no problems) to 5 (extreme problems).  The EQ VAS is measured from 0 (“The 
worst health you can imagine”) to 100 (“The best health you can imagine”).   
The EQ-5D-5L questionnaire is collected at Randomization/Baseline and Week 12/ET.  
Summaries of the number and percentage of subjects at each level in each dimension will be 
presented at the two time points.  Summary statistics will be provided for the EQ VAS at 
Randomization/Baseline and Week 12/ET, and for change from Baseline to Week 12/ET.  
8.9.4 
Subgroups 
The primary and secondary analyses will be performed for the following subgroups: 
• Sex (male versus female) 
• Age (< 65 versus ≥ 65 years) 
• Type 1 or Type 2 diabetes mellitus (presence versus absence at baseline) 
• Baseline potassium category (4.3 to < 4.7 mEq/L versus 4.7 to 5.1 mEq/L) from central 
lab 
• Region (Group A versus Group B) 
• History of heart failure (presence versus absence at baseline) 
• Baseline eGFR (< 30 versus ≥ 30 mL/min/1.73 m2) 
The test for interaction between treatment and a subgroup will be performed. 


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8.9.5 
Exploratory Efficacy Analysis 
7dHBP over time 
Summaries of 7dHBP SBP/DBP will be provided at each visit and for change from Baseline, 
by treatment group.  Summaries of change at each post-baseline time point will include only 
subjects who have non-missing values at baseline and at the post-baseline time point of 
interest.  
Mean SBP/DBP and mean change from baseline will be presented graphically.  
8.10 
Safety Analyses 
8.10.1 
Adverse Events 
AEs and SAEs will be coded to system organ class (SOC) and preferred term (PT) in 
accordance with MedDRA 18.1.  Adverse event analyses will include only treatment-
emergent AEs (TEAEs). A TEAE is defined as any AE that newly appeared or worsened in 
severity following initiation of study drug administration.  If the onset date of an AE is 
missing, the AE will be considered treatment-emergent unless there is evidence to conclude 
that it is not.  AE listings will include all AEs. 
Central laboratory serum pregnancy tests will be done at S1 and Week 12/ET.  Local urine 
pregnancy tests will be done at Randomization/Baseline. Pregnancy is not considered an AE 
but is reported separately (please see Protocol Amendment 2 Section 8.4 regarding 
Procedures for Reporting Pregnancy Exposure and Birth Events).   
The incidence of TEAEs will be summarized by system organ class (SOC), preferred term 
(PT) and severity.  For those TEAEs that occur more than once during the study period, the 
maximum severity will be used in the summary by severity. 
Descriptive statistical summaries (frequencies and percentages) will be provided by treatment 
group for the followings: 
• Overall summary of TEAEs, including summaries of severity, TEAEs related to study 
drug, SAEs, SAEs related to study drug, TEAEs leading to study drug modification and 
TEAEs leading to study drug discontinuation 
• Summary of all TEAEs by SOC, PT and severity 
• Summary of TEAEs related to study drug by SOC, PT, separately for spironolactone and 
patiromer/placebo 
• Summary of TEAEs leading to study drug modification by SOC, PT, separately for 
spironolactone and patiromer/placebo 
• Summary of TEAEs leading to early study drug discontinuation by SOC, PT, separately 
for spironolactone and patiromer/placebo 


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• Summary of SAEs by SOC, PT, and severity 
• Summary of SAEs related to study drug by SOC, PT, separately for spironolactone and 
patiromer/placebo 
• Summary of TEAEs of special interest (e.g. allergic reactions, gastrointestinal events, 
renal events) 
A listing for all AEs will be provided, including verbatim term, PT, SOC, severity, whether 
serious, relationship to each study drug, onset and end date, action taken and outcome of 
event will be provided.  Listings of SAEs and TEAEs leading to study drug modification and 
to early study drug discontinuation will be provided.  Listings will also be provided for 
events of special interest. 
8.10.2 
Emergency Room Visits and Revascularization Procedures 
Listings will be provided for all reported emergency room visits and revascularization 
procedures. 
8.10.3 
Death 
A listing of all deaths will be provided.  The listing will include date of death, primary cause 
of death and any associated AE.  
8.10.4 
Clinical Laboratory Tests 
Clinical laboratory tests to be performed in this study are listed in detail in Appendix C. 
For central laboratory test summaries by visit, the central laboratory measurements at 
scheduled visits will be used if available. The visit information from the central laboratory 
will be used to determine whether a visit is scheduled or unscheduled.  
If a laboratory result from a visit is retested and the central laboratory subsequently 
determines the original result to be valid, the original result for that visit will be used in 
analysis, and the second (i.e. ‘retested’) value will be ignored. Otherwise, if the central 
laboratory detects an error through the retesting, the retested value will be used in analysis as 
the measurement for that visit. 
The baseline central laboratory value is defined as the last non-missing central laboratory 
value collected on or before the date of the first dose of study medication.  
8.10.4.1 
Serum Chemistry 
Serum chemistry tests will be performed at S1, S3, Randomization/Baseline and all 
scheduled visits during the study, including the FU Visit. Tests may also be done at 
unscheduled visits. 
All serum chemistry results will be summarized by treatment group with descriptive statistics 
at each scheduled visit, and for the change from baseline to the corresponding time points. 


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The incidence of laboratory test results in ranges of interest will be summarized by treatment 
group. These summaries will include but are not limited to the following: 
• Serum potassium < 3.0, < 3.5, < 3.8, > 5.0, and ≥ 5.5 mEq/L 
• Serum magnesium < 1.4, < 1.2, and < 1.0 mg/dL 
• Serum calcium > 10.2 mg/dL 
Laboratory shift tables from Baseline to End of Treatment will be provided for selected 
laboratory results. 
Listings will be provided for all serum chemistry parameters.  Listings will include test 
results at both scheduled and unscheduled visits. 
8.10.4.2 
Hematology 
Hematology tests will be performed at S1, Randomization/Baseline, Week 4 and Week 
12/ET.  Tests may also be done at unscheduled visits. 
All hematology results will be summarized by treatment group with descriptive statistics at 
Randomization/Baseline, Week 4, and at Week 12/ET, and for the change from Baseline at 
each time point. 
A listing of hematology will be provided.  The listing will include test results at both 
scheduled and unscheduled visits. 
8.10.4.3 
Special Laboratory Tests 
The following special laboratory tests will be conducted for this study:  NT-proBNP; 
aldosterone and plasma renin activity; spironolactone level. 
Special laboratory test results will be summarized by treatment group with descriptive 
statistics at each time point at which they were collected, and for change from Baseline to 
each post-baseline time point. 
A listing for special laboratory tests will be provided. 
8.10.4.4 
24-hour Urine  
24-hour urine for sodium, potassium, creatinine, and albumin tests will be performed at 
Randomization/Baseline. 
Raw test results will be adjusted to correct for the actual observed duration of the collection 
time in hours.  The 24-hour-adjusted values for sodium, potassium, creatinine, and albumin 
will be calculated as: 
24-hour-adjusted value = [(raw test value) / (sample collection time in hours)] × 24 


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The 24-hour ACR will be calculated as: 
24-hour ACR = (24-hour albumin / (24-hour creatinine) 
Descriptive summary statistics will be presented at Baseline, by treatment group, for the 
following variables: 
• 24-hour-adjusted sodium, potassium, creatinine, and albumin 
• Ratio of 24-hour urine albumin and creatinine 
A listing for 24-hour urine results will be provided. 
8.10.4.5 
Spot Urine (ACR) 
Spot urine will be collected for measuring ACR at Randomization/Baseline, Week 4, Week 
8, and Week 12/ET.  At Randomization/Baseline spot urine samples will be from 2 first 
morning voids, collected 1 and 2 days prior to the Randomization/Baseline Visit.  At Weeks 
4, 8, and 12, spot urine samples will be from 3 first morning voids collected on the day of the 
visit and on 1 and 2 days prior to the visit. 
Mean values will be calculated for albumin and creatinine over the spot urine samples 
collected for each visit.  The value of ACR at a visit will be the mean albumin value divided 
by the mean creatinine value. 
Spot urine ACR will be summarized by treatment group with descriptive statistics at 
Randomization/Baseline, Week 4, Week 8, and Week 12.  Note that change in ACR from 
Randomization/Baseline to Week 12/ET is an efficacy endpoint in this study (see Section 
6.1.3). 
A listing for spot urine results will be provided. 
8.10.5 
Vital Signs 
Blood pressure summaries have been described in Section 8.9. 
Heart rate will be summarized, by treatment group, with descriptive statistics for each 
scheduled visit, and for the change from baseline to the corresponding time points. 
Height is assessed only at S1 and will be summarized as part of the baseline characteristics.  
Weight is assessed at S1, Randomization/Baseline, and at Week 12/ET. Weight will be 
summarized, by treatment group, with descriptive statistics for Randomization/Baseline and 
Week 12/ET, and for the change from baseline to Week 12/ET. 
A listing for vital signs, weight and height will be provided. 


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8.10.6 
Physical Examination 
Physical examinations will be performed at S1 and Week 12/ET. 
Abnormalities found in physical examinations will be summarized by treatment group at 
Screening and at Week 12/ET.  Clinically significant abnormalities after the start of study 
drug are reported as AEs and summarized as described in Section 8.10. 
A listing for physical examination will be provided. 
8.10.7 
12-lead Electrocardiogram (ECG) 
Standard 12-lead ECGs will be performed in all subjects at the S1 and Week 12/ET. Number 
and percentage of subjects with normal/abnormal and clinically significant abnormal ECG 
findings will be summarized at S1 and Week 12/ET. 
A listing for 12-lead ECG will be provided. 
8.10.8 
Pregnancy Test 
A listing for all pregnancy tests will be provided. 
 
9 
REFERENCES 
1. International Conference on Harmonization (ICH) E6, “Guideline for Good Clinical 
Practice”; 1996. 
2. International Conference on Harmonization (ICH) E9, “Statistical Principles for Clinical 
Trials”; 1998. 
3. van Reenen M, Janssen B. EQ-5D-5L User Guide Version 2.1, April 2015 
4. RLY5016-301 Statistical Analysis Plan, Amendment 1, Dated 20 March 2013. 
5. Williams B, MacDonald T, et al. Spironolactone Versus Placebo, Bisoprolol, and 
Doxazosin to Determine the Optimal Treatment for Drug-Resistant Hypertension 
(PATHWAY-2): a Randomised, Double-blind, Crossover Trial. Lancet, 386[10008], 
2059-2068, 2015.


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APPENDIX A: 
SCHEDULE OF EVENTS 
Study Period 
Screening/Run-in 
Period 
Screening/ 
Randomization 
Double-Blind Treatment 
Follow-
Upa 
Unscheduled 
Visit 
Visit/Day/Week 
S1 
S2 
S3 
S4/BL(D0)b 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 
or ET 
Visit 
2W after 
W12 or 
ET Visit 
 
Window 
1 week (≥ 4 d but ≤ 10 d) apart 
±3 d 
±3 d 
±3 d 
±3 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
 
Study Activity 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IWRS Entry 
X 
X 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion Exclusion Criteria 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heart Rate (resting for 5 
minutes) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xd 
 
 
 
 
 
 
 
X 
 
X, optional 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X, optional 
12-lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X, optional 
AOBP performed onsite             
(triplicate measurements)e 
X 
X 
X 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
X 
X 
SMBP performed onsite and 
HBP training, as necessary         
(triplicate measurements)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X, if 
available 
SMBP performed at home          
(triplicate measurements)h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X, if 
available 
Potassiumi 
L&C 
 
L&C 
L&Cd 
Lj&C 
Lj&C 
Lj&C 
Lj&C 
Lj&C 
Lj&C 
Lj&C 
L&C 
L&C 
L&C 
Serum Chemistry (including 
creatinine, eGFR) 
C 
 
C 
Cd 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C, optional 
Hematology 
C 
 
 
Cd 
 
 
 
C 
 
 
 
C 
 
C, optional 
Serum Pregnancy 
C 
 
 
 
 
 
 
 
 
 
 
C 
 
 
NT-proBNP 
 
 
 
Cd 
 
 
 
 
 
 
 
C 
 
 


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Schedule of Events (Cont’d) 
Study Period 
Screening/Run-in 
Period 
Screening/ 
Randomization 
Double-Blind Treatment 
Follow-
Upa 
Unscheduled 
Visit 
Visit/Day/Week 
S1 
S2 
S3 
S4/BL(D0)b 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 
or ET 
Visit 
2W after 
W12 or 
ET Visit 
 
Window 
1 week (≥ 4 d but ≤ 10 d) apart 
±3 d 
±3 d 
±3 d 
±3 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
 
Study Activity 
Aldosterone and plasma renin 
activity 
 
 
 
Cd 
 
 
 
 
 
 
 
 
 
 
Spironolactone Level 
 
 
 
 
C 
 
 
C 
 
C 
 
C 
 
 
Urinalysis 
C 
 
 
Cd 
 
 
 
 
 
 
 
C 
 
 
24 hr urine collection container 
(dispense and train) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
24 hr urine for sodium, 
potassium, creatinine, albumin 
(for ACR) 
 
 
 
Cd 
 
 
 
 
 
 
 
 
 
 
ACR urine sample collection 
cups (dispense and train) 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Urine ACR (3 first morning 
void samples) 
 
 
 
Cd,k 
 
 
 
C 
 
C 
 
C 
 
 
Urine pregnancy test 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L Questionnairel 
 
 
 
Xd 
 
 
 
 
 
 
 
X 
 
 
IWRS Randomization to 
Patiromer / Placebo 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
Patiromer/placebo Dispensingm  
 
 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
 
 
X, optional 
Spironolactone Dispensingn  
 
 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
 
 
X, optional 
Drug Accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X, optional 
Dietary Counselling 
X 
X 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 


RLY5016–207 
Statistical Analysis Plan 
NDA 205739
 
Confidential 
Page 28 of 32 
 
      11 December 2018 
 
 
Schedule of Events (Cont’d) 
Study Period 
Screening/Run-in 
Period 
Screening/ 
Randomization 
Double-Blind Treatment 
Follow-
Upa 
Unscheduled 
Visit 
Visit/Day/Week 
S1 
S2 
S3 
S4/BL(D0)b 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 
or ET 
Visit 
2W after 
W12 or 
ET Visit 
 
Window 
1 week (≥ 4 d but ≤ 10 d) apart 
±3 d 
±3 d 
±3 d 
±3 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
 
Study Activity 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AOBP = automated office blood pressure; ACR = albumin to creatinine ratio; AE = adverse event; BP = blood pressure; C = central laboratory; D (or d) = day; D0 = Day 0; ET = Early Termination 
Visit; hr = hour; IWRS = Interactive Web Response System; L = local; R = Randomization; S = Screening Visit; SMBP = subject-measured blood pressure.  
a 
If a subject completes the Follow-up Visit prior to 2 Weeks, the subject will receive a Follow-up Phone Call at 2 weeks after Week 12 or ET Visit (+ up to 7 days) 
b 
If hemolysis of the local sample is detected or is suspected), subject is not randomized at S4, and a repeat of the potassium measurement from a separate blood draw will be performed within 1 
day.  If subject qualifies they will be randomized and this Visit will be the Randomization/Baseline (Day0) Visit.  All assessments at S4, aside from the repeat potassium level, will be 
considered the baseline. 
c 
For subjects who meet all inclusion criteria, this Visit becomes the Randomization/Baseline Visit (Day0).  For subjects who screen fail at this visit, this is Visit S4. 
d 
Assessment or event will occur only if subject meets all inclusion criteria. 
e 
Measured automatically using office device (while unobserved by the study staff) after 5 minutes of quiet seating prior to triplicate measures. 
f 
Review AOBP results and adjust study medications according to titration rules. 
g 
HBP device issued on Visit S1 and measured by subject using their issued HBP device (while unobserved by the study staff) after 5 minutes of quiet seating prior to triplicate measures .  HBP 
monitors are collected from subjects at the Visit Week-12.  
h 
HBP will be measured by subject twice daily (e.g., at approximately 08:00 hrs and 20:00 hrs) after sitting quietly for at least 5 minutes.  The subject will perform triplicate measures, 1 minute 
apart.  HBP training will be performed at the first screening visit and retraining can be performed at any Visit, as needed.  HBP monitors are collected from subjects at the Visit Week-12. 
i 
If hemolysis of the local sample is detected or is suspected, the sample must repeated within 1 .day for reassessment of potassium. 
j 
Review potassium results and adjust study medications according to titration rules.. 
k 
One of the ACR measurements will be from the 24-hour urine collection. 
l 
Subjects will complete the EQ-5D-5L questionnaire before study staff performs any clinic or study assessments to avoid biasing the subjects’ responses. 
m 
On Day1 patiromer/placebo two packets QD will be taken at home with food and at least 3 hours before or 3 hours after other oral medications including spironolactone.  
n 
On Day 1 spironolactone (25 mg QD) will be taken at home and increased to 50 mg at Week 3 for subjects with blood pressure ≥ 120 mmHg.. 


RLY5016–207 
Relypsa, Inc. 
Statistical Analysis Plan 
NDA 205739 
 
Confidential 
Page 29 of 32 
 
      11 December 2018 
 
 
APPENDIX B: 
IMPUTATION OF DATES 
1 
Imputation of Missing/Partially Missing Adverse Event Dates 
1.1 
Incomplete Start Date: 
Partially missing AE start/stop dates will be imputed in the ADaM dataset for AEs, according to 
the rules below.  However, listings of AE data will present the date as is, with missing date 
components left blank. 
If the AE end date is complete with no missing year, month, or day, and a partially missing start 
date imputed by the rules below is after the AE end date, then the imputed start date will be equal 
to the end date. 
Missing day and month 
• If the year is the same as the year of the first dosing date, then the day and month of the first 
doing date will be assigned to the missing fields. 
• If the year is prior to the year of first dosing date, then December 31 will be assigned to the 
missing fields. 
• If the year is after the year of first dosing, then January 1 will be assigned to the missing 
fields. 
Missing day only 
• If the month and year are the same as the year and month of first dosing date, then the first 
dosing date will be assigned to the missing day. 
• If either the year of the partial date is before the year of the first dosing date or the years of 
the partial date and the first dosing date are the same but the month of partial date is before 
the month of the first dosing date, then the last day of the month will be assigned to the 
missing day. 
• If either the year of the partial date is after the year of the first dosing date or the years of the 
partial date and the first dose date are the same but the month of partial date is after the month 
of the first dosing date, then the first day of the month will be assigned to the missing day. 
Missing day, month, and year 
• No imputation is needed.  The corresponding AE will be included as TEAE. 
1.2 
Incomplete Stop Date: 
If the imputed stop date is before the start date, then the imputed stop date will be equal to the 
start date. 


RLY5016–207 
Relypsa, Inc. 
Statistical Analysis Plan 
NDA 205739 
 
Confidential 
Page 30 of 32 
 
      11 December 2018 
 
 
Missing day and month 
• If the year of the incomplete stop date is the same as the year of the last dosing date, then the 
day and month of the last dosing date will be assigned to the missing fields. 
• If the year of the incomplete stop date is prior to the year of the last dosing date or prior to 
the year of the first dosing date, then December 31 will be assigned to the missing fields. 
• If the year of the incomplete stop date is prior to the year of the last dosing date but is the 
same as the year of the first dosing date, then the first dosing date will be assigned to the 
missing date. 
• If the year of the incomplete stop date is after the year of the last dosing date, then January 1 
will be assigned to the missing fields. 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year of the 
last dosing date, then the day of the last dosing date will be assigned to the missing day. 
• If either the year of the partial date is not equal to the year of the last dosing date or the years 
of the partial date and the last dosing date are the same but the month of partial date is not 
equal to the month of the last dosing date, then the last day of the month will be assigned to 
the missing day. 
2 
Imputation of Dates for Prior/Concomitant Medications/Procedures 
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the ADaM dataset for 
prior/concomitant medications/procedures.  However, listings of prior/concomitant 
medications/procedures data will present the date as is, with missing date components left blank. 
For prior/concomitant medications, if the stop date is complete with no missing year, month, or 
day, and the partially missing start date imputed by the rule below is after the stop date, then the 
start date will be imputed by the stop date. 
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date. 
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date. 
3. 
Imputation of Dates for Pre-specified Medical History 
 
 


RLY5016–207 
Relypsa, Inc. 
Statistical Analysis Plan 
NDA 205739 
 
Confidential 
Page 31 of 32 
 
      11 December 2018 
 
 
Partially missing start dates for pre-specified medical history will be imputed in the ADaM 
dataset for pre-specified medical history. However, listings of pre-specified medical history data 
will present the date as is, with missing date components left blank. 
Partially missing pre-specified medical history start dates will be imputed by the earliest possible 
date given the non-missing field(s) of the date. 
 
 
 


RLY5016–207 
Relypsa, Inc. 
Statistical Analysis Plan 
NDA 205739 
 
Confidential 
Page 32 of 32 
 
      11 December 2018 
 
 
APPENDIX C: 
LIST OF CENTRAL LABORATORY ASSAYS 
Serum Chemistry Panel: 
Hematology: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (total) 
Blood Urea Nitrogen 
Calcium 
Creatine kinase  
Creatinine (with eGFR) 
Glucose 
Inorganic phosphate 
Iron 
Lactate dehydrogenase 
Magnesium 
Potassium  
Sodium 
Total cholesterol 
Total protein 
Uric acid 
White blood cell count (WBC) 
Red blood cell count  
Hemoglobin 
Hematocrit (Packed Cell Volume) 
Mean cell volume  
Mean cell hemoglobin  
Mean cell hemoglobin concentration  
Platelet count 
Differential WBC 
Urine: 
Specific gravity 
pH 
Protein 
Glucose 
Creatinine 
Ketones 
Blood 
Urobilinogen 
Leukocytes 
Leukocyte esterase 
Nitrites 
Bilirubin 
24-hour urine collection for sodium, creatinine, albumin 
(for ACR) 
Spot urine for albumin and creatinine (for ACR) 
Urine pregnancy 
Other: 
Serum pregnancy  
NT-proBNP 
Aldosterone and plasma renin activity 
Spironolactone level