Clinical trial NCT03087058
Conditions: Hyperkalemia
Keywords: Treatment of Hyperkalemia Hyperkalemia Potassium Chronic Kidney Disease
Sponsor: Vifor Pharma, Inc.
Start date: 2017-07-07; Completion date: 2021-04-30
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the change in serum potassium levels from start of treatment to Day 14, when patiromer is administered at different doses, once daily, in children 2 - \< 18 years of age with chronic kidney disease (CKD) and hyperkalemia (too much potassium in the blood). Another purpose of the study is to evaluate the safety and tolerability of patiromer in children 2 - \< 18 years of age with CKD and hyperkalemia.

Detailed description:
Up to 54 subjects, 2 - \< 18 years of age with CKD (estimated glomerular filtration rate \[eGFR\] \< 90 mL/min/1.73 m2 ) and hyperkalemia (two potassium measurements of 5.1 to \< 6.5 mEq/L performed on separate days) will be enrolled in this open-label, multiple-dose, Phase 2 study.

The study will include two treatment phases: Pharmacodynamic (PD; drug effect on potassium) / Dose Finding Phase consisting of the initial 14-day dose finding period followed by an up to 5.5-month Long-Term Treatment Phase for a total study participation duration for individual subjects of up to 6.5 months (includes a 2 week follow up period).

Arms: arm 1: Patiromer for age 12 to \< 18 years arm 2: Patiromer for age 6 to \< 12 years arm 3: Patiromer for age 2 to \< 6 years
Interventions: intervention 1: Patiromer intervention 2: Patiromer intervention 3: Patiromer
Intervention descriptions: intervention 1: 4.2 g/day, 8.4 g/day and 16.8 g/day intervention 2: 2 g/day, 4 g/day and 8 g/day intervention 3: 1 g/day, 2 g/day and 4 g/day

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
Title: 
A Phase 2, Open-Label, Multiple Dose Study to 
Evaluate the Pharmacodynamic Effects, Safety, 
and Tolerability of Patiromer for Oral Suspension 
in Children and Adolescents 2 to < 18 Years of 
Age with Chronic Kidney Disease and 
Hyperkalemia (EMERALD) 
Investigation Drug: 
Patiromer for Oral Suspension 
US IND #: 
75,615 
Protocol Number: 
RLY5016-206p 
EudraCT: 
2016-002785-31 
Sponsor: 
Relypsa, Inc. 
100 Cardinal Way 
Redwood City, CA 94063 
USA. 
 
 
Relypsa Medical Monitor: 
 
Executive Medical Director, Clinical Development 
 
 
Protocol Date: 
14 March, 2016 
Amendment 1 Date: 
9 September, 2016 
Amendment 2 Date: 
10 April 2017 
Amendment 3 Date: 
27 October 2017 
Amendment 4 Date 
20 May 2019 


Protocol RLY5016-206p 
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Page 2 of 91 
 
PROTOCOL SIGNATURE FORM 
 
Protocol Title: 
A Phase 2, Open-Label, Multiple Dose Study to 
Evaluate the Pharmacodynamic Effects, Safety, 
and Tolerability of Patiromer for Oral Suspension 
in Children and Adolescents 2 to < 18 Years of 
Age with Chronic Kidney Disease and 
Hyperkalemia (EMERALD) 
Protocol Number: 
RLY5016-206p 
Protocol Date: 
14 March 2016 
Amendment 1 Date: 
9 September 2016  
Amendment 2 Date: 
10 April 2017 
Amendment 3 Date:  
27 October 2017 
Amendment 4 Date: 
20 May 2019 
 
I agree to conduct the study as detailed herein and in compliance with the protocol, International 
Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP) and other 
applicable regulatory requirements. 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
Principal Investigator Name (print) 
 
 
 
 
 
 
 




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RLY5016-206P 
PROTOCOL AMENDMENT #1 
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: 
Typographical 
/Administrative 
• 
Updated title page, Protocol and Review Signature Form, 
footers and text to reflect amended protocol version and 
date 
• 
Updated the Table of Contents 
• 
Updated the glossary of abbreviations 
• 
Update protocol content with punctuation, grammatical, 
and formatting changes 
• 
Updated references 
2 
Synopsis 
Added “EMERALD” study name to the study title 
Title update 
3 
Synopsis 
3.2.1 
6.1.4 
Revised to allow under certain circumstances, upon 
approval of the Medical Monitor, an additional screening 
potassium sample for subjects who meet all eligibility 
criteria except the last screening potassium value rather 
than be a screen failure and re-screen  
Revised to provide 
clarity  
4 
Synopsis 
3.2.1 
6.1 
6.1.1 
6.1.2.2 
Provided additional guidance for eligible subjects who 
cannot have their last Screening Visit be converted to a 
Day 1 visit 
Clarification and 
additional guidance 
 
 
5 
Synopsis 
6.2.2 
6.2.3 
7.5 
Appendix A 
ECG will be performed at Day 3 and Day 7 regardless of 
potassium value 
Simplify study 
assessments 
6 
Synopsis 
5.3.1 
Added 2 g packet kits 
Additional product 
presentation for 
dosing in the 6 to 
< 12 year age 
group 
7 
Synopsis 
4.1 
7.2 
Included the equation for the Schwartz formula 
Clarification 


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No. 
Section(s) 
Description of Changes 
Rationale 
8 
Synopsis 
Figure 1 
Table 1 
5.2 
Updated the starting dose levels for the younger age groups 
from 8.4 g/day to 8 g/day and 4.2 g/day to 4 g/day 
Changed to ensure 
a single packet size 
can be used for an 
age group 
9 
Synopsis 
4.1 
Subject age limitations was updated in the inclusion 
criteria #2 to ensure that the age does not exceed maximum 
age specified during the PD / Dose Finding Phase in the 
age cohort in which they were enrolled 
Clarification to 
avoid confusion 
with age cohort 
assignment 
10 
Synopsis 
3.2.2 
8.6.1 
Clarification provided on pausing enrollment during DSMC 
data review 
Clarification on 
study process 
during DSMC 
review 
11 
Synopsis 
1.4 
3.2.2 
8.6.1 
Clarification of subject enrollment sequence 
Clarification for 
cases where fewer 
than nine additional 
subjects may need 
to be enrolled 
“(or fewer if more than three subjects were initially 
enrolled)” when describing the nine additional subjects to be 
enrolled after the first three subjects in the same age group 
12 
Synopsis 
Number of study sites updated to 38 from 35 global sites 
Correction 
13 
Synopsis 
5.5 
Broadened recommendation to allow patiromer to replace 
one of the TID dose for all phosphate binders  
Clarification to 
include all 
phosphate binders 
and not just 
calcium-based 
14 
Synopsis 
4.1 
Revised inclusion criteria #3 by removing “of any stage as 
defined by” 
Correction 
15 
Synopsis 
4.2 
Update exclusion criteria #4 
Clarification and 
providing examples 
of “other intestinal 
obstruction” 
• 
Added “uncorrected” to pyloric stenosis 
• 
Added “[e.g. Hirschsprung disease, chronic intestinal 
pseudo-obstruction, clinically significant postsurgical 
abdominal adhesions]” to any other intestinal obstruction 
16 
4.3 
Inclusion of potassium-related ECG change as one of the 
withdrawal criteria 
Administrative 
17 
4.3 
Updated instructions on subject replacement at Day 14 
Provide further 
clarification and 
instructions 
• 
“If a subject withdrew within the 14-Day PD / Dose 
Finding Phase, the DSMC may be consulted regarding 
possibility of replacing the withdrawn subject.” 
18 
5.2.1 
6.5.1 
Clarification added for anticipated highest dose for subjects 
in the 2 – < 6 year and 6 – < 12 year age groups 
Provide 
clarification 
regarding 
anticipated highest 
dose for the two 
younger age groups 


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No. 
Section(s) 
Description of Changes 
Rationale 
19 
Figure 2 
Updated Figure 2 
Typographical 
corrections and 
administrative 
changes for 
consistency with 
protocol 
20 
Table 2 
Table 3 
Table 4 
Updated Table 2 and included Table 3 and Table 4 with the 
mixing instructions for possible patiromer doses for each 
age group 
Provide further 
patiromer mixing 
instructions 
21 
5.3.2 
Updated Patiromer mixing instructions  
Clarified mixing 
instructions 
22 
5.3.2 
Guidance provided for subjects with enteral feeding tubes 
added the following statement: 
Additional 
guidance and 
clarification 
“Contact the Relypsa Medical Monitor prior to patiromer 
administration through an enteral feeding tube.” 
23 
5.3.3 
6.2.1 
6.2.2 
6.2.3 
6.2.4 
Appendix A 
Included description of a Subject Dosing Diary 
Documentation 
added  
24 
6.1.1 
6.1.2.2 
Clarified which assessments will be performed by the local 
laboratory for Screening 
Clarification 
26 
6.2.1 
6.2.4 
6.2.6 
6.4 
Appendix A 
Appendix B 
Appendix C 
Changed serum PTH to plasma PTH 
Correction 
27 
6.2.1 
Appendix C 
Revised to indicate that both urine and serum samples will 
be used to evaluate pregnancy 
Update 
28 
6.2 
Appendix A 
Updated visit labels to be more consistent throughout the 
protocol 
Administrative 
29 
6.2.5 
Appendix B 
Added height to assessments during the Long-Term 
Treatment Phase 
To ensure the a 
more complete set 
of data 
30 
6.5.1 
Clarified Safety Visit instructions 
Clarification 
31 
7.7 
Added guidance on fluoride intake 
Added guidance for 
safety 
32 
7.8 
Instructions to continue subjects’ usual diet during the 
study 
Added guidance  


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No. 
Section(s) 
Description of Changes 
Rationale 
33 
Appendix B 
Corrected Schedule of Events 
• 
Patiromer administration at the Week 26 Visit was 
marked in error as the last dose of patiromer is taken 
the day prior to the Week 26 Visit 
Correction 
34 
Appendix C 
The following clarifications were made to Appendix C: 
• 
Add total bilirubin to Serum Chemistry panel 
• 
Include “(with eGFR by Schwartz formula)” next to 
Creatinine under Serum Chemistry panel 
• 
Under urinalysis, leukocytes changed to “leukocyte 
esterase” 
• 
Deleted “Total CO2” 
Clarification 
 
 


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RLY5016-206P 
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 
Title Page, 
Table of Contents 
Administrative Changes: 
• 
Updated company logo 
• 
Updated title page with study the 
name “EMERALD” 
• 
Updated title page, Protocol and 
Review Signature Form, footers and 
text to reflect amended protocol 
version and date 
• 
Updated the Table of Contents 
Typographical /Administrative 
2 
Table of Summary 
and Rationale of 
Changes in 
RLY5016-206p 
Amendment-1 
Deletion in the Summary of Changes 
• 
No. 25 in the summary table of 
changes in protocol RLY5016-206p 
Amendment-1 was included as an 
error  
• 
Item was never included in 
protocol. 
Typographical correction 
3 
Synopsis, 
Section 4.1, 
Section 7.2 
Appendix C 
Added Original Schwartz Formula for 
Calculating eGFR: 
• 
Changed from using Bedside to 
Original or Bedside Schwartz 
formula to calculate eGFR in 
Inclusion Criteria #3 
• 
Additional detail on eGFR 
calculation provided in Section 7.2 
Some institutions continue to 
use older Jaffe methodology 
for creatinine assay which is 
only compatible with the 
Original Schwartz formula for 
eGFR calculation.  This 
change will allow sites to use 
the correct GFR estimating 
formula that corresponds to 
their intuitional laboratory 
creatinine assay methodology.  
This modification applies only 
to local eGFR measurement.  
4 
Synopsis 
Section 3.2.3 
Section 6.2.5 
Section 6.3.1 
Section 7.5 
Appendix B 
 
Clarification of ECG Evaluation at 
Week 7 and Week 14 Visits and 
Follow-Up Visit 1 
 
Clarification  


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No. 
Section(s) 
Description of Changes 
Rationale 
5 
Synopsis 
Section 4.1 
Inclusion Criteria #7 
• 
Removed “highly” 
Clarification  
6 
Synopsis, 
Section 4.2 
Section 5.5.3, 
Section 5.6 
Updated Permitted Medications: 
• 
Removed trimethoprim and 
cotrimoxazole from Exclusion 
Criteria #10 and the list of 
prohibited medications 
• 
Allowed trimethoprim for 
prophylaxis of infections (e.g. 
urinary tract infection, 
Pneumocystis carinii pneumonia) 
• 
Must be on a stable dose for 
14 days prior to Screening and 
expected to remain on the stable 
dose during the 14-Day PD / 
Dose Finding Phase 
Many children with CKD may 
be on low doses of 
trimethoprim for prophylaxis 
of UTI or Pneumocystis carinii 
pneumonia and these low 
doses are typically 
administered long-term and 
are not usually associated with 
increases in potassium. This 
update will enhance 
enrollment and not impact or 
confound safety or efficacy. 
7 
Section 3.2.1 
Appendix D 
Added Screening Schema 
• 
Included schema to provide further 
clarity regarding screening visits 
Clarification 
8 
Section 4.3 
Burden of Risk Monitoring:  
• 
Provided clarification that the 
investigator should monitor the 
burden and risk of participation on 
an ongoing basis.   
• 
Participation in the study should 
only be continued if the investigator 
determines there is no more than a 
minimal increase over the burden 
and risk that are described in the 
protocol or associated with routine 
clinical examinations, clinical care 
and treatment of patients with 
chronic kidney disease and 
hyperkalemia. 
Clarification 
9 
Section 5.3 
Additional Instructions on Patiromer 
Use: 
• 
Updated with the following 
statement: “Consult the Pharmacy 
Manual for details on patiromer 
administration through an enteral 
feeding tube.”  
To allow patiromer to be 
administered through an 
enteral feeding tube in subjects 
with gastrostomy or NG tubes.  


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No. 
Section(s) 
Description of Changes 
Rationale 
10 
Figure 2 
Section 5.5.1.1 
Section 6.5.1 
Clarification of Unscheduled Safety 
Visits 
• 
Revised text to clarify that an 
unscheduled visit may occur at any 
phase of the study, including during 
the Follow-Up Phase prior to the 
scheduled Day 7 visit at the 
investigator’s discretion  
• 
Rationale for possible unscheduled 
visit prior to Day 7 of Follow-Up 
Phase is included 
• 
Figure 2 footnote was also updated 
Clarification  
11 
Section 5.5.2 
Additional Instructions Provided for 
Anti-rejection Medication 
• 
Additional instructions provided in 
the event that the dose of anti-
rejection medication requires 
adjustment during the 14-Day 
PD/Dose Finding Phase 
Additional guidance and 
clarification 
12 
Section 5.5.4 
 
Additional Guidance on Peritoneal 
Dialysis Prescription: 
• 
Added “The prescription for 
peritoneal dialysis should not be 
modified during the 14-Day PD / 
Dose Finding Phase of the study” 
For safety reasons and to 
minimize effects that may 
confound the efficacy 
parameters  
13 
Section 6.1.4 
Correction of Section Reference 
• 
Section 6.1.4 should be referenced 
not 6.1.3 
Typographical correction 
14 
Section 6.2.1 
Correction of Typographical Error in 
Study Assessments  
• 
Removal of “other” when 
referencing central laboratory test to 
avoid confusion 
Typographical correction and 
clarification 
15 
Section 7.6 
Clarification of Palatability 
Assessment at Day 1 
• 
Patiromer should be mixed in water 
for palatability assessment 
Clarification  
16. 
Section 8.3.2  
Clarification of the Suspected 
Unexpected Serious Adverse Reaction 
(SUSAR) Reporting Obligations 
Clarification 
17 
Section 8.6.2 
Updated Stopping Criteria  
• 
Provided further guidance regarding 
stopping rules in the case of a 
SUSAR 
Revision 


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RLY5016-206P 
PROTOCOL AMENDMENT #3 
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 
Title Page, 
Table of 
Contents, 
Abbreviations 
Synopsis,  
Section 1, 
Section 1.2 
Section 4.2, 
Section 5.5.1.2,  
Section 15 
Administrative Changes: 
• 
Updated title page, Protocol and Review 
Signature Form, footers and text to reflect 
amended protocol version and date 
• 
Updated the title page with new company 
logo 
• 
Updated the Table of Contents 
• 
Added EU approval of Veltassa and 
SmPC reference 
• 
Heart failure is written out rather than 
abbreviated as “HF” 
Typographical 
/Administrative 
2 
Synopsis, 
Section 3.2.1, 
Section 6.1 
Section 6.1.3 
Rescreening of Subjects: 
• 
Retest of screening serum potassium was 
removed 
• 
Subjects who screen fail may be 
rescreened once after approval from the 
Medical Monitor  
To simplify subject 
rescreening and the study 
operationally 
3 
Synopsis, 
Section 3.2.2,  
Section 5.2.1, 
Section 5.3.3, 
Section 6.2.2, 
Section 7.5, 
Appendix A 
 
 
Day 3 Visit: 
• 
Day 3 Visit may be optional (at the 
investigator’s discretion) for enrolled 
subjects whose last screening K+ is 
< 5.5 mEq/L  
• 
Day 3 Visit is mandatory for enrolled 
subjects whose last screening K+ is 
≥ 5.5 mEq/L 
To reduce the burden of the 
number of visits for 
qualifying subjects while 
maintaining subject safety 
4 
Synopsis, 
Section 5.3.2, 
Section 5.3.3, 
 
Dosing Patiromer without Food: 
• 
Subjects may take patiromer with food or 
without food 
Simplified dosing instructions 
based on findings from a 
recent Patiromer food effect 
study which showed 
patiromer demonstrated the 
same efficacy and safety 
when taken either with or 
without food 


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No. 
Section(s) 
Description of Changes 
Rationale 
5 
Synopsis 
Section 4.2, 
Section 5.6 
Prohibiting Use of or Sodium Zirconium 
Cyclosilicate 
In anticipation of marketing 
of sodium zirconium 
cyclosilicate, it was added to 
the list of prohibited 
medications as use may 
confound the study findings  
6 
Synopsis, 
Section 4.1 
Section 7.2 
Clarification of Schwartz Formula Use: 
• 
Removed “Original or Bedside” and 
added Section 7.2 reference for the 
Schwartz formula in Inclusion Criteria #3 
• 
For local labs that use the Jaffe assay to 
calculate eGFR, if the assay is isotope 
dilution mass spectrometry (IDMS) 
traceable, then the bedside Schwartz 
formula should be used  
Clarified when to use the 
Original or Bedside versions 
of the Schwartz formula in 
Section 7.2 of the protocol, 
and cross referenced other 
mentions of the Schwartz 
Formula in the protocol 
 
Central laboratory is using an 
IDMS traceable Jaffe assay; 
therefore, the clarification is 
added to ensure consistency 
across study sites 
7 
Synopsis 
 
Alignment of Efficacy Analysis, Safety 
Outcomes and Analysis, and Additional 
Analysis Described in Synopsis with 
Section 9: Data Analysis / Statistical 
Methods   
Correcting misalignment 
between synopsis and 
Section 9 
8 
Synopsis, 
Section 5.5.4 
 
Use of Fludrocortisone: 
• 
Fludrocortisone dose must be stable for at 
least 28 days prior to screening 
• 
During the 14-Day PD/Dose Finding 
Phase, dose adjustments to 
fludrocortisone should not be made 
• 
During the Long-Term Treatment Phase 
adjustments to fludrocortisone are 
permitted for safety reasons 
Fludrocortisone was not 
previously described in the 
protocol; however, this 
medication decreases serum 
potassium and could interfere 
with evaluation of patiromer 
effect, chronic use with stable 
doses should have minimal 
effect on serum potassium 
and thus can be allowed in 
these situations 
98 
Section 6.1 
Clarification of Subject Identifier  
• 
Updated “unique subject identification 
number” with “unique study subject 
identification number” 
Clarification  


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No. 
Section(s) 
Description of Changes 
Rationale 
10 
Section 6.1.2.2,  
Section 6.2.6, 
Section 6.4, 
Section 7.2, 
Appendix A 
Appendix B 
Urine Pregnancy Test in the Case of Anuric 
Subjects: 
• 
Anuric subjects may have a serum 
pregnancy test instead of urine pregnancy 
test at Day 1 
To allow anuric subjects into 
the study 
11 
Section 6.2.1, 
Section 6.2.4,  
Section 6.2.6,  
Section 6.4, 
Section 7.2, 
Appendix A, 
Appendix B 
Urinalysis in the Case of Anuric Subjects 
• 
No urinalysis will be performed on these 
subjects 
To allow anuric subjects into 
the study 
12 
Section 7.7 
Further Clarification of Items to be 
Carefully Supervised by Guardian Due to 
Fluoride Content: 
• 
Added dental rinse 
Clarification 
13 
Section 8.5 
Added Reference to “SMC Plan” 
Erroneously omitted  
14 
Section 8.6.3 
Clarification of Frequency of DSMC 
Meetings 
• 
Added information regarding DSMC 
meetings after the dose expansion group 
of 9 subjects complete their 14-day PD / 
Dose Finding Phase 
• 
Added information that if a subject 
withdraws from the study within the 
14-Day PD / Dose Find Phase, the SMC 
determines if sufficient information is 
provided for DSMC review, and the 
DSMC meeting may be delayed if 
insufficient information is provided 
Clarification / erroneously 
omitted 


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RLY5016-206P 
PROTOCOL AMENDMENT #4 
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 
Synopsis 
Section 4.1 
Section 7.2 
Updated Inclusion Criteria #3: 
• 
Raised eGFR eligibility from < 60 
mL/min/1.73m2 to < 90 mL/min/1.73m2 
• 
Removed peritoneal dialysis. 
To allow hyperkalemic 
subjects with earlier stages of 
CKD (CKD2) to enroll  
Updated per 25Sep18 DSMC 
guidelines for management of 
subjects transitioning to 
dialysis during the study 
2 
Synopsis 
Section 3.2.2 
Section 3.2.3 
Section 6.2.2 
Section 6.2.3 
Section 6.2.4 
Section 6.2.5 
Section 6.3.1 
Section 6.5.1 
Section 7.5 
Appendix A 
Appendix B 
Updated Requirements for ECG Evaluation: 
• 
12-lead ECG is only required at baseline 
and Week 26 or if the local K+ is > 6.0 
mEq/L at that visit 
• 
A 12-lead ECG is required at an MSV if 
the most recent local potassium is > 6.0 
mEq/L 
Reduce burden on subjects 
during study visits while 
maintaining safety; 
clarification for use of only 
local potassium level in 
determining need for ECG 
3 
Synopsis 
Section 4.2 
Updated Exclusion Criteria #3: 
• 
Removed restriction on planned need for 
hemodialysis during the study 
• 
Added exclusion of subjects on 
maintenance peritoneal dialysis  
Updated per 25Sep18 DSMC 
guidelines for management of 
subjects transitioning to 
dialysis during the study 
4 
Section 4.3 
Section 4.4 
Additional Guidance on Hemodialysis and 
Peritoneal Dialysis: 
• 
Added transition to dialysis during study 
and reason for study withdrawal 
• 
Added DSMC guidance for subjects 
transitioning to maintenance hemodialysis 
and peritoneal dialysis 
• 
Patients who are anticipated to require 
dialysis shortly after enrollment (within 6-
8 weeks of Day 1) may not be suitable for 
enrollment due to unstable medical status 
and fluctuating potassium levels. 
Updated per 25Sep18 DSMC 
guidelines for management of 
subjects transitioning to 
dialysis during the study; 
improves management of 
subjects with progression of 
CKD 


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Removed Section 5.5.5 
5 
Section 5.2.1 
Section 6.5.1 
Updated Timing Requirement for an MSV 
• 
Extended the requirement for Mandatory 
Safety Visits from within 72 hours to 
within 7 days  
 
 
To simplify the study 
operationally and reduce 
burden on subjects while 
maintaining safety 
6 
Synopsis 
Section 3.2.3 
Section 6.2.5 
Appendix B 
Updated Long-Term Treatment Phase 
Schedule of Events  
• 
Week 3, Week 10 and Week 22 may be 
omitted under certain circumstances; refer 
to section 3.2.3 for details 
• 
Addition of home care visits during the 
long-term treatment phase. Up to 2 non-
sequential study visits may be conducted 
remotely using the Sponsor approved 
Home Care vendor at certain approved 
investigational sites in certain countries 
• 
Certain study procedures may be omitted 
at Home Care Visits. 
To reduce the burden of the 
number of visits for 
qualifying subjects while 
maintaining subject safety 


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STUDY SYNOPSIS 
Title: 
A Phase 2, Open-Label, Multiple Dose Study to Evaluate the Pharmacodynamic Effects, 
Safety, and Tolerability of Patiromer for Oral Suspension in Children and Adolescents 2 to 
< 18 Years of Age with Chronic Kidney Disease and Hyperkalemia (EMERALD) 
Protocol Number: 
RLY5016-206p 
Phase: 
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.  Patiromer (Veltassa®) is approved by the Food 
and Drug Administration (FDA) and the EMA (European Medicines Agency) for the 
treatment of hyperkalemia in adult patients. 
Study Objectives 
Study Objectives: 
Primary: 
To assess change from baseline in serum potassium levels to Day 14 following 
administration of different doses of patiromer administered once daily in children 
2 – < 18 years of age with chronic kidney disease (CKD) and hyperkalemia. 
Secondary: 
To assess the safety and tolerability of patiromer in children 2 – < 18 years of age with CKD 
and hyperkalemia. 
Study Outcomes 
Primary Efficacy: 
Change in serum potassium levels from baseline to Day 14. 
Secondary Efficacy: 
• 
Proportion of subjects with serum potassium levels in the range of 3.8 – 5.0 mEq/L 
at Day 14 (Initial Pharmacodynamic [PD] / Dose Finding Phase) 
• 
Proportion of subjects with serum potassium levels in the range of 3.8 – 5.0 mEq/L 
by visit through Month 6 (Long-Term Treatment Phase) 
Safety: 
Safety analyses will include: 
• 
Incidence and severity of adverse events (AEs) 
• 
Changes from baseline in clinical laboratory values (hematology and serum 
chemistry including serum magnesium, serum calcium and serum fluoride) 
• 
Changes from baseline in vital signs and electrocardiogram (ECG) 
Study Design 
Description: 
Up to 54 subjects, 2 – < 18 years of age with CKD (estimated glomerular filtration rate 
[eGFR] < 90 mL/min/1.73 m2 calculated using the Schwartz formula (see Section 7.2) and 
hyperkalemia (two potassium measurements of 5.1 to < 6.5 mEq/L performed on separate 
days) will be enrolled in this open-label, multiple-dose, Phase 2 study.  Subjects must be < 
18 years of age from the time of study consent until anticipated completion of Day 14 of the 
study. 
 
The study will include two treatment phases:  PD / Dose Finding Phase consisting of the 
initial 14-day dose finding period followed by an up to 5.5-month Long-Term Treatment 
Phase for a total study participation duration for individual subjects of up to 6.5 months (see 
Study Schema). 
 
The overall design of the study is presented schematically below. 
 
 
 
 


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Study Schema: 
 
 
 
 
 
Screening (up to 7 Days): 
Subject’s eligibility will be assessed during a Screening Period with up to two visits 
(Screening Visit 1, Screening Visit 2).  Eligibility for this study requires the presence of 
hyperkalemia assessed by two blood or serum potassium measurements performed on 
separate days; qualifying potassium values are 5.1 to < 6.5 mEq/L.  A standard of care 
potassium value measured within 42 days to 2 days prior to Screening may be used for one 
of the potassium values to assess eligibility.  The following scenarios are allowed for 
obtaining the two qualifying potassium values (5.1 to < 6.5 mEq/L): 
• 
For subjects with a recent standard of care potassium measurement, the two 
qualifying potassium values will be the most recent standard of care potassium 
measurement obtained from 42 days to 2 days prior to Screening Visit 1 and the 
local potassium measurement at Screening Visit 1. 
• 
For subjects without a recent standard of care potassium measurement within 
42 days to 2 days prior to Screening Visit 1, the first qualifying potassium value 
will be obtained at Screening Visit 1 and the second at Screening Visit 2, occurring 
2 to 7 days after Screening Visit 1. 
For subjects who meet all eligibility criteria at either Screening Visit 1 or Screening Visit 2, 
that visit should be converted to the Day 1 Visit (Baseline).  In cases where this is not 
possible, eligible subjects must return the next day to complete the Day 1 Visit.  
Subjects who screen fail may be rescreened once upon approval of the Medical Monitor, see 
Section 6.1.3).  


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14-Day PD / Dose Finding Phase: 
Study visits will occur at Day 1, Day 3, Day 7 and Day 14 when potassium concentrations 
will be measured locally and by the central laboratory (see Schedule of Events, 
Appendix A).  Note:  At the discretion of the Investigator, the Day 3 Visit is optional for 
subjects whose last screening K+ is < 5.5 mEq/L; for subjects whose last screening K+ is 
≥ 5.5 mEq/L, the Day 3 Visit is mandatory (see Section 6.2.2).  
 
Additional laboratory assays (Appendix C) will be performed at specified visits according to 
the Schedule of Events Appendix A).  12-lead ECGs will be performed at Day 3, 7, and 14 
Visits if the local K+ is >6.0 mEq/L at that visit.  A full list of central laboratory assays is 
provided in Appendix C. 
Eligible subjects will be categorized into three different age cohorts (12 – < 18 years, 
6 – < 12 years, and 2 – < 6 years).  Enrollment will start with the oldest age cohort first; this 
is to ensure safety of younger age subjects who might be the most vulnerable to potential 
adverse events associated with patiromer.  Initiation of enrollment of subjects in the younger 
age cohorts will depend on Data and Safety Monitoring Committee (DSMC) review (See 
DSMC Review section below for further details). 
Up to three starting dose levels will be evaluated in each age group.  The initial dose 
evaluated will be the lowest of the planned starting dose levels for each age group.  The 
planned starting dose levels are: 
• 
Age 12 ‒ < 18 years:  4.2 g/day, 8.4 g/day, 16.8 g/day 
• 
Age 6 – < 12 years:  2 g/day, 4 g/day and 8 g/day 
• 
Age 2 – < 6 years:  1 g/day, 2 g/day and 4 g/day 
Note:  the starting doses may require modification based upon the DSMC recommendation 
after their review of the safety and PD data (see DSMC Review section below for further 
details). 
Patiromer dose titration is allowed per a protocol-specified algorithm (see Section 5.2.1).  
The titrated increment or decrement is planned to be the lowest starting dose for each age 
group. 
Long-Term Treatment Phase: 
The Long-Term Treatment Phase consists of eight visits over a period of 5.5 months.  Study 
visits occur at Week 3, Week 5, Week 7, Week 10, Week 14, Week 18, Week 22 and 
Week 26. At each study visit potassium levels, measured locally and by central laboratory, 
will be obtained.  ECG evaluations will be performed as soon as possible whenever the K+ 
level is > 6.0 mEq/L; at the Week 26 Visit, an ECG will be performed regardless of 
potassium level.  Additional laboratory assays and assessments will be performed according 
to the Schedule of Events (see Appendix B).  A full list of central laboratory assays is 
provided in Appendix C. 
Study visits at Week 3, Week 10 and Week 22 may be omitted if specific criteria are met 
including achieving potassium levels in the target range (3.8-5.0 mEq/L) at the prior visit 
(see Section 3.2.3). During the Long-Term Treatment Phase, up to 2 non-sequential study 
visits may be conducted remotely using a Sponsor approved Home Care vendor at certain 
investigational sites in certain countries; Week 26 may not be a Home Care visit. 
Dose adjustments in the Long-Term Treatment Phase may be made at each study visit 
starting with the Week 2 (Day 14) Visit according to the titration algorithm (see 
Section 5.2.1).  The titrated increment or decrement is planned to be the lowest starting dose 
for each age group. 
Follow-up Period: 
After the patiromer Treatment Periods, subjects will enter the Follow-up Period, which will 
consist of one Visit at 7 days (Follow-up Visit 1) and one phone call at 14 days after 


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stopping patiromer treatment (Follow-up Visit 2).  All subjects who withdraw early from 
treatment will enter the Follow-up Period.   
DSMC Review / 
Starting Dose Level 
Assessment: 
The DSMC will determine a recommended starting dose for each age group.  After three 
subjects at a given starting dose level provide data from the 14-Day PD / Dose Finding 
Phase, the DSMC will evaluate safety and PD data, including achievement of serum 
potassium within the target range (serum K+ 3.8 – 5.0 mEq/L) and the PD response pattern 
as well as the number of subjects requiring dose titration.  Based on this review, the DSMC 
will provide a recommendation to evaluate another starting dose in the age group or to 
evaluate the current starting dose in additional subjects in the age group.  Details regarding 
DSMC review criteria will be described in a charter and are summarized in the DSMC 
section of the protocol (Section 8.6). 
The initial number of subjects for each starting dose level will be three, and up to three 
starting doses per age group can be evaluated.  Subject screening will pause periodically 
throughout the study to allow for preparation of data and DSMC review and provision of 
recommendations.  Any subjects who are in the Screening Period when the pause is 
announced may be enrolled provided they meet all eligibility criteria.  When the Study 
Management Committee (SMC; see Section 8.5) and DSMC agree upon the recommended 
patiromer starting dose for a particular age group based upon safety and PD data review, 
nine additional subjects (or fewer if more than three subjects were initially enrolled) will be 
added in that age group to receive the recommended patiromer starting dose.  Subjects will 
not be enrolled into higher starting dose levels once the recommended patiromer starting 
dose is determined for a particular age group.  This will yield a total of 12 subjects per age 
group at the recommended starting dose and a maximum of 18 subjects per age group. 
Based on findings from the 12 – < 18 years of age cohort, the DSMC will provide a 
recommendation to initiate dosing in a younger age group, and provide further guidance 
regarding the starting doses and titration increments for the younger age groups. 
In addition, the DSMC will review safety and PD data on an ongoing basis during the Long-
Term Treatment Phase for all age groups. 
Study Duration: 
Individual subject participation up to 6.5 months consisting of:  Screening / Day 1 followed 
by 14-day PD / Dose Finding Phase, 5.5-month Long Term Treatment Phase, and a 2-week 
Follow-up Period consisting of one Follow-up Visit and one Follow-up Phone Call. 
Study Sites: 
Up to 38 sites globally. 
Study Population: 
Up to 54 subjects aged 2 to < 18 years old. 
Study Treatments 
Dose and Route of 
Administration: 
Investigational Product:  Patiromer 
Patiromer will be given once daily (QD).  The starting doses of patiromer in each age cohort 
were selected based on the median weights for boys and girls within each of the three age 
categories using standard growth data (CDC 2010).  The initial weight-based doses selected 
were guided by the starting dose in adults (8.4 g/day patiromer), a higher commonly used 
dose in adults (16.8 g/day) and a dose below the adult efficacy range (4.2 g/day patiromer) 
in the event children have a different response profile than in adults. 
Patiromer will be provided open-label to subjects as a powder for oral suspension in packets 
with appropriate labeling.  The individual packets will be assembled as a kit for dispensing 
the adequate amount of patiromer for each subject.  Each packet inside an individual kit will 
contain either 4.2 g, 2.0 g, or 1.0 g patiromer.  Subjects and their parent or legally authorized 
representative will be instructed to mix patiromer with water, apple juice or cranberry juice.  
Subjects and their legally authorized representative will be instructed that patiromer can be 
taken with or without food. 
Patiromer should be taken 3 hours before or 3 hours after administration of other 
concomitant medications.  At the discretion of the Investigator, the following drugs may be 
coadministered with patiromer:  allopurinol, amlodipine, amoxicillin, apixaban, aspirin, 
atorvastatin, cephalexin, cinacalcet, clopidogrel, digoxin, furosemide, glipizide, lisinopril, 


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lithium, metoprolol, phenytoin, rivaroxaban, spironolactone, trimethoprim, valsartan, 
verapamil, and warfarin. 
For subjects taking phosphate binders three times daily (TID) and for whom in the opinion 
of the investigator one dose per day of the phosphate binder can be replaced by patiromer, 
patiromer may be dosed with the same meal each day and the phosphate binder dosed with 
two other meals each day. 
Eligibility Criteria 
 
Inclusion Criteria: 
Subjects must meet ALL the following criteria: 
1. 
Written assent (when applicable) and written informed consent by a legally authorized 
representative provided prior to participation in the study 
2. 
Age 2 – < 18 years old (subject’s age should not exceed that of the age cohort into 
which s/he is enrolled for at least the entire 14 days of the PD / Dose Finding Phase) 
3. 
Pediatric subjects with CKD and eGFR < 90 mL/min/1.73m2 calculated using the 
Schwartz formula as described in Section 7.2, including renal transplant subjects, 
based on local creatinine measurement at Screening 
4. 
Two blood or serum potassium measurements of 5.1 to < 6.5 mEq/L performed on 
separate days (see Section 6.1) 
5. 
In the opinion of the Investigator, the subject is expected to require treatment for 
hyperkalemia for at least 6 months 
6. 
If taking any renin-angiotensin aldosterone system inhibitors (RAASi), beta blockers, 
fludrocortisone or diuretic medications, must be on a stable dose for at least 28 days 
prior to Screening 
7. 
Females of child-bearing potential must be non-lactating, must have a negative 
pregnancy test at Screening, and must have used an effective form of contraception 
(e.g. abstinence, hormonal, chemical, physical barrier, etc.) for at least 1 month before 
patiromer administration.  Subjects of child-bearing potential must agree to continue 
using contraception throughout the study and for 1 month after the last dose of 
patiromer 
Exclusion Criteria: 
Subjects must NOT meet ANY of the following exclusion criteria: 
1. 
Subjects with pseudohyperkalemia due to hemolysis or to abnormally high numbers 
of platelets (> 500,000/mm³), leukocytes (> 70,000/mm³), or erythrocytes (hematocrit 
> 55%) at Screening based on results obtained locally 
2. 
Any subject with evidence of potential potassium-related ECG changes (i.e., changes 
consistent with hyper- or hypokalemia) at Screening 
3. 
Any of the following renal conditions:  maintenance hemodialysis or peritoneal 
dialysis, renal artery stenosis, and acute kidney injury (defined by 2012 Kidney 
Disease Improving Global Outcomes [KDIGO], 2012) or a history of acute renal 
insufficiency in the past 3 months 
4. 
A history of or current diagnosis of a severe gastrointestinal diagnosis or surgery that 
could affect gastrointestinal transit of the drug (e.g. a severe swallowing disorder, 
uncorrected pyloric stenosis, intussusception, any other intestinal obstruction [e.g., 
Hirschsprung disease, chronic intestinal pseudo-obstruction, clinically significant 
postsurgical abdominal adhesions] or any gut-shortening surgical procedure prior to 
Screening) 
5. 
A history of or current diagnosis of a condition that in the opinion of the investigator 
increases the risk of aspiration of patiromer if it will be given orally 


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6. 
Liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST) 
> three times upper limit of normal at Screening, based on the local laboratory ALT 
and AST 
7. 
Active cancer, currently on cancer treatment or history of cancer in the past 2 years 
(except for non-melanoma skin cancer) 
8. 
Heart or liver transplant recipient, or anticipated need for transplant during the study 
Treatment Period, including a scheduled kidney transplant recipient (note:  patients 
currently on a kidney transplant wait list are not excluded unless there is an identified 
donor) 
9. 
Chronic alcohol abuse or substance use disorder within 1 year of Screening  
10. 
Subjects currently being treated with or having taken any one of the following 
medications (includes resins) in the 7 days prior to Screening:  sodium or calcium 
polystyrene sulfonate, sodium zirconium cyclosilicate, and drospirenone  
11. 
Use of the following medications if doses have not been stable for at least 14 days 
prior to Screening or if doses are anticipated to change during the 14-day PD / Dose 
Finding Phase: 
- 
digoxin;  
- 
bronchodilators;  
- 
theophylline;  
- 
heparins (including low molecular heparins);  
- 
canagliflozin; 
- 
tacrolimus; 
- 
mycophenolate mofetil; 
- 
cyclosporine 
- 
trimethoprim or cotrimoxazole 
12. 
Use of any investigational product for an unapproved indication within 30 days prior 
to Screening or within 5 half-lives, whichever is longer 
13. 
Known hypersensitivity to patiromer or its components 
14. 
In the opinion of the Investigator, inability to comply with the protocol 
15. 
In the opinion of the Investigator, any medical condition, uncontrolled systemic 
disease, or serious intercurrent illness that would significantly decrease study 
compliance or jeopardize the safety of the subject or potentially affect the quality of 
the data such as:  hyperkalemia at Screening that requires emergency intervention; 
cardiovascular event or intervention within 3 months prior to Screening; a 
hemodynamically unstable arrhythmia; hospitalization for heart failure within the past 
3 months; poorly controlled blood pressure (BP); poorly controlled diabetes mellitus 
or frequent need for adjustment in insulin prescription or recent hospitalization for 
treatment of hyper or hypoglycemia 
Statistical Methods 
Determination of 
Sample Size: 
This study will enroll up to 54 subjects. 
For children ages 2 to < 18 years, the total sample size could be as low as 36 (three initially 
treated subjects plus an additional nine if the first dose is chosen as safe and effective for 
each of the three different age cohorts) or up to 54 if all three dose levels are studied for 
each age group. 


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Randomization: 
This is an open-label, non-randomized study. 
Efficacy Analysis: 
Change in serum potassium will be summarized by starting dose and age group using 
descriptive statistics.  The proportion (number and percentage of subjects) with serum K+ 
levels in the range of 3.8 – 5.0 mEq/L will be summarized by visit; the 95% confidence 
interval will be presented. 
Safety Analysis 
Safety variables will consist of all AEs, severe adverse events (SAEs), clinical laboratory 
test results (including serum potassium, calcium, magnesium, phosphate, and fluoride), vital 
signs and ECG, and reasons for dosing interruption or discontinuation. 
Additional Analysis 
For children ≥ 6 years old, evaluation of patiromer palatability at first dose (Day 1) will be 
performed using a visual analogue scale score; for children < 6 years old parental or 
authorized legal representative response of the subject’s acceptance of patiromer will be 
assessed on Day 14. These assessments will be summarized using descriptive statistics.   


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TABLE OF CONTENTS 
GLOSSARY OF ABBREVIATIONS .....................................................................................27 
1 
INTRODUCTION .................................................................................................29 
 
Background ................................................................................................29 
 
Effects in Humans ......................................................................................30 
 
Rationale ....................................................................................................32 
 
Rationale for Study Design ........................................................................32 
 
Rationale for Patiromer Starting Doses .....................................................33 
2 
TRIAL OBJECTIVES ...........................................................................................33 
3 
TRIAL DESIGN ....................................................................................................33 
 
Description .................................................................................................33 
 
Study Period ...............................................................................................34 
3.2.1 
Screening Visit(s).................................................................................34 
3.2.2 
14-Day PD / Dose Finding Phase: .......................................................35 
3.2.3 
Long-Term Treatment Phase: ..............................................................36 
3.2.4 
Follow-up Period .................................................................................37 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................37 
 
Inclusion Criteria .......................................................................................38 
 
Exclusion Criteria ......................................................................................38 
 
Subject Withdrawal ....................................................................................40 
 
Dialysis ......................................................................................................41 
5 
STUDY TREATMENTS .......................................................................................42 
 
Treatment Blinding ....................................................................................42 
 
Allocation to Treatment .............................................................................42 
5.2.1 
Patiromer Titration ...............................................................................42 
 
Drug Supplies.............................................................................................44 
5.3.1 
Formulation and Packaging .................................................................44 
5.3.2 
Preparation and Dispensing of Patiromer ............................................45 
5.3.3 
Dosing and Administration of Patiromer .............................................46 
5.3.4 
Compliance ..........................................................................................47 
 
Investigational Product Storage and Accountability..................................47 
 
Concomitant Medications ..........................................................................48 
5.5.1 
Permitted Antihypertensive Medications and Medications for Heart 
Failure ..................................................................................................48 
5.5.1.1 
RAAS inhibitor Medications, Digitalis Glycosides and Diuretics48 
5.5.1.2 
Other Antihypertensive Medications and Medications for Heart 
Failure .........................................................................................49 
5.5.2 
Permitted Medications for Anti-Rejection of Transplant ....................50 
5.5.3 
Permitted Prophylactic Trimethoprim Antibiotic ................................50 


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5.5.4 
Permitted Fludrocortisone ....................................................................50 
 
Prohibited Medications ..............................................................................50 
6 
TRIAL PROCEDURES .........................................................................................51 
 
Screening Visit(s).......................................................................................51 
6.1.1 
Subjects with Standard of Care Potassium Measurement ....................52 
6.1.2 
Subjects without Standard of Care Potassium Measurement ..............53 
6.1.2.1 
Screening Visit 1 .........................................................................53 
6.1.2.2 
Screening Visit 2 .........................................................................53 
6.1.3 
Re-screening of Subjects......................................................................54 
 
Treatment Period ........................................................................................54 
6.2.1 
Day 1 Visit (Baseline) ..........................................................................54 
6.2.2 
Day 3 Visit ...........................................................................................55 
6.2.3 
Day 7 Visit ...........................................................................................56 
6.2.4 
Day 14 Visit .........................................................................................56 
6.2.5 
Week 3, Week 5, Week 7, Week 10, Week 14, Week 18, and Week 22 
Visits ....................................................................................................57 
6.2.6 
Week 26 Visit ......................................................................................58 
 
Follow-up Period .......................................................................................59 
6.3.1 
Follow-up Visit 1 (F1) .........................................................................59 
6.3.2 
Follow-up Visit 2 (F2) .........................................................................59 
 
Early Termination Visit .............................................................................60 
 
Other Visits ................................................................................................60 
6.5.1 
Safety Visit...........................................................................................60 
7 
ASSESSMENTS ....................................................................................................62 
 
Potassium ...................................................................................................62 
7.1.1 
Preventing, Identifying and Handling Hemolyzed Samples ................62 
7.1.2 
Early Withdrawal from the Study due to Potassium Levels ................63 
 
Laboratory Tests ........................................................................................63 
 
Vital Signs ..................................................................................................64 
7.3.1 
Heart Rate ............................................................................................64 
7.3.2 
Blood Pressure .....................................................................................64 
 
Physical Examination.................................................................................65 
 
ECG Assessment ........................................................................................65 
 
Patiromer Palatability.................................................................................65 
 
Fluoride ......................................................................................................66 
 
Diet .............................................................................................................66 
8 
ADVERSE EVENT REPORTING........................................................................66 
 
Definition of an Adverse Event .................................................................66 
8.1.1 
Definition of Serious Adverse Event ...................................................67 


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Procedures for Eliciting, Recording and Reporting Adverse Events .........68 
8.2.1 
Adverse Event Reporting Period .........................................................68 
8.2.2 
Eliciting Adverse Events......................................................................68 
8.2.3 
Assessing Adverse Events ...................................................................68 
8.2.4 
Causality Assessments .........................................................................70 
8.2.5 
Recording Adverse Events ...................................................................71 
 
Serious Adverse Events Reporting ............................................................71 
8.3.1 
SAE Notification ..................................................................................71 
8.3.2 
SAE Expedited Reporting ....................................................................72 
 
Procedures for Reporting Pregnancy Exposure and Birth Events .............73 
 
Study Management Committee..................................................................73 
 
Data and Safety Monitoring Committee ....................................................73 
8.6.1 
Dose Escalation ....................................................................................74 
8.6.2 
Stopping Criteria ..................................................................................75 
8.6.3 
Frequency of DSMC Meetings ............................................................75 
9 
DATA ANALYSIS / STATISTICAL METHODS ...............................................76 
 
Randomization ...........................................................................................76 
 
General Considerations ..............................................................................76 
 
Sample Size Determination........................................................................77 
 
Efficacy Analysis .......................................................................................77 
9.4.1 
Primary Efficacy Variable ...................................................................77 
9.4.2 
Secondary Efficacy Variables ..............................................................77 
9.4.3 
Subgroups of Interest ...........................................................................77 
 
Safety Analysis ..........................................................................................77 
 
Additional Analyses ...................................................................................78 
 
Handling of Missing Data ..........................................................................78 
10 
DATA HANDLING AND RECORDKEEPING ..................................................78 
 
Case Report Forms / Electronic Data Record ............................................78 
 
Record Retention .......................................................................................79 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................79 
12 
ETHICS..................................................................................................................80 
 
Institutional Review Board / Independent Ethics Committee....................80 
 
Ethical Conduct of the Trial .......................................................................81 
 
Subject’s Information and Informed Consent/Assent ................................81 
13 
RELYPSA DISCONTINUATION CRITERIA ....................................................82 
14 
PUBLICATION OF TRIAL RESULTS ................................................................82 
15 
REFERENCES ......................................................................................................82 
 


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LIST OF TABLES 
Table 1: 
Planned Patiromer Starting Dose Levels for Each Age Cohort .................36 
Table 2: 
Mixing Volumes for 12 – < 18 Years Age Group Patiromer Doses 
(4.2 g Packets) ..............................................................................................................45 
Table 3: 
Mixing Volumes for 6 – < 12 Years Age Group Patiromer Doses 
(2 g Packets) .................................................................................................................46 
Table 4: 
Mixing Volumes for 2 – < 6 Years Age Group Patiromer Doses (1 g Packets)
 
46 
Table 5: 
Categories of Severity for Specified GI AEs .............................................69 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.............................................................................................34 
Figure 2: 
Planned Patiromer Dose Titration Algorithm. ...........................................44 
 
LIST OF APPENDICES 
A – Schedule of Events (Screening and Pharmacodynamics / Dose Finding Phase) 
B – Schedule of Events (Long-Term Treatment Phase) 
C – List of Central Laboratory Assays 
D – Screening Schema 


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GLOSSARY OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ARB 
Angiotensin II Receptor Blocker 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BID 
Twice Daily 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
C 
Central Laboratory 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
Con Meds 
Concomitant Medications 
CKD 
Chronic Kidney Disease 
CRF 
Case Report Form 
Cmax 
Maximum Concentration 
D 
Day 
DAIDS 
Division of AIDS 
DSMC 
Data and Safety Monitoring Committee 
E 
Exclusion 
EC 
Ethics Committee 
ECG 
Electrocardiograms 
EMA 
European Medicines Agency 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ET 
Early Termination 
EUCTD 
European Union Clinical Trials Directive 2001/20/EC 
F1 
Follow-up Visit 1 
F2 
Follow-up Phone Call 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ID 
Identification 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 


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IWRS 
Interactive Web Response System 
K+ 
Potassium 
KDIGO 
Kidney Disease Improving Global Outcomes 
M 
Months 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
NSAID 
Non-Steroidal Anti-Inflammatory Drugs 
PD 
Pharmacodynamic 
QD 
Once Daily 
RAASi 
Renin-Angiotensin Aldosterone System Inhibitors 
RBC 
Red Blood Cell Count 
S 
Screening 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
SmPC 
Summary of Product Characteristics 
TID 
Three Times Daily 
US 
United States 
W 
Week 
WBC 
White Blood Cell Count 
 


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1 
INTRODUCTION 
Patiromer for Oral Suspension (patiromer) is a nonabsorbed, cation-exchange polymer that has been 
developed for the treatment of hyperkalemia.  Patiromer binds potassium (K+) predominantly in the 
lumen of the colon and increases fecal potassium excretion, leading to removal of potassium from 
the body and lowering of serum potassium levels.  The drug substance consists of the polymer 
anion (the active moiety, patiromer) and a calcium-sorbitol counterion complex. 
Patiromer (Veltassa®) is approved by the FDA and EMA for the treatment of hyperkalemia in 
adults (Veltassa PI, 2016, Veltassa SmPC, 2017). 
 
Background 
Serum potassium concentration is carefully regulated within a normal range of 3.8 – 5.0 mEq/L in 
adults (Rodriguez-Soriano, 1995) and approximately 90% of potassium is excreted by the kidney 
and 10% is excreted by the colon (Schaefer, 2005).  Hyperkalemia is commonly defined as a serum 
potassium level above the upper limit of normal (i.e., > 5.0 mEq/L in both adults and pediatric 
patients).  The physiologic effects of hyperkalemia can cause muscle weakness, paralysis and life 
threatening effects on cardiac conduction (e.g., QRS widening), arrhythmias, such as ventricular 
fibrillation, and sudden death (Ahmed, 2001).  The deleterious effects of elevated potassium have 
been observed at levels as low as 5.0 mEq/L (Jain, 2012, Miao, 2011). 
As in adults, children most at risk for hyperkalemia are those with CKD.  In patients with CKD, the 
primary cause of hyperkalemia is a decrease in renal elimination of potassium, and the risk of 
hyperkalemia increases as renal function deteriorates (Wong, 2006).  Furthermore, the use of drugs 
that block the renin angiotensin aldosterone system (RAAS) can increase the risk and severity of 
hyperkalemia in patients with underlying CKD.  Given that this class of drugs has been proven to 
slow progression of renal disease among children with progressive CKD due to primary 
glomerulopathies or renal hypoplasia-dysplasia (The ESCAPE Trial Group, 2009), the management 
and treatment of hyperkalemia is critically important to enable the use of these agents 
(Wong, 2006). 
Approximately 8 – 36% of adults with CKD develop hyperkalemia (Einhorn, 2009, Tzamaloukas, 
1987) as defined by a serum potassium concentration > 5.0 mEq/L, which is often treated or 
prevented with diet, dose modifications of contributing medications, and/or dialysis (Lu, 2009).  In 
children with CKD, the prevalence estimate of hyperkalemia has been reported in 366 patients 
(mean age 9.9  5.1 years) at a single large pediatric nephrology center in Canada (Wong, 2006).  A 
patient was considered to demonstrate hyperkalemia if any of the following three criteria were met:  
1) any treatment with potassium binders; 2) potassium dietary restrictions; or 3) the most recent 
serum potassium was > 6.0 mmol/L.  While the high cutoff for serum potassium as an inclusion 
criterion in this study may lead to an underestimation of the prevalence of hyperkalemia in CKD 
pediatric patients, the general tendency of increasing frequency of hyperkalemia with increasing 
stage of CKD is similar to the observed pattern in adults:  the prevalence of hyperkalemia in 
children with CKD ranged from 0.9% in CKD stage 2 (GFR range 60 – 90 mL/min/1.73m2) to 
5.3% in CKD stage 3 (GFR range 30 - < 60 mL/min/1.73m2) and 18.2 % in CKD stage 4 and 5 
combined (GFR range 15 – < 30 mL/min/1.73m2 and < 15 mL/min/1.73m2). 


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An analysis of the serum potassium data from the ongoing Cardiovascular Comorbidity in Children 
with Chronic Kidney Disease (4C) Study in Europe provides additional estimates of the frequency 
of hyperkalemia in the pediatric CKD population.  The 4C study is a longitudinal observational 
study following approximately 700 children with CKD ages 6 to 17 years at the time of enrollment, 
and is evaluating the prevalence, clinical symptoms and progression of cardiovascular and kidney 
disease (Querfeld, 2010).  Mild hyperkalemia defined as serum potassium of 4.8 - 5.4 mEq/L, 
occurred in 11.6 % of the samples analyzed in children with CKD stage 2 and increased up to 
28.6 % in children with CKD stage 4 and 33.8 % in children on hemodialysis.  Moderate 
hyperkalemia (5.5 – 5.9 mEq/L) and severe hyperkalemia (≥ 6 mEq/L), although both occurring at a 
lower rate, showed a similar pattern in increasing frequency with worsening kidney disease. 
Hyperkalemia can occur acutely and also can be a recurring condition in patients with the above 
chronic conditions and drug treatments; however, the utility of current options for the management 
of hyperkalemia (e.g., dietary potassium restriction, diuretics, sodium bicarbonate, sodium and 
calcium polystyrene sulfonate) are limited and not all of them have been well studied for treatment 
of hyperkalemia.  Some treatments for hyperkalemia such as insulin and bicarbonate, shift 
potassium intracellularly, but do not reduce total body potassium. 
Given the limitations with current therapies and the need for a well-tolerated potassium binder to be 
used in both acute and chronic clinical settings, patiromer was developed as an alternative therapy 
for patients with hyperkalemia. 
 
Effects in Humans 
The clinical development program for patiromer to date includes eight completed studies:  three 
Phase 1 studies, four Phase 2 studies and one two-part Phase 3 study (RLY5016-301).  A total of 
791 subjects participated in these eight clinical studies, including patients with hyperkalemia, CKD, 
heart failure, diabetes mellitus, hypertension and/or patients on hemodialysis, and healthy volunteer 
subjects.  The 734 subjects received at least one dose of patiromer and the duration of dosing 
ranged from a single dose to up to 1 year. 
The pivotal two-part 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 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. 


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Two Phase 1 studies in healthy volunteers (RLY5016-101 and RLY5016-102) demonstrated that 
doses of up to 50.4 g/day patiromer were pharmacologically active (resulting in increased fecal 
potassium excretion in a dose-dependent manner) and well-tolerated, and that 25.2 g/day patiromer 
administered either QD, BID, or TID had similar pharmacological activity and tolerability.  The 
safety, tolerability, and pharmacologic activity of QD dosing of patiromer were assessed in Study 
RLY5016-102.  This open-label, multiple-dose crossover Phase 1 study evaluated the 
pharmacology, safety and tolerability of three dosing regimens of patiromer in 12 healthy subjects.  
Patiromer was administered orally as an aqueous suspension of 8.4 g patiromer TID for 6 days, 
12.6 g patiromer BID for 6 days and 25.2 g patiromer QD for 6 days in a randomly assigned order 
based on one of six dosing sequences.  Administration of 25.2 g/day patiromer led to a mean 
increase in fecal potassium excretion of approximately 1400 mg/day, with a corresponding similar 
decrease in urinary potassium excretion.  No statistically significant difference was observed among 
the TID/BID/QD treatment groups with respect to the mean daily fecal or urinary potassium 
excretion.  This was true for the overall comparison among the three treatment groups, as well as 
for the pairwise comparisons. 
The onset of action Phase 1 study RLY5016-103 in subjects with hyperkalemia provided additional 
information supporting QD dosing of patiromer (Bushinsky, 2015).  This was an open-label, single 
arm study that evaluated the time to onset of the potassium-lowering action of patiromer.  Twenty-
five (25) subjects with CKD (baseline mean eGFR of 34.8 mL/min/1.73m2) who had a serum 
potassium at Screening of 5.5 to < 6.2 mEq/L and who were not on dialysis were entered into a 
3-day in-patient run-in period during which they began receiving a potassium- and 
sodium-controlled diet, followed by a 48-hour treatment period (fixed dose of 8.4 grams patiromer 
BID for a total of 4 doses, administered at Hours 0, 10, 24 and 34) during which serum potassium 
was assessed repeatedly.  From a mean baseline serum potassium of 5.93 mEq/L, statistically 
significant reductions were observed at 7 hours after the first dose (0.21 mEq/L) and throughout the 
48-hour treatment period (p ≤ 0.001).  After the last dose of patiromer at Hour 34, mean serum 
potassium values continued to decline, reaching a mean (standard deviation [SD]) maximal 
reduction of 0.83 (0.454) mEq/L at 7 hours after the last dose (Hour 41).  By Hour 58 (i.e., 24 hours 
following the last dose), the mean serum potassium had returned to a level similar to that at the time 
of the last dose (mean [SD] serum potassium at Hour 34:  5.28 [0.373] mEq/L; at Hour 41:  
5.11 [0.391] mEq/L; at Hour 58:  5.27 [0.548] mEq/L). 
A comprehensive assessment of safety of patiromer for the treatment of hyperkalemia was 
conducted.  A total number of 734 adults were exposed to at least one dose of patiromer and a 
pooled safety analysis was conducted in 666 subjects receiving patiromer (including 219 exposed 
for at least 6 months and 149 exposed for at least one year) and 49 subjects receiving placebo for up 
to 28 days.  Data from the overall safety population demonstrated that patiromer was well tolerated.  
AEs and 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.  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. 


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The most common adverse reactions (occurring in ≥ 2% of subjects) in subjects treated with 
patiromer in the clinical trials were constipation, hypomagnesaemia, diarrhea, nausea, abdominal 
discomfort, and flatulence.  Most adverse reactions were mild to moderate.  Constipation generally 
resolved during the course of treatment.  Refer to the current version of the Investigator’s Brochure 
for additional information (Investigator’s Brochure, 2016). 
Potassium levels < 3.5 mEq/L occurred in approximately 4.7% of subjects and none of these events 
were serious AEs.  Approximately 9% of subjects in clinical trials developed hypomagnesemia with 
a serum magnesium value < 1.4 mg/dL.  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, heart failure, and coronary artery disease. 
During the clinical studies, the most commonly reported adverse reactions leading to 
discontinuation of patiromer were gastrointestinal adverse reactions (2.7%), including vomiting 
(0.8%), diarrhea (0.6%), constipation (0.5%) and flatulence (0.5%). 
To date, no clinical studies with patiromer have been performed in children. 
Refer to the current version of the Investigator’s Brochure for a more detailed summary of these 
clinical studies. 
 
Rationale 
The safety and effectiveness of patiromer has not been evaluated in children.  The current study 
RLY5016-206p is the first study to explore the use of patiromer in children and adolescents 
2 – < 18 years of age. 
 
Rationale for Study Design 
Patiromer binds potassium predominantly in the lumen of the colon and increases fecal potassium 
excretion, leading to removal of potassium from the body and lowering of serum potassium levels.  
Given its mechanism of action, patiromer is expected to act similarly in adults and children and 
should be effective in lowering serum potassium levels in pediatric patients with hyperkalemia.  
Therefore, the current study focuses on patiromer dose finding in the first 14 days of the study 
followed by an additional 5.5-month safety follow-up. 
The pediatric subjects, children and adolescents 2 – < 18 years of age, are divided into three age 
cohorts (2 – < 6 years, 6 – < 12 years and 12 – < 18 years).  The study will commence with the 
oldest age cohort (12 – < 18 years) and the lowest of three patiromer starting dose levels; this is to 
ensure safety of younger age subjects who might be the most vulnerable to potential adverse events 
associated with patiromer.  The SMC and DSMC will review safety and PD data from the three 
initial subjects.  If the SMC and DSMC agree that the patiromer starting dose evaluated is 
appropriate, then nine additional subjects (or fewer if more than three subjects were initially 
enrolled) will be evaluated at this starting dose level for a total of 12 subjects at the recommended 
starting dose.  If the SMC and DSMC do not agree that the initial patiromer starting dose evaluated 
is appropriate, then the next higher patiromer starting dose level will be evaluated in 
three additional subjects.  The SMC and DSMC review process and determination of whether the 


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recommended starting dose was achieved or not will be repeated for these three subjects.  Once the 
recommended patiromer starting dose is determined for a particular age cohort, no additional dose 
levels will be evaluated.  The safety and PD data from the older age cohort will be used by the SMC 
and DSMC to determine the starting dose for the younger age cohorts.  The total sample size could 
be as low as 36 (three initially treated subjects plus an additional nine if the first dose is chosen as 
the recommended dose for each of the three different age cohorts) or up to 54 if all three patiromer 
starting dose levels are studied for each age cohort. 
The proposed dosing regimen in adults is once daily administration; the same dosing regimen is 
proposed for the pediatric population. 
 
Rationale for Patiromer Starting Doses 
The starting doses of patiromer in each age cohort were selected based on the median weights for 
boys and girls within each of the three age categories using standard growth data (CDC, 2010).  The 
initial weight-based doses selected were guided by the starting dose in adults (8.4 g/day patiromer), 
a higher commonly used dose in adults (16.8 g/day) and a dose below the adult efficacy range 
(4.2 g/day patiromer) in the event children have a different response profile than adults. 
Patiromer dose titrations up and down are allowed to achieve and maintain potassium in the target 
range of 3.8 – 5.0 mEq/L.  The titrated increment or decrement is planned to be the lowest starting 
dose for each age group. 
2 
TRIAL OBJECTIVES 
Primary:  To assess change from baseline in serum K+ levels to Day 14 following administration 
of different doses of patiromer administered once daily in children 2 – < 18 years of age with CKD 
and hyperkalemia. 
Secondary:  To assess the safety and tolerability of patiromer in children 2 – < 18 years of age with 
CKD and hyperkalemia. 
3 
TRIAL DESIGN 
 
Description 
Up to 54 subjects, 2 – < 18 years of age with CKD and hyperkalemia will be enrolled in this open-
label, multiple-dose, Phase 2 study.  Subjects must be < 18 years of age from the time of study 
consent until anticipated completion of Day 14 of the study. 
The study will include two treatment phases:  PD / Dose Finding Phase consisting of the initial 14-
day dose finding period followed by an up to 5.5-month Long-Term Treatment Phase for a total 
study participation duration for individual subjects of up to 6.5 months (see Figure 1).  The overall 
design of the study is presented schematically below. 
The study periods comprised of the following (Figure 1): 
• Screening Period (up to 7 Days)  


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• PD / Dose Finding Phase (14 Days) 
• Long-Term Treatment Phase (5.5 Months) 
• Follow-up Period (14 days after discontinuation of treatment whether subjects complete 
treatment or discontinue early) 
Figure 1: 
Study Schema 
 
 
 
Study Period 
3.2.1 
Screening Visit(s) 
At screening, subjects should arrive in the morning of the Screening Visit(s) and will be assigned a 
subject identification (Subject ID) number.  This will be a unique number generated by the 
interactive web response system (IWRS).  Section 4 lists the inclusion and exclusion criteria for 
study entry. 
Screening (up to 7 Days): 
Subject’s eligibility will be assessed during a Screening Period with up to two visits (Screening 
Visit 1, Screening Visit 2).  Eligibility for this study requires the presence of hyperkalemia assessed 
by two blood or serum potassium measurements performed on separate days; qualifying potassium 
values are 5.1 to < 6.5 mEq/L.  A standard of care potassium value measured within 42 days to 


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2 days prior to Screening may be used for one of the potassium values to assess eligibility.  The 
following scenarios are allowed for obtaining the two qualifying potassium values (5.1 to 
< 6.5 mEq/L) (see schema in Appendix D): 
• For subjects with a recent standard of care potassium measurement, the two qualifying 
potassium values will be the most recent standard of care potassium measurement obtained 
from 42 days to 2 days prior to Screening Visit 1 and the local potassium measurement at 
Screening Visit 1  
• For subjects without a recent standard of care potassium measurement within 42 days to 
2 days prior to Screening Visit 1, the first qualifying potassium value will be obtained at 
Screening Visit 1 and the second at Screening Visit 2, occurring 2 to 7 days after Screening 
Visit 1  
A potassium level of < 5.1 or ≥ 6.5 mEq/L for either screening local potassium value will result in 
screen failure.  Subjects who screen fail may be rescreened once upon the approval of the Medical 
Monitor; see Section 6.1.3 for details.   
For subjects who meet the hyperkalemia eligibility criterion, additional assessments will also be 
performed at Screening Visit 1 and/or Screening Visit 2 to determine eligibility for study entry 
(see Section 6.1 and Appendix A for further details). 
For subjects who meet all eligibility criteria at either Screening Visit 1 or Screening Visit 2, that 
visit should be converted to the Day 1 Visit (Baseline).  In cases where this is not possible, eligible 
subjects must return the next day to complete the Day 1 Visit. 
Subjects may be re-screened (see Section 6.1.3 for further details). 
3.2.2 
14-Day PD / Dose Finding Phase: 
Eligible subjects will enter a 14-Day PD / Dose Finding Phase consisting of four scheduled visits:  
Day 1, Day 3, Day 7 and Day 14.  Blood or serum potassium concentrations will be measured 
locally and by the central laboratory at each of the 4 scheduled visits (see Appendix A). Note:  At 
the discretion of the Investigator, the Day 3 Visit is optional for subjects whose last screening K+ is 
< 5.5 mEq/L; for subjects whose last screening K+ is ≥ 5.5 mEq/L, the Day 3 Visit is mandatory 
(see Section 6.2.2).  Additional laboratory assays (Appendix C) will be performed at specified visits 
according to the Schedule of Events (see Appendix A).  12-lead ECG will be performed at Day 3, 7, 
and 14 Visits if the local K+ is >6.0 mEq/L at that visit. 
Eligible subjects will be categorized into three different age cohorts (12 – < 18 years, 
6 – < 12 years, and 2 – < 6 years).  Enrollment will start with three subjects at the oldest age cohort 
first; this is to ensure safety of younger age subjects who might be the most vulnerable to potential 
adverse events associated with patiromer.  Initiation of enrollment of subjects in the younger age 
cohorts will depend on DSMC review (See Section 8.6 for further details). 
Up to three starting dose levels will be evaluated in each age group.  The initial dose evaluated will 
be the lowest of the planned starting dose levels for each age group (see Table 1). 


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Table 1: 
Planned Patiromer Starting Dose Levels for Each Age Cohort 
Age Cohort (years) 
Starting Dose Levels (g/day) 
Lowest 
Mid 
Highest 
12 ‒ < 18 
4.2 
8.4 
16.8 
6 – < 12 
2 
4 
8 
2 – < 6 
1 
2 
4 
Note:  the starting doses for the 6 – < 12 years of age and 2 – < 6 years of age cohorts may require modification 
based upon the DSMC recommendation after their review of the safety and PD data of the older cohorts (see 
Section 8.6 for further details). 
Once the initial group of subjects at a given starting dose level complete their 14-Day PD / Dose 
Finding Phase, PD and safety data will be provided to the DSMC.  The DSMC will evaluate safety 
and PD data, as well as the number of subjects requiring dose titration.  Based on its review, the 
DSMC will determine if the starting dose for subjects under review was appropriate, in which case, 
nine additional subjects (or fewer if more than three subjects were initially enrolled) in the same age 
group will be enrolled at the same starting dose.  If the DSMC determines that the starting dose did 
not result in an acceptable PD response, and the safety is acceptable, the DSMC will provide a 
recommendation to evaluate the next starting dose in the age group (see Section 8.6 for detailed 
information on the DSMC). 
Subject screening will pause periodically throughout the study to allow for preparation of data and 
DSMC review and provision of recommendations.  Any subjects who are in the Screening Period 
when the pause is announced may be enrolled provided they meet all eligibility criteria. 
Patiromer dose titration is allowed per a protocol-specified algorithm (See Section 5.2.1).  The 
titrated increment or decrement is planned to be the lowest starting dose for each age group. 
All patients treated in the PD / Dose Finding Phase will be included in the Long-Term Treatment 
Phase. 
3.2.3 
Long-Term Treatment Phase: 
After completion of the 14-Day PD / Dose Finding Phase, subjects then enter a Long-Term 
Treatment Phase that consists of eight visits over a period of 5.5 months.  Study visits consist of 
Week 3, Week 5, Week 7, Week 10, Week 14, Week 18, Week 22 and Week 26 (see Appendix B).  
Dose adjustments in the Long-Term Treatment Phase may be made at each study visit starting with 
the Week 2 (Day 14) Visit according to the titration algorithm (see Section 5.2.1). 
At each study visit in the Long-Term Treatment Phase, potassium levels will be measured locally 
and by central laboratory.  ECG evaluations will be performed as soon as possible whenever the 
local K+ level is > 6.0 mEq/L; at the Week 26 (or ET) Visit, an ECG will be performed regardless 
of potassium level.  Additional laboratory assays and assessments will be performed according to 
the Schedule of Events (see Appendix B).  A full list of central laboratory assays is provided in 
Appendix C. 
Study visits at Week 3, Week 10 and Week 22 are optional and may be omitted under the following 
circumstances: 


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• For the Week 3 visit, the local potassium at Day 14 was in the target range (3.8-5.0 mEq/L) 
and no dose adjustment was made at Day 14 
• For the Week 10 and/or Week 22 visits, the local and central potassium were both in the 
target range (3.8-5.0 mEq/L) at the prior visit (Week 7 and Week 18), respectively  
• An unscheduled visit did not occur between the most recent scheduled visit and the planned 
visit to be omitted (e.g., there must not be an unscheduled visit between Week 7 and Week 
10 to omit the Week 10 visit). An exception to this unscheduled visit criterion is an 
unscheduled visit that is solely for resupply of study drug.  
• No dose adjustment in patiromer was made at the prior visit (Day 14, Week 7, Week 18, 
respectively) and the investigator considers additional dose adjustments to be unlikely based 
potassium control to date during the study 
• The investigator determines that there is no ongoing medical issue that needs follow up prior 
to the next scheduled visit at Week 5, Week 14, Week 26, respectively 
During the Long-Term Treatment Phase, up to 2 non-sequential study visits may be conducted 
remotely using the Sponsor approved Home Care vendor at certain investigational sites in certain 
countries. Certain study procedures may be omitted at Home Care Visits (see Section 6.2.5). Home 
Care visits may not be conducted at the visit just prior or just after an optional visits at Week 3, 
Week 10 or Week 22 that was skipped.  The Week 26 (or ET) visit must occur at the investigational 
site and may not occur as a Home Care visit.  
 
3.2.4 
Follow-up Period 
All subjects will enter the Follow-up Period including: 
• Subjects who completed the Long-Term Treatment Phase (i.e., attended the Week 26 Visit) 
• Subjects who did not complete the Long-Term Treatment Phase and were withdrawn early 
prior to the Week 26 Visit 
The Follow-up Period will consist of one visit at 7 days and one phone call at 14 days after stopping 
patiromer treatment.  The investigator may require the Phone Call Follow-up to be converted into 
an onsite visit if the potassium level measured during Follow-up Visit at 7 days after stopping 
patiromer treatment is of concern. 
 
4 
SUBJECT SELECTION AND WITHDRAWAL 
All potential study subjects will be evaluated using the inclusion and exclusion criteria, described 
below. 


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Inclusion Criteria 
Subjects must meet ALL the following criteria: 
1. Written assent (when applicable) and written informed consent by a legally authorized 
representative provided prior to participation in the study 
2. Age 2 – < 18 years old (subject’s age should not exceed that of the age cohort into which 
s/he is enrolled for at least the entire 14 days of the PD / Dose Finding Phase) 
3. Pediatric subjects with CKD and eGFR < 90 mL/min/1.73 m2 calculated using the Schwartz 
formula as described in Section 7.2, including renal transplant subjects, based on local 
creatinine measurement at Screening 
4. Two blood or serum potassium measurements of 5.1 to < 6.5 mEq/L performed on separate 
days (see Section 6.1) 
5. In the opinion of the Investigator, the subject is expected to require treatment for 
hyperkalemia for at least 6 months 
6. If taking any RAASi, beta blockers, fludrocortisone or diuretic medications, must be on a 
stable dose for at least 28 days prior to Screening 
7. Females of child-bearing potential must be non-lactating, must have a negative pregnancy 
test at Screening, and must have used an effective form of contraception (e.g., abstinence, 
hormonal, chemical, physical barrier, etc.) for at least 1 month before patiromer 
administration.  Subjects of child-bearing potential must agree to continue using 
contraception throughout the study and for 1 month after the last dose of patiromer 
 
Exclusion Criteria 
Subjects must NOT meet ANY of the following exclusion criteria: 
1. Subjects with pseudohyperkalemia due to hemolysis or to abnormally high numbers of 
platelets (> 500,000/mm³), leukocytes (> 70,000/mm³), or erythrocytes (hematocrit > 55%) 
at Screening based on results obtained locally 
2. Any subject with evidence of potential potassium-related ECG changes (i.e., changes 
consistent with hyper- or hypokalemia) at Screening 
3. Any of the following renal conditions:  maintenance hemodialysis or peritoneal dialysis, 
renal artery stenosis, and acute kidney injury (defined by 2012 Kidney Disease Improving 
Global Outcomes (KDIGO, 2012) or a history of acute renal insufficiency in the past 3 
months 
4. A history of or current diagnosis of a severe gastrointestinal diagnosis or surgery that could 
affect gastrointestinal transit of the drug (e.g. a severe swallowing disorder, uncorrected 
pyloric stenosis, intussusception, any other intestinal obstruction [e.g. Hirschsprung disease, 


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chronic intestinal pseudo-obstruction, clinically significant postsurgical abdominal 
adhesions] or any gut-shortening surgical procedure prior to Screening) 
5. A history of or current diagnosis of a condition that in the opinion of the investigator 
increases the risk of aspiration of patiromer if it will be given orally 
6. Liver enzymes ALT, AST > three times upper limit of normal at Screening, based on the 
local laboratory ALT and AST 
7. Active cancer, currently on cancer treatment or history of cancer in the past 2 years (except 
for non-melanoma skin cancer) 
8. Heart or liver transplant recipient, or anticipated need for transplant during the study 
Treatment Period, including a scheduled kidney transplant recipient (note:  patients 
currently on a kidney transplant wait list are not excluded unless there is an identified 
donor) 
9. Chronic alcohol abuse or substance use disorder within 1 year of Screening 
10. Subjects currently being treated with or having taken any one of the following medications 
(includes resins) in the 7 days prior to Screening:  sodium or calcium polystyrene sulfonate, 
sodium zirconium cyclosilicate, and drospirenone   
11. Use of the following medications if doses have not been stable for at least 14 days prior to 
Screening or if doses are anticipated to change during the 14-day PD / Dose Finding Phase: 
– digoxin;  
– bronchodilators;  
– theophylline;  
– heparins (including low molecular heparins);  
– canagliflozin; 
– tacrolimus; 
– mycophenolate mofetil; 
– cyclosporine 
– trimethoprim or cotrimoxazole 
12. Use of any investigational product for an unapproved indication within 30 days prior to 
Screening or within 5 half-lives, whichever is longer  
13. Known hypersensitivity to patiromer or its components  
14. In the opinion of the Investigator, inability to comply with the protocol 


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15. In the opinion of the Investigator, any medical condition, uncontrolled systemic disease, or 
serious intercurrent illness that would significantly decrease study compliance or jeopardize 
the safety of the subject or potentially affect the quality of the data such as:  hyperkalemia at 
Screening that requires emergency intervention; cardiovascular event or intervention within 
3 months prior to Screening; a hemodynamically unstable arrhythmia; hospitalization for 
heart failure within the past 3 months; poorly controlled BP; poorly controlled diabetes 
mellitus or frequent need for adjustment in insulin prescription or recent hospitalization for 
treatment of hyper or hypoglycemia 
 
Subject Withdrawal 
Within the provisions of informed consent and assent (if required) and good clinical judgment with 
respect to the subject’s safety, every attempt should be made to have subjects complete both 
Treatment Periods and Follow-up Period.  Subjects and subject’s legally authorized representatives 
will be informed that they are free to withdraw from the study at any time.  The Investigator and/or 
the Medical Monitor may exercise his or her medical judgment to terminate a subject’s participation 
in the study because of clinically significant changes in any clinical or laboratory parameter.  If the 
Investigator is concerned regarding any potassium value, a re-test of potassium level and/or ECG 
evaluation for electrophysiological consequences can be initiated by the Investigator at his/her 
discretion. 
On an ongoing basis, the investigator will monitor the degree of burden of participation in the study 
as well as the associated risk. Participation in this study should only be continued if the investigator 
determines there is no more than a minimal increase over the burden and risk that are described in 
the protocol or associated with routine clinical examinations, clinical care and treatment of patients 
with chronic kidney disease and hyperkalemia. 
All subjects withdrawn early from the study for any reason will be followed for safety for 2 weeks 
after receiving the last dose of patiromer.  Subjects who meet any of the following criteria at any 
time during the study must be withdrawn from the study and should be medically managed as per 
standard of care by the Investigator: 
• Serum magnesium < 1.0 mg/dL (< 0.41 mmol/L) confirmed by re-test 
• Potassium-related ECG changes 
• Treatment-related SAE (SAE form must be completed) 
• Pregnancy (pregnancy form must be completed) 
• Withdrawal of assent by subject (if required) or informed consent by legally authorized 
representative 
Other reasons for withdrawal may include: 
• Adverse Event 
• Protocol deviation 
• Subject’s non-compliance:  poor compliance with study treatment 


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• Investigator’s decision (e.g., in the Investigator’s judgment discontinuation is in the 
subject’s best interest; e.g., need for prohibited medication) 
• Subject is lost to follow-up:  the subject did not return for visits and study personnel were 
unable to contact the subject 
• Subject transitions to dialysis during the study and does not require additional patiromer 
treatment (see Section 4.4 for details) 
• Other:  the subject’s participation in the study was terminated for a reason other than those 
listed above.  The Investigator must specify the detailed reason. 
 
In addition, a variety of reasons may lead either Relypsa or a regulatory agency to terminate the 
study early, in which case all subjects would be withdrawn from the study. 
It is important to collect information explaining why subjects withdrew from the study.  This 
information, together with AEs occurring at those times, may be very informative of the cause-
specific reasons for why some subjects remain in the study or on the assigned treatment while 
others do not.  Therefore, although the subject’s legally authorized representatives are not obliged 
to give their reason for withdrawing consent, the Investigator will make a reasonable effort to 
obtain the reason while fully respecting the subjects’ rights.  Reasons for withdrawal of consent, 
when provided by the subject’s legally authorized representatives, will be recorded in the electronic 
case report form (eCRF).  The procedures described for Early Termination (ET, see Section 6.4) 
will be performed, if possible.  Every effort will be made to contact the legally authorized 
representatives of a subject who fails to attend a study visit, or does not respond by telephone, in 
order to ensure that the subject is in satisfactory health.  The Investigator will immediately inform 
the Medical Monitor of removal or early withdrawal of a subject from the study. 
If a subject withdrew within the 14-Day PD / Dose Finding Phase, the DSMC may be consulted 
regarding possibility of replacing the withdrawn subject.  
 
Dialysis 
The medical monitor should be contacted prior to enrolling a subject if it is anticipated that subject 
will transition to dialysis any time during the study.  In addition, the medical monitor should be 
consulted when the investigator determines that an enrolled subject will require dialysis. Patients 
who are anticipated to require dialysis shortly after enrollment (within 6-8 weeks of Day 1) may not 
be suitable for enrollment due to unstable medical status and fluctuating potassium levels. In most 
cases for subjects who transition to maintenance hemodialysis or peritoneal dialysis during the 
study patiromer should be discontinued as soon as feasible. Continuation of patiromer (including a 
dose of 0 g/day) may be allowed for patients transitioning to dialysis under the following 
conditions:  
• The Investigator determines continuation of patiromer may be needed to control 
hyperkalemia; (documentation of medical justification must be provided)  


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• Agreement to follow additional guidance for potassium monitoring (to be provided as 
needed)  
• Approval by the medical monitor  
Alternative strategies to control hyperkalemia (e.g., adherence to low potassium diet, dialysis 
prescription) should be utilized to facilitate withdrawal of patiromer and management of 
hyperkalemia once patiromer is discontinued. 
Dialysis sessions conducted during the study should be documented in eCRF.  Subjects who 
undergo dialysis and discontinue patiromer should be withdrawn from the study. Subjects on a 
patiromer dose of 0 g/day should be withdrawn from the study once the investigator determines 
patiromer will no longer be required. Any subject discontinuing the study early should complete the 
Early Termination visit (see Section 6.4) and the follow up visits.  
5 
STUDY TREATMENTS 
 
Treatment Blinding 
The study is open-label and non-randomized. 
 
Allocation to Treatment 
At the Baseline Visit, the IWRS will assign all subjects who meet the entry criteria to their 
patiromer starting dose.  Enrollment will start with the oldest age cohort (age 12 – < 18 years) first, 
followed by the cohort aged 6 – < 12 years, and subsequently the youngest cohort aged 
2 – < 6 years of age.  Up to three starting dose levels will be evaluated in each age group.  The 
initial dose evaluated will be the lowest of the planned starting dose levels for each age group. 
The planned starting dose levels of patiromer for each age cohort are: 
• Age 12 ‒ < 18 years:  4.2 g/day, 8.4 g/day and 16.8 g/day  
• Age:  6 – < 12 years:  2 g/day, 4 g/day and 8 g/day 
• Age:  2 – < 6 years:  1 g/day, 2 g/day and 4 g/day  
Note:  the starting doses for the 6 – < 12 years of age and 2 – < 6 years of age cohorts may require 
modification based upon the DSMC recommendation after their review of the safety and PD data of 
the older cohorts (see Section 8.6 for further details). 
5.2.1 
Patiromer Titration 
Patiromer dose titration is allowed during study visits to achieve and maintain K+ levels in the 
3.8 – 5.0 mEq/L range.  Titrations will be based on potassium levels measured locally and per the 
protocol-specified algorithm. 
Patiromer dose adjustments are planned to be made in increments or decrements that represent the 
lowest starting dose of patiromer for each age group.  Specifically, the following dose adjustments 
are allowed: 


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• For subjects Age 12 ‒ < 18 years:  titrations up or down by 4.2 g/day 
• For subjects Age 6 – < 12 years:  titrations up or down by 2 g/day 
• For subjects Age 2 – < 6 years:  titrations up or down by 1 g/day 
The DSMC may adjust the titration algorithm for each age cohort after their review of PD and 
Safety data from the previously enrolled subjects.  The maximum dose of patiromer is 25.2 g/day 
during the study.  For subjects in the 2 – < 6 year and 6 – < 12 year age groups the highest 
anticipated doses are 7 g/day and 14 g/day, respectively; the DSMC may modify these doses for 
these age groups based on review of safety and PD data (See section 8.6). 
During the 14 Day PD / Dose Finding Phase, patiromer dose up-titration by the permitted titration 
increment for each age group is allowed beginning at Day 7 for K+ value > 5.0 mEq/L.  Dose 
titration may not be required if the potassium decrease from the previous visit was ≥ 0.5 mEq/L.  
Patiromer dose down-titration by the permitted titration decrement for each age group or more is 
allowed for any K+ value < 3.8 mEq/L to a minimum patiromer dose of 0 g/day.  If patiromer dose 
requires titration, then initiation of the titrated patiromer dose should occur at the next planned 
administration. 
Day 3 Safety Assessment:  As a safety measure to ensure that subject exposure to hyperkalemia is 
not prolonged, the patiromer dose may be up-titrated at Day 3 only if the K+ level is ≥ 5.5 mEq/L 
and is greater than the most recent locally obtained screening potassium value.  Note:  At the 
discretion of the Investigator, the Day 3 Visit is optional for subjects whose last screening K+ is 
< 5.5 mEq/L; for subjects whose last screening K+ is ≥ 5.5 mEq/L, the Day 3 Visit is mandatory 
(see Section 6.2.2). 
During the Long-Term Treatment Phase, patiromer dose up-titration by the permitted titration 
increment for each age group is allowed for any K+ value > 5.0 mEq/L.  Dose titration may not be 
required if the potassium decrease from the previous visit was ≥ 0.5 mEq/L.  Patiromer dose down-
titration by the permitted titration decrement for each age group, or more, is allowed for any K+ 
value < 3.8 mEq/L to a minimum patiromer dose of 0 g/day.  If patiromer dose requires titration, 
then initiation of the titrated patiromer dose should occur at the next planned administration. 
A description of the patiromer dose titration algorithm for each age group is described in Figure 2 
below. 
 
 


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Figure 2: 
Planned Patiromer Dose Titration Algorithm. 
 
 
a 
At Day 3, as a safety measure to ensure that subject exposure to hyperkalemia is not prolonged, patiromer dose 
may be up-titrated only if the K+ level is ≥ 5.5 mEq/L and is greater than the most recent locally obtained screening 
potassium value.  Note:  At the discretion of the Investigator, the Day 3 Visit is optional for subjects whose last 
screening K+ is < 5.5 mEq/L; for subjects whose last screening K+ is ≥ 5.5 mEq/L, the Day 3 Visit is mandatory 
(see Section 6.2.2). 
b 
Down titration of patiromer dose by the designated decrement for each age cohort or more is allowed for any K+ 
values < 3.8 mEq/L to a minimum patiromer dose of 0 g/day.  If patiromer dose requires titration, then initiation of 
the titrated patiromer dose should occur at the next planned administration. 
c 
Dose titration may not be required if the potassium decrease from the previous visit was ≥ 0.5 mEq/L. 
d 
If patiromer dose requires titration, then initiation of the titrated patiromer dose should occur at the next planned 
administration.  Subjects are required to return for a Mandatory Safety Visit within 7 days if the next scheduled 
study visit is > 1 week after a dose increase has been initiated.  Unscheduled visits may occur during any phase of 
the study at the discretion of the Investigator.  Refer to Section 6.5.1 for additional information and criteria for 
Mandatory Safety Visits.   
 
 
Drug Supplies 
5.3.1 
Formulation and Packaging 
Patiromer will be provided open-label to subjects as a powder for oral suspension in packets with 
appropriate labeling.  The individual packets will be assembled as a kit for dispensing the adequate 
amount of patiromer for each subject.  Each packet inside an individual kit will contain either 4.2 g 
patiromer, 2.0 g or 1.0 g patiromer.  Subject’s legally authorized representative will be instructed to 
mix patiromer with water, apple juice, or cranberry juice.  Patiromer shipped to study site should be 
stored refrigerated (2 – 8°C).  Study subject’s legally authorized representatives will be instructed 
to store patiromer refrigerated (2 – 8°C) for the duration of the study. 


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Refer to the current version of the Investigator’s Brochure for a more detailed description of the 
investigational drug. 
5.3.2 
Preparation and Dispensing of Patiromer 
Patiromer is for oral administration.  The subject’s legally authorized representative and the subject 
will be instructed to mix patiromer with water, apple juice, or cranberry juice.  Each patiromer dose 
should be individually prepared under the supervision of the subject’s legally authorized 
representative immediately prior to administration. 
Patiromer should not be heated (e.g., microwaved) or added to heated foods or liquids.  Patiromer 
should not be taken in its dry form but mixed with water, apple, or cranberry juice only.  Patiromer 
doses should be prepared following the steps below: 
• Measure the initial volume of water (or cranberry or apple juice) needed for the assigned 
daily dose, see Table 2, Table 3, and Table 4 for details.  Pour the initial volume of the 
water (or cranberry or apple juice) into a cup or glass, then add patiromer and stir.  Add the 
additional volume of the water (or cranberry or apple juice) and stir thoroughly.  The 
powder will not dissolve and the mixture will look cloudy.  Add more water (or cranberry or 
apple juice) to the mixture as needed for desired consistency 
• Drink the mixture immediately.  If powder remains in the cup or glass after drinking, add 
more water (or cranberry or apple juice), stir and drink immediately.  Repeat as needed to 
ensure the entire dose is administered.  Subjects and their legally authorized representative 
will be instructed that patiromer can be taken either with or without food 
Consult the Pharmacy Manual for details on patiromer administration through an enteral feeding 
tube. 
Table 2: 
Mixing Volumes for 12 – < 18 Years Age Group Patiromer Doses 
(4.2 g Packets) 
Possible Daily Dosesa 
(g/day patiromer) 
Initial Volume per 
Dose (mL) 
(Step 1) 
Additional Volume 
(mL) 
(Step 2) 
Total Volume (mL) 
4.2 (1 packet) 
15 
30 
45 
8.4 (2 packets) 
15 
30 
45 
12.6 (3 packets) 
30 
60 
90 
16.8 (4 packets) 
30 
60 
90 
21.0 (5 packets)  
30 
60 
90 
25.2 (6 packets) 
30 
60 
90 
a 
Doses described include starting doses and potential escalated doses. 
 
 


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Table 3: 
Mixing Volumes for 6 – < 12 Years Age Group Patiromer Doses (2 g Packets) 
Possible Daily Dosesa 
(g/day patiromer) 
Initial Volume per 
Dose (mL) 
(Step 1) 
Additional Volume 
(mL) 
(Step 2) 
Total Volume (mL) 
2 (1 packet) 
5 
10 
15 
4 (2 packets) 
10 
20 
30 
6 (3 packets) 
15 
30 
45 
8 (4 packets) 
15 
30 
45 
10 (5 packets) 
30 
60 
90 
12 (6 packets) 
30 
60 
90 
14b (7 packets) 
30 
60 
90 
a 
Doses described include starting doses and potential escalated doses. 
b 
Equivalent to the adult dose of 25.2 g/day based on weight-based scaling. 
 
Table 4: 
Mixing Volumes for 2 – < 6 Years Age Group Patiromer Doses (1 g Packets) 
Possible Daily Dosesa 
(g/day patiromer) 
Initial Volume per 
Dose (mL) 
(Step 1) 
Additional Volume 
(mL) 
(Step 2) 
Total Volume (mL) 
1 (1 packet) 
2.5 
5 
7.5 
2 (2 packets) 
5 
10 
15 
3 (3 packets) 
5 
10 
15 
4 (4 packets) 
10 
20 
30 
5 (5 packets) 
15 
30 
45 
6 (6 packets) 
15 
30 
45 
7b (7 packets) 
15 
30 
45 
a 
Doses described include starting doses and potential escalated doses. 
b 
Equivalent to the adult dose of 25.2 g/day based on weight-based scaling. 
 
The Investigator or qualified designee will be responsible for dispensing patiromer and for 
documenting the date dispensed, lot number, study visit, and subject identification number on the 
appropriate drug accountability records at the time of dispensation. 
5.3.3 
Dosing and Administration of Patiromer 
Subjects should arrive in the morning of the Screening Visit(s), if possible, since dosing with 
patiromer may be initiated on the same day as the Screening visit.  Patiromer will be administered 
QD and doses should be taken approximately 24 hours apart.  In this study, there should be a 
3 hours separation between patiromer dosing and that of other oral medications; certain medications 
may be co-administered with patiromer at the discretion of the Investigator (see Section 5.5).  
Subjects and their legally authorized representative will be instructed that patiromer can be taken 
with or without food. 


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Patiromer dose titration is allowed per a protocol-specified algorithm to achieve and maintain 
potassium levels (measured locally) within the target range of 3.8 – 5.0 mEq/L.  A description of 
the patiromer dose titration algorithm is provided in Section 5.2.1. 
If patiromer dose requires titration, then initiation of the titrated patiromer dose should occur at the 
next planned administration.  The last dose of patiromer for all subjects in the study will be taken 
on the day before the Week 26 Visit (see Appendix B). 
All subjects will be provided with a Subject Dosing Diary at Day 1. Subjects and their legally 
authorized representative will be instructed how to document each patiromer dose and to bring back 
the Diary for the Investigator and/or designee to review at Day 3, Day 7 and Day 14. The 
Investigator and/or designee will collect the completed Diary at Day 14. 
Note:  If the Investigator determines a Day 3 Visit is not needed for a subject whose last screening 
K+ is < 5.5 (see Section 6.2.2), then the Diary will only be reviewed at Day 7 and Day 14 Visits.  
5.3.4 
Compliance 
Subject’s legally authorized representative will be trained at the Screening / Day 1 Visit and 
retrained at subsequent visits regarding proper dosing and preparation of patiromer to encourage 
compliance. 
Study staff will assess compliance at every study visit after dispensation to confirm that the subject 
is taking patiromer according to the protocol instructions and document compliance in the eCRF as 
detailed in the electronic data capture (EDC) completion guidelines.  Compliance will be assessed 
on the basis of treatment group assignment and on the assigned patiromer dose, duration of 
treatment and quantity of dispensed and returned kits/packets (used and unused). 
 
Investigational Product Storage and Accountability 
The Investigator or designee will verify and acknowledge receipt of patiromer.  Patiromer must be 
stored in a secure area under the proper storage requirements with access restricted to the 
Investigator or designees.  No subject other than those enrolled in this specific investigation shall 
take patiromer designated for this clinical study.  Patiromer may not be utilized for any laboratory 
or animal research.  Patiromer dispensed to subjects must be accurately recorded on the Drug 
Accountability Record maintained at the Study Center.  Subject’s legally authorized representatives 
should be instructed to return all investigational product dispensed to them (used and unused 
kits/packets) at each study visit. 
All used and unused kits/packets of patiromer will be retained at the site for Study Monitor’s 
verification. 
Patiromer should be shipped and stored under refrigeration (2 – 8°C) in a secure location. 


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Concomitant Medications 
Information on all concomitant medications (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) until the last study visit. 
The use of magnesium supplementation is allowed during the study and should be considered for 
subjects whose serum magnesium is near or below the lower limit of normal. 
Patiromer should be taken 3 hours before or 3 hours after administration of other concomitant 
medications.  At the discretion of the Investigator, the following drugs may be coadministered with 
patiromer:  allopurinol, amlodipine, amoxicillin, apixaban, aspirin, atorvastatin, cephalexin, 
cinacalcet, clopidogrel, digoxin, furosemide, glipizide, lisinopril, lithium, metoprolol, phenytoin, 
rivaroxaban, spironolactone, trimethoprim, valsartan, verapamil, and warfarin. 
For subjects taking phosphate binders TID and for whom in the opinion of the Investigator one dose 
per day of the phosphate binder can be replaced by patiromer, patiromer may be dosed with the 
same meal each day and the phosphate binder dosed with two other meals each day. 
In general, subjects should continue on regular doses of their usual medications, including non-
steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, bronchodilators and theophylline, 
laxatives, and contraceptives.  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 do not form an exclusion criterion for 
participation in this study are generally allowed.  If new medications for mild to moderate pain 
relief are required, it is preferred that NSAIDs and COX-2 inhibitors are avoided and alternatives 
such as acetaminophen are used. 
For subjects taking medications with a narrow therapeutic index, careful monitoring is advised. 
5.5.1 
Permitted Antihypertensive Medications and Medications for Heart Failure 
5.5.1.1 
RAAS inhibitor Medications, Digitalis Glycosides and Diuretics 
For subjects taking any RAAS inhibitor medications or diuretic medications, the dose of these 
medications must be stable for at least 28 days prior to Screening.  The use of digitalis glycosides 
(such as digoxin) are permitted if the subject has been on a stable dose at least 14 days prior to 
Screening. 
14-Day PD / Dose Finding Phase 
During subject’s participation in the 14-day PD / Dose Finding Phase of the study, no new RAAS 
inhibitor medications, digitals glycosides or diuretics should be initiated and doses of concomitant 
RAAS inhibitor medications, digoxin and diuretics should not be changed.  In the event that the 
dose of the RAAS inhibitor, digoxin or potassium-sparing diuretic needs to be adjusted during the 
14-day PD / Dose Finding Phase the subject may need to be early withdrawn from the study and the 
Medical Monitor should be contacted prior to a final decision regarding the discontinuation of 
patiromer. 


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Recommendations regarding the timing of any medication as described in Section 5.5 should be 
followed to minimize the possibility of a drug interaction.  Clinical response and/or blood levels 
where possible should be monitored as higher doses may be required during concomitant treatment 
with patiromer. 
Long-Term Treatment Phase 
During the subject’s participation in the Long-Term Treatment Phase, if needed, adjustments to 
RAAS inhibitor medications, digitalis glycosides or diuretics are permitted.  However, if the subject 
is prescribed non-RAAS inhibitor antihypertensive medications or non-potassium sparing diuretics 
every effort should be made to adjust the non-RAAS inhibitor medication or non-potassium sparing 
diuretics prior to adjusting the RAAS inhibitor medications or potassium-sparing diuretics. 
If at any time during the study a subject develops symptomatic postural hypotension, or subject’s 
BP is too low in the opinion of the Investigator, non-RAAS inhibitor antihypertensive treatments 
should either be removed, or their doses reduced before adjustments are made to the RAAS 
inhibitor medications for patients taking these medications.  If hypotension persists after reducing 
or discontinuing non-RAAS inhibitor antihypertensive medications in the Long-Term Treatment 
Phase, it is acceptable to alter RAASi medications per the Investigator’s discretion. 
Recommendations regarding the timing of any medication as described in Section 5.5 should be 
followed to minimize the possibility of a drug interaction.  Clinical response and/or blood levels 
where possible should be monitored as higher doses may be required during concomitant treatment 
with patiromer. 
Increases in potassium levels may occur as early as 2 days after discontinuation of patiromer, which 
may be more likely in subjects who continue taking RAASi medications after stopping patiromer.  
In the Follow-Up Phase, an unscheduled visit may occur at the investigator’s discretion for 
measurement of potassium level (See Section 6.5.1). 
5.5.1.2 
Other Antihypertensive Medications and Medications for Heart Failure 
The use of beta-adrenergic blockers (bisoprolol, sustained release metoprolol and carvedilol are the 
preferred beta-adrenergic blockers but are not required) and diuretics are permitted if the subject 
has been on a stable dose at least 28 days prior to Screening.  However, recommendations regarding 
the timing of any medication as described in Section 5.5 should be followed to minimize the 
possibility of a drug interaction.  For all medications, clinical response should be monitored as 
higher doses may be required during concomitant treatment with patiromer (see Section 5.5). 
In order to control BP at any time during the study, non-RAAS inhibitor, non-potassium sparing 
diuretics and antihypertensive drugs that do not affect potassium levels (e.g., calcium channel 
blocker, alpha blocker and alpha-2 agonist) may be added or modified per the Investigator’s 
discretion. 
While every effort should be made to keep the above medications stable during the entire study, 
doses may be adjusted at the discretion of the Investigator.  Subjects being treated with a diuretic 
and who are not on a consecutive daily dosing regimen and who are scheduled to take a dose of the 
diuretic on the day of the study visit must be instructed to take their diuretic dose after the local and 


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central laboratory blood has been drawn for potassium evaluation.  Additional medications that are 
permitted to treat the symptoms or complications of heart failure are aspirin, hydralazine, and 
nitrates.  Doses of these medications do not need to have been stable prior to screening and can be 
adjusted during the study. 
5.5.2 
Permitted Medications for Anti-Rejection of Transplant 
Subjects treated with tacrolimus, mycophenolate mofetil or cyclosporine should be on a stable dose 
for at least 14 days prior to Screening and expected to remain on the stable dose during the PD / 
Dose Finding Phase (first 14 days) of the study.  In the event that the dose of the anti-rejection 
medication requires adjustment during the 14-Day PD / Dose Finding Phase, the study Medical 
Monitor should be contacted to determine if discontinuation of patiromer and potential early 
termination from the study is required. Small changes in dose during the 14-Day PD / Dose Finding 
Phase may be acceptable.  During the Long-term Treatment Phase, dose adjustments of tacrolimus, 
mycophenolate mofetil or cyclosporine are allowed at the discretion of the Investigator.  
Recommendations regarding the timing of any medication as described in Section 5.5 should be 
followed to minimize the possibility of a drug interaction.  Clinical response and/or blood levels 
where possible should be monitored as higher doses may be required during concomitant treatment 
with patiromer. 
5.5.3 
Permitted Prophylactic Trimethoprim Antibiotic  
Trimethoprim (including cotrimoxazole) used for prophylaxis of infections (e.g., Pneumocystis 
carinii pneumonia, urinary tract infection) is permitted provided the dose has been stable for 
14 days prior to Screening and is expected to remain stable during the 14-Day PD / Dose Finding 
Phase.   
5.5.4 
Permitted Fludrocortisone 
Fludrocortisone use is permitted provided that the subject has been on a stable dose at least 28 days 
prior to screening and the dose is expected to remain stable during the 14-day PD / Dose Finding 
Phase.  In the event that prescription for fludrocortisone requires adjustment during the 14 Day PD / 
Dose Finding Phase, the study Medical Monitor should be contacted.  During the Long-Term 
Treatment phase, investigators should avoid making changes in fludrocortisone dose; however, 
changes in this medication are acceptable for safety reasons (e.g., hypokalemia, increase blood 
pressure, edema).  For subjects taking fludrocortisone who experience hypokalemia, the 
investigator should adjust fludrocortisone dose prior to making changes in the patiromer dose if 
possible, giving due consideration to patient safety and the degree of hypokalemia. 
 
Prohibited Medications 
During the 14-day PD / Dose Finding Phase, the following medications will be prohibited: 
• sodium or calcium polystyrene sulfonate 
• sodium zirconium cyclosilicate  
• drospirenone 


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During the Long-Term Treatment Phase, the following medications will be prohibited: 
• sodium or calcium polystyrene sulfonate 
• sodium zirconium cyclosilicate 
• drospirenone 
 
6 
TRIAL PROCEDURES 
Refer to the Schedule of Events (see Appendix A and Appendix B) for the frequency and timing of 
the required study assessments. 
Laboratory-related eligibility criteria will be based on values obtained locally, specifically 
potassium, creatinine, ALT/AST, CBC, and pregnancy test (females of child-bearing potential).  
The central laboratory results will be used for the establishment of baseline values, safety, and for 
all statistical analyses. 
The Investigator should base decisions related to potassium (e.g., patiromer titration) on the values 
obtained locally at the study site only.  Central laboratory potassium results will be used for the 
efficacy analyses and, for the purpose of the Investigator, as supplemental safety information.  
Central laboratory potassium results should not override any decisions made by the Investigator 
based on local potassium measurements. 
The Investigator must review all laboratory and any ECG results as soon as possible after the results 
are available.  Of particular importance are the timely identification of any out-of-range potassium 
laboratory results.  If the Investigator is concerned regarding any potassium value, a re-test of 
potassium level and/or ECG evaluation for electrophysiological consequences can be initiated by 
the Investigator at his/her discretion. 
To avoid hemolysis of samples, specimen collection and handling must strictly follow specific 
instructions provided in the Laboratory Manual.  Blood samples for potassium assessment (local 
and central laboratory) should be collected at approximately the same time (preferably in the 
morning) for the same subject at all Study Visits (Sections 6.1 and 6.2). 
 
Screening Visit(s) 
Before any study-specific procedures are performed, the legally authorized representative and 
subject must receive an explanation of all study procedures that is described using age appropriate 
language.  The legally authorized representative must sign and date a written informed consent form 
(ICF) and the subject must sign and date the assent (when applicable) approved by an institutional 
review board (IRB) or Ethics Committee (EC) (see Section 12.1 for additional requirements).  The 
timing of the Screening Visit (and all subsequent visits) should take into account planned absences 
at the research facility and the need for study visits according to the Schedule of Events (see 
Appendix A and Appendix B). 
The subject will be assigned a unique study subject identification number, which will be generated 
during Screening Visit registration in IWRS. 


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Subject’s eligibility will be assessed during a Screening Period with up to two visits (Screening 
Visit 1, Screening Visit 2).  Eligibility for this study requires the presence of hyperkalemia assessed 
by two blood or serum potassium measurements performed on separate days; qualifying potassium 
values are 5.1 to < 6.5 mEq/L.  A standard of care local potassium value measured within 42 days 
to 2 days prior to Screening may be used for one of the potassium values to assess eligibility.  The 
following scenarios are allowed for obtaining the two qualifying potassium values (5.1 to 
< 6.5 mEq/L): 
• For subjects with a recent standard of care potassium measurement, the two qualifying 
potassium values will be the most recent standard of care potassium measurement obtained 
from 42 days to 2 days prior to Screening Visit 1 and the local potassium measurement at 
Screening Visit 1 
• For subjects without a recent standard of care potassium measurement within 42 days to 
2 days prior to Screening Visit 1, the first qualifying potassium value will be obtained at 
Screening Visit 1 and the second at Screening Visit 2, occurring 2 to 7 days after Screening 
Visit 1 
Subjects who screen fail may be rescreened once upon approval of the Medical Monitor, see 
Section 6.1.3 for details. 
For subjects who meet all eligibility criteria at either Screening Visit 1 or Screening Visit 2, that 
visit should be converted to the Day 1 Visit (Baseline).  In cases where this is not possible, eligible 
subjects must return the next day to complete the Day 1 Visit.     
6.1.1 
Subjects with Standard of Care Potassium Measurement 
Subjects are requested to arrive in the morning of Screening Visit 1.  The blood specimen obtained 
will be used to measure potassium locally (a serum sample from the specimen will be sent to the 
central laboratory for subjects with confirmed eligibility).  The following screening activities will 
be performed at Screening Visit 1: 
• Legally authorized representative informed consent and subjects’ assent (when applicable) 
signing 
• Subject’s registration in IWRS 
• Review of inclusion and exclusion criteria  
• Demographics  
• Review of medical history 
• Physical examination 
• Body weight and height 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG 
• Blood or serum potassium levels measured locally 


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• Blood or serum chemistry tests including AST, ALT, magnesium, creatinine and eGFR 
measured locally 
• Local hematology (CBC including WBC, RBC, hemoglobin, hematocrit, and platelet count) 
• Local urine pregnancy test (female subjects of child-bearing potential only).  A serum 
pregnancy test will be performed in the event of a positive or equivocal urine pregnancy test 
result  
• AE assessment 
• Concomitant medication assessment 
The Investigator shall review all screening information as soon as possible for safety and eligibility.  
Subjects who meet all eligibility criteria should have their Screening Visit 1 converted to the Day 1 
(Baseline Visit) where the starting dose of patiromer is administered to the subjects if scheduling 
allows.  In cases where this is not possible, eligible subjects must return the next day to complete 
the Day 1 Visit.  
6.1.2 
Subjects without Standard of Care Potassium Measurement 
6.1.2.1 
Screening Visit 1 
The following screening activities will be performed at Screening Visit 1: 
• Legally authorized representative informed consent and subjects’ assent (when applicable) 
signing 
• Subject’s registration in IWRS 
• Blood or serum potassium levels (measured locally) 
• Demographics 
• Medical history (can be performed at Screening Visit 1 or Screening Visit 2) 
• Physical Examination (can be performed at Screening Visit 1 or Screening Visit 2) 
• Height (can be measured at Screening Visit 1 or Screening Visit 2) 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG (can be measured at Screening Visit 1 or Screening Visit 2) 
• AE assessment 
• Concomitant medication assessment 
6.1.2.2 
Screening Visit 2 
Subjects with confirmed eligibility for hyperkalemia (a local potassium level of 5.1 to < 6.5 mEq/L) 
from Screening Visit 1 will be requested to return 2 to 7 days after Screening Visit 1 for 
Screening Visit 2.  Subjects should arrive in the morning of Screening Visit 2.  The blood 
specimen obtained will be used to measure potassium locally (a serum sample from the specimen 
will be sent to the central laboratory for subjects with confirmed eligibility). 


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The following screening activities will be performed at Screening Visit 2: 
• Subject’s registration in IWRS 
• Review of inclusion and exclusion criteria  
• Body weight  
• Vital Signs (resting heart rate and sitting BP) 
• Blood or serum potassium levels measured locally 
• Blood or serum chemistry tests including AST, ALT, magnesium, creatinine and eGFR 
measured locally 
• Local hematology (CBC including WBC, RBC, hemoglobin, hematocrit, and platelet count) 
• Local urine pregnancy test (female subjects of child-bearing potential only).  A serum 
pregnancy test will be performed in the event of a positive or equivocal urine pregnancy test 
result or if the subject is anuric 
• AE assessment 
• Concomitant Medication Assessment 
The Investigator shall review all screening information as soon as possible for safety and eligibility.  
Subjects who meet all eligibility criteria should have their Screening Visit 2 converted to the Day 1 
(Baseline Visit) where the starting dose of patiromer is administered to the subjects if scheduling 
allows.  In cases where this is not possible, eligible subjects must return the next day to complete 
the Day 1 Visit. 
6.1.3 
Re-screening of Subjects 
Re-screening will be allowed for subjects who screen fail after approval by the Medical Monitor.  
A subject may only be re-screened one time. 
To re-screen a subject: 
• The Medical Monitor must be contacted for re-screening approval 
• The subject’s legally authorized representative must be re-consented and assent (if required) 
must be re-obtained 
• The subject must receive a new subject identification number assigned by IWRS. 
• All screening evaluations must be repeated (see Section 6.1)  
• All inclusion and exclusion criteria must be met (see Section 4) 
 
Treatment Period 
6.2.1 
Day 1 Visit (Baseline) 
The following baseline assessments will be performed for subjects who meet all eligibility criteria 
(Section 6.1, Appendix A): 


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• Subject’s visit registration in IWRS 
• Central laboratory tests (see Appendix C): 
- 
Serum potassium  
- 
Serum chemistry 
- 
Plasma parathyroid hormone 
- 
Serum fluoride 
- 
Urinalysis (not required for anuric subjects, see section 7.2) 
- 
Hematology (CBC) 
- 
Local urine and central serum pregnancy test (female subjects of child-bearing potential 
only) 
• Patiromer dispensation, administration (if possible based on individualized administration 
time as described in Section 5.5; first dose only) 
• Patiromer palatability assessments for subjects ≥ 6 years of age who consume patiromer at 
the site  
• Train parents or representative and, if applicable, subjects on patiromer dosing (including 
preparation, accountability and compliance) 
• Provide parents or representative and, if applicable, subjects with study materials (i.e., 
Subject Dosing Diary, dosing instructions and emergency card) 
• Assessment of AEs 
• Assessment of concomitant medications 
• Next visit scheduling 
6.2.2 
Day 3 Visit  
Patiromer dose may be adjusted on the Day 3 Visit based on the potassium level measured locally 
according to the titration algorithm.  A description of the patiromer dose titration algorithm is 
provided in Section 5.2.1.    
At the discretion of the Investigator, the Day 3 Visit is optional for subjects whose most recent 
Screening local K+ is < 5.5 mEq/L. 
The Day 3 Visit is mandatory for subjects whose most recent Screening local K+ is ≥ 5.5 mEq/L.  
The activities for Day 3 (± 1 day) are detailed below and in Appendix A: 
• Subject’s visit registration in IWRS 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG (Only if local K+ is > 6.0 mEq) 


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• Blood or serum potassium levels (measured locally) and serum potassium measured by 
central laboratory  
• Patiromer dose down titration if needed (see Section 5.2.1) 
Note:  Patiromer dose up titration may occur only if the K+ level is ≥ 5.5 mEq/L and greater 
than the most recent locally obtained screening potassium value  
• Patiromer dispensation, reconciliation, accountability, compliance, and subject retraining (as 
applicable) 
• Review of Subject Dosing Diary by Investigator and/or designee 
• Assessment of AEs 
• Assessment of concomitant medications 
• Next visit scheduling 
 
6.2.3 
Day 7 Visit 
Patiromer dose may be adjusted on Day 7 based on the potassium level measured locally according 
to the titration algorithm.  A description of the patiromer dose titration algorithm is provided in 
Section 5.2.1. 
The activities for Day 7 (± 3 days) are detailed below and in Appendix A: 
• Subject’s visit registration in IWRS 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG (Only if local K+ is > 6.0 mEq) 
• Blood or serum potassium levels (measured locally) and serum potassium measured by 
central laboratory 
• Serum chemistry (measured by central laboratory) 
• Patiromer dose titration (if needed), dispensation, reconciliation, accountability, compliance, 
and subject retraining (as applicable) 
• Review of Subject Dosing Diary by Investigator and/or designee 
• Assessment of AEs 
• Assessment of concomitant medications 
• Next visit scheduling 
6.2.4 
Day 14 Visit 
Patiromer dose may be adjusted at the Week 2 (Day 14) Visit based on the potassium level 
measured locally according to the titration algorithm.  A description of the patiromer dose titration 
algorithm is provided in Section 5.2.1. 


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The activities for Day 14 (± 3 day) are detailed below and in Appendix A: 
• Subject’s visit registration in IWRS 
• Physical examination 
• Body weight and height 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG (Only if local K+ is > 6.0 mEq) 
• Potassium levels (measured locally and by central laboratory). 
• Other central laboratory tests (see Appendix B): 
- 
Serum chemistry 
- 
Plasma parathyroid hormone 
- 
Serum fluoride 
- 
Urinalysis (not required for anuric subjects, see section 7.2) 
- 
Hematology (CBC) 
• Patiromer dose titration (if needed), dispensation, reconciliation, accountability, compliance, 
and subject retraining (as applicable) 
• Parent’s or legally authorized representative’s assessment of subject’s (< 6 years of age) 
acceptance of patiromer  
• Review of Subject Dosing Diary by Investigator and/or designee 
• Assessment of AEs 
• Assessment of concomitant medications 
• Next visit scheduling 
6.2.5 
Week 3, Week 5, Week 7, Week 10, Week 14, Week 18, and Week 22 Visits 
Patiromer dose may be adjusted at any scheduled visit based on the potassium level measured 
locally according to the titration algorithm.  A description of the patiromer dose titration algorithm 
is provided in Section 5.2.1. Study visits at Week 3, Week 10 and Week 22 may be omitted under 
certain circumstances; refer to Section 3.2.3 for details. During the Long-Term Treatment Phase, up 
to 2 non-sequential study visits may be conducted remotely using the Sponsor approved Home Care 
vendor at certain investigational sites in certain countries; refer to Section 3.2.3 for details.  
The activities for Week 3 (± 3 days) and Weeks 5, 7, 10, 14, 18, and 22 (± 7 days) are detailed 
below and in Appendix B: 
• Subject’s visit registration in IWRS 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG (Only if local K+ is > 6.0 mEq) 


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•  
• Physical examination (Week 7 and Week 14 only); may be omitted for Home Care visit 
• Body weight and height (Week 7 and Week 14 only); may be omitted for Home Care visit 
• Potassium levels (measured locally and by central laboratory); the investigator will review 
local potassium results within 24 hours for any Home Care visit. 
• Other central laboratory tests for Week 7 and Week 14 only (see Appendix B): 
- 
Serum chemistry 
- 
Serum fluoride 
- 
Hematology (CBC) 
• Patiromer dose titration (if needed), dispensation, reconciliation, accountability, compliance, 
and subject retraining (as applicable). For Home Care visits, the investigator will make 
decisions about patiromer dose titration within 24 hours after the visit; the subject or 
guardian will be contacted as soon as feasible if the investigator determines that a dose 
adjustment is required; any dose adjustment will take place at the next administered dose 
• Assessment of AEs 
• Assessment of concomitant medications 
• Next visit scheduling 
6.2.6 
Week 26 Visit 
The Week 26 Visit is the last visit of the Long-Term Treatment Phase.  This visit is performed 
approximately 6 months after the Baseline Visit (Day 1) and the next day following administration 
of the last dose of patiromer. 
The activities for Week 26 (± 7 days) are detailed below and Appendix B: 
• Subject’s visit registration in IWRS 
• Physical examination 
• Body weight and height 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG 
• Potassium levels (measured locally and by central laboratory) 
• Other central laboratory tests (see Appendix C): 
- 
Serum chemistry 
- 
Plasma parathyroid hormone 
- 
Serum fluoride 
- 
Urinalysis (not required for anuric subjects, see section 7.2) 


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- 
Hematology (CBC) 
• Urine pregnancy test (female subjects of child-bearing potential only; measured locally and 
by central laboratory).  In the event of a positive or equivocal urine pregnancy test result or 
if the subject is anuric, a serum Pregnancy test will be performed. 
• Patiromer reconciliation, accountability and compliance 
• Assessment of AEs 
• Assessment of concomitant medications 
• Next visit scheduling 
 
Follow-up Period 
Subjects who complete the Long-Term Treatment Phase will enter the 2-week Follow-up Period 
thereafter.  Subjects who discontinue treatment with patiromer early during either the 14-day PD / 
Dose Finding Phase or Long-Term Treatment Phase enter directly into the Follow-up Period.  The 
Follow-up Period consists of one visit (Follow-up Visit 1) at 1 week after the last patiromer 
treatment and one phone call (Follow-up Visit 2) at 2 weeks after the last patiromer treatment.  
Follow-up Visit 2 may be converted into an onsite visit at the investigator’s discretion if potassium 
level from Follow-up Visit 1 is of concern. 
6.3.1 
Follow-up Visit 1 (F1) 
Subjects must return for the F1 Visit 7 days (± 3 days) after stopping patiromer treatment (see 
Section 6.3 and Appendix B). 
The following activities will be performed: 
• Subject’s visit registration in IWRS 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG (Only if local K+ is > 6.0 mEq) 
• Potassium levels (measured locally and by central laboratory) 
• Serum chemistry (see Appendix C)  
• Assessment of AEs 
• Assessment of concomitant medications 
• Next phone call scheduling 
6.3.2 
Follow-up Visit 2 (F2) 
Follow-up Visit 2 is a phone call to the subject’s parent or legal guardian 14 days (± 3 days) after 
stopping patiromer treatment (see Section 6.3 and Appendix B).  If subjects are requested to return 
for an onsite visit, the same activities will be performed as those listed in Section 6.3.1. 
The following activities will be performed based on the phone call: 


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• Subject’s visit registration in IWRS 
• Assessment of AEs 
• Assessment of concomitant medications 
 
Early Termination Visit 
Subjects who withdraw prematurely from the study before the Week 26 Visit will need to complete 
the ET Visit, which should be performed on the day of withdrawal or as soon as possible after the 
last dose of patiromer.  Subjects who prematurely stop study drug should be encouraged to 
complete the Follow-up Period Visits (Section 6.3, Appendix A and Appendix B). 
The following activities will be performed: 
• Subject’s visit registration in IWRS 
• Physical examination 
• Body weight and height 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG 
• Potassium levels (measured locally and by central laboratory). 
• Other central laboratory tests (see Appendix C): 
- 
Serum chemistry 
- 
Plasma parathyroid hormone 
- 
Serum fluoride 
- 
Urinalysis (not required for anuric subjects, see section 7.2) 
- 
Hematology (CBC) 
• Urine pregnancy test (women of child-bearing potential only; measured locally and by 
central laboratory).  In the event of a positive or equivocal urine pregnancy test result or if 
the subject is anuric, a serum Pregnancy test will be performed  
• Follow-up visit scheduling 
• Patiromer reconciliation, accountability, compliance 
• Assessment of AEs 
• Assessment of concomitant medications 
 
Other Visits 
6.5.1 
Safety Visit 
Safety Visits are mandatory in certain situations.  Mandatory Safety Visits are required within 7 
days if subject meets any of the following criteria: 


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• Local potassium is > 6.0 mEq/L.  If the patiromer dose is already at the maximum dose (or 
anticipated highest dose) for the age group, standard of care for hyperkalemia should be 
applied including RAASi dose decrease 
• Any increase in patiromer dose that is initiated and the next scheduled study visit is 
> 1 week after the dose increase has been initiated 
• Discontinuation per the Investigator’s discretion 
Note: During the 14-Day PD/Dose finding phase when local potassium measurements > 6.0 mEq/L, 
the Mandatory Safety Visit is not required if a standard study visit takes place within 3 days, 
however all listed MSV study procedures must be completed (i.e. ECG) at the standard study visit. 
Treatment of these subjects with emergency care for hyperkalemia or prohibited standard of care 
medications (i.e., sodium polystyrene sulfonate or calcium polystyrene sulfonate) may result in the 
subject being removed from the study; see Section 5.6 for a complete list of prohibited medications.  
Investigator must contact the medical monitor to determine if the subject should continue in the 
study. 
The following activities will occur during a Mandatory Safety Visit: 
• Subject’s visit registration in IWRS 
• Vital Signs (resting heart rate and sitting BP) 
• 12-Lead ECG if the current or most recent local potassium is > 6.0 mEq/L 
• Potassium levels (measured locally and by central laboratory) 
• Patiromer dose titration (if needed), dispensation, reconciliation, accountability, compliance, 
and subject retraining (as applicable) 
• Assessment of AEs 
• Assessment of concomitant medications 
• Next visit scheduling 
An unscheduled visit may occur at the discretion of the Investigator.  At an unscheduled visit 
during any phase of the study, the following activities will be performed: 
• Subject’s visit registration in IWRS 
• Assessment of AEs 
• Assessment of concomitant medications 
Other study procedures described in the protocol including the assessment of potassium levels 
(measured locally and by central laboratory) may be conducted at the discretion of the Investigator 
depending upon the reason for the visit. 


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7 
ASSESSMENTS 
 
Potassium 
Eligible subjects must have K+ levels of 5.1 – < 6.5 mEq/L determined by two blood or serum 
potassium measurements performed on separate days.  A standard of care potassium value 
measured within 42 days to 2 days prior to Screening may be used for one of the potassium values 
to assess eligibility.  Subject’s eligibility will be assessed during a Screening Period with up to two 
visits (Screening Visit 1, Screening Visit 2). 
The following scenarios are allowed for obtaining the two qualifying potassium values (5.1 to 
< 6.5 mEq/L): 
• For subjects with a recent standard of care potassium measurement, the two qualifying 
potassium values will be the most recent standard of care potassium measurement obtained 
from 42 days to 2 days prior to Screening Visit 1 and the local potassium measurement at 
Screening Visit 1  
• For subjects without a recent qualifying standard of care potassium measurement within 
42 days to 2 days prior to Screening Visit 1, the first qualifying potassium values will be 
obtained at Screening Visit 1 and the second at Screening Visit 2, occurring 2 to 7 days after 
Screening Visit 1 
Blood and/or serum potassium levels will be assessed at every study visit (with the exception of 
Follow-up Visit 2, which is a phone call) and measured both locally and by central laboratory.  
Serum samples will be used for central laboratory potassium measurements.  For Follow-up Visit 2, 
if the subject is requested to return for an onsite visit, then blood/serum potassium levels will be 
assessed (see Section 6.3.2 for details). 
7.1.1 
Preventing, Identifying and Handling Hemolyzed Samples 
Hemolysis of blood specimens may result in spuriously high potassium levels, leading to 
inappropriate up-titrating of the investigational product and causing difficulties in interpreting the 
efficacy analyses. 
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 
semi-quantitative test to assess for evidence of hemolysis.  Pre-defined criteria have been 
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 before it has been 
sent to the central laboratory, a repeat blood draw can be performed if the subject is still at the site. 


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When a blood sample, which is used by the site for titration and subject management, has 
hemolyzed (e.g., by visual inspection of the central laboratory serum sample), the site will need to 
repeat the potassium measurement from a separate blood draw in order to ensure accurate decision-
making regarding patiromer titration. 
7.1.2 
Early Withdrawal from the Study due to Potassium Levels 
Study withdrawal based on potassium level is at the discretion of the Investigator, except in the 
situations described in Section 6.5.1.  The Investigator should perform a confirmatory local 
potassium level before initiating subject withdrawal.  Aside from adjustment of diet or adjustment 
of concomitant medications (e.g., RAASi dose decrease or discontinuation in the Long-Term 
Treatment Phase), a potassium level that requires treatment with additional medications may be a 
reason for ET.  If a subject is early terminated because of high or low potassium, the Investigator 
will provide the appropriate medical management for high or low potassium according to standard 
of care practices. 
 
Laboratory Tests 
AST, ALT and creatinine levels will be analyzed at the local laboratory at the Screening Visit(s) to 
assure eligibility for the study.  Magnesium level will also be analyzed at the local laboratory at the 
Screening Visit(s).  At other time points, the AST, ALT, magnesium and creatinine levels will be 
analyzed by the central laboratory as per Appendix A and Appendix B.  Additional tests included in 
the chemistry panel (Appendix C) will be analyzed by the central laboratory at time points included 
in Appendix A and Appendix B.  For subjects that have one dose of phosphate binder replaced by 
patiromer, calcium and/or phosphate levels may be tested by the central laboratory more frequently 
per Investigator’s decision. 
To qualify for study entry, the subject must have an eGFR < 90 mL/min/1.73m2 at screening based 
on local measurements.  Either the Original or Bedside Schwartz formula should be used to 
calculate eGFR based upon the current serum creatinine assay methodology being used at the 
investigative site’s local clinical laboratory.  
• The Bedside Schwartz formula [eGFR = 0.413 × [height (cm)/serum creatinine (mg/dL)] 
(Schwartz, 2009) requires enzymatic creatinine assay, which may not be available at all 
institutions. In cases where the study site’s local laboratory uses the Jaffe creatinine assay that is 
isotope dilution mass spectrometry (IDMS) traceable, then the Bedside Schwartz formula 
should be used to calculate eGFR 
• In clinical laboratories that use the Jaffe method for creatinine determination that is not isotope 
dilution mass spectrometry (IDMS) traceable, eGFR should be calculated using the Original 
Schwartz formula [eGFR = k × [height (cm)/serum creatinine (mg/dL), where the value for k is 
0.45 for term infants through the first year of life, 0.55 for children and adolescent girls and 0.7 
for adolescent boys] (Schwartz, 2009) 
Hematology (CBC including WBC, RBC, hemoglobin, hematocrit, and platelet count) will be 
analyzed by the local laboratory at the Screening Visit(s) to assure eligibility for the study.  At other 


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time points, the hematology panel (Appendix C) will be assessed by central laboratory as per 
Appendix A and Appendix B. 
For female subjects of child bearing potential only, a urine pregnancy test will be assessed locally 
and a serum pregnancy test will be performed by the central laboratory.  For anuric female subjects 
of child bearing potential, a serum pregnancy test will be assessed locally and by the central 
laboratory.  Anuric female subjects of child bearing potential cannot be enrolled into the study until 
a local negative serum pregnancy test is demonstrated.  
Urinalysis (see Appendix C) will be assessed by central laboratory.  Urinalysis will not be required 
for anuric subjects.  
 
Vital Signs 
7.3.1 
Heart Rate 
In children over 2 years of age, heart rate can accurately be assessed by measuring the pulse radially 
in most children.  In the event peripheral pulses are difficult to palpate, heart rate may be assessed 
by auscultation of the apical pulse for one full minute.  The apical pulse is assessed over the point 
of maximum impulse (PMI) on the child’s chest.  In children up to 7 years old, the PMI is usually 
found at the 4th rib interspace medial to the nipple (the midclavicular line).  After Age 7 - 8, the 
PMI is found between the 5th and 6th interspace, as it is in the adult. 
Heart rate should be measured prior to BP measurement, and should be measured for a full 
60 seconds.  Heart rate data for each visit should be recorded in the respective eCRF. 
7.3.2 
Blood Pressure 
When taking BP measurements, Investigators shall follow the following recommendations: 
• Throughout the study, BP measurements should be performed using the same device for 
each subject. 
• Correct measurement requires a cuff that is appropriate to the size of the child’s upper arm 
(US Department of Health and Human Services, 2005) 
• Measurements should be taken in a quiet place.  The child whose BP is to be measured 
should have avoided stimulant drugs or foods and have been sitting quietly for 5 minutes 
• Tight-fitting clothing should be removed from the arm to be measured.  The same arm 
should be used for all BP measurements 
• During the measurement, the subject should be seated with feet flat on the floor, back 
supported and arm rested on a table so that the cuff is at the subject’s heart level.  If this is 
not possible, the same positioning of the subject should be maintained for BP measurement 
at each visit 
Subject should remain still and should not talk during the measurement.  BP data for each visit 
should be recorded in the respective eCRF. 


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Physical Examination 
Physical examination should be performed as indicated in the Schedule of Events (see Appendix A 
and Appendix B).  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 should 
be reported as an AE. 
 
ECG Assessment 
The baseline 12-lead ECG may be performed on either Screening Visit 1 or Screening Visit 2; the 
end of study ECG will be performed at the Week 26 Visit or ET visit. 
If the Investigator is concerned regarding any potassium value, a re-test of potassium level and/or 
ECG evaluation for electrophysiological consequences can be initiated by the Investigator at their 
discretion.  An ECG is required when the local K+ is > 6.0 mEq/L and must be followed by a 
Mandatory Safety Visit (See Section 6.5.1) 
If a potassium-related ECG change is observed, the Investigator should apply the appropriate 
standard of care to stabilize the myocardium, which may include any or all of the following 
depending on the subject’s clinical situation:  intravenous calcium, intravenous insulin and glucose, 
inhaled beta2 agonists.  In all cases, the ECG should be repeated within 2 to 3 minutes following 
any of the above interventions, and the subject should be assessed for referral to an emergency care 
facility.  Any subject with a potassium-related ECG change must be withdrawn early and once 
stable, should return for the ET Visit (see Section 6.4). 
 
Patiromer Palatability 
The palatability of patiromer will be evaluated in children ≥ 6 years of age when the initial dose is 
administered at the study site on Day 1 using a 5-point facial hedonic scale for taste and overall 
liking. Patiromer should be mixed with water on Day 1 for the palatability assessment. Parental or 
authorized legal representative response on a 5-point agreement/disagreement scale to a statement 
of the subject’s (< 6 years of age) acceptance of patiromer will be assessed on Day 14. 


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Fluoride 
Serum fluoride levels will be assessed as a part of the safety analysis and will be performed at 
Screening Visit 1 or Screening Visit 2, in addition to Week 2 (Day 14), Week 7, Week 14, Week 26 
and ET Visits. 
Systemic fluoride supplementation, other than local municipal water supply, is not recommended 
and careful parental or legal guardian supervision of fluoride containing toothpaste and or dental 
rinse (if applicable) use by younger subjects (< 6 years of age) is advised to prevent accidental 
ingestion. 
 
Diet 
Subjects will be instructed to continue their usual diet during the study. 
8 
ADVERSE EVENT REPORTING 
 
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 legally 
authorized representative signs the informed consent and subject signs the assent (if required) 
during the AE reporting period; and 3) complications 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 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 
should 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) 


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For the purposes of this protocol, events that are not 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: 
• Results in 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 in-patient 
admission 
- 
Elective surgery for a pre-existing condition that has not worsened 
- 
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 seriousness.  If 
either believes that the event is serious, the event must be considered serious and evaluated by 
Relypsa for expedited reporting. 


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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 
ICF is signed until the subject’s last study visit (normally the last follow-up visit).  Any AE or SAE 
will be followed until it resolves or becomes stable.  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 an open-ended question such as: “Since you were last asked, have 
you felt unwell or different from usual in any way?”  The subject or the subject’s legally authorized 
representative may report AEs spontaneously at any time. 
8.2.3 
Assessing Adverse Events 
The Investigator should follow the guidelines for rating severity of AEs: 
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 any of the seriousness criteria (see Section 8.1.1). 
To allow for an objective comparison of the severity of the drug-related gastrointestinal (GI) AEs, 
severity of specific GI AEs (i.e., constipation, diarrhea, abdominal discomfort, nausea, flatulence 
and vomiting) will be evaluated by using the descriptors listed in  
Table 5, which are based on the DAIDS Table for Grading the Severity of Adult and Pediatric AE 
(Division of AIDS National Institute of Allergy and Infectious Diseases, Version 2.0, 2014). 
The DAIDS grading system does not provide any grading for flatulence.  In children, gas-related 
symptoms are reported more frequently as bloating, distension or abdominal discomfort.  Therefore, 
bloating or distension are evaluated by the Investigator based on the severity according to the 
descriptions specified in Table 5. The DAIDS grading system does not include an exact term for 
abdominal discomfort; the term “pain” is modified to describe abdominal discomfort. For these GI 
events, the Investigator should assess severity according to the descriptions specified in, which are 


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based on the DAIDS grading system but have been modified to account for the study population 
and drug safety profile.  AEs that are life-threatening (DAIDS Grade 4) or resulting in death 
(DAIDS Grade 5) meet reporting criteria for SAEs. 
Table 5: Categories of Severity for Specified GI AEs 
PARAMETER 
MILDa 
MODERATEb 
SEVEREc 
Abdominal 
discomfort or 
pain 
Pain or discomfort 
causing no or minimal 
interference with 
usual social & 
functional activities 
Pain or discomfort 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Pain or discomfort causing inability to 
perform usual social & functional 
activities 
Or 
Disabling pain or discomfort causing 
inability to perform basic self-care 
functions OR Hospitalization 
indicated 
Bloating or 
Distension 
Report only one 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing inability to 
perform usual social and functional 
activities 
Constipationd 
Occasional or 
intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or 
enema 
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or 
enemas 
Obstipation with manual evacuation 
indicated 
Or 
Life-threatening consequences 
(e.g., obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent episodes 
of unformed stools 
OR Increase of 
≤ three stools over 
baseline per 24-hour 
period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to 6 
stools over 
baseline per 24-
hour period 
Increase of ≥ 7 stools per 24-hour 
period OR IV fluid replacement 
indicated  
Or 
Life-threatening consequences 
(e.g., hypotensive shock) 
Nausea 
Transient (< 24 hours) 
or intermittent AND 
No or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea resulting in minimal 
oral intake for > 48 hours OR 
Rehydration indicated (e.g., IV fluids) 
Or 
Life-threatening consequences 
(e.g., hypotensive shock) 
a 
Based on DAIDS Grade 1 as described in the table. 
b 
Based on DAIDS Grade 2 as described in the table. 
c 
Based on DAIDS Grade 3 and 4 but does not include events resulting in death (DAIDS Grade 5). 
d 
DAIDS grading system does not include a description for Grade 1 constipation; therefore, Grade 1 constipation 
from CTCAE version 4.03 criteria is used. 
 


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Table 5: Categories of Severity for Specified GI AEs (Cont’d) 
 
PARAMETER 
MILDa 
MODERATEb 
SEVEREc 
Vomiting 
Transient or intermittent 
AND No or minimal 
interference with oral 
intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting resulting in orthostatic 
hypotension OR Aggressive rehydration 
indicated (e.g., IV fluids) 
Or 
Life-threatening consequences 
(e.g., hypovolemic shock) 
a 
Based on DAIDS Grade 1 as described in the table. 
b 
Based on DAIDS Grade 2 as described in the table. 
c 
Based on DAIDS Grade 3 and 4 but does not include events resulting in death (DAIDS Grade 5). 
d 
DAIDS grading system does not include a description for Grade 1 constipation; therefore, Grade 1 constipation 
from CTCAE version 4.03 criteria is used. 
 
 
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 drug, 
patiromer, 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 drug (the alternative 
etiology, 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 
procedures  


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For causality assessment purposes “reasonable possibility” is defined as 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, subject’s legally authorized 
representatives or elicited or noted by study staff, will be recorded in the subject’s medical record 
and on the appropriate AE CRF or eCRF page.  In addition, the SAE Report Form must be 
completed for each SAE. 
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 should be recorded using the words of the subject or subject’s legally authorized 
representatives (verbatim term) to describe the AE whenever possible.  However, if the verbatim 
term is vague or ambiguous (e.g., cramps), the study staff should try to obtain clarification by 
asking a follow-up question (e.g., what kind of cramps?) and record the words the subject used to 
clarify the event (e.g., menstrual cramps, calf muscle cramps).  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 should be recorded on 
the Concomitant Medication CRF and/or Surgical and Medical Procedure CRF as applicable. 
 
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 the same time as the initial 
report (within 24 hours) as additional information becomes available.  If the Investigator learns of 
any SAE that occurred after the Follow-up Period for which there is a reasonable possibility of 
relatedness to the investigational drug, that event 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 should 
be provided.  If an autopsy was not conducted, a Death Certificate should be provided if obtainable.  
Death should be reported as an outcome and not as an event. 


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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 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 and Pregnancy Reporting Guidelines. 
The SAE information must be entered onto the SAE CRF as soon as the EDC system becomes 
accessible, and before additional new information is entered.  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 center 
• 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 
Additional information must be provided when available, and any relevant records (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 
Brochure. 
Relypsa is responsible for notifying the applicable Health Authorities of SAEs in accordance with 
applicable laws and regulations. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
Relypsa, or designee, will be responsible for submitting expedited safety reports to the Regulatory 
Authorities, as required by the current local regulations.  Relypsa or designee will be responsible 
for reporting SUSARs to the Regulatory Authorities concerned and the IRBs/IECs as soon as 
possible but within a maximum of 15 calendar days of Relypsa’s first knowledge of the event.  All 


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SUSARs that are fatal or life-threatening will be reported to the Regulatory Authorities concerned 
and the IRBs/IECs within 7 calendar days of the first knowledge of the event; relevant follow-up 
information regarding fatal or life-threatening SUSARs will be subsequently communicated within 
an additional 8 days. 
 
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 
12 weeks. 
 
Study Management Committee  
The SMC includes Sponsor representatives and the lead study investigator.  The SMC will review 
data from the study on an ongoing basis.  Within pre-specified guidelines, the SMC will have the 
authority to make modifications to the study dose and titration plan between meetings of the 
independent DSMC.  For instance, the SMC could extend the number of subjects being treated in an 
age/dose cohort, even if no specific safety issues were encountered, to allow collection of additional 
data.  The prespecified guidelines will be detailed in the DSMC Charter and SMC Plan. 
 
Data and Safety Monitoring Committee 
Prior to initiation of the study, an independent DSMC will be established.  The DSMC will act in an 
advisory capacity to Relypsa to monitor the safety of patiromer in subjects who participate in the 
study.  In general, the DSMC responsibilities will include: 
• Protect the safety of the study participants in accordance with the study protocol and DSMC 
Charter 
• Review and evaluate all relevant information that may have an impact on the safety of the 
study participants or the ethics of the study 
• Assess risks and benefits to study participants 
• Make recommendations to Relypsa concerning continuation, termination or other 
modifications of the study 
• Review safety, dosing and pharmacodynamic data throughout the study 


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Based on this review, the DSMC will provide a recommendation to evaluate another starting dose 
in an age group or to evaluate the current dose in additional subjects in that age group.  Dose 
escalation and/or stopping criteria are pre-identified based on pre-specified safety criteria or on the 
lack of sufficient response as described below. 
The DSMC charter will provide additional details concerning the review and recommendation 
process. 
8.6.1 
Dose Escalation 
Evaluation of Starting Dose Levels: 
During the 14-day PD / Dose Finding Phase the Investigator will be allowed to up-titrate the 
patiromer dose according to a protocol-specified algorithm.  A description of the patiromer dose 
titration algorithm is provided in Section 5.2.1. 
After three subjects complete their 14-Day PD / Dose Finding Phase, PD, dosing and safety data 
will be provided to the DSMC.  The DSMC will evaluate these data, as well as the number of 
subjects requiring dose titration.  Based on its review, the DSMC will determine if the starting dose 
for subjects under review was acceptable for a recommended starting dose, in which case 
nine additional subjects (or fewer if more than three subjects were initially enrolled) in the same age 
group will be enrolled at the same starting dose.  If the DSMC determines that the starting dose 
and/or titration pattern did not result in an acceptable PD response, but the safety was acceptable, 
the DSMC will provide a recommendation to evaluate the next higher starting dose in the age 
group. 
Subject screening will pause periodically throughout the study to allow for preparation of data and 
DSMC review and provision of recommendations.  Any subjects who are in the Screening Period 
when the pause is announced may be enrolled provided they meet all eligibility criteria.  Details 
regarding DSMC review criteria are described in the DSMC charter. 
The DSMC will evaluate the following subject-level parameters in assessing a patiromer starting 
dose level: 
• Achieving a target serum potassium range of 3.8 – 5.0 mEq/L 
• Clinically relevant decrease in serum potassium 
• Number of dose up-titrations above the starting dose 
• Patient safety information 
The DSMC will consider the baseline and change in serum potassium level in determining if an 
observed decrease in serum potassium is clinically relevant for subjects that do not achieve the 
target potassium range.  In addition, the DSMC will consider the proportion of subjects that had 
up-titrations of patiromer to ensure a recommended starting dose is close to the effective dose (e.g., 
up-titrations required in all three subjects may suggest the starting dose was too low). 
Section 5.2 describes the planned starting doses in all age groups.  The DSMC will recommend the 
starting doses for the 6 – <12 year old age group upon evaluation of PD and safety data for the 


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entire 12 – <18 year old age group through Day 14.  Similarly, such an evaluation also will occur 
when the entire 6 – <12 year old group completes Day 14 in order to recommend starting doses for 
the 2 – <6 year old group. 
8.6.2 
Stopping Criteria 
Safety Criteria: 
The safety profile of patiromer in children > 2 years of age is expected to be similar to the safety 
profile of patiromer observed in adults (see Section 1.2). 
In addition to the AEs mentioned in  
Table 5 (see Section8.2.3) that will be evaluated by the Investigator based on the descriptions in  
Table 5 (see Section8.2.3), the DSMC will review all other AEs (including SAEs) using standard 
severity descriptors (mild, moderate and severe) included in the protocol.  The DSMC will also 
review all central laboratory data, including occurrences of serum magnesium and potassium below 
the lower limit of normal as provided in the laboratory reports (see Section 8.6). 
Deaths that are assessed as due to hypokalemia will be assessed as related to the investigational 
drug.  Deaths that are assessed as due to hyperkalemia will be assessed as due to failure of the 
investigational drug. 
Study or Dose Level Stopping Criteria: 
• If two subjects experience the same severe GI AEs that in the opinion of the Investigator(s) 
and SMC are related to patiromer, the DSMC will be consulted to review the available 
safety data and either provide approval to continue dosing for all subjects or make 
recommendations regarding modification of starting dose and/or titration algorithms within 
an age group and sequentially in younger age groups by dose category 
• If two subjects experience medically similar unexpected SAEs that in the opinion of the 
Investigator and SMC are related to patiromer the DSMC will be consulted to review the 
available safety data and either provide approval to continue dosing for all subjects or make 
recommendations regarding modification of starting dose and/or titration algorithms within 
an age group and sequentially in younger age groups by dose category 
• If one subject experiences an unexpected SAE that is confirmed to be related to patiromer, 
no additional subjects in the same age cohort will be started on or up-titrated to the dose 
level at which the SUSAR occurred 
For individual subjects experiencing any unexpected drug-related SAE or AE leading to 
withdrawal, the SMC will review the event and the DSMC will be notified at an ad hoc basis. 
8.6.3 
Frequency of DSMC Meetings 
14-Day PD / Dose Finding Phase 
The DSMC will meet after all three subjects in each age and dose cohort complete their 14-day PD / 
Dose Finding Phase to review their safety, dosing and pharmacodynamic data as described in 


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Section 8.6.  An additional DSMC meeting will occur after the dose expansion group (n = 9) 
provide sufficient information from their 14-day PD / Dose Finding Phase.  If a subject withdraws 
from the study within the 14-Day PD / Dose Finding Phase, the SMC will determine if sufficient 
information is provided for DSMC review.  If insufficient information is provided, the DSMC 
meeting may be delayed. 
Long-Term Treatment Phase 
The DSMC will meet at regular intervals to conduct ongoing review of PD, dosing and safety data 
throughout the Long-Term Treatment Phase to monitor safety and evaluate the effectiveness of 
patiromer dose titration algorithms.  The DSMC may make recommendations to modify the 
patiromer dose titration algorithms based upon their review.  Additional details are provided in the 
DSMC Charter. 
Ongoing DSMC Review 
During the study, ad-hoc DSMC meetings may be requested by either the DSMC or SMC to review 
relevant information that may have an impact on patiromer dosing or the safety of the participants 
in the study. 
9 
DATA ANALYSIS / STATISTICAL METHODS 
This section briefly describes the planned statistical methods for this study.  A 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. 
 
Randomization 
No randomization is applied in this study. 
 
General Considerations 
Tables and listings will present results by age cohort and starting dose and will include 
demography, subject disposition, baseline disease characteristics and other medical history, and 
concomitant medications.  Efficacy variables and analyses are discussed in Section 9.4.  Safety 
variables and analyses are discussed in Section 9.5. 
All analyses of potassium levels will use central laboratory values.  The potassium values obtained 
locally and used to manage subjects’ dose levels at study sites, may also be used in estimating 
missing central laboratory values. 
The efficacy and safety populations will include all subjects who have taken at least one dose of 
patiromer. For subjects who transition to maintenance hemodialysis or peritoneal dialysis during the 
study, their data after the start of dialysis will be excluded from summary statistics and will be 
included in listings only. 


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Sample Size Determination 
The sample size was selected in a manner that will maximize information for selected starting doses 
while minimizing exposure of children to ineffective starting doses.  The initial number of subjects 
per age/dose cohort will be 3.  When the DSMC agrees that a safe and effective starting dose (i.e., 
the recommended dose) has been identified for a particular age group, nine additional subjects in 
the age group will receive the selected starting dose.  This will yield a total of 12 subjects per age 
group.  The total sample size for all three age groups could be as low as 36, if the first dose is 
chosen as safe and effective, and up to 54 if all three dose levels are studied for each age group. 
With a sample size of 12 subjects in each age cohort at the identified efficacious and safe starting 
dose, and assuming a 100% probability of achieving potassium level within the normal range 
(3.8 – 5.0 mEq/L), the lower bound of the 95% exact confidence interval for achieving this success 
rate is 73%. 
 
Efficacy Analysis 
9.4.1 
Primary Efficacy Variable 
Changes from baseline to Day 14 in serum potassium levels will be summarized by starting dose 
and age group using descriptive statistics.  Baseline potassium will be the last central laboratory 
serum potassium value prior to first dose of patiromer.  Descriptive statistics include mean, standard 
deviation, and 95% confidence intervals. 
9.4.2 
Secondary Efficacy Variables 
• Proportion of subjects with serum K+ levels in the range of 3.8 – 5.0 mEq/L at Day 14 
(Initial PD / Dose Finding Phase) 
• Proportion of subjects with serum K+ levels in the range of 3.8 – 5.0 mEq/L by visit at any 
time through Month 6 (Long-Term Treatment Phase) 
Proportions and associated exact 95% confidence interval will be presented. 
9.4.3 
Subgroups of Interest 
The following baseline variables will be used to define subgroups of interest:  gender, race and age 
groups.  Additional subgroups of interest that may be examined will be included in the SAP. 
 
Safety Analysis 
Safety variables will include: 
• All AEs 
• SAEs 
• Clinical laboratory test results 
• Vital signs 


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• ECG 
• Deaths 
• Reasons for dosing interruption or discontinuation 
• Laboratory safety summaries will include: 
- 
Incidence of potassium (1) < 3.0 mEq/L, (2) < 3.5 mEq/L, (3) ≥ 5.1 mEq/L and (4) 
≥ 5.5 mEq/L (measured by central laboratory) 
- 
Incidence of serum magnesium (1) < 1.4 mg/dL (< 0.58 mmol/L), (2) < 1.2 mg/dL (< 0.49 
mmol/L) and (3) < 1.0 mg/dL (< 0.41 mmol/L) (central laboratory) 
- 
Calcium levels, phosphate levels, and serum fluoride levels will be assessed based on 
central laboratory analysis of samples collected at each of the scheduled study visits 
The analysis of treatment-emergent AEs will include all events with onset or worsening on or after 
the date of first dose of patiromer. 
Complete details of the safety analyses will be presented in the SAP. 
 
Additional Analyses 
In children ≥ 6 years old, if patiromer is administered onsite, patiromer palatability assessments 
(taste and overall liking) will be performed at Day 1, using a visual analog scale and will be 
summarized using descriptive statistics.  For children < 6 years old parental or authorized legal 
representative assessment of the subject’s acceptance of patiromer will be performed on Day 14 and 
will be summarized using descriptive statistics.  Additional analyses that may be examined will be 
included in the SAP. 
 
Handling of Missing Data 
Detailed procedures for managing missing data in all analyses will be provided in the SAP. 
10 DATA HANDLING AND RECORDKEEPING 
 
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. 


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Any change or correction to an eCRF will be tracked via an audit trail within the EDC system.  The 
audit trail will contain the original data value, new data value, date changed, the user who made the 
change, and the reason(s) for the change. 
CRFs should be completed in a timely manner to support the study timeline (i.e., the site should not 
wait for a monitoring visit before entering data into the eCRF). 
Data from the eCRFs and queries will be tracked and entered into a 21 CFR Part 11 compliant 
clinical database.  The database system will be a secured, password-protected system with full audit 
trail utility. 
Subject data will be reviewed via programmed quality checks and manually via data listings review 
by 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). 
 
Record Retention 
The Investigator must maintain adequate records for the study including completed CRFs, medical 
records, laboratory reports, signed ICFs, drug disposition records, adverse experience reports, 
information regarding subjects who discontinued, all correspondence with the IRB/IEC and 
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 


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documentation, regulatory and essential documents, CRFs, and drug accountability records.  If the 
FDA or other regulatory agencies should schedule an inspection, the Investigator should notify 
Relypsa immediately. 
The following steps will be taken to ensure that the trial is conducted by the investigational site in 
compliance with the study protocol, GCP, and other applicable regulatory requirements: 
• Investigator meeting and/or Investigator site initiation 
• Routine site monitoring 
• Documented protocol and GCP training 
• eCRF and query review against source documents 
• Collection of local laboratory normal ranges 
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. 
 
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 assent (if 
required), 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, the ICF and the assent (if required) 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. 


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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. 
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. 
 
Subject’s Information and Informed Consent/Assent 
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 legally authorized representative’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. 
Subjects under the age of 18 years (or 16 years, depending on the region) will provide written 
assent (if required), and his/her legally authorized representative (parent or legal representative) will 
provide written informed consent for such subjects. 
In compliance with GCP guidelines, all subjects and legally authorized representatives 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’s legally authorized representative and subject must agree to cooperate in all aspects 
of the study and must give informed written acknowledgment (signed ICF) and assent (if required) 
to the Investigator prior to participation in the study.  If the ICF and assent are revised during the 
study, active subject’s legally authorized representatives and subject (if required) 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 and assent (if required) was obtained for the 
updated/revised consent and assent (if required) form for continued participation in the trial.  The 
ICF should be revised whenever there are changes to procedures in the amended protocol associated 


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with procedures in the ICF or when new information becomes available that may affect the 
willingness of the subject to participate.  Every legally authorized representative 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 Health Information Portability and Accountability Act (HIPAA). 
No subject is to participate in study activities until informed consent and assent (if required) has 
been obtained.  Documentation of the informed consent and assent (if required) process and subject 
information discussion must appear in the subject’s medical record, and include a statement that 
informed consent and assent (if required) was obtained prior to participation in the study.  Signed 
acknowledgments (ICFs and assent forms) 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 and assent (if required) must be provided to Relypsa for regulatory 
purposes. 
13 RELYPSA DISCONTINUATION CRITERIA 
Discontinuation criteria for individual subjects and the study are included in the DSMC Charter.  In 
addition, a variety of reasons may lead either Relypsa or a regulatory agency to terminate the study 
early. 
14 PUBLICATION OF TRIAL RESULTS 
The Clinical Trial Agreement describes Relypsa’s publication terms. 
15 REFERENCES 
1. Ahmed J, Weisberg LS.  Hyperkalemia in Dialysis Patients.  Semin Dial, 14[5], 348-356, 
2001. 
2. Bushinsky DA, Williams GH, Pitt B, et al.  Patiromer Induces Rapid and Sustained 
Potassium Lowering in Patients With Chronic Kidney Disease and Hyperkalemia.  Kidney 
Int, 88[6], 1427-1433, 2015. 
3. Clinical Safety Data Management.  Definitions and Standards for Expedited Reporting, ICH 
Guideline E2A, Current Step 5 Version.  1995 Available from:  URL:  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC
500002749.pdf. 
4. Einhorn LM, Zhan M, Hsu VD, et al.  The Frequency of Hyperkalemia and Its Significance 
in Chronic Kidney Disease.  Arch Intern Med, 169[12], 1156-1162, 2009. 
5. Jain N, Kotla S, Little BB, et al.  Predictors of Hyperkalemia and Death in Patients With 
Cardiac and Renal Disease.  Am J Cardiol, 109[10], 1510-1513, 2012. 


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6. Lu XH, Su CY, Sun LH, Chen W, Wang T.  Implementing Continuous Quality 
Improvement Process in Potassium Management in Peritoneal Dialysis Patients.  J Ren 
Nutr, 19[6], 469-474, 2009. 
7. Miao Y, Dobre D, Lambers Heerspink HJ, et al.  Increased Serum Potassium Affects Renal 
Outcomes:  a Post Hoc Analysis of the Reduction of Endpoints in NIDDM With the 
Angiotensin II Antagonist Losartan (RENAAL) Trial.  Diabetologia, 54[1], 44-50, 2011. 
8. Querfeld U, Anarat A, Bayazit AK, et al.  The Cardiovascular Comorbidity in Children 
With Chronic Kidney Disease (4C) Study:  Objectives, Design, and Methodology.  Clin J 
Am Soc Nephrol, 5[9], 1642-1648, 2010. 
9. Relypsa Inc.  Investigators Brochure.  Investigational Drug:  Patiromer for Oral Suspension.  
Version Number 9, 2016.  Relypsa, Inc. 
10. Rodriguez-Soriano J.  Potassium Homeostasis and Its Disturbances in Children.  Pediatr 
Nephrol, 9[3], 364-374, 1995. 
11. Schaefer TJ, Wolford RW.  Disorders of Potassium.  Emerg Med Clin North Am, 23[3], 
723-47, viii, 2005. 
12. Schwartz GJ, Work DF.  Measurement and Estimation of GFR in Children and Adolescents.  
Clinical Journal of the American Society of Nephrology, 4[11], 1832-1843, 2009. 
13. The ESCAPE Trial Group.  Strict Blood-Pressure Control and Progression of Renal Failure 
in Children.  N Engl J Med 3(1):1639-1650, 2009. 
14. Tzamaloukas AH, Avasthi PS.  Temporal Profile of Serum Potassium Concentration in 
Nondiabetic and Diabetic Outpatients on Chronic Dialysis.  Am J Nephrol, 7[2], 101-109, 
1987. 
15. U.S.Department of Health and Human Services, National Institutes of Health, National 
Heart LaBI.  The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents.  2005.  Report No.:  05-5267. 
16. U.S.Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, and Division of AIDS (DAIDS).  Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0.  11-2014 [Accessed on:  1-7-2016]; Available from:  URL:  http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GRADING_TABLE_v2_NO
V2014.pdf. 
17. Veltassa PI.  Veltassa (Patiromer) [Package Insert], Revised May-2016.  Relypsa, Inc., 
2016. 
18. Veltassa SmPC. Veltassa (Patiromer) [Summary of Product Characteristics], Revised Aug-
2017. Vifor Fresenius Medical Care Renal Pharma UK Ltd, 2017. 


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19. Wong H, Mylrea K, Feber J, Drukker A, Filler G.  Prevalence of Complications in Children 
With Chronic Kidney Disease According to KDOQI.  Kidney Int, 70[3], 585-590, 2006. 


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Appendix A: Schedule of Events (Screening and Pharmacodynamic / Dose Finding Phase) 
Study 
Activity 
Phase 
Screening 
Pharmacodynamic / Dose 
Finding Phase 
ETb 
MSVc 
Scenario 
Subject With Standard 
of Care Potassium 
Subject Without Standard of 
Care Potassium 
Visit 
SV1/D1 
SV1 
SV2/D1 
(2 to 7 days after SV1) 
D3a  
(± 1d) 
D7  
(± 3d) 
D14  
(± 3d) 
Informed Consent 
X 
X 
 
 
 
 
 
 
I/E Criteria 
X 
 
X 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
Medical History 
X 
Xd 
 
 
 
 
 
 
Physical Examination 
X 
Xd 
 
 
 
X 
X 
 
Body Weight 
X 
 
X 
 
 
X 
X 
 
Height 
X 
Xd 
 
 
 
X 
X 
 
Vital Signs (Resting Heart 
Rate and Sitting BP) 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
Xd 
 
Xm 
Xm 
Xm 
X 
Xl 
Potassium 
L&Ce 
L 
L&Ce 
L&C 
L&C 
L&C 
L&C 
L&C 
Chemistryf 
L&Ce 
 
L&Ce 
 
C 
C 
C 
 
Hematology (CBC) 
L&Ce 
 
L&Ce 
 
 
C 
C 
 
Plasma Parathyroid 
hormone 
Ce 
 
Ce 
 
 
C 
C 
 
Serum Fluoride 
Ce 
 
Ce 
 
 
C 
C 
 
Urinalysisg 
Ce 
 
Ce 
 
 
C 
C 
 
Pregnancy Testh 
L&Ce 
 
L&Ce 
 
 
 
L&C 
 
IWRS Entry 
X 
X 
X 
X 
X 
X 
X 
X 
Patiromer Administrationi 
Xe 
 
Xe 
Xj 
X 
X 
 
X 
Patiromer Palatability and 
Parental Assessmentk 
Xe 
 
Xe 
 
 
X 
 
 
 


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Appendix A: Schedule of Events (Screening and Pharmacodynamic / Dose Finding Phase) (Cont’d)  
 
Study 
Activity 
Phase 
Screening 
Pharmacodynamic / Dose 
Finding Phase 
ETb 
MSVc 
Scenario 
Subject With Standard 
of Care Potassium 
Subject Without Standard of 
Care Potassium 
Visit 
SV1/D1 
SV1 
SV2/D1 
(2 to 7 days after SV1) 
D3a  
(± 1d) 
D7  
(± 3d) 
D14  
(± 3d) 
Dosing Diary Dispensation  
X 
 
X 
 
 
 
 
 
Dosing Diary Review by 
Investigator/Designee 
 
 
 
X 
X 
X 
 
 
Dosing Diary Collection 
 
 
 
 
 
X 
 
 
Drug Accountability & 
Compliance 
Xe 
 
Xe 
X 
X 
X 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds Assessment 
X 
X 
X 
X 
X 
X 
X 
X 


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AE = Adverse Event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; C= Central; D = Day; d = day/days; Laboratory; CBC = 
Complete Blood Count; Con Meds = concomitant medications; E = exclusion; ET = Early Termination; ECG = Electrocardiogram; eGFR = Estimated 
Glomerular Filtration Rate; I = inclusion; IWRS = Interactive Web Response System; L= Local Laboratory; SV1= Screening Visit 1; SV2 = Screening 
Visit 2 (2 to 7 days after SV1); W = Week 
a 
Note:  At the discretion of the Investigator, the Day 3 Visit is optional for subjects whose last screening K+ is < 5.5 mEq/L; for subjects whose last 
screening K+ is ≥ 5.5 mEq/L, the Day 3 Visit is mandatory (see Section 6.2.2).. 
b 
After ET subjects should be encouraged to complete the Follow-up Period Visits (see Section 6.4). 
c 
Or any unscheduled visit. 
d 
Assessment may be performed either on SV1 or SV2. 
e 
Central laboratory measurement or event will not be performed unless subject meets study entry criteria.  
f 
For screening, local hematology (CBC including WBC, RBC, hemoglobin, hematocrit, and platelet count) will be performed.  Per Investigator’s 
decision, central laboratory assessment of calcium and/or phosphate levels may be tested more frequently for subjects that have one dose of phosphate 
binder replaced by patiromer.  
g 
Not required for anuric subjects; see Section  7.2 for details.  
h 
Female subjects of child bearing potential only.  For anuric subjects, a serum pregnancy test is required; please Section 7.2 for details.   
i 
If patiromer dose requires titration, then initiation of the titrated patiromer dose should occur at the next planned administration (see Section 5.2.1 for 
details) 
j 
Up-titration of patiromer can occur only if the K+ level is ≥ 5.5 mEq/L and greater than the most recent locally obtained screening potassium value. 
k 
Palatability of patiromer will be evaluated in children ≥ 6 years of age when the initial dose is administered at the study site on Day 1 and parental or 
legal authorized representative response on the subject’s (< 6 years of age) acceptance of patiromer will be assessed on Day 14 (see Section 7.6 for 
further details). 
l 
ECG at the Mandatory Safety Visit required only if the local potassium is >6.0 mEq/L at the current or prior visit (see Section 6.5.1) 
m 
ECG is only required if the local potassium is > 6.0 mEq/L 


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Appendix B: Schedule of Events (Long-Term Treatment Phase) 
Study 
Activity 
Study Period 
Long-Term Treatment Phase 
F1 
7d ± 3d 
F2a 
14d ± 3d 
ET 
MSVb 
Visit 
W3i 
± 3d 
W5 
± 7d 
W7 
± 7d 
W10 i 
± 7d 
W14 
± 7d 
W18 
± 7d 
W22 i 
± 7d 
W26 
± 7d 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationk 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Body Weightk 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Heightk 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Vital Signs (Resting Heart 
Rate and Sitting BP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
12-Lead ECGc 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
 
X 
Xj 
Potassium 
L&C 
L&C 
L&C 
L&C 
L&C 
L&C 
L&C 
L&C 
L&C 
 
L&C 
L&C 
Chemistrye 
 
 
C 
 
C 
 
 
C 
C 
 
C 
 
Hematology (CBC) 
 
 
C 
 
C 
 
 
C 
 
 
C 
 
Plasma Parathyroid 
hormone 
 
 
 
 
 
 
 
C 
 
 
C 
 
Serum Fluoride 
 
 
C 
 
C 
 
 
C 
 
 
C 
 
Urinalysisf 
 
 
 
 
 
 
 
C 
 
 
C 
 
Pregnancy Testg 
 
 
 
 
 
 
 
L&C 
 
 
L&C 
 
IWRS Entry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Appendix B: Schedule of Events (Long-Term Treatment Phase) (Cont’d) 
  
Study 
Activity 
Study Period 
Long-Term Treatment Phase 
F1 
7d ± 3d 
F2a 
14d ± 3d 
ET 
MSVb 
Visit 
W3i 
± 3d 
W5 
± 7d 
W7 
± 7d 
W10i 
± 7d 
W14 
± 7d 
W18 
± 7d 
W22i 
± 7d 
W26 
± 7d 
Patiromer 
Administrationh 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Drug Accountability & 
Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = Adverse Event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; d = days; C= Central Laboratory; CBC = Complete Blood 
Count; Con Meds = concomitant medications; E = exclusion; ET = Early Termination; ECG = Electrocardiogram; eGFR = Estimated Glomerular 
Filtration Rate; F1 = Follow-up Visit 1 at 7 Days (± 3 days) after the last dose of patiromer; F2 = Follow-up Visit 2 at 14 Days after the last dose of 
patiromer; I = inclusion; IWRS = Interactive Web Response System L= Local Laboratory; M = months; MSV = Mandatory Safety Visit; W = week 
a 
The Phone Call Follow-up may be converted into an Onsite Visit if potassium levels from F1 is of concern by the Investigator and require a re-test.  
If subjects are requested to return for an onsite visit, the same activities will be performed as those in (F1) 
b 
Or any unscheduled visit 
c 
When K+ is > 6.0 mEq/L during the Long-Term Treatment Phase of the study, additional ECG evaluations will be performed. 
d 
Per Investigator’s decision, central laboratory assessment of calcium and/or phosphate levels may be tested more frequently for subjects that have one 
dose of phosphate binder replaced by patiromer. 
e 
Not required for anuric subjects, see Section 7.2 for details.   
f 
Female subjects of child bearing potential only. For anuric subjects, a serum pregnancy test is required; see Section 7.2 for details.  
g 
If patiromer dose requires titration, then initiation of the titrated patiromer dose should occur at the next planned administration (see Section 5.2.1 for 
details). 
h 
The last dose of patiromer will be taken the day before the Week 26 Visit. 
i 
Week 3, Week 10 and Week 22 visits may be skipped under specific conditions (See Section 3.2.3) 
j 
ECG at the Mandatory Safety Visit required only if the local potassium is >6.0 mEq/L at the current or prior visit (see Section 6.5.1) 
k 
Study activity may be omitted for Home Care visit (see Section 6.2.5) 
l 
ECG is only required if the local potassium is > 6.0 mEq/L 
 


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Appendix C: List of Central Laboratory Assays 
Serum chemistry panel: 
Hematology (CBC): 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Bicarbonate  
Blood Urea Nitrogen (BUN) 
Calcium 
Chloride 
Creatinine (with eGFR by Bedside 
Schwartz formula) 
Glucose 
Inorganic phosphate 
Magnesium 
Potassium (primary endpoint) 
Sodium 
Total bilirubin 
Total protein 
White blood cell count (WBC) 
Red blood cell count (RBC) 
Hemoglobin 
Hematocrit (Packed Cell Volume) 
Mean cell volume (MCV) 
Mean cell hemoglobin (MCH) 
Mean cell hemoglobin concentration (MCHC) 
Platelet count 
Differential WBC 
Urinalysisa: 
Specific gravity 
pH 
Protein 
Glucose 
Ketones 
Blood 
Urobilinogen 
Leukocyte esterase 
Nitrites 
Bilirubin 
Other: 
Plasma parathyroid hormone 
Serum Fluoride 
Urine and Serum Pregnancy test (only for females of 
child-bearing potential) 
a 
Urinalysis is not required for anuric subjects, see section 7.2.  
 


 
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Appendix D: Screening Schema 
 

SAP_001.pdf: 
RLY5016–206p 
Statistical Analysis Plan 
 
©Vifor Pharma 
Page 1 of 23 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
Investigational Drug: 
Patiromer for Oral Suspension 
 
 
 
 
Treatment: 
Chronic Kidney Disease and Hyperkalemia 
 
 
Study Phase: 
Phase 2 
Study Title: 
Open-Label, Multiple Dose Study to Evaluate the 
Pharmacodynamic Effects, Safety, and Tolerability of 
Patiromer for Oral Suspension in Children and 
Adolescents 2 to < 18 Years of Age with Chronic Kidney 
Disease and Hyperkalemia 
 
 
Protocol Number: 
RLY5016-206p 
Protocol Version: 
4.0 
Protocol Version date: 
20 May 2019 
Sponsor: 
Relypsa, Inc. 
100 Cardinal Way 
Redwood City, CA 94063, USA 
 
 
 
 
SAP Version: 
1.0 
SAP Version Date: 
17 September 2020 
SAP Author: 
 
Director, Biostatistics 
Relypsa, a Vifor Pharma Company 
 
 
 


 
RLY5016–206p 
Statistical Analysis Plan 
 
©Vifor Pharma 
Page 2 of 23 
 
GLOSSARY OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ARB 
Angiotensin II Receptor Blocker 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BID 
Twice Daily 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
C 
Central Laboratory 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
Cmax 
Maximum Concentration 
Con Meds 
Concomitant Medications 
COVID-19 
Coronavirus Disease 2019  
CRF 
Case Report Form 
D 
Day 
DAIDS 
Division of AIDS 
DSMC 
Data and Safety Monitoring Committee 
E 
Exclusion 
EC 
Ethics Committee 
ECG 
Electrocardiograms 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ET 
Early Termination 
EUCTD 
European Union Clinical Trials Directive 2001/20/EC 
F1 
Follow-up Visit 1 
F2 
Follow-up Phone Call 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HF 
Heart Failure 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ID 
Identification 
IMP 
Investigational Medicinal Product 


 
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IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
K+ 
Potassium 
KDIGO 
Kidney Disease Improving Global Outcomes 
M 
Months 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
NSAID 
Non-Steroidal Anti-Inflammatory Drugs 
PD 
Pharmacodynamic 
QD 
Once Daily 
RAASi 
Renin-Angiotensin Aldosterone System Inhibitors 
RBC 
Red Blood Cell Count 
S 
Screening 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
TID 
Three Times Daily 
US 
United States 
W 
Week 
WBC 
White Blood Cell Count 
 
 


 
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TABLE OF CONTENTS 
1 
INTRODUCTION ....................................................................................................................................... 6 
2 
STUDY OBJECTIVES AND STUDY DESIGN .................................................................................................. 6 
2.1 
STUDY OBJECTIVES...................................................................................................................................... 6 
2.1.1 
Primary Efficacy Objectives ............................................................................................................... 6 
2.1.2 
Safety Objectives ............................................................................................................................... 6 
2.2 
STUDY DESIGN ........................................................................................................................................... 6 
2.3 
SAMPLE SIZE DETERMINATION ...................................................................................................................... 7 
3 
INTERIM ANALYSES, FINAL ANALYSIS AND UNBLINDING ......................................................................... 8 
4 
ANALYSIS SETS ......................................................................................................................................... 8 
4.1 
EFFICACY POPULATION ................................................................................................................................ 8 
4.2 
SAFETY POPULATION ................................................................................................................................... 8 
4.3 
PROTOCOL DEVIATIONS ............................................................................................................................... 8 
5 
ENDPOINTS AND VISIT WINDOWS ........................................................................................................... 9 
5.1 
EFFICACY ENDPOINTS .................................................................................................................................. 9 
5.1.1 
Primary Efficacy Endpoint ................................................................................................................. 9 
5.1.2 
Secondary Efficacy Endpoints ............................................................................................................ 9 
5.1.3 
Subgroups .......................................................................................................................................... 9 
5.2 
SAFETY ENDPOINTS ..................................................................................................................................... 9 
5.3 
PALATABILITY ASSESSMENTS ....................................................................................................................... 10 
5.4 
STUDY DAY AND VISIT WINDOWS ................................................................................................................ 10 
6 
HANDLING OF DROPOUTS AND MISSING DATA ..................................................................................... 11 
6.1 
MISSING INFORMATION FOR ADVERSE EVENT ................................................................................................ 11 
6.2 
MISSING DATES OR PARTIALLY MISSING DATES .............................................................................................. 11 
7 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................................................... 11 
7.1 
GENERAL CONSIDERATIONS AND STATISTICAL METHODS .................................................................................. 11 
7.2 
SUBJECT DISPOSITION ................................................................................................................................ 12 
7.3 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .......................................................................................... 12 
7.4 
MEDICAL HISTORY .................................................................................................................................... 12 
7.5 
PRIOR AND CONCOMITANT MEDICATIONS ..................................................................................................... 12 
7.6 
EXPOSURE TO STUDY DRUG ........................................................................................................................ 13 
7.7 
TREATMENT COMPLIANCE .......................................................................................................................... 13 
7.8 
PROTOCOL DEVIATIONS ............................................................................................................................. 13 
7.9 
EFFICACY ANALYSES .................................................................................................................................. 13 
7.9.1 
Primary Efficacy Analysis ................................................................................................................. 13 
7.9.2 
Secondary Efficacy Analysis ............................................................................................................. 13 
7.9.3 
Additional Subgroup Analyses ......................................................................................................... 13 
7.10 
SAFETY ANALYSES ..................................................................................................................................... 14 
7.10.1 
Adverse Events ............................................................................................................................ 14 
7.10.2 
Death .......................................................................................................................................... 14 
7.10.3 
Clinical Laboratory Tests ............................................................................................................. 15 


 
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7.10.4 
Vital Signs.................................................................................................................................... 15 
7.10.5 
Physical Examination .................................................................................................................. 15 
7.10.6 
12-lead Electrocardiogram (ECG) ................................................................................................ 16 
7.10.7 
Pregnancy Test ............................................................................................................................ 16 
7.11 
PALATABILITY ASSESSMENTS ....................................................................................................................... 16 
APPENDIX C: 
MISSING DATA IMPUTATION ................................................................................... 22 
1 
IMPUTATION OF MISSING/PARTIALLY MISSING ADVERSE EVENT DATES ................................................................... 22 
1.1 
INCOMPLETE START DATE .......................................................................................................................... 22 
1.2 
INCOMPLETE STOP DATE ............................................................................................................................ 22 


 
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1 
INTRODUCTION 
This document details the planned analyses for Study RLY5016-206p (EMERALD). 
Results obtained from the analyses outlined in this document will provide the basis of the 
study Clinical Study Report (CSR).  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 
2.1.1 
Primary Efficacy Objectives 
To assess change from baseline in serum potassium levels to Day 14 following administration 
of different doses of patiromer administered once daily in children 2 – < 18 years of age with 
chronic kidney disease (CKD) and hyperkalemia. 
2.1.2 
Safety Objectives 
To assess the safety and tolerability of patiromer in children 2 – < 18 years of age with CKD 
and hyperkalemia. 
2.2 
Study Design 
Up to 54 subjects, 2 – < 18 years of age with CKD and hyperkalemia will be enrolled in this 
open-label, multiple-dose, Phase 2 study.  Subjects must be < 18 years of age from the time of 
study consent until anticipated completion of Day 14 of the study. 
The study will include two treatment phases:  PD / Dose Finding Phase consisting of the 
initial 14-day dose finding period followed by an up to 5.5-month Long-Term Treatment 
Phase for a total study participation duration for individual subjects of up to 6.5 months (see 
Figure 1).  The overall design of the study is presented schematically below. 
The study periods comprised of the following (Figure 1): 
• Screening Period (up to 7 Days)  
• PD / Dose Finding Phase (14 Days) 
• Long-Term Treatment Phase (5.5 Months) 
• Follow-up Period (14 days after discontinuation of treatment, whether subject completes 
treatment or discontinues early) 


 
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Figure 1: 
Study Schema 
 
2.3 
Sample Size Determination 
The sample size was selected in a manner that will maximize information for selected starting 
doses while minimizing exposure of children to ineffective starting doses.  The initial number 
of subjects per age/dose cohort will be 3.  When the DSMC agrees that a safe and effective 
starting dose (i.e., the recommended dose) has been identified for a particular age group, nine 
additional subjects in the age group will receive the selected starting dose.  This will yield a 
total of 12 subjects per age group.  The total sample size for all three age groups could be as 
low as 36, if the first dose is chosen as safe and effective, and up to 54 if all three dose levels 
are studied for each age group. 
With a sample size of 12 subjects in each age cohort at the identified efficacious and safe 
starting dose, and assuming a 100% probability of achieving potassium level within the 
normal range (3.8 – 5.0 mEq/L), the lower bound of the 95% exact confidence interval for 
achieving this success rate is 73%. 
 
 


 
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3 
INTERIM ANALYSES, FINAL ANALYSIS AND UNBLINDING 
This is an open-label multiple dose study to evaluate the pharmacodynamic (PD) effects, 
safety, and tolerability of patiromer. Subjects and sites study staff will not be blinded to 
treatment assignment. The data will be periodically evaluated by an independent external data 
safety monitoring committee (DSMC) and by an internal Relypsa safety committee (SMC).  
The schedule of the data reviews is detailed in the protocol and in the DSMC charter.    
No efficacy interim analysis is planned for this study.  The final analysis will be performed 
after database lock. 
4 
ANALYSIS SETS 
4.1 
Efficacy Population 
The efficacy population will include all subjects who have taken at least one dose of 
patiromer. 
4.2 
Safety Population  
The safety population will include all subjects who have taken at least one dose of patiromer. 
The safety population and efficacy population are same in this study, so all analyses will be 
displayed with one population, i.e. safety population. 
4.3 
Protocol Deviations 
All protocol deviations will be recorded in the protocol deviation log.  Prior to database lock, 
all protocol deviations will be compiled.  
The following deviations are considered, a priori, to be important protocol deviations: 
• Violations of initial informed consent 
• Enrolled in violation of the entry criteria 
• 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 
 


 
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5 
ENDPOINTS AND VISIT WINDOWS  
5.1 
Efficacy Endpoints 
5.1.1 
Primary Efficacy Endpoint 
Changes from baseline to Day 14 in serum potassium levels will be summarized by starting 
dose and age group using descriptive statistics.  Baseline potassium will be the last non-
missing central laboratory serum potassium value prior to first dose of patiromer.  Descriptive 
statistics include mean, standard deviation, and 95% confidence intervals. 
5.1.2 
Secondary Efficacy Endpoints 
• Proportion of subjects with serum K+ levels in the range of 3.8 – 5.0 mEq/L at Day 14 
(Initial PD / Dose Finding Phase) 
• Proportion of subjects with serum K+ levels in the range of 3.8 – 5.0 mEq/L by visit at any 
time through Month 6 (Long-Term Treatment Phase) 
Proportions and associated exact 95% confidence interval will be presented. 
5.1.3 
Subgroups 
The primary and secondary efficacy analyses may be performed for the following subgroups: 
• Sex (male versus female) 
• Age (12 – <18 versus 6 – <12 versus 2 – <6 years) 
• Race (white versus non-white) 
5.2 
Safety Endpoints 
Safety variables will include: 
• All treatment-emergent adverse events (TEAEs) 
• Reasons for dosing interruption or discontinuation 
• Serious adverse events (SAEs) 
• Clinical laboratory test results 
• Vital signs 
• ECG 
• Deaths 
• Laboratory safety summaries will include: 


 
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- 
Incidence of potassium (1) < 3.0 mEq/L, (2) < 3.5 mEq/L, (3) ≥ 5.1 mEq/L and (4) 
≥ 5.5 mEq/L (measured by central laboratory) 
- 
Incidence of serum magnesium (1) < 1.4 mg/dL (< 0.58 mmol/L), (2) < 1.2 mg/dL 
(< 0.49 mmol/L) and (3) < 1.0 mg/dL (< 0.41 mmol/L) (central laboratory) 
- 
Calcium levels, phosphate levels, and serum fluoride levels will be assessed based on 
central laboratory analysis of samples collected at each of the scheduled study visits 
5.3 
Palatability Assessments 
In children ≥ 6 years old, if patiromer is administered onsite, patiromer palatability 
assessments (taste and overall liking) will be performed on Day 1, using a 5-point facial 
hedonic scale. For children < 6 years old, parental or authorized legal representative 
assessment of the subject’s acceptance of patiromer on a 5-point agreement/disagreement 
scale will be performed on Day 14.    
5.4 
Study Day and Visit Windows 
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 first dosing 
day) is defined as Day -1.  
• If a date is on or after the Reference Date, Study Day is defined as [date] - [date of the 
first dose] +1; hence, the Study Day for the day after first dose is defined as Day 2.  
The protocol specified windows for scheduled visits are included in the Schedule of Events 
(Appendix A and Appendix B).   
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.   
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.  
Modifications to visit schedules may be required due to Coronavirus Disease 2019 (COVID-
19). Depending on the scope of changes needed, additional analyses may be undertaken in 
order to clarify and assess the impact of the modifications to visit schedules. Descriptions of 


 
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the additional analyses to be done in relation to COVID-19, if any, will be provided in the 
SAP prior to database lock. 
6 
HANDLING OF DROPOUTS AND MISSING DATA 
6.1 
Missing Information for Adverse Event 
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 will be assigned to possible 
relationship (i.e. related). 
6.2 
Missing Dates or Partially Missing Dates 
Missing or partially missing dates will be imputed for concomitant medications, procedures 
and adverse events (AEs).  Specific rules for handling missing or partially missing dates are 
provided in the Appendix C.  
7 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
7.1 
General Considerations and Statistical Methods 
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. 
When mean change from baseline is assessed, a subject will be included in the analysis if 
he/she has a baseline and a post-baseline measurement. 
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. 
All table results, unless otherwise specified, will be displayed by age cohort, starting dose, 
and overall. For subjects who transition to maintenance hemodialysis or peritoneal dialysis 
during the study, their data after the start of dialysis will be excluded from summary tables 
and will be included in listings only. 


 
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7.2 
Subject Disposition  
The number of subjects screened, subjects enrolled, subjects who received at least one dose of 
study drug, subjects who completed the Day 14 visit, subjects who completed the Week-26 
visit, subjects who withdrew from the study before the Week-26, the primary reasons for early 
study termination will be summarized.  
Listings of data supporting subject disposition and the reason for screening failures will be 
provided. 
7.3 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the ITT and safety 
population. 
The summary of demographic information will include age, gender, race and ethnicity.  The 
summary of patient characteristics at baseline will include, weight, height, and BMI.  Baseline 
medical history will include chronic kidney disease and its etiology, whether patient was on 
peritoneal dialysis, whether patient ever received a renal transplant, whether patient had 
diabetes mellitus and its type, , heart failure and its type, ejection fraction percentage, baseline 
serum potassium and eGFR. 
Listings of demographics and baseline characteristics will also be provided. 
7.4 
Medical History 
General medical history will be coded in accordance with the latest MedDRA version and will 
be summarized by body system (or procedure). 
A listing of general medical history will be provided. 
7.5 
Prior and Concomitant Medications 
All prior and concomitant medications will be coded using the latest version of the World 
Health Organization Drug (WHO Drug) dictionary. 
Prior medications are defined as medications with start date before the date of first dose of 
study drug.  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 drug and end date on 
or after the date of first dose of study drug, or no end date.  
Prior and concomitant medications will be separately summarized by ATC2 class and 
preferred drug name.  Additional summaries may be provided for concomitant medications of 
interest.   
Listings of all prior and concomitant medications will be provided. 


 
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7.6 
Exposure to Study Drug  
The actual prescribed dose of patiromer by cohort, starting dose, and study day will be 
summarized. 
A listing for drug exposure will be provided. 
7.7 
Treatment Compliance 
Treatment compliance for each subject will be estimated and listed separately for the 14-day 
PD/dose finding period and the long-term treatment phase. 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 for the subject, multiplied by 100. 
7.8 
Protocol Deviations 
The number and percentage of patients with important protocol deviations by category of 
deviation will be summarized.  A listing of important protocol deviations will be provided. 
7.9 
Efficacy Analyses 
7.9.1 
Primary Efficacy Analysis 
Changes from baseline to Day 14 in serum potassium levels from a central laboratory will be 
summarized using descriptive statistics.  Baseline potassium will be the last non-missing 
central serum potassium value prior to first dose of patiromer.  Descriptive statistics include 
mean, standard deviation, and 95% confidence intervals. 
7.9.2 
Secondary Efficacy Analysis 
Number and proportion of subjects with central serum potassium levels in the range of 
3.8 – 5.0 mEq/L at Day 14 (Initial Pharmacodynamic / Dose Finding Phase) and proportion of 
subjects with central serum potassium levels in the range of 3.8 – 5.0 mEq/L by visit through 
Month 6 (Long-Term Treatment Phase) will be presented. 
Proportions will be provided along with the 95% confidence intervals, obtained using Exact 
(Clopper-Pearson) method. 
Central serum potassium and mean changes in serum potassium at each scheduled visit will 
be presented graphically. Central and local laboratory potassium values from serum samples 
will be included in listings. 
7.9.3 
Additional Subgroup Analyses 
The primary and secondary analyses may be performed for the following subgroups: 
• Sex (male versus female) 
• Age (12 – <18 versus 6 – <12 versus 2 – <6 years) 


 
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• Race (white versus non-white) 
 
7.10 
Safety Analyses  
7.10.1 
Adverse Events 
AEs and SAEs will be coded to system organ class (SOC) and preferred term (PT) with the 
latest available MedDRA.  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. 
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 for the 
followings: 
• Overall summary of number of subjects with: any TEAE; any TEAE related to study drug; 
any SAE; any SAE related to study drug; any TEAE leading to study drug dose increase, 
dose reduction, dose interruption; any TEAE leading to study drug discontinuation  
• Summary of all TEAEs by SOC, PT and severity 
• Summary of TEAEs related to study drug by SOC and PT 
• Summaries of TEAEs leading to study drug dose increase, dose reduction, and 
interruptions by SOC and PT  
• Summary of TEAEs leading to early study drug discontinuation by SOC and PT 
• Summary of SAEs by SOC, PT, and severity 
• Summary of SAEs related to study drug by SOC and PT 
• Summaries 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 study drug, onset and end date, action taken, and outcome of event 
will be provided.  A listing of SAEs and TEAEs leading to any study drug modification or 
discontinuation (increase, reduction, interruption or discontinuation) will also be provided.  In 
addition, listings will be provided for events of special interest. 
7.10.2 
Death 
If there are any deaths, a listing of deaths will be provided. 


 
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7.10.3 
Clinical Laboratory Tests 
For central laboratory test summaries by visit, the central laboratory measurements at 
scheduled visits will be used if available. The visit name 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.  
All serum chemistry, hematology, serum fluoride, and plasma parathyroid hormone level 
results and change from baseline will be summarized with descriptive statistics at each 
scheduled visit. 
The incidence of laboratory test results in ranges of interest will be summarized. 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 dose finding period and baseline to end of 
treatment will be presented for serum calcium, magnesium and phosphate.  
Listings will be provided for all laboratory parameters. Listings will include test results at 
both scheduled and unscheduled visits. 
7.10.4 
Vital Signs  
Vital Signs and changes from baseline, including resting heart rate, diastolic and systolic 
blood pressure (BP), weight, and height, will be summarized using descriptive statistics at 
each scheduled visit for vital signs. A listing for vital signs, weight, and height will be 
provided. 
7.10.5 
Physical Examination 
Abnormalities found in physical examinations will be listed at each scheduled visit for 
physical examination.   


 
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7.10.6 
12-lead Electrocardiogram (ECG) 
Number and percentage of subjects with normal/abnormal and clinically significant abnormal 
ECG findings will be summarized at each scheduled visit for 12-lead ECG. 
A listing for 12-lead ECG will be provided. 
7.10.7 
Pregnancy Test 
A listing of all pregnancy tests results will be provided. 
7.11 
Palatability Assessments 
In children ≥ 6 years old, patiromer palatability assessments (taste and overall liking) will be 
summarized using descriptive statistics. A 5-point scale for taste and overall liking includes 
dislike very much, dislike somewhat, neigher like nor dislike, like somewhat, and like very 
much. 
For children < 6 years old, assessment of the subject’s parental acceptance of patiromer will 
be summarized using descriptive statistics.  A 5-point agreement/disagreement scale to a 
statement of the subject’s (< 6 years of age) acceptance of patiromer includes strongly 
disagree, somewhat disagree, neither agree nor disagree, somewhat agree, and strongly agree. 
 
 


 
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Appendix A: Schedule of Events (Screening and Pharmacodynamic / Dose Finding 
Phase) 
Study 
Activit
y 
Phase 
Screening 
Pharmacodynamic / 
Dose Finding Phase 
ET
b 
MS
Vc 
Scenari
o 
Subject With 
Standard of 
Care 
Potassium 
Subject Without 
Standard of Care 
Potassium 
Visit 
SV1/D1 
SV
1 
SV2/D1 
(2 to 7 days 
after SV1) 
D3a  
(± 1d
) 
D7  
(± 3d
) 
D14  
(± 3
d) 
Informed Consent 
X 
X 
 
 
 
 
 
 
I/E Criteria 
X 
 
X 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
Medical History 
X 
Xd 
 
 
 
 
 
 
Physical 
Examination 
X 
Xd 
 
 
 
X 
X 
 
Body Weight 
X 
 
X 
 
 
X 
X 
 
Height 
X 
Xd 
 
 
 
X 
X 
 
Vital Signs 
(Resting Heart 
Rate and Sitting 
BP) 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
Xd 
 
Xm 
Xm 
Xm 
X 
Xl 
Potassium 
L&Ce 
L 
L&Ce 
L&C 
L&C 
L&C 
L&
C 
L&
C 
Chemistryf 
L&Ce 
 
L&Ce 
 
C 
C 
C 
 
Hematology 
(CBC) 
L&Ce 
 
L&Ce 
 
 
C 
C 
 
Plasma 
Parathyroid 
hormone 
Ce 
 
Ce 
 
 
C 
C 
 
Serum Fluoride 
Ce 
 
Ce 
 
 
C 
C 
 
Urinalysisg 
Ce 
 
Ce 
 
 
C 
C 
 
Pregnancy Testh 
L&Ce 
 
L&Ce 
 
 
 
L&
C 
 
IWRS Entry 
X 
X 
X 
X 
X 
X 
X 
X 
Patiromer 
Administrationi 
Xe 
 
Xe 
Xj 
X 
X 
 
X 
Patiromer 
Palatability and 
Parental 
Assessmentk 
Xe 
 
Xe 
 
 
X 
 
 
 


 
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Appendix A: Schedule of Events (Screening and Pharmacodynamic / Dose Finding 
Phase) (Cont’d)  
 
Stud
y 
Activ
ity 
Phase 
Screening 
Pharmacodynamic / 
Dose Finding Phase 
ET
b 
MS
Vc 
Scenario 
Subject With 
Standard of 
Care 
Potassium 
Subject Without 
Standard of Care 
Potassium 
Visit 
SV1/D1 
SV
1 
SV2/D1 
(2 to 7 days 
after SV1) 
D3a  
(± 1d
) 
D7  
(± 3d
) 
D14  
(± 3
d) 
Dosing Diary 
Dispensation  
X 
 
X 
 
 
 
 
 
Dosing Diary 
Review by 
Investigator/Desig
nee 
 
 
 
X 
X 
X 
 
 
Dosing Diary 
Collection 
 
 
 
 
 
X 
 
 
Drug 
Accountability & 
Compliance 
Xe 
 
Xe 
X 
X 
X 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 


 
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AE = Adverse Event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; C= Central; D = 
Day; d = day/days; Laboratory; CBC = Complete Blood Count; Con Meds = concomitant medications; E = 
exclusion; ET = Early Termination; ECG = Electrocardiogram; eGFR = Estimated Glomerular Filtration Rate; 
I = inclusion; IWRS = Interactive Web Response System; L= Local Laboratory; SV1= Screening Visit 1; SV2 
= Screening Visit 2 (2 to 7 days after SV1); W = Week 
a 
Note:  At the discretion of the Investigator, the Day 3 Visit is optional for subjects whose last screening 
K+ is < 5.5 mEq/L; for subjects whose last screening K+ is ≥ 5.5 mEq/L, the Day 3 Visit is mandatory 
(see Section 6.2.2).. 
b 
After ET subjects should be encouraged to complete the Follow-up Period Visits (see Section 6.4). 
c 
Or any unscheduled visit. 
d 
Assessment may be performed either on SV1 or SV2. 
e 
Central laboratory measurement or event will not be performed unless subject meets study entry criteria.  
f 
For screening, local hematology (CBC including WBC, RBC, hemoglobin, hematocrit, and platelet count) 
will be performed.  Per Investigator’s decision, central laboratory assessment of calcium and/or phosphate 
levels may be tested more frequently for subjects that have one dose of phosphate binder replaced by 
patiromer.  
g 
Not required for anuric subjects; see Section  7.2 for details.  
h 
Female subjects of child bearing potential only.  For anuric subjects, a serum pregnancy test is required; 
please Section 7.2 for details.   
i 
If patiromer dose requires titration, then initiation of the titrated patiromer dose should occur at the next 
planned administration (see Section 5.2.1 for details) 
j 
Up-titration of patiromer can occur only if the K+ level is ≥ 5.5 mEq/L and greater than the most recent 
locally obtained screening potassium value. 
k 
Palatability of patiromer will be evaluated in children ≥ 6 years of age when the initial dose is 
administered at the study site on Day 1 and parental or legal authorized representative response on the 
subject’s (< 6 years of age) acceptance of patiromer will be assessed on Day 14 (see Section 7.6 for 
further details). 
l 
ECG at the Mandatory Safety Visit required only if the local potassium is >6.0 mEq/L at the current or 
prior visit (see Section 6.5.1) 
m 
ECG is only required if the local potassium is > 6.0 mEq/L 


 
RLY5016–206p 
Statistical Analysis Plan 
 
©Vifor Pharma 
Page 20 of 23 
 
Appendix B: Schedule of Events (Long-Term Treatment Phase) 
Stud
y 
Acti
vity 
Study 
Period 
Long-Term Treatment Phase 
F1 
7d ± 3d 
F2a 
14d ± 
3d 
ET 
MS
Vb 
Visit 
W
3i 
± 
3d 
W5 
± 
7d 
W
7 
± 
7d 
W10 
i 
± 7d 
W1
4 
± 
7d 
W
18 
± 
7d 
W2
2 i 
± 7d 
W2
6 
± 
7d 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examinationk 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Body Weightk 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Heightk 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Vital Signs 
(Resting Heart Rate 
and Sitting BP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
12-Lead ECGc 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
 
X 
Xj 
Potassium 
L
&
C 
L&
C 
L
&
C 
L&
C 
L&
C 
L
&
C 
L&
C 
L&
C 
L&C 
 
L&
C 
L&
C 
Chemistrye 
 
 
C 
 
C 
 
 
C 
C 
 
C 
 
Hematology (CBC) 
 
 
C 
 
C 
 
 
C 
 
 
C 
 
Plasma Parathyroid 
hormone 
 
 
 
 
 
 
 
C 
 
 
C 
 
Serum Fluoride 
 
 
C 
 
C 
 
 
C 
 
 
C 
 
Urinalysisf 
 
 
 
 
 
 
 
C 
 
 
C 
 
Pregnancy Testg 
 
 
 
 
 
 
 
L&
C 
 
 
L&
C 
 
IWRS Entry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


 
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Statistical Analysis Plan 
 
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Page 21 of 23 
 
Appendix B: Schedule of Events (Long-Term Treatment Phase) (Cont’d) 
  
Stud
y 
Acti
vity 
Study 
Period 
Long-Term Treatment Phase 
F1 
7d ± 3d 
F2a 
14d ± 
3d 
ET 
MS
Vb 
Visit 
W
3i 
± 
3d 
W5 
± 
7d 
W
7 
± 
7d 
W
10i 
± 
7d 
W1
4 
± 
7d 
W
18 
± 
7d 
W
22i 
± 
7d 
W2
6 
± 
7d 
Patiromer 
Administrationh 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Drug 
Accountability & 
Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = Adverse Event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; d = days; C= 
Central Laboratory; CBC = Complete Blood Count; Con Meds = concomitant medications; E = exclusion; ET 
= Early Termination; ECG = Electrocardiogram; eGFR = Estimated Glomerular Filtration Rate; F1 = Follow-
up Visit 1 at 7 Days (± 3 days) after the last dose of patiromer; F2 = Follow-up Visit 2 at 14 Days after the 
last dose of patiromer; I = inclusion; IWRS = Interactive Web Response System L= Local Laboratory; M = 
months; MSV = Mandatory Safety Visit; W = week 
n 
The Phone Call Follow-up may be converted into an Onsite Visit if potassium levels from F1 is of 
concern by the Investigator and require a re-test.  If subjects are requested to return for an onsite visit, the 
same activities will be performed as those in (F1) 
o 
Or any unscheduled visit 
p 
When K+ is > 6.0 mEq/L during the Long-Term Treatment Phase of the study, additional ECG 
evaluations will be performed. 
q 
Per Investigator’s decision, central laboratory assessment of calcium and/or phosphate levels may be 
tested more frequently for subjects that have one dose of phosphate binder replaced by patiromer. 
r 
Not required for anuric subjects, see Section 7.2 for details.   
s 
Female subjects of child bearing potential only. For anuric subjects, a serum pregnancy test is required; 
see Section 7.2 for details.  
t 
If patiromer dose requires titration, then initiation of the titrated patiromer dose should occur at the next 
planned administration (see Section 5.2.1 for details). 
u 
The last dose of patiromer will be taken the day before the Week 26 Visit. 
v 
Week 3, Week 10 and Week 22 visits may be skipped under specific conditions (See Section 3.2.3) 
w 
ECG at the Mandatory Safety Visit required only if the local potassium is >6.0 mEq/L at the current or 
prior visit (see Section 6.5.1) 
x 
Study activity may be omitted for Home Care visit (see Section 6.2.5) 
y 
ECG is only required if the local potassium is > 6.0 mEq/L 


 
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Statistical Analysis Plan 
 
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Appendix C: Missing Data Imputation 
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. 


 
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Statistical Analysis Plan 
 
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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.